<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/NCT03757507</url>
  </required_header>
  <id_info>
    <org_study_id>201800515</org_study_id>
    <nct_id>NCT03757507</nct_id>
  </id_info>
  <brief_title>Investigation of Plaque Instability Using Bevacizumab-800CW and MSOT</brief_title>
  <acronym>Carotid</acronym>
  <official_title>Investigation of Plaque Instability: Identification of Atherosclerotic Plaque Angiogenesis Using Bevacizumab-800CW and Optoacoustic Imaging: a Single Center Proof of Concept Study (CAROTID-OPTOLIGHT)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>G.M. van Dam</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Medical Center Groningen</source>
  <oversight_info>
    <has_dmc>Yes</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>
      Determining whether we could visualize uptake of the fluorescent tracer Bevacizumab-800CW,&#xD;
      targeting VEGF-A in atherosclerotic plaques by using the new imaging technique Multispectral&#xD;
      Optoacoustic Tomography both in- and ex vivo.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Rationale: This project consists of the realization followed by the clinical validation of a&#xD;
      procedure dedicated to detect vulnerable atherosclerotic plaques patients with a symptomatic&#xD;
      carotid stenosis. If in the future it would be possible to detect a symptomatic carotid&#xD;
      atherosclerotic plaque non- invasively (i.e. those plaques resulting in cerebrovascular&#xD;
      accidents and/or transient ischemic attacks), this would strongly improve risk assessment&#xD;
      among this large cohort of patients. At the moment, indications for intervention are&#xD;
      primarily based on degree of stenosis, and not on degree of vulnerability. Symptomatology is&#xD;
      considered, but clinicians are not capable of predicting the consequences of a first event,&#xD;
      while two thirds of all patients with a major stroke are not preceded by previous minor&#xD;
      symptoms. Previous trials (NASCET and ECST) showed a significant absolute risk reduction for&#xD;
      symptomatic patients with a stenotic lesion of the internal carotid artery greater than 70%&#xD;
      after the performance of a carotid endarterectomy (CEA; excision of the atherosclerotic&#xD;
      plaque). However, surgery can be associated with significant morbidity and even mortality. On&#xD;
      the other hand, reliable prediction prior to surgery whether an atherosclerotic plaque is&#xD;
      going to become symptomatic could also prevent unnecessary surgery, which again significantly&#xD;
      reduces morbidity and mortality.&#xD;
&#xD;
      In literature and our preliminary ex vivo data with a nuclear imaging tracer&#xD;
      89Zr-Bevacizumab, it appears that vulnerable atherosclerotic plaques (i.e. those likely to&#xD;
      become symptomatic) have an increased rate of angiogenesis at the site of the rupture (i.e.&#xD;
      the site of the vulnerable plaque) which expose highly upregulated Vascular Endothelial&#xD;
      Growth Factor-A (VEGF-A) production as part of the inflammatory response within the plaque&#xD;
      and subsequently which can be visualized with a tracer targeting specifically VEGF-A.&#xD;
      Recently, these experiments have been repeated using Bevacizumab- CW800 showing similar&#xD;
      results (Huisman et al, preliminary data).&#xD;
&#xD;
      An intraoperative near-infrared fluorescence (NIRF) imaging camera, among a NIR fluorescence&#xD;
      endoscopy system, and the use of the optical contrast agent Bevacizumab-800CW in now more&#xD;
      than 250 patients has been evaluated for its feasibility to detect tumor lesions in patients&#xD;
      with colorectal cancer, colon polyps, Barret's esophagus, peritoneal carcinomatosis of&#xD;
      colorectal cancer origin and breast cancer. These studies showed that bevacizumab-800CW is&#xD;
      safe in clinical use and feasible to detect even small tumor lesions with a high sensitivity.&#xD;
      While Bevacizumab-800CW can also detect the soluble ligand VEGF-A, as shown by ex vivo&#xD;
      analyses of excised CEA specimen, we aim to investigate whether systemic administered&#xD;
      Bevacizumab-800CW can be applied to patients preoperatively for the detection of vulnerable&#xD;
      plaques by non-invasive optoacoustic imaging and subsequently ex vivo mesoscopic imaging for&#xD;
      validation purposes. The primary objective for the proposed study is to achieve pre-operative&#xD;
      detection of the atherosclerotic plaque for patients with a symptomatic carotid artery&#xD;
      stenosis by non-invasive optoacoustic imaging. In this study we will introduce the following&#xD;
      concept: a preoperative non-invasive optoacoustic-scan guided by the © UMCG october 2018&#xD;
      Version 2.0 7 of 40&#xD;
&#xD;
      Bevacizumab-800CW targeted VEGF-A. This will help us to detect if and at what time point&#xD;
      within the atherosclerotic plaque there is an upregulation of angiogenesis which can&#xD;
