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NCT number NCT03392740
Study type Interventional
Source Genesys Regional Medical Center
Contact Andrew Hinojos, DO
Phone 602-399-1174
Email andrew.hinojos@ascension.org
Status Not yet recruiting
Phase Phase 4
Start date January 15, 2018
Completion date December 15, 2019

Clinical Trial Summary

The intent of the study is to show the potential benefits of angiotensin converting enzyme inhibitors in preventing anthracycline induced cardiotoxicity.

In a prospective 1:1 randomized, double-blinded and placebo-controlled clinical trial we plan to enroll patients who are to be treated with anthracycline chemotherapy (doxorubicin, epirubicin, idrarubicin, or mitoxantone) to either lisinopril or placebo group. The study will be performed at the Genesys Hurley Cancer Institute. The treating oncologist who intends to start the patient on anthracycline chemotherapeutic agent will provide the patient with a recruitment flyer and informed consent form and then referred to the research nurse. Subjects interested in participation, that do not meet any of the exclusion criteria, will be consented and enrolled by the research nurse at the time of their first treatment. Over a period of 1 to 3 weeks the study medication will be titrated in a stepwise fashion to a target of 20 mg daily, maintaining a systolic blood pressure greater than 90 mmHg. A baseline echocardiogram with strain and strain rate imaging will be obtained prior to initiation of anthracycline chemotherapy. Subsequent echocardiograms with strain and strain rate imaging will be performed every 3 months for a total of 12 months.

Patients will be followed for a total of 12 months, starting on the day of enrollment. We intend to recruit a total of 200 patients.

The primary endpoint of this study is a change in change in strain and strain rate parameters prior to, during, and after anthracycline chemotherapy compared to placebo.

Study data will be collected and managed using the Ascension installation of REDCap (Research Electronic Data Capture). REDCap is a secure, web application designed to support data capture for research studies, providing user-friendly web-based case report forms, real-time data entry validation (e.g. for data types and range checks), audit trails and a de-identified data export mechanism to common statistical packages.

Echocardiographic data will be stored in cine-loop format on a private, password protected echocardiogram viewing software and analyzed by a separate blinded cardiologist.

Patients will be evaluated according to the standard oncologic evaluation. The treating oncologist will make decisions on their treatment based on their personal standards and clinical judgement.


Clinical Trial Description

To date anthracycline chemotherapy regimens still play a major role in many cancer treatments, approximately 32% of breast cancer patients, 57-70% of elderly lymphoma patients, and 50-60% of childhood cancers survivors are treated with an anthracycline regimen.

Of these patients, approximately 9-24%% of patients on anthracycline chemotherapy will develop anthracycline cardiomyopathy and the majority will present with signs and/or symptoms within the first 12 months of starting chemotherapy. The onset of anthracycline cardiomyopathy, even asymptomatic, not only negatively impacts the cardiac outcome of cancer patients, but also limits their therapeutic opportunities to less aggressive and, consequently, less effective therapies

There is limited evidence based research for treatment of anthracycline induced cardiomyopathy and is mainly targeted towards standard heart failure therapy. In 2006, Cardinale et al. found early treatment of myocardial cell injury, as defined by a rise in troponin, with enalapril prevents left ventricular ejection fraction decrease as well as the occurrence of cardiac events. Subsequently in 2010, Cardinale et al. also found that treatment of anthracycline cardiomyopathy with standard heart failure therapy (enalapril, carvedilol) at the onset of cardiomyopathy, defined as ejection fraction of ≤ 45%, lead to complete recovery of left ventricular ejection fraction and improved cardiac outcomes. Indeed, much of the research has been focused on management of patients who develop early signs of left ventricular dysfunction. Unfortunately, despite this strategy up to 11% still go on to develop New York Heart Association class 3 or 4 heart failure symptoms.

A crucial issue remains is whether or not, and eventually how, to treat patients still asymptomatic who do not yet demonstrate left ventricular dysfunction. Lisinopril use has been well studied in patients with systolic heart failure and is a class I indication in all patients with an ejection fraction of <40 %. Randomized control trials have established their benefit in reducing morbidity and mortality in heart failure with reduced ejection fraction. Since anthracycline induced-cardiotoxicity has a significant impact on overall prognosis in cancer patients and despite treatment after the development of left ventricular dysfunction from anthracyclines will still result in a large amount of the patient population developing heart failure, there is an urgent need in prophylactic treatment in preventing anthracycline-induced left ventricular dysfunction.

