xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT05983406</url>
    </required_header>
    <id_info>
      <org_study_id>KarolinskaUH 2019-05404</org_study_id>
      <secondary_id>2019-05404</secondary_id>
      <nct_id>NCT05983406</nct_id>
    </id_info>
    <brief_title>Role of Doppler Endoscopic Probe in the Diagnosis of Subepithelial Gastrointestinal Lesions.</brief_title>
    <acronym>DopplerSEL</acronym>
    <official_title>Role of Doppler Endoscopic Probe in the Diagnosis of Subepithelial Gastrointestinal Lesions.</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Francisco Baldaque-Silva</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Karolinska University Hospital</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        RESEARCH PLAN I-TITLE Role of Doppler endoscopic probe in the diagnosis of subepithelial&#xD;
        gastrointestinal lesions.&#xD;
  &#xD;
        II-BACKGROUND Subepithelial lesions (SEL) are commonly encountered during routine endoscopies&#xD;
        with an estimated prevalence of 3.5%. Most of the SELs are detected during upper&#xD;
        gastrointestinal endoscopy. Subsequently, endoscopic ultrasound (EUS) is performed to better&#xD;
        characterize the lesion and to rule out the presence of a vascular lesion before tissue&#xD;
        sampling due to the high risk of severe bleeding with tissue acquisition in vascular injury.&#xD;
        However, EUS can rarely establish a definitive diagnosis per se with limited accuracy.&#xD;
  &#xD;
        In large lesions, it is possible to use cytology or histology needles via the EUS instrument&#xD;
        to collect cells/tissue within the lesion. It can lead to accurate diagnosis and consistent&#xD;
        management. However, EUS-guided tissue sampling can be technically challenging, with poor&#xD;
        yield for small or mobile SELs. In addition, EUS is an expensive technique, high operator&#xD;
        dependency and performed only in tertiary centers. It creates a time gap between endoscopic&#xD;
        detection and the EUS examination and increases costs. That delay in diagnosis is a source of&#xD;
        anxiety for the patient and for the caregivers.&#xD;
  &#xD;
        Several methods were proposed to increase the diagnostic yield of tissue acquisition&#xD;
        techniques, such as &quot;bite-on-bite&quot; biopsies which showed a limited diagnostic yield.&#xD;
        Alternatively, the &quot;unroofing&quot; technique has also been advocated for histological diagnosis.&#xD;
        In unroofing, a loop is used to remove the normal epithelium covering the subepithelial&#xD;
        lesions and after epithelial removal, a biopsy forceps or loop is used to sample&#xD;
        subepithelial lesions. Other techniques include endoscopic resection by snare or submucosal&#xD;
        dissection. These enable a surgical specimen but are technically demanding and have been&#xD;
        complicated by perforation and bleeding in most series.&#xD;
  &#xD;
        There is a need for a method that enables rapid diagnosis in the same session as endoscopic&#xD;
        detection of SEL regardless of their size. That method should ideally enable histological&#xD;
        diagnosis with low risks of complications and should not require high technical expertise and&#xD;
        should not be highly dependent on the operator. The ideal solution to address the diagnosis&#xD;
        of gastrointestinal (GI) SEL would be one that would provide a tissue sampling after&#xD;
        exclusion of a highly vascular lesion, in the same session as endoscopic detection.&#xD;
  &#xD;
        Doppler endoscopic probe (DEP) is a Doppler endoscopic probe specially developed for the GI&#xD;
        system, which enables blood flow detection during endoscopy.&#xD;
  &#xD;
        DEP is CE and FDA approved and can be used through the working channel of the endoscope.&#xD;
        Unlike standard EUS, which requires advanced endoscopic training, DEP is much easier to use.&#xD;
        It allows the characterization of lesions as non-vascular, venous or arterial. Recent studies&#xD;
        have demonstrated the safety and efficacy of DEP in vascular characterization in the&#xD;
        gastrointestinal tract.&#xD;
  &#xD;
        III PURPOSE&#xD;
  &#xD;
        Primary objective:&#xD;
  &#xD;
          -  Proof of concept evaluation of the role of DEP in the characterization of GI SEL as&#xD;
             non-vascular or vascular (arterial or venous)&#xD;
  &#xD;
          -  Relationship between findings on DEP versus findings on EUS (considered the gold&#xD;
             standard) regarding SEL characterization as non-vascular or vascular (arterial or&#xD;
             venous).&#xD;
  &#xD;
        Secondary purposes:&#xD;
  &#xD;
          -  Accuracy in removing the histological characterization of subepithelial GI lesions.&#xD;
  &#xD;
          -  Complications in connection with tissue acquisition&#xD;
  &#xD;
          -  Inter-observer agreement of DEP and EUS results. IV METHODS This is a pilot projective&#xD;
             feasibility study that will be run by Karolinska University Hospital in Stockholm&#xD;
             Patients with subepithelial GI lesions were referred for EUS evaluation. The study will&#xD;
             include 30 patients.&#xD;
  &#xD;
        A conventional gastroscopy will be performed. After identification of the lesion, DEP is&#xD;
        performed. The DEP probe is lubricated and deployed through the working channel of the&#xD;
        endoscope. The probe will contact the mucosa slightly, covering the SEL. Then evaluate the&#xD;
        lesion in 2 different angels. The results will be characterized and recorded qualitatively:&#xD;
        no flow / arterial flow / venous flow and in terms of intensity: soft, medium or high.&#xD;
  &#xD;
        After DEP, evaluation EUS will be performed by another endoscopist who will be tied to the&#xD;
        DEP results. EUS will be considered the gold standard.&#xD;
  &#xD;
        After both assessments, the lesion is characterized as no vessel / arterial / venous and as&#xD;
        soft / medium / high flow intensity.&#xD;
  &#xD;
        EUS will be followed by removal of SEL in patients where EUS excludes the presence of high&#xD;