      cross-correlated by ex vivo analyses of characteristics of the vulnerable plaque (i.e.&#xD;
      atheroma, foam cells, influx of activated macrophages and angiogenesis as a result of&#xD;
      pro-inflammatory responses present in the plaque). The end-goal of the proposed dual pre- and&#xD;
      intra-operative imaging procedure is to prove that the symptomatic carotid atherosclerotic&#xD;
      plaque can be accurately and safely detected by VEGF-A targeted optical imaging agents. In&#xD;
      addition, this study serves as a step-up to a larger non-invasive VEGF-A targeted optical&#xD;
      imaging study expanding the detection technology by using a new non- invasive multispectral&#xD;
      optoacoustic detection system. Ultimately, VEGF-A targeted imaging in carotid stenosis could&#xD;
      be used to predict vulnerability of the atherosclerotic plaque non-invasively in order to&#xD;
      select those patients who will benefit the most of a surgical procedure.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      This feasibility study has two objectives:&#xD;
&#xD;
        -  To investigate whether it's feasible to detect plaques within the carotid artery using&#xD;
           optoacoustic imaging with the innovative MSOT Acuity Echo in patients with symptomatic&#xD;
           carotid stenosis.&#xD;
&#xD;
        -  To investigate whether the VEGF-targeted optical imaging agent Bevacizumab-800CW is able&#xD;
           to detect VEGF upregulation as a characteristic of the vulnerable plaque in carotid&#xD;
           tissue by means of pre-operative Bevacizumab-800CW optoacoustic imaging in patients with&#xD;
           symptomatic carotid stenosis cross-correlated by ex vivo histopathological analyses.&#xD;
&#xD;
      Study design: Interventional phase 1 technical feasibility study: non-randomized, open label,&#xD;
      uncontrolled with single group proof of concept study. This study will be carried out at the&#xD;
      University Medical Center Groningen, Department of Surgery and Department of Nuclear Medicine&#xD;
      and Molecular Imaging. Further analysis of sections of the plaques will be done at the&#xD;
      Department of Pathology at the UMCG and by the Helmholtz Institute, Biomedical Research&#xD;
      Centre, München.&#xD;
&#xD;
      Study population: Patients planned for elective endarterectomy for symptomatic carotid&#xD;
      stenosis will undergo prior to surgery imaging with an optoacoustic device before and after&#xD;
      intravenous injection with the VEGF-targeted optical imaging agent Bevacizumab-800CW.&#xD;
&#xD;
      Intervention: Patients planned to undergo endarterectomy for symptomatic carotid stenosis&#xD;
      will be consented for this study. The procedure will in no way delay the time interval&#xD;
      between onset of symptoms and intervention. Three days before the planned fluorescent&#xD;
      optoacoustic scanning, the patients will undergo optoacoustic imaging as a reference.&#xD;
      Patients then receive an intravenous injection of 4,5 mg flat-dose of Bevacizumab-800CW.&#xD;
      Three days after tracer administration, mostly&#xD;
&#xD;
      © UMCG october 2018 Version 2.0 8 of 40&#xD;
&#xD;
      the day patients are admitted to the hospital as standard-of-care, patients will undergo&#xD;
      final optoacoustic imaging.&#xD;
&#xD;
      Main study parameters/endpoints:&#xD;
&#xD;
      Primary Objective:&#xD;
&#xD;
        -  Feasibility of optoacoustic imaging to image the carotid artery and detect plaque&#xD;
           formation in patients with symptomatic carotid artery disease.&#xD;
&#xD;
        -  Pre-operative detection of the atherosclerotic plaque in symptomatic carotid stenosis by&#xD;
           the VEGF-targeted optical imaging agent optical imaging agent Bevacizumab-800CW using&#xD;
           optoacoustic imaging subsequently correlated ex vivo for VEGF upregulation within the&#xD;
           plaque indicative for increased angiogenesis.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">April 10, 2019</start_date>
  <completion_date type="Anticipated">March 1, 2020</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2019</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>
    <intervention_model_description>Open label, single group</intervention_model_description>
    <primary_purpose>Device Feasibility</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Feasibility of MSOT imaging</measure>
    <time_frame>12 months</time_frame>
    <description>Feasibility of optoacoustic imaging to image the carotid artery and detect plaque formation in patients with symptomatic carotid artery disease.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Ex vivo imaging</measure>
    <time_frame>12 months</time_frame>
    <description>Pre-operative detection of the atherosclerotic plaque in symptomatic carotid stenosis by the VEGF-targeted optical imaging agent optical imaging agent Bevacizumab-800CW using optoacoustic imaging subsequently correlated ex vivo for VEGF upregulation within the plaque indicative for increased angiogenesis.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Location of Fluorescence</measure>
