xml: <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/NCT06033092</url>
    </required_header>
    <id_info>
      <org_study_id>UID 3751</org_study_id>
      <secondary_id>2023-503994-39-00</secondary_id>
      <nct_id>NCT06033092</nct_id>
    </id_info>
    <brief_title>Low Dose TamOxifen and LifestylE Changes for bReast cANcer prevenTion</brief_title>
    <acronym>TOLERANT</acronym>
    <official_title>Low Dose TamOxifen and LifestylE Changes for bReast cANcer prevenTion: a Randomized Phase II Biomarker Trial in Subjects at Increased Risk</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>European Institute of Oncology</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Ente Ospedaliero Ospedali Galliera</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>Istituto Oncologico Veneto IRCCS</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>Istituto Nazionale Tumori IRCCS - Fondazione G. Pascale</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>European Institute of Oncology</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        Circulating levels of Sex Hormone Binding Globulin (SHBG) are significantly associated with a&#xD;
        decreased risk of breast cancer.&#xD;
  &#xD;
        The main aim of this clinical trial is to verify whether Low Dose Tamoxifen (LDT) increases&#xD;
        circulating levels of SHBG more than lifestyle intervention (LI) with or without intermittent&#xD;
        caloric restriction (ICR) after 6 months in women at increased risk of breast cancer&#xD;
        (unaffected BRCA1-2 OR PALB2 mutation carriers; or with a &gt;5% risk of developing breast&#xD;
        cancer at 10 years according to the &quot;Tyrer-Cuzick model&quot;) or with a recently resected&#xD;
        intraepithelial neoplasia of the breast (IEN).&#xD;
  &#xD;
        The secondary aims are:&#xD;
  &#xD;
          -  to verify whether ICR significantly modulates primary and secondary endpoints such as&#xD;
             Homeostasis Model Assessment (HOMA) index, immune and inflammatory markers, lipid&#xD;
             profile, Adiponectin/Leptin (A/L) ratio, quality of life (QoL), Body mass index (BMI),&#xD;
             fat body composition, safety and toxicity;&#xD;
  &#xD;
          -  to verify whether LDT significantly modulates secondary endpoints, such as HOMA-index,&#xD;
             immune and inflammatory markers, lipid profile, A/L ratio, QoL, BMI, fat body&#xD;
             composition, safety and toxicity;&#xD;
  &#xD;
          -  to investigate differences in microbiome composition by arms and the effect of changes&#xD;
             in microbiome on QoL taking into account circulating biomarkers, cytokines, immune&#xD;
             modulators, and inflammatory proteins in serum;&#xD;
  &#xD;
          -  to investigate MD (Mammographic Breast Density) changes by LDT vs. LI, with or without&#xD;
             ICR. This aim will be performed in a subgroup of participants (not all the participants&#xD;
             will undergo mammography due to younger age).&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Italian, multicenter, phase II, biomarker trial. A total of 200 women aged 18-70 years will&#xD;
        be randomly assigned (1:1:1:1) to one of the four intervention arms Arm 1: Low dose Tamoxifen&#xD;
        (LDT) i.e. 10 mg every other day; Arm 2: Low dose Tamoxifen (LDT) + Intermittent Caloric&#xD;
        Restriction (ICR); Arm 3: Lifestyle intervention (LI) using a step counter; Arm 4: Lifestyle&#xD;
        intervention (LI) using a step counter + Intermittent Caloric Restriction (ICR).&#xD;
  &#xD;
        Participants will be stratified by center and by disease status (high risk vs. previous IEN)&#xD;
        and intervention will last six months for all arms.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">September 1, 2023</start_date>
    <completion_date type="Anticipated">July 31, 2026</completion_date>
    <primary_completion_date type="Anticipated">July 31, 2025</primary_completion_date>
    <phase>Phase 2</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>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Post intervention levels of circulating binding globulin</measure>
      <time_frame>Through study completion, an average of 6 months</time_frame>
      <description>Sex hormone binding globulin level after 6 months of intervention</description>
    </primary_outcome>
    <number_of_arms>4</number_of_arms>
    <enrollment type="Anticipated">200</enrollment>
    <condition>BRCA Mutation</condition>
