<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/NCT03297346</url>
  </required_header>
  <id_info>
    <org_study_id>MEDIRAD EARLY-HEART_1.2</org_study_id>
    <nct_id>NCT03297346</nct_id>
  </id_info>
  <brief_title>Early Detection of Cardiovascular Changes After Radiotherapy for Breast Cancer</brief_title>
  <acronym>EARLY-HEART</acronym>
  <official_title>Early Detection of Cardiovascular Changes After Radiotherapy for Breast Cancer (EARLY HEART Study) in the Frame of the Implications of MEDIcal Low Dose RADiation Exposure (MEDIRAD) European Project</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Institut de Radioprotection et de Surete Nucleaire</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Academisch Ziekenhuis Groningen</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Technical University of Munich</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Institut Català d'Oncologia</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Hospital de Santa Maria, Portugal</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Paris 5 - Rene Descartes</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Institut de Radioprotection et de Surete Nucleaire</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Breast cancer (BC) radiotherapy leads to coincidental radiation of the heart, resulting in&#xD;
      increased risk of a variety of heart diseases. Identifying BC patients with the highest risk&#xD;
      of radiation-induced cardiac complications is crucial for developing strategies for primary&#xD;
      and secondary prevention. Little has been done on the relationship between dose distribution&#xD;
      to different anatomical cardiac structures during radiotherapy and early cardiovascular&#xD;
      changes that may lead to cardiac complications.&#xD;
&#xD;
      In the framework of the European project MEDIRAD, the EARLY-HEART multicenter prospective&#xD;
      cohort was launched in August 2017, involving 5 investigating centers from France,&#xD;
      Netherlands, Germany, Spain and Portugal. With 250 BC patients prospectively followed for 2&#xD;
      years, the main objective is to identify and validate the most important cardiac imaging&#xD;
      (echocardiography, computed tomography coronary angiography, cardiac magnetic resonance&#xD;
      imaging) and circulating biomarkers of radiation-induced cardiovascular changes arising in&#xD;
      the first 2 years after BC radiotherapy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      EARLY-HEART is a multicentre prospective cohort study that will include 250 female primary&#xD;
      breast cancer cases aged 40-75 years treated with postoperative radiotherapy (RT) alone after&#xD;
      breast-conserving surgery using modern planning-CT based RT technologies and followed for 2&#xD;
      years after RT in one of the 5 participating hospitals. In addition to the standard&#xD;
      follow-up, patients will need to give repeated blood samples and will undergo repeated&#xD;
      cardiac imaging:&#xD;
&#xD;
        -  Functional and anatomical cardiac imaging biomarkers will be based on automated&#xD;
           2D-speckle-tracking echocardiography (ECHO-ST); Computed Tomography Coronary Angiography&#xD;
           (CT) and cardiac magnetic resonance imaging (MRI).&#xD;
&#xD;
        -  Circulating biomarkers (BLOOD) will be based on a panel of multiple classical or novel&#xD;
           blood-based biomarkers.&#xD;
&#xD;
      Imaging and circulating biomarkers measurements will be assessed at baseline before RT (ECHO,&#xD;
      CT, MRI, BLOOD); at the end of RT (BLOOD); 6 months after RT (ECHO, MRI, BLOOD) and 24 months&#xD;
      after RT (ECHO, CT, MRI, BLOOD).&#xD;
&#xD;
      Changes in functional and anatomical cardiac imaging and circulating biomarkers between&#xD;
      unexposed status before RT and exposed status after RT at different time points will be first&#xD;
      analysed to evaluate the effects of RT on the heart.&#xD;
&#xD;
      All relevant DICOM-data (including planning-CT scans and the ECHO, MRI and CT) will be&#xD;
      centralized to the MEDIRAD-ENACT database managed by University of Groningen for automated&#xD;
      segmentation of all cardiac substructures (including coronary arteries) to ensure uniformity&#xD;
      of the segmentation procedure between centres. The RT planning CTs will be used to generate&#xD;
      dose volume histograms and 3D dose maps of the heart and cardiac substructures in order to&#xD;
      correlate the localization of any cardiovascular change with the anatomical dose&#xD;
      distribution.&#xD;
&#xD;
      In the presence of a cardiac outcome, a multimetric Normal Tissue Complication Probability&#xD;
      (NTCP) individual risk model will be constructed and an integrative clinical-biologic risk&#xD;
