<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/NCT03785782</url>
  </required_header>
  <id_info>
    <org_study_id>LCCC1745</org_study_id>
    <nct_id>NCT03785782</nct_id>
  </id_info>
  <brief_title>ARFI, VisR and DDAI Ultrasound for Improving Discrimination of Malignant and Unresponsive Breast Cancer</brief_title>
  <official_title>ARFI, VisR and DDAI Ultrasound for Improving Discrimination of Malignant and Unresponsive Breast Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>UNC Lineberger Comprehensive Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>UNC Lineberger Comprehensive Cancer Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_unapproved_device>Yes</is_unapproved_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Purpose: The purpose of this study is to evaluate in vivo the diagnostic relevance of&#xD;
      ultrasound-derived metrics for stiffness, elasticity, viscosity, and anisotropy.&#xD;
&#xD;
      Participants: Forty women with breast lesions that have a BIRADS-4 or BIRADS-5 rating and&#xD;
      forty women undergoing neoadjuvant chemotherapy (NAC) for malignant breast lesions will be&#xD;
      recruited. Subjects will be recruited from the Breast Imaging Division of UNC Hospitals.&#xD;
&#xD;
      Procedures (methods): In this exploratory clinical study, the investigators will attempt to&#xD;
      demonstrate that ARFI, VisR, and DDAI ultrasound reliably detect malignant breast masses (Aim&#xD;
      #1) and distinguish masses that respond to chemotherapy from those that do not (Aim #2). The&#xD;
      ARFI, VisR, and DDAI imaging location will be on the surface of the breast, above the&#xD;
      suspicious or malignant mass. This unblinded, open-label, exploratory study will be conducted&#xD;
      in 40 women with diagnosed BIRADS-4 or -5 masses in Aim #1 and in 40 women with malignant&#xD;
      masses undergoing neoadjuvant chemotherapy (NAC) in Aim #2.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The primary objective of breast cancer screening is to identify early stage cancer, or&#xD;
      precancerous lesions, at a time before symptoms emerge and when treatment is likely to result&#xD;
      in a cure. Screening is beneficial when it averts progression of disease to metastasis and/or&#xD;
      death, but adverse effects to patients (and unnecessary medical expense) may result&#xD;
      downstream from false positives and indiscrimination of masses that will not respond to&#xD;
      treatment. The sensitivity of digital mammography, the current screening standard in the US,&#xD;
      has been reported in the range of 0.40 to 0.85, with a positive predictive value of 0.31.&#xD;
      Sensitivity is increased by augmenting mammography with MRI and B-Mode ultrasound, but false&#xD;
      positive rates may also increase3. There exists a vital need for a screening technology that&#xD;
      exhibits high sensitivity and specificity for cancer detection with early identification of&#xD;
      unresponsive masses.&#xD;
&#xD;
      This urgent need could be met by exploiting new imaging biomarkers. Specifically, the&#xD;
      mechanical properties of breast tissue have been used for cancer detection, with both&#xD;
      elasticity and viscosity demonstrated for discriminating malignant from benign lesions.&#xD;
      Further, tissue anisotropy has been shown to correlate with core biopsy result and tumor&#xD;
      grade, with large cancers significantly more anisotropic than small cancers. Importantly,&#xD;
      while both MRI and ultrasound can be used to measure these biomarkers, ultrasound's cost&#xD;
      effectiveness and ease of implementation render it an efficient platform to pursue.&#xD;
&#xD;
      The long-term goal of this research program is to develop a new ultrasound-based&#xD;
      breast-screening tool to augment mammography. As a critical first step toward achieving this&#xD;
      goal, the primary objective of the proposed research is to evaluate in vivo the diagnostic&#xD;
      relevance of ultrasound-derived metrics for stiffness, elasticity, viscosity, and anisotropy.&#xD;
      These biomarkers will be measured using novel, noninvasive ultrasound technologies under&#xD;
      development in Dr. Gallippi's laboratory: 1) Acoustic Radiation Force Impulse (ARFI)&#xD;
      ultrasound for interrogating tissue stiffness, 2) Viscoelastic Response (VisR) ultrasound for&#xD;
      assessing tissue elasticity and viscosity, and 3) Dynamic Displacement Anisotropy Imaging&#xD;
      (DDAI) for measuring tissue anisotropy. These technologies have been demonstrated previously&#xD;
      for delineating atherosclerosis, muscular dystrophy, and renal dysfunction.&#xD;
&#xD;
      A.1.2.State the research question(s) (i.e., specific study aims and/or hypotheses).&#xD;
&#xD;
      The investigators hypothesize that ultrasound-derived stiffness, elasticity, viscosity, and&#xD;
      anisotropy will correlate with lesion malignancy and response to treatment. To test this&#xD;
      hypothesis, they will pursue the following specific aims:&#xD;
&#xD;
      Aim #1: Quantify the ability of ultrasound-derived stiffness, elasticity, viscosity, and&#xD;
      anisotropy to detect malignancy. ARFI, VisR, and DDAI imaging will be performed on suspicious&#xD;
      breast lesions in 40 women with BIRADS-4a, 4b, 4c, or -5 ratings. The diagnostic accuracy of&#xD;
      imaging metrics will analyzed, with malignancy confirmed by histology as the outcome.&#xD;
&#xD;
      Aim #2: Quantify the ability of ultrasound-derived stiffness, elasticity, viscosity, and&#xD;
      anisotropy to predict a positive response to treatment. ARFI, VisR, and DDAI imaging will be&#xD;
      performed serially - once every four weeks over the course of neoadjuvant chemotherapy (NAC)&#xD;
      - on malignant breast lesions in 40 women. Changes in outcome metrics over time will be&#xD;
      correlated to overall reduction in tumor size (diameter and area). The ability of ultrasound&#xD;
      metrics to predict a positive response to treatment will be examined. A positive response to&#xD;
