Cardiotoxicity Prevention in Breast Cancer Patients Treated With Anthracyclines and/or Trastuzumab (SAFE)

January 16, 2022 updated by: Lorenzo Livi, Azienda Ospedaliero-Universitaria Careggi

Role of ACE Inhibitors and Beta Blockers as Cardiotoxicity Prevention in Breast Cancer Patients Treated With (Neo)Adjuvant Anthracyclines and/or Trastuzumab: a Four Arm, Placebo Control, Randomized Trial

The aim of the study is to analyze the protective impact on the cardiac damage of beta blockers and ACE inhibitors for breast cancer patients treated with anthracyclines-based chemotherapy with or without trastuzumab.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

Over the years, due to the use of new generation therapeutic regimens, as well as the use of advanced radiation techniques, the curability of breast cancer reached an overall 10-year survival rate of approximately 80%.

Anthracyclines have a key role in the treatment of breast cancer. Many published studies showed a benefit of disease-free survival in patients with positive lymph nodes treated with anthracyclines-based regimens. Many anthracyclines and taxanes-based regimens are currently used in clinical practice in the treatment of breast cancer. Numerous randomized trials have confirmed the benefit of the addition of taxanes to anthracyclines.

Trastuzumab is a recombinant humanized monoclonal antibody with specificity for the extracellular domain of human epidermal growth factor receptor 2 (HER2). The use of trastuzumab administered sequentially or concurrently with adjuvant chemotherapy compared to chemotherapy in patients with HER2 positive was evaluated in several randomized trials. Many data concerning the incidence of adverse cardiovascular events acute, subacute and late are now available. The cardiac toxicity of anthracyclines may be acute, subacute and chronic. The acute toxicity occurs during or shortly after the infusion of the drug with arrhythmias, which in some cases leads to heart failure, pericarditis-myocarditis and electrocardiographic abnormalities. The acute toxicity is usually reversible in a dose-dependent manner. The acute and subacute toxicity are rare (1-4%). Data are available concerning clinically relevant cardiac toxicity with a chronic progressive deterioration of ventricular function up to heart failure.

Beside the cumulative dose risk factor, other unfavourable features such as advanced age, female sex, and the combination of anthracyclines and trastuzumab should be evaluated. In most cases, the late toxicity occurs within the first year following completion of chemotherapy but nevertheless the clinical manifestations can occur even after 10-20 years. This fact suggests that in women treated in (neo)adjuvant setting is strongly necessary an echocardiographic monitoring even after a longer time.

The aim of the study is to analyze the protective impact on the cardiac damage of beta blockers and ACE inhibitors for breast cancer patients treated with anthracyclines-based chemotherapy with or without trastuzumab, using myocardial strain imaging monitoring.

Study Type

Interventional

Enrollment (Actual)

262

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Florence, Italy, 50141
        • Azienda Ospedaliero-Universitaria Careggi, Florence University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • Female
  • Age >18 years
  • Non-metastatic histologically confirmed primary invasive breast cancer
  • Scheduled to receive neoadjuvant and/or adjuvant anthracyclines with or without anti-HER2 therapy
  • Provided informed consent
  • Able to swallow capsules
  • LVEF > 50%

Exclusion Criteria:

  • Pregnant or lactating women
  • Treatment with ACE-inhibitors or beta blockers at diagnosis
  • History of NCI Common Toxicity Criteria for Adverse Effects (CTCAE) (version 4.0) Grade >2 symptomatic congestive heart failure (CHF), previous myocardial infarction, significant symptoms (Grade>2) relating to LVEF dysfunction, valvular disease, cardiac arrhythmia (Grade>3)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Arm 1
bisoprolol plus ramipril
Drug: Bisoprolol
5 mg daily
Drug: Ramipril
5 mg daily
Active Comparator: Arm 2
Bisoprolol plus placebo
Drug: Bisoprolol
5 mg daily
Drug: Placebo
1 capsule daily
Active Comparator: Arm 3
Ramipril plus placebo
Drug: Ramipril
5 mg daily
Drug: Placebo
1 capsule daily
Placebo Comparator: Arm 4
Placebo
Drug: Placebo
1 capsule daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Left ventricular ejection fraction (LVEF)
Time Frame: at months 6,9,12,24
Change in LVEF (3-dimensional and 2-dimensional) at time-frame
at months 6,9,12,24
Global longitudinal strain (GLS)
Time Frame: at months 6,9,12,24
Change in GLS at time-frame
at months 6,9,12,24

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Indexed left ventricular end diastolic volume (EDVI)
Time Frame: at months 6,9,12,24
Change in EDVI at time-frame
at months 6,9,12,24
Indexed left ventricular end systolic volume (ESVI)
Time Frame: at months 6,9,12,24
Change in ESVI at time-frame
at months 6,9,12,24

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Azienda Ospedaliero-Universitaria Careggi

Collaborators

University of Florence

Investigators

  • Study Chair: Lorenzo Livi, MD, Prof, Azienda Ospedaliero-Universitaria Careggi
  • Principal Investigator: Icro Meattini, MD, Prof, University of Florence

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 1, 2015

Primary Completion (Anticipated)

June 1, 2022

Study Completion (Anticipated)

June 1, 2022

Study Registration Dates

First Submitted

September 9, 2014

First Submitted That Met QC Criteria

September 9, 2014

First Posted (Estimate)

September 11, 2014

Study Record Updates

Last Update Posted (Actual)

February 1, 2022

Last Update Submitted That Met QC Criteria

January 16, 2022

Last Verified

January 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • SAFE2014

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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