      score will be developed for individual risk prediction.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">September 1, 2017</start_date>
  <completion_date type="Anticipated">May 31, 2021</completion_date>
  <primary_completion_date type="Anticipated">October 1, 2020</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of patients with decreased myocardial function assessed by echocardiography</measure>
    <time_frame>2 years after radiotherapy (baseline measurements performed before radiotherapy)</time_frame>
    <description>Number of patients with an increased of at least 2.5% in the Global Longitudinal Strain (GLS) between baseline and 2 years after radiotherapy</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Changes in myocardial function measurements assessed by echocardiography</measure>
    <time_frame>6 months and 2 years after radiotherapy (baseline measurements performed before radiotherapy)</time_frame>
    <description>Increase of the segmental strain measurements (unit of measures:%)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Anatomical changes in coronary arteries assessed by cardiac CT</measure>
    <time_frame>2 years after radiotherapy (baseline measurements performed before radiotherapy)</time_frame>
    <description>Increase of the number of coronary segments containing any plaque or increase of the calcium score</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Myocardial tissue abnormalities assessed by cardiac MRI</measure>
    <time_frame>6 months and 2 years after radiotherapy (baseline measurements performed before radiotherapy)</time_frame>
    <description>Increase of the native mean myocardial T1 mapping value</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in circulating biomarkers measurements</measure>
    <time_frame>at the end of radiotherapy (through radiotherapy completion, an average of 5 weeks after starting date of radiotherapy), 6 months and 2 years after radiotherapy (baseline measurements performed before radiotherapy)</time_frame>
    <description>Significant increase or decrease in the following biomarkers:&#xD;
classical biomarkers of cardiac injury (C-reactive protein, Troponin I, Troponin T, B-type natriuretic peptide (BNP), N-terminal pro-brain natriuretic peptide (NT-Pro BNP), beta2-Microglobulin, Galectin 3); Inflammatory cytokines; biomarkers of endothelial activation and dysfunction; Microparticles; MicroRNAs; circulating DNA methylation</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">250</enrollment>
  <condition>Breast Cancer Female</condition>
  <arm_group>
    <arm_group_label>Breast cancer patients treated with RT</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Cardiac imaging and circulating biomarkers measurements to evaluate:&#xD;
myocardial dysfunction and deformation (ECHO-ST)&#xD;
coronary artery lesions and coronary artery calcium score (CT)&#xD;
myocardium including tissue abnormalities, cardiac morphology and function (MRI)&#xD;
blood-based biomarkers of cardiovascular changes (BLOOD)</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Cardiac imaging and circulating biomarkers</intervention_name>
    <description>Automated 2D-speckle-tracking echocardiography (ECHO-ST); Computed tomography coronary angiography (CT); Cardiac magnetic resonance imaging (MRI); Blood samples for circulating biomarkers measurements (BLOOD)</description>
    <arm_group_label>Breast cancer patients treated with RT</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Female unilateral breast cancer patients&#xD;
&#xD;
          -  Treated with primary breast conserving surgery for stage I-III invasive adenocarcinoma&#xD;
             of the breast or ductal carcinoma in situ (DCIS)&#xD;
&#xD;
          -  Age between 40-75 years at time of start radiotherapy&#xD;
&#xD;
          -  World Health Organisation (WHO) performance status 0-1&#xD;
&#xD;
          -  Planned for radiotherapy alone to the breast with or without the lymph node areas&#xD;
&#xD;
          -  Radiotherapy based on planning-CT scan using either three dimensional conformal&#xD;
             radiation therapy (3D-CRT), Intensity-modulated radiotherapy (IMRT), or Volumetric Arc&#xD;
             Therapy (VMAT/RapidArc)&#xD;
&#xD;
          -  Written Informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Male breast cancer patients&#xD;
&#xD;
          -  Neoadjuvant or adjuvant chemotherapy&#xD;
&#xD;
          -  M1 disease (metastatic breast cancer)&#xD;
&#xD;
          -  Medical history of coronary artery disease and/or myocardial infarction and/or atrial&#xD;
             fibrillation&#xD;
&#xD;
          -  Previous thoracic or mediastinal radiation&#xD;
&#xD;
          -  Contraindications to injection of iodinated contrast such as allergy or renal failure&#xD;
