<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/NCT03246152</url>
  </required_header>
  <id_info>
    <org_study_id>N-79-2017</org_study_id>
    <nct_id>NCT03246152</nct_id>
  </id_info>
  <brief_title>Evaluation of the Effect of Intravitreal Injections of Anti-VEGF on Macular Perfusion in Diabetic Patients Using OCTA</brief_title>
  <acronym>IMPACT</acronym>
  <official_title>Evaluation of the Effect of Repeated Intravitreal Injections of Anti-VEGF on Macular Perfusion in Diabetic Patients Using Optical Coherence Tomography Angiography</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Cairo University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Cairo University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Anti-vascular endothelial growth factor (VEGF) drugs are the mainstay of therapy for diabetic&#xD;
      macular edema (DME), substantially improving visual acuity for many diabetics worldwide, and&#xD;
      proving effective for treatment of both non-proliferative and proliferative diabetic&#xD;
      retinopathy.&#xD;
&#xD;
      Many studies such as Diabetic Retinopathy Clinical Research Network studies, RESTORE Study,&#xD;
      and The BOLT Study have supported the use of different anti-VEGF agents in the treatment of&#xD;
      DME with better visual outcomes using anti-VEGF injections alone or in combination with other&#xD;
      treatments.&#xD;
&#xD;
      Several ocular complications of intravitreal anti-VEGF injections have been reported&#xD;
      including endophthalmitis, cataract and retinal detachment. The effect of anti-VEGF drugs on&#xD;
      macular perfusion has been inconclusive, with mixed reports of increase, decrease or no&#xD;
      effect on perfusion in response to anti-VEGF treatment. In many of these studies, however,&#xD;
      patients with more ischaemic retinas were not included. Retinal ischemia is an important&#xD;
      factor in the progression and prognosis of diabetic retinopathy.&#xD;
&#xD;
      Fluorescein angiography (FA) was the method used to assess changes in macular perfusion after&#xD;
      anti-VEGF injections in most of the studies. Despite its clinical usefulness, however, FA is&#xD;
      known to have documented risks. Optical coherence tomography angiography (OCTA) is a new&#xD;
      noninvasive method of acquiring high-resolution images of the retinal vasculature that can be&#xD;
      utilized in the treatment of retinal disease without the need for dye injection. It allows&#xD;
      the visualization of the superficial and deep retinal capillary layers separately and the&#xD;
      construction of microvascular flow maps.&#xD;
&#xD;
      Several studies have proved the reliability of OCTA in detecting and quantifying macular&#xD;
      ischemia in diabetics.&#xD;
&#xD;
      In this study, investigators aim to evaluate the effect of repeated intravitreal injections&#xD;
      of different Anti-VEGF agents on the perfusion of different capillary layers in the macula of&#xD;
      diabetic patients using OCTA.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a prospective interventional study to evaluate the effect of repeated intravitreal&#xD;
      injections of Anti-VEGF on macular perfusion in diabetic patients using optical coherence&#xD;
      tomography angiography (OCTA).&#xD;
&#xD;
      Each patient will receive a detailed ophthalmologic examination including measurement of BCVA&#xD;
      as well as applanation tonometry, undilated and dilated slit-lamp biomicroscopic examination&#xD;
      and indirect fundus examination.&#xD;
&#xD;
      Duration of diabetes and its control through HbA1C measurement will be recorded for each&#xD;
      patient.&#xD;
&#xD;
      Type 1 and 2 diabetic patients found to have BCVA worse than 6/6 and clinical evidence of&#xD;
      macular edema will undergo SD OCT and FA.&#xD;
&#xD;
      Patients with center involved macula edema detected by SD OCT will be included in the study&#xD;
      and will undergo baseline macular OCTA.&#xD;
&#xD;
      These patients will then undergo intravitreal injections of Anti-VEGF monthly for 3 months&#xD;
      then OCTA will be repeated to evaluate changes in macular perfusion and SD OCT will be&#xD;
      repeated to assess retinal thickness. Patients with center involving macular edema on SD-OCT&#xD;
      after the first 3 injections will continue to receive intravitreal Anti-VEGF injections&#xD;
      monthly until the edema subsides or the study duration ends. These patients then undergo a&#xD;
      final macular OCTA for perfusion evaluation and SD OCT for thickness assessment.&#xD;
&#xD;
      OCTA will be performed with an Avanti RTVue XR system (Optovue, Inc., Fremont, CA, USA). Area&#xD;