Thus, the intent of our study is to show the potential benefits of angiotensin converting enzyme inhibitors in preventing anthracycline induced cardiotoxicity.

In a prospective 1:1 randomized, double-blinded and placebo-controlled clinical trial we plan to enroll patients who are to be treated with anthracycline chemotherapy (doxorubicin, epirubicin, idrarubicin, or mitoxantone) to either lisinopril or placebo group. The study will be performed at the Genesys Hurley Cancer Institute. The treating oncologist who intends to start the patient on anthracycline chemotherapeutic agent will provide the patient with a recruitment flyer and informed consent form and referred to the research nurse. Subjects interested in participation, that do not meet any of the exclusion criteria, will be consented and enrolled by the research nurse at the time of their first treatment. Treatment will start with an initial dose of 5mg lisinopril daily and over a period of 1 to 3 weeks the medication will be titrated in a stepwise fashion of 5mg, to 10mg, and finally to a target of 20 mg daily, as blood pressure permits. Systolic blood pressure will be recorded and monitored at every office visit, if systolic blood pressure is less than or equal to 90 mmHg the medication will be titrated down to the highest tolerated dose by the research nurse.

Patients will be followed for a total of 12 months, starting on the day of enrollment. We intend to recruit a total of 200 patients.

The primary endpoint of this study is a change in change in strain and strain rate parameters prior to, during, and after anthracycline chemotherapy compared to placebo.

Secondary outcomes are based on the American Society of Echocardiography consensus on cancer therapeutics-related cardiac dysfunction (CTRCD). CTRCD is defined as a decrease in ejection >10% below 53% with at least 2 signs and symptoms of heart failure (lower extremity swelling, elevated jugular venous pulsation, orthopnea, paroxysmal nocturnal dyspnea, dyspnea on exertion). Those with a baseline ejection fraction <53% at baseline will be placed in the secondary endpoint if their ejection fraction decreases by >10% from their baseline with at least 2 signs and/or symptoms of heart failure. We will also examine, subclinical anthracycline cardiomyopathy defined as a decrease in ejection fraction >10% below 53% without signs and/or symptoms of heart failure. In those with a baseline ejection fraction <53% at baseline will be placed in the secondary endpoint if their ejection fraction decreases by >10% from their baseline without at least 2 signs and/or symptoms of heart failure. We will also examine the occurrence of cardiac events during the 1-year follow-up defined as death from any cause, death resulting from a cardiac cause, acute pulmonary edema, overt heart failure, and life-threatening arrhythmias requiring treatment.

Blind conventional 2 dimensional echocardiography will be performed using standard commercially available equipment. Imaging will be conducted with patients either supine or in the left lateral decubitus position. Data will be acquired using a 3.5-MHz transducer in the apical (2- and 4-chamber and apical long axis) and parasternal (long and short axis) views according to the American Society of Echocardiography. Transmitral flow velocity signals will be obtained in the four-chamber view by placing a 2-mm pulsed doppler sample volume at the tips of the valve leaflets, aligned with the left ventricular inflow by color flow imaging. Peak early (E) and late diastolic (A) velocities, E-wave deceleration time, ratio of E and A wave and A-wave duration will be measured.

A comprehensive assessment of the strain and strain rate for the left ventricular myocardium using tissue Doppler-based imaging (TDI). Standard 2D gray-scale images of the left ventricle with a mean frame rate of 90 ± 5 frames per second at conventional apical 2- and 4-chamber views will be acquired. The parameters measured will be the peak systolic velocity, early and late systolic velocities, early and late diastolic velocities. Basal values are considered to represent the best reproducibility for TDI-based strain assessment. Peak systolic longitudinal strain and strain-rate parameters will be calculated and derived from four segments of the two apical chambers (2- and 4-chamber views).

Study data will be collected and managed using the Ascension installation of REDCap (Research Electronic Data Capture). REDCap is a secure, web application designed to support data capture for research studies, providing user-friendly web-based case report forms, real-time data entry validation (e.g. for data types and range checks), audit trails and a de-identified data export mechanism to common statistical packages.

Echocardiographic data will be stored in cine-loop format on a private, password protected echocardiogram viewing software and analyzed by a separate blinded cardiologist.

Patients will be evaluated according to the standard oncologic evaluation. The treating oncologist will make decisions on their treatment based on their personal standards and clinical judgement.

Patients who develop anthracycline induced heart failure will be treated according to the treating oncologist and clinical scenario.


Study Design


Related Conditions & MeSH terms


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