Clinical trial NCT01988571
Conditions: Breast Cancer Lymphoma
Keywords: Stage I breast cancer Stage II breast cancer Stage III breast cancer Stage I Lymphoma Stage II Lymphoma Stage III Lymphoma Stage IV Lymphoma
Sponsor: Wake Forest University Health Sciences
Start date: 2014-02-01; Completion date: 2020-09-24
Enrollment: 279 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this research study is to see if Atorvastatin (Lipitor) 40 mg by mouth daily decreases the chance of developing heart problems in individuals receiving adjuvant anthracycline-based chemotherapy for breast cancer of lymphoma.

Detailed description:
PRIMARY OBJECTIVES:

Specific Aim 1:

To determine if Atorvastatin(Lipitor) administration preserves left ventricular ejection fraction (LVEF) 24 months after initiation of Anthracycline-based adjuvant therapy for adjuvant treatment of breast cancer or lymphoma.

Specific Aim 2:

To determine if baseline to 6-month differences in LVEF predict baseline to 24-month differences in LVEF after Anthracycline-based adjuvant therapy and concomitant atorvastatin therapy.

To achieve these aims, we will perform a double-blind, placebo-controlled, randomized clinical trial of 0 or 40 mg of atorvastatin/day in 278 individuals scheduled to receive Anthracycline-based chemotherapy for treatment of Stage I-III breast cancer or lymphoma Stage I-IV with a projected \> 2 year life expectancy. We will use innovative noninvasive magnetic resonance imaging (MRI) procedures to accurately measure LVEF. In addition, we will measure left ventricle (LV) volumes, myocardial strain, fibrosis, aortic pulse wave velocity (PWV) and wall thickness, all factors that can influence LVEF by altering LV pre-load, after-load, and contractility.19,20 Advanced serum biomarkers will be measured that assess for the presence of oxidative/nitrosative stress, systemic inflammation and circulating neurohormones that also may influence LVEF.

This study will test a new clinical paradigm to manage breast cancer: primary prevention of Anthracycline-based adjuvant therapy-related LV dysfunction using pre-treatment with low-cost statins. In addition, this trial will be the first systematic collection of data regarding the mechanism(s) and time course by which LV dysfunction and subsequent chronic heart failure (CHF) evolve in individuals given Anthracycline-based chemotherapy for breast cancer or lymphoma. These data will be useful to physicians trying to determine the optimal cardiac protection strategies when administering adjuvant chemotherapeutic regimens to their breast cancer or lymphoma patients. The objective of this research is to use inexpensive medications to preserve cardiovascular (CV) health and thereby improve overall survival in the growing number of breast cancer and lymphoma patients.

SECONDARY OBJECTIVES

Specific Aim 1:

To document the effect of Atorvastatin (Lipitor) on cognitive function using a battery of neurocognitive tests (HVLT, Rey-osterrieth Figure, controlled oral word association test (COWA), Trail-making Parts A and B, Digit Span and Grooved Pegboard) in breast cancer and lymphoma patients receiving an anthracycline.

Specific Aim 2:

To document the effect of Atorvastatin(Lipitor) on self-reported quality of life using validated questionnaires (PROMIS including: General form, Cog Concerns, Cog Abilities, Fatigue, Pain intensity and interference, Sleep Disturbance, Physical Functioning and Social Functioning) in breast cancer and lymphoma patients receiving an anthracycline.

Arms: arm 1: One 40 mg Atorvastatin tablet each morning by mouth for 24 months arm 2: One placebo tablet each morning by mouth for 24 months.
Interventions: intervention 1: Atorvastatin intervention 2: Placebo
Intervention descriptions: intervention 1: 40 mg tablet taken by mouth each morning for 24 months. intervention 2: One placebo tablet taken each morning orally for 24 months.

Protocol documents:
Prot_SAP_001.pdf: 
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NCI Protocol #:  
 
 
 
 
WF-98213                                 
 
 
 
 
  
WF Protocol #: 
 
 
98213 
 
IND # (If applicable):  
 
 
 
N/A 
 
Protocol title: 
 Preventing Anthracycline Cardiovascular Toxicity with Statins (PREVENT) 
 
Organization Name: 
 
Wake Forest School of Medicine 
Protocol Principal Investigator:  
W. Gregory Hundley, MD 
 
Departments of Internal Medicine-Cardiology and Radiology 
 
1 Medical Center Blvd. 
 
Winston-Salem, NC 27157 
 
Telephone: (336) 716-0607 
 
Fax: (336) 716-9188 
 
E-mail address: ghundley@wakehealth.edu 
 
Consortium Name: 
 
Wake Forest NCORP Research Base 
Name of Consortium  
 
Glenn Lesser, MD 
Multi-Principal  
 
 
Wake Forest School of Medicine 
Investigator:  
 
 
Department of Internal Medicine  
 
 
Section on Hematology and Oncology 
 
 
 
 
 
Medical Center Boulevard 
 
 
 
 
 
Winston-Salem, NC  27157 
 
 
 
 
 
Telephone: (336) 716-0891 
 
Fax: (336) 716-6275 
 
E-mail address: glesser@wakehealth.edu  
 
Organization: 
 
Wake Forest School of Medicine 
Co-Investigator: 
 
Stephen R. Rapp, PhD 
 
Psychiatry and Behavioral Medicine 
 
Medical Center Boulevard 
 
Winston-Salem, NC 27157 
 
Telephone: (336) 716-6995 
 
Fax: (336) 716-6830 
 
 
E-mail address: srapp@wakehealth.edu 
 
Organization: 
  Wake Forest School of Medicine 
Co-Investigator: 
  Heidi Klepin, MD 
 
  Department of Internal Medicine 
 
  Section on Hematology and Oncology 
 
  Medical Center Boulevard 
 
  Winston-Salem, NC 27157 
 
  Telephone: (336) 716-5772 
 
  Fax: (336) 716-5687 
 
  E-mail: hklepin@wakehealth.edu 
 
 
 


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Organization: 
  Wake Forest School of Medicine 
Co-Investigator: 
  David Herrington, MD 
 
  Department of Internal Medicine 
 
  Section on Cardiology 
 
  Medical Center Boulevard 
 
  Winston-Salem, NC 27157 
 
  Telephone: (336) 716-4950 
 
  Fax: (336) 716-9188 
 
  E-mail Address: dherring@wakehealth.edu 
 
Organization: 
  Wake Forest School of Medicine 
Co-Investigator: 
  Joseph Yeboah, MBChB 
 
  Department of Internal Medicine 
 
  Section on Cardiology 
 
  Medical Center Boulevard 
 
  Winston-Salem, NC 27157 
 
  Telephone: (336) 716-7015 
 
  Fax: (336) 716-5324 
 
  E-mail address: jyeboah@wakehealth.edu 
 
Organization: 
  Wake Forest School of Medicine 
Co-Investigator: 
  Sujethra Vasu, MBBS 
 
  Department of Internal Medicine 
 
  Section on Cardiology 
 
  Medical Center Boulevard 
 
  Winston-Salem, NC 27157 
 
  Telephone: (336) 716-7015 
 
  Fax: (336) 716-5324 
 
 
E-mail: svasu@wakehealth.edu 
 
Organization: 
 
Wake Forest School of Medicine 
Protocol Statistician: 
 
Ralph D’Agostino, Jr., PhD 
 
 
Biostatistics Core Director 
 
 
Department of Biostatistical Sciences 
 
 
Division of Public Health Sciences 
 
 
Medical Center Boulevard 
 
 
Winston-Salem, NC 27157 
 
 
Telephone: (336) 716-9410 
 
 
Fax: (336) 716-5425 
 
 
Email address: rdagosti@wakehealth.edu 
 
Organization: 
 
Wake Forest School of Medicine 
Site Coordinator: 
 
Tammy Vogler, RN 
 
 
Department of Social Sciences and Health Policy 
 
 
NCORP Research Base – 525@Vine, 4th floor 
 
 
P.O. Box 573152 
 
 
Medical Center Boulevard 
 
 
Winston-Salem, NC 27157 
 
 
Telephone: (336) 713-6907 
 
 
Fax: (336) 716-6275 
 
 
E-mail address: tvogler@wakehealth.edu 
 
 
 
 


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Organization: 
 
Mayo Clinic 
 
 
Kathryn J. Ruddy, MD, MPH 
 
Mayo Clinic 
 
200 First Street SW 
 
Rochester, MN 55905 
 
Telephone: (507) 266-9160 
 
Email: Ruddy.Kathryn@mayo.edu  
 
 
 
 
 
Grant: 
 
1R01 HL118740-01 
 
 
NCI/National Heart Lung Blood Institute 
 
6130 Executive Blvd., Room 2117 
 
Bethesda, MD  20892 (For FedEx, use Rockville, MD  20852) 
 
(301) 496-8563 
 
 
 
3U10CA081851-12 
 
 
NCI/Division of Cancer Prevention 
 
 
Community Oncology & Prevention Trials Research Group 
 
 
9609 Medical Center Drive, Room 5E502 
 
 
Rockville, MD  20850 
 
 
(240) 276-7050 
 
Participating Organizations: 
 
WAKE / Wake Forest Research Base NCORP 
 
ALLIANCE / Alliance for Clinical Trials in Oncology  
 
ECOG-ACRIN / ECOG-ACRIN Cancer Research Group 
 
Agent(s)/Supplier: 
 
 
Initial Approval Dates: 
PRC: 06/13/13 
 
 
NCI: 09/04/13 
 
 
 
 
FDA: 06/28/13 (exempt) 
 
IRB: 08/02/13 
 
Activation Date: 
 
WF: 02/05/2014 
 
 
 
 
Sites: 02/10/2014 
 
NCI Version Date: 
 
03/27/2020 
 
Renewal Dates: 
CR1: 06/04/14 
 
CR2: 05/11/15 
 
CR3: 04/25/16 
 
CR4: 08/21/17 
 
CR5: 07/03/18 
 
CR6: 05/24/19 
 
 


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IRB Amendment Approval Dates: 
 
 
Amend 1: 02/05/14 
 
Amend 2: 02/10/14 
 
Amend 3: 02/19/14 
 
Amend 4: 05/05/14 
 
Amend 5: 08/04/14 
 
Amend 6: 08/28/14 
 
Amend 7: 09/30/14 - WF Staff Change 
 
Amend 8: 02/16/15 
 
Amend 9: 04/17/15 
 
Amend 10: 06/09/15 
 
Amend 11: 06/24/15 - WF Staff Change 
 
Amend 12: 07/29/15 
 
Amend 13: 01/12/16 - WF Staff Change 
 
Amend 14: 03/15/16 - WF Staff Change 
 
Amend 15: 04/08/16 
 
Amend 16: 04/21/16 - WF Staff Change 
 
Amend 17: 07/25/16 
 
Amend 18: 10/12/16 
 
Amend 19: 11/01/16 - WF Staff Change 
 
Amend 20: 03/21/17 
 
Amend 21: 09/22/17 
 
Amend 22: 10/25/17 
 
Amend 23:  10/29/18 – WF Staff Change 
 
Amend 24:  09/21/18 – flyer to pdf 
 
Amend 25:  11/21/18 – WF Staff Change 
 
Amend 26:  01/14/19 – WF Staff Change 
 
Amend 27:  04/22/19 – Testing of stored samples 
 
Amend 28:  07/10/19 – WF Staff Change 
 
Amend 29:  09/21/16 
 
Amend 30:  02/14/20 – WF Staff Change 
 
Amend 31:  03/03/20 – WF Staff Change 
 
Amend 32:   
 
 
 
 
 


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CONTACT INFORMATION 
 
For regulatory requirements: 
For patient enrollments: 
For study data submission: 
Regulatory documentation must 
be submitted to the CTSU via the 
Regulatory Submission Portal. 
 (Sign in at www.ctsu.org, and 
select Regulatory > Regulatory 
Submission.  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 1-866-651-
2878 to receive further instruction 
and support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 for 
regulatory assistance. 
 
Please refer to the patient 
enrollment section 6.8  of the 
protocol for detailed instructions. 
Data forms will be submitted to the 
WF NCORP Research Base.   
 
NCORP Research Base Data  
Wake Forest Baptist Medical Center 
Building 525@Vine, 4th floor 
Medical Center Boulevard 
Winston-Salem, NC 27157 
 
Fax to (336) 713-6476 according to 
the timetable in Section 11.1 
 
Do not submit study data or forms to 
CTSU Data Operations. Do not copy 
the CTSU on data submissions. 
 
The most current version of the study protocol and all supporting documents must be downloaded from the 
protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  Access to the 
CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - Identity and 
Access Management (CTEP-IAM) registration system and requires user log on with CTEP-IAM username and 
password.   Permission to view and download this protocol and its supporting documents is restricted and is 
based on person and site roster assignment housed in the CTSU RSS.   
 
 
For clinical questions (i.e. patient eligibility or treatment-related) contact the Study PI Dr, Gregory Hundley, 
ghundley@wakehealth.edu   
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data submission) contact 
the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and correspondence 
will be triaged to the appropriate CTSU representative.  
 
The CTSU Website is located at https://www.ctsu.org. 


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SCHEMA 
 
Preventing Anthracycline Cardiovascular Toxicity with Statins (PREVENT)  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recruitment & Consent 
Baseline ** 
MRI 
 
 
Biomarkers 
Labs 
 
 
Cognitive 
 
 
 
QOL 
Screening Labs 
Randomization ** 
Group 1 
Statin 
40mg/day 
Group 2 
Placebo 
Daily
6 Month 
MRI 
 
 
Biomarkers 
Labs 
 
 
12 Month  
Telephone 
Contact  
Cognitive  
QOL 
18 Month  
Telephone 
Contact  
Cognitive  
QOL 
24 – 27 Month  
MRI, Labs,  
Biomarkers,  
Cognitive,  
QOL 
1 Month 
Post Final 
Assessment  
In‐Person or 
Telephone 
Contact 


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Stratification Factors: Breast Cancer Doxorubicin Total dose:   ≤ 239 mg/m2  vs.  ≥ 240 mg/m2      
                                                         or 
                                      Breast Cancer Epirubicin Total dose:      ≤ 399 mg/m2  vs.  ≥ 400 mg/m2 
 
 
          or 
   Lymphoma Doxorubicin Total dose:        ≤ 239 mg/m2  vs.  ≥ 240 mg/m2      
 
** Due to the scheduling complexity of protocol requirements prior to the start of the first chemotherapy 
treatment, baseline procedures and randomization may be performed at the sites discretion once the 
patient has signed the consent.  The patient should be registered within 30 days of screening labs.  
 
 
 
Study Sample: n=278 
 
Study Duration: at least 24 months per subject but no greater than 27 months.  
Patients completing at least 24 months of study medication will be followed for an additional 30 days 
after the last dose of study medication to evaluate any study related adverse events.  
 
Brief Eligibility Criteria: 
 
Stage I-III breast cancer (including inflammatory and newly diagnosed recurrent breast cancer) or 
lymphoma Stage I-IV 
 
Scheduled to receive chemotherapy with any anthracycline 
 
Age: > 21 years of age 


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INDEX 
 
 
COVER PAGE 
 
SCHEMA 
 
1. OBJECTIVES ........................................................................................................................ 9 
  
2. BACKGROUND ................................................................................................................... 11 
 
 
3. SUMMARY OF STUDY PLAN…………………………………………………………………... 15 
 
4. PARTICIPANT SELECTION ............................................................................................... 17 
 
5. AGENT ADMINISTRATION ................................................................................................ 19 
 
6. PHARMACEUTICAL INFORMATION ................................................................................. 21 
 
7. CLINICAL EVALUATIONS AND PROCEDURES .............................................................. 31 
 
8. PROTOCOL SPECIFIC TRAINING REQUIREMENTS ....................................................... 38 
 
9. SPECIMEN MANAGEMENT ............................................................................................... 39 
 
10.  REPORTING ADVERSE EVENTS ..................................................................................... 39 
 
11. STUDY MONITORING ........................................................................................................ 42 
 
12. STATISTICAL CONSIDERATIONS .................................................................................... 44 
 
REFERENCES 
 
Consent Form 
FDA Letter  
 
APPENDICES 
 
 
 
1. Data Submission Checklist 
2. Eligibility Checklist-Enrollment 
3. CV Risk Calculator and Instructions 
4. Patient Medication Diary 
5. Screening Form 
6. Flow Sheet / Addenda 
7. Current Medication Form  
8. Radiation Treatment Form 
9. Chemotherapy Treatment Form 
10. Lab Instructions 
11. Telephone Contact Form 
12. Physician Statin Update  
(Includes Open Label Form) 
13. Baseline Neurocognitive Booklet  
14. 6 Month Neurocognitive Booklet  
15. 12 Month  Booklet 
16. 18 Month  Booklet 
17. 24 Month  Neurocognitive Booklet 
18. Early Withdrawal Form 
19. 1 Month Contact Form 
 
 
  
 


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1. 
OBJECTIVES 
 
The overall goal of this proposal is to determine if atorvastatin administration attenuates deterioration 
in left ventricular ejection fraction (LVEF) in men and women receiving Anthracycline-based 
chemotherapy. Left ventricular (LV) dysfunction precedes the development of congestive heart failure 
(CHF), a major contributor to cardiovascular (CV) events, and the 2nd leading cause of morbidity and 
mortality for 7-year survivors treated with adjuvant chemotherapy for breast cancer.1-7 This heightened 
incidence of CV events threatens to offset cancer-related survival and raise healthcare expenditures 
for breast cancer survivors. An intervention that reduces LV dysfunction and CHF would be 
significant.1-7  
 
Anthracycline-based  chemotherapy is an important component of therapy for those with advanced 
disease;8 for breast cancer alone, 5-year survival exceeds 70% after Anthracycline-based adjuvant 
therapy.9 Not only is doxorubicin an essential element in modern therapy of breast, soft tissue 
sarcomas and other solid tumors,i,ii it is thought to be an essential element of curative combination 
chemotherapy for acute leukemia, Hodgkin’s disease, non-Hodgkin’s lymphoma, and many childhood 
cancers.iii,iv Thus, for many individuals with advanced stages of cancer, Doxorubicin serves as an 
important part of their medical regimen.   
 
The cytotoxic anti-tumor effects from Anthracycline-based adjuvant therapy are related to its 
interactions with the enzyme topoisomerase-IIα, production of double-strand DNA breaks, and the 
generation of intracellular cytotoxic free radicals.10 Unfortunately, in cardiomyocytes, these cytotoxic 
free radicals promote oxidative and nitrosative stress that, in combination with other Anthracycline-
based adjuvant therapy effects (inflammation and neurohormonal activation), promote LV dysfunction, 
myocardial replacement fibrosis, CHF, and CV events.11 Primary prevention strategies that reduce 
Anthracycline-based chemotherapy mediated myocellular oxidative/nitrosative stress could diminish 
LV dysfunction and the subsequent CHF often experienced by patients after Anthracycline-based 
adjuvant therapy. No such strategies currently exist. 
 