    <time_frame>12 months</time_frame>
    <description>Presence of fluorescent signaling after excision of the atherosclerotic plaque ex vivo as determined by flatbed scanning and fluorescence microscopy.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">15</enrollment>
  <condition>Atherosclerosis</condition>
  <condition>Carotid Stenosis</condition>
  <condition>Fluorescence</condition>
  <arm_group>
    <arm_group_label>Optoacoustic imaging</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Optoacoustic Imaging before and after tracer administration</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>MultiSpectral Optoacoustic Tomography</intervention_name>
    <description>Multispectral Optoacoustic Tomography is a new emerging imaging technique which uses laser light to heat up molecules with a high pulsed laser. The molecules undergo thermal expansion and produces sound waves, which can be detected by special transducers. The device can pick up different signals in different wavelength to produce images with anatomic and biological information.</description>
    <arm_group_label>Optoacoustic imaging</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients above the age of 21 with an indication to undergo a carotid endarterectomy&#xD;
             for suspected symptomatic atherosclerotic plaque based on the presence of a CVA and/or&#xD;
             transient ischemic attacks (TIA's), including amourosis fugax.&#xD;
&#xD;
               1. Patients with significant and symptomatic carotid stenosis who are scheduled for&#xD;
                  carotid endarterectomy as decided by the surgeon or the Multi-Disciplinary&#xD;
                  Carotid Board&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Medical or psychiatric condition that compromises the patient's ability to give&#xD;
             informed consent&#xD;
&#xD;
          2. Pregnant or lactating women&#xD;
&#xD;
          3. Significantrenal(creatinine&gt;110μmol/L)dysfunction&#xD;
&#xD;
          4. History of iodine allergy or anaphylactic reactions to insect bites or medication or&#xD;
             previous allergic reaction to bevacizumab&#xD;
&#xD;
          5. Presence or history of hyperthyroidism&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <verification_date>April 2019</verification_date>
  <study_first_submitted>November 26, 2018</study_first_submitted>
  <study_first_submitted_qc>November 26, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 29, 2018</study_first_posted>
  <last_update_submitted>April 10, 2019</last_update_submitted>
  <last_update_submitted_qc>April 10, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">April 12, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University Medical Center Groningen</investigator_affiliation>
    <investigator_full_name>G.M. van Dam</investigator_full_name>
    <investigator_title>Professor van Dam</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carotid Stenosis</mesh_term>
    <mesh_term>Atherosclerosis</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03757507
org study id: 201800515
nct id: NCT03757507
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Determining whether we could visualize uptake of the fluorescent tracer Bevacizumab-800CW,
      targeting VEGF-A in atherosclerotic plaques by using the new imaging technique Multispectral
      Optoacoustic Tomography both in- and ex vivo.
Rationale: This project consists of the realization followed by the clinical validation of a
      procedure dedicated to detect vulnerable atherosclerotic plaques patients with a symptomatic
      carotid stenosis. If in the future it would be possible to detect a symptomatic carotid
      atherosclerotic plaque non- invasively (i.e. those plaques resulting in cerebrovascular
      accidents and/or transient ischemic attacks), this would strongly improve risk assessment
      among this large cohort of patients. At the moment, indications for intervention are
      primarily based on degree of stenosis, and not on degree of vulnerability. Symptomatology is
      considered, but clinicians are not capable of predicting the consequences of a first event,
      while two thirds of all patients with a major stroke are not preceded by previous minor
      symptoms. Previous trials (NASCET and ECST) showed a significant absolute risk reduction for
      symptomatic patients with a stenotic lesion of the internal carotid artery greater than 70%
      after the performance of a carotid endarterectomy (CEA; excision of the atherosclerotic
      plaque). However, surgery can be associated with significant morbidity and even mortality. On
      the other hand, reliable prediction prior to surgery whether an atherosclerotic plaque is
      going to become symptomatic could also prevent unnecessary surgery, which again significantly
      reduces morbidity and mortality.