        vessel disease. &quot;Unroofing&quot; will be performed using a conventional endoscopic loop, through&#xD;
        the working channel of the endoscope. After the surface of the lesion is disturbed, a biopsy&#xD;
        forceps will be used for tissue acquisition. Tissue will be stored in formalin and processed&#xD;
        and evaluated by the pathologist.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        RESEARCH PLAN&#xD;
  &#xD;
        I-TITLE Role of doppler endoscopic probe in the diagnosis of subepithelial gastrointestinal&#xD;
        lesions.&#xD;
  &#xD;
        II-BACKGROUND&#xD;
  &#xD;
        Subepithelial lesions (SELs) are commonly encountered on routine endoscopies with estimated&#xD;
        prevalence of 3.5% (PMID: 24238309). Most small SELs are asymptomatic and benign, but their&#xD;
        pathological diagnosis may be challenging, and sometimes impossible with conventional&#xD;
        technology.&#xD;
  &#xD;
        Most of SELs are detected during upper gastrointestinal endoscopy. Afterwards, endoscopic&#xD;
        ultrasound (EUS) is usually performed in order to better characterize the lesion and to&#xD;
        exclude the presence of a vascular lesion. EUS enables evaluation of the size, structure and&#xD;
        location of the lesion within the GI wall (submucosa/muscularis mucosa/ submucosa/muscularis&#xD;
        propria), but can seldom stablish a definitive diagnosis per se. EUS provides valuable&#xD;
        information regarding the layer of origin and can suggest a diagnosis, but it has been shown&#xD;
        to have limited accuracy. (PMID: 12190103).&#xD;
  &#xD;
        In lesions larger than 2cm, it is possible to use dedicated cytologi (FNA) or histology (FNB)&#xD;
        needles thought the EUS instrument in order to collect cells/tissue from within the lesion.&#xD;
        That may lead to proper diagnosis and consequent management. However, EUS-guided tissue&#xD;
        sampling can be technically challenging, with poor yields for small or mobile SELs&#xD;
        (20306384). Additionally, EUS is an expensive technique, highly operator dependent and&#xD;
        usually only performed in tertiary centers. That creates a time gap between the endoscopic&#xD;
        detection and the EUS investigation, and increases the costs. That delay in the diagnosis is&#xD;
        a source of anxiety for the patient and for health care providers alike.&#xD;
  &#xD;
        In cases with small or mobile SEL, in which a definitive diagnosis cannot be stablished with&#xD;
        EUS plus FNA/FNB, surveillance is recommended. But the later, is associated with high costs&#xD;
        and high burden for the health care system.&#xD;
  &#xD;
        Several methods were advocated to increase the diagnostic yield of tissue acquisition&#xD;
        techniques such as &quot;bite- on-bite&quot; forceps biopsy that showed a limited diagnostic yield&#xD;
        (PMID: 12518134), with one prospective study showing a diagnostic yield of only 17% compared&#xD;
        with 87% with endoscopic resection (PMID: 16813799). Alternatively, unroofing technique has&#xD;
        also been advocated in this context. With unroofing a snare is used to remove the normal&#xD;
        epithelium that is covering the subepithelial lesion, and after epithelial removal a biopsy&#xD;
        forceps is used to sample the subepithelial lesion. Other techniques include endoscopic&#xD;
        resection by snaring or submucosal dissection. These enable a surgical specimen but are&#xD;
        technically demanding and have been complicated by perforation and bleeding in most series.&#xD;
  &#xD;
        Although endoscopic resection may have the advantage of providing both a complete&#xD;
        pathological diagnosis as well as treatment for the tumor in selected patients, it is&#xD;
        questionable whether endoscopic resection of the entire lesion is needed for diagnostic&#xD;
        purposes, because of the associated long procedure time and potentially serious&#xD;
        complications, such as bleeding and perforation.&#xD;
  &#xD;
        EUS is usually performed before biopsy sampling, snaring or endoscopic resection in order to&#xD;
        exclude the presence of a highly vascular SEL, due to the high risk of severe bleeding in&#xD;
        case of tissue acquisition in a vascular lesion.&#xD;
  &#xD;
        There is a need for a method that would enable rapid diagnosis in the same session as&#xD;
        endoscopic detection of SELs irrespective of their size. That method should ideally enable&#xD;
        histological diagnosis with low risks of complications and should not demand high technical&#xD;
        expertise and should not be highly operator dependent. The ideal solution to address the&#xD;
        diagnosis of gastrointestinal (GI) SEL would be one that would provide a tissue sampling&#xD;
        after exclusion of a highly vascular lesion, in the same session as the endoscopic diagnosis.&#xD;
  &#xD;
        Doppler endoscopic probe (DEP) is a 2-mm diameter, single-use, Doppler endoscopic probe&#xD;
        (Vascular Technology Inc, Nashua, NH) specifically developed for GI tract, that enables blood&#xD;
        flow detection during endoscopy. As lesions are unlikely to bleed substantially without a&#xD;
        major supply of blood flow, the applicability of endoscopic DEP resides in the ability to&#xD;
        detect blood flow within submucosal blood vessels that feed a potentially bleeding lesion&#xD;
        within the GI tract.&#xD;
  &#xD;
        DEP is CE and FDA approved and may be used through the working channel of the endoscope. The&#xD;
        DEP system is a 20-MHz, pulsed-wave Doppler ultrasound unit with 3 preset scanning depths:&#xD;
        from the surface to 1.5, 4, and 7 mm. It has an audible Doppler output signal but does not&#xD;
        have a visual monitor display. The unit is portable and battery-powered. Unlike standard EUS,&#xD;
        which requires advanced endoscopic training, DEP is much more straightforward to use&#xD;
        (15557966). The applicability of endoscopic Doppler US resides in the ability to detect blood&#xD;
        flow within submucosal blood vessels that feed a potentially bleeding lesion within the GI&#xD;