In the secondary prevention setting, the notion that modulating Anthracycline-based chemo therapy 
mediated oxidative/nitrosative stress can preserve LV function has been applied to women with poor 
resting LV function in need of Anthracycline-based adjuvant therapy.12,13 In these women, intravenous 
pre-treatment with dexrazoxane, a free iron binding agent that reduces the generation of reactive 
oxygen and consequent nitrogen species, decreases further LV dysfunction and CV events.12,13 This 
therapy is not utilized for primary prevention because of its expense, associated side effects, and the 
potential concern it may reduce anthracycline-mediated tumor regression. 
 
Several lines of evidence suggest that generic, inexpensive, oral 3-hydroxy-3-methylglutaryl-
coenzyme A (HMG-CoA) reductase inhibitors (statins) may prevent cardiomyocyte injury during and 
after Anthracycline-based adjuvant therapy.14 This class of drugs is used commonly to treat 
hypercholesterolemia, but also reduces oxidative/nitrosative stress, inflammatory cytokines, and 
circulating neurohormones.15,16 In animal models, statins diminish LV dysfunction and 
oxidative/nitrosative stress after Anthracycline-based chemotherapy.14 In our pilot studies, we find that 
LV injury occurs early (in the first 6 months of Anthracycline-based chemo therapy administration), and 
LV performance is preserved in men and women receiving Anthracycline-based --chemo therapy 
when statins are co-administered for pre-existing CV disease during these 6 months.19 Unlike some 
cardioprotective medications, statins do not promote hypotension, and recent data indicate that breast 
cancer recurrence does not increase among 18,000 5-year survivors receiving statins during and after 
treatment for breast cancer.18 
 
Given the propensity of statins to ameliorate LV dysfunction and reduce CHF and other CV events, we 
seek to conduct a clinical trial to determine if statin therapy attenuates the early onset of LV 
dysfunction in men and women treated with Anthracycline-based chemotherapy for breast cancer or 
lymphoma. Accordingly, we propose the following.  
 


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Primary Objectives 
 
Specific Aim 1: To determine if atorvastatin administration preserves LVEF 24 months after initiation 
of Anthracycline-based chemo-therapy for breast cancer or lymphoma.  
 
Specific Aim 2: To determine if baseline to 6-month differences in LVEF predict baseline to 24-month 
differences in LVEF after Anthracycline-based chemotherapy and concomitant atorvastatin therapy. 
 
To achieve these aims, we will perform a double-blind, placebo-controlled, randomized clinical trial of 
0 or 40 mg of atorvastatin/day in 278 individuals scheduled to receive Anthracycline-based 
chemotherapy for treatment of Stage I-III breast cancer or lymphoma Stage I-IV with a projected > 2 
year life expectancy. We will use innovative noninvasive magnetic resonance imaging (MRI) 
procedures to accurately measure LVEF. In addition, we will measure LV volumes, myocardial strain, 
fibrosis, aortic pulse wave velocity (PWV) and wall thickness, all factors that can influence LVEF by 
altering LV pre-load, after-load, and contractility.19,20 Advanced serum biomarkers will be measured 
that assess for the presence of oxidative/nitrosative stress, systemic inflammation and circulating 
neurohormones that also may influence LVEF.  
 
This study will test a new clinical paradigm to manage cancer patients scheduled to receive 
anthracyclines: primary prevention of Anthracycline-based chemotherapy-related LV dysfunction using 
pre-treatment with low-cost statins. In addition, this trial will be the first systematic collection of data 
regarding the mechanism(s) and time course by which LV dysfunction and subsequent CHF evolve in 
individuals given Anthracycline-based chemotherapy for breast cancer or lymphoma. These data will 
be useful to physicians trying to determine the optimal cardiac protection strategies when 
administering chemotherapeutic regimens to their breast cancer or lymphoma patients. The objective 
of this research is to use inexpensive medications to preserve CV health and thereby improve overall 
survival in the growing number of breast cancer and lymphoma patients.  
 
Secondary Objectives 
 
Specific Aim 1: 
 
To document the effect of atorvastatin on cognitive function using a battery of neurocognitive tests 
(HVLT, Rey-Osterreith Figure, COWA, Trail-making Parts A and B, Digit Span and Grooved Pegboard) 
in breast cancer and lymphoma patients receiving an anthracycline. 
 
Specific Aim 2: 
 
To document the effect of atorvastatin on self-reported quality of life using validated questionnaires 
(PROMIS including: General form, Cog Concerns, Cog Abilities, Fatigue, Pain intensity and 
interference, Sleep Disturbance, Physical Functioning and Social Functioning) in breast cancer and 
lymphoma patients receiving an anthracycline. 


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2. 
BACKGROUND 
 
This study is significant in that it addresses: 
1) A prevalent clinical problem. CHF and CV events (34,000 annual events in the US) together are the 2nd 
most common cause of morbidity and mortality in women who receive adjuvant treatment for breast 
cancer.21 Administration of Anthracycline-based chemotherapy is a major factor related to development of 
CHF in this population.22   
2) A therapeutic intervention to counter the mechanism(s) by which Anthracycline-based chemo therapy 
injures the heart. To date, no therapies are routinely given to cancer patients to prevent oxidative and 
nitrosative stress, systemic inflammation, LV replacement fibrosis, and neurohormonal activation–all 
initiated on receipt of Anthracycline-based  chemotherapy. Identifying a therapeutic intervention to address 
underlying mechanisms of Anthracycline-based chemotherapy-related LV dysfunction would be a significant 
clinical innovation. 
3) The concept of pre-treatment and primary prevention of myocellular injury in cancer survivors.  Existing 
clinical strategies for Anthracycline-based chemotherapy-related CHF are based on post-event clinical 
management. This study will test a new clinical paradigm: primary prevention of Anthracycline-based 
therapy-related LV dysfunction using low-cost statin pre-treatment.  
4) The evolution of CHF and other subclinical CV disease in cancer and lymphoma survivors. The studies 
planned in this proposal will record the evolution of subclinical processes observed in other large 
epidemiologic investigations of CHF and CV disease. These data will provide important new information on 
how cancer or lymphoma survivors develop LV dysfunction that often precedes adverse CV events.  
5) CV healthcare expenditures in patients with cancer. Over $800,000,000 per year in the US is spent 
providing CV-related care for patients experiencing LV dysfunction and CHF after treatment for breast 
cancer or lymphoma.3 We will test the effectiveness of a generic, cost-efficient (2 to 5 cents/day), widely 
available medication that may prevent LV dysfunction in patients receiving Anthracycline-based 
chemotherapy for cancer.  
6) NHLBI and NCI mandates including: a) the NHLBI strategic plan goal to improve understanding of the 
clinical mechanisms of CV disease and thereby enable better prevention, diagnosis and treatment; and b) 
the NCI’s commitment to determine actionable strategies to reduce the burden of morbidity and mortality in 
patients with cancer.  
 
In this section, we document the significant background data/information substantiating these statements. 
 
Today, CV events including primarily CHF are the 2nd leading cause of morbidity and mortality in 5-year 
survivors of breast cancer.1-7 Because both the number of long-term survivors and the use of complex cancer 
treatment regimens are increasing, the prevalence of CHF and CV events is growing in all patients receiving 
Anthracycline-based chemotherapy. The long-term consequences of CHF and CV events after breast cancer 
and treatment for lymphoma are staggering: 
 
 In 236,000 breast cancer survivors treated and followed between 1975 and 2002, CV event rates increased 
by 25%, offsetting a 15% decrease in cancer-related mortality.3,6  
 Using the Surveillance, Epidemiology and End Results (SEER) database of 66- to 80-year-old women 
(n=7,724) treated for adjuvant breast cancer, the incidence of CHF ranged from 29% to 38% depending on 
the adjuvant treatment regimen received.23  
 In a study of 63,566 women with breast cancer aged >65 years, CV disease was the leading cause of death 
(15.9%) followed by breast cancer (15.1%) in 5-year survivors; and, of those women who died as a result of 
CV disease, only 25% had existing comorbid CV disease at their breast cancer diagnosis.23 Similar findings 
were reported in women below the age of 65 years.24 
 In 179 breast cancer survivors experiencing a stroke (from a cohort of 11,045), events were 2.5 fold higher 
in those receiving versus not receiving chemotherapy containing primarily Anthracycline-based 
chemotherapy.22,25 
 
These findings suggest breast cancer survivors with no prior history of CV disease exhibit high rates of CV 
events, and a relationship exists between breast cancer therapy and survivors’ subsequent CV events. 


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2.1.  Anthracycline-based adjuvant therapy’s cytotoxic tumor effects also injure cardiomyocytes by 
promoting peroxynitrite 
o(ONOO-) induced stress.   
Anthracyclines interact with 
the enzyme topoisomerase-IIα 
and produce double-strand 
DNA breaks that inhibit tumor 
cell DNA synthesis, 
transcription, and replication.31 
This class of agents also 
generates oxygen- and 
nitrogen-derived free radicals 
that are highly cytotoxic for 
malignant cells.32   
  Generation of oxygen- and 
nitrogen-derived free radicals 
can be harmful to 
cardiomyocytes. In healthy 
cardiomyocytes, nitric oxide 
(NO) is beneficial (green, Fig. 
1); however, after 
Anthracycline-based adjuvant 
therapy, the increased 
bioavailability of NO and 
superoxide (O2-) promotes 
preferential production of 
ONOO- that induces 
myocellular injury (red, Fig. 
1).32 Unlike most other organs, 
the heart has few free radical 
scavengers, so it is particularly 
susceptible to injury from free radical production.32 
   Several studies have linked the production of peroxynitrite (Fig. 1) after anthracycline exposure to both 
cellular myocyte (tension) and global (catheter-based measures of derivatives of pressure and time [dP/dt], 
LVEF, stroke volume, and cardiac output) abnormalities of LV myocardial performance.32-34 In C57BL/6J mice 
receiving single intraperitoneal doses (up to 20 mg/kg) of doxorubicin (DOX, an anthracycline), myocardial 
apoptosis, levels of inducible nitric oxide synthase (iNOS) expression, mitochondrial superoxide generation, 3-
nitrotyrosine (NT) formation (a downstream byproduct of elevated peroxynitrite), myocardial dysfunction, 
catalase, and glutathione peroxidase were all elevated.32 These elevations were attenuated by peroxynitrite 
scavengers.32 DOX-induced cell death and nitrotyrosine formation were also attenuated by iNOS inhibitors or 
in iNOS knockout mice.32 These studies indicate that Anthracycline-based adjuvant therapy promotes oxidative 
and nitrosative stress, thus initiating a cascade of events mediated by peroxynitrite formation that injures 
myocytes and promotes overall LV dysfunction. 
 
2.2  Statin pre-treatment reduces nitrotyrosine production (related to elevated peroxynitrite formation; 
red, Figure 1) and subsequent LV dysfunction during and after Anthracycline-based adjuvant therapy. 
Five days after a single intraperitoneal injection of DOX at 20 mg/kg, LV function (measured as a change in 
dP/dt) was reduced in mice receiving DOX alone but not in mice receiving placebo or DOX + fluvastatin (Fig. 
2B; red vs. blue and green bars).14 DOX animals had increased myocellular lipid peroxidation and nitrotyrosine 
formation (a byproduct of elevated levels of peroxynitrite; Fig. 2A, red bar), increased tumor necrosis alpha 
(TNFα, a marker of systemic inflammation), and myocellular apoptosis (p<0.05 for all).14 Mice given fluvastatin 
had lower cardiac expression of nitrotyrosine, an absence of LV dysfunction (Fig. 2B; green  
 
Figure 1: Mechanisms by which anthracycline chemotherapy causes cardiotoxicity. Doxorubicin increases 
oxidative and nitrosative stress, leading to increased peroxynitrite (ONOO). Peroxynitrite reacts further in 
both the cytoplasm and the mitochondria, leading to myocardial injury, contractile dysfunction, endothelial 
dysfunction and heart failure. 


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bar), and no increases in markers of systemic inflammation (TNFα) or 
myocellular apoptosis.14  
  In a recent study of 40 patients scheduled to receive Anthracycline-based 
adjuvant therapy, those randomized to receive atorvastatin (40 mg per day 
before and during Anthracycline-based adjuvant therapy) had no decrease 
in LVEF at 6 months, but those randomized to receive Anthracycline-based 
adjuvant therapy without statins had an 8% reduction in LVEF (Table 1).17 In 
other patients at high risk for CV events not receiving Anthracycline-based 
adjuvant therapy, pre-treatment with statin therapy before coronary artery 
interventions or elective surgery 
reduces subsequent CV events by 
reducing oxidative stress, 
inflammatory cytokines, and 
circulating neurohormones.38-40 
These data suggest that statin pre-
treatment may attenuate LV 
dysfunction upon receipt of 
Anthracycline-based adjuvant 
therapy.   
  
 
2.3. Statins are well-tolerated and 
do not interfere with cancer 
therapy response rates or 
breast cancer recurrence after treatment for stage I-III breast cancer. 
Degreef et al. found that statins were highly tolerated and contributed to lowering of adverse serum lipid 
levels during cancer treatment.41 Statins plus classical cytotoxic agents in breast cancer cell lines often 
enhance anti-cancer effects.42 Statins appear to stimulate apoptotic cell death in breast cancer cells and 
inhibit cancer cell proliferation by arresting the cell cycle at the G1S phase and inducing apoptosis.43 
Statins did not increase breast cancer recurrence in a population-based prospective cohort study of 
18,769 women diagnosed with stage I-III invasive breast carcinoma.18  
 
2.4. Preliminary Data 
Six months after Anthracycline-based adjuvant therapy, PWV increases and LVEF and myocardial 
strain diminish.  
Aortic stiffness increases upon receipt of anthracycline chemotherapy. J Clin Oncol. 2010;28(1):166-172.19 
Early and persistent evidence of subclinical cardiovascular injury after receipt of anthracycline 
chemotherapy. Circulation. 2010;122(21) Supplement:A1276647 Supported by NIH-R33CA12196 
 
Table 1: Comparison of 
Echocardiographic Parameters: Baseline 
vs. Follow-Up Values in Pilot Study 
LVEF (%) 
Statin 
Group 
(n=20) 
Control 
Group 
(n=20) 
p Value
Baseline 
61±8 
63±7 
 
After 6 months 
63±9 
55±10
 
Mean change 
+1±4 
-8±8 
<0.001
Figure 2: (A; left panel) Cardiac nitrotyrosine expression and (B; right panel) 
systolic LV function in 3 groups treated with placebo, doxorubicin, and a combination 
of fluvastatin and DOX. Columns, mean; bars, SE.14 
Figure 3: Time-dependent changes in left ventricular (LV) end diastolic volume (left y-axis; panel A) and LV end systolic volume (right 
y-axis; panel A); in LV ejection fraction (LVEF) (left y-axis; panel B); and mid-wall circumferential strain (right y-axis; panel C). The 
mean ± the standard error are shown. LV end systolic volumes increase and LVEF and myocardial strain decrease (less negative is a 
decrease), all indicating a subclinical deterioration in LV systolic performance. These subclinical abnormalities of LV and aortic function 
are associated with 2-4 fold increases in CV events.47 


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We measured LV volumes, EF and circumferential strain; aortic PWV (a measure of aortic stiffness that 
contributes to LV after-load; and serum troponin I (TnI); before and 1, 3, and 6 months after initiating 3-month 
courses of low to moderately dosed Anthracycline-based adjuvant therapy in 51 individuals with breast cancer, 
leukemia or lymphoma. Participants averaged 52±2 (range 19 to 81) years in age; 65% were women, and 20% 
were black. LV end systolic volume (LVESV), aortic PWV, and serum TnI increased, and LVEF and 
circumferential strain decreased after Anthracycline-based adjuvant therapy (Fig. 3, in color). These findings 
persisted after adjustment for age, gender, race (white-black), doxorubicin (DOX) equivalent chemotherapy 
dose, CV co-morbidities, cancer diagnosis (breast vs. not breast), and resting cardiac or vascular function 
(p=0.032 to 0.0001 for all).47 Change in LV or aortic function parameters was not DOX equivalent dose-related 
(r=0.01 to 0.05; p=0.85-0.92 for both). In a separate study, we substantiated early decreases in LVEF and 
increases in PWV after Anthracycline-based adjuvant therapy will be compared to a control population after 
accounting for age, sex, cardiac output, cancer diagnosis, cardioactive medications, and underlying clinical 
conditions known to influence PWV, such as hypertension or diabetes (p<0.0001).19 The 3- to 6-month 
increase in PWV was similar in effect to aging the vascular system by 15 years. Cardiac dysfunction occurs 
early after relatively low to moderate doses of Anthracycline-based adjuvant therapy, and persists 6 months 
after initiation (3 months after completion) of Anthracycline-based adjuvant therapy.     
 
In a retrospective study from our institution, statin therapy appears to preserve LVEF after exposure to 
Anthracycline-based adjuvant therapy. Preservation of left ventricular ejection fraction with statins 
during receipt of anthracycline-based adjuvant therapy. J Am Coll 
Cardiol 2012;59:E986.51      In 50 participants (33 women, 17 men; aged 
48±14 years), we performed blinded MRI measurements of LVEF prior to 
and 6 months after initiation of Anthracycline-based adjuvant therapy for 
patients with breast cancer, leukemia, or lymphoma. 14 individuals received 
a statin for guideline-based indications and 36 did not. Statin therapy was 
38±31 mg (range 5-80 mg) atorvastatin (n=6) or simvastatin (n=8). The 
cumulative anthracycline dose and DOX equivalent doses ranged from 30-
450 mg/m2 with means of 193±95 mg/m2 and 201±99 mg/m2 in statin and 
non-statin users, respectively. At baseline, the LVEF was 57±5% and 57±9% 
for those taking and not taking a statin, respectively. In a multivariable model 
accounting for age, gender, co-morbidities (DM, HTN, HLD), and the dose of 
anthracycline, the LVEF decline after statin use was -0.5% compared to -
7.8% in non-statin users (Fig. 4; p=0.0005). Moreover, in those receiving 40-
80 mg/day of a statin, LVEF increased 2%; it decreased 3% after low (5-20 
mg/day) dose statin (p<0.03).  
 
These data indicate that patients on statins for other guideline-based indications may be protected against 
deterioration in LVEF after Anthracycline-based therapy. 
 
Observational studies suggest that cognitive changes associated with statin use are uncommon and only 
temporarily affect cognition. Higher doses and advanced age were more associated with the predilection to 
develop cognitive decline. In our study, a moderate dose of atorvastatin (40 mg) per day will be utilized, and 
assessments of cognitive functioning across primary domains and cognitive symptoms will be collected using 
standardized methods from ongoing studies in the NCORPs. Subjective cognitive complaints are reported 
during chemotherapy by almost 70% of women;75,84,85 75% of breast cancer patients evaluated a year after 
adjuvant chemotherapy performed below age, education, and gender-adjusted means on a variety of 
neurocognitive tests.86 Structural changes in cortical and subcortical brain regions have been identified; 
however, the cause and cognitive correlation are unknown.87,88 Finally, cognitive deficits associated with LV 
dysfunction and CVD are well-documented,89,90 therefore, possible cardio-protective effects of statin therapy on 
cognition and quality of life, which can be negatively impacted by deterioration in cognition, are important to 
assess. Based on studies of chemotherapy and cognition, cardio-function and cognition and statin therapy and 
cognition, we propose a battery of validated neurocognitive measures to evaluate memory (verbal and non-
verbal), attention/concentration, working memory, language, psychomotor speed, processing speed, and 
executive functions, according to procedures utilized currently in the NCORP network by Stephen Rapp, PhD, 
Figure 4: In a multivariable model 
adjusted for age, gender, co-
morbidities, and the anthracycline 
dose, those who received statin had an 
LVEF decline of 0.5% compared to the 
non-statin group 7.8%. 