      of FAZ and capillary density at each capillary layer will be calculated before and after&#xD;
      interventions using the OCTA machine software and ImageJ software.&#xD;
&#xD;
      All statistical analyses will be done using IBM SPSS v20.0 statistical software (IBM&#xD;
      Corporation, NY, USA). Descriptive statistics will be calculated, and the data will be&#xD;
      summarized as mean ± SD for numerical data, and as frequencies and percentages for&#xD;
      categorical data.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 23, 2017</start_date>
  <completion_date type="Actual">December 24, 2018</completion_date>
  <primary_completion_date type="Actual">December 24, 2018</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>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>FAZ Area Change</measure>
    <time_frame>At baseline and after 3-6 consecutive monthly injections.</time_frame>
    <description>Effect of repeated intravitreal Anti-VEGF injections on Foveal Avascular Zone (FAZ) area measured using the freehand tool of ImageJ</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Macular Capillary Density Change at Full Retinal Thickness</measure>
    <time_frame>At baseline and after 3-6 consecutive monthly injections.</time_frame>
    <description>Effect of repeated intravitreal Anti-VEGF injections on macular capillary density using the change in the skeletonized vascular density and fractal dimension measured by ImageJ</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>BCVA Change</measure>
    <time_frame>At baseline and after 3-6 consecutive monthly injections.</time_frame>
    <description>Correlation of BCVA change with degree of capillary non-perfusion before and after injections</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">31</enrollment>
  <condition>Diabetic Macular Edema</condition>
  <condition>Ischemic Maculopathy</condition>
  <arm_group>
    <arm_group_label>Bevacizumab group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Monthly intravitreal injection of 2.5 mg of Bevacizumab for at least 3 consecutive months. This is followed by treat and extend regimen after resolution of macular edema.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bevacizumab</intervention_name>
    <description>Repeated intravitreal injections of Bevacizumab monthly</description>
    <arm_group_label>Bevacizumab group</arm_group_label>
    <other_name>Avastin</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients ≥ 18 years old&#xD;
&#xD;
          2. Type 1 or 2 diabetes mellitus&#xD;
&#xD;
          3. Decreased BCVA due to diabetic macular edema&#xD;
&#xD;
          4. Center involvement by the edema on spectral domain optical coherence tomography (SD&#xD;
             OCT)&#xD;
&#xD;
          5. Any stage of diabetic retinopathy&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Ocular conditions that may affect macular perfusion (e.g. retinal vascular diseases,&#xD;
             uveitis, vasculitis etc.)&#xD;
&#xD;
          2. History of vitreoretinal surgeries (excluding intravitreal injections)&#xD;
&#xD;
          3. Any previous treatment for diabetic macular edema&#xD;
&#xD;
          4. Presence of epiretinal membrane involving the macula or vitreomacular traction&#xD;
&#xD;
          5. Media opacity preventing good image quality&#xD;
&#xD;
          6. Uncontrolled glaucoma&#xD;
&#xD;
          7. Thromboembolic events within 6 months&#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>Khaled E El Rakhawy, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Cairo University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Karim A Raafat, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Cairo University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Ahmed AA Abdel Kader, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Cairo University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Ayman GA Elnahry, MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>Cairo University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cairo University Faculty of Medicine</name>
      <address>
        <city>Cairo</city>
        <country>Egypt</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Egypt</country>
  </location_countries>
  <reference>
    <citation>Ajlan RS, Silva PS, Sun JK. Vascular Endothelial Growth Factor and Diabetic Retinal Disease. Semin Ophthalmol. 2016;31(1-2):40-8. doi: 10.3109/08820538.2015.1114833.</citation>
    <PMID>26959128</PMID>
  </reference>
  <reference>
