<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/NCT03006081</url>
  </required_header>
  <id_info>
    <org_study_id>FLOW_001</org_study_id>
    <nct_id>NCT03006081</nct_id>
  </id_info>
  <brief_title>The Efficacy of Intravitreal Aflibercept Injection in Improvement of Retinal Nonperfusion in Diabetic Retinopathy</brief_title>
  <official_title>The Efficacy of Intravitreal Aflibercept Injection in Improvement of Retinal Nonperfusion in Patients With Diabetic Retinopathy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Asan Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Asan Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Retinal nonperfusion drives vision-threatening complications such as pathological&#xD;
      neovascularization, which can lead to neovascular glaucoma, vitreous hemorrhage, or&#xD;
      tractional retinal detachments and macular edema in diabetic retinopathy. Thus, decreasing&#xD;
      nonperfusion area with aid of anti-VEGF agents might be a useful way to prevent deteriorating&#xD;
      course of diabetic retinopathy. The main purpose of this study is to determine the efficacy&#xD;
      of intravitreal aflibercept injection in improvement of retinal nonperfusion and identify&#xD;
      associated factors in patients with nonproliferative diabetic retinopathy with moderate&#xD;
      retinal nonperfusion.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Retinal nonperfusion drives vision-threatening complications such as pathological&#xD;
      neovascularization, which can lead to neovascular glaucoma, vitreous hemorrhage, or&#xD;
      tractional retinal detachments and macular edema in various retinal vascular diseases&#xD;
      including diabetic retinopathy and retinal vein occlusion. Silva et al revealed that retinal&#xD;
      nonperfusion area was correlated highly with diabetic retinopathy severity in their recent&#xD;
      paper. It should be clarified that retinal nonperfusion is not synonymous with retinal&#xD;
      ischemia, which implies tissue hypoxia, but is a useful surrogate.&#xD;
&#xD;
      Retinal nonperfusion has known to be associated with the production of vascular endothelial&#xD;
      factor (VEGF). Recently, Campochiaro et al reported that neutralization of VEGF using&#xD;
      ranibizumab improved macular edema and reversed the worsening of retinal nonperfusion in&#xD;
      patients with retinal vein occlusion and diabetic macular edema. The precise mechanism for&#xD;
      improved perfusion in the VEGF treated eye is uncertain. The authors suggested that VEGF&#xD;
      exacerbates retinal ischemia by increasing leukostasis, and intravitreal anti-VEGF agents may&#xD;
      break the feedback loop, allowing reperfusion to occur. There might be a portion of&#xD;
      circulation that is closed but not permanently, and this reversible closure is modulated by&#xD;
      VEGF.&#xD;
&#xD;
      The study by Campochiaro et al, however, was limited in that they reviewed retinal&#xD;
      nonperfusion within a template consisting of the Early Treatment Diabetic Retinopathy&#xD;
      subfields mainly confined to posterior pole of the fundus. Wide-field retinal imaging is an&#xD;
      imaging technique that allows a view of almost 200° of the fundus in a single image. It has&#xD;
      been well shown that wide-field scans allow the detection of peripheral pathology that may be&#xD;
      missed on 75 degrees of achieved by montaging the Early Treatment Diabetic Retinopathy Study&#xD;
      7-standard fields.&#xD;
&#xD;
      To investigators knowledge, there has been no previous study evaluating the longitudinal&#xD;
      change of retinal nonperfusion after aflibercept treatment in a larger area of the retina by&#xD;
      taking advantage of the 200° field of view in diabetic retinopathy. The main purpose of this&#xD;
      study is to determine the efficacy of intravitreal aflibercept injection in improvement of&#xD;
      retinal nonperfusion and identify associated factors in patients with nonproliferative&#xD;
      diabetic retinopathy with moderate retinal nonperfusion.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>May 2016</start_date>
  <completion_date type="Anticipated">June 2018</completion_date>
  <primary_completion_date type="Anticipated">June 2017</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Improvement of retinal nonperfusion</measure>
    <time_frame>1 year</time_frame>
    <description>Mean changes (%) of retinal nonperfusion (Ischemic index) from baseline</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>progression of diabetic retinopathy to proliferative diabetic retinopathy (PDR)</measure>
    <time_frame>1 year</time_frame>
    <description>Number of patients who receive rescue treatment due to PDR and time to rescue treatment due to PDR</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>development of diabetic macular edema</measure>
    <time_frame>1 year</time_frame>
    <description>Number of patients who receive rescue treatment due to DME and time to rescue treatment due to DME</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Factors associated with the progression of retinal nonperfusion 1 (Functional)</measure>