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one of our co-investigators.74,75 Additionally, key patient reported outcomes (cognitive symptoms, fatigue, 
mood, pain, social and physical functioning and sleep) will be assessed with brief, well-validated self-report 
questionnaires. 
 
3. SUMMARY OF STUDY PLAN 
 
3.1. 
Overview of Study and Study Design 
We propose a double-blind, placebo-controlled randomized clinical trial of 40 mg of atorvastatin 
(Lipitor®) or  placebo per day in 278 men and women age > 21 years old scheduled to receive 
Anthracycline-based chemotherapy for Stage l-lll including inflammatory Breast Cancer, or 
lymphoma Stage I-IV with a > 2 year life expectancy. Innovative noninvasive MRI measures of LV 
volumes, EF, myocardial strain, PWV, arterial wall thickness, and other serum markers plus key 
patient reported outcomes including cognition and quality of life measures will be collected at 
baseline, 6 and 24 months after initiating treatment with Anthracycline-based therapy. In addition, 
participants will be contacted by telephone to assess medication compliance/toxicities and Quality of 
Life at 12 and 18 months. Patients completing at least 24 months but no longer than 27 months of 
study medication will be followed for an additional 30 days after the last dose of study medication to 
evaluate any study related adverse events. 
 
3.1.1  COVID-19 - Due to the inability to obtain a final 24 month assessment (related to social 
distancing because of Coronavirus) of the primary outcome measures for the Prevent study, this 
study has been amended to provide additional study drug to remaining participants for an additional 
3 months.   This provision extends the window of opportunity to collect the final study outcome 
measures within 27 months of beginning the study at a time when social distancing is not required 
due to the presence of the coronavirus in our communities.  This amendment allows for final study 
related assessments to be accomplished with participants still receiving the study drug.  Our 
statistical analyses which is ongoing  to examine the  change in outcomes over time allows the exact 
time between baseline and follow up to be accounted for (I.e. the exact number of days between 
visits). This modification to allow patients to have their final measurements after 24 months (I.e. 27 
months) will not negatively impact our ability to evaluate the stated hypotheses and outcomes for this 
study.   Moreover, this change we will ensure that to the best of our ability we will  evaluate the 
efficacy of the study drug on patients who take the drug until their final outcome assessments, as 
was the intention of our trial.  
 
3.2. 
We will use the established NCORP structure of the Wake Forest NCORP Research Base (WF 
NCORP RB). We will recruit from NCORP Community sites and/or NCI NCORP Research Bases 
with appropriate MRI facilities that treat modest numbers of breast cancer and lymphoma patients 
with Anthracycline-based therapy. Importantly, the PI has visited and conducted interviews with all 
participating NCORP Community sites and/or NCI NCORP Research Bases to verify their MRI and 
breast cancer and lymphoma recruitment capabilities. 
 
 
3.3. 
MRI was selected to provide the endpoints of left ventricular volumes, LVEF, myocardial strain and 
PWV because of its: 
 
 
Reliability (>90% of the valuable subjects in the Jackson Heart Study for which Dr. Hundley 
serves as the Co-PI of the core lab and the preliminary cancer studies mentioned in Section 
C.1.), 
 
Reproducibility (<2% discordance for repeated measures in the pilot data from the cancer 
participants), 
 
Accuracy (its ability to detect informative changes indicative of both CV disease and 
forecasting prognosis), 
 
Translational capability (its association with large NHLBI efforts to assess CV disease and 
thereby make additional comparisons), and 


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 
Versatility (in that with a single imaging modality one cannot only collect information 
regarding the measurement of LVEF but also the factors such as pre-load and after-load that 
can also impact the measurement of LVEF). 
 
Importantly, all sites have been verified as to the performance of these procedures via onsite 
interviews and case image recovery. 
 
Ultrasound and radioisotope studies can be used to assess cardiac function. These measures, 
however, exhibit high variance, are operator-dependent, and are difficult to obtain in individuals with 
unfavorable body habitus. Radioisotope studies require exposure to ionizing radiation. Catheter-
based assessments of left ventricular and vascular structure or function can be acquired but these 
techniques are associated with the risks of an interventional procedure. Thus, we selected MRI for 
this study.  
 
 
 
 


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4. 
PARTICIPANT SELECTION 
 
4.1. Inclusion Criteria 
  
4.1.1 Stage I-III breast cancer (including inflammatory and newly diagnosed recurrent breast 
cancer) or lymphoma Stage I-IV.  (Patients should have a > 2 year life expectancy)   
4.1.2 Scheduled to receive chemotherapy with an Anthracycline (doxorubicin or epirubicin) 
4.1.3 > 21 years of age  
4.1.4 Patients that are receiving or have received chemotherapy regimens are allowed.  
4.1.5 Prior administration of anthracyclines is acceptable if therapy was completed > 6 months prior 
to study enrollment.   
4.1.6 Able to hold breath for 10 seconds 
4.1.7 ECOG 0 or 1 
4.1.8  See section 4.2.14 for new exclusion criteria for breast patients with tissue expanders.  
4.1.9 Patients with breast implants are usually permitted to have an MRI. Check with the MRI 
technician to confirm.  
4.1.10 Participants must have required labs (within 30 days prior to enrollment) as defined below: 
 
It is recommended the Lipid Profile and Glucose be drawn Fasting > 8 hrs.  
 
X    Serum Lipid Profile: Total Cholesterol/HDL/LDL/Triglycerides   
   
(LDL levels prior to chemotherapy must be ≤ 190 mg/dl) 
X    Alanine aminotransferase level (ALT) ≤ 3 x ULN 
X    Aspartate aminotransferase level (AST) ≤ 3 x ULN 
X    Total bilirubin ≤ 2.0  
X    TSH ≤ 1.5 times ULN 
X    Creatine kinase ≤ 2.5 x the ULN 
X    Glucose < 126 (Diabetics 40–75 years of age are not eligible, See 4.2.2) 
           
If labs are drawn non-fasting and LDL levels are > 190 mg/dl the Lipid Profile should be 
repeated fasting to determine eligibility. If glucose is > 126 the glucose should be repeated 
fasting to determine eligibility. 
 
4.2 
Exclusion Criteria 
 
4.2.1    Atherosclerotic cardiovascular disease (ASCVD) defined by history of acute coronary 
syndromes, MI, stable or unstable angina, coronary or other arterial revascularization, 
stroke, TIA, or peripheral arterial disease presumed to be of atherosclerotic origin.  
4.2.2   40 to 75 years of age with diabetes per ACC/AHA 2013 Guidelines 
4.2.3  
Significant ventricular arrhythmias (>20 PVCs/min due to gating difficulty) atrial fibrillation 
with uncontrolled ventricular response 
 
 
4.2.4 
Current use of statin therapy  
 
 
4.2.5 
Current or history of hepatic dysfunction 
     
4.2.6 
Uncontrolled hypothyroidism 
 
4.2.7 
Recent extended history of constant-recurrent substance abuse or another medical 
condition that might compromise safety or the successful completion of the study. 
 
4.2.8 
Patients with ferromagnetic cerebral aneurysm clips or other intraorbital/intracranial metal; 
 
pacemakers, defibrillators, functioning neurostimulator devices or other implanted 
 
electronic devices.  
 
4.2.9 
Current use of the following CYP 3A4 inhibitors are not allowed: Boceprevir, Clarithromycin,  
Cyclosporine (oral), Darunavir plus ritonavir, Fosamprenavir, Fosamprenavir plus ritonavir, 
Gemfibrozil, Grapefruit juice >1 liter per day, Itraconazole, Lopinavir plus ritonavir, 
Nelfinavir, Saquinavir plus ritonavir, Telaprevir, Tipranavir plus ritonavir 


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4.2.10 Current use of Rifampin and Digoxin  
 
4.2.11 Unable to provide informed consent 
 
4.2.12 Symptomatic Claustrophobia 
4.2.13 Pregnant or breast feeding. Due to unknown risks and potential harm to the unborn fetus a 
negative serum pregnancy test within 10 days prior to enrollment is required in women 
with child-bearing potential. For this reason women of child-bearing potential must agree 
to use adequate contraception (hormonal or barrier method of birth control; abstinence 
(not having sex), oral contraceptives, intrauterine device (IUD), DeProvera, tubal ligation, 
or vasectomy of the partner (with confirmed negative sperm counts) in a monogamous 
relationship (same partner). An acceptable, although less reliable method involves the 
careful use of condoms and spermicidal foam or gel and/or cervical cap or sponge prior to 
study entry and for the duration of study participation. Should a woman become pregnant 
or suspect she is pregnant while participating in this study, she should inform her study 
physician immediately. 
 
Due to the potential effect of atorvastatin when excreted in breast milk, women who are 
currently breast-feeding are not eligible for this study. 
 
4.2.14   Breast patients with tissue expanders are not allowed with the exception of tissue 
expanders made of material that are MRI compatible. Check with the MRI technician to 
confirm.  
 
 
4.3.     Inclusion of Women and Minorities 
Table 2:  Race/Ethnicity 
 
Gender 
White 
Black or 
African-
American 
 
Hispanic 
or Latino 
Asian or 
Pacific 
Islander 
 
Unknown 
 
Total 
Male 
  30 
  8 
0 
0 
0 
38 
Female 
193 
43 
2 
2 
0 
240 
Total 
223 
51 
2 
2 
0 
278 
 
4.4. 
Recruitment and Retention Plan 
4.4.1 
Over 600 breast and lymphoma patients should be eligible for enrollment among the 
NCORP sites, approximately 14% of whom will be males. Assuming conservatively that 
17% (1 in 6) of the patients will consent to the study, we expect ~100 patients to be 
enrolled annually once the study is active at all planned sites. We will enroll 278 patients. 
We anticipate 28% of our cohort will drop out, so we expect 200 individuals to complete the 
study. In addition to NCORP sites, study enrollment will be opened to Alliance site 
members in which study coordinators, imaging expertise, and patient populations are 
readily available.  
 
 
4.4.2. 
At each site, specific recruitment plans may include the following according to the site’s 
institutional policy: screening clinic charts; tumor registry data; referral sources such as 
patient advocate groups, retirement communities, churches, support organizations, 
community organizations, newspapers, radio; or patient recruitment posters and recruitment 
letters. 
 
 
4.4.3. 
The research PI or designee at each WF NCORP Research Base NCORP, which may 
include the clinic physician, resident, research nurse or research assistant, will review 
cancer registry and medical chart information to identify patients eligible for this protocol.  
Patients identified using these methods will be asked to join the study during their next clinic 
visit/consultation. 
 


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Accrual is expected to be 8 patients per month. Targeted accrual should be met in 
approximately 3 years for the 5 year study. A maximum of 278 patients will be enrolled on 
this trial. Patients will be followed for at least 24 months. Patients completing at least 24 
months of study medication but no longer than 27 months will be followed for an additional 
30 days after the last dose of study medication to evaluate any study related adverse 
events. After the Final  assessment, the patient is no longer followed and data is no longer 
collected. 
 
5. AGENT ADMINISTRATION 
 
 
5.1. 
Dose Regimen and Dose Groups: 
 
Group 1 (one 40 mg atorvastatin tablet each morning by mouth for at least 24 months but no longer 
than 27 months) and Group 2 (one placebo tablet each morning by mouth for at least 24 months but 
no longer than 27 months). 
 
 
5.2. 
Atorvastatin/Placebo Administration   
 
Patients will be 1:1 randomized to receive the study agent, (one 40 mg atorvastatin tablet daily by 
mouth for at least 24 months but no longer than 27 months) or a placebo (one tablet daily by mouth 
for at least 24 months but no longer than 27 months). The study agent or placebo should be started 
within 48 hours (2 days) prior to first chemotherapy treatment. The patient must receive 2 doses prior 
to first chemotherapy treatment. When possible those 2 doses may be given at least 12 hours apart. 
If necessary, due to time constraints, the patient may be given two tablets at the same time at least 
90 minutes prior to first chemotherapy treatment.98  
 
Either agent will be taken once any time of day, with or without food, 7 days per week, on an 
outpatient basis, for a total of at least 24 months but no longer than 27 months. The atorvastatin pills 
and matching placebo pills used for this study will be provided free of charge to the patient.  
 
 
5.3. 
Run-in Procedures. N/A 
  
5.4 
Contraindications  
Active liver disease, which may include unexplained persistent elevations in hepatic transaminase 
levels, or hypersensitivity to any component of this medication. 
 
5.5. 
Concomitant Medications  
Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant administration of this statin with 
inhibitors of CYP 3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of 
interaction and potentiation of effects depend on the variability of effect on CYP 3A4. The following 
CYP 3A4 inhibitors are not allowed:  Boceprevir, Clarithromycin, Cyclosporine (oral), Darunavir plus 
ritonavir, Fosamprenavir, Fosamprenavir plus ritonavir, Gemfibrozil, Grapefruit juice >1 liter per day, 
Itraconazole, Lopinavir plus ritonavir, Nelfinavir, Saquinavir plus ritonavir, Telaprevir, Tipranavir plus 
ritonavir.  It is also recommended due to possible reactions to not use Rifampin and Digoxin.   
 
5.6 
Medication Modification  
 
5.6.1 Medication Modification for Myalgias  
 
Grade 1 Myalgias – If needed patient may take NSAIDs/analgesics at the discretion of the 
treating physician. Frequently this type of skeletal pain is not relieved with these medications. 
 


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Grade 2 or 3 Myalgias -  Study medication should be held and patient instructed in the use 
of NSAIDS/analgesics per treating physician orders. ALT, AST and CK should be drawn 
within 24 hours.  
 
If labs are in acceptable range (ALT and AST are < 3 x ULN and CK < 2.5 x ULN) 
study medication should be resumed.  
 
If Grade 2 or 3 myalgias redevelop, study medication should be discontinued. Patient 
will be considered off study medication but will continue to be followed. 
 
If ALT and/or AST are >3 x ULN and/or CK >2.5 x ULN study medication should be 
discontinued. Patient will be considered off study medication but will continue to be 
followed. 
Any patient with suspected rhabdomyolysis/compartment syndrome of lower 
leg or rupture of tendon should stop the study medication immediately. The treating 
physician should assess the patient and order CK isoenzymes and/or other labs as 
deemed necessary. Patient will remain on study (off study medication) and be followed 
as usual. 
5.6.2    Medication Modification for Elevated ALT, AST and/or CK Labs 
5.6.2.1   Elevated baseline ALT, AST and/or CK 
 
At one and three months (+ or – 7 days) additional labs will be drawn on patients with a 
baseline AST/ALT between ULN and < 3 x ULN and CK between ULN and < 2.5 x ULN. Labs 
are only repeated if baseline labs were above normal but within eligibility limits.  
 
5.6.2.2   Elevated ALT, AST and/or CK while taking study medication  
 
If AST, ALT is > 3 x ULN and/or CK is > 2.5 x ULN while patient is taking study medication 
lab should be repeated in 1 week. If still elevated in 1 week, study medication should be 
stopped and AST, ALT, CK repeated in 6 weeks.  
 
At 6 weeks the site PI/treating physician should review labs and patients clinical status. If 
labs are within eligibility range patient may be re-challenged with study medication. The 
decision regarding re-challenging the patient is at the site PI/treating physician’s discretion. 
 
5.6.2.3   General Medication Modification  
 
Contact Robin Rosdhal RN OCN at (336) 713-6519 for any medication related issues. This 
includes but is not limited to the patient experiencing difficulty with their medication regimen 
due to chemotherapy treatment and delays or interruptions in taking study medication.  
 
5.7 Adherence  
 
5.7.1 Adherence will be estimated as: 1) the proportion of expected pills taken while on treatment 
and 2) the proportion of the total number of pills that could be taken if the participant 
completed the study. We will calculate and report the mean adherence across all individuals 
as well as the proportion of patients who were 75% adherent (using both definitions of 
adherence). The primary analyses will include all randomized participants, regardless of 
adherence. Secondary analyses will be done using participants who were at least 75% 
adherent, separately using each definition.  
 
5.7.2 To determine patients’ adherence with the study agent, a medication diary will be utilized. It 
will be given to the patient by staff with instructions on how to complete. Every other month, 
medication diaries will be collected to verify medication usage. In addition, at 6 and 24 


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months any remaining bottle(s) of study agent will be collected from the patient and a pill 
count will be performed to verify the patient-recorded information in their medication diary.  
 
6.  PHARMACEUTICAL INFORMATION 
 
 6.1 Atorvastatin (Lipitor): The dosing for this study will be a daily dose of 40mg for at least 24 months 
but no longer than 27 months. Atorvastatin can be administered as a single dose at any time of the 
day, with or without food. Pharmaceutical tests of atorvastatin suggests aggressive dosing of HMG-
CoA reductase inhibitors (statins) reduce lipid levels and cardiovascular mortality and morbidity to a 
significantly greater extent than standard statin doses, according to the PROVE IT and REVERSAL 
trials. However, in our study, dosage has been set at 40mg daily in consideration of cancer 
chemotherapy treatment.     
 
Pharmacological Description: Atorvastatin is a synthetic lipid-lowering agent. Atorvastatin 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. 
 
Atorvastatin calcium is [R-(R*, R*)]-2-(4-fluorophenyl)-ß, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-
[(phenylamino)carbonyl]-1Hpyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate. The empirical 
formula of atorvastatin calcium is (C33H34 FN2O5)2Ca•3H2O and its molecular weight is 1209.42. 
Its structural formula is: 
 
 
 
 
 
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. Lipitor tablets for 
oral administration contain 10, 20, 40, or 80 mg atorvastatin and the following inactive ingredients: 
calcium carbonate, USP; candelilla wax, FCC; croscarmellose sodium, NF; hydroxypropyl cellulose, 
NF; lactose monohydrate, NF; magnesium stearate, NF; microcrystalline cellulose, NF; Opadry 
White YS-1-7040 (hypromellose, polyethylene glycol, talc, titanium dioxide); polysorbate 80, NF; 
simethicone emulsion. 
 
ProHance® (Gadoteridol) Injection is a nonionic contrast medium for magnetic resonance imaging 
(MRI), available in vials for intravenous injection into either a vein or currently placed central line 
(port-a-cath) to help identify structures within the body during a MRI scan. 
  
The ProHance® injection dose is 0.15 mmol/kg, infused at 1 ml/sec, followed by a saline  
flush of 20 ml. If the IV gauge is small, the infusion rate may be decreased and is not critical. 


