<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/NCT03780361</url>
  </required_header>
  <id_info>
    <org_study_id>20658</org_study_id>
    <nct_id>NCT03780361</nct_id>
  </id_info>
  <brief_title>Changes in Inflammatory Biomarkers Including Soluble CD14 and Hyperreflective Foci in DME Patients Treated With Aflibercept (FORESIGHT)</brief_title>
  <acronym>FORESIGHT</acronym>
  <official_title>Changes in Inflammatory Biomarkers Including Soluble CD14 and Hyperreflective Foci in Diabetic Macular Edema Patients Treated With Aflibercept (FORESIGHT)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hyewon Chung</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bayer</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Konkuk University Medical Center</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>
      This study evaluates the effect of aflibercept on the change of cytokines incluing sCD14,&#xD;
      MCP-1, IL-6, and ICAM-1 in the aqueous humor of DME patients. Additionally, changes of visual&#xD;
      acuity (ETDRS), optical coherence tomography parameters including hyperreflective foci and&#xD;
      thickness of macula are also investigated.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Intraocular steroid agents have been shown to decrease inflammatory cytokines in diabetic&#xD;
      macular edema (DME) patients and thus have roles in the treatment of these patients. However,&#xD;
      I believe that anti-VEGF could effectively decrease intraocular inflammatory responses in&#xD;
      these patients with much fewer side effects than intraocular steroid agents.&#xD;
&#xD;
      Since soluble CD14 (sCD14) is the known marker of inflammatory cells including microglia,&#xD;
      increased or decreased retinal inflammation accompanied by DME could be monitored using sCD14&#xD;
      in patients with DME. Recently, I published an article regarding the strong association of&#xD;
      increased sCD14 in the aqueous humor (AH) from DME patients, especially in increased inner&#xD;
      retinal edema as well as increased hyper reflective foci (HF) in optical coherence tomography&#xD;
      (OCT). This associated changes of sCD14 levels and HF in the retina suggested that the HF&#xD;
      might represent the activated microglia in DME. I also showed that the intravitreal&#xD;
      bevacizumab injection resulted in a reduction of sCD14 in the AH and HF in OCT. However, that&#xD;
      study was retrospective and I could not have many patients' follow-up data after bevacizumab&#xD;
      treatments and thus was not able to get conclusive results regarding decreased retinal&#xD;
      inflammation after anti-VEGF. Therefore, I believe that a well-desinged prospective study is&#xD;
      needed to clarify whether retinal inflammation is ameliorated after anti-VEGF treatment.&#xD;
      Moreover, I believe that aflibercept is more appropriate and better drug than bevacizumab to&#xD;
      investigate the changes in the cytokine levels along with the improvement of inflammatory&#xD;
      milieu in DME due to the following reasons. First, recent DRCR.net Protocol-T reported the&#xD;
      superior clinical outome of aflibercept compared to bevacizumab on DME. Second, aflibercept&#xD;
      has significantly higher binding affinity to VEGF-A compared to ranibizumab or bevacizumab.&#xD;
      Third, aflibercept also binds to VEGF-B and placental growth factor (PlGF), unlike&#xD;
      ranibizumab or bevacizumab. PlGF-VEGFR1 pathway contributes to inflammation by triggering&#xD;
      production of proinflammatory cytokines.&#xD;
&#xD;
      Thus, I would like to investigate the efficacy of aflibercept for reducing inflammation in&#xD;
      DME. Therapeutic effects of aflibercept on reduction of DME in the context of amelioration of&#xD;
      inflammation will be proved using sCD14 and HF as surrogate markers in this proposed study.&#xD;
      Besides sCD14, tracking the cytokines including MCP-1, IL-6, and ICAM-1 in the AH in a&#xD;
      well-controlled prospective setting of aflibercept treatments will enhance our understanding&#xD;
      regarding the role of inflammation on DME, and the importance of aflibercept for decreasing&#xD;
      ocular inflammation in DME patients.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">May 17, 2019</start_date>
  <completion_date type="Anticipated">September 1, 2022</completion_date>
