Preventing Anthracycline Cardiovascular Toxicity With Statins (PREVENT)

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.

Study Overview

• Status: Completed
• Conditions: Lymphoma; Breast Cancer
• Intervention / Treatment: Drug: Atorvastatin; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 279
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90027
      • Kaiser Permanente Los Angeles Medical Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • MedStar Washington Hospital Center
    • Washington, District of Columbia, United States, 20007
      • MedStar Georgetown University Hospital
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60637
      • University of Chicago Comprehensive Cancer Center
  • Kansas
    • Wichita, Kansas, United States, 67208
      • Cancer Center of Kansas-Wichita Medical Arts Tower
    • Wichita, Kansas, United States, 67214
      • Cancer Center of Kansas - Wichita
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Medical Center Jefferson
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health at Butterworth Campus
    • Royal Oak, Michigan, United States, 48073
      • William Beaumont Hospital-Royal Oak
    • Troy, Michigan, United States, 48085
      • William Beaumont Hospital - Troy
  • Minnesota
    • Maplewood, Minnesota, United States, 55109
      • Saint John's Hospital - Healtheast
    • Minneapolis, Minnesota, United States, 55407
      • Abbott-Northwestern Hospital
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester
    • Saint Louis Park, Minnesota, United States, 55416
      • Park Nicollet Clinic - Saint Louis Park
    • Saint Paul, Minnesota, United States, 55101
      • Regions Hospital
    • Saint Paul, Minnesota, United States, 55102
      • United Hospital
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Mission Hospital
    • Asheville, North Carolina, United States, 28816
      • Hope Women's Cancer Centers-Asheville
    • Burlington, North Carolina, United States, 27215
      • Cone Health Cancer Center at Alamance Regional
    • Charlotte, North Carolina, United States, 28204
      • Novant Health Presbyterian Medical Center
    • Charlotte, North Carolina, United States, 28207
      • Oncology Specialists of Charlotte
    • Greensboro, North Carolina, United States, 27403
      • Cone Health Cancer Center
    • Huntersville, North Carolina, United States, 28078
      • Novant Health Cancer Institute - Huntersville
    • Huntersville, North Carolina, United States, 28078
      • Southern Oncology Specialists-Huntersville
    • Kernersville, North Carolina, United States, 27284
      • Novant Health Cancer Institute - Kernersville
    • Matthews, North Carolina, United States, 28105
      • Novant Health Cancer Specialists-Matthews
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
    • Winston-Salem, North Carolina, United States, 27103
      • Novant Health Forsyth Medical Center
    • Winston-Salem, North Carolina, United States, 27103
      • Novant Health Oncology Specialists
  • Ohio
    • Columbus, Ohio, United States, 43214
      • Columbus Oncology and Hematology Associates Inc
    • Columbus, Ohio, United States, 43228
      • Doctors Hospital
    • Delaware, Ohio, United States, 43015
      • Delaware Health Center-Grady Cancer Center
    • Zanesville, Ohio, United States, 43701
      • Genesis Healthcare System Cancer Care Center
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822
      • Geisinger Medical Center
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania/Abramson Cancer Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
    • Easley, South Carolina, United States, 29640
      • Prisma Health Cancer Institute - Easley
    • Greenville, South Carolina, United States, 29605
      • Prisma Health Cancer Institute - Faris
    • Greenville, South Carolina, United States, 29615
      • Prisma Health Cancer Institute - Eastside
    • Greenville, South Carolina, United States, 29605
      • Prisma Health Cancer Institute - Butternut
    • Seneca, South Carolina, United States, 29672
      • Prisma Health Cancer Institute - Seneca
  • Virginia
    • Lynchburg, Virginia, United States, 24501
      • Centra Lynchburg Hematology-Oncology Clinic Inc
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University/Massey Cancer Center
    • Richmond, Virginia, United States, 23230
      • Virginia Cancer Institute
    • Winchester, Virginia, United States, 22601
      • Shenandoah Oncology PC
  • Wisconsin
    • Burlington, Wisconsin, United States, 53105
      • Aurora Cancer Care-Southern Lakes VLCC
    • Grafton, Wisconsin, United States, 53024
      • Aurora Cancer Care-Grafton
    • Oshkosh, Wisconsin, United States, 54904
      • Vince Lombardi Cancer Clinic - Oshkosh
    • Summit, Wisconsin, United States, 53066
      • Aurora Medical Center in Summit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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)
• Scheduled to receive adjuvant chemotherapy with an Anthracycline (doxorubicin and epirubicin)
• 21 years of age or older
• LVEF > 50% (Most recent within the last 5 years)
• Prior administration of anthracyclines is acceptable if therapy was completed > 6 months prior to study enrollment
• Patients that are receiving or have received chemotherapy regimens are allowed
• Able to hold breath for 10 seconds
• Prior cancers allowed if no evidence of disease in last 5 years
• Eastern Cooperative Oncology Group (ECOG) 0 or 1

Exclusion Criteria:

• Prior use of lipid-lowering therapy within the last 6 months
• Current postmenopausal hormone-replacement therapy
• Uncontrolled hypertension (systolic blood pressure >190 mm Hg or diastolic blood pressure >100 mm Hg)
• Scheduled to receive neoadjuvant chemotherapy with an anthracycline
• No active liver disease allowed
• Uncontrolled hypothyroidism
• Recent history (within past 3 years) of alcohol or drug abuse, inflammatory conditions such as lupus or inflammatory bowel disease, use of immunosuppressant agents, or another medical condition that might compromise safety or the successful completion of the study.
• Patients with ferromagnetic cerebral aneurysm clips or other intraorbital/intracranial metal;pacemakers, defibrillators, functioning neurostimulator devices or other implanted electronic devices.
• Unstable angina; significant ventricular arrhythmias (>20 premature ventricular complexes (PVCs)/min due to gating difficulty) atrial fibrillation with uncontrolled ventricular response; coronary artery disease; acute myocardial infarction within 28 days
• Current use of Cytochrome P450 (CYP3A4) inhibitors. These include Clarithromycin, HIV protease inhibitors, Itraconazole, grapefruit juice, Cyclosporine, Rifampin or Digoxin
• Current or history of hepatic dysfunction
• Unable to provide informed consent
• Claustrophobia
• Planning to move within 24 months of trial enrollment
• Pregnant or breast-feeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm 1 - Atorvastatin; One 40 mg Atorvastatin tablet each morning by mouth for 24 months	Drug: Atorvastatin; 40 mg tablet taken by mouth each morning for 24 months.; Other Names: Lipitor
Placebo Comparator: Arm 2 - Placebo; One placebo tablet each morning by mouth for 24 months.	Drug: Atorvastatin; 40 mg tablet taken by mouth each morning for 24 months.; Other Names: Lipitor; Drug: Placebo; One placebo tablet taken each morning orally for 24 months.; Other Names: sugar pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left Ventricular Ejection Fraction (LVEF)	24 month estimated values of clinical measurements obtained from Cardiac MRI left ventricular ejection fraction by group. Linear model adjusts for baseline value and group assignment and multiple imputation was utilized for missing data.	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
End Diastolic Volume	24 month estimated values of clinical measurements obtained from Cardiac MRI End Diastolic Volume by group. Linear model adjusts for baseline value and group assignment and multiple imputation was utilized for missing data.	24 months
End Systolic Volume	24 month estimated values of clinical measurements obtained from Cardiac MRI End Systolic Volume by group. Linear model adjusts for baseline value and group assignment and multiple imputation was utilized for missing data.	24 months
Stroke Volume	24 month estimated values of clinical measurements obtained from Cardiac MRI Stroke Volume by group. Linear model adjusts for baseline value and group assignment and multiple imputation was utilized for missing data.	24 months
Left Ventricular (LV) Mass	24 month estimated values of clinical measurements obtained from Cardiac MRI left ventricular mass by group. Linear model adjusts for baseline value and group assignment and multiple imputation was utilized for missing data.	24 months
Pulse Wave Velocity	24 month estimated values of clinical measurements obtained from Cardiac MRI pulse wave velocity by group. Linear model adjusts for baseline value and group assignment and multiple imputation was utilized for missing data.	24 months
Hopkins Verbal Learning Test (HVLT) Total Recall	24 month estimated values Hopkins Verbal Learning test (HVLT) total recall by group. Linear model adjusts for baseline value and group assignment. No missing imputation performed. Ranges from 0 to 36 and higher numbers reflect better recall.	24 months
Controlled Oral Word Association (COWA)	24 month estimated values Controlled Oral Word Association (COWA) by group. Linear model adjusts for baseline value and group assignment. No missing imputation performed. The COWA uses the three letter set of C, F, and L to assess phonemic fluency. Individuals are given 1 min to name as many words as possible beginning with one of the letters. The procedure is then repeated for the remaining two letters. Ranges from 0 to the total number of correct words that begin with one of the letters in the set. There is no ceiling of a maximum score. Higher numbers reflect better verbal fluency.	24 months
Patient-reported Outcomes Measurement (PROMIS) Questionnaire - Applied Cognition - General Concerns - Short Form 4a	Patient reported quality of life outcomes obtained from patient-reported outcomes measurement (PROMIS) questionnaire - Applied Cognition - General Concerns - Short Form 4a . Scores range from 4-20 and then adjusted by t-scores ranging from 30.1-63.8. Higher scores reflect better cognition. Linear models include baseline assessment and group and multiple imputation was utilized.	24 months
Patient-reported Outcomes Measurement (PROMIS) Questionnaire - Fatigue Short Form 41	Patient reported quality of life outcomes obtained from patient-reported outcomes measurement (PROMIS) questionnaire - Fatigue Short Form 41. Scores range from 4-20 and then adjusted by t-scores ranging from 33.7-75.8. Higher scores reflect worse fatigue. Linear models include baseline assessment and group and multiple imputation was utilized.	24 months

Collaborators and Investigators

• Sponsor: Wake Forest University Health Sciences
• Collaborators: National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI)

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2014
• Primary Completion (Actual): September 24, 2020
• Study Completion (Actual): September 24, 2020

Study Registration Dates

• First Submitted: November 1, 2013
• First Submitted That Met QC Criteria: November 19, 2013
• First Posted (Estimate): November 20, 2013

Study Record Updates

• Last Update Posted (Actual): January 4, 2022
• Last Update Submitted That Met QC Criteria: December 6, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• 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
• Additional Relevant MeSH Terms: Skin Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Neoplasms by Site; Breast Diseases; Lymphoma; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin
• Other Study ID Numbers: IRB00038639; U10CA081851 (U.S. NIH Grant/Contract); 1R01HL118740-01 (U.S. NIH Grant/Contract); REBACCCWFU 98213 (Other Identifier: NCI); NCI-2013-01760 (Registry Identifier: NCI CTRP)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No