<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/NCT02204917</url>
  </required_header>
  <id_info>
    <org_study_id>IRB 13-010618</org_study_id>
    <nct_id>NCT02204917</nct_id>
  </id_info>
  <brief_title>CeVUS With Intravesical Administration of OPTISON TM (Trademark) in Children</brief_title>
  <acronym>ceVUS</acronym>
  <official_title>Contrast Enhanced Voiding Urosonography (ceVUS) With the Intravesical Administration of the Ultrasound Contrast Agent OPTISON TM (Trademark) for Vesicoureteral Reflux Detection and Urethral Imaging in Children.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Kassa Darge</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Children's Hospital of Philadelphia</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      In this clinical trial the investigators aim to evaluate the diagnostic feasibility and&#xD;
      safety of ceVUS with the intravesical use of OPTISON for vesicoureteral reflux detection and&#xD;
      urethral imaging in children.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Contrast enhanced Voiding Urosonography (ceVUS) is a radiation free, highly sensitive imaging&#xD;
      modality for vesicoureteral reflux (VUR) and urethral imaging in children. It employs&#xD;
      ultrasound technology in combination with ultrasound contrast agent, which is administered&#xD;
      intravesically via a bladder catheter. Currently, second generation ultrasound contrast&#xD;
      agents are commercially available, comprising of gas-filled microbubbles. CeVUS in children&#xD;
      is being widely practiced, primarily in Europe, despite the fact that none of the&#xD;
      commercially available ultrasound contrast agents are yet approved for clinical applications&#xD;
      in pediatric population. In the United States, there is limited clinical experience with&#xD;
      ceVUS in children. Among the currently commercially available ultrasound contrast agents,&#xD;
      OPTISON has already been used in research and off-label in clinical settings involving adults&#xD;
      and children. One in-vitro study has been conducted aiming to optimize the ultrasound&#xD;
      technical parameters and the dose of OPTISON for intravesical administration in children. In&#xD;
      this clinical trial the investigators aim to evaluate the diagnostic feasibility and safety&#xD;
      of ceVUS with the intravesical use of OPTISON for vesicoureteral reflux detection and&#xD;
      urethral imaging in children.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>July 2014</start_date>
  <completion_date type="Actual">March 2017</completion_date>
  <primary_completion_date type="Actual">March 2016</primary_completion_date>
  <phase>Phase 1/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>
    <intervention_model_description>Comparative performance of contrast enhanced Voiding Urosonography (ceVUS) and Voiding Cystourethrography (VCUG) in the same participant and in the same session.</intervention_model_description>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Pelvic-ureter-units (PUUs) Detected With Vesicoureteral Reflux by Contrast Enhanced Voiding Urosonography (ceVUS) and by Voiding Cystourethrography (VCUG).</measure>
    <time_frame>10-15 minutes.</time_frame>
    <description>Presence or absence of vesicoureteral reflux identified by ceVUS and VCUG in each pelvic-ureter-unit (PUU) of each participant. PUU is an anatomic term that is used to describe the part of the urinary tract consisting of the renal calyces, pelvis and ureter.&#xD;
Grading the severity of reflux detected by ceVUS and VCUG. Grade 0: absence of reflux. If reflux is present, a 5 grade scale (grades I-V) is used to evaluate its severity. Grade I: reflux in the ureter, grade II: reflux up to the renal pelvis, grade III: reflux up to the renal pelvis with mild dilation of the ureter and pelvicalyceal system, grade IV reflux up to the renal pelvis with moderate dilation but preserved papillary impressions, grade V: reflux up to the renal pelvis with severe dilation and loss of papillary impressions. Higher grades of reflux are associated with increased risk of urinary tract infection.&#xD;
Imaging of the urethra during voiding (urethra visualized or not) and urethra pathology detection.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Participants With Adverse Events Following Contrast Enhanced Voiding Urosonography (ceVUS) With OPTISON and Voiding Cystourethrography (VCUG).</measure>
    <time_frame>Within 1 hour and up to 2 days after ceVUS and VCUG examinations completion.</time_frame>
    <description>The overall safety and tolerability of ceVUS with OPTISON was assessed before, during and immediately after each ceVUS and VCUG examinations, and in follow-up telephone interviews. Assessments included:&#xD;
evaluation of body systems for signs of generalized hypersensitivity, allergic or anaphylactoid reactions&#xD;
monitoring of heart rate and pulse oxygen saturation&#xD;
telephone questionnaire-based interview of parents/guardians and children 48 hours after the examinations for delayed adverse events.&#xD;