  <primary_completion_date type="Anticipated">November 30, 2021</primary_completion_date>
  <phase>Phase 4</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>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in the level of sCD14 in the aqueous humor</measure>
    <time_frame>From baseline to week 20</time_frame>
    <description>Change in the level of sCD14 in the aqueous humor measured by ELISA</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in the levels of cytokines (MCP-1, IL-6, ICAM-1) in the aqueous humor</measure>
    <time_frame>From baseline to week 20</time_frame>
    <description>Change in the levels of cytokines (MCP-1, IL-6, ICAM-1) in the aqueous humor measured by ELISA</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in the number of hyperreflective foci (HF) on optical coherence tomography (OCT)</measure>
    <time_frame>From baseline to week 20</time_frame>
    <description>Change in the number of HF on optical coherence tomography OCT B-scan</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in the thickeness of macula on OCT</measure>
    <time_frame>From baseline to week 20</time_frame>
    <description>Change in the thickeness of macula on OCT</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in mean visual acuity (ETDRS)</measure>
    <time_frame>From baseline to week 20</time_frame>
    <description>Change in mean visual acuity (ETDRS)</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">47</enrollment>
  <condition>Diabetic Macular Edema</condition>
  <arm_group>
    <arm_group_label>Aflibercept injection group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>drug: Eylea (aflibercept) (11.12mg/0.278ml) dose: 2mg (0.05ml) usage: With topical anesthesia and intravitreal injection of aflibercpt in aseptic condition.&#xD;
frequency and duration: monthly intravitreal aflibercept injections.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Aflibercept Injection</intervention_name>
    <description>Total 5 times of monthly intravitreal aflibercept injections will be done.</description>
    <arm_group_label>Aflibercept injection group</arm_group_label>
    <other_name>Eylea</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Adults ≥ 19 years with type 1 or 2 diabetes mellitus.&#xD;
&#xD;
          2. Patients with DME secondary to diabetes mellitus involving the center of the macula&#xD;
             (defined as the OCT center subfield) in the study eye.&#xD;
&#xD;
          3. Decrease in vision determined to be primarily the result of DME in the study eye.&#xD;
&#xD;
          4. BCVA ETDRS letter score of 80 to 24 (20/25 to 20/320) in the study eye.&#xD;
&#xD;
          5. Retinal thickness ≥ 300 µm as assessed by OCT in the study eye.&#xD;
&#xD;
          6. Willing and able to comply with clinic visits and study-related procedures.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Ocular conditions with a poorer prognosis in the fellow eye than in the study eye.&#xD;
&#xD;
          2. History of vitreoretinal surgery in the study eye.&#xD;
&#xD;
          3. Previous treatment with intraocular anti-angiogenic drugs (bevacizumab, ranibizumab&#xD;
             etc.) or laser photocoagulation in the study eye within 90 days.&#xD;
&#xD;
          4. Previous use of intraocular or periocular corticosteroids in the study eye within 120&#xD;
             days of day 1.&#xD;
&#xD;
          5. Invasive intraocular surgery incluing cataract surgery within 90 days of day 1.&#xD;
&#xD;
          6. Yttrium-aluminium-garnet capsulotomy in the study eye within 30 days before day 1.&#xD;
&#xD;
          7. Aphakia in the study eye.&#xD;
&#xD;
          8. Vitreomacular traction or epiretinal membrane in the study eye evident on OCT that is&#xD;
             thought to affect central vision.&#xD;
&#xD;
          9. Active proliferative diabetic retinopathy in the study eye.&#xD;
&#xD;
         10. Current iris neovascularization in the study eye.&#xD;
&#xD;
         11. Evidence of infection including infectious blepharitis, keratitis, scleritis, or&#xD;
             conjunctivitis in either eye.&#xD;
&#xD;
         12. Uncontrolled glaucoma in the study eye or filtration surgery for glaucoma in the past&#xD;
             or likely to be needed in the future on the study eye.&#xD;
&#xD;
         13. Intraocular pressure ≥25 mmHg in the study eye.&#xD;
&#xD;
         14. Myopia of a spherical equivalent prior to any possible refractive or cataract surgery&#xD;