&#xD;
          -  Pregnancy or lactation&#xD;
&#xD;
          -  Atrial fibrillation detected during electrocardiogram before radiotherapy&#xD;
&#xD;
          -  Abnormal echocardiography before radiotherapy defined as: Left Ventricular Ejection&#xD;
             Fraction&lt;50%; longitudinal strain ≤ -16%; longitudinal strain rate &lt;-1%, and/or&#xD;
             abnormal wall motion&#xD;
&#xD;
          -  Presence of myocardial infarction detected during MRI before radiotherapy&#xD;
&#xD;
          -  CT or MRI results before radiotherapy requiring revascularisation&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sophie Jacob, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Institut de Radioprotection et de Sûreté Nucléaire</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Sophie Jacob, PhD</last_name>
    <phone>+33561145608</phone>
    <email>sophie.jacob@irsn.fr</email>
  </overall_contact>
  <location>
    <facility>
      <name>IRSN - Clinique Pasteur</name>
      <address>
        <city>Toulouse</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Sophie Jacob, PhD</last_name>
      <phone>+33561145608</phone>
      <email>sophie.jacob@irsn.fr</email>
    </contact>
    <investigator>
      <last_name>Atul Pathak, Md, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Klinikum rechts der Isar der Technischen Universität München</name>
      <address>
        <city>Munich</city>
        <country>Germany</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Michael Mayinger, MD</last_name>
      <email>michael.mayinger@tum.de</email>
    </contact>
    <investigator>
      <last_name>Stephanie Combs, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Academisch Ziekenhuis Groningen</name>
      <address>
        <city>Groningen</city>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Anne Crijns, MD, PhD</last_name>
      <phone>+31652724432</phone>
      <email>a.p.g.crijns@umcg.nl</email>
    </contact>
    <investigator>
      <last_name>Anne Crijns, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Associação para Investigação e Desenvolvimento da Faculdade de Medicina</name>
      <address>
        <city>Lisbon</city>
        <country>Portugal</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Constantino Susana, PhD</last_name>
      <email>sconstantino@medicina.ulisboa.pt</email>
    </contact>
    <investigator>
      <last_name>Manuela Fiuza, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Institut Català d'Oncologia</name>
      <address>
        <city>Girona</city>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Arantxa Eraso, MD, PhD</last_name>
      <email>aeraso@iconcologia.net</email>
    </contact>
    <investigator>
      <last_name>Arantxa Eraso, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>France</country>
    <country>Germany</country>
    <country>Netherlands</country>
    <country>Portugal</country>
    <country>Spain</country>
  </location_countries>
  <verification_date>June 2018</verification_date>
  <study_first_submitted>September 21, 2017</study_first_submitted>
  <study_first_submitted_qc>September 28, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 29, 2017</study_first_posted>
  <last_update_submitted>June 18, 2018</last_update_submitted>
  <last_update_submitted_qc>June 18, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">June 19, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Institut de Radioprotection et de Surete Nucleaire</investigator_affiliation>
    <investigator_full_name>Sophie JACOB</investigator_full_name>
    <investigator_title>PhD</investigator_title>
  </responsible_party>
  <keyword>radiotherapy</keyword>
  <keyword>cardiovascular changes</keyword>
  <keyword>cardiac imaging</keyword>
  <keyword>circulating biomarkers</keyword>
  <keyword>dosimetry</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol, Statistical Analysis Plan, and Informed Consent Form</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>July 5, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/46/NCT03297346/Prot_SAP_ICF_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT03297346
org study id: MEDIRAD EARLY-HEART_1.2
nct id: NCT03297346
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
Breast cancer (BC) radiotherapy leads to coincidental radiation of the heart, resulting in
      increased risk of a variety of heart diseases. Identifying BC patients with the highest risk
      of radiation-induced cardiac complications is crucial for developing strategies for primary
      and secondary prevention. Little has been done on the relationship between dose distribution
      to different anatomical cardiac structures during radiotherapy and early cardiovascular
      changes that may lead to cardiac complications.