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6.2  
Reported Adverse Events and Potential Risks 
  
Atorvastatin   
 
 
 
Most Common Events 
 Gastrointestinal: Abdominal pain (In pre-marketing and open extension studies with a  
 median follow-up period of 18 months, abdominal pain was reported in 7.3% of enrolled 
 patients [n=2423]), constipation (In pre-marketing and open extension studies with a median 
 follow-up period of 18 months, constipation was reported in 6.6% of enrolled patients 
 [n=2423]), nausea (In pre-marketing and open extension studies with a median follow-up 
 period of 18 months, nausea was reported in 5.4% of enrolled patients [n=2423])  
 Neurologic: Headache (In pre-marketing and open extension studies with a median follow-up 
 period of 18 months, headache was reported in 7.4% of all patients enrolled [n=2423])  
 Respiratory: Upper respiratory infection (9%) 
 Muscle Pain (Myalgia):  Soreness usually in upper arms and shoulders or hip and thighs 
 about 6%.  
 
Less Common 
 Confusion  < 2% 
 
Rare but Serious Events 
 Hepatic: Cholestatic hepatitis, increased liver enzymes (1%)  
 Musculoskeletal: Compartment syndrome of lower leg, disorder of muscle (20 to 40 mg/day, 
0.02% to 0.08%; 80 mg/day, 0.53% to 0.9%), rhabdomyolysis, rupture of tendon 
 Endocrine: Diabetes < 0.25% or 1 per 400. 
 
ProHance® 
 
Most Common Events 
 
headache, nausea, vomiting, itching, watery eyes, skin rash, facial and/or tongue swelling,  
 
wheezing, chest tightness, or troubled breathing, hypotension (a decrease in blood 
pressure) may occur in about 2% of patients. 
 
Less Common 
 
Extravasation happens in one out of every 250 to 500 procedures. <0.2 to 0.4% 
 
Rare but Serious Events 
 
renal failure   
 
nephrogenic systemic fibrosis (NSF) 
 
confusion 
 
The MRI contrast agent is used to help identify structures within the body on a MRI scan.  Minor reactions 
{principally headache, nausea, vomiting, itching, watery eyes, skin rash, facial swelling, thickening of the 
tongue, wheezing, chest tightness, or troubled breathing, hypotension (a decrease in blood pressure)} may 
occur in about 2% of patients.  Serious or life-threatening reactions have been reported in about 1 in 
400,000 patients who receive these agents.  All standard of care, medications and monitoring will be 
provided during this MRI scan. You may still participate in this study if a) you cannot receive Gadolinium-
contrast because you have known allergies to this contrast or have other severe drug allergies or b) you 
are not allergic to gadolinium-contrast but choose not to receive this contrast due the risks associated with 
the procedure. 


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 
Sometimes contrast may leak out of the IV and into the fatty tissue around a vein which is called an 
extravasation (x TRAH vuh SAY shun).  This happens in one out of every 250 to 500 procedures.  
Nonionic contrast is not likely to cause tissue damage and the contrast is reabsorbed.  If extravasation 
occurs, MRI staff will manage according to established protocols at Wake Forest Baptist Health. 
 
 
In very rare circumstances associated with dialysis and complete renal failure, gadolinium in very high 
doses has been reported to be associated with nephrogenic systemic fibrosis (NSF), a condition that 
causes hardening of tissue under the skin and potentially death.  To minimize the risk of developing this 
disorder, this study complies with all FDA criteria for administration of gadolinium. Dialysis patients are 
excluded from receipt of gadolinium contrast as part of this study.  As a consequence, an estimation of 
your kidney function obtained within a month of your MRI scans will be used to identify potential risk to 
study participation as defined by the FDA.  Those with a glomerular filtration rate <60 ml/min will not 
receive contrast as part of this study.       
 
 
Recent medical literature publications have reported that patients receiving gadolinium contrast may 
accumulate gadolinium in parts of the brain long after the last administration. Currently available 
information has not identified any adverse health effects resulting from this accumulation of gadolinium 
based contrast agents. Participants will be notified of any new information related to gadolinium-based 
contrast as it becomes available. 
 
MRI Sedation 
In the event a patient is claustrophobic (extreme discomfort or fear of small spaces) they may be 
offered an intravenous injection of a sedative medication to make the patient drowsy, relaxed and 
comfortable during the MRI scan. This is at the discretion of the site physician. Because sedatives may 
decrease alertness and cause lightheadedness or dizziness, the patient must have another adult drive 
them home from the clinic if they are given sedation. 
 
Possible risks and side effects of frequently used sedative medications may include: 
 
Most Common Events may occur in about 2% of patients. 
 
dizziness  
 
headache 
 
Less Common 
 
unusually fast/slow/irregular heartbeat, 
 
fainting,  
 
confusion, 
 
mental/mood changes, 
 
trouble breathing, 
 
muscle twitching and involuntary movements, 
 
Rare but Serious Events 
 
throat discomfort, 
 
skin rash and hives. 
. 
6.3 
Drug Availability and Description   
Atorvastatin will be manufactured and supplied by Greenstone. The study agent will be directly supplied 
to Biologics, Inc. who will fill pill bottles and create labeled prescriptions.  
 
 
 
Biologics, Inc. will provide procurement, over encapsulation and placebo manufacture services. 
 
Atorvastatin - supplied as 40mg capsules packaged in 90-count bottles. Biologics will procure the 
active supply from wholesaler for use in this study. The active supply will then be over encapsulated to 


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maintain the blind of the study. Each bottle of over encapsulated Atorvastatin will be 180-ct. Biologics 
anticipates making two purchases of active supply, one prior to the start of the study and one at year 
two, to accommodate the five year length of the trial and expirations of the product. 
 
Prior to study launch, Biologics will procure and over encapsulate approximately 54,720 tablets. 
At year two, Biologics will procure and over encapsulate approximately 54,720 tablets to complete the 
study. 
 
Placebo - A placebo is a substance, like a sugar pill, that is not thought to have any effect on the 
disease or condition. Placebos are used in research studies to see if the drug being studied really does 
have an effect. 
 
Matching placebo supplied as capsules packaged in 90-count bottles. Biologics will facilitate the 
manufacture of a matching placebo to maintain the blind of the study. Each bottle of matching Placebo 
will be 180-ct. Biologics anticipates the manufacture of two batches of the matching placebo, one prior 
to the start of the study and one at year two, to accommodate the five year length of the trial and 
expirations of the product. 
 
Prior to study launch, Biologics will facilitate the manufacture of approximately 54,720 placebo 
capsules.  At year two, Biologics will facilitate the manufacture of approximately 54,720 placebo 
capsules to complete the study. 
 
Shipment 1 
12 Month Patient Specific Supply 
 Biologics will ship 2 bottles of study drug to the study site 
  Months 1-12: 2 bottles (180-ct) 
 
At approximately month 11, Biologics will contact the site to prepare the subsequent shipment of study 
drug for the patient to complete months 13-24. 
 
Shipment 2 
12 Month Patient Specific Supply 
 Biologics will ship 2 bottles of study drug to the study site 
 Months 13-24: 2 bottles (180-ct) 
 
Shipment 3 (if applicable) 
12 Month Patient Specific Supply 
 Biologics will ship 1 bottle (180 ct) of study drug to the patient if needed. 
 Patient will return all unused study drug to the site upon final assessment. 
 
ProHance® - supplied and shipped to each individual site according to their site specific research 
agreement with Bracco Diagnostics Inc.  MRI may be performed without contrast until all arrangements 
for administering contrast at a site has been established.  For more information, please contact 
Kimberly Lane at klane@wakehealth.edu. 
 
6.4  
Agent Ordering and Distribution  
Biologics, Inc. will provide with atorvastatin 40mg pills and matching placebo and will distribute study 
drug/placebo directly to participating sites (WF exempt). The contact information for Biologics, Inc. is: 
 
Biologics Clinical Research Services 
120 Weston Oaks Court 
Cary, NC 27513  
(1-800) 693-4906 
clinicaltrials@biologicsinc.com 


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6.5. 
Agent Accountability    
 
Atorvastatin or placebo pills  
Each participating NCORP and Alliance site will maintain a careful record of the inventory and 
disposition of the study agents received (atorvastatin or placebo pills) using the NCI Drug Accountability 
Record Form (DARF). This will include adequate records of receipt, dispensing, quantities, dates and 
final disposition of study agent. 
 
ProHance®:  Each participating MRI NCORP site will maintain a careful record of the inventory and 
disposition of the ProHance® received using the NCI Drug Accountability Record Form (DARF) or drug 
accountability form used at site. This will include adequate records of receipt, dispensing, quantities, 
dates and final disposition of the ProHance®.  All remaining and or expired ProHance® must be 
disposed of according to site institutional policy. The site is responsible for maintaining the drug 
accountability record.  
 
Each participating MRI NCORP site will maintain a careful record of the inventory and disposition of any 
sedative medication given to the patient according to institutional policy.  
 
6.6  
Packaging and Labels  
    
 
  
Summary 
 
  
The study will remain open approximately 5 years or until all 278 patients have been accrued and can 
complete the study. Biologics, Inc. will send to the participating site the 24-month supply for each 
patient randomized to the study, except for those patients who may be extending to within 27 months 
from the  start of study  For these patients, Biologics may ship directly to patients. 
 
Packaging 
 
All study drugs will include a patient specific label adhered to the bottles. Biologics will place the 
bottles in a Ziploc bag and include a patient specific label on the outside. Biologics will also include 
the study number on the label to avoid confusion at the sites. 
 
Each shipment includes a label on the Ziploc bags with the following information (as needed): 
 
The Study Number 
 
The Patient study ID number 
 
The Patient’s name or initials 
 
The number of capsules 
 
Administration instructions: Take one tablet daily by mouth Drug identification (Atorvastatin 40mg 
OR Placebo) 
 
Expiration Date 
 
Dosing instructions (Administer as Directed per Protocol) 
 
Storage instructions (“Store at controlled room temperature, 20-25°C (68-77°F)”) 
 
Date dispensed 
 
IND caution statement and/or local regulatory statements 
 
Emergency contact instructions 
 
For all drug shipments from Biologics, Inc., a packing slip will be enclosed that includes the date and 
quantity of drug provided patient name/initials, study ID number, drug identification and expiration date. 
 
Biologics, Inc. will process and ship “same day” of patient randomization if received before 5:00 p.m. 
EST Monday through Friday.   Orders received after 5:00 pm EST Monday through Friday will be 
processed and shipped the next business morning. 
 
All drug orders are shipped via FedEx for Priority Overnight delivery. Study drug is shipped in boxes 
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Once study drug is received at the clinical trial site, the designated site coordinator validates contents of 
package match information provided on packing slip with study medication received. The inventory and 
disposition of atorvastatin or placebo pills must be recorded using the NCI Drug Accountability Record 
Form (DARF).  
 
ProHance®will be supplied by Bracco Diagnostics Inc. ProHance® is not dispensed as a patient specific 
medication; it is shipped in bulk to each individual site with appropriate manufacturing labeling and 
directions.  
 
6.7.  
Storage    
 
Atorvastatin pills are supplied as 40mg pills in 90 count bottles and stored at 20-25°C (68-77°F). 
   
ProHance® will be stored according to Bracco Diagnostics Inc. package insert.  
 
6.8. 
Registration Process  
 
All patient enrollments for Wake and non-Wake sites will go through the Wake Forest NCORP 
Research Base (see Section 6.8.2).  NCORP sites can request membership through the Wake Forest 
NCORP Research Base. 
 
6.8.1 Non-Wake sites can register through CTSU. 
 
 
CTSU Registration Procedures for Wake and non-Wake NCORP Sites: 
 
 
Cancer Therapy Evaluation Program Investigator Registration Procedures 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to OPEN, RAVE, or acting as a primary site contact) must complete their 
annual registration using CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr).   
 
RCR utilizes five person registration types. 
 
IVR — MD, DO, or international equivalent; 
 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., 
PhD); 
 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications (e.g., 
Roster Update Management System (RUMS), OPEN, Rave,); 
 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; and 
 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with limited 
access to NCI-supported systems. 
 
 
 
 


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RCR requires the following registration documents: 
Documentation Required
IVR
NPIVR
AP 
A 
AB
FDA Form 1572 
✔ 
✔ 
 
 
 
Financial Disclosure Form 
✔ 
✔ 
✔ 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
✔ 
✔ 
✔ 
 
 
GCP training 
✔ 
✔ 
✔ 
 
 
Agent Shipment Form (if applicable) 
✔ 
 
 
 
CV (optional) 
✔ 
✔ 
✔ 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
• Addition to a site roster; 
• Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• Act as the site-protocol Principal Investigator PI on the IRB approval; and  
• Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     
 
In addition, all investigators act as the Site-Protocol PI, consenting/treating/drug shipment, or as 
the CI on the DTL must be rostered at the enrolling site with a participating organization (i.e., 
Alliance).  
Additional information can be found on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please contact the RCR 
Help Desk by email at RCRHelpDesk@nih.gov. 
 
Cancer Trials Support Unit Registration Procedures: 
 
This study is supported by the NCI CTSU 
 
IRB Approval:   
 
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical Trials 
Network (NCTN) and NCI Community Oncology Research Program (NCORP) Research Bases 
after March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional 
Review Board (NCI CIRB). In addition, U.S.-based sites must accept the NCI CIRB review to 
activate new studies at the site after March 1, 2019. Local IRB review will continue to be 
accepted for studies that are not reviewed by the CIRB, or if the study was previously open at 
the site under the local IRB. International sites should continue to submit Research Ethics Board 
(REB) approval to the CTSU Regulatory Office following country-specific regulations. 
 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory Office 
using the Regulatory Submission Portal located in the Regulatory section of the CTSU website. 
Acceptable documentation of local IRB/REB approval includes: 
 
Local IRB documentation; 
 
IRB-signed CTSU IRB Certification Form; and/or 


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 
Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form. 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the IRB/REB 
approval) must meet the following criteria to complete processing of the IRB/REB approval 
record: 
 
Holds an Active CTEP status; 
 
Rostered at the site on the IRB/REB approval (applies to US and Canadian sites only) and 
on at least one participating roster; 
 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the RCR 
profile; and 
 
Holds the appropriate CTEP registration type for the protocol.  
 
 
Additional Requirements 
 
Additional requirements to obtain an approved site registration status include: 
 
An active Federal Wide Assurance (FWA) number. 
 
An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO); and 
 
Compliance with all protocol-specific requirements (PSRs). 
 
 
Downloading Site Registration Documents:   
 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website.  Permission to view and download this protocol and its supporting 
documents is restricted based on person and site roster assignment. To participate, the 
institution and its associated investigators and staff must be associated with the LPO or a PO on 
the protocol.  
 
Log on to the CTSU members’ website https://www.ctsu.org using your CTEP-IAM 
username and password; 
 
Click on the Protocols tab in the upper left of your screen 
 
Enter the protocol number in the search field at the top of the protocol tree, or  
 Click on the By Lead Organization folder to expand, then select [Corresponding 
Organization], and protocol number [NCI Protocol #]; 
 
 
Protocol Specific Requirements for WF- 98213 Site Registration: 
 
 
CTSU IRB Certification (for sites not participating via the NCI CIRB) 
 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via the NCI 
CIRB)  
 
See Section 8 for protocol specific training requirements. This must be completed 
prior to enrollment.   
 
 
Submitting Regulatory Documents:  
 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU website.  
 


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To access the Regulatory Submission Portal log on to the CTSU members’ website   
Regulatory Regulatory Submission  
 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive further 
instruction and support. 
 
Checking Your Site’s Registration Status: 
 
You can verify your site’s registration status on the members’ side of the CTSU website.  
 
 
Log on to the CTSU members’ website; 
 
Click on Regulatory  at the top of your screen; 
 
Click on Site Registration;  
 
Enter your 5-character CTEP Institution Code and click on Go. 
 
Note: The status shown only reflects institutional compliance with site registration requirements 
as outlined above. It does not reflect compliance with protocol requirements for individuals 
participating on the protocol or the enrolling investigator’s status with the NCI or their affiliated 
networks. 
 
6.8.2 Online Patient Enrollment Procedures for Sites (Wake and non-Wake sites) 
 
 
 
Do Not Enroll Patients Through “OPEN” 
 
 IRB letter of approval and an IRB approved consent form must be received by the Research 
Base Protocol Information Office – Attn:  Site Coordinator prior to patient enrollment. Fax: (336) 
716-6275.  An “Eligibility Checklist / Enrollment Form” will be used to complete the on-line 
enrollment. 
 
 
       
Online Enrollment 
Log on to the Wake Forest NCORP Research Base enrollment web site at 
https://ccrbis.phs.wakehealth.edu.  Enter your user name and password (which may be 
obtained by contacting Robin Rosdhal, RN at rosdhal@wakehealth.edu In the ‘Patient 
Enrollment and Protocol Information’ table, click the ‘Register Patient/Patient Info’, with the 
corresponding protocol number found in the drop down box to the right.  Fill in the eligibility 
criteria forms using the drop down boxes.  If further information is needed by Biologics or Data 
Management, they will contact you.  Once the patient information has been entered online print 
a copy of the eligibility checklist/enrollment form for your records. Press the submit button, 
a confirmation page will appear.  Print this confirmation sheet for your records.  The Wake 
Forest NCORP On-line Protocol Enrollment/Eligibility form, initial flow sheet, signed consent, 
should be faxed to 336-713-6476 or mailed to Data Management: 
 
Wake Forest NCORP Research Base 
Data Management Center 
Wake Forest Baptist Medical Center 
Building 525@Vine, 4th floor 
Medical Center Boulevard 
Winston-Salem, NC 27157 
 
 These forms should be retained in the patient’s study file. These forms will be evaluated during 
an institutional NCI/Wake Forest NCORP Research Base site member audit. 
 


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 If you have questions related to the enrollment process or require assistance with enrollment, 
please contact the Wake Forest NCORP Research Base DMC between 8:30am and 
4:00pm EST, Monday through Friday at (336) 713-3172 or 713-6507. 
 
 6.8.3 Randomization Process 
  
 
See Section 12.1 
 
6.9. Unblinding Methods   
 
In the event a patient on this study develops a toxicity (adverse event or severe adverse event) for 
which the patient’s physician or other health care professional feels that it is in the patient’s best 
interest to know what drug they are taking (active study drug or placebo), the following procedure 
should be followed: 
 
 Step 1: The patient’s physician or a designated health care professional should call the Wake 
Forest University Baptist Medical Center Physician Access Line at (336) 716-7654 and ask that 
Dr. Glenn Lesser, Director of the WF NCORP Research Base, be contacted immediately either 
in his office, by pager, or at home. In the event Dr. Lesser cannot be reached, the PAL operator 
should contact Dr. Kate Weaver, Director, Symptom Treatment Protocols, in her office, by pager, 
or at home. If neither Dr. Lesser nor Dr. Weaver can be reached, the PAL operator should 
contact Dr. David Herrington, Co-Investigator, in his office, by pager, or at home.  If Dr. Lesser, 
Dr. Weaver or Dr. Herrington cannot be reached, the PAL operator should contact Dr. Joseph 
Yeboah, Co-Investigator, in his office, by pager, or at home. 
 