             of ≥ -8 diopters.&#xD;
&#xD;
         15. Concurrent disease in the study eye, other than DME, that could compromise VA, require&#xD;
             medical or surgical intervention during the study period, or could confound&#xD;
             interpretation of the results (including uveitis, retinal vascular occlusion, retinal&#xD;
             detachment, macular hole, significanlty large hard exudate at macula, atrophy of&#xD;
             retinal pigment epithelium, submacular scar, macular isdhemia, or choroidal&#xD;
             neovascularization).&#xD;
&#xD;
         16. Only one functional eye even if that eye is otherwise eligible for the study.&#xD;
&#xD;
         17. Ocular media of insufficient quality to obtain fundus and OCT images.&#xD;
&#xD;
         18. Current treatment for a serious systemic infection.&#xD;
&#xD;
         19. Administration of systemic anti-angiogenic agents within 180 days before day 1.&#xD;
&#xD;
         20. Pregnant women, pregnancy planning during the study period, lactating&#xD;
&#xD;
         21. Severe active intraocular inflammation is observed in the eyes injected with&#xD;
             Aflibercept&#xD;
&#xD;
         22. History of hypersensitivity to Aflibercept or excipient&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>19 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Hyewon Chung</last_name>
    <phone>+82-2-2030-7657</phone>
    <email>hwchung711@gmail.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Hyungwoo Lee</last_name>
    <phone>+82-2-2030-8198</phone>
    <email>superpunch@hanmail.net</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Konkuk medical center</name>
      <address>
        <city>Seoul</city>
        <zip>05030</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Hyewon Chung, MD, PhD</last_name>
      <email>hwchung711@gmail.com</email>
    </contact>
    <contact_backup>
      <last_name>Hyungwoo Lee, MD, PhD</last_name>
      <phone>821062236014</phone>
      <email>20110128@kuh.ac.kr</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Korea, Republic of</country>
  </location_countries>
  <reference>
    <citation>Lee H, Jang H, Choi YA, Kim HC, Chung H. Association Between Soluble CD14 in the Aqueous Humor and Hyperreflective Foci on Optical Coherence Tomography in Patients With Diabetic Macular Edema. Invest Ophthalmol Vis Sci. 2018 Feb 1;59(2):715-721. doi: 10.1167/iovs.17-23042.</citation>
    <PMID>29392317</PMID>
  </reference>
  <verification_date>September 2020</verification_date>
  <study_first_submitted>December 17, 2018</study_first_submitted>
  <study_first_submitted_qc>December 17, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 19, 2018</study_first_posted>
  <last_update_submitted>September 21, 2020</last_update_submitted>
  <last_update_submitted_qc>September 21, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">September 22, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Konkuk University Medical Center</investigator_affiliation>
    <investigator_full_name>Hyewon Chung</investigator_full_name>
    <investigator_title>Associate professor</investigator_title>
  </responsible_party>
  <keyword>soluble CD14</keyword>
  <keyword>MCP-1</keyword>
  <keyword>IL-6</keyword>
  <keyword>ICAM-1</keyword>
  <keyword>cytokine</keyword>
  <keyword>visual acuity</keyword>
  <keyword>optical coherence tomography</keyword>
  <keyword>macular thickness</keyword>
  <keyword>hyperreflective foci</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Macular Edema</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aflibercept</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT03780361
org study id: 20658
nct id: NCT03780361
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This study evaluates the effect of aflibercept on the change of cytokines incluing sCD14,
      MCP-1, IL-6, and ICAM-1 in the aqueous humor of DME patients. Additionally, changes of visual
      acuity (ETDRS), optical coherence tomography parameters including hyperreflective foci and
      thickness of macula are also investigated.
Intraocular steroid agents have been shown to decrease inflammatory cytokines in diabetic
      macular edema (DME) patients and thus have roles in the treatment of these patients. However,
      I believe that anti-VEGF could effectively decrease intraocular inflammatory responses in
      these patients with much fewer side effects than intraocular steroid agents.

