<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/NCT02967458</url>
  </required_header>
  <id_info>
    <org_study_id>15F.607</org_study_id>
    <secondary_id>R21CA202214</secondary_id>
    <nct_id>NCT02967458</nct_id>
  </id_info>
  <brief_title>Detection of High Grade Prostate Cancer With Subharmonic Ultrasound Imaging, A Pilot Study</brief_title>
  <official_title>Detection of High Grade Prostate Cancer With Subharmonic Ultrasound Imaging, A Pilot Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Thomas Jefferson University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Thomas Jefferson University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a phase II single center study using contrast-enhanced ultrasound to identify&#xD;
      aggressive forms of prostate cancer with subharmonic imaging.&#xD;
&#xD;
      The following are the study objectives:&#xD;
&#xD;
        1. To implement subharmonic imaging technology on a transrectal probe suitable for prostate&#xD;
           imaging and biopsy&#xD;
&#xD;
        2. To demonstrate visualization of prostatic vascularity using subharmonic&#xD;
           contrast-enhanced imaging.&#xD;
&#xD;
        3. To provide a preliminary estimate of the diagnostic accuracy of contrast-enhanced&#xD;
           subharmonic imaging for detection of clinically significant PCa.&#xD;
&#xD;
      The study will include 50 subjects who are scheduled for prostate biopsy. Each subject will&#xD;
      receive an intravenous infusion of microbubble contrast material immediately prior to a&#xD;
      prostate biopsy procedure. The study will demonstrate whether subharmonic imaging with a&#xD;
      microbubble contrast agent allows for detection of clinically significant prostate cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background: Prostate cancer (PCa) is the most frequently diagnosed cancer among American&#xD;
      males, accounting for 27 % of new cancer diagnoses, but it is directly responsible for only&#xD;
      9.5 % of cancer related deaths. Two recently published clinical trials suggest that&#xD;
      overdiagnosis and overtreatment of potentially insignificant cancer is a major drawback of&#xD;
      prostate cancer screening, and point to the need for a more specific screening tool that can&#xD;
      identify clinically significant prostate cancer. The US-based Prostate, Lung, Colorectal, and&#xD;
      Ovarian (PLCO) Cancer Screening Trial failed to show a mortality benefit from screening and&#xD;
      treatment of prostate cancer. The European Randomized Study of Screening for Prostate Cancer&#xD;
      (ERSPC) suggests that with the current standard of care, 1410 men must be screened and 48&#xD;
      additional cases of prostate cancer treated to prevent one death from prostate cancer. Based&#xD;
      upon these trials, the U.S. Preventive Services Task Force (USPSTF) has issued a grade &quot;D&quot;&#xD;
      recommendation against PSA-based screening for PCa.&#xD;
&#xD;
      Contrast-Enhanced Ultrasound: Recent studies have demonstrated that contrast-enhanced&#xD;
      harmonic imaging (HI) can identify enhancement related to vascular flow in higher grade PCa,&#xD;
      and that HI can selectively detect patients with &quot;clinically significant&quot; PCa that are most&#xD;
      likely to benefit from therapy. Subharmonic imaging (SHI) is a newer technology for&#xD;
      contrast-enhanced ultrasound imaging that provides a 10-fold improvement in the signal to&#xD;
      background ratio for visualization of small vascular structures, but has not been previously&#xD;
      implemented on a transrectal ultrasound probe. SHI of the prostate is expected to advance the&#xD;
      imaging of prostatic neovascularity and to improve selective biopsy of clinically significant&#xD;
      PCa.&#xD;
&#xD;
      Objective: To adapt SHI to a transrectal probe appropriate for prostate imaging and biopsy&#xD;
      (over the first 6 months of this study). The subsequent 18 month pilot clinical study will&#xD;
      enroll 50 participants who have a clinical indication for prostate biopsy to quantify SHI for&#xD;
      the detection of clinically significant PCa (defined as: Gleason score ≥ 7, a single core&#xD;
      with &gt; 50 % involvement, or &gt; 25 % of biopsy cores positive for PCa).&#xD;
&#xD;
      Approach: Each participant will undergo a transrectal ultrasound evaluation of the prostate&#xD;
      with conventional grayscale and color Doppler imaging, as well as contrast-enhanced imaging&#xD;
      with color Doppler, HI and SHI approaches. Imaging results from each of these techniques will&#xD;
      be recorded, but only the SHI findings will be used to guide a targeted biopsy of the&#xD;