    <time_frame>1 year</time_frame>
    <description>- Visual acuity parameters: Mean changes of BCVA from baseline at every 3 month visit The proportion of subjects with gaining / losing ≥ 15letters or more in BCVA</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Factors associated with the progression of retinal nonperfusion 2 (Anatomical)</measure>
    <time_frame>1 year</time_frame>
    <description>- Optical coherence tomography (OCT) parameters: Mean changes of Central Retinal Thickness (CRT) from baseline at every 3 month visit Mean changes of Central Retinal Volume from baseline at every 3 month visit Mean change subfoveal choroidal thickness (SFChT) from baseline at every 3 month visit</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Factors associated with the progression of retinal nonperfusion 3 (Anatomical)</measure>
    <time_frame>1year</time_frame>
    <description>- Fluorescein angiography (FA) parameters: Baselinenonperfusion area(Ischemic index) at posterior and peripheral retina Baseline degree of vascular leakage at posterior and peripheral retina</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Safety outcome; Adverse effect of intravitreal aflibercept (Eylea) injection</measure>
    <time_frame>1 year</time_frame>
    <description>Ocular and systemic adverse event</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Diabetic Retinopathy</condition>
  <arm_group>
    <arm_group_label>2mg intravitreal aflibercept injection</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>2mg intravitreal aflibercept (Eylea) injection at baseline, 1M, 2M, 3M, 4M, and 5M</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Intravitreal Aflibercept injection</intervention_name>
    <description>Six number of injections at baseline, 1M, 2M, 3M, 4M, and 5M</description>
    <arm_group_label>2mg intravitreal aflibercept injection</arm_group_label>
    <other_name>Eylea</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  A subject must meet the following criteria to be eligible for inclusion in the study:&#xD;
&#xD;
               1. Adults ≥ 18 years with type 1 or 2 diabetes mellitus&#xD;
&#xD;
               2. Patients diagnosed as nonproliferative diabetic retinopathy with retinal&#xD;
                  nonperfusion (Ischemic index &gt;20%) Severe nonproliferative diabetic retinopathy -&#xD;
                  Early proliferative diabetic retinopathy&#xD;
&#xD;
               3. Willing and able to comply with clinic visits and study-related procedures&#xD;
&#xD;
               4. Provide a signed informed consent form&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  A subject who meets any of the following criteria will be excluded from the study.&#xD;
&#xD;
               1. Systemic exclusion criteria 1. Renal failure requiring hemodialysis or peritoneal&#xD;
                  dialysis within 6 months prior to baseline or anticipated need for hemodialysis,&#xD;
                  peritoneal dialysis at any time during the study 2. Acute cardiovascular events&#xD;
                  (acute myocardiac infarction and/or cerebral infarction) within 1 year before&#xD;
                  Visit 1 3. Blood HbA1c level greater than 12% at Visit 0&#xD;
&#xD;
               2. Ocular exclusion criteria&#xD;
&#xD;
               1. Diabetic macular edema involving the center of the macula (Defined as the area of&#xD;
                  the center subfield of OCT, Heidelberg Spectralis: ≥305 in women; ≥320 in men) in&#xD;
                  the study eye&#xD;
&#xD;
               2. Presence of rubeosis (neovascularization of the iris or the angle) in the study&#xD;
                  eye&#xD;
&#xD;
               3. Any current or history of retinal diseases that affects visual acuity in the&#xD;
                  study eye&#xD;
&#xD;
               4. Previous treatment of panretinal photocoagulation&#xD;
&#xD;
               5. Previous treatment with anti-VEGF in study eye within 6 months before Visit 1&#xD;
&#xD;
               6. Previous treatment with intraocular or periocular corticosteroids in the study&#xD;
                  eye within 6 months before Visit 1&#xD;
&#xD;
               7. Previous history of intraocular surgery other than cataract surgery in the study&#xD;
                  eye&#xD;
&#xD;
               8. Cataract surgery within 3 months before Visit 1 in the study eye&#xD;
&#xD;
               9. Yttrium-aluminium-garnet (YAG) capsulotomy in the study eye within 1 month before&#xD;
                  Visit 1&#xD;
&#xD;
              10. Aphakia in the study eye&#xD;
&#xD;
              11. Elevated intraocular pressure (≥ 22 mmHg) in spite of using topical IOP lowering&#xD;
                  agents at Visit 1 or a diagnosis of glaucoma (Visual field defect corresponding&#xD;
                  to glaucomatous optic neuropathy) in the study eye&#xD;
&#xD;
              12. Presence of a visually significant cataract in the study eye&#xD;
&#xD;
              13. BCVA score &lt; 34 letters in the fellow eye&#xD;
