<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02236806</url>
  </required_header>
  <id_info>
    <org_study_id>SAFE2014</org_study_id>
    <nct_id>NCT02236806</nct_id>
  </id_info>
  <brief_title>Cardiotoxicity Prevention in Breast Cancer Patients Treated With Anthracyclines and/or Trastuzumab</brief_title>
  <acronym>SAFE</acronym>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Azienda Ospedaliero-Universitaria Careggi</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Florence</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Azienda Ospedaliero-Universitaria Careggi</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The aim of the study is to analyze the protective impact on the cardiac damage of beta&#xD;
      blockers and ACE inhibitors for breast cancer patients treated with anthracyclines-based&#xD;
      chemotherapy with or without trastuzumab.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Over the years, due to the use of new generation therapeutic regimens, as well as the use of&#xD;
      advanced radiation techniques, the curability of breast cancer reached an overall 10-year&#xD;
      survival rate of approximately 80%.&#xD;
&#xD;
      Anthracyclines have a key role in the treatment of breast cancer. Many published studies&#xD;
      showed a benefit of disease-free survival in patients with positive lymph nodes treated with&#xD;
      anthracyclines-based regimens. Many anthracyclines and taxanes-based regimens are currently&#xD;
      used in clinical practice in the treatment of breast cancer. Numerous randomized trials have&#xD;
      confirmed the benefit of the addition of taxanes to anthracyclines.&#xD;
&#xD;
      Trastuzumab is a recombinant humanized monoclonal antibody with specificity for the&#xD;
      extracellular domain of human epidermal growth factor receptor 2 (HER2). The use of&#xD;
      trastuzumab administered sequentially or concurrently with adjuvant chemotherapy compared to&#xD;
      chemotherapy in patients with HER2 positive was evaluated in several randomized trials. Many&#xD;
      data concerning the incidence of adverse cardiovascular events acute, subacute and late are&#xD;
      now available. The cardiac toxicity of anthracyclines may be acute, subacute and chronic. The&#xD;
      acute toxicity occurs during or shortly after the infusion of the drug with arrhythmias,&#xD;
      which in some cases leads to heart failure, pericarditis-myocarditis and electrocardiographic&#xD;
      abnormalities. The acute toxicity is usually reversible in a dose-dependent manner. The acute&#xD;
      and subacute toxicity are rare (1-4%). Data are available concerning clinically relevant&#xD;
      cardiac toxicity with a chronic progressive deterioration of ventricular function up to heart&#xD;
      failure.&#xD;
&#xD;
      Beside the cumulative dose risk factor, other unfavourable features such as advanced age,&#xD;
      female sex, and the combination of anthracyclines and trastuzumab should be evaluated. In&#xD;
      most cases, the late toxicity occurs within the first year following completion of&#xD;
      chemotherapy but nevertheless the clinical manifestations can occur even after 10-20 years.&#xD;
      This fact suggests that in women treated in (neo)adjuvant setting is strongly necessary an&#xD;
      echocardiographic monitoring even after a longer time.&#xD;
&#xD;
      The aim of the study is to analyze the protective impact on the cardiac damage of beta&#xD;
      blockers and ACE inhibitors for breast cancer patients treated with anthracyclines-based&#xD;
      chemotherapy with or without trastuzumab, using myocardial strain imaging monitoring.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">July 2015</start_date>
  <completion_date type="Anticipated">June 2022</completion_date>
  <primary_completion_date type="Anticipated">June 2022</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Double (Participant, Care Provider)</masking>
    <masking_description>Both participants and Care Providers are not aware of intervention allocation.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Left ventricular ejection fraction (LVEF)</measure>
    <time_frame>at months 6,9,12,24</time_frame>
    <description>Change in LVEF (3-dimensional and 2-dimensional) at time-frame</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Global longitudinal strain (GLS)</measure>
    <time_frame>at months 6,9,12,24</time_frame>
    <description>Change in GLS at time-frame</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Indexed left ventricular end diastolic volume (EDVI)</measure>
    <time_frame>at months 6,9,12,24</time_frame>
    <description>Change in EDVI at time-frame</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Indexed left ventricular end systolic volume (ESVI)</measure>
    <time_frame>at months 6,9,12,24</time_frame>
    <description>Change in ESVI at time-frame</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">262</enrollment>
  <condition>Breast Cancer</condition>
  <condition>Cardiotoxicity</condition>
  <arm_group>
    <arm_group_label>Arm 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>bisoprolol plus ramipril</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm 2</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Bisoprolol plus placebo</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm 3</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Ramipril plus placebo</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm 4</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bisoprolol</intervention_name>
    <description>5 mg daily</description>
    <arm_group_label>Arm 1</arm_group_label>
    <arm_group_label>Arm 2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ramipril</intervention_name>