        tract. A positive DEP signal has been defined as a repetitive and similar visual spiking&#xD;
        waveform (or audible signal) of at least 3 consecutive cycle duration (indicating pulsatile&#xD;
        blood flow and minimizing the chance of a false-positive signal) (PMID: 10968843).&#xD;
  &#xD;
        Recent studies had demonstrated the safety and efficacy of DEP in the vascular&#xD;
        characterization of gastrointestinal peptic ulcers (26318834, 28167214).&#xD;
  &#xD;
        III- AIMS&#xD;
  &#xD;
        Primary aims:&#xD;
  &#xD;
          -  Proof-of-concept evaluation of the role of DEP in the characterization of GI SEL as&#xD;
             highly vascular or non-highly vascular.&#xD;
  &#xD;
          -  Correlation between findings on DEP versus finding on EUS (considered the gold standard)&#xD;
             in terms of SEL characterization as highly vascular or non-highly vascular.&#xD;
  &#xD;
        Secondary aims:&#xD;
  &#xD;
          -  Accuracy of unroofing in the histological characterization of subepitelial GI lesions.&#xD;
  &#xD;
          -  Complications associated with tissue acquisition through unroofing technique such as&#xD;
             bleeding or perforation&#xD;
  &#xD;
          -  Inter-observer agreement of the DEP findings.&#xD;
  &#xD;
        IV- METHODS&#xD;
  &#xD;
        STUDY DESIGN&#xD;
  &#xD;
        This is a pilot prospective feasibility study that will be run by Karolinska University&#xD;
        Hospital in Stockholm&#xD;
  &#xD;
        STUDY POPULATION Patients with subepithelial GI lesions referred for EUS evaluation. The&#xD;
        study will include 20 patients.&#xD;
  &#xD;
        Inclusion criteria&#xD;
  &#xD;
        - Presence of subepithelial lesion on the GI tract.&#xD;
  &#xD;
        Exclusion criteria&#xD;
  &#xD;
          -  Anticoagulation therapy that cannot be discontinued&#xD;
  &#xD;
          -  Liver cirrhosis with coagulopathy or varices&#xD;
  &#xD;
          -  Malignancy&#xD;
  &#xD;
        All patients will receive a detailed explanation regarding the procedure, its risks,&#xD;
        benefits, and alternatives, and provided written informed consent before inclusion (Appendix&#xD;
        1).&#xD;
  &#xD;
        Participants clinical, demographic, and procedural information will be obtained and recorded&#xD;
        at enrollment (Appendix 2).&#xD;
  &#xD;
        Patients under antiplatelet or anticoagulant drugs will be handled according to published&#xD;
        guidelines.&#xD;
  &#xD;
        OUTCOME PARAMETERS PRIMARY OUTCOME PARAMETERS DEP. The auditory sound from arterial flow&#xD;
        corresponds to a sound like a blood pressure &quot;swish-swish,&quot; whereas venous flow is a&#xD;
        low-pitched venous hum. Intensity will be recorded as soft, medium, or loud.&#xD;
  &#xD;
        Doppler on EUS will be evaluated as standard using the color-doppler and also wave flow&#xD;
        assessment.&#xD;
  &#xD;
        SECONDARY OUTCOME PARAMETERS Adverse events are defined as any complication in which DEP,&#xD;
        EUS, unroofing or related procedures are a contributing factor and include bleeding and&#xD;
        perforation.&#xD;
  &#xD;
        Perforation is defined as a full thickness breach in the GI wall with or without symptoms.&#xD;
  &#xD;
        Intraprocedural bleeding is considered significant and a complication when:&#xD;
  &#xD;
          -  blood transfusion is needed&#xD;
  &#xD;
          -  premature termination of endoscopic occurs&#xD;
  &#xD;
        Delayed bleeding is defined as clinical evidence of bleeding manifested by melena or&#xD;
        hematochezia from up to 14 days after the procedure that demanded presentation to the&#xD;
        emergency department, hospital admission or medical intervention.&#xD;
  &#xD;
        Adverse events are classified as:&#xD;
  &#xD;
          -  acute (during procedure)&#xD;
  &#xD;
          -  early (&lt;48 h)&#xD;
  &#xD;
          -  late (&gt;48 h).&#xD;
  &#xD;
        In terms of severity they are characterized as:&#xD;
  &#xD;
          -  mild (unplanned medical assistance, hospital admission, hospitalization &lt;3 days,&#xD;
             hemoglobin drop &lt;3 g, no transfusion)&#xD;
  &#xD;
          -  moderate (4-10 days hospitalization, &lt;4 units blood transfusion, repeat endoscopic&#xD;
             intervention, radiological intervention)&#xD;
  &#xD;
          -  severe (hospitalization &gt;10 days, intensive care unit (ICU) admission, need for surgery,&#xD;
             &gt;4 units blood transfusion) or fatal (death attributable to procedure) [7, 8].&#xD;
  &#xD;
        ENDOSCOPIC PROTOCOL&#xD;
  &#xD;
        A conventional gastroscopy will be performed. After identification of the lesion, DEP will be&#xD;
        performed. The DEP probe will be lubricated and deployed through the working channel of the&#xD;
        endoscope. The probe will contact slightly the mucosa covering the SEL. Then will evaluate&#xD;
        the lesion in 2 different angels (one at the top and one at the base of the lesion). First,&#xD;
        the superficial Doppler depth setting (&lt; 1.5 mm) will be used, followed by the middle setting&#xD;
        (&lt; 4 mm). Assessment will be recorded and endoscopist diagnosis (arterial flow/venous flow,&#xD;
        soft/medium/loud intensity) will be registered. All DEP will be performed by the same&#xD;
        endoscopist (MO). Findings will be characterized and registered qualitatively: no&#xD;
        flow/arterial flow/venous flow and in terms of intensity: soft, medium, or loud.&#xD;
  &#xD;
        After DEP, evaluation EUS will be performed by another endoscopists (FBS) that will be&#xD;
        blinded to the DEP findings. EUS will be considered the gold standard.&#xD;
  &#xD;
        After both assessments the lesion will be characterized as no vascular/low vascular/highly&#xD;
        vascular flow.&#xD;
  &#xD;
        EUS will be followed by unroofing of the SEL in patients in which EUS excluded the presence&#xD;
        of a highly vascular lesion. Unroofing will be performed using a conventional endoscopic&#xD;
        snare, through the working channel of the endoscope. After the surface of the lesion is&#xD;
        unroofed, a biopsy forceps will be used for tissue acquisition. Tissue will be stored in&#xD;