&#xD;
              14. Hypersensitivity to aflibercept&#xD;
&#xD;
              15. Ocular or periocular infection&#xD;
&#xD;
              16. Active intraocular inflammation&#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_official>
    <last_name>Young Hee Yoon</last_name>
    <role>Principal Investigator</role>
    <affiliation>Asan Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Yoon Jeon Kim, MD</last_name>
    <phone>82-2-3010-3680</phone>
    <email>anne215@gmail.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>Asan medical center</name>
      <address>
        <city>Olympicro 43 gil 88, Seoul</city>
        <zip>05505</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Young Hee Yoon, MD</last_name>
      <phone>82-2-3010-3680</phone>
    </contact>
  </location>
  <location_countries>
    <country>Korea, Republic of</country>
  </location_countries>
  <reference>
    <citation>Silva PS, Dela Cruz AJ, Ledesma MG, van Hemert J, Radwan A, Cavallerano JD, Aiello LM, Sun JK, Aiello LP. Diabetic Retinopathy Severity and Peripheral Lesions Are Associated with Nonperfusion on Ultrawide Field Angiography. Ophthalmology. 2015 Dec;122(12):2465-72. doi: 10.1016/j.ophtha.2015.07.034. Epub 2015 Sep 6.</citation>
    <PMID>26350546</PMID>
  </reference>
  <reference>
    <citation>Campochiaro PA, Wykoff CC, Shapiro H, Rubio RG, Ehrlich JS. Neutralization of vascular endothelial growth factor slows progression of retinal nonperfusion in patients with diabetic macular edema. Ophthalmology. 2014 Sep;121(9):1783-9. doi: 10.1016/j.ophtha.2014.03.021. Epub 2014 Apr 24.</citation>
    <PMID>24768239</PMID>
  </reference>
  <reference>
    <citation>Silva PS, Cavallerano JD, Haddad NM, Kwak H, Dyer KH, Omar AF, Shikari H, Aiello LM, Sun JK, Aiello LP. Peripheral Lesions Identified on Ultrawide Field Imaging Predict Increased Risk of Diabetic Retinopathy Progression over 4 Years. Ophthalmology. 2015 May;122(5):949-56. doi: 10.1016/j.ophtha.2015.01.008. Epub 2015 Feb 19.</citation>
    <PMID>25704318</PMID>
  </reference>
  <verification_date>December 2016</verification_date>
  <study_first_submitted>December 5, 2016</study_first_submitted>
  <study_first_submitted_qc>December 29, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 30, 2016</study_first_posted>
  <last_update_submitted>December 29, 2016</last_update_submitted>
  <last_update_submitted_qc>December 29, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">December 30, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Asan Medical Center</investigator_affiliation>
    <investigator_full_name>Young Hee Yoon</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>Retinal nonperfusion</keyword>
  <keyword>Aflibercept</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Retinal Diseases</mesh_term>
    <mesh_term>Diabetic Retinopathy</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>Yes</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/NCT03006081
org study id: FLOW_001
nct id: NCT03006081
lead sponsor: 
has dmc: Yes
Retinal nonperfusion drives vision-threatening complications such as pathological
      neovascularization, which can lead to neovascular glaucoma, vitreous hemorrhage, or
      tractional retinal detachments and macular edema in diabetic retinopathy. Thus, decreasing
      nonperfusion area with aid of anti-VEGF agents might be a useful way to prevent deteriorating
      course of diabetic retinopathy. The main purpose of this study is to determine the efficacy
      of intravitreal aflibercept injection in improvement of retinal nonperfusion and identify
      associated factors in patients with nonproliferative diabetic retinopathy with moderate
      retinal nonperfusion.
Retinal nonperfusion drives vision-threatening complications such as pathological
      neovascularization, which can lead to neovascular glaucoma, vitreous hemorrhage, or
      tractional retinal detachments and macular edema in various retinal vascular diseases
      including diabetic retinopathy and retinal vein occlusion. Silva et al revealed that retinal
      nonperfusion area was correlated highly with diabetic retinopathy severity in their recent
      paper. It should be clarified that retinal nonperfusion is not synonymous with retinal
      ischemia, which implies tissue hypoxia, but is a useful surrogate.

      Retinal nonperfusion has known to be associated with the production of vascular endothelial
      factor (VEGF). Recently, Campochiaro et al reported that neutralization of VEGF using
      ranibizumab improved macular edema and reversed the worsening of retinal nonperfusion in
      patients with retinal vein occlusion and diabetic macular edema. The precise mechanism for
      improved perfusion in the VEGF treated eye is uncertain. The authors suggested that VEGF
      exacerbates retinal ischemia by increasing leukostasis, and intravitreal anti-VEGF agents may
      break the feedback loop, allowing reperfusion to occur. There might be a portion of
      circulation that is closed but not permanently, and this reversible closure is modulated by
      VEGF.