      prostate. A maximum of 6 targeted biopsy cores will be obtained from each participant, based&#xD;
      upon suspicious areas identified with SHI. Following the targeted biopsy, each participant&#xD;
      will also receive a 12-part systematic biopsy consisting of 6 laterally directed biopsy cores&#xD;
      and 6 medially directed biopsy cores. The pilot study is designed to estimate the detection&#xD;
      of clinically significant cancer that will be obtained with targeted biopsy based upon SHI&#xD;
      along with the medially directed systematic sextant biopsy cores (≤ 12 cores total).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 1, 2017</start_date>
  <completion_date type="Actual">September 20, 2018</completion_date>
  <primary_completion_date type="Actual">February 1, 2018</primary_completion_date>
  <phase>Phase 2</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>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Percentage of Subjects Whose Prostate Cancer Was Detected With Subharmonic Imaging</measure>
    <time_frame>One week from baseline</time_frame>
    <description>The initial phase of the trial will develop and test subharmonic imaging to demonstrate enhanced visualization of prostate vascularity in all study participants. We will report the percentage of study subjects in whom visualization of prostate vascularity is increased with subharmonic imaging.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Percentage of Biopsy Cores in Which Prostate Cancer Was Detected Using Subharmonic Imaging</measure>
    <time_frame>One week from baseline</time_frame>
    <description>Study subjects will be scanned with subharmonic imaging during infusion of the microbubble contrast agent. Imaging results will be compared to pathology on prostate biopsy.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Percentage of Subjects With Previously Unidentified Prostate Cancer Using Magnetic Resonance Imaging</measure>
    <time_frame>One week from baseline</time_frame>
    <description>Study subjects will be scanned with subharmonic imaging during infusion of the microbubble contrast agent. Imaging results will be compared to pathology on prostate biopsy.</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">55</enrollment>
  <condition>Prostatic Neoplasm</condition>
  <arm_group>
    <arm_group_label>Prostate Biopsy Patients</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Fifty patients who are scheduled for a clinically indicated prostate biopsy, and who are able to undergo contrast enhanced transrectal ultrasound will be included in this single arm study. Each of the study subjects will receive in intravenous infusion of a microbubble contrast agent known as Definity™, (Perflutren Lipid Microsphere, Lantheus Medical Imaging, Inc; N. Billerica, MA). Based upon our previous experience, two vials of Perflutren Lipid Microsphere will be mixed and diluted in 50 ml of normal saline, yielding a concentration of 49.4 μl/ml. For the purpose of contrast-enhanced imaging, Perflutren Lipid Microsphere will be infused over approximately 10-12 minutes, during which time ultrasound imaging and biopsy will be performed.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Perflutren Lipid Microsphere Intravenous Suspension</intervention_name>
    <description>The intravenous administration of Perflutren Lipid Microsphere will provide enhancement of vascular tissue when performing subharmonic prostate ultrasound imaging. This enhancement will be used to guide targeted biopsy of the prostate to vascular areas which are more likely to contain aggressive prostate cancer.</description>
    <arm_group_label>Prostate Biopsy Patients</arm_group_label>
    <other_name>Definity™ (Lantheus Medical Imaging, Inc; N. Billerica, MA)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Subject must be scheduled for a clinically indicated needle biopsy of the prostate&#xD;
             based upon an elevated PSA, abnormal digital rectal examination, or based upon active&#xD;
             surveillance of prostate cancer.&#xD;
&#xD;
          2. Subject must be able and willing to give written informed consent for a contrast&#xD;
             enhanced ultrasound study of the prostate.&#xD;
&#xD;
          3. Subject must be a male at least 18 years of age when informed consent is obtained.&#xD;
&#xD;
          4. Subject must have a life expectancy that exceeds the duration of the clinical trial.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Participant in a clinical trial involving an investigational drug within the past 30&#xD;
             days.&#xD;
&#xD;
          2. Prior allergic reaction to the ultrasound contrast agent Definity™&#xD;
&#xD;