        formalin and processed and evaluated by pathologist.&#xD;
  &#xD;
        All data will be registered. All procedures will be recorded in video and audio (DEP).&#xD;
  &#xD;
        POST PROCEDURE PROTOCOL&#xD;
  &#xD;
        Before Discharge After unroofing, patients will be closely monitored for 2-4 hours under&#xD;
        continuous monitoring and then discharged if no complications detected.&#xD;
  &#xD;
        After Discharge At week 8 after discharge, patients will have a hospital visit for assessment&#xD;
        of complications and control endoscopy.&#xD;
  &#xD;
        V-SIGNIFICANCE With this study it will be possible to evaluate the strategy of DEP and&#xD;
        unroofing in the assessment of GI SEL. In case of positive results: good accuracy in the&#xD;
        diagnosis/exclusion of vascular lesions with DEP and good histological yield with unroofing,&#xD;
        this strategy may be further validated and might change the paradigm of management of GI SEL.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">August 1, 2023</start_date>
    <completion_date type="Anticipated">December 31, 2023</completion_date>
    <primary_completion_date type="Anticipated">December 31, 2023</primary_completion_date>
    <phase>N/A</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>N/A</allocation>
      <intervention_model>Single Group Assignment</intervention_model>
      <primary_purpose>Diagnostic</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>DEP accuracy</measure>
      <time_frame>From enrollment to the end of study at 8 weeks</time_frame>
      <description>DEP. The auditory sound from arterial flow corresponds to a sound like a blood pressure &quot;swish-swish,&quot; whereas venous flow is a low-pitched venous hum. Intensity will be recorded as soft, medium, or loud. Doppler on EUS will be evaluated as standard using the color-doppler and also wave flow assessment.</description>
    </primary_outcome>
    <number_of_arms>1</number_of_arms>
    <enrollment type="Anticipated">20</enrollment>
    <condition>Subepithelial Tumors of the Upper Gastrointestinal Tract</condition>
    <arm_group>
      <arm_group_label>Intervention</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Doppler endoscopic probe in the diagnosis of subepithelial gastrointestinal lesions</description>
    </arm_group>
    <intervention>
      <intervention_type>Device</intervention_type>
      <intervention_name>Doppler investigation</intervention_name>
      <description>Doppler investigation</description>
      <arm_group_label>Intervention</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Presence of subepithelial lesion on the GI tract.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Anticoagulation therapy that cannot be discontinued&#xD;
  &#xD;
            -  Liver cirrhosis with coagulopathy or varices&#xD;
  &#xD;
            -  Malignancy&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_contact>
      <last_name>Francisco Baldaque-Silva, MD PhD</last_name>
      <phone>+46704997219</phone>
      <email>fbaldaquesilva@gmail.com</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Masami Omae, MD</last_name>
      <phone>+46702578413</phone>
      <email>achami242000@gmail.com</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Karolinska University Hospital &amp; Karolinska Institute</name>
        <address>
          <city>Stockholm</city>
          <zip>11346</zip>
          <country>Sweden</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Karolinska University Hospital &amp; K Institute</last_name>
      </contact>
    </location>
    <location_countries>
      <country>Sweden</country>
    </location_countries>
    <reference>
      <citation>Hunt GC, Smith PP, Faigel DO. Yield of tissue sampling for submucosal lesions evaluated by EUS. Gastrointest Endosc. 2003 Jan;57(1):68-72. doi: 10.1067/mge.2003.34.</citation>
      <PMID>12518134</PMID>
    </reference>
    <reference>
      <citation>Philipper M, Hollerbach S, Gabbert HE, Heikaus S, Bocking A, Pomjanski N, Neuhaus H, Frieling T, Schumacher B. Prospective comparison of endoscopic ultrasound-guided fine-needle aspiration and surgical histology in upper gastrointestinal submucosal tumors. Endoscopy. 2010 Apr;42(4):300-5. doi: 10.1055/s-0029-1244006. Epub 2010 Mar 19.</citation>
      <PMID>20306384</PMID>
    </reference>
    <reference>
      <citation>Rosch T, Kapfer B, Will U, Baronius W, Strobel M, Lorenz R, Ulm K; German EUS Club. Endoscopic ultrasonography. Accuracy of endoscopic ultrasonography in upper gastrointestinal submucosal lesions: a prospective multicenter study. Scand J Gastroenterol. 2002 Jul;37(7):856-62.</citation>
      <PMID>12190103</PMID>
    </reference>
    <reference>
      <citation>Binmoeller KF, Shah JN, Bhat YM, Kane SD. Suck-ligate-unroof-biopsy by using a detachable 20-mm loop for the diagnosis and therapy of small subepithelial tumors (with video). Gastrointest Endosc. 2014 May;79(5):750-5. doi: 10.1016/j.gie.2013.09.028. Epub 2013 Nov 12. Erratum In: Gastrointest Endosc. 2014 Jul;80(1):196.</citation>
      <PMID>24238309</PMID>
    </reference>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 1, 2023</study_first_submitted>
    <study_first_submitted_qc>August 1, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 9, 2023</study_first_posted>
    <last_update_submitted>August 1, 2023</last_update_submitted>
    <last_update_submitted_qc>August 1, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 9, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor-Investigator</responsible_party_type>
      <investigator_affiliation>Karolinska University Hospital</investigator_affiliation>
      <investigator_full_name>Francisco Baldaque-Silva</investigator_full_name>
      <investigator_title>MD PhD, Senior consultant</investigator_title>
    </responsible_party>
    <keyword>Doppler, EUS, SEL</keyword>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT05983406
  org study id: KarolinskaUH 2019-05404
  secondary id: 2019-05404
  nct id: NCT05983406
  lead sponsor: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  RESEARCH PLAN I-TITLE Role of Doppler endoscopic probe in the diagnosis of subepithelial
        gastrointestinal lesions.
  