    <condition>PALB2 Gene Mutation</condition>
    <condition>Ductal Carcinoma in Situ</condition>
    <condition>Lobular Carcinoma in Situ</condition>
    <arm_group>
      <arm_group_label>Low dose tamoxifen</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Tamoxifen 10 mg (1 tablet) every other day for 6 months.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Low dose tamoxifen + Intermittent Caloric Restriction</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Tamoxifen 10 mg (1 tablet) every other day for 6 months + 5:2 diet (5 days/week at regular energy intake+2 days a week at an average 75% energy deficit)</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Lifestyle intervention</arm_group_label>
      <arm_group_type>Placebo Comparator</arm_group_type>
      <description>Step counter device</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Lifestyle Intervention + Intermittent Caloric Restriction</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Step counter device + 5:2 diet (5 days/week at regular energy intake+2 days a week at an average 75% energy deficit)</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Tamoxifen 10 Mg Tablet</intervention_name>
      <description>One tablet of Tamoxifen 10 mg every other day for 6 months</description>
      <arm_group_label>Low dose tamoxifen</arm_group_label>
      <arm_group_label>Low dose tamoxifen + Intermittent Caloric Restriction</arm_group_label>
      <other_name>Low dose tamoxifen</other_name>
    </intervention>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>Intermittent caloric restriction</intervention_name>
      <description>&quot;5:2 diet&quot;: 5 days a week at regular energy intake and 2 days/week at 75% energy deficit (diet will be restricted at 500-800 kcal corresponding to a 75% reduction compared to normal size)</description>
      <arm_group_label>Lifestyle Intervention + Intermittent Caloric Restriction</arm_group_label>
      <arm_group_label>Low dose tamoxifen + Intermittent Caloric Restriction</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Behavioral</intervention_type>
      <intervention_name>Step counter Device</intervention_name>
      <description>Participants will receive personal advice on healthy lifestyle and a step counter</description>
      <arm_group_label>Lifestyle Intervention + Intermittent Caloric Restriction</arm_group_label>
      <arm_group_label>Lifestyle intervention</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            1. Women between 18 and 70 years old;&#xD;
  &#xD;
            2. Healthy participants carriers of a germline pathogenic/likely pathogenetic variant&#xD;
               (BRCA1 or BRCA2 or PALB2), or&#xD;
  &#xD;
               with a &gt; 5% risk of developing breast cancer at 10 years according to the&#xD;
               &quot;Tyrer-Cuzick model&quot;, or&#xD;
  &#xD;
               with a previous diagnosis of intraepithelial neoplasia of the breast (atypical ductal&#xD;
               hyperplasia (ADH), lobular carcinoma in situ (LCIS), estrogen receptor (ER) positive&#xD;
               ductal carcinoma in situ (DCIS)) within the last 3 years;&#xD;
  &#xD;
            3. Ability to understand and the willingness to sign a written informed consent document;&#xD;
  &#xD;
            4. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1;&#xD;
  &#xD;
          5a. For high-risk strata: A negative mammogram or any radiological image based on age and&#xD;
          center protocol screening within 6 months before baseline visit;&#xD;
  &#xD;
          5b. For IEN Strata: A negative mammogram within 12 months before baseline visit&#xD;
  &#xD;
          6. A negative transvaginal ultrasound within 6 months before baseline visit.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            1. Diagnosis of ER-negative (&lt;10%) DCIS, or history of invasive breast cancer;&#xD;
  &#xD;
            2. Previous treatment with selective estrogen receptor modulators (SERMs) or any other&#xD;
               hormonal treatment for breast neoplasms;&#xD;
  &#xD;
            3. BMI &lt; 18.5 Kg/m2 and/or Malnutrition Universal Screening Tool (MUST) score ≥2 and/or&#xD;
               any current or past eating disorders;&#xD;
  &#xD;
            4. Any diagnosis of invasive neoplasia, except non-melanoma skin cancer, in the previous&#xD;
               5 years;&#xD;
  &#xD;
            5. Any tamoxifen contraindications (abnormal liver function, previous ischemic heart&#xD;