    <citation>Michaelides M, Kaines A, Hamilton RD, Fraser-Bell S, Rajendram R, Quhill F, Boos CJ, Xing W, Egan C, Peto T, Bunce C, Leslie RD, Hykin PG. A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study) 12-month data: report 2. Ophthalmology. 2010 Jun;117(6):1078-1086.e2. doi: 10.1016/j.ophtha.2010.03.045. Epub 2010 Apr 22.</citation>
    <PMID>20416952</PMID>
  </reference>
  <reference>
    <citation>Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol. 1985 Dec;103(12):1796-806.</citation>
    <PMID>2866759</PMID>
  </reference>
  <reference>
    <citation>Avery RL. Regression of retinal and iris neovascularization after intravitreal bevacizumab (Avastin) treatment. Retina. 2006 Mar;26(3):352-4. doi: 10.1097/00006982-200603000-00016. No abstract available.</citation>
    <PMID>16508438</PMID>
  </reference>
  <reference>
    <citation>Chapman JA, Beckey C. Pegaptanib: a novel approach to ocular neovascularization. Ann Pharmacother. 2006 Jul-Aug;40(7-8):1322-6. doi: 10.1345/aph.1G604. Epub 2006 Jul 18.</citation>
    <PMID>16849623</PMID>
  </reference>
  <reference>
    <citation>Zhang X, Bao S, Hambly BD, Gillies MC. Vascular endothelial growth factor-A: a multifunctional molecular player in diabetic retinopathy. Int J Biochem Cell Biol. 2009 Dec;41(12):2368-71. doi: 10.1016/j.biocel.2009.07.011. Epub 2009 Jul 29.</citation>
    <PMID>19646547</PMID>
  </reference>
  <reference>
    <citation>Hwang TS, Gao SS, Liu L, Lauer AK, Bailey ST, Flaxel CJ, Wilson DJ, Huang D, Jia Y. Automated Quantification of Capillary Nonperfusion Using Optical Coherence Tomography Angiography in Diabetic Retinopathy. JAMA Ophthalmol. 2016 Apr;134(4):367-73. doi: 10.1001/jamaophthalmol.2015.5658.</citation>
    <PMID>26795548</PMID>
  </reference>
  <reference>
    <citation>Bradley PD, Sim DA, Keane PA, Cardoso J, Agrawal R, Tufail A, Egan CA. The Evaluation of Diabetic Macular Ischemia Using Optical Coherence Tomography Angiography. Invest Ophthalmol Vis Sci. 2016 Feb;57(2):626-31. doi: 10.1167/iovs.15-18034.</citation>
    <PMID>26903223</PMID>
  </reference>
  <reference>
    <citation>Freiberg FJ, Pfau M, Wons J, Wirth MA, Becker MD, Michels S. Optical coherence tomography angiography of the foveal avascular zone in diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol. 2016 Jun;254(6):1051-8. doi: 10.1007/s00417-015-3148-2. Epub 2015 Sep 4.</citation>
    <PMID>26338819</PMID>
  </reference>
  <reference>
    <citation>Spaide RF, Klancnik JM Jr, Cooney MJ. Retinal vascular layers imaged by fluorescein angiography and optical coherence tomography angiography. JAMA Ophthalmol. 2015 Jan;133(1):45-50. doi: 10.1001/jamaophthalmol.2014.3616.</citation>
    <PMID>25317632</PMID>
  </reference>
  <reference>
    <citation>Yannuzzi LA, Rohrer KT, Tindel LJ, Sobel RS, Costanza MA, Shields W, Zang E. Fluorescein angiography complication survey. Ophthalmology. 1986 May;93(5):611-7. doi: 10.1016/s0161-6420(86)33697-2.</citation>
    <PMID>3523356</PMID>
  </reference>
  <reference>
    <citation>Bonnin P, Pournaras JA, Lazrak Z, Cohen SY, Legargasson JF, Gaudric A, Levy BI, Massin P. Ultrasound assessment of short-term ocular vascular effects of intravitreal injection of bevacizumab (Avastin((R)) ) in neovascular age-related macular degeneration. Acta Ophthalmol. 2010 Sep;88(6):641-5. doi: 10.1111/j.1755-3768.2009.01526.x.</citation>
    <PMID>19563370</PMID>
  </reference>
  <reference>
    <citation>Papadopoulou DN, Mendrinos E, Mangioris G, Donati G, Pournaras CJ. Intravitreal ranibizumab may induce retinal arteriolar vasoconstriction in patients with neovascular age-related macular degeneration. Ophthalmology. 2009 Sep;116(9):1755-61. doi: 10.1016/j.ophtha.2009.03.017. Epub 2009 Jun 27.</citation>
    <PMID>19560206</PMID>
  </reference>
  <reference>
    <citation>Manousaridis K, Talks J. Macular ischaemia: a contraindication for anti-VEGF treatment in retinal vascular disease? Br J Ophthalmol. 2012 Feb;96(2):179-84. doi: 10.1136/bjophthalmol-2011-301087.</citation>
    <PMID>22250209</PMID>
  </reference>
  <reference>
    <citation>Nguyen QD, Brown DM, Marcus DM, Boyer DS, Patel S, Feiner L, Gibson A, Sy J, Rundle AC, Hopkins JJ, Rubio RG, Ehrlich JS; RISE and RIDE Research Group. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012 Apr;119(4):789-801. doi: 10.1016/j.ophtha.2011.12.039. Epub 2012 Feb 11.</citation>
    <PMID>22330964</PMID>
  </reference>
  <reference>
    <citation>Mitchell P, Bandello F, Schmidt-Erfurth U, Lang GE, Massin P, Schlingemann RO, Sutter F, Simader C, Burian G, Gerstner O, Weichselberger A; RESTORE study group. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011 Apr;118(4):615-25. doi: 10.1016/j.ophtha.2011.01.031.</citation>
    <PMID>21459215</PMID>
  </reference>