        II-BACKGROUND Subepithelial lesions (SEL) are commonly encountered during routine endoscopies
        with an estimated prevalence of 3.5%. Most of the SELs are detected during upper
        gastrointestinal endoscopy. Subsequently, endoscopic ultrasound (EUS) is performed to better
        characterize the lesion and to rule out the presence of a vascular lesion before tissue
        sampling due to the high risk of severe bleeding with tissue acquisition in vascular injury.
        However, EUS can rarely establish a definitive diagnosis per se with limited accuracy.
  
        In large lesions, it is possible to use cytology or histology needles via the EUS instrument
        to collect cells/tissue within the lesion. It can lead to accurate diagnosis and consistent
        management. However, EUS-guided tissue sampling can be technically challenging, with poor
        yield for small or mobile SELs. In addition, EUS is an expensive technique, high operator
        dependency and performed only in tertiary centers. It creates a time gap between endoscopic
        detection and the EUS examination and increases costs. That delay in diagnosis is a source of
        anxiety for the patient and for the caregivers.
  
        Several methods were proposed to increase the diagnostic yield of tissue acquisition
        techniques, such as "bite-on-bite" biopsies which showed a limited diagnostic yield.
        Alternatively, the "unroofing" technique has also been advocated for histological diagnosis.
        In unroofing, a loop is used to remove the normal epithelium covering the subepithelial
        lesions and after epithelial removal, a biopsy forceps or loop is used to sample
        subepithelial lesions. Other techniques include endoscopic resection by snare or submucosal
        dissection. These enable a surgical specimen but are technically demanding and have been
        complicated by perforation and bleeding in most series.
  