               disease, endometrial disorder, previous deep venous thrombosis, history of pulmonary&#xD;
               embolus, current or suspected glaucoma, retinopathy, and cataract);&#xD;
  &#xD;
            6. Current use of warfarin or other anticoagulant drugs&#xD;
  &#xD;
            7. Bilateral mastectomy;&#xD;
  &#xD;
            8. Pregnancy or desire to become pregnant in the subsequent 9 months after treatment&#xD;
               cessation;&#xD;
  &#xD;
            9. Diabetes or any other clinical condition that, at the investigator's discretion,&#xD;
               contraindicates the proposed intervention.&#xD;
  &#xD;
           10. No hormonal contraception is allowed during study intervention. Non-hormonal methods&#xD;
               will be advised for women of childbearing potential (WOCBP).&#xD;
        </textblock>
      </criteria>
      <gender>Female</gender>
      <gender_based>Yes</gender_based>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>70 Years</maximum_age>
      <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Bernardo Bonanni, MD</last_name>
      <role>Principal Investigator</role>
      <affiliation>Istituto Europeo di Oncologia</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Bernardo Bonanni, MD</last_name>
      <phone>+39025749022</phone>
      <email>bernardo.bonanni@ieo.it</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Aliana Guerrieri-Gonzaga, MSc</last_name>
      <phone>+390257489893</phone>
      <email>aliana.guerrierigonzaga@ieo.it</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>E.O. Galliera</name>
        <address>
          <city>Genoa</city>
          <country>Italy</country>
        </address>
      </facility>
      <contact>
        <last_name>Andrea DeCensi, MD</last_name>
        <email>andrea.decensi@galliera.it</email>
      </contact>
    </location>
    <location>
      <facility>
        <name>Istituto Europeo di Oncologia</name>
        <address>
          <city>Milan</city>
          <zip>20141</zip>
          <country>Italy</country>
        </address>
      </facility>
      <contact>
        <last_name>Bernardo Bonanni, MD</last_name>
        <phone>+390257489022</phone>
        <email>bernardo.bonanni@ieo.it</email>
      </contact>
    </location>
    <location>
      <facility>
        <name>Istituto Nazionale Tumori G. Pascale</name>
        <address>
          <city>Napoli</city>
          <country>Italy</country>
        </address>
      </facility>
      <contact>
        <last_name>Matilde Pensabene, MD</last_name>
        <email>m.pensabene@istitutotumori.na.it</email>
      </contact>
    </location>
    <location>
      <facility>
        <name>Istituto Oncologico Veneto</name>
        <address>
          <city>Padova</city>
          <country>Italy</country>
        </address>
      </facility>
      <contact>
        <last_name>Stefania Zovato, MD</last_name>
        <email>stefania.zovato@iov.veneto.it</email>
      </contact>
    </location>
    <location_countries>
      <country>Italy</country>
    </location_countries>
    <verification_date>July 2023</verification_date>
    <study_first_submitted>August 23, 2023</study_first_submitted>
    <study_first_submitted_qc>September 11, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 13, 2023</study_first_posted>
    <last_update_submitted>September 11, 2023</last_update_submitted>
    <last_update_submitted_qc>September 11, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 13, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <keyword>Low Dose Tamoxifen</keyword>
    <keyword>Intermittent Caloric Restriction</keyword>
    <keyword>Sex Hormone Binding Globulin</keyword>
    <keyword>Lifestyle</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Carcinoma</mesh_term>
      <mesh_term>Carcinoma in Situ</mesh_term>
      <mesh_term>Carcinoma, Ductal</mesh_term>
      <mesh_term>Carcinoma, Intraductal, Noninfiltrating</mesh_term>
      <mesh_term>Carcinoma, Lobular</mesh_term>
      <mesh_term>Breast Carcinoma In Situ</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Tamoxifen</mesh_term>
    </intervention_browse>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06033092
  org study id: UID 3751
  secondary id: 2023-503994-39-00
  nct id: NCT06033092
  lead sponsor: 
  collaborator: 
  collaborator: 
  collaborator: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  Circulating levels of Sex Hormone Binding Globulin (SHBG) are significantly associated with a
        decreased risk of breast cancer.
  