          3. Previous treatment for PCa.&#xD;
&#xD;
          4. Clinically unstable, severely ill, or moribund.&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ethan J Halpern, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Thomas Jefferson University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Flemming Forsberg, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Thomas Jefferson University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Thomas Jefferson University Hospital</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19107</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Halpern EJ, Gomella LG, Forsberg F, McCue PA, Trabulsi EJ. Contrast enhanced transrectal ultrasound for the detection of prostate cancer: a randomized, double-blind trial of dutasteride pretreatment. J Urol. 2012 Nov;188(5):1739-45. doi: 10.1016/j.juro.2012.07.021. Epub 2012 Sep 19.</citation>
    <PMID>22998915</PMID>
  </reference>
  <reference>
    <citation>Aigner F, Schafer G, Steiner E, Jaschke W, Horninger W, Herrmann TR, Nagele U, Halpern EJ, Frauscher F. Value of enhanced transrectal ultrasound targeted biopsy for prostate cancer diagnosis: a retrospective data analysis. World J Urol. 2012 Jun;30(3):341-6. doi: 10.1007/s00345-011-0809-6. Epub 2011 Dec 18.</citation>
    <PMID>22179312</PMID>
  </reference>
  <reference>
    <citation>Trabulsi EJ, Sackett D, Gomella LG, Halpern EJ. Enhanced transrectal ultrasound modalities in the diagnosis of prostate cancer. Urology. 2010 Nov;76(5):1025-33. doi: 10.1016/j.urology.2010.05.022. Epub 2010 Aug 16.</citation>
    <PMID>20719368</PMID>
  </reference>
  <reference>
    <citation>Nelson ED, Slotoroff CB, Gomella LG, Halpern EJ. Targeted biopsy of the prostate: the impact of color Doppler imaging and elastography on prostate cancer detection and Gleason score. Urology. 2007 Dec;70(6):1136-40. doi: 10.1016/j.urology.2007.07.067.</citation>
    <PMID>18158034</PMID>
  </reference>
  <reference>
    <citation>Linden RA, Trabulsi EJ, Forsberg F, Gittens PR, Gomella LG, Halpern EJ. Contrast enhanced ultrasound flash replenishment method for directed prostate biopsies. J Urol. 2007 Dec;178(6):2354-8. doi: 10.1016/j.juro.2007.08.022. Epub 2007 Oct 22.</citation>
    <PMID>17936814</PMID>
  </reference>
  <reference>
    <citation>Halpern EJ, Ramey JR, Strup SE, Frauscher F, McCue P, Gomella LG. Detection of prostate carcinoma with contrast-enhanced sonography using intermittent harmonic imaging. Cancer. 2005 Dec 1;104(11):2373-83. doi: 10.1002/cncr.21440.</citation>
    <PMID>16240450</PMID>
  </reference>
  <verification_date>April 2019</verification_date>
  <study_first_submitted>November 16, 2016</study_first_submitted>
  <study_first_submitted_qc>November 16, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 18, 2016</study_first_posted>
  <results_first_submitted>November 20, 2018</results_first_submitted>
  <results_first_submitted_qc>April 30, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">May 21, 2019</results_first_posted>
  <last_update_submitted>April 30, 2019</last_update_submitted>
  <last_update_submitted_qc>April 30, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">May 21, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>prostate cancer</keyword>
  <keyword>prostate ultrasound</keyword>
  <keyword>subharmonic imaging</keyword>
  <keyword>prostate biopsy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prostatic Neoplasms</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>December 1, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/58/NCT02967458/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Prostate Biopsy Patients</title>
          <description>Fifty five patients who are scheduled for a clinically indicated prostate biopsy, and who are able to undergo contrast enhanced transrectal ultrasound will be included in this single arm study. Each of the study subjects will receive in intravenous infusion of a microbubble contrast agent known as Definity™, (Perflutren Lipid Microsphere, Lantheus Medical Imaging, Inc; N. Billerica, MA). Based upon our previous experience, two vials of Perflutren Lipid Microsphere will be mixed and diluted in 50 ml of normal saline, yielding a concentration of 49.4 μl/ml. For the purpose of contrast-enhanced imaging, Perflutren Lipid Microsphere will be infused over approximately 10-12 minutes, during which time ultrasound imaging and biopsy will be performed.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="55"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="55"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Prostate Biopsy Patients</title>