The severity of any possible adverse event was classified as mild, moderate or serious and the onset of symptoms was categorized as acute, subacute or delayed according to the World Health Organization (WHO) classifications. In addition, the adverse event was classified as anticipated if it was expected given the study related procedures or unanticipated if the subject was exposed to greater risk than previously known or recognized.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Compare the Diagnostic Accuracy of Contrast Enhanced Voiding Urosonography (ceVUS) With Voiding CystoUrethroGraphy (VCUG) for Vesicoureteral Reflux Detection and Urethral Imaging in Children.</measure>
    <time_frame>10-15 minutes.</time_frame>
    <description>The diagnostic accuracy of ceVUS will be assessed by evaluation of the true positive, true negative, false positive and false negative cases of reflux and urethral imaging findings detected by ceVUS and VCUG examinations.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">31</enrollment>
  <condition>Vesico-Ureteral Reflux</condition>
  <arm_group>
    <arm_group_label>Comparative performance of ceVUS &amp; VCUG</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Contrast enhanced Voiding Urosonography (ceVUS) will be performed with the intravesical administration of 0.1%-0.5% OPTISON / normal saline solution. The exact OPTISON dose (ml) that will be adjusted according to the age-related bladder filling capacity with a dose (ml) range from 0.3 mL in newborns to 3 mL in 18 year-old children. Voiding Cystourethrography (VCUG) exam will be subsequently performed using the same bladder catheter with intravesical administration of the x-ray contrast agent.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>OPTISON</intervention_name>
    <description>Contrast enhanced Voiding Urosonography (ceVUS) with intravesical administration of OPTISON for vesicoureteral reflux detection and urethral imaging in children. Voiding Cystourethrography (VCUG) examination will be subsequently performed as part of the standard care.</description>
    <arm_group_label>Comparative performance of ceVUS &amp; VCUG</arm_group_label>
    <other_name>Perflutren Protein-Type A Microspheres</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
          1. Children 2-18 years (first age cohort).&#xD;
&#xD;
          2. Children 0-18 years (second age cohort).&#xD;
&#xD;
          3. Referred to the Children's Hospital of Philadelphia (CHOP) for the performance of the&#xD;
             clinically indicated Voiding Cystourethrography (VCUG) examination.&#xD;
&#xD;
          4. Parental/guardian permission (informed consent) and if appropriate, child's assent for&#xD;
             additional performance of contrast enhanced Voiding Urosonography (ceVUS) examination.&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          1. Hypersensitivity to perflutren, blood, blood products or albumin.&#xD;
&#xD;
          2. Children requiring sedation for VCUG or ceVUS examinations.&#xD;
&#xD;
          3. Parents/guardians or subjects who, in the opinion of the principal investigator, may&#xD;
             be non-compliant with study schedules or procedures.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>18 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kassa Darge, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Department of Radiology, the Children's Hospital of Philadelphia</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Department of Radiology, the Children's Hospital of Philadelphia</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2018</verification_date>
  <study_first_submitted>June 25, 2014</study_first_submitted>
  <study_first_submitted_qc>July 29, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 31, 2014</study_first_posted>
  <results_first_submitted>July 19, 2017</results_first_submitted>
  <results_first_submitted_qc>October 29, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">November 27, 2018</results_first_posted>
  <last_update_submitted>October 29, 2018</last_update_submitted>
  <last_update_submitted_qc>October 29, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">November 27, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Children's Hospital of Philadelphia</investigator_affiliation>
    <investigator_full_name>Kassa Darge</investigator_full_name>
    <investigator_title>Sponsor-Investigator</investigator_title>
  </responsible_party>
  <keyword>Ultrasound</keyword>
  <keyword>Ultrasound Contrast Agents</keyword>
  <keyword>Optison</keyword>
  <keyword>contrast enhanced Voiding Urosonography (ceVUS)</keyword>
  <keyword>ceVUS</keyword>
  <keyword>Vesicoureteral Reflux</keyword>
  <keyword>Children</keyword>
  <keyword>Kidney</keyword>
  <keyword>Bladder</keyword>
  <keyword>Urethra</keyword>
  <keyword>Voiding Cystourethrography (VCUG)</keyword>
  <keyword>VCUG</keyword>
  <keyword>Safety</keyword>
  <keyword>Urinary tract</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vesico-Ureteral Reflux</mesh_term>
  </condition_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>From September 2014 to April 2015, the study team recruited and enrolled 31 eligible subjects scheduled for the clinically indicated voiding cysteourethrography (VCUG) examination from the daily inpatients/outpatients program of the Radiology Department at the Children's Hospital of Philadelphia.</recruitment_details>
      <pre_assignment_details>One subject was enrolled into the study (informed consent signed), however, sedation was required as standard of care to perform the clinically indicated VCUG examination. Sedation constitutes an exclusion criterion. Therefore, this subject although enrolled into the study, did not actually complete it.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>ceVUS With the Use of OPTISON &amp; VCUG in the Same Session</title>