    <description>5 mg daily</description>
    <arm_group_label>Arm 1</arm_group_label>
    <arm_group_label>Arm 3</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>1 capsule daily</description>
    <arm_group_label>Arm 2</arm_group_label>
    <arm_group_label>Arm 3</arm_group_label>
    <arm_group_label>Arm 4</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Female&#xD;
&#xD;
          -  Age &gt;18 years&#xD;
&#xD;
          -  Non-metastatic histologically confirmed primary invasive breast cancer&#xD;
&#xD;
          -  Scheduled to receive neoadjuvant and/or adjuvant anthracyclines with or without&#xD;
             anti-HER2 therapy&#xD;
&#xD;
          -  Provided informed consent&#xD;
&#xD;
          -  Able to swallow capsules&#xD;
&#xD;
          -  LVEF &gt; 50%&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnant or lactating women&#xD;
&#xD;
          -  Treatment with ACE-inhibitors or beta blockers at diagnosis&#xD;
&#xD;
          -  History of NCI Common Toxicity Criteria for Adverse Effects (CTCAE) (version 4.0)&#xD;
             Grade &gt;2 symptomatic congestive heart failure (CHF), previous myocardial infarction,&#xD;
             significant symptoms (Grade&gt;2) relating to LVEF dysfunction, valvular disease, cardiac&#xD;
             arrhythmia (Grade&gt;3)&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Lorenzo Livi, MD, Prof</last_name>
    <role>Study Chair</role>
    <affiliation>Azienda Ospedaliero-Universitaria Careggi</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Icro Meattini, MD, Prof</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Florence</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Azienda Ospedaliero-Universitaria Careggi, Florence University</name>
      <address>
        <city>Florence</city>
        <zip>50141</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <reference>
    <citation>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.</citation>
    <PMID>30406290</PMID>
  </reference>
  <reference>
    <citation>Meattini 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.</citation>
    <PMID>28364270</PMID>
  </reference>
  <results_reference>
    <citation>Livi 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.</citation>
    <PMID>34436523</PMID>
  </results_reference>
  <verification_date>January 2022</verification_date>
  <study_first_submitted>September 9, 2014</study_first_submitted>
  <study_first_submitted_qc>September 9, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 11, 2014</study_first_posted>
  <last_update_submitted>January 16, 2022</last_update_submitted>
  <last_update_submitted_qc>January 16, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">February 1, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Azienda Ospedaliero-Universitaria Careggi</investigator_affiliation>
    <investigator_full_name>Lorenzo Livi</investigator_full_name>
    <investigator_title>Full Professor</investigator_title>
  </responsible_party>
  <keyword>Breast cancer</keyword>
  <keyword>Adjuvant chemotherapy</keyword>
  <keyword>Neoadjuvant chemotherapy</keyword>
  <keyword>Cardioprotection</keyword>
  <keyword>Anthracyclines</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
    <mesh_term>Cardiotoxicity</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ramipril</mesh_term>
    <mesh_term>Bisoprolol</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02236806
org study id: SAFE2014
nct id: NCT02236806
lead sponsor: 
collaborator: 
has dmc: No
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Double (Participant, Care Provider)
masking description: Both participants and Care Providers are not aware of intervention allocation.
measure: Left ventricular ejection fraction (LVEF)
time frame: at months 6,9,12,24
description: Change in LVEF (3-dimensional and 2-dimensional) at time-frame
measure: Global longitudinal strain (GLS)
time frame: at months 6,9,12,24
description: Change in GLS at time-frame
measure: Indexed left ventricular end diastolic volume (EDVI)
time frame: at months 6,9,12,24
description: Change in EDVI at time-frame
measure: Indexed left ventricular end systolic volume (ESVI)
time frame: at months 6,9,12,24
description: Change in ESVI at time-frame
arm group label: Arm 1
arm group type: Experimental
description: bisoprolol plus ramipril
arm group label: Arm 2
arm group type: Active Comparator
description: Bisoprolol plus placebo
arm group label: Arm 3
arm group type: Active Comparator
description: Ramipril plus placebo
arm group label: Arm 4
arm group type: Placebo Comparator
description: Placebo
intervention type: Drug
intervention name: Bisoprolol
description: 5 mg daily
arm group label: Arm 1
arm group label: Arm 2
intervention type: Drug
intervention name: Ramipril
description: 5 mg daily
arm group label: Arm 1
arm group label: Arm 3
intervention type: Drug
intervention name: Placebo
description: 1 capsule daily
arm group label: Arm 2
arm group label: Arm 3
arm group label: Arm 4
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Lorenzo Livi, MD, Prof
role: Study Chair
affiliation: Azienda Ospedaliero-Universitaria Careggi
last name: Icro Meattini, MD, Prof
role: Principal Investigator
affiliation: University of Florence
facility: 
country: Italy
citation: 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.
PMID: 30406290
citation: Meattini 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.
PMID: 28364270
citation: Livi 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.
PMID: 34436523
responsible party type: Principal Investigator
investigator affiliation: Azienda Ospedaliero-Universitaria Careggi
investigator full name: Lorenzo Livi
investigator title: Full Professor
mesh term: Breast Neoplasms
mesh term: Cardiotoxicity
mesh term: Ramipril
mesh term: Bisoprolol
sharing ipd: No