      treatment will be determined according to the Response Evaluation Criteria in Solid Tumors&#xD;
      (RECIST) guidelines.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 10, 2018</start_date>
  <completion_date type="Actual">July 15, 2021</completion_date>
  <primary_completion_date type="Actual">July 15, 2021</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Correlation of ultrasound metrics for detecting malignancy. (no units)</measure>
    <time_frame>1 year</time_frame>
    <description>The correlation of each ultrasound metric will be analyzed by constructing separate receiver operating characteristic (ROC) curves. The ultrasound data will be processed to calculate the following outcome metrics: peak displacement (PD), displacement at a given time (TD) for ARFI; τ, relative elasticity (RE), relative viscosity (RV), and tissue mass (TM) for VisR; ratio of ARFI PD and ratio of VisR RE values at 90o versus 0o transducer orientations for DDAI. These eight outcome metrics, alone and in combinations, will be statistically correlated with biopsy finding of malignant or benign.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Correlate ultrasound metrics to predict response to neoadjuvant chemotherapy. (no units)</measure>
    <time_frame>1 year</time_frame>
    <description>The ultrasound data will be processed to calculate the following outcome metrics: peak displacement (PD), displacement at a given time (TD) for ARFI; τ, relative elasticity (RE), relative viscosity (RV), and tissue mass (TM) for VisR; ratio of ARFI PD and ratio of VisR RE values at 90o versus 0o transducer orientations for DDAI. These eight outcome metrics, alone and in combinations, will be statistically correlated to response of treatment with neoadjuvant chemotherapy.</description>
  </primary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">45</enrollment>
  <condition>Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Women scheduled for biopsy</arm_group_label>
    <description>40 participants with diagnosed BIRADS-4a, 4b, 4c, or -5 masses will be recruited. The investigators aim to have approximately 10 in each of the BIRADS categories (4a, 4b, 4c, 5), resulting in 40 total subjects for Aim #1.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Women scheduled for neoadjuvant chemo</arm_group_label>
    <description>40 participants with malignant masses undergoing neoadjuvant chemotherapy (NAC) will be recruited.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Ultrasound</intervention_name>
    <description>Breast ultrasound</description>
    <arm_group_label>Women scheduled for biopsy</arm_group_label>
    <arm_group_label>Women scheduled for neoadjuvant chemo</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Forty women with breast lesions that have a BIRADS-4 or BIRADS-5 rating and forty women&#xD;
        undergoing neoadjuvant chemotherapy (NAC) for malignant breast lesions will be recruited.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        -&#xD;
&#xD;
        Aim 1:&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients are 30-90 years of age&#xD;
&#xD;
          -  Patients have breast masses with BIRADS 4a, 4b, 4c, or 5 rating&#xD;
&#xD;
          -  Lesion is sonographically visible with B-Mode ultrasound on diagnostic workup&#xD;
&#xD;
          -  Informed consent obtained and signed&#xD;
&#xD;
        Aim 2:&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients are 30-90 years&#xD;
&#xD;
          -  Patients who are or will be undergoing neoadjuvant chemotherapy (NAC) for stage 2 or 3&#xD;
             malignant breast lesions&#xD;
&#xD;
          -  Lesion is sonographically visible with B-Mode ultrasound on diagnostic workup&#xD;
&#xD;
          -  Informed consent is obtained and signed&#xD;
&#xD;
        Exclusion Criteria: Subjects who meet any of the exclusion criteria will be excluded from&#xD;
        study participation for both Aim 1 and Aim 2.&#xD;
&#xD;
          -  Inability to provide informed consent&#xD;
&#xD;
          -  Inability to communicate in English&#xD;
&#xD;
          -  Inability to remain motionless for 15 minutes&#xD;
&#xD;
          -  Suspicious or malignant breast mass deeper than 3 cm from skin surface&#xD;
&#xD;
          -  Previous biopsy or surgery to the site of the suspicious or malignant mass&#xD;
&#xD;
          -  Patients who are pregnant&#xD;
&#xD;
          -  Patients who are lactating&#xD;
&#xD;
          -  Patients with a history of masectomy&#xD;
&#xD;
          -  Patients with breast implants&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Female only</gender_description>
    <minimum_age>30 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Caterina Gallippi, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of North Carolina</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of North Carolina</name>
      <address>
        <city>Chapel Hill</city>
        <state>North Carolina</state>
        <zip>27599</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2021</verification_date>
  <study_first_submitted>December 14, 2018</study_first_submitted>
  <study_first_submitted_qc>December 19, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 24, 2018</study_first_posted>
  <last_update_submitted>July 16, 2021</last_update_submitted>
  <last_update_submitted_qc>July 16, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">July 19, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Screening</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>Undecided</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>April 27, 2022</submitted>
    <returned>January 27, 2023</returned>
    <submitted>February 1, 2023</submitted>
  </pending_results>
  <!-- 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/NCT03785782
org study id: LCCC1745
nct id: NCT03785782
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: Yes
is unapproved device: Yes
is us export: No
Purpose: The purpose of this study is to evaluate in vivo the diagnostic relevance of
      ultrasound-derived metrics for stiffness, elasticity, viscosity, and anisotropy.