          <description>OPTISON will be resuspended just before the performance of ceVUS examination, and 0.1%-0.5% of the bladder filling volume OPTISON / normal saline solution will be used for intravesical administration. The exact OPTISON dose (ml) will be adjusted according to the age-related bladder filling capacity with the maximum OPTISON dose (ml) range from 0.3 mL in newborns to 3 mL in 18 year-old children.&#xD;
VCUG exam will be performed using the same bladder catheter with intravesical administration of the x-ray contrast agent.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="31"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="30"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>ceVUS With the Use of OPTISON &amp; VCUG in the Same Session</title>
          <description>OPTISON will be resuspended just before the performance of ceVUS examination, and 01%-0.5% OPTISON solution will be used for intravesical administration. The exact OPTISON dose (ml) will be adjusted according to the age-related bladder filling capacity with a maximum dose (ml) range from 0.3 mL in newborns to 3 mL in 18 year-old children. VCUG exam will be performed as part of the standard care using the same bladder catheter with intravesical administration of the x-ray contrast agent.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="30"/>
          </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="30"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </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="21"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                  </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="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="27"/>
                  </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="2"/>
                  </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="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </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>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Pelvic-ureter-units (PUUs) Detected With Vesicoureteral Reflux by Contrast Enhanced Voiding Urosonography (ceVUS) and by Voiding Cystourethrography (VCUG).</title>
        <description>Presence or absence of vesicoureteral reflux identified by ceVUS and VCUG in each pelvic-ureter-unit (PUU) of each participant. PUU is an anatomic term that is used to describe the part of the urinary tract consisting of the renal calyces, pelvis and ureter.&#xD;
Grading the severity of reflux detected by ceVUS and VCUG. Grade 0: absence of reflux. If reflux is present, a 5 grade scale (grades I-V) is used to evaluate its severity. Grade I: reflux in the ureter, grade II: reflux up to the renal pelvis, grade III: reflux up to the renal pelvis with mild dilation of the ureter and pelvicalyceal system, grade IV reflux up to the renal pelvis with moderate dilation but preserved papillary impressions, grade V: reflux up to the renal pelvis with severe dilation and loss of papillary impressions. Higher grades of reflux are associated with increased risk of urinary tract infection.&#xD;
Imaging of the urethra during voiding (urethra visualized or not) and urethra pathology detection.</description>
        <time_frame>10-15 minutes.</time_frame>
        <population>In total, 59 kidneys with 62 pelvic-ureteric units (PUUs) in 30 children were analyzed.</population>
        <group_list>
          <group group_id="O1">
            <title>Severity of Reflux With ceVUS</title>
            <description>Contrast enhanced Voiding Urosonography (ceVUS) OPTISON will be performed with the intravesical administration of 0.1%-0.5% OPTISON/normal saline solution. The exact OPTISON dose (ml) will be adjusted according to the age-related bladder filling capacity with a maximum dose (ml) range from 0.3 mL in newborns to 3 mL in 18 year-old children.</description>
          </group>
          <group group_id="O2">
            <title>Severity of Reflux With VCUG</title>
            <description>Voiding Cystourethrography (VCUG) exam will be performed after ceVUS using the same bladder catheter with intravesical administration of the x-ray contrast agent.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Pelvic-ureter-units (PUUs) Detected With Vesicoureteral Reflux by Contrast Enhanced Voiding Urosonography (ceVUS) and by Voiding Cystourethrography (VCUG).</title>
          <description>Presence or absence of vesicoureteral reflux identified by ceVUS and VCUG in each pelvic-ureter-unit (PUU) of each participant. PUU is an anatomic term that is used to describe the part of the urinary tract consisting of the renal calyces, pelvis and ureter.&#xD;
Grading the severity of reflux detected by ceVUS and VCUG. Grade 0: absence of reflux. If reflux is present, a 5 grade scale (grades I-V) is used to evaluate its severity. Grade I: reflux in the ureter, grade II: reflux up to the renal pelvis, grade III: reflux up to the renal pelvis with mild dilation of the ureter and pelvicalyceal system, grade IV reflux up to the renal pelvis with moderate dilation but preserved papillary impressions, grade V: reflux up to the renal pelvis with severe dilation and loss of papillary impressions. Higher grades of reflux are associated with increased risk of urinary tract infection.&#xD;