      In the framework of the European project MEDIRAD, the EARLY-HEART multicenter prospective
      cohort was launched in August 2017, involving 5 investigating centers from France,
      Netherlands, Germany, Spain and Portugal. With 250 BC patients prospectively followed for 2
      years, the main objective is to identify and validate the most important cardiac imaging
      (echocardiography, computed tomography coronary angiography, cardiac magnetic resonance
      imaging) and circulating biomarkers of radiation-induced cardiovascular changes arising in
      the first 2 years after BC radiotherapy.
EARLY-HEART is a multicentre prospective cohort study that will include 250 female primary
      breast cancer cases aged 40-75 years treated with postoperative radiotherapy (RT) alone after
      breast-conserving surgery using modern planning-CT based RT technologies and followed for 2
      years after RT in one of the 5 participating hospitals. In addition to the standard
      follow-up, patients will need to give repeated blood samples and will undergo repeated
      cardiac imaging:

        -  Functional and anatomical cardiac imaging biomarkers will be based on automated
           2D-speckle-tracking echocardiography (ECHO-ST); Computed Tomography Coronary Angiography
           (CT) and cardiac magnetic resonance imaging (MRI).

        -  Circulating biomarkers (BLOOD) will be based on a panel of multiple classical or novel
           blood-based biomarkers.

      Imaging and circulating biomarkers measurements will be assessed at baseline before RT (ECHO,
      CT, MRI, BLOOD); at the end of RT (BLOOD); 6 months after RT (ECHO, MRI, BLOOD) and 24 months
      after RT (ECHO, CT, MRI, BLOOD).

      Changes in functional and anatomical cardiac imaging and circulating biomarkers between
      unexposed status before RT and exposed status after RT at different time points will be first
      analysed to evaluate the effects of RT on the heart.

      All relevant DICOM-data (including planning-CT scans and the ECHO, MRI and CT) will be
      centralized to the MEDIRAD-ENACT database managed by University of Groningen for automated
      segmentation of all cardiac substructures (including coronary arteries) to ensure uniformity
      of the segmentation procedure between centres. The RT planning CTs will be used to generate
      dose volume histograms and 3D dose maps of the heart and cardiac substructures in order to
      correlate the localization of any cardiovascular change with the anatomical dose
      distribution.

      In the presence of a cardiac outcome, a multimetric Normal Tissue Complication Probability
      (NTCP) individual risk model will be constructed and an integrative clinical-biologic risk
      score will be developed for individual risk prediction.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: Number of patients with decreased myocardial function assessed by echocardiography
time frame: 2 years after radiotherapy (baseline measurements performed before radiotherapy)
description: Number of patients with an increased of at least 2.5% in the Global Longitudinal Strain (GLS) between baseline and 2 years after radiotherapy
measure: Changes in myocardial function measurements assessed by echocardiography
time frame: 6 months and 2 years after radiotherapy (baseline measurements performed before radiotherapy)
description: Increase of the segmental strain measurements (unit of measures:%)
measure: Anatomical changes in coronary arteries assessed by cardiac CT
time frame: 2 years after radiotherapy (baseline measurements performed before radiotherapy)
description: Increase of the number of coronary segments containing any plaque or increase of the calcium score
measure: Myocardial tissue abnormalities assessed by cardiac MRI
time frame: 6 months and 2 years after radiotherapy (baseline measurements performed before radiotherapy)
description: Increase of the native mean myocardial T1 mapping value
measure: Changes in circulating biomarkers measurements
time frame: at the end of radiotherapy (through radiotherapy completion, an average of 5 weeks after starting date of radiotherapy), 6 months and 2 years after radiotherapy (baseline measurements performed before radiotherapy)
description: Significant increase or decrease in the following biomarkers:
classical biomarkers of cardiac injury (C-reactive protein, Troponin I, Troponin T, B-type natriuretic peptide (BNP), N-terminal pro-brain natriuretic peptide (NT-Pro BNP), beta2-Microglobulin, Galectin 3); Inflammatory cytokines; biomarkers of endothelial activation and dysfunction; Microparticles; MicroRNAs; circulating DNA methylation
arm group label: Breast cancer patients treated with RT
arm group type: Other
description: Cardiac imaging and circulating biomarkers measurements to evaluate:
myocardial dysfunction and deformation (ECHO-ST)
coronary artery lesions and coronary artery calcium score (CT)
myocardium including tissue abnormalities, cardiac morphology and function (MRI)
blood-based biomarkers of cardiovascular changes (BLOOD)
intervention type: Other
intervention name: Cardiac imaging and circulating biomarkers
description: Automated 2D-speckle-tracking echocardiography (ECHO-ST); Computed tomography coronary angiography (CT); Cardiac magnetic resonance imaging (MRI); Blood samples for circulating biomarkers measurements (BLOOD)
arm group label: Breast cancer patients treated with RT
criteria: 
gender: Female
minimum age: 40 Years
maximum age: 75 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Sophie Jacob, PhD
role: Study Chair
affiliation: Institut de Radioprotection et de Sûreté Nucléaire
last name: Sophie Jacob, PhD
phone: +33561145608
email: sophie.jacob@irsn.fr
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Not yet recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
country: France
country: Germany
country: Netherlands
country: Portugal
country: Spain
responsible party type: Principal Investigator
investigator affiliation: Institut de Radioprotection et de Surete Nucleaire
investigator full name: Sophie JACOB
investigator title: PhD
mesh term: Breast Neoplasms
sharing ipd: No
provided document: 