Preventing Anthracycline Cardiovascular Toxicity With Statins (PREVENT)

Study Overview
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Brief Summary
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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
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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.

Official Title
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Preventing Anthracycline Cardiovascular Toxicity With Statins (PREVENT)

Conditions
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Breast Cancer, Lymphoma

Intervention / Treatment
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* Drug: Atorvastatin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stage I breast cancer, Stage II breast cancer, Stage III breast cancer, Stage I Lymphoma, Stage II Lymphoma, Stage III Lymphoma, Stage IV Lymphoma