        There is a need for a method that enables rapid diagnosis in the same session as endoscopic
        detection of SEL regardless of their size. That method should ideally enable histological
        diagnosis with low risks of complications and should not require high technical expertise and
        should not be highly dependent on the operator. The ideal solution to address the diagnosis
        of gastrointestinal (GI) SEL would be one that would provide a tissue sampling after
        exclusion of a highly vascular lesion, in the same session as endoscopic detection.
  
        Doppler endoscopic probe (DEP) is a Doppler endoscopic probe specially developed for the GI
        system, which enables blood flow detection during endoscopy.
  
        DEP is CE and FDA approved and can be used through the working channel of the endoscope.
        Unlike standard EUS, which requires advanced endoscopic training, DEP is much easier to use.
        It allows the characterization of lesions as non-vascular, venous or arterial. Recent studies
        have demonstrated the safety and efficacy of DEP in vascular characterization in the
        gastrointestinal tract.
  
        III PURPOSE
  
        Primary objective:
  
          -  Proof of concept evaluation of the role of DEP in the characterization of GI SEL as
             non-vascular or vascular (arterial or venous)
  
          -  Relationship between findings on DEP versus findings on EUS (considered the gold
             standard) regarding SEL characterization as non-vascular or vascular (arterial or
             venous).
  
        Secondary purposes:
  
          -  Accuracy in removing the histological characterization of subepithelial GI lesions.
  
          -  Complications in connection with tissue acquisition
  
          -  Inter-observer agreement of DEP and EUS results. IV METHODS This is a pilot projective
             feasibility study that will be run by Karolinska University Hospital in Stockholm
             Patients with subepithelial GI lesions were referred for EUS evaluation. The study will
             include 30 patients.
  
        A conventional gastroscopy will be performed. After identification of the lesion, DEP is
        performed. The DEP probe is lubricated and deployed through the working channel of the
        endoscope. The probe will contact the mucosa slightly, covering the SEL. Then evaluate the
        lesion in 2 different angels. The results will be characterized and recorded qualitatively:
        no flow / arterial flow / venous flow and in terms of intensity: soft, medium or high.
  
        After DEP, evaluation EUS will be performed by another endoscopist who will be tied to the
        DEP results. EUS will be considered the gold standard.
  
        After both assessments, the lesion is characterized as no vessel / arterial / venous and as
        soft / medium / high flow intensity.
  
        EUS will be followed by removal of SEL in patients where EUS excludes the presence of high
        vessel disease. "Unroofing" will be performed using a conventional endoscopic loop, through
        the working channel of the endoscope. After the surface of the lesion is disturbed, a biopsy
        forceps will be used for tissue acquisition. Tissue will be stored in formalin and processed
        and evaluated by the pathologist.
  RESEARCH PLAN
  
        I-TITLE Role of doppler endoscopic probe in the diagnosis of subepithelial gastrointestinal
        lesions.
  
        II-BACKGROUND
  
        Subepithelial lesions (SELs) are commonly encountered on routine endoscopies with estimated
        prevalence of 3.5% (PMID: 24238309). Most small SELs are asymptomatic and benign, but their
        pathological diagnosis may be challenging, and sometimes impossible with conventional
        technology.
  
        Most of SELs are detected during upper gastrointestinal endoscopy. Afterwards, endoscopic
        ultrasound (EUS) is usually performed in order to better characterize the lesion and to
        exclude the presence of a vascular lesion. EUS enables evaluation of the size, structure and
        location of the lesion within the GI wall (submucosa/muscularis mucosa/ submucosa/muscularis
        propria), but can seldom stablish a definitive diagnosis per se. EUS provides valuable
        information regarding the layer of origin and can suggest a diagnosis, but it has been shown
        to have limited accuracy. (PMID: 12190103).
  
        In lesions larger than 2cm, it is possible to use dedicated cytologi (FNA) or histology (FNB)
        needles thought the EUS instrument in order to collect cells/tissue from within the lesion.
        That may lead to proper diagnosis and consequent management. However, EUS-guided tissue
        sampling can be technically challenging, with poor yields for small or mobile SELs
        (20306384). Additionally, EUS is an expensive technique, highly operator dependent and
        usually only performed in tertiary centers. That creates a time gap between the endoscopic
        detection and the EUS investigation, and increases the costs. That delay in the diagnosis is
        a source of anxiety for the patient and for health care providers alike.
  
        In cases with small or mobile SEL, in which a definitive diagnosis cannot be stablished with
        EUS plus FNA/FNB, surveillance is recommended. But the later, is associated with high costs
        and high burden for the health care system.
  
        Several methods were advocated to increase the diagnostic yield of tissue acquisition
        techniques such as "bite- on-bite" forceps biopsy that showed a limited diagnostic yield
        (PMID: 12518134), with one prospective study showing a diagnostic yield of only 17% compared
        with 87% with endoscopic resection (PMID: 16813799). Alternatively, unroofing technique has
        also been advocated in this context. With unroofing a snare is used to remove the normal
        epithelium that is covering the subepithelial lesion, and after epithelial removal a biopsy
        forceps is used to sample the subepithelial lesion. Other techniques include endoscopic
        resection by snaring or submucosal dissection. These enable a surgical specimen but are
        technically demanding and have been complicated by perforation and bleeding in most series.
  
        Although endoscopic resection may have the advantage of providing both a complete
        pathological diagnosis as well as treatment for the tumor in selected patients, it is
        questionable whether endoscopic resection of the entire lesion is needed for diagnostic
        purposes, because of the associated long procedure time and potentially serious
        complications, such as bleeding and perforation.
  
