Breast CancerPhase 3SAFENCT02236806
Cardiotoxicity Prevention in Breast Cancer Patients Treated With Anthracyclines and/or Trastuzumab
A Phase 3 study testing Bisoprolol and Ramipril in people with Breast Cancer and Cardiotoxicity, run by Azienda Ospedaliero-Universitaria Careggi at 1 site in Italy.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Breast Cancer, Cardiotoxicity
- What is being tested?
- Bisoprolol and Ramipril
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 262 participants
- Where
- 1 siteItaly
- Study dates
- Jul 2015to Jun 2022
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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%
Who cannot join
- 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)
Trial locations and contacts
1 site in 1 country.
Italy1 site
Azienda Ospedaliero-Universitaria Careggi, Florence University
Florence, 50141
About this study
Official title: 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.
Read the 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.
- Conditions
- Breast Cancer, Cardiotoxicity
- Being tested
- Bisoprolol, Ramipril, Placebo
- Keywords
- Breast cancer, Adjuvant chemotherapy, Neoadjuvant chemotherapy, Cardioprotection, Anthracyclines
- Medical subject headings
- Breast Neoplasms, Cardiotoxicity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BisoprololDrug
5 mg daily
RamiprilDrug
5 mg daily
PlaceboDrug
1 capsule daily
| Study group | Role | What they receive |
|---|---|---|
| Arm 1 | Experimental | bisoprolol plus ramipril Receives: Drug: Bisoprolol; Drug: Ramipril |
| Arm 2 | Active comparator | Bisoprolol plus placebo Receives: Drug: Bisoprolol; Drug: Placebo |
| Arm 3 | Active comparator | Ramipril plus placebo Receives: Drug: Ramipril; Drug: Placebo |
| Arm 4 | Placebo comparator | Placebo Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Left ventricular ejection fraction (LVEF)
Change in LVEF (3-dimensional and 2-dimensional) at time-frame
Measured: at months 6,9,12,24
Global longitudinal strain (GLS)
Change in GLS at time-frame
Measured: at months 6,9,12,24
Secondary outcomes (2)
Indexed left ventricular end diastolic volume (EDVI)
Change in EDVI at time-frame
Measured: at months 6,9,12,24
Indexed left ventricular end systolic volume (ESVI)
Change in ESVI at time-frame
Measured: at months 6,9,12,24
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Sep 2014 (estimated)
- Study startJul 2015
- Primary completionJun 2022 (estimated)
- Study completionJun 2022 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Breast CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Care provider
- Enrolment
- 262 participants (actual)
Sponsor and investigators
- Lead sponsor
- Azienda Ospedaliero-Universitaria Careggi
- Sponsor type
- University, hospital or other
- Collaborators
- University of Florence
- Responsible party
- Principal investigator, Lorenzo Livi, Azienda Ospedaliero-Universitaria Careggi
- Investigators
- Lorenzo Livi, MD, Prof, Study chair, Azienda Ospedaliero-Universitaria CareggiIcro Meattini, MD, Prof, Principal investigator, University of Florence
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02236806
- Sponsor's protocol ID
- SAFE2014
- Acronym
- SAFE
- Status last verified
- Jan 2022
- First submitted
- 9 Sep 2014
- Last updated
- 1 Feb 2022
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No
Publications
Francolini G, Desideri I, Meattini I, Becherini C, Terziani F, Olmetto E, Delli Paoli C, Pezzulla D, Loi M, Bonomo P, Greto D, Calusi S, Casati M, Pallotta S, Livi L. Assessment of a guideline-based heart substructures delineation in left-sided breast cancer patients undergoing adjuvant radiotherapy : Quality assessment within a randomized phase III trial testing a cardioprotective treatment strategy (SAFE-2014). Strahlenther Onkol. 2019 Jan;195(1):43-51. doi: 10.1007/s00066-018-1388-x. Epub 2018 Nov 7.
PubMed 30406290Meattini I, Curigliano G, Terziani F, Becherini C, Airoldi M, Allegrini G, Amoroso D, Barni S, Bengala C, Guarneri V, Marchetti P, Martella F, Piovano P, Vannini A, Desideri I, Tarquini R, Galanti G, Barletta G, Livi L. SAFE trial: an ongoing randomized clinical study to assess the role of cardiotoxicity prevention in breast cancer patients treated with anthracyclines with or without trastuzumab. Med Oncol. 2017 May;34(5):75. doi: 10.1007/s12032-017-0938-x. Epub 2017 Mar 31.
PubMed 28364270Livi L, Barletta G, Martella F, Saieva C, Desideri I, Bacci C, Del Bene MR, Airoldi M, Amoroso D, Coltelli L, Scotti V, Becherini C, Visani L, Salvestrini V, Mariotti M, Pedani F, Bernini M, Sanchez L, Orzalesi L, Nori J, Bianchi S, Olivotto I, Meattini I. Cardioprotective Strategy for Patients With Nonmetastatic Breast Cancer Who Are Receiving an Anthracycline-Based Chemotherapy: A Randomized Clinical Trial. JAMA Oncol. 2021 Oct 1;7(10):1544-1549. doi: 10.1001/jamaoncol.2021.3395.