      The study by Campochiaro et al, however, was limited in that they reviewed retinal
      nonperfusion within a template consisting of the Early Treatment Diabetic Retinopathy
      subfields mainly confined to posterior pole of the fundus. Wide-field retinal imaging is an
      imaging technique that allows a view of almost 200° of the fundus in a single image. It has
      been well shown that wide-field scans allow the detection of peripheral pathology that may be
      missed on 75 degrees of achieved by montaging the Early Treatment Diabetic Retinopathy Study
      7-standard fields.

      To investigators knowledge, there has been no previous study evaluating the longitudinal
      change of retinal nonperfusion after aflibercept treatment in a larger area of the retina by
      taking advantage of the 200° field of view in diabetic retinopathy. The main purpose of this
      study is to determine the efficacy of intravitreal aflibercept injection in improvement of
      retinal nonperfusion and identify associated factors in patients with nonproliferative
      diabetic retinopathy with moderate retinal nonperfusion.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Improvement of retinal nonperfusion
time frame: 1 year
description: Mean changes (%) of retinal nonperfusion (Ischemic index) from baseline
measure: progression of diabetic retinopathy to proliferative diabetic retinopathy (PDR)
time frame: 1 year
description: Number of patients who receive rescue treatment due to PDR and time to rescue treatment due to PDR
measure: development of diabetic macular edema
time frame: 1 year
description: Number of patients who receive rescue treatment due to DME and time to rescue treatment due to DME
measure: Factors associated with the progression of retinal nonperfusion 1 (Functional)
time frame: 1 year
description: - Visual acuity parameters: Mean changes of BCVA from baseline at every 3 month visit The proportion of subjects with gaining / losing ≥ 15letters or more in BCVA
measure: Factors associated with the progression of retinal nonperfusion 2 (Anatomical)
time frame: 1 year
description: - Optical coherence tomography (OCT) parameters: Mean changes of Central Retinal Thickness (CRT) from baseline at every 3 month visit Mean changes of Central Retinal Volume from baseline at every 3 month visit Mean change subfoveal choroidal thickness (SFChT) from baseline at every 3 month visit
measure: Factors associated with the progression of retinal nonperfusion 3 (Anatomical)
time frame: 1year
description: - Fluorescein angiography (FA) parameters: Baselinenonperfusion area(Ischemic index) at posterior and peripheral retina Baseline degree of vascular leakage at posterior and peripheral retina
measure: Safety outcome; Adverse effect of intravitreal aflibercept (Eylea) injection
time frame: 1 year
description: Ocular and systemic adverse event
arm group label: 2mg intravitreal aflibercept injection
arm group type: Experimental
description: 2mg intravitreal aflibercept (Eylea) injection at baseline, 1M, 2M, 3M, 4M, and 5M
intervention type: Drug
intervention name: Intravitreal Aflibercept injection
description: Six number of injections at baseline, 1M, 2M, 3M, 4M, and 5M
arm group label: 2mg intravitreal aflibercept injection
other name: Eylea
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Young Hee Yoon
role: Principal Investigator
affiliation: Asan Medical Center
last name: Yoon Jeon Kim, MD
phone: 82-2-3010-3680
email: anne215@gmail.com
facility: 
status: Recruiting
contact: 
country: Korea, Republic of
citation: Silva PS, Dela Cruz AJ, Ledesma MG, van Hemert J, Radwan A, Cavallerano JD, Aiello LM, Sun JK, Aiello LP. Diabetic Retinopathy Severity and Peripheral Lesions Are Associated with Nonperfusion on Ultrawide Field Angiography. Ophthalmology. 2015 Dec;122(12):2465-72. doi: 10.1016/j.ophtha.2015.07.034. Epub 2015 Sep 6.
PMID: 26350546
citation: Campochiaro PA, Wykoff CC, Shapiro H, Rubio RG, Ehrlich JS. Neutralization of vascular endothelial growth factor slows progression of retinal nonperfusion in patients with diabetic macular edema. Ophthalmology. 2014 Sep;121(9):1783-9. doi: 10.1016/j.ophtha.2014.03.021. Epub 2014 Apr 24.
PMID: 24768239
citation: Silva PS, Cavallerano JD, Haddad NM, Kwak H, Dyer KH, Omar AF, Shikari H, Aiello LM, Sun JK, Aiello LP. Peripheral Lesions Identified on Ultrawide Field Imaging Predict Increased Risk of Diabetic Retinopathy Progression over 4 Years. Ophthalmology. 2015 May;122(5):949-56. doi: 10.1016/j.ophtha.2015.01.008. Epub 2015 Feb 19.
PMID: 25704318
responsible party type: Principal Investigator
investigator affiliation: Asan Medical Center
investigator full name: Young Hee Yoon
investigator title: Professor
mesh term: Retinal Diseases
mesh term: Diabetic Retinopathy
mesh term: Aflibercept
sharing ipd: Yes