 Step 2: Once contact has been made, the patient’s physician or health care professional should 
explain the reason for the request to unblind the treatment arm that the patient is on. If the  
Research Base representative feels that the toxicity (AE/SAE) is possibly, probably or definitely 
related to the study drug, then the next step will be followed. 
 
 Step 3: The responsible Research Base representative will call the pharmacist @ Biologics, Inc. 
(phone: 1-800-850-4306). There is an “on-call” service provided 24 hours a day, seven days a 
week for the Chemical Drug Trials unblinding service. The Biologics pharmacist may contact the 
patients’ physician and/or health care professional directly with the unblinding information. 
Written documentations of the unblinding process will be sent to the Research Base Principal 
Investigator by Biologics, Inc. 
 
 Step 4: In the event that the patient’s treatment is unblinded, that patient will be taken off study 
with no further study follow-up. Appropriate procedures for grading toxicities, assigning causality, 
and reporting severe adverse events (if applicable), should be followed. The event will be 
reviewed by the WF NCORP Safety and Toxicity Review Committee and reviewed by the 
NCORP Research Base Data Safety and Monitoring Board.  
 
Record the details of the adverse event and/or unblinding in the site source documentation and 
complete appropriate AE forms. 
 
  
Unblinding Study Participants at Study Completion 
Study participants may be unblinded at the conclusion of the study if all patient specific data for the 
requesting site are completed and submitted to the Data Management Center (DMC) and all of the 
primary study outcomes have been determined and the final data set is cleaned and prepared for 
analysis. Site members can obtain unblinding information by sending an email request to the WF 
NCORP Administrator or Data Management Supervisor with a list of PID #s. After confirming with the 
DMC that patient specific data for all patients at the requesting site have been received, completed 
and entered into the RB database, the Research Pharmacy will be notified. An email from the 
Research Pharmacy containing the unblinding information will be sent directly to the requesting site. 
 


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6.10. Agent Destruction/Disposal  
    
 
Unused drug should be destroyed on site following site institutional policies and procedures. 
 
 
7. CLINICAL EVALUATIONS AND PROCEDURES 
 
 
7.1 Schedule of Events 
At each participating Research Base site, medical charts will be screened to determine potential 
eligibility by physicians (including residents or fellows, if applicable), research nurses, or clinical 
research associates. This information should be recorded on the Screening Form. Patients identified 
as potentially eligible will then be asked to consider joining the study. Patients meeting initial eligibility 
criteria and who agree to participate in the study will sign informed consent and then undergo a 
baseline nurse exam, laboratory tests and quality of life tests. At baseline, 6, and 24 months (or within 
27 months), the entire battery of neurocognitive tests and questionnaires will be administered by a 
trained and certified examiner. At 12 and 18 months participants will be contacted by phone to assess 
toxicities and medication compliance. Quality of Life Questionnaires will be completed via mail. 
Patients will be instructed in the self-administration of the study agent. Patients will take one pill daily 
beginning within 48 hours (2 days) prior to the start of chemotherapy. It may be helpful if the patient 
receives 2 doses prior to first chemotherapy treatment and those 2 doses be at least 12 hours apart. 
If necessary however due to time constraints, the patient may be given 2 tablets at the same time at 
least 90 minutes prior to first chemotherapy treatment. Potential side effects and risks are described 
in Section 6.2. Adverse event reporting is described in Section 10. Study outcomes will be assessed 
at baseline, after 6 months and at the end of 24 month (or within 27 months). Patients completing at 
least 24 months of study medication but no more than 27 months will be followed for an additional 30 
days after the last dose of study medication to evaluate any study related adverse events. 
 
 
 
7.2. Screening/ Baseline Evaluations 
Due to the scheduling complexity of protocol requirements prior to the start of the first chemotherapy 
treatment, screening and baseline procedures and randomization may be performed at the sites 
discretion once the patient has signed the consent. The patient should be registered within 30 days of 
screening labs. 
 
         Subjects will be checked for height, weight, waist circumference, heart rate and blood pressure. 
 Body Mass Index (BMI) will be calculated at the data center. Patient physical exam including 
peripheral edema, smoking status and family history will be collected by study personnel.  
 
Waist circumference Measuring Directions  
 Patient should be instructed to not hold their breath. 
 The measuring tape should be secure but not tight. 
 The area being measured can be found by placing the hands on the waist and moving them 
downward until the top curve of the hip bone can be felt. 
 The area being measured can be found by placing the hands on the waist and moving them 
downward until the top curve of the hip bone can be felt. 
 Place the tape measure around the top of the hip curve and wrap around at the level of the belly 
button. (This may not be the same level as the top of the pants.) 
 Record this measurement in inches on the flow sheet.   
 
Study personnel will download the CV Risk Calculator according to specifications in Appendix 3.  After 
collecting the appropriate information, it will be entered in the CV Risk Calculator. Note: If the patient is 
< 40 years old, data cannot be entered in CV Risk Calculator. The result will be documented on the 
flow sheet and the Physician Statin Update Letter to be mailed to the treating and primary care 
physician. If the study participant should have statin therapy initiated, the study coordinator 
should complete the Open Label Form (Appendix 12) and submit to the Data Management 
Center. 


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Serum and blood derived biomarkers - A blood sample of approximately 4 tablespoons will be taken 
from a vein in the arm/central line for lab analysis.  
 
Statins exert pleiotropic effects (modulation of systemic inflammation and the neurohormonal axis) that 
in other models of heart failure influence LV function,57,58 and have been modulated in pilot animal 
studies.14 In this study, we will determine the relationship between Anthracycline-based therapy 
administration, statin use and biomarker evidence of systemic inflammation59 and neurohormonal axis 
activation.60 We will associate these relationships with changes in both LV and vascular function. 
 
Labs for future testing - Participants who consent to have blood stored for future research will have 
an additional 1 tablespoon of blood drawn. These labs will be picked up and processed by LabCorp. 
Blood samples will be shipped and stored with a unique identifier and will not include any information 
protected by HIPAA regulations. LabCorp’s Bio-repository for blood samples is located in Kannapolis, 
North Carolina.  
 
MRI Variables - MRI exams will be accomplished according to previously published techniques  
described on the Research Base website under “Helpful Guides” located in the Appendices section.  
Our research group and Dr. Hundley (PI) has extensive experience developing and utilizing these 
techniques in single center or multi-center efforts including the Jackson Heart Study (Dr. Hundley is 
Co-PI for the core lab) and the MESA study.  
 
LVEF is the primary outcome because it is the most widely clinically implemented assessment of LV 
performance, and is used to guide therapeutic intervention. LVEF has limitations as it can vary 
dependent on LV pre-load or after-load. To account for these limitations we are utilizing MRI to measure 
LVEDV (pre-load) and PWV (after-load). Also, we will perform advanced assessments of LV contractility 
including myocardial strain which is utilized in other NHLBI studies (such as MESA). This will allow us 
to measure systolic performance independent of LV pre-load and enable cross. Aortic distensibility will 
be assessed as an exploratory aim. 
 
The MRI is for study purposes only, the imaging results will not be reviewed at the site. The WF 
NCORP Research Base will send a clinical update when the MRI is reviewed and/or alert the site 
study staff if an unrecognized myocardial infarction was identified. 
                              
At baseline, if a routine standard of care ECHO or MUGA is obtained and available at the time of 
enrollment, the LVEF result should be documented on the enrollment form.  If the LVEF result is 
available after enrollment, record the result on the flow sheet. . 
 
An MRI should be obtained between 5 and 7 ½ months. All anthracycline therapy should be completed 
and tissue expanders (if applicable) removed before obtaining the cardiac MRI. For time periods 
outside of these ranges, special permission for extenuating circumstances (e.g., significant healthcare 
issue warranting hospitalization) may be obtained by direct contact with Dr. Hundley, the study PI. If it 
is determined a patient cannot have a 6 month (5-7 1/2 month) MRI, the patient will continue on study 
as per protocol.  
 
The 24 – 27 month MRI should be obtained within 30 days prior to the last dose of study medication. 
For time periods outside of these ranges, special permission for extenuating circumstances (e.g., 
significant healthcare issue warranting hospitalization) may be obtained by direct contact with Dr. 
Hundley, the study PI.   
 
Due to unknown risks and potential harm to the unborn fetus and because some methods of birth 
control are not 100% reliable, it is suggested that women of childbearing potential take a pregnancy 
test prior to each MRI exam, as written in the informed consent form. It is also suggested that a 


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negative serum or urine pregnancy test be performed within 10 days of each MRI exam. Each site 
should follow their institution’s policies. 
 
MRI may be performed without contrast but it is preferred contrast be used to better define the cardiac 
structures.  If the site has a signed contract with Bracco and ProHance is supplied, the site will be 
responsible for maintaining a careful record of the inventory and disposition of the ProHance® 
received.  
  
Neurocognitive Function 
    
 
Cognition and Quality of Life 
Once eligibility has been established the neurocognitive test battery and the study questionnaires will 
be completed. Individual components of the full battery are described below. Tests have been selected 
to represent a range of cognitive abilities which have been reported in the literature to be affected by 
chemotherapy including attention, verbal memory, working memory, executive functions, speed of 
mental processing and verbal fluency. An abbreviated battery consisting of two tests has been 
developed for the baseline assessment to reduce participant burden (see below). All cognitive testing 
will be performed by a trained and certified research assistant blinded to treatment assignment. The 
WF NCORP Research Base has conducted training workshops and produced videos for administering 
this cognitive test battery for our completed trials among irradiated brain tumor patients and breast 
cancer patients exposed to chemotherapy, and maintains a stringent certification process (Section 
8.2).  
 
An abbreviated  battery of the cognitive tests and shorter versions of quality of life questionnaires will 
be used at baseline to reduce participant burden and due to time constraints related to the start of the 
first chemotherapy treatment. The shorter battery includes the same tests  in the longer version used 
at 6 and between 24 - 27 months to ensure we have adequate consistency across assessment points. 
Each cognitive test has adequate psychometric properties and has been used in cancer research 
including large national and international clinical trials (Ahles & Saykin, 2002; Mehta et al., 2002; 
Meyers et al., 2004). The entire cognitive test battery takes 10 minutes to administer at baseline and 
30 minutes to administer at 6 months and 24 months..It will be administered with the questionnaires 
which takes 10 minutes at baseline 6 months and 24 months. 
 
Controlled Oral Word Association Test (COWA) 
The COWA (Benton & Hamsher, 1976) measures speed of mental processing, verbal fluency, and 
executive function. Subjects are asked to name as many words as possible all beginning with a 
specified letter.  A total of three trials are administered, each with a different letter (C-F-L).  The score 
on the COWA is the total number of words named across the three trials minus repetitions.  The 
COWA has two equivalent forms (C-F-L and P-R-W) that will reduce practice effects. Internal 
consistency reliability (alpha=0.83) and test-retest reliability (r = 0.74) are excellent (Ruff et al., 1996). 
 
Hopkins Verbal Learning Test-Revised (HVLT-R) 
The HVLT-R measures verbal learning and memory.  It consists of a 12-item word list which is read to 
subjects on three successive learning trials. Free recall scores are recorded for each learning trial.  
After a 20-minute interval during which subjects complete other non-interfering tasks and 
questionnaires they are asked to recall the target words. Lastly, a yes/no recognition task is then 
presented in which subjects are asked to identify all target words by responding “yes,” and to reject 12 
non-target words by responding “no.” The HVLT has six equivalent alternate forms (Brandt, 1991) to 
minimize confounding by practice effects. Test-retest reliability of the HVLT is quite good (0.74).  The 
test is brief, taking only 10 minutes to administer, and it is well-tolerated by compromised (geriatric and 
dementia) populations. Scores for immediate recall (total of three trials), delayed recall (total number 
of words recalled after 20 minutes), and recognition (total number of words correctly identified) will be 
the variables derived from the HVLT-R. 
 


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Trail Making Test, Parts A & B (TMT-A, TMT-B) 
Part A of the TMT(Reitan, 1958)  measures attention and visual motor skills and processing speed and 
requires subjects to connect 25 numbered circles in the proper sequence (1-2-3-…) as quickly as 
possible. TMT-B is similar except subjects are required to connect dots in an alternating numerical and 
alphabetical sequence (1-A-2-B-…). TMT-B with its added complexity and set shifting requirements is 
a widely used measure of executive function. The score for TMT-A and TMT-B is the total time in 
seconds required to complete the task. Scores can also be generated for number of errors and 
number of circles correctly connected. The TMT has excellent reliability and validity (Reitan, 1992). 
 
Digit Span Test (DST) 
The DST (Wechsler, 1981) assesses attention and working memory.  It requires respondents to repeat 
back gradually increasing spans of numbers. Seven series of two spans of each length are presented 
and repeated backwards.  A total score is the sum of the longest span backwards. 
  
Self-Report Questionnaires: 
The Patient Reported Outcomes Measurement Information System (PROMIS) is a collection of well-
validated, brief, fee-free instruments assessing key patient reported outcomes related to this study. 
Each PROMIS scale has excellent psychometric properties (reliability and validity) and are being used 
in many clinical trials and observational studies. For this study, we will include the short forms for:  
 
PROMIS Applied Cognition – General Concerns – Short Form 4a (4 items)  
 
PROMIS Applied Cognition – Abilities – Short Form 4a (4 items)  
 
PROMIS Fatigue – Short Form 4a (4 items)  
 
PROMIS Mood – Emotional Distress - Anger – Short Form 5a (5 items)  
       
Emotional Distress - Anxiety – Short Form 4a (4 items)  
 
Emotional Distress - Depression – Short Form 4a (4 items)  
  
PROMIS Pain Intensity - Short Form 3a (3 items) 
 
PROMIS Pain Interference - Short Form 4a (4 items) 
 
PROMIS Sleep Disturbance - Short Form 4a (4 items) 
 
PROMIS Physical Function - Short Form 4a (4 items) 
 
PROMIS Ability to Participate in Social Roles and Activities - Short Form 4a (4 items)  
 
The total administration time for these questionnaires is 10 minutes. 
 
 
7.3. Evaluations During Study Intervention 
Study participants in both statin and placebo groups will have a Cardiac MRI (see Section 7.2 for 
pregnancy testing prior to MRI exams), and blood drawn for a cardio profile, lipids, CK, ALT, AST, 
Total Bilirubin, glucose, TSH, Hematocrit (only if gadolinium contrast is administered for the MRI) and 
neurohormonal biomarkers at screening/baseline, 6 months and between 24 - 27 months. Biomarkers 
studied include ultrasensitive troponin I (for myocellular injury); C-reactive protein, interleuken-6, 
tumor necrosis factor-a (systemic inflammation); and renin and aldosterone (circulating 
neurohormones). Additional blood samples will be drawn on participants who consented to have 
blood stored for future research.  
 
See section 5.6.1 for Modification of Study Medication related to Myalgias which may require 
additional labs at 1 and 3 months.  


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              See section 5.6.2 for Modification of Study Medication related to   
              Elevated ALT, AST and CK Labs. 
Neurocognitive test battery and Quality of Life Questionnaires will be obtained.  At 12 and 18 months 
participants will be contacted by phone to assess toxicities and medication compliance. Quality of Life 
Questionnaires will be completed via mail. 
 
 
7.4. Evaluations at Completion of Study Intervention 
All study participants will have an Cardiac MRI (see Section 7.2 for pregnancy testing prior to MRI 
exams) and blood drawn for a cardio profile, Lipids, CK, ALT, AST, Total Bilirubin, glucose, TSH, 
Hematocrit (only if gadolinium contrast is administered for the MRI procedure) and neurohormonal 
biomarkers noted in 7.3, between 24 – 27 months. Additional blood samples will be drawn on 
participants who consented to have blood stored for future research  
 
               Neurocognitive testing and Quality of Life Questionnaires will be obtained. Follow-up assessments 
will include laboratory evaluations, pill counts, and structured interviews assessing outcomes and 
potential adverse events.  
 
 
7.5.  Post-intervention Follow-up Period.  
               Patients completing 24 months of study medication will be followed for an additional 30 days after the  
               last dose of study medication to evaluate any related adverse events. After the 25 month contact, the  
               patient is no longer followed and data is no longer collected from the patient. 
 
 
 
7.6 Methods for Clinical Procedures   
 
 
Processes for obtaining the MRI and lab sample data are provided in Appendices 11 and 12 
 
MRI invoices should be emailed to Teresa Crotts at tcrotts@wakehealth.edu or mailed to: 
 
Attn: Teresa Crotts 
Wake Forest Baptist Health 
Department of Internal Medicine 
Section on Cardiology 
Medical Center Boulevard 
Winston-Salem, NC 27157 
 
 


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7.7. Study Parameters Table    
Study agent or placebo should be started when received. The patient must receive 2 doses prior to first 
chemotherapy tx. and those 2 doses may be given at least 12 hours apart. If necessary, due to time 
constraints, patient may be given 2 tablets at the same time at least 90 minutes prior to first chemotherapy 
tx.  All evaluations/procedures are to be completed within + or – 30 days of specified time unless indicated 
otherwise. Note: 24 month MRI should be obtained within 30 days prior to the last dose of study medication. 
Evaluation 
Procedure 
Screening 
(C) 
Baseline 
(D) 
1 & 3 
Mths (G) 
6 
Mths 
12 
Mths 
18 
Mths 
between
24 - 27 
Mths 
1  
Mth 
Post 
Final 
Assess
ment 
Informed Consent  
X 
 
 
 
 
 
 
 
Demographics  
(p. 6 of enrollment form)  
 
X 
 
 
 
 
 
 
 
Nurse Exam 
 
X 
       
X 
 
 
X 
 
Cardiac/Vascular MRI (A)(B) 
 
X (A1)(B) 
 
X (A2)(B) 
 
 
X (A3)(B) 
 
Screening labs (C) 
X 
 
 
 
 
 
 
 
CV Risk Calculator 
 
X 
 
 
 
 
 
 
General Labs (D) (E) 
 
X 
 
X 
 
 
X 
 
Biomarker Labs (F) 
 
X 
 
X 
 
 
X 
 
Future Research Lab  
(if pt. consents) 
 
X 
 
X 
 
 
X 
 
ALT/AST and CK - Above 
normal at baseline (G) 
 
 
X 
 
 
 
 
 
Unscheduled ALT/AST/ CK 
for myalgias/ elevated levels  
(See Section 5.6)   
 
 
 
 
 
 
 
 
Baseline Booklet (H) 
 
X 
 
 
 
 
 
 
6 Month Booklet (H) 
 
 
 
X 
 
 
 
 
12 Month Booklet (H) 
 
 
 
 
X 
 
 
 
18 Month Booklet (H) 
 
 
 
 
 
X 
 
 
24 Month Booklet (H) 
 
 
 
 
 
 
X 
 
Flow Sheet/Addenda 
 
X 
X 
X 
X 
X 
X 
 
Phone Contact Form 
 
 
 
 
X 
X 
 
 
MRI Encounter Form (I) 
 
X 
 
X 
 
 
X 
 
Current Med Form 
 
X 
 
X 
X 
X 
X 
 
Medication Diaries & pill 
count (J) 
 
Every other month 
 
Chemo Form 
Submit this form after each course (not cycle) of chemotherapy   
 
RT Form 
To be completed when last RT tx. is received or indicating patient will not receive 
RT. 
 