        EUS is usually performed before biopsy sampling, snaring or endoscopic resection in order to
        exclude the presence of a highly vascular SEL, due to the high risk of severe bleeding in
        case of tissue acquisition in a vascular lesion.
  
        There is a need for a method that would enable rapid diagnosis in the same session as
        endoscopic detection of SELs irrespective of their size. That method should ideally enable
        histological diagnosis with low risks of complications and should not demand high technical
        expertise and should not be highly operator dependent. The ideal solution to address the
        diagnosis of gastrointestinal (GI) SEL would be one that would provide a tissue sampling
        after exclusion of a highly vascular lesion, in the same session as the endoscopic diagnosis.
  
        Doppler endoscopic probe (DEP) is a 2-mm diameter, single-use, Doppler endoscopic probe
        (Vascular Technology Inc, Nashua, NH) specifically developed for GI tract, that enables blood
        flow detection during endoscopy. As lesions are unlikely to bleed substantially without a
        major supply of blood flow, the applicability of endoscopic DEP resides in the ability to
        detect blood flow within submucosal blood vessels that feed a potentially bleeding lesion
        within the GI tract.
  
        DEP is CE and FDA approved and may be used through the working channel of the endoscope. The
        DEP system is a 20-MHz, pulsed-wave Doppler ultrasound unit with 3 preset scanning depths:
        from the surface to 1.5, 4, and 7 mm. It has an audible Doppler output signal but does not
        have a visual monitor display. The unit is portable and battery-powered. Unlike standard EUS,
        which requires advanced endoscopic training, DEP is much more straightforward to use
        (15557966). The applicability of endoscopic Doppler US resides in the ability to detect blood
        flow within submucosal blood vessels that feed a potentially bleeding lesion within the GI
        tract. A positive DEP signal has been defined as a repetitive and similar visual spiking
        waveform (or audible signal) of at least 3 consecutive cycle duration (indicating pulsatile
        blood flow and minimizing the chance of a false-positive signal) (PMID: 10968843).
  
        Recent studies had demonstrated the safety and efficacy of DEP in the vascular
        characterization of gastrointestinal peptic ulcers (26318834, 28167214).
  
        III- AIMS
  
        Primary aims:
  
          -  Proof-of-concept evaluation of the role of DEP in the characterization of GI SEL as
             highly vascular or non-highly vascular.
  
          -  Correlation between findings on DEP versus finding on EUS (considered the gold standard)
             in terms of SEL characterization as highly vascular or non-highly vascular.
  
        Secondary aims:
  
          -  Accuracy of unroofing in the histological characterization of subepitelial GI lesions.
  
          -  Complications associated with tissue acquisition through unroofing technique such as
             bleeding or perforation
  
          -  Inter-observer agreement of the DEP findings.
  
        IV- METHODS
  
        STUDY DESIGN
  
        This is a pilot prospective feasibility study that will be run by Karolinska University
        Hospital in Stockholm
  
        STUDY POPULATION Patients with subepithelial GI lesions referred for EUS evaluation. The
        study will include 20 patients.
  
        Inclusion criteria
  
        - Presence of subepithelial lesion on the GI tract.
  
        Exclusion criteria
  
          -  Anticoagulation therapy that cannot be discontinued
  
          -  Liver cirrhosis with coagulopathy or varices
  
          -  Malignancy
  
        All patients will receive a detailed explanation regarding the procedure, its risks,
        benefits, and alternatives, and provided written informed consent before inclusion (Appendix
        1).
  
        Participants clinical, demographic, and procedural information will be obtained and recorded
        at enrollment (Appendix 2).
  
        Patients under antiplatelet or anticoagulant drugs will be handled according to published
        guidelines.
  
        OUTCOME PARAMETERS PRIMARY OUTCOME PARAMETERS DEP. The auditory sound from arterial flow
        corresponds to a sound like a blood pressure "swish-swish," whereas venous flow is a
        low-pitched venous hum. Intensity will be recorded as soft, medium, or loud.
  
        Doppler on EUS will be evaluated as standard using the color-doppler and also wave flow
        assessment.
  
        SECONDARY OUTCOME PARAMETERS Adverse events are defined as any complication in which DEP,
        EUS, unroofing or related procedures are a contributing factor and include bleeding and
        perforation.
  
        Perforation is defined as a full thickness breach in the GI wall with or without symptoms.
  
        Intraprocedural bleeding is considered significant and a complication when:
  
          -  blood transfusion is needed
  
          -  premature termination of endoscopic occurs
  
        Delayed bleeding is defined as clinical evidence of bleeding manifested by melena or
        hematochezia from up to 14 days after the procedure that demanded presentation to the
        emergency department, hospital admission or medical intervention.
  
        Adverse events are classified as:
  
          -  acute (during procedure)
  
          -  early (<48 h)
  
          -  late (>48 h).
  
        In terms of severity they are characterized as:
  
          -  mild (unplanned medical assistance, hospital admission, hospitalization <3 days,
             hemoglobin drop <3 g, no transfusion)
  
          -  moderate (4-10 days hospitalization, <4 units blood transfusion, repeat endoscopic
             intervention, radiological intervention)
  
          -  severe (hospitalization >10 days, intensive care unit (ICU) admission, need for surgery,
             >4 units blood transfusion) or fatal (death attributable to procedure) [7, 8].
  