          <description>Fifty patients who are scheduled for a clinically indicated prostate biopsy, and who are able to undergo contrast enhanced transrectal ultrasound will be included in this single arm study. Each of the study subjects will receive in intravenous infusion of a microbubble contrast agent known as Definity™, (Perflutren Lipid Microsphere, Lantheus Medical Imaging, Inc; N. Billerica, MA). Based upon our previous experience, two vials of Perflutren Lipid Microsphere will be mixed and diluted in 50 ml of normal saline, yielding a concentration of 49.4 μl/ml. For the purpose of contrast-enhanced imaging, Perflutren Lipid Microsphere will be infused over approximately 10-12 minutes, during which time ultrasound imaging and biopsy will be performed.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="55"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="26"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="29"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="55"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="53"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="42"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="55"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Percentage of Subjects Whose Prostate Cancer Was Detected With Subharmonic Imaging</title>
        <description>The initial phase of the trial will develop and test subharmonic imaging to demonstrate enhanced visualization of prostate vascularity in all study participants. We will report the percentage of study subjects in whom visualization of prostate vascularity is increased with subharmonic imaging.</description>
        <time_frame>One week from baseline</time_frame>
        <group_list>
          <group group_id="O1">
            <title>1Prostate Biopsy Patients</title>
            <description>Patients who are scheduled for a clinically indicated prostate biopsy, and who are able to undergo contrast enhanced transrectal ultrasound will be included in this single arm study. Each of the study subjects will receive in intravenous infusion of a microbubble contrast agent known as Definity™, (Perflutren Lipid Microsphere, Lantheus Medical Imaging, Inc; N. Billerica, MA). Based upon our previous experience, two vials of Perflutren Lipid Microsphere will be mixed and diluted in 50 ml of normal saline, yielding a concentration of 49.4 μl/ml. For the purpose of contrast-enhanced imaging&#xD;
Perflutren Lipid Microsphere Intravenous Suspension: The intravenous administration of Perflutren Lipid Microsphere will provide enhancement of vascular tissue when performing subharmonic prostate ultrasound imaging. This enhancement will be used</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Subjects Whose Prostate Cancer Was Detected With Subharmonic Imaging</title>
          <description>The initial phase of the trial will develop and test subharmonic imaging to demonstrate enhanced visualization of prostate vascularity in all study participants. We will report the percentage of study subjects in whom visualization of prostate vascularity is increased with subharmonic imaging.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="55"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Percentage of Biopsy Cores in Which Prostate Cancer Was Detected Using Subharmonic Imaging</title>
        <description>Study subjects will be scanned with subharmonic imaging during infusion of the microbubble contrast agent. Imaging results will be compared to pathology on prostate biopsy.</description>
        <time_frame>One week from baseline</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Prostate Biopsy Patients</title>
            <description>Patients who are scheduled for a clinically indicated prostate biopsy, and who are able to undergo contrast enhanced transrectal ultrasound will be included in this single arm study. Each of the study subjects will receive in intravenous infusion of a microbubble contrast agent known as Definity™, (Perflutren Lipid Microsphere, Lantheus Medical Imaging, Inc; N. Billerica, MA). Based upon our previous experience, two vials of Perflutren Lipid Microsphere will be mixed and diluted in 50 ml of normal saline, yielding a concentration of 49.4 μl/ml. For the purpose of contrast-enhanced imaging.&#xD;
Perflutren Lipid Microsphere Intravenous Suspension: The intravenous administration of Perflutren Lipid Microsphere will provide enhancement of vascular tissue when performing subharmonic prostate ultrasound imaging. This enhancement will be used</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Biopsy Cores in Which Prostate Cancer Was Detected Using Subharmonic Imaging</title>
          <description>Study subjects will be scanned with subharmonic imaging during infusion of the microbubble contrast agent. Imaging results will be compared to pathology on prostate biopsy.</description>