Imaging of the urethra during voiding (urethra visualized or not) and urethra pathology detection.</description>
          <population>In total, 59 kidneys with 62 pelvic-ureteric units (PUUs) in 30 children were analyzed.</population>
          <units>pelvic-ureteric units (PUUs)</units>
          <param>Number</param>
          <units_analyzed>Number of Pelvic-Ureteric-Units (PUUs)</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>Number of Pelvic-Ureteric-Units (PUUs)</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="62"/>
                <count group_id="O2" value="62"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Grade 0 reflux</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="50"/>
                    <measurement group_id="O2" value="50"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade I reflux</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade II reflux</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8"/>
                    <measurement group_id="O2" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade III reflux</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade IV reflux</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade V reflux</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Adverse Events Following Contrast Enhanced Voiding Urosonography (ceVUS) With OPTISON and Voiding Cystourethrography (VCUG).</title>
        <description>The overall safety and tolerability of ceVUS with OPTISON was assessed before, during and immediately after each ceVUS and VCUG examinations, and in follow-up telephone interviews. Assessments included:&#xD;
evaluation of body systems for signs of generalized hypersensitivity, allergic or anaphylactoid reactions&#xD;
monitoring of heart rate and pulse oxygen saturation&#xD;
telephone questionnaire-based interview of parents/guardians and children 48 hours after the examinations for delayed adverse events.&#xD;
The severity of any possible adverse event was classified as mild, moderate or serious and the onset of symptoms was categorized as acute, subacute or delayed according to the World Health Organization (WHO) classifications. In addition, the adverse event was classified as anticipated if it was expected given the study related procedures or unanticipated if the subject was exposed to greater risk than previously known or recognized.</description>
        <time_frame>Within 1 hour and up to 2 days after ceVUS and VCUG examinations completion.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>ceVUS With the Use of OPTISON &amp; VCUG in the Same Session</title>
            <description>OPTISON will be resuspended just before the performance of ceVUS examination, 0.1%-0.5% OPTISON solution will be used for intravesical administration. The exact OPTISON dose (ml) will be adjusted according to the age-related bladder filling capacity with the maximum dose (ml) range from 0.3 mL in newborns to 3 mL in 18 year-old children. VCUG exam will be performed as part of the standard care using the same bladder catheter with intravesical administration of the x-ray contrast agent.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Adverse Events Following Contrast Enhanced Voiding Urosonography (ceVUS) With OPTISON and Voiding Cystourethrography (VCUG).</title>
          <description>The overall safety and tolerability of ceVUS with OPTISON was assessed before, during and immediately after each ceVUS and VCUG examinations, and in follow-up telephone interviews. Assessments included:&#xD;
evaluation of body systems for signs of generalized hypersensitivity, allergic or anaphylactoid reactions&#xD;
monitoring of heart rate and pulse oxygen saturation&#xD;
telephone questionnaire-based interview of parents/guardians and children 48 hours after the examinations for delayed adverse events.&#xD;
The severity of any possible adverse event was classified as mild, moderate or serious and the onset of symptoms was categorized as acute, subacute or delayed according to the World Health Organization (WHO) classifications. In addition, the adverse event was classified as anticipated if it was expected given the study related procedures or unanticipated if the subject was exposed to greater risk than previously known or recognized.</description>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Number of Participants without Adverse Events</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="29"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Number of Participants with Adverse Events</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Compare the Diagnostic Accuracy of Contrast Enhanced Voiding Urosonography (ceVUS) With Voiding CystoUrethroGraphy (VCUG) for Vesicoureteral Reflux Detection and Urethral Imaging in Children.</title>
        <description>The diagnostic accuracy of ceVUS will be assessed by evaluation of the true positive, true negative, false positive and false negative cases of reflux and urethral imaging findings detected by ceVUS and VCUG examinations.</description>
        <time_frame>10-15 minutes.</time_frame>
        <population>Voiding Cysteourethrography (VCUG) is used as the reference standard the results for ceVUS.</population>
        <group_list>
          <group group_id="O1">
            <title>ceVUS With the Use of OPTISON &amp; VCUG in the Same Session</title>