  <verification_date>January 2020</verification_date>
  <study_first_submitted>August 6, 2017</study_first_submitted>
  <study_first_submitted_qc>August 8, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 11, 2017</study_first_posted>
  <results_first_submitted>December 25, 2019</results_first_submitted>
  <results_first_submitted_qc>January 21, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">January 30, 2020</results_first_posted>
  <last_update_submitted>January 21, 2020</last_update_submitted>
  <last_update_submitted_qc>January 21, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">January 30, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Cairo University</investigator_affiliation>
    <investigator_full_name>Ayman Gehad Elnahry</investigator_full_name>
    <investigator_title>Clinical Demonstrator</investigator_title>
  </responsible_party>
  <keyword>Anti-VEGF safety</keyword>
  <keyword>Ischemic Maculopathy</keyword>
  <keyword>Diabetic Macular Edema</keyword>
  <keyword>OCTA</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Macular Edema</mesh_term>
    <mesh_term>Macular Degeneration</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bevacizumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>April 3, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/52/NCT03246152/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>May 16, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/52/NCT03246152/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>This is the number of enrolled patients that completed the study.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Bevacizumab Group</title>
          <description>Monthly intravitreal injection of Bevacizumab for at least 3 consecutive months. This is followed by treat and extend regimen after resolution of macular edema.&#xD;
Bevacizumab: Repeated intravitreal injections of Bevacizumab monthly</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="31"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="28"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Bevacizumab Group</title>
          <description>Monthly intravitreal injection of Bevacizumab for at least 3 consecutive months. This is followed by treat and extend regimen after resolution of macular edema.&#xD;
Bevacizumab: Repeated intravitreal injections of Bevacizumab monthly</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="31"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="28"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>Years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="54.8" spread="6.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="31"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Egypt</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="31"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>FAZ Area Change</title>
        <description>Effect of repeated intravitreal Anti-VEGF injections on Foveal Avascular Zone (FAZ) area measured using the freehand tool of ImageJ</description>
        <time_frame>At baseline and after 3-6 consecutive monthly injections.</time_frame>
        <population>Patients with adequate image quality</population>
        <group_list>
          <group group_id="O1">
            <title>Bevacizumab Group</title>
            <description>Monthly intravitreal injection of Bevacizumab for at least 3 consecutive months. This is followed by treat and extend regimen after resolution of macular edema.&#xD;
Bevacizumab: Repeated intravitreal injections of Bevacizumab monthly</description>
          </group>
        </group_list>
        <measure>
          <title>FAZ Area Change</title>
          <description>Effect of repeated intravitreal Anti-VEGF injections on Foveal Avascular Zone (FAZ) area measured using the freehand tool of ImageJ</description>
          <population>Patients with adequate image quality</population>
          <units>mm^2</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="26"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.03" spread="0.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Macular Capillary Density Change at Full Retinal Thickness</title>
        <description>Effect of repeated intravitreal Anti-VEGF injections on macular capillary density using the change in the skeletonized vascular density and fractal dimension measured by ImageJ</description>
        <time_frame>At baseline and after 3-6 consecutive monthly injections.</time_frame>
        <population>Patients with adequate image quality</population>
        <group_list>
          <group group_id="O1">
            <title>Bevacizumab Group</title>