      In literature and our preliminary ex vivo data with a nuclear imaging tracer
      89Zr-Bevacizumab, it appears that vulnerable atherosclerotic plaques (i.e. those likely to
      become symptomatic) have an increased rate of angiogenesis at the site of the rupture (i.e.
      the site of the vulnerable plaque) which expose highly upregulated Vascular Endothelial
      Growth Factor-A (VEGF-A) production as part of the inflammatory response within the plaque
      and subsequently which can be visualized with a tracer targeting specifically VEGF-A.
      Recently, these experiments have been repeated using Bevacizumab- CW800 showing similar
      results (Huisman et al, preliminary data).

      An intraoperative near-infrared fluorescence (NIRF) imaging camera, among a NIR fluorescence
      endoscopy system, and the use of the optical contrast agent Bevacizumab-800CW in now more
      than 250 patients has been evaluated for its feasibility to detect tumor lesions in patients
      with colorectal cancer, colon polyps, Barret's esophagus, peritoneal carcinomatosis of
      colorectal cancer origin and breast cancer. These studies showed that bevacizumab-800CW is
      safe in clinical use and feasible to detect even small tumor lesions with a high sensitivity.
      While Bevacizumab-800CW can also detect the soluble ligand VEGF-A, as shown by ex vivo
      analyses of excised CEA specimen, we aim to investigate whether systemic administered
      Bevacizumab-800CW can be applied to patients preoperatively for the detection of vulnerable
      plaques by non-invasive optoacoustic imaging and subsequently ex vivo mesoscopic imaging for
      validation purposes. The primary objective for the proposed study is to achieve pre-operative
      detection of the atherosclerotic plaque for patients with a symptomatic carotid artery
      stenosis by non-invasive optoacoustic imaging. In this study we will introduce the following
      concept: a preoperative non-invasive optoacoustic-scan guided by the © UMCG october 2018
      Version 2.0 7 of 40