        ENDOSCOPIC PROTOCOL
  
        A conventional gastroscopy will be performed. After identification of the lesion, DEP will be
        performed. The DEP probe will be lubricated and deployed through the working channel of the
        endoscope. The probe will contact slightly the mucosa covering the SEL. Then will evaluate
        the lesion in 2 different angels (one at the top and one at the base of the lesion). First,
        the superficial Doppler depth setting (< 1.5 mm) will be used, followed by the middle setting
        (< 4 mm). Assessment will be recorded and endoscopist diagnosis (arterial flow/venous flow,
        soft/medium/loud intensity) will be registered. All DEP will be performed by the same
        endoscopist (MO). Findings will be characterized and registered qualitatively: no
        flow/arterial flow/venous flow and in terms of intensity: soft, medium, or loud.
  
        After DEP, evaluation EUS will be performed by another endoscopists (FBS) that will be
        blinded to the DEP findings. EUS will be considered the gold standard.
  
        After both assessments the lesion will be characterized as no vascular/low vascular/highly
        vascular flow.
  
        EUS will be followed by unroofing of the SEL in patients in which EUS excluded the presence
        of a highly vascular lesion. Unroofing will be performed using a conventional endoscopic
        snare, through the working channel of the endoscope. After the surface of the lesion is
        unroofed, a biopsy forceps will be used for tissue acquisition. Tissue will be stored in
        formalin and processed and evaluated by pathologist.
  
        All data will be registered. All procedures will be recorded in video and audio (DEP).
  
        POST PROCEDURE PROTOCOL
  
        Before Discharge After unroofing, patients will be closely monitored for 2-4 hours under
        continuous monitoring and then discharged if no complications detected.
  
        After Discharge At week 8 after discharge, patients will have a hospital visit for assessment
        of complications and control endoscopy.
  
        V-SIGNIFICANCE With this study it will be possible to evaluate the strategy of DEP and
        unroofing in the assessment of GI SEL. In case of positive results: good accuracy in the
        diagnosis/exclusion of vascular lesions with DEP and good histological yield with unroofing,
        this strategy may be further validated and might change the paradigm of management of GI SEL.
  allocation: N/A
  intervention model: Single Group Assignment
  primary purpose: Diagnostic
  masking: None (Open Label)
  measure: DEP accuracy
  time frame: From enrollment to the end of study at 8 weeks
  description: DEP. The auditory sound from arterial flow corresponds to a sound like a blood pressure "swish-swish," whereas venous flow is a low-pitched venous hum. Intensity will be recorded as soft, medium, or loud. Doppler on EUS will be evaluated as standard using the color-doppler and also wave flow assessment.
  arm group label: Intervention
  arm group type: Experimental
  description: Doppler endoscopic probe in the diagnosis of subepithelial gastrointestinal lesions
  intervention type: Device
  intervention name: Doppler investigation
  description: Doppler investigation
  arm group label: Intervention
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Francisco Baldaque-Silva, MD PhD
  phone: +46704997219
  email: fbaldaquesilva@gmail.com
  last name: Masami Omae, MD
  phone: +46702578413
  email: achami242000@gmail.com
  facility: 
  status: Recruiting
  contact: 
  country: Sweden
  citation: Hunt GC, Smith PP, Faigel DO. Yield of tissue sampling for submucosal lesions evaluated by EUS. Gastrointest Endosc. 2003 Jan;57(1):68-72. doi: 10.1067/mge.2003.34.
  PMID: 12518134
  citation: Philipper M, Hollerbach S, Gabbert HE, Heikaus S, Bocking A, Pomjanski N, Neuhaus H, Frieling T, Schumacher B. Prospective comparison of endoscopic ultrasound-guided fine-needle aspiration and surgical histology in upper gastrointestinal submucosal tumors. Endoscopy. 2010 Apr;42(4):300-5. doi: 10.1055/s-0029-1244006. Epub 2010 Mar 19.
  PMID: 20306384
  citation: Rosch T, Kapfer B, Will U, Baronius W, Strobel M, Lorenz R, Ulm K; German EUS Club. Endoscopic ultrasonography. Accuracy of endoscopic ultrasonography in upper gastrointestinal submucosal lesions: a prospective multicenter study. Scand J Gastroenterol. 2002 Jul;37(7):856-62.
  PMID: 12190103
  citation: Binmoeller KF, Shah JN, Bhat YM, Kane SD. Suck-ligate-unroof-biopsy by using a detachable 20-mm loop for the diagnosis and therapy of small subepithelial tumors (with video). Gastrointest Endosc. 2014 May;79(5):750-5. doi: 10.1016/j.gie.2013.09.028. Epub 2013 Nov 12. Erratum In: Gastrointest Endosc. 2014 Jul;80(1):196.
  PMID: 24238309
  responsible party type: Sponsor-Investigator
  investigator affiliation: Karolinska University Hospital
  investigator full name: Francisco Baldaque-Silva
  investigator title: MD PhD, Senior consultant
  sharing ipd: No