Open Label Form 
If placed on a statin by their physician. (See Appendix 12 Statin Physician Update) 
 
Early Withdrawal 
Treatment/Consent 
Submit if patient withdraws from active tx, or withdraws consent prior to end of 
.study. 
 


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Screening Form 
Submit this form every month. 
 
1 Month Post Contact Form 
(K) 
For patients completing between 24 -27 months of study med – Submit this form 
30 days after last dose of study medication. 
X 
 A1 - Baseline MRI’s are required. If a routine standard of care LVEF is obtained by ECHO or MUGA this result should be 
documented on the flow sheet or the enrollment form. 
 A2 - 6 month MRI should be obtained between 5 and 7 ½ months once anthracycline therapy has been completed and 
tissue expanders (if applicable) have been removed. For time periods outside of these ranges, special permission for 
extenuating circumstances (e.g., significant healthcare issue warranting hospitalization) may be obtained  
by direct contact with Dr. Hundley, the study PI. If it is determined a patient cannot have a 6 month (5-7 1/2 month) 
MRI, the patient will continue on study as per protocol.    
A3 - 24 – 27 month MRI should be obtained within 30 days prior to the last dose of study medication. It is important to 
recognize that this sample point is very important for the conduct of the study.  For scans that need to be performed 
outside of this range of time, special permission for extenuating circumstances (e.g., significant healthcare issue 
warranting hospitalization) may be obtained by direct contact with Dr. Hundley, the study PI.    
B - 
It is suggested that a negative serum or urine pregnancy test be performed within 10 days of each MRI exam for all 
women of childbearing potential.  
C - 
Screening labs must be within 30 days prior to enrollment. Screening CMP results should be used for Baseline CMP 
(ALT, AST, Glucose, Total Bili), Lipid Panel, Creatine Kinase, TSH  -- Serum HCG must be drawn within 10 days prior 
to enrollment in women of child-bearing potential 
D - 
Baseline evaluations must be completed prior to start of chemo. 
E -  Hematocrit - Obtain only when gadolinium contrast is administered for the Cardiac MRI. 
F - 
Biomarkers (C-reactive Protein, Troponin-I, Aldosterone, Interleukin-6, TNFα, Renin) 
G - 
Repeat labs at 1 and 3 months should be collected within + or - 7 days if baseline values are above normal but within 
eligibility limits. 
H - 
Booklets for the additional cognitive and QOL questionnaires are described in Section 11.1.  
I - 
Submit MRI Encounter Form on all patients. If MRI not performed, indicate this on MRI Encounter Form and submit to 
the Wake Forest NCORP Research Base. 
J - 
For both blinded and open label patients, medication diaries should be collected in-person or by mail every other 
month. A pill count is required when the patient is seen at 6 months, 24 months or at any time the patient discontinues 
the study medication. 
K - 
1 Month Post Final Assessment contact form - Patients completing 24 - 27 months of study medication should be 
followed for an additional 30 days after last dose of study medication for related adverse events.  
 
7.8. Off Treatment Criteria  
Participants may stop taking atorvastatin for the following reasons: completed the protocol-prescribed 
intervention, adverse event or serious adverse event, inadequate agent supply, concomitant 
medications, medical contraindication, or interruption of chemotherapy due to adverse events or 
death. 
Participants will continue to be followed, if possible, for safety reasons and in order to collect endpoint 
data according to the schedule of events.  The study is designed to account for drop-outs due to poor 
health or death or loss to follow-up; thus, there will be no replacement of subjects that must drop out 
of the study after enrollment. 
 
 7.9 Off-Study Criteria 
Participants may go ‘off-study’ for the following reasons: the protocol intervention and any protocol-
required follow-up period is completed, adverse event/serious adverse event, lost to follow-up, 
concomitant medication, medical contraindication, withdraw consent, or death.   
 
Since the study inception and development of the inclusion/exclusion criteria, guidelines regarding the 
potential administration of statins have been released by the ACC/AHA on November 12, 
2013.  These new guidelines suggest the use of a calculator to assess cardiovascular risk with 
subsequent initiation of statin therapy based on that risk.  Concomitant with the release of the 
guidelines, however, have been several articles suggesting that the calibration of the calculator was 
somewhat imperfect, particularly in regards to data from both the Nurses’ Health and Physicians’ 
Health studies.    
 


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As a result of these controversies, the study investigators elected to leave the initial entry and 
exclusion criteria intact.  Importantly however, their respective primary care physician will be mailed a 
letter raising their awareness to the publication of these guidelines.  If the study participant and their 
primary care physician elect to initiate statin therapy, they will be counseled to stop their study drug 
and notify the respective investigators at their study site.  They will still be allowed to participate in all 
other aspects of the trial as an open label statin user.  Data analyses regarding intention to treat as 
well as treatment effect will be performed.   
 
8. PROTOCOL SPECIFIC TRAINING REQUIREMENTS 
 
8.1 MRI Training 
 Refer to the “Helpful Guides” located on the Research Base website in the Appendices section. 
 The study PI presented the MRI protocol for review and discussion with the MRI technologists 
 
and associated study coordinators during the Investigator meeting held at the 2013 Annual 
 
Research Base NCORP Meeting. 
Prior to the start of participant enrollment into the study, Wake Forest University Medical Center 
cardiology imaging specialists observe and continue MRI training at each of the study locations.   
 
Each site will be required to submit 2 satisfactorily performed studies to the image coordinating center 
at Wake Forest before initiating the study. 
 
 
8.2  NEUROCOGNITIVE TRAINING  
 
 
 
8.2.1 Certification Requirement 
Certification for the administration of the neurocognitive battery and questionnaires will 
include self-study, internet-based training, didactic presentations, role-played 
administrations, and Q&A and feedback. All training will be supervised by experienced test 
administrators (Dr. Rapp at WFUSM, Robin Rosdhal RN OCN, Site Coordinator or other 
trained/certified administrator who will be responsible for certifying test administrators.) They 
will also be responsible for helping staff maintain certification by having regular meetings to 
discuss the procedures and providing supplemental training as needed.   
 
Bilingual staff must be certified to administer neurocognitive battery to non-English speaking 
patients. Certification procedure must be completed by staff prior to patient enrollment.   
 
 
 
 
8.2.2 Certification Procedures 
 
All neurocognitive assessments will be conducted by trained and certified research 
personnel.  Training and certification procedures must be completed by research staff prior 
to patient enrollment. Certification for administration of the neurocognitive battery will include 
viewing of a training video on the Wake Forest University Health Sciences website, 
reviewing the content of the protocol-specific test booklets including all aspects of 
administration and scoring, a didactic presentation of each test and questionnaire to be 
administered, and role-playing of administrations with Q&A and feedback. All training will be 
supervised by experienced test administrators (Dr. Stephen Rapp, psychologist and co-PI of 
this study, and other trained/certified administrators designated by the WF NCORP 
Research Base.)  
 
There are 3 ways to become certified: 1) Training and certification on-site by WF NCORP 
certified personnel, contact NCORP@wakehealth.edu; 2) Training and certification at the 
annual meeting of the WF NCORP Research Base, held each fall (contact the Research 
Base Administrative Secretary at (336) 716-0891 for date of next meeting; 3) By sending in a 
recorded presentation  and administration booklet to NCORP@wakehealth.edu for 


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certification review. Alliance sites that have current credentialing for Alliance neurocognitive 
studies may choose #3 for WF certification. 
 
Periodic re-certifications will be required if it has been more than 6 months since the staff 
member administered the tests. This procedure has been successfully used in our studies of 
cognitive effects of cancer and its treatments as well as by Dr. Rapp and his team in large 
scale, multi-site clinical trials and observational studies (e.g., WHIMS, CoSTAR, SPRINT, 
Look AHEAD, LIFE, MESA). 
 
9. SPECIMEN MANAGEMENT  
 
 
 9.1 Storage of Blood for Future Research Testing (if applicable)  
At baseline, 6 months and 2 years an additional 2 tubes of blood will be collected on patients who 
have given consent to store blood for future research testing.  
 
These future tests may include searches for combinations of genetic nucleotide polymorphisms that 
are associated with susceptibility to a fall in LVEF in patients receiving chemotherapy. At present, 
planned testing is not specified and thus not included in our specific aims. All blood samples will be 
de-identified and stored in LabCorp’s Bio-repository located in Greenfield, IN. Only researchers 
approved by Dr. Greg Hundley, the principal investigator at Wake Forest School of Medicine will 
receive the sample.  Lab supplies and instructions for blood stored for future research testing will be 
provided by LabCorp.  (See Appendix 10 for further lab instructions). 
 
Labs for future research testing should not be drawn and sent to LabCorp  until specific 
consent for future research testing has been verified and eligibility established. 
 
       9.2 Lab Corp: Routine Labs required Per Protocol  
Lab Corp will be utilized for all labs. LabCorp couriers will deploy to each site from local LabCorp 
facilties for specimen pick-up as samples are drawn. All specimens should be collected in containers 
provided by LabCorp. Note storage times and temperature instructions for each test.                                        
 
Eligibility and baseline labs (Cholesterol, LDL, HDL, Triglycerides, Glucose, Creatine Kinase, 
TSH, ALT, AST, Total Bilirubin, Hematocrit [only if gadolinium contrast is to be administered 
for the MRI procedure] and BHCG if applicable) will be drawn and analyzed by LabCorp. Once 
eligibility has been determined the remaining protocol labs (Hematocrit preferred within 8 
hours but acceptable to within 40 hours of MRI for patient’s receiving gadolinium contrast) 
CRP, Troponin 1, Aldosterone, IL-6, TNF-a, and Renin will be drawn and sent to LabCorp.  
 
9.3 Collection and Handling Procedures 
Refer to Appendix 10 for instructions. 
 
10. 
REPORTING ADVERSE EVENTS   
    
 A list of serious adverse events that have occurred or might occur that are related to this study 
intervention can be found in Section 6.2. 
 Serious Adverse Event reporting begins after the informed consent is signed. 
 Serious Adverse Events occurring within 30 days of study completion must be reported via FDA 
Form 3500 (MedWatch). 
 
10.1 Protocol Specific Reporting for Serious Adverse Events (SAEs) 
 
 
 
DEFINITION: ICH Guideline E2A and Fed. Reg. 62, Oct. 7, 1997 define serious adverse events as 
those events which meet any of the following criteria? 
 
Results in death 


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 
Is life threatening (Note: the term life-threatening refers to an event in which the patient was 
at risk of death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe). 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
 
Is a congenital abnormality/birth defect 
 
Events that may not meet these criteria, but which the investigator finds very unusual and/or 
potentially serious, will also be reported in the same manner. 
 
 
 
Grades 4 and 5 expected (solicited) and unexpected (unsolicited) SAEs that meet the 
above definition for SAEs and/or regardless of attribution (i.e. regardless of whether 
they are related to this study intervention or not) should be reported to the RB DMC 
using the FDA Form 3500 (MedWatch).  
 
 
Site staff and/or Principal Investigators will report to the RB Data Management Staff within 
24 hours of discovering the details of all unexpected severe, life-threatening (grade 4) 
and/or fatal adverse events (grade 5) if there is reasonable suspicion that the event was 
definitely, probably, or possibly related to the study intervention.  
 
Otherwise, the MedWatch should be sent to the RB DMC by fax or email within 10 working days 
of discovering the details of the SAE. 
 
 
 
 
Data Elements to include on the MedWatch are: 
 
SAE reported date 
 
CTCAE Term (v4.03) 
 
Event onset date and event ended date 
 
Severity grade (use table provided in Section 10.1.3 below) 
 
Attribution to study intervention (relatedness) 
 
Action taken with the study participant and intervention 
 
Outcome of the event 
 
Comments 
 
10.2 Guidelines to determine grade and severity of AEs and/or SAEs 
Identify the adverse event using the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03.  The CTCAE provides descriptive terminology and a grading scale for each 
adverse event listed.  A copy of the CTCAE can be found at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 
 
AEs will be assessed according to the CTCAE grade associated with the AE term.  AEs that do not 
have a corresponding CTCAE term will be assessed according to the general guidelines for grading 
used in the CTCAE v4.03. as stated below. 
 
 
Grade 
Severity 
Description  
1 
Mild 
Mild; asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not indicated. 
2 
Moderate 
Moderate; minimal, local or noninvasive intervention 
indicated; limiting age-appropriate instrumental ADL*. 
3 
Severe 
Severe or medically significant but not immediately life-
threatening; 
Hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self-care ADL**. 


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4 
Life threatening 
Life-threatening consequences; urgent intervention 
indicated. 
5 
Fatal 
Death related to AE. 
 
 
          Activities of Daily Living (ADL) 
 
* 
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
 
** Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 
The Research Base Grant PI, Safety and Toxicity Review Committee and/or Study Chair will take 
appropriate action to inform the membership and statistical personnel of any protocol modifications 
and/or precautionary measures, if this is warranted. 
 
The RB DMC is responsible for communicating AEs/SAEs to the FDA, the drug sponsor, WF IRB, the 
WF Safety and Toxicity Review Committee (STRC) and/or other regulatory agencies as appropriate per 
agency reporting requirements. 
 
Institutions must comply with their individual Institutional Review Board (IRB) policy regarding 
submission of documentation of adverse events. All MedWatch reports should be sent to the local IRB 
in accordance with the local IRB policies. 
 
 
10.3 
Follow-up of SAEs  
 
 
Site staff should send follow-up reports as requested when additional information is available. 
Additional information should be entered on the MedWatch form in the appropriate format.  Follow-
up information should be sent to the RB Data Management Center as soon as available. 
 
SAEs (Grade 4 and/or Grade 5) for this protocol should be followed for those related to the study 
intervention.  Documentation should include: 
 
 PID 
 Date of SAE 
 Description of the event  
 Relationship of the SAE to the study intervention 
 Severity 
 Intervention/Resolution 
 
 
10.4 
Adverse Event Posting 
Adverse event summaries are posted on the WF RB website each month. New MedWatches are 
emailed to sites the 1St week of each month and posted on the password protected CCRBIS. 


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11.  STUDY MONITORING    
 
 
 11.1 Data Management Schedule 
 
The Eligibility checklist/Enrollment Form should be completed on-line prior to placing the patient 
on study.   Data forms will be submitted to the WF NCORP Research Base.  See Section 6.8.2 
for mailing address, or fax to (336) 713-6476 according to the timetable below:  
 
Form 
Submission Schedule 
Consent Form, MRI Encounter Form, Baseline 
Neurocognitive Booklet, Flow Sheet/Addenda, Current 
Medication Form 
Baseline within 14 days of enrollment 
MRI Encounter Form, 6 month Neurocognitive Booklet, 
Flow Sheet/Addenda, Current Medication Form 
6 months within 14 days of assessment 
Flow Sheet/Addenda 
1 and 3 months within 14 days of 
assessment 
Radiation Treatment Form 
Complete within 14 days of pt. receiving 
last RT tx. or indicating patient will not 
receive RT. 
12 month Neurocognitive Booklet, Flow Sheet/Addenda, 
Telephone Contact Form, Current Medication Form  
12 months within 14 days of assessment 
18 month Neurocognitive Booklet, Flow Sheet/Addenda, 
Telephone Contact, Current Medication Form 
18 months within 14 days of assessment 
MRI Encounter Form, 24 month Neurocognitive Booklet, 
Flow Sheet/Addenda, Current Medication Form 
24 months within 14 days of assessment 
Medication Diaries 
Every other month within 14 days of 
completion 
Early Withdrawal Form 
Participants who withdraw from treatment 
or study prior to completion. Submit 
within 14 days of withdrawal.  
Open Label Form (See page 2 Physician Update) 
If placed on a statin by their physician 
within 14 days of occurrence. 
Chemotherapy Treatment Form 
Within 14 days of completion. of each 
course (not cycle)  
Screening Form 
Every month within 14 days of 
completion 
1 Month Post Final Assessment Contact Form 
(For patients completing at least 24 months of study 
medication but no more than 27 months) 
Complete this form 30 days after last 
dose of study medication. Submit within 
14 days of assessment.  
 
               
  
11.2 
Case Report Forms 
  
Participant data will be collected using protocol-specific case report forms (CRF).  


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11.3  Source Documents 
 
Source documents are the original signed and dated records of participant information (e.g., the 
medical record, shadow chart) which may include electronic documents containing all the information 
related to a participant’s protocol participation. Source documents are used to verify the integrity of 
the study data, to verify participant eligibility, and to verify that mandatory protocol procedures were 
followed. An investigator and other designated staff are required to prepare and maintain adequate 
and accurate documentation that records all observations and other data pertinent to the 
investigation for each individual participating in the study. All data recorded in the research record 
(including data recorded on CRFs) must originate in the participant’s medical record, study record, or 
other official document sources. 
 
Source documents substantiate CRF information. All participant case records (e.g., flow sheets, 
clinical records, physician notes, correspondence) must adhere to the following standards: 
 
 Clearly labeled in accordance with HIPAA practices so that they can be associated with a 
particular participant or PID; 
 
 Legibly written in ink; 
 
 Signed and dated in a real time basis by health care practitioner evaluating or treating the 
participant;  
 
 Correction liquid or tape must not be used in source documents or on CRFs. 
 
 Corrections are made by drawing a single line through the error. Do not obliterate the original 
entry. Insert the correct information, initial, and date the entry. 
 
All laboratory reports and imaging study and scans must have: 
 
 Complete identifying information (name and address of the organization performing, analyzing, 
and/or reporting the results of the test); and 
 
 Range of normal values for each result listed. 
 
      11.4 Data and Safety Monitoring Board 
The Data Safety Monitoring Board meets every six months to review all phase II and phase III 
protocols. The Board includes members demonstrating experience and expertise in oncology, 
biological sciences, biostatistics and ethics. The DSMB report is generated by the RB statistician. 
Areas of review may include the following: Date study Opened; Study Objectives; Patient Accrual; 
Patient Status and Retention; Study Status; Last Contact Status; Patient Compliance; Number of 
Biopsies/Labs as needed; Patient Characteristics; Summary of Observed Toxicities; Adverse Events; 
Date, Event briefly described, Relationship to Drug, Arm assigned; Summary of Primary and 
Secondary Measures. Following each meeting, WF RB will provide DSMB reports to all accruing sites 
via the regular weekly email correspondence. 
          
      11.5 Record retention  
Clinical records for all participants, including CRFs, all source documentation (containing evidence to 
study eligibility, history and physical findings, laboratory data, results of consultations, etc.), as well 
as IRB records and other regulatory documentation will be retained by the Investigator in a secure  
storage facility in compliance with HIPAA, OHRP, FDA regulations and guidance, and NCI/DCP 
requirements unless the standard at the site is more stringent. 