          <units>percentage of biopsy cores</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="55"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.33"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Percentage of Subjects With Previously Unidentified Prostate Cancer Using Magnetic Resonance Imaging</title>
        <description>Study subjects will be scanned with subharmonic imaging during infusion of the microbubble contrast agent. Imaging results will be compared to pathology on prostate biopsy.</description>
        <time_frame>One week from baseline</time_frame>
        <population>Thirty one subjects of the total 55 had prior negative MRI or negative MRI guided biopsy</population>
        <group_list>
          <group group_id="O1">
            <title>Prostate Biopsy Patients</title>
            <description>Patients who are scheduled for a clinically indicated prostate biopsy, and who are able to undergo contrast enhanced transrectal ultrasound will be included in this single arm study. Each of the study subjects will receive in intravenous infusion of a microbubble contrast agent known as Definity™, (Perflutren Lipid Microsphere, Lantheus Medical Imaging, Inc; N. Billerica, MA). Based upon our previous experience, two vials of Perflutren Lipid Microsphere will be mixed and diluted in 50 ml of normal saline, yielding a concentration of 49.4 μl/ml. For the purpose of contrast-enhanced imaging.&#xD;
Perflutren Lipid Microsphere Intravenous Suspension: The intravenous administration of Perflutren Lipid Microsphere will provide enhancement of vascular tissue when performing subharmonic prostate ultrasound imaging. This enhancement will be used</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Subjects With Previously Unidentified Prostate Cancer Using Magnetic Resonance Imaging</title>
          <description>Study subjects will be scanned with subharmonic imaging during infusion of the microbubble contrast agent. Imaging results will be compared to pathology on prostate biopsy.</description>
          <population>Thirty one subjects of the total 55 had prior negative MRI or negative MRI guided biopsy</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="31"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Assessed for 30 minutes post-injection</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Prostate Biopsy Patients</title>
          <description>Patients who are scheduled for a clinically indicated prostate biopsy, and who are able to undergo contrast enhanced transrectal ultrasound will be included in this single arm study. Each of the study subjects will receive in intravenous infusion of a microbubble contrast agent known as Definity™, (Perflutren Lipid Microsphere, Lantheus Medical Imaging, Inc; N. Billerica, MA). Based upon our previous experience, two vials of Perflutren Lipid Microsphere will be mixed and diluted in 50 ml of normal saline, yielding a concentration of 49.4 μl/ml. For the purpose of contrast-enhanced imaging, Perflutren Lipid Microsphere will be infused over approximately 10-12 minutes, during which time ultrasound imaging and biopsy will be performed.&#xD;
Perflutren Lipid Microsphere Intravenous Suspension: The intravenous administration of Perflutren Lipid Microsphere will provide enhancement of vascular tissue when performing subharmonic prostate ultrasound imaging. This enhancement will be used</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="55"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="55"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="55"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Throat Tightness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="55"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Hives</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="55"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Ethan Halpern</name_or_title>
      <organization>Sidney Kimmel Cancer Center at Thomas Jefferson University</organization>
      <phone>215-955-5345</phone>
      <email>ethan.halpern@jefferson.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT02967458
org study id: 15F.607
secondary id: R21CA202214
nct id: NCT02967458
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This is a phase II single center study using contrast-enhanced ultrasound to identify
      aggressive forms of prostate cancer with subharmonic imaging.

      The following are the study objectives:

        1. To implement subharmonic imaging technology on a transrectal probe suitable for prostate
           imaging and biopsy

        2. To demonstrate visualization of prostatic vascularity using subharmonic
           contrast-enhanced imaging.