      Participants: Forty women with breast lesions that have a BIRADS-4 or BIRADS-5 rating and
      forty women undergoing neoadjuvant chemotherapy (NAC) for malignant breast lesions will be
      recruited. Subjects will be recruited from the Breast Imaging Division of UNC Hospitals.

      Procedures (methods): In this exploratory clinical study, the investigators will attempt to
      demonstrate that ARFI, VisR, and DDAI ultrasound reliably detect malignant breast masses (Aim
      #1) and distinguish masses that respond to chemotherapy from those that do not (Aim #2). The
      ARFI, VisR, and DDAI imaging location will be on the surface of the breast, above the
      suspicious or malignant mass. This unblinded, open-label, exploratory study will be conducted
      in 40 women with diagnosed BIRADS-4 or -5 masses in Aim #1 and in 40 women with malignant
      masses undergoing neoadjuvant chemotherapy (NAC) in Aim #2.
The primary objective of breast cancer screening is to identify early stage cancer, or
      precancerous lesions, at a time before symptoms emerge and when treatment is likely to result
      in a cure. Screening is beneficial when it averts progression of disease to metastasis and/or
      death, but adverse effects to patients (and unnecessary medical expense) may result
      downstream from false positives and indiscrimination of masses that will not respond to
      treatment. The sensitivity of digital mammography, the current screening standard in the US,
      has been reported in the range of 0.40 to 0.85, with a positive predictive value of 0.31.
      Sensitivity is increased by augmenting mammography with MRI and B-Mode ultrasound, but false
      positive rates may also increase3. There exists a vital need for a screening technology that
      exhibits high sensitivity and specificity for cancer detection with early identification of
      unresponsive masses.

      This urgent need could be met by exploiting new imaging biomarkers. Specifically, the
      mechanical properties of breast tissue have been used for cancer detection, with both
      elasticity and viscosity demonstrated for discriminating malignant from benign lesions.
      Further, tissue anisotropy has been shown to correlate with core biopsy result and tumor
      grade, with large cancers significantly more anisotropic than small cancers. Importantly,
      while both MRI and ultrasound can be used to measure these biomarkers, ultrasound's cost
      effectiveness and ease of implementation render it an efficient platform to pursue.