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11.6 CDUS Reporting 
The WF NCORP Research Base Data Management Center will submit quarterly reports to 
DCP/CTEP by electronic means using the Clinical Data Update System (CDUS) 
 
12. STATISTICAL CONSIDERATIONS  
 
12.1. Study Design/Endpoints 
This is a multi-center, double-blind, placebo-controlled clinical trial that randomizes 278 participants 
into 1 of 2 treatment arms: Group 1 (one 40 mg atorvastatin tablet each morning by mouth for 24 
months) or Group 2 (one placebo tablet each morning by mouth for at least 24 months but no more 
than 27 months) with the goal of having at least 200 remaining at the trial’s end for final assessments 
(assuming an approximate 28% loss to follow-up). A permuted block randomization stratified by 
cancer type (breast vs lymphoma) and planned Anthracycline-based therapy doses of Doxorubicin < 
or ≥ 240 mg/m2 or Epirubucin < or ≥ 400mg/ m2; close to the median dose of our pilot studies) will 
ensure treatment group balance is achieved within strata.  As in all our pilot studies and clinical 
practice, Doxorubicin and Epirubicin doses will be assessed to account for receipt of different 
anthracyclines.  The primary endpoint in this trial is LVEF, and thus the primary efficacy analysis will 
examine whether the statin therapy can attenuate the reduction in LVEF in patients with breast 
cancer or lymphoma who receive Anthracycline-based therapy. Primary endpoints include LVESV, 
LV end diastolic volume (LVEDV), LV mid-wall circumferential strain, T1-ECV (a measure of 
replacement fibrosis), PWV, aortic wall thickness, CRP and TNF-α, serum lipoprotein levels, and 
circulating neurohormones.  
 
  
12.2. Primary Aims 
Specific Aim 1: To determine if atorvastatin administration preserves LVEF 24 – 27 months after 
receipt of Anthracycline-based therapy for breast cancer and lymphoma. 
  
Specific Aim 2: To determine if baseline to 6-month differences in LVEF predict baseline to 24- 27 
month differences in LVEF after Anthracycline-based therapy and concomitant atorvastatin therapy. 
 
12.3. Analysis Plan 
The primary hypothesis for Specific Aim 1 is that statin use will protect against a harmful reduction in 
LVEF measured over 24 – 27 months for patients with breast cancer or lymphoma who receive 
Anthracycline-based therapy. All randomized patients will be used in the analysis to compare groups 
(“intent to treat” approach). Since LVEF is measured on a continuous scale and this is a randomized 
trial, our primary analysis will fit an analysis of covariance (ANCOVA) model that compares the 24- 
27 month values of LVEF between groups adjusting for the baseline (pre-treatment) levels of LVEF 
and stratification factors. Note that patients are stratified by planned dose and that is the stratification 
that will be used in the analysis, even if the patient ends up getting a different dose. This analysis will 
address the first specific aim. 
 
To address the second primary aim, we will examine whether the early treatment effect of statin use 
(6 months post randomization) predicts the long-term (24 – 27 month) effect of statins. Pilot data 
(Section 2) suggest that Anthracycline-based therapy injury occurs early and concomitant statin use 
attenuates this early Anthracycline-based therapy-mediated injury. We will fit an ANCOVA model 
that compares the 24- 27 month LVEF values for the treated and control groups and will also include 
covariates for the baseline LVEF and 6-month change in LVEF values. We will examine the 
treatment by 6-month LVEF change interaction to determine whether the correlation between early 
and late changes in LVEF differs by treatment.  Thus, this model will have 4 terms of interest: the 
main effect for treatment, the main effect for the change in LVEF after 6 months, the main effect for 
baseline pre-treatment LVEF, and the treatment by change in LVEF after 6-month interaction. If the 
interaction is non-significant, we will examine the model with the 3 main effects. Since there may be 
limited power to test this interaction, we will use a 0.15 threshold for testing significance of the 


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interaction term in the model. 
 
After primary efficacy analyses, additional analyses of the primary hypotheses will be done to assess 
relationships between treatment and outcome. We will fit ANCOVA models that consider the 24-27 
month LVEF measure as the outcome, the baseline LVEF measure as a covariate, and other 
patient-level characteristics (e.g. age, cancer type, stage, and race) in order to control for other 
baseline covariates possibly related to LVEF in the model.  Interactions between the treatment and 
covariates will be examined to determine whether the treatment effect is consistent across 
subgroups (e.g., black/white race by treatment interaction). Finally, we will conduct a repeated 
measures ANCOVA model that incorporates the intermediate (6-month) LVEF measurement into the 
model. We anticipate examining different covariance structures. Past experience suggests that a 
compound symmetry structure is usually appropriate; we will also examine whether an unstructured 
covariance is needed. We will fit these models using a mixed models approach, where the individual 
patient will be treated as a random effect in the model and the treatment indicator as patient 
characteristics (and baseline LVEF) will be considered as fixed effects. A mixed models approach for 
modeling the longitudinal data will allow for appropriate inference to be made in the presence of 
missing data (i.e., patient drop-outs) if the missing data are missing at random (MAR). Below, we 
describe methods to address MAR assumptions. Diagnostics and residual plots will be reviewed to 
ensure that all assumptions are met. If not, transformations of the outcome data will be considered, 
where the order of the priority in choosing a transformation will be to satisfy the (1) linearity 
assumption, (2) homogeneity assumption (homoscedasticity), and (3) normality assumption. 
 
  12.4. Potential Analytic Concerns in Primary Efficacy Analyses 
Lost to Follow-up: We designed this study to recruit 278 total patients so that 200 are available at 
the end of the study. Thus, we will need to consider how to analyze data from the 78 patients who 
may drop out. To examine whether the missing data are either missing completely at random or 
missing at random, we will compare the baseline characteristics of those who drop out and those 
who complete the trial. If there is no evidence of informative missing data, analyses will be done 
using the repeated measures ANCOVA with a mixed models approach (PROC MIXED in SAS). 
However, if there is evidence that the missing data are informative and treatment-related (e.g. if 
there are fewer dropouts in the statin group or if missingness is related to other medical outcomes 
that are strongly associated with the outcome of interest) and not MAR, then we will use more 
sophisticated statistical methods.78-80 One possible approach is to model the probability of dropping-out 
for each participant conditional on their baseline characteristics and treatment assignment. These 
probabilities would then be used to stratify participants (both completers and drop-outs) before making 
treatment comparisons. Thus each stratum would contain participants with similar predicted 
probabilities of trial completion (although only a subset would be completers). The final treatment effect 
estimates could be made using the completers with weights assigned to them based on the ratio of 
drop-outs to completers within each stratum. This approach and other methods for handling missing 
data have been by previously described by Dr. D’Agostino.78-80 
 
 
12.5. Secondary Analyses: Once the primary efficacy analysis is completed, secondary efficacy 
variables will be examined to provide insight into mechanisms by which statins may influence LVEF. 
These include: LVESV and strain (reflective of LV contractility), LVEDV (reflective of LV pre-load), 
PWV and aortic wall thickness (reflective of LV after-load), and LVECV (a measure of myocellular 
replacement fibrosis). In addition, we will measure a series of subclinical biomarkers, including 
serum lipids (LDL, TC, HDL), glucose, serum troponin I, CRP, IL-6, TNF-α, renin, and aldosterone at 
the 6- and 24-27 month endpoints. For each, we will fit ANCOVA models that will examine the 24-27 
month endpoints adjusted for baseline assessments, followed by ANCOVA models  
 
 
that also include patient-level characteristics. Next, we will fit repeated measures ANCOVA models 
that incorporate intermediate (6-month) time point assessments. This approach will be repeated for 
the cognitive and patient reported outcomes.  The latter analyses will also include data for the 12 
and 18 months follow-ups. 
 
 


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12.6. Power and Sample Size considerations for the primary hypothesis 
For the primary hypothesis, sample size and power calculations can be made based on direct 
comparisons between the expected changes in outcome means in the different treatment groups. 
These calculations need to account for the proportion of the variance in the primary efficacy of 
outcome (LVEF) explained by the other terms in the model (i.e., baseline values). To adjust for the 
proportion of variance explained by the baseline measurement when estimating the variance for the 
follow-up outcome measure, we used the formula [Vfollow-up adjusted for baseline covariates = Vfollow-up (1-r2)], 
where r2 is the square of the correlation between the baseline and follow-up measure. Our primary 
efficacy analysis is based on comparing the change in LVEF levels from baseline to 24 – 27 months, 
and r above is the correlation between these two measurements. These power calculations may be 
conservative, since intermediate assessments of LVEF at 6 months are not included. In other words, 
the mixed models approach (described in the additional analyses) would likely provide greater power 
than the ANCOVA model used here, but further assumptions concerning the covariance structure to 
be used and correlation among intermediate measures would need to be made. Thus, we believe 
that the power described by the simpler method (ANCOVA) is adequate to address our hypotheses 
and is expected to be conservative. 
 
The following formula was used to describe the minimum detectable difference for the LVEF 
between the statin and placebo groups:   
 
 
 
 
 
In the above, r2 is the percent of the variance of the follow-up outcome explained by the baseline 
measurement (LVEF), Z1-α/2 is the value from the standard normal distribution corresponding to the 
alpha level chosen (1.96, which corresponds to alpha=0.05 [two sided]), Z1-β is the value from the 
standard normal distribution that corresponds to the power chosen for the study (here 80% and 
90%), and n=100 corresponds to the total number of patients studied for the statin group. We chose 
this sample size (100 per group) for power calculations to allow for up to 78 patients out of the 278 
accrued to potentially drop-out. Note that this will somewhat conservative for the mixed models as 
those with partial data will also provide information.  Based on preliminary data examining LVEF 
levels in comparable patients measured over a 6-month period we found that the standard deviation 
was approximately 7.7 and the correlation between baseline and 6-months was 0.5. Since we do not 
know what the correlation will be after 2 years, Table 5 depicts detectable differences for different 
correlations and power values. In addition, we show detectable differences for key secondary 
variables for which we have preliminary data (LVEDV, LVESV, and PWV).  
 
Thus, for example, we have 80% power to detect a difference of 2.6% in LVEF between groups if the 
correlation between the baseline and 24-month LVEF is 0.5. In preliminary observational data, we 
saw a difference in LVEF between statin users vs. those who were not of 2.5% at 6 months. Thus, 
effect sizes of the magnitude in Table 5 are plausible and clinically meaningful. 2-6 ml increases in 
LVESV, or 3-5% drops in LVEF (from a normal resting LVEF) have been associated with adverse 
CV prognoses in a recent large trial of patients with HF and a preserved resting LVEF.81 In 483 
hypertensive patients aged 50±13 years, aortic PWV measures of 11 m/s were associated with odds 
ratio of 2.14 for cardiac events (p<0.0001).82 Other studies that have initiated generic therapies such 
as ACE inhibitors or beta blockers with antioxidant properties have shown a reduced occurrence of 
CV events in cancer survivors.83 Importantly however, it remains to be seen whether early initiation 
of statin therapy reduces the onset of subclinical CV disease in patients with breast cancer or 
lymphoma. 
 
 
 


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12.7.  Reporting and Exclusions 
We will measure the level of compliance in randomized patients. If a patient drops out of the study 
early due to an adverse event that may be related to statin use, they will be non-compliant for 
subsequent treatment, and thus still inform the primary endpoint for our analyses, and their outcome 
will be considered as “non-compliant”.  For patients who drop out early due to a non-statin related 
adverse event or die during the study we will analyze them in the following ways. 
 
        First we will conservatively assume that all drop-outs/deaths are non-compliant.  Since there is a 
placebo group in this study we can assume that the rates would be similar between groups and still 
allow a comparison of compliance rates between groups.  Next, we will consider two forms of 
imputation for secondary analyses.  The first will use early compliance data (if available) to 
determine a compliance rate and that value will be carried forward to the end (i.e., Last observation 
carried forward) and the second would be to use a multiple imputation procedure to impute final 
compliance rates for participants based on modeling the compliance rates for those with complete 
data.  
.  
 
12.8. Evaluation of Toxicity 
   
 
  All participants will be evaluable for toxicity from the time of their first dose of atorvastatin. 
 
 
 
  
12.9. Evaluation of Response 
All participants will be assessed for compliance once they are randomized to treatment and receive 
at least one dose of treatment.  The primary analysis will consist of all randomized patients who 
receive at least one dose of study drug.  Secondary analyses will consist of patients who either 
complete the trial (with ≥ 75% compliance) or who drop out for adverse events that are related to the 
use of statins.  Patients who drop out for non-related adverse events or die for reasons not related to 
statin use will be removed from the secondary analysis. Adverse events described by the Data 
Safety Monitoring Committee as related to statin use will be differentiated so as to render decisions 
regarding study drug compliance. 
 
12.10. Interim Analysis 
Interim reviews will be performed by the Data Safety Monitoring Committee every six months to 
assess accrual, retention, compliance, the incidence of AEs, SAEs, diabetes and LV function 
measures.  
 
Table 5: Detectable Differences for Different Power and 
Correlation Values 
 Outcome 
Estimated 
SD 
80% Power 
90% Power 
Correlation between baseline and 2-yr 
measure 
0.4 
0.5 
0.6 
0.4 
0.5 
0.6 
LVEF (%) 
7.7 
2.79 
2.64 
2.44 
3.23 
3.06 
2.82 
LV-EDV 
(ml) 
33.1 
12.0 
11.4 
10.5 
13.9 
13.1 
12.1 
LV-ESV 
(ml) 
19.7 
7.1 
6.8 
6.2 
8.3 
7.8 
7.2 
PWV 
(m/sec) 
3.7 
1.34 
1.27 
1.2 
1.6 
1.5 
1.4 


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.  
 
 
 
                                                           

ICF_000.pdf: 
Title:  Preventing Anthracycline Cardiovascular Toxicity With Statins (PREVENT)  
NCT:  NCT01988571
Date:  2/1/2018


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University of Wisconsin-Madison
Consent to Participate in Research
Study Title: PREVENTING ANTHRACYCLINE CARDIOVASCULAR TOXICITY WITH 
STATINS (PREVENT)
Lead Researcher: Toby Campbell, MD 
Where Lead Researcher works: University of Wisconsin Carbone Cancer Center
INTRODUCTION
You are invited to be in a research study. Research studies are designed to gain 
scientific knowledge that may help other people in the future. This study is being done to 
find out if a drug called Atorvastatin can decrease the chance of developing heart 
problems while receiving chemotherapy. You are being invited to take part in this study 
because you have breast cancer or lymphoma, are 21 years or older, and will be treated 
with chemotherapy that may cause heart problems. This study involves approximately 
four to six visits over two years. The main study procedures are MRIs of your heart, 
blood samples, tests of your memory and thinking abilities, quality of life questionnaires 
as well as telephone calls and recording when you take the study drug on a medication 
diary.
Your participation is voluntary. Please take your time in making your decision as to 
whether or not you wish to participate. Ask your study doctor or the study staff to explain 
any words or information contained in this informed consent document that you do not 
understand. You may also discuss the study with your friends and family. If you decide 
not to participate, any relationship you have with the University of Wisconsin-Madison 
(UW-Madison) or the University of Wisconsin Hospitals and Clinics (UWHC) will not be 
affected in any way.
WHY IS THIS STUDY BEING DONE?
The purpose of this research study is to see if Atorvastatin (generic for Lipitor) 40 mg by 
mouth daily decreases the chance of developing heart problems in patients receiving 
anthracycline based chemotherapy for breast cancer or lymphoma.
Atorvastatin has been approved by the US Food and Drug Administration (FDA), but it 
has not been approved to lessen the chance of heart problems related to chemotherapy.
In this study Atorvastatin will be compared to placebo. A placebo is a substance, like a 
sugar pill, that is not thought to have any effect on your disease or condition. In this study 
you will either receive the active study medication (Atorvastatin) or placebo, which is not 
active. Placebos are used in research studies to see if the drug being studied really does 
have an effect.
This study will also include questions related to your thinking process and quality of life.
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00038639
Meeting Date Approved 2/1/2018
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HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?
Approximately 278 people will take part in this study nationally. Approximately 20 people 
will be enrolled at this institution.
WHAT IS INVOLVED IN THE STUDY?
You will be randomized into one of the study groups described below. Randomization 
means that you are put into a group by chance. It is like flipping a coin. You will have an 
equal chance of being placed in any group.
One group will receive Atorvastatin 40mg by mouth once daily. The other group will 
receive a Placebo by mouth once daily.
In some instances subjects may receive an initial one-time dose of 80 mg Atorvastatin 
(two tablets by mouth) or placebo (two tablets by mouth). No increase in anticipated side 
effects is expected if a one-time dose is taken.
Neither you nor the investigator will know which study drug or placebo you are receiving. 
This is done so that a fair evaluation of results can be made. This information is available 
to the researchers if needed in an emergency.
If you take part in this study, you will have the following tests and procedures:

MRI exams of your heart at baseline, 6 months and 24 months

If you receive a MUGA or ECHO as part of your routine care to look at your heart 
function prior to receiving chemotherapy, the study will require that heart function 
measures from either of those studies be incorporated into the database.

Blood samples and biomarker blood samples drawn at baseline, 6 months and 24 
months

Memory and Thinking Ability Testing completed at baseline, 6 months and 24 
months

Quality of Life Questionnaires completed at baseline, 6 months, 12 months, 18 
months and 24 months

You will be contacted by telephone at 12 and 18 months to evaluate if you are 
having any problems taking your study medication.