        3. To provide a preliminary estimate of the diagnostic accuracy of contrast-enhanced
           subharmonic imaging for detection of clinically significant PCa.

      The study will include 50 subjects who are scheduled for prostate biopsy. Each subject will
      receive an intravenous infusion of microbubble contrast material immediately prior to a
      prostate biopsy procedure. The study will demonstrate whether subharmonic imaging with a
      microbubble contrast agent allows for detection of clinically significant prostate cancer.
Background: Prostate cancer (PCa) is the most frequently diagnosed cancer among American
      males, accounting for 27 % of new cancer diagnoses, but it is directly responsible for only
      9.5 % of cancer related deaths. Two recently published clinical trials suggest that
      overdiagnosis and overtreatment of potentially insignificant cancer is a major drawback of
      prostate cancer screening, and point to the need for a more specific screening tool that can
      identify clinically significant prostate cancer. The US-based Prostate, Lung, Colorectal, and
      Ovarian (PLCO) Cancer Screening Trial failed to show a mortality benefit from screening and
      treatment of prostate cancer. The European Randomized Study of Screening for Prostate Cancer
      (ERSPC) suggests that with the current standard of care, 1410 men must be screened and 48
      additional cases of prostate cancer treated to prevent one death from prostate cancer. Based
      upon these trials, the U.S. Preventive Services Task Force (USPSTF) has issued a grade "D"
      recommendation against PSA-based screening for PCa.

      Contrast-Enhanced Ultrasound: Recent studies have demonstrated that contrast-enhanced
      harmonic imaging (HI) can identify enhancement related to vascular flow in higher grade PCa,
      and that HI can selectively detect patients with "clinically significant" PCa that are most
      likely to benefit from therapy. Subharmonic imaging (SHI) is a newer technology for
      contrast-enhanced ultrasound imaging that provides a 10-fold improvement in the signal to
      background ratio for visualization of small vascular structures, but has not been previously
      implemented on a transrectal ultrasound probe. SHI of the prostate is expected to advance the
      imaging of prostatic neovascularity and to improve selective biopsy of clinically significant
      PCa.

      Objective: To adapt SHI to a transrectal probe appropriate for prostate imaging and biopsy
      (over the first 6 months of this study). The subsequent 18 month pilot clinical study will
      enroll 50 participants who have a clinical indication for prostate biopsy to quantify SHI for
      the detection of clinically significant PCa (defined as: Gleason score ≥ 7, a single core
      with > 50 % involvement, or > 25 % of biopsy cores positive for PCa).

      Approach: Each participant will undergo a transrectal ultrasound evaluation of the prostate
      with conventional grayscale and color Doppler imaging, as well as contrast-enhanced imaging
      with color Doppler, HI and SHI approaches. Imaging results from each of these techniques will
      be recorded, but only the SHI findings will be used to guide a targeted biopsy of the
      prostate. A maximum of 6 targeted biopsy cores will be obtained from each participant, based
      upon suspicious areas identified with SHI. Following the targeted biopsy, each participant
      will also receive a 12-part systematic biopsy consisting of 6 laterally directed biopsy cores
      and 6 medially directed biopsy cores. The pilot study is designed to estimate the detection
      of clinically significant cancer that will be obtained with targeted biopsy based upon SHI
      along with the medially directed systematic sextant biopsy cores (≤ 12 cores total).
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Diagnostic
masking: None (Open Label)
measure: Percentage of Subjects Whose Prostate Cancer Was Detected With Subharmonic Imaging
time frame: One week from baseline
description: The initial phase of the trial will develop and test subharmonic imaging to demonstrate enhanced visualization of prostate vascularity in all study participants. We will report the percentage of study subjects in whom visualization of prostate vascularity is increased with subharmonic imaging.
measure: Percentage of Biopsy Cores in Which Prostate Cancer Was Detected Using Subharmonic Imaging
time frame: One week from baseline
description: Study subjects will be scanned with subharmonic imaging during infusion of the microbubble contrast agent. Imaging results will be compared to pathology on prostate biopsy.