            <description>OPTISON will be resuspended just before the performance of ceVUS examination, and 0.1%-0.5% OPTISON solution will be used for intravesical administration. The exact OPTISON dose (ml) will be adjusted according to the age-related bladder filling capacity with het maximum dose (ml) range from 0.3 mL in newborns to 3 mL in 18 year-old children. VCUG exam as part of the standard care will be performed using the same bladder catheter with intravesical administration of the x-ray contrast agent.</description>
          </group>
        </group_list>
        <measure>
          <title>Compare the Diagnostic Accuracy of Contrast Enhanced Voiding Urosonography (ceVUS) With Voiding CystoUrethroGraphy (VCUG) for Vesicoureteral Reflux Detection and Urethral Imaging in Children.</title>
          <description>The diagnostic accuracy of ceVUS will be assessed by evaluation of the true positive, true negative, false positive and false negative cases of reflux and urethral imaging findings detected by ceVUS and VCUG examinations.</description>
          <population>Voiding Cysteourethrography (VCUG) is used as the reference standard the results for ceVUS.</population>
          <units>percentage</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>sensitivity</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="91.7" lower_limit="61.5" upper_limit="99.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>specificity</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="98.0" lower_limit="89.4" upper_limit="99.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>positive predictive value</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="91.7" lower_limit="61.1" upper_limit="98.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>negative predictive value</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="98.0" lower_limit="88.2" upper_limit="99.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>During 48 hours following the study participation</time_frame>
      <group_list>
        <group group_id="E1">
          <title>ceVUS With the Use of OPTISON &amp; VCUG in the Same Session</title>
          <description>OPTISON will be resuspended just before the performance of ceVUS examination, and 0.1%-0.5% of the bladder filling volume OPTISON / normal saline solution will be used for intravesical administration. The exact OPTISON dose (ml) will be adjusted according to the age-related bladder filling capacity with the maximum OPTISON dose (ml) range from 0.3 mL in newborns to 3 mL in 18 year-old children.&#xD;
VCUG exam will be performed using the same bladder catheter with intravesical administration of the x-ray contrast agent.</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="30"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>WHO</default_vocab>
        <default_assessment>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="1" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Dysuria</sub_title>
                <description>The dysuria was an anticipated adverse event and it was categorized as mild in severity, subacute in onset and self-limited in course. No medical consultation, no medication or other intervention was required or performed.</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="30"/>
              </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. Kassa Darge, MD, PhD, Radiologist-in-Chief</name_or_title>
      <organization>Children's Hospital of Philadelphia</organization>
      <phone>267-425-7110</phone>
      <email>DARGE@email.chop.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/NCT02204917
org study id: IRB 13-010618
nct id: NCT02204917
lead sponsor: 
has dmc: Yes
In this clinical trial the investigators aim to evaluate the diagnostic feasibility and
      safety of ceVUS with the intravesical use of OPTISON for vesicoureteral reflux detection and
      urethral imaging in children.
Contrast enhanced Voiding Urosonography (ceVUS) is a radiation free, highly sensitive imaging
      modality for vesicoureteral reflux (VUR) and urethral imaging in children. It employs
      ultrasound technology in combination with ultrasound contrast agent, which is administered
      intravesically via a bladder catheter. Currently, second generation ultrasound contrast
      agents are commercially available, comprising of gas-filled microbubbles. CeVUS in children
      is being widely practiced, primarily in Europe, despite the fact that none of the
      commercially available ultrasound contrast agents are yet approved for clinical applications
      in pediatric population. In the United States, there is limited clinical experience with
      ceVUS in children. Among the currently commercially available ultrasound contrast agents,
      OPTISON has already been used in research and off-label in clinical settings involving adults
      and children. One in-vitro study has been conducted aiming to optimize the ultrasound
      technical parameters and the dose of OPTISON for intravesical administration in children. In
      this clinical trial the investigators aim to evaluate the diagnostic feasibility and safety
      of ceVUS with the intravesical use of OPTISON for vesicoureteral reflux detection and
      urethral imaging in children.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Comparative performance of contrast enhanced Voiding Urosonography (ceVUS) and Voiding Cystourethrography (VCUG) in the same participant and in the same session.