Medication diaries will be provided for you to record when you take your study 
medication. Staff personnel will provide instructions on completing and returning 
the diaries.
The questionnaires will take about 10 minutes to complete. The Memory and Thinking 
Ability Testing will take about 10 minutes at baseline and 30 minutes at 6 and 24 months 
to complete.
After 24 months of study medication, you will be followed for an additional 30 days after 
the last dose of study medication. The research staff will contact you to ask if you have 
experienced any problems related to the study medication since it was stopped.
WFU School of Medicine 
Institutional Review Board 
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Meeting Date Approved 2/1/2018
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You will have approximately 4 tablespoons of blood withdrawn from a vein or currently 
placed central line (port-a-cath) to test several types of blood cell levels including liver 
and kidney function. These blood samples and biomarker blood samples will be drawn at 
baseline, 6 months and 24 months. The total amount of blood withdrawn during the study 
will be approximately 12 tablespoons. If your blood sugar or cholesterol is above normal, 
you will be asked to not eat or drink anything except water for 8 hours and return to the 
clinic. You will have 1 teaspoon of blood drawn to repeat these labs. If your physician 
decides you should have additional lab work to check your liver and kidney function, you 
will have one teaspoon of blood drawn at one and three months.
Each MRI exam will take about 1 hour. The MRI exam, or your own clinical MUGA or 
ECHO, is to evaluate specific parts of your heart. The MRI is for study purposes only, 
the imaging results will not be reviewed by your local health care team and only alert 
values pertaining to severely abnormal heart or aorta size will be furnished to your 
physicians. No other reports of these studies will be furnished to you or your physicians.
HOW LONG WILL I BE IN THE STUDY?
You will be in the study for about 24 months. You will receive one additional contact 30 
days after the last dose of study medication. 
You can stop participating at any time. If you decide to stop participating in the study, we 
encourage you to talk to the investigators or study staff first to learn about any potential 
health or safety consequences.
WHAT ARE THE RISKS OF THE STUDY?
Being in this study involves some risk to you. You should discuss the risk of being in this 
study with the study staff. Risks and side effects related to the Atorvastatin include:
Most Common:

Abdominal pain - 7.3%

Constipation - 6.6%

Nausea - 5.4%

Headache – 7.4%

Upper Respiratory Infection – 9%

Muscle pain – 6%
Less Common:

Confusion < 2%
Rare but serious:

Cholestatic hepatitis (1%)

Increased liver enzymes (1%)

Decreased blood supply to the lower leg (1%)

Abnormal muscle breakdown (1%)

Endocrine: Diabetes < 0.25% or 1 per 400
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You may experience discomfort, bruising and/or bleeding where the needle is inserted 
during blood draws. Occasionally some people become dizzy lightheaded or feel faint. 
Infection may occur on rare occasions. Frequent donation of blood can result in low iron 
in your blood (iron deficient anemia).
An MRI is a procedure in which a magnet linked to a computer is used to create detailed 
pictures of areas inside the body. MRI scans are not associated with any known side 
effects. Some subjects experience discomfort associated with enclosed spaces during 
MRI scanning.
If you receive contrast, additional data from your MRI will be collected to examine the 
development of scar tissue in the heart. If your site has contrast available and it is 
determined that you may receive the Federal Drug Administration (FDA) approved 
contrast, ProHance® (Gadoteridol), it will be injected into either a vein or currently 
placed central line (port-a-cath). The MRI contrast is used to help identify structures 
within the body on a MRI scan. Serious or life-threatening reactions have been reported 
in about 1 in 400,000 patients who receive contrast agents. All standard of care, 
medications and monitoring will be provided during this MRI scan. You may still 
participate in this study if a) you cannot receive Gadolinium-contrast because you have 
known allergies to this contrast or have other severe drug allergies or b) you are not 
allergic to gadolinium-contrast but choose not to receive this contrast due to the risks 
associated with the procedure or c) the contrast is not available.
Sometimes contrast may leak out of the IV into the fatty tissue around a vein. This 
happens in one out of every 250 to 500 procedures and is not likely to cause tissue 
damage. 
In very rare circumstances, gadolinium in very high doses has been reported to be 
associated with nephrogenic systemic fibrosis (NSF), a condition that causes hardening 
of tissue under the skin and potentially death. To minimize the risk of developing this 
disorder, this study complies with all FDA criteria for administration of gadolinium.  To 
identify potential risk to study participation an estimation of your kidney function will be 
obtained within 30 days prior to your MRI scans. Those with decreased kidney function 
will not receive contrast as part of this study.
Recent medical literature publications have reported that patients receiving gadolinium 
contrast may accumulate gadolinium in parts of the brain long after the last 
administration. Currently available information has not identified any adverse health 
effects resulting from this accumulation of gadolinium-based contrast. You may still 
participate in this study if you do not choose to receive the gadolinium-based contrast. 
You will be notified of new information related to gadolinium as it becomes available. If 
you receive contrast (gadolinium) the risks and side effects include: 
WFU School of Medicine 
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Most Common Events (may occur in about 2% of patients)

headache,

nausea,

vomiting,

itching,

watery eyes,

skin rash,

facial and/or tongue swelling,

wheezing,

chest tightness, or troubled breathing,

hypotension (a decrease in blood pressure)
Less Common (<0.2 to 0.4%):

extravasation happens in one out of every 250 to 500 procedures.
Rare but Serious Events (<1%):

renal failure

nephrogenic systemic fibrosis (NSF) (a condition that causes hardening 
of tissue under the skin)

confusion
If contrast is available at your site and you are eligible to receive contrast, please circle 
your answer and initial on the line provided to show whether or not you choose to 
receive contrast.
YES        NO           Subject Initials ______
Participants will be required to wear earplugs or a headset during their MRI scan, to 
protect their hearing against the noise generated by the MRI scanner.
There also may be other side effects that we cannot predict. You should tell the 
research staff about all the medications, vitamins and supplements you take and any 
medical conditions you have. This may help avoid side effects, interactions and other 
risks. The risk of harm or discomfort that may happen as a result of taking part in this 
research study is not expected to be more than in daily life or from routine physical or 
psychological examinations or tests. You should discuss the risk of being in this study 
with the study staff.
In addition, there is a risk of a breach of confidentiality. We will do our best to protect 
your confidential information. Taking part in this research study may involve providing 
information that you consider confidential or private. Efforts, such as coding research 
records, keeping research records secure and allowing only authorized people to have 
access to research records, will be made to keep your information safe.
WFU School of Medicine 
Institutional Review Board 
IRB Number: IRB00038639
Meeting Date Approved 2/1/2018
Version Valid Until: 8/20/2018


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We may request your email address so we can stay in touch with you throughout the 
study. This may include setting up clinic visits, sending study-related reminders, or 
answering any general questions you may have. Email is generally not a secure way to 
communicate about your health as there are many ways for unauthorized users to 
access email. You should avoid sending sensitive, detailed personal information by 
email. Email should also not be used to convey information of an urgent nature. If you 
need to talk to someone immediately, please contact the nurse triage line at 
. You do not have to provide your email address to participate in this study.
A Data Safety and Monitoring Committee, an independent group of experts, will be 
reviewing the data from this research throughout the study.
REPRODUCTIVE RISKS AND OTHER ISSUES TO PARTICIPATING IN RESEARCH
Women who are currently breast-feeding and pregnant women are excluded from 
participation in this study. If you become pregnant while on this study you must notify 
your physician and study staff immediately.
Due to unknown risks and potential harm to the unborn fetus, women of childbearing 
potential must use a reliable method of birth control while participating in this study. 
Reliable methods of birth control are: abstinence (not having sex), oral contraceptives, 
intrauterine device (IUD), DepoProvera, tubal ligation, or vasectomy of the partner (with 
confirmed negative sperm counts) in a monogamous relationship (same partner). An 
acceptable, although less reliable, method involves the careful use of condoms and 
spermicidal foam or gel and/or a cervical cap or sponge. We encourage you to discuss 
this issue further with your physicians if you have any questions.
Because some methods of birth control are not 100% reliable, a negative pregnancy test 
is required at least 10 days prior to study registration for women of childbearing potential 
and a negative pregnancy test may be required at least 10 days prior to each MRI 
exam.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
If you agree to take part in this study, there may or may not be direct benefit to you. We 
hope the information learned from this study will benefit other people in the future.
WHAT OTHER CHOICES ARE THERE?
You do not have to be in this study to receive treatment. You should talk to your doctor 
about all the choices you have.
Currently, there is not a standard treatment for possible heart problems that may occur 
from your standard cancer treatment. Your alternative is to not participate in this study.
If your primary care physician determines you need to be on Atorvastatin or a similar 
medication used to decrease your cholesterol and/or triglycerides your study drug should 
be stopped before starting the new medication. You should notify study personnel 
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immediately.
WHAT ABOUT MY HEALTH INFORMATION?
In this research study, any new information we collect from you and/or information we 
get from your medical records or other facilities about your health or behaviors is 
considered Protected Health Information.
If this research study involves the diagnosis or treatment of a medical condition, then 
Protected Health Information collected from you during this study may be placed in your 
medical record, and may be used to help treat you, arrange payment for your care, or 
assist with Medical Center operations.
We will make every effort to keep your Protected Health Information private. We will 
store records of your Protected Health Information in a cabinet in a locked office or on a 
password protected computer. Only the following people or organizations will be 
granted access to your Protected Health Information:
1) The study investigator and his/her staff, or others at The Comprehensive 
Cancer Center of Wake Forest University (CCCWFU) and Wake Forest 
University Health Sciences who oversee research
2) Other people or laboratories providing services for this research project on 
behalf of Wake Forest University Health Sciences and Wake Forest University 
Baptist Medical Center
3) The National Cancer Institute and the National Heart, Lung and Blood Institute 
(NHLBI)
4) FDA (Food and Drug Administration)
5) LabCorp (Bio-repository facility specifically for storing of specimens)
6) University of Wisconsin Carbone Cancer Center
7)
University of Wisconsin Hospital and Clinics Health Information Systems 
including billing
8)
University of Wisconsin Hospital and Clinics and your local providers
9)
UW Investigators for the research study and their staff
10) UW-Madison regulatory and research oversight boards and offices
11) Research support services staff at the UW-Madison and its affiliates
12) The Alliance for Clinical Trials in Oncology
13) Wake Forest NCORP Research Base Data Management Center
14) Biologics – the company who supplies the study drug and bottles
15) Greenstone – the company who manufactures the study drug
If required by law or court order, we might also have to share your Protected Health 
Information with a judge, law enforcement officer, government agencies, or others. If 
your Protected Health Information is shared with any of these groups, it may no longer 
be protected by federal or state law.
Any Protected Health Information collected from you in this study that is maintained in 
the research records will be kept for an indeterminate period of time. This authorization 
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does not expire and/or any research information entered into your medical record will be 
kept for as long as your medical record is kept by the Medical Center.
You can tell Dr. Toby Campbell that you want to take away your permission to use and 
share your Protected Health Information at any time by sending a letter to this address:
Toby Campbell, MD
However, if you take away permission to use your Protected Health Information you will 
not be able to be in the study any longer. We will stop collecting any more information 
about you, but any information we have already collected can still be used for the 
purposes of the research study.
By signing this form you give us permission to use your Protected Health Information for 
this study.
If you choose to participate in this study, your medical record will indicate that you are 
enrolled in a clinical trial. Information about the research and any medications or 
devices you are being given as a participant may also be included in your medical 
record. This part of the medical record will only be available to people who have 
authorized access to your medical record. If you are not a patient at this Medical Center, 
a medical record will be created for you anyway to ensure that this important information 
is available to doctors in case of an emergency.
Laboratory test results and other medical reports created as a result of your 
participation in the research study may be entered into the computer systems of Wake 
Forest University Health Sciences and North Carolina Baptist Hospital. These will be 
kept secure, with access to this information limited to individuals with proper authority, 
but who may not be directly involved with this research study.
WILL MY CONFIDENTIALITY BE PROTECTED?
The researchers might use information learned from this study in scientific journal 
articles or in presentations. None of this information will identify you personally. The US 
Food and Drug Administration may look at study records. Your information will be 
protected by coding research records, keeping research records secure in a cabinet in a 
locked office, on password protected computers, and allowing only authorized people to 
have access to research records.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site 
at any time.
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WHAT ARE THE COSTS?
There are no costs to you for taking part in this study. All study costs, including 
Atorvastatin or placebo and procedures, MRI, and blood draws that are related directly to 
the study will be paid for by the study. Costs for your regular medical care, including 
chemotherapy treatment and associated tests/procedures which are not related to this study, 
will be your own responsibility.
WILL YOU BE PAID FOR PARTICIPATING?
You will receive no payment or other compensation for taking part in this study
WHO IS SPONSORING THIS STUDY?
This study is being sponsored by the National Cancer Institute and the National Heart, 
Lung and Blood Institute. The sponsor is providing money or other support to Wake 
Forest University Health Sciences to help conduct this study. The researchers do not, 
however, hold a direct financial interest in the sponsor or the product being studied.
WHAT HAPPENS IF YOU EXPERIENCE AN INJURY OR ILLNESS AS A RESULT OF 
PARTICIPATING IN THIS STUDY?
If you are injured or get sick because of this study, medical care is available to you 
through UW Health, your local provider, or emergency services, as it is to all sick or 
injured people. 

If it is an emergency, call 911 right away or go to the emergency room. 

For non-emergency medical problems, contact your regular health care provider 
or the nurse triage line at 
.

Call the Lead Researcher, Dr. Toby Campbell at 
, to report your 
sickness or injury.
Here are some things you need to know if you get sick or are injured because of this 
research: 

If the sickness or injury requires medical care, the costs for the care will be billed 
to you or your insurance, just like any other medical costs. 

Your health insurance company may or may not pay for this care.

No other compensation (such as lost wages or damages) is usually available.

UW-Madison and UW Health do not have a program to pay you if you get sick or 
are injured because of this study.

By signing this consent form and taking part in this study, you are not giving up 
any legal rights you may have. You keep your legal rights to seek payment for 
care required because of a sickness or injury resulting from this study. 
WHAT ARE MY RIGHTS AS A RESEARCH STUDY PARTICIPANT?
Taking part in this study is voluntary. You may choose not to take part or you may leave 
the study at any time. Refusing to participate or leaving the study will not result in any 
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penalty or loss of benefits to which you are entitled. Your decision of whether or not to 
participate in this study will not affect the quality of your medical care at this institution.
If you decide to stop participating in the study we encourage you to talk to the 
investigators or study staff first to learn about any potential health or safety 
consequences. The investigators also have the right to stop your participation in the 
study at any time. This could be because it is in your best medical interest, new 
information becomes available, you had an unexpected reaction, you failed to follow 
instructions, or because the entire study has been stopped.
You will be given any new information we become aware of that would affect your 
willingness to continue to participate in the study. 
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or in the event of a research-related injury, contact the 
study investigator, Dr. Toby Campbell at 
.
If you have any questions about your rights as a research subject or have complaints 
about the research study or study team, contact UW Health Patient Relations at
. The Patient Relations Representatives work with research subjects to 
address concerns about research participation and assist in resolving problems.
You will be given a copy of this signed consent form.
OPTIONAL BLOOD COLLECTIONS AND BIOBANKING FOR POSSIBLE FUTURE 
STUDIES
Researchers are trying to learn more about other health problems. Much of this research 
is done using samples from your blood. Through these studies, researchers hope to find 
new ways to prevent, detect, treat, or cure health problems.
Blood samples are being drawn for biomarker testing at baseline, 6 months and 24 
months for the main study.
If you choose to take part in this study, the main study doctor would like to collect an 
additional 1 Tablespoon of blood at baseline, 6 months and 24 months.
We would like this additional blood to be banked for future testing. Any future testing may 
include new blood tests to look for changes in your heart related to chemotherapy. 
Future testing may also include problems related to other heart diseases or other 
diseases in general.
The researchers ask your permission to store and use your samples and related health 
information (for example, your response to cancer treatment, results of study tests 
and medicines you are given) for medical research. The research that may be done is 
unknown at this time. Storing samples for future studies is called “biobanking”. Your 
sample will be obtained at the University of Wisconsin. The sample will be stored in a 
LabCorp bio-repository  (a facility specifically for storing of specimens), Covance 
Biorepository, 
. It 
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will be given only to researchers approved by Dr. W. Greg Hundley, the primary 
investigator of this study. An Institutional Review Board (IRB) must also approve any 
future research study using your blood sample.
WHAT IS INVOLVED?
If you agree to take part, here is what will happen next:
1) If you agree to participate in the storing of blood for future research you will have 
approximately 1 additional tablespoon of blood drawn at baseline, 6 months and 
24 months for a total of 3 additional tablespoons of blood drawn during the study.
2) Your sample and some related health information may be stored in the Biobank, 
along with samples and information from other people who take part. The 
samples will be kept until they are used up. Information from your medical record 
will be updated from time to time.
3) Qualified researchers can submit a request to use the materials stored in the 
Biobanks. A science committee at the clinical trials organization, and/or the 
National Cancer Institute, will review each request. There will also be an ethics 
review to ensure that the request is necessary and proper. Researchers will not 
be given your name or any other information that could directly identify you.
4) Neither you nor your study doctor will be notified when research will be conducted 
or given reports or other information about any research that is done using your 
samples.
5) Some of your health information may be placed in central databases that may be 
public, along with information from many other people. Information that could 
directly identify you will not be included.
WHAT ARE THE POSSIBLE RISKS?
1) The most common risks related to drawing blood from your arm are brief pain and 
possibly a bruise.
2) There is a risk that someone could get access to the personal information in your 
medical records or other information researchers have stored about you.
3) There is a risk that someone could trace the information in a central database 
back to you. Even without your name or other identifiers. The researchers 
believe the chance that someone will identify you is very small, but the risk may 
change in the future as people come up with new ways of tracing information.
HOW WILL INFORMATION ABOUT ME BE KEPT PRIVATE?
Your privacy is very important to the researchers and they will make every effort to 
protect it. Here are just a few of the steps they will take:
1) When your sample(s) is sent to the researchers, no information identifying you 
(such as your name) will be sent. Samples will be identified by a unique code 
only.
2) The list that links the unique code to your name will be kept separate from your 
sample and health information. Any Biobank and staff with access to the list must 
sign an agreement to keep your identity confidential.
3) Researchers to whom Wake Forest NCORP Research Base sends your sample 
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and information will not know who you are. They must also sign an agreement 
that they will not try to find out who you are.
4) Information that identifies you will not be given to anyone, unless required by law.
5) If research results are published, your name and other personal information will 
not be used.
WHAT ARE THE POSSIBLE BENEFITS?
You will not benefit from taking part.
The researchers, using the samples from you and others, might make discoveries that 
could help people in the future.
ARE THERE ANY COSTS OR PAYMENTS?
There are no costs to you or your insurance. You will not be paid for taking part. If any of 
the research leads to new tests, drugs, or other commercial products, you will not share 
in any profits.
WHAT IF I CHANGE MY MIND?
If you decide you no longer want your samples to be used, you can call the study 
doctor, Toby Campbell at 
 who will let the researchers know. Then, any 
sample that remains in the bank will no longer be used and related health information 
will no longer be collected. Samples or related information that have already been given 
to or used by researchers will not be returned.
WHAT IF I HAVE MORE QUESTIONS?
If you have questions about the use of your samples for research, contact the study 
doctor, Toby Campbell at 
.
 
BLOOD FOR FUTURE RESEARCH STUDIES:
My blood and related information may be kept in a Biobank for use in future health 
research. If I do not choose for my blood to be saved for future research, I am still 
eligible to participate in the study.
Please circle your answer and initial on the line provided to show whether or not you 
would like to take part in biobanking for future research.
YES        NO           Subject Initials ______
Authorization to participate in the research study:
I have read the information in this consent form. I voluntarily agree to take part in this 
study. I authorize the use and disclosure of my health information as described in this 
consent and authorization form. If I have not already received a copy of the Privacy 
Notice, I may request one or one will be made available to me. I have had a chance to 
ask questions about being in this study and have those questions answered. By signing 
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this consent and authorization form, I am not releasing or agreeing to release the 
investigator, the sponsor, the institution or its agents from liability for negligence.
Subject Name (Printed): ______________________________
Subject Signature: __________________________________ 
Date: ______________ Time:_ ______________ am pm
Person Obtaining Consent: 
__________________ 
Date: ______________ Time: 
 am pm
**You will receive a copy of this form**
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