measure: Percentage of Subjects With Previously Unidentified Prostate Cancer Using Magnetic Resonance Imaging
time frame: One week from baseline
description: Study subjects will be scanned with subharmonic imaging during infusion of the microbubble contrast agent. Imaging results will be compared to pathology on prostate biopsy.
arm group label: Prostate Biopsy Patients
arm group type: Experimental
description: Fifty patients who are scheduled for a clinically indicated prostate biopsy, and who are able to undergo contrast enhanced transrectal ultrasound will be included in this single arm study. Each of the study subjects will receive in intravenous infusion of a microbubble contrast agent known as Definity™, (Perflutren Lipid Microsphere, Lantheus Medical Imaging, Inc; N. Billerica, MA). Based upon our previous experience, two vials of Perflutren Lipid Microsphere will be mixed and diluted in 50 ml of normal saline, yielding a concentration of 49.4 μl/ml. For the purpose of contrast-enhanced imaging, Perflutren Lipid Microsphere will be infused over approximately 10-12 minutes, during which time ultrasound imaging and biopsy will be performed.
intervention type: Drug
intervention name: Perflutren Lipid Microsphere Intravenous Suspension
description: The intravenous administration of Perflutren Lipid Microsphere will provide enhancement of vascular tissue when performing subharmonic prostate ultrasound imaging. This enhancement will be used to guide targeted biopsy of the prostate to vascular areas which are more likely to contain aggressive prostate cancer.
arm group label: Prostate Biopsy Patients
other name: Definity™ (Lantheus Medical Imaging, Inc; N. Billerica, MA)
criteria: 
gender: Male
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Ethan J Halpern, MD
role: Principal Investigator
affiliation: Thomas Jefferson University
last name: Flemming Forsberg, PhD
role: Principal Investigator
affiliation: Thomas Jefferson University
facility: 
country: United States
citation: Halpern EJ, Gomella LG, Forsberg F, McCue PA, Trabulsi EJ. Contrast enhanced transrectal ultrasound for the detection of prostate cancer: a randomized, double-blind trial of dutasteride pretreatment. J Urol. 2012 Nov;188(5):1739-45. doi: 10.1016/j.juro.2012.07.021. Epub 2012 Sep 19.
PMID: 22998915
citation: Aigner F, Schafer G, Steiner E, Jaschke W, Horninger W, Herrmann TR, Nagele U, Halpern EJ, Frauscher F. Value of enhanced transrectal ultrasound targeted biopsy for prostate cancer diagnosis: a retrospective data analysis. World J Urol. 2012 Jun;30(3):341-6. doi: 10.1007/s00345-011-0809-6. Epub 2011 Dec 18.
PMID: 22179312
citation: Trabulsi EJ, Sackett D, Gomella LG, Halpern EJ. Enhanced transrectal ultrasound modalities in the diagnosis of prostate cancer. Urology. 2010 Nov;76(5):1025-33. doi: 10.1016/j.urology.2010.05.022. Epub 2010 Aug 16.
PMID: 20719368
citation: Nelson ED, Slotoroff CB, Gomella LG, Halpern EJ. Targeted biopsy of the prostate: the impact of color Doppler imaging and elastography on prostate cancer detection and Gleason score. Urology. 2007 Dec;70(6):1136-40. doi: 10.1016/j.urology.2007.07.067.
PMID: 18158034
citation: Linden RA, Trabulsi EJ, Forsberg F, Gittens PR, Gomella LG, Halpern EJ. Contrast enhanced ultrasound flash replenishment method for directed prostate biopsies. J Urol. 2007 Dec;178(6):2354-8. doi: 10.1016/j.juro.2007.08.022. Epub 2007 Oct 22.
PMID: 17936814
citation: Halpern EJ, Ramey JR, Strup SE, Frauscher F, McCue P, Gomella LG. Detection of prostate carcinoma with contrast-enhanced sonography using intermittent harmonic imaging. Cancer. 2005 Dec 1;104(11):2373-83. doi: 10.1002/cncr.21440.
PMID: 16240450
responsible party type: Sponsor
mesh term: Prostatic Neoplasms
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 