primary purpose: Diagnostic
masking: None (Open Label)
measure: Number of Pelvic-ureter-units (PUUs) Detected With Vesicoureteral Reflux by Contrast Enhanced Voiding Urosonography (ceVUS) and by Voiding Cystourethrography (VCUG).
time frame: 10-15 minutes.
description: Presence or absence of vesicoureteral reflux identified by ceVUS and VCUG in each pelvic-ureter-unit (PUU) of each participant. PUU is an anatomic term that is used to describe the part of the urinary tract consisting of the renal calyces, pelvis and ureter.
Grading the severity of reflux detected by ceVUS and VCUG. Grade 0: absence of reflux. If reflux is present, a 5 grade scale (grades I-V) is used to evaluate its severity. Grade I: reflux in the ureter, grade II: reflux up to the renal pelvis, grade III: reflux up to the renal pelvis with mild dilation of the ureter and pelvicalyceal system, grade IV reflux up to the renal pelvis with moderate dilation but preserved papillary impressions, grade V: reflux up to the renal pelvis with severe dilation and loss of papillary impressions. Higher grades of reflux are associated with increased risk of urinary tract infection.
Imaging of the urethra during voiding (urethra visualized or not) and urethra pathology detection.
measure: Number of Participants With Adverse Events Following Contrast Enhanced Voiding Urosonography (ceVUS) With OPTISON and Voiding Cystourethrography (VCUG).
time frame: Within 1 hour and up to 2 days after ceVUS and VCUG examinations completion.
description: The overall safety and tolerability of ceVUS with OPTISON was assessed before, during and immediately after each ceVUS and VCUG examinations, and in follow-up telephone interviews. Assessments included:
evaluation of body systems for signs of generalized hypersensitivity, allergic or anaphylactoid reactions
monitoring of heart rate and pulse oxygen saturation
telephone questionnaire-based interview of parents/guardians and children 48 hours after the examinations for delayed adverse events.
The severity of any possible adverse event was classified as mild, moderate or serious and the onset of symptoms was categorized as acute, subacute or delayed according to the World Health Organization (WHO) classifications. In addition, the adverse event was classified as anticipated if it was expected given the study related procedures or unanticipated if the subject was exposed to greater risk than previously known or recognized.
measure: Compare the Diagnostic Accuracy of Contrast Enhanced Voiding Urosonography (ceVUS) With Voiding CystoUrethroGraphy (VCUG) for Vesicoureteral Reflux Detection and Urethral Imaging in Children.
time frame: 10-15 minutes.
description: The diagnostic accuracy of ceVUS will be assessed by evaluation of the true positive, true negative, false positive and false negative cases of reflux and urethral imaging findings detected by ceVUS and VCUG examinations.
arm group label: Comparative performance of ceVUS & VCUG
arm group type: Experimental
description: Contrast enhanced Voiding Urosonography (ceVUS) will be performed with the intravesical administration of 0.1%-0.5% OPTISON / normal saline solution. The exact OPTISON dose (ml) that will be adjusted according to the age-related bladder filling capacity with a dose (ml) range from 0.3 mL in newborns to 3 mL in 18 year-old children. Voiding Cystourethrography (VCUG) exam will be subsequently performed using the same bladder catheter with intravesical administration of the x-ray contrast agent.
intervention type: Drug
intervention name: OPTISON
description: Contrast enhanced Voiding Urosonography (ceVUS) with intravesical administration of OPTISON for vesicoureteral reflux detection and urethral imaging in children. Voiding Cystourethrography (VCUG) examination will be subsequently performed as part of the standard care.
arm group label: Comparative performance of ceVUS & VCUG
other name: Perflutren Protein-Type A Microspheres
criteria: 
gender: All
minimum age: N/A
maximum age: 18 Years
healthy volunteers: No
last name: Kassa Darge, MD, PhD
role: Principal Investigator
affiliation: Department of Radiology, the Children's Hospital of Philadelphia
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: Children's Hospital of Philadelphia
investigator full name: Kassa Darge
investigator title: Sponsor-Investigator
mesh term: Vesico-Ureteral Reflux
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 