        The main aim of this clinical trial is to verify whether Low Dose Tamoxifen (LDT) increases
        circulating levels of SHBG more than lifestyle intervention (LI) with or without intermittent
        caloric restriction (ICR) after 6 months in women at increased risk of breast cancer
        (unaffected BRCA1-2 OR PALB2 mutation carriers; or with a >5% risk of developing breast
        cancer at 10 years according to the "Tyrer-Cuzick model") or with a recently resected
        intraepithelial neoplasia of the breast (IEN).
  
        The secondary aims are:
  
          -  to verify whether ICR significantly modulates primary and secondary endpoints such as
             Homeostasis Model Assessment (HOMA) index, immune and inflammatory markers, lipid
             profile, Adiponectin/Leptin (A/L) ratio, quality of life (QoL), Body mass index (BMI),
             fat body composition, safety and toxicity;
  
          -  to verify whether LDT significantly modulates secondary endpoints, such as HOMA-index,
             immune and inflammatory markers, lipid profile, A/L ratio, QoL, BMI, fat body
             composition, safety and toxicity;
  
          -  to investigate differences in microbiome composition by arms and the effect of changes
             in microbiome on QoL taking into account circulating biomarkers, cytokines, immune
             modulators, and inflammatory proteins in serum;
  
          -  to investigate MD (Mammographic Breast Density) changes by LDT vs. LI, with or without
             ICR. This aim will be performed in a subgroup of participants (not all the participants
             will undergo mammography due to younger age).
  Italian, multicenter, phase II, biomarker trial. A total of 200 women aged 18-70 years will
        be randomly assigned (1:1:1:1) to one of the four intervention arms Arm 1: Low dose Tamoxifen
        (LDT) i.e. 10 mg every other day; Arm 2: Low dose Tamoxifen (LDT) + Intermittent Caloric
        Restriction (ICR); Arm 3: Lifestyle intervention (LI) using a step counter; Arm 4: Lifestyle
        intervention (LI) using a step counter + Intermittent Caloric Restriction (ICR).
  
        Participants will be stratified by center and by disease status (high risk vs. previous IEN)
        and intervention will last six months for all arms.
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Prevention
  masking: None (Open Label)
  measure: Post intervention levels of circulating binding globulin
  time frame: Through study completion, an average of 6 months
  description: Sex hormone binding globulin level after 6 months of intervention
  arm group label: Low dose tamoxifen
  arm group type: Active Comparator
  description: Tamoxifen 10 mg (1 tablet) every other day for 6 months.
  arm group label: Low dose tamoxifen + Intermittent Caloric Restriction
  arm group type: Active Comparator
  description: Tamoxifen 10 mg (1 tablet) every other day for 6 months + 5:2 diet (5 days/week at regular energy intake+2 days a week at an average 75% energy deficit)
  arm group label: Lifestyle intervention
  arm group type: Placebo Comparator
  description: Step counter device
  arm group label: Lifestyle Intervention + Intermittent Caloric Restriction
  arm group type: Active Comparator
  description: Step counter device + 5:2 diet (5 days/week at regular energy intake+2 days a week at an average 75% energy deficit)
  intervention type: Drug
  intervention name: Tamoxifen 10 Mg Tablet
  description: One tablet of Tamoxifen 10 mg every other day for 6 months
  arm group label: Low dose tamoxifen
  arm group label: Low dose tamoxifen + Intermittent Caloric Restriction
  other name: Low dose tamoxifen
  intervention type: Other
  intervention name: Intermittent caloric restriction
  description: "5:2 diet": 5 days a week at regular energy intake and 2 days/week at 75% energy deficit (diet will be restricted at 500-800 kcal corresponding to a 75% reduction compared to normal size)
  arm group label: Lifestyle Intervention + Intermittent Caloric Restriction
  arm group label: Low dose tamoxifen + Intermittent Caloric Restriction
  intervention type: Behavioral
  intervention name: Step counter Device
  description: Participants will receive personal advice on healthy lifestyle and a step counter
  arm group label: Lifestyle Intervention + Intermittent Caloric Restriction
  arm group label: Lifestyle intervention
  criteria: 
  gender: Female
  gender based: Yes
  minimum age: 18 Years
  maximum age: 70 Years
  healthy volunteers: Accepts Healthy Volunteers
  last name: Bernardo Bonanni, MD
  role: Principal Investigator
  affiliation: Istituto Europeo di Oncologia
  last name: Bernardo Bonanni, MD
  phone: +39025749022
  email: bernardo.bonanni@ieo.it
  last name: Aliana Guerrieri-Gonzaga, MSc
  phone: +390257489893
  email: aliana.guerrierigonzaga@ieo.it
  facility: 
  contact: 
  facility: 
  contact: 
  facility: 
  contact: 
  facility: 
  contact: 
  country: Italy
  responsible party type: Sponsor
  mesh term: Carcinoma
  mesh term: Carcinoma in Situ
  mesh term: Carcinoma, Ductal
  mesh term: Carcinoma, Intraductal, Noninfiltrating
  mesh term: Carcinoma, Lobular
  mesh term: Breast Carcinoma In Situ
  mesh term: Tamoxifen