      Since soluble CD14 (sCD14) is the known marker of inflammatory cells including microglia,
      increased or decreased retinal inflammation accompanied by DME could be monitored using sCD14
      in patients with DME. Recently, I published an article regarding the strong association of
      increased sCD14 in the aqueous humor (AH) from DME patients, especially in increased inner
      retinal edema as well as increased hyper reflective foci (HF) in optical coherence tomography
      (OCT). This associated changes of sCD14 levels and HF in the retina suggested that the HF
      might represent the activated microglia in DME. I also showed that the intravitreal
      bevacizumab injection resulted in a reduction of sCD14 in the AH and HF in OCT. However, that
      study was retrospective and I could not have many patients' follow-up data after bevacizumab
      treatments and thus was not able to get conclusive results regarding decreased retinal
      inflammation after anti-VEGF. Therefore, I believe that a well-desinged prospective study is
      needed to clarify whether retinal inflammation is ameliorated after anti-VEGF treatment.
      Moreover, I believe that aflibercept is more appropriate and better drug than bevacizumab to
      investigate the changes in the cytokine levels along with the improvement of inflammatory
      milieu in DME due to the following reasons. First, recent DRCR.net Protocol-T reported the
      superior clinical outome of aflibercept compared to bevacizumab on DME. Second, aflibercept
      has significantly higher binding affinity to VEGF-A compared to ranibizumab or bevacizumab.
      Third, aflibercept also binds to VEGF-B and placental growth factor (PlGF), unlike
      ranibizumab or bevacizumab. PlGF-VEGFR1 pathway contributes to inflammation by triggering
      production of proinflammatory cytokines.

      Thus, I would like to investigate the efficacy of aflibercept for reducing inflammation in
      DME. Therapeutic effects of aflibercept on reduction of DME in the context of amelioration of
      inflammation will be proved using sCD14 and HF as surrogate markers in this proposed study.
      Besides sCD14, tracking the cytokines including MCP-1, IL-6, and ICAM-1 in the AH in a
      well-controlled prospective setting of aflibercept treatments will enhance our understanding
      regarding the role of inflammation on DME, and the importance of aflibercept for decreasing
      ocular inflammation in DME patients.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Change in the level of sCD14 in the aqueous humor
time frame: From baseline to week 20
description: Change in the level of sCD14 in the aqueous humor measured by ELISA
measure: Change in the levels of cytokines (MCP-1, IL-6, ICAM-1) in the aqueous humor
time frame: From baseline to week 20
description: Change in the levels of cytokines (MCP-1, IL-6, ICAM-1) in the aqueous humor measured by ELISA
measure: Change in the number of hyperreflective foci (HF) on optical coherence tomography (OCT)
time frame: From baseline to week 20
description: Change in the number of HF on optical coherence tomography OCT B-scan
measure: Change in the thickeness of macula on OCT
time frame: From baseline to week 20
description: Change in the thickeness of macula on OCT
measure: Change in mean visual acuity (ETDRS)
time frame: From baseline to week 20
description: Change in mean visual acuity (ETDRS)
arm group label: Aflibercept injection group
arm group type: Experimental
description: drug: Eylea (aflibercept) (11.12mg/0.278ml) dose: 2mg (0.05ml) usage: With topical anesthesia and intravitreal injection of aflibercpt in aseptic condition.
frequency and duration: monthly intravitreal aflibercept injections.
intervention type: Drug
intervention name: Aflibercept Injection
description: Total 5 times of monthly intravitreal aflibercept injections will be done.
arm group label: Aflibercept injection group
other name: Eylea
criteria: 
gender: All
minimum age: 19 Years
maximum age: N/A
healthy volunteers: No
last name: Hyewon Chung
phone: +82-2-2030-7657
email: hwchung711@gmail.com
last name: Hyungwoo Lee
phone: +82-2-2030-8198
email: superpunch@hanmail.net
facility: 
status: Recruiting
contact: 
contact backup: 
country: Korea, Republic of
citation: Lee H, Jang H, Choi YA, Kim HC, Chung H. Association Between Soluble CD14 in the Aqueous Humor and Hyperreflective Foci on Optical Coherence Tomography in Patients With Diabetic Macular Edema. Invest Ophthalmol Vis Sci. 2018 Feb 1;59(2):715-721. doi: 10.1167/iovs.17-23042.
PMID: 29392317
responsible party type: Sponsor-Investigator
investigator affiliation: Konkuk University Medical Center
investigator full name: Hyewon Chung
investigator title: Associate professor
mesh term: Macular Edema
mesh term: Aflibercept
sharing ipd: No