      Bevacizumab-800CW targeted VEGF-A. This will help us to detect if and at what time point
      within the atherosclerotic plaque there is an upregulation of angiogenesis which can
      cross-correlated by ex vivo analyses of characteristics of the vulnerable plaque (i.e.
      atheroma, foam cells, influx of activated macrophages and angiogenesis as a result of
      pro-inflammatory responses present in the plaque). The end-goal of the proposed dual pre- and
      intra-operative imaging procedure is to prove that the symptomatic carotid atherosclerotic
      plaque can be accurately and safely detected by VEGF-A targeted optical imaging agents. In
      addition, this study serves as a step-up to a larger non-invasive VEGF-A targeted optical
      imaging study expanding the detection technology by using a new non- invasive multispectral
      optoacoustic detection system. Ultimately, VEGF-A targeted imaging in carotid stenosis could
      be used to predict vulnerability of the atherosclerotic plaque non-invasively in order to
      select those patients who will benefit the most of a surgical procedure.

      Objective:

      This feasibility study has two objectives:

        -  To investigate whether it's feasible to detect plaques within the carotid artery using
           optoacoustic imaging with the innovative MSOT Acuity Echo in patients with symptomatic
           carotid stenosis.

        -  To investigate whether the VEGF-targeted optical imaging agent Bevacizumab-800CW is able
           to detect VEGF upregulation as a characteristic of the vulnerable plaque in carotid
           tissue by means of pre-operative Bevacizumab-800CW optoacoustic imaging in patients with
           symptomatic carotid stenosis cross-correlated by ex vivo histopathological analyses.

      Study design: Interventional phase 1 technical feasibility study: non-randomized, open label,
      uncontrolled with single group proof of concept study. This study will be carried out at the
      University Medical Center Groningen, Department of Surgery and Department of Nuclear Medicine
      and Molecular Imaging. Further analysis of sections of the plaques will be done at the
      Department of Pathology at the UMCG and by the Helmholtz Institute, Biomedical Research
      Centre, München.

      Study population: Patients planned for elective endarterectomy for symptomatic carotid
      stenosis will undergo prior to surgery imaging with an optoacoustic device before and after
      intravenous injection with the VEGF-targeted optical imaging agent Bevacizumab-800CW.

      Intervention: Patients planned to undergo endarterectomy for symptomatic carotid stenosis
      will be consented for this study. The procedure will in no way delay the time interval
      between onset of symptoms and intervention. Three days before the planned fluorescent
      optoacoustic scanning, the patients will undergo optoacoustic imaging as a reference.
      Patients then receive an intravenous injection of 4,5 mg flat-dose of Bevacizumab-800CW.
      Three days after tracer administration, mostly

      © UMCG october 2018 Version 2.0 8 of 40

      the day patients are admitted to the hospital as standard-of-care, patients will undergo
      final optoacoustic imaging.

      Main study parameters/endpoints:

      Primary Objective:

        -  Feasibility of optoacoustic imaging to image the carotid artery and detect plaque
           formation in patients with symptomatic carotid artery disease.

        -  Pre-operative detection of the atherosclerotic plaque in symptomatic carotid stenosis by
           the VEGF-targeted optical imaging agent optical imaging agent Bevacizumab-800CW using
           optoacoustic imaging subsequently correlated ex vivo for VEGF upregulation within the
           plaque indicative for increased angiogenesis.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Open label, single group
primary purpose: Device Feasibility
masking: None (Open Label)
measure: Feasibility of MSOT imaging
time frame: 12 months
description: Feasibility of optoacoustic imaging to image the carotid artery and detect plaque formation in patients with symptomatic carotid artery disease.
measure: Ex vivo imaging
time frame: 12 months
description: Pre-operative detection of the atherosclerotic plaque in symptomatic carotid stenosis by the VEGF-targeted optical imaging agent optical imaging agent Bevacizumab-800CW using optoacoustic imaging subsequently correlated ex vivo for VEGF upregulation within the plaque indicative for increased angiogenesis.
measure: Location of Fluorescence
time frame: 12 months
description: Presence of fluorescent signaling after excision of the atherosclerotic plaque ex vivo as determined by flatbed scanning and fluorescence microscopy.
arm group label: Optoacoustic imaging
arm group type: Experimental
description: Optoacoustic Imaging before and after tracer administration
intervention type: Device
intervention name: MultiSpectral Optoacoustic Tomography
description: Multispectral Optoacoustic Tomography is a new emerging imaging technique which uses laser light to heat up molecules with a high pulsed laser. The molecules undergo thermal expansion and produces sound waves, which can be detected by special transducers. The device can pick up different signals in different wavelength to produce images with anatomic and biological information.
arm group label: Optoacoustic imaging
criteria: 
gender: All
minimum age: 21 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
responsible party type: Sponsor-Investigator
investigator affiliation: University Medical Center Groningen
investigator full name: G.M. van Dam
investigator title: Professor van Dam
mesh term: Carotid Stenosis
mesh term: Atherosclerosis
sharing ipd: Undecided