      The long-term goal of this research program is to develop a new ultrasound-based
      breast-screening tool to augment mammography. As a critical first step toward achieving this
      goal, the primary objective of the proposed research is to evaluate in vivo the diagnostic
      relevance of ultrasound-derived metrics for stiffness, elasticity, viscosity, and anisotropy.
      These biomarkers will be measured using novel, noninvasive ultrasound technologies under
      development in Dr. Gallippi's laboratory: 1) Acoustic Radiation Force Impulse (ARFI)
      ultrasound for interrogating tissue stiffness, 2) Viscoelastic Response (VisR) ultrasound for
      assessing tissue elasticity and viscosity, and 3) Dynamic Displacement Anisotropy Imaging
      (DDAI) for measuring tissue anisotropy. These technologies have been demonstrated previously
      for delineating atherosclerosis, muscular dystrophy, and renal dysfunction.

      A.1.2.State the research question(s) (i.e., specific study aims and/or hypotheses).

      The investigators hypothesize that ultrasound-derived stiffness, elasticity, viscosity, and
      anisotropy will correlate with lesion malignancy and response to treatment. To test this
      hypothesis, they will pursue the following specific aims:

      Aim #1: Quantify the ability of ultrasound-derived stiffness, elasticity, viscosity, and
      anisotropy to detect malignancy. ARFI, VisR, and DDAI imaging will be performed on suspicious
      breast lesions in 40 women with BIRADS-4a, 4b, 4c, or -5 ratings. The diagnostic accuracy of
      imaging metrics will analyzed, with malignancy confirmed by histology as the outcome.

      Aim #2: Quantify the ability of ultrasound-derived stiffness, elasticity, viscosity, and
      anisotropy to predict a positive response to treatment. ARFI, VisR, and DDAI imaging will be
      performed serially - once every four weeks over the course of neoadjuvant chemotherapy (NAC)
      - on malignant breast lesions in 40 women. Changes in outcome metrics over time will be
      correlated to overall reduction in tumor size (diameter and area). The ability of ultrasound
      metrics to predict a positive response to treatment will be examined. A positive response to
      treatment will be determined according to the Response Evaluation Criteria in Solid Tumors
      (RECIST) guidelines.
observational model: Cohort
time perspective: Prospective
measure: Correlation of ultrasound metrics for detecting malignancy. (no units)
time frame: 1 year
description: The correlation of each ultrasound metric will be analyzed by constructing separate receiver operating characteristic (ROC) curves. The ultrasound data will be processed to calculate the following outcome metrics: peak displacement (PD), displacement at a given time (TD) for ARFI; τ, relative elasticity (RE), relative viscosity (RV), and tissue mass (TM) for VisR; ratio of ARFI PD and ratio of VisR RE values at 90o versus 0o transducer orientations for DDAI. These eight outcome metrics, alone and in combinations, will be statistically correlated with biopsy finding of malignant or benign.
measure: Correlate ultrasound metrics to predict response to neoadjuvant chemotherapy. (no units)
time frame: 1 year
description: The ultrasound data will be processed to calculate the following outcome metrics: peak displacement (PD), displacement at a given time (TD) for ARFI; τ, relative elasticity (RE), relative viscosity (RV), and tissue mass (TM) for VisR; ratio of ARFI PD and ratio of VisR RE values at 90o versus 0o transducer orientations for DDAI. These eight outcome metrics, alone and in combinations, will be statistically correlated to response of treatment with neoadjuvant chemotherapy.
arm group label: Women scheduled for biopsy
description: 40 participants with diagnosed BIRADS-4a, 4b, 4c, or -5 masses will be recruited. The investigators aim to have approximately 10 in each of the BIRADS categories (4a, 4b, 4c, 5), resulting in 40 total subjects for Aim #1.
arm group label: Women scheduled for neoadjuvant chemo
description: 40 participants with malignant masses undergoing neoadjuvant chemotherapy (NAC) will be recruited.
intervention type: Device
intervention name: Ultrasound
description: Breast ultrasound
arm group label: Women scheduled for biopsy
arm group label: Women scheduled for neoadjuvant chemo
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: Female
gender based: Yes
gender description: Female only
minimum age: 30 Years
maximum age: 90 Years
healthy volunteers: No
last name: Caterina Gallippi, PhD
role: Principal Investigator
affiliation: University of North Carolina
facility: 
country: United States
responsible party type: Sponsor
mesh term: Breast Neoplasms
sharing ipd: Undecided
submitted: April 27, 2022
returned: January 27, 2023
submitted: February 1, 2023