PubMed 34436523Marrazzo L, Meattini I, Becherini C, Salvestrini V, Visani L, Barletta G, Saieva C, Del Bene MR, Pilato G, Desideri I, Arilli C, Paoletti L, Russo S, Scoccianti S, Martella F, Francolini G, Simontacchi G, Nori Cucchiari J, Pellegrini R, Livi L, Pallotta S. Subclinical cardiac damage monitoring in breast cancer patients treated with an anthracycline-based chemotherapy receiving left-sided breast radiation therapy: subgroup analysis from a phase 3 trial. Radiol Med. 2024 Dec;129(12):1926-1935. doi: 10.1007/s11547-024-01897-6. Epub 2024 Oct 22.
PubMed 39436588
Study at a glance
From the registry record, last updated by the sponsor on 1 Feb 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT02236806
- Acronym / sponsor ID
- SAFE / SAFE2014
- Conditions
- Breast Cancer, Cardiotoxicity
- Keywords
- Breast cancer, Adjuvant chemotherapy, Neoadjuvant chemotherapy, Cardioprotection, Anthracyclines
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 262 participants (actual)
- Lead sponsor
- Azienda Ospedaliero-Universitaria CareggiUniversity, hospital or other
- Collaborators
- University of Florence
- Study start
- Jul 2015 (actual)
- Primary completion
- Jun 2022 (estimated)
- Study completion
- Jun 2022 (estimated)
- First posted
- 11 Sep 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, care provider)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Arm 1 | Experimental | Drug: Bisoprolol, Drug: Ramiprilbisoprolol plus ramipril |
| Arm 2 | Active comparator | Drug: Bisoprolol, Drug: PlaceboBisoprolol plus placebo |
| Arm 3 | Active comparator | Drug: Ramipril, Drug: PlaceboRamipril plus placebo |
| Arm 4 | Placebo comparator | Drug: PlaceboPlacebo |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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
Key exclusion criteria (3 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Bisoprolol5 mg daily | Drug | Arm 1, Arm 2 |
| Ramipril5 mg daily | Drug | Arm 1, Arm 3 |
| Placebo1 capsule daily | Drug | Arm 2, Arm 3, Arm 4 |
Primary outcome
Left ventricular ejection fraction (LVEF)
Time frame: at months 6,9,12,24
Change in LVEF (3-dimensional and 2-dimensional) at time-frame
Global longitudinal strain (GLS)
Time frame: at months 6,9,12,24
Change in GLS at time-frame
2 secondary outcomes
Indexed left ventricular end diastolic volume (EDVI)
Time frame: at months 6,9,12,24
Indexed left ventricular end systolic volume (ESVI)
Time frame: at months 6,9,12,24
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Feb 2022.
- Background: PubMed 30406290Francolini G, Desideri I, Meattini I, Becherini C, Terziani F, Olmetto E, Delli Paoli C, Pezzulla D, Loi M, Bonomo P, Greto D, Calusi S, Casati M, Pallotta S, Livi L. Assessment of a guideline-based heart substructures delineation in left-sided breast cancer patients undergoing adjuvant radiotherapy : Quality assessment within a randomized phase III trial testing a cardioprotective treatment strategy (SAFE-2014). Strahlenther Onkol. 2019 Jan;195(1):43-51. doi: 10.1007/s00066-018-1388-x. Epub 2018 Nov 7.
- Background: PubMed 28364270Meattini I, Curigliano G, Terziani F, Becherini C, Airoldi M, Allegrini G, Amoroso D, Barni S, Bengala C, Guarneri V, Marchetti P, Martella F, Piovano P, Vannini A, Desideri I, Tarquini R, Galanti G, Barletta G, Livi L. SAFE trial: an ongoing randomized clinical study to assess the role of cardiotoxicity prevention in breast cancer patients treated with anthracyclines with or without trastuzumab. Med Oncol. 2017 May;34(5):75. doi: 10.1007/s12032-017-0938-x. Epub 2017 Mar 31.
- Results publication: PubMed 34436523Livi L, Barletta G, Martella F, Saieva C, Desideri I, Bacci C, Del Bene MR, Airoldi M, Amoroso D, Coltelli L, Scotti V, Becherini C, Visani L, Salvestrini V, Mariotti M, Pedani F, Bernini M, Sanchez L, Orzalesi L, Nori J, Bianchi S, Olivotto I, Meattini I. Cardioprotective Strategy for Patients With Nonmetastatic Breast Cancer Who Are Receiving an Anthracycline-Based Chemotherapy: A Randomized Clinical Trial. JAMA Oncol. 2021 Oct 1;7(10):1544-1549. doi: 10.1001/jamaoncol.2021.3395.
- Derived from this study: PubMed 39436588Marrazzo L, Meattini I, Becherini C, Salvestrini V, Visani L, Barletta G, Saieva C, Del Bene MR, Pilato G, Desideri I, Arilli C, Paoletti L, Russo S, Scoccianti S, Martella F, Francolini G, Simontacchi G, Nori Cucchiari J, Pellegrini R, Livi L, Pallotta S. Subclinical cardiac damage monitoring in breast cancer patients treated with an anthracycline-based chemotherapy receiving left-sided breast radiation therapy: subgroup analysis from a phase 3 trial. Radiol Med. 2024 Dec;129(12):1926-1935. doi: 10.1007/s11547-024-01897-6. Epub 2024 Oct 22.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Lorenzo Livi, MD, Prof study chair
Azienda Ospedaliero-Universitaria Careggi
Icro Meattini, MD, Prof principal investigator
University of Florence
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Bisoprolol and Ramipril in people with Breast Cancer and Cardiotoxicity, run by Azienda Ospedaliero-Universitaria Careggi at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 1 Feb 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Left ventricular ejection fraction (LVEF) (time frame: at months 6,9,12,24). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02236806, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Feb 2022.