            <description>Monthly intravitreal injection of Bevacizumab for at least 3 consecutive months. This is followed by treat and extend regimen after resolution of macular edema.&#xD;
Bevacizumab: Repeated intravitreal injections of Bevacizumab monthly</description>
          </group>
        </group_list>
        <measure>
          <title>Macular Capillary Density Change at Full Retinal Thickness</title>
          <description>Effect of repeated intravitreal Anti-VEGF injections on macular capillary density using the change in the skeletonized vascular density and fractal dimension measured by ImageJ</description>
          <population>Patients with adequate image quality</population>
          <units>percentage of vascularity</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="26"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-2.5" spread="5.72"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>BCVA Change</title>
        <description>Correlation of BCVA change with degree of capillary non-perfusion before and after injections</description>
        <time_frame>At baseline and after 3-6 consecutive monthly injections.</time_frame>
        <population>Patients with good image quality</population>
        <group_list>
          <group group_id="O1">
            <title>Bevacizumab Group</title>
            <description>Monthly intravitreal injection of Bevacizumab for at least 3 consecutive months. This is followed by treat and extend regimen after resolution of macular edema.&#xD;
Bevacizumab: Repeated intravitreal injections of Bevacizumab monthly</description>
          </group>
        </group_list>
        <measure>
          <title>BCVA Change</title>
          <description>Correlation of BCVA change with degree of capillary non-perfusion before and after injections</description>
          <population>Patients with good image quality</population>
          <units>Logmar</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="26"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.21" spread="0.27"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Correlation between change in BCVA and the pre treatment, post treatment, and change in vascular density following 3-6 injections was performed.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>&gt;0.05</p_value>
            <method>Pearson's correlation coefficient</method>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>3 months</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Bevacizumab Group</title>
          <description>Monthly intravitreal injection of Bevacizumab for at least 3 consecutive months. This is followed by treat and extend regimen after resolution of macular edema.&#xD;
Bevacizumab: Repeated intravitreal injections of Bevacizumab monthly</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="31"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="31"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="18" subjects_at_risk="31"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Subconjunctival hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="31"/>
              </event>
              <event>
                <sub_title>Ocular irritation</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="31"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Ayman Elnahry</name_or_title>
      <organization>Cairo University</organization>
      <phone>00201224927604</phone>
      <email>ayman_elnahri@hotmail.com</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03246152
org study id: N-79-2017
nct id: NCT03246152
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
Anti-vascular endothelial growth factor (VEGF) drugs are the mainstay of therapy for diabetic
      macular edema (DME), substantially improving visual acuity for many diabetics worldwide, and
      proving effective for treatment of both non-proliferative and proliferative diabetic
      retinopathy.

      Many studies such as Diabetic Retinopathy Clinical Research Network studies, RESTORE Study,
      and The BOLT Study have supported the use of different anti-VEGF agents in the treatment of
      DME with better visual outcomes using anti-VEGF injections alone or in combination with other
      treatments.

      Several ocular complications of intravitreal anti-VEGF injections have been reported
      including endophthalmitis, cataract and retinal detachment. The effect of anti-VEGF drugs on
      macular perfusion has been inconclusive, with mixed reports of increase, decrease or no
      effect on perfusion in response to anti-VEGF treatment. In many of these studies, however,
      patients with more ischaemic retinas were not included. Retinal ischemia is an important
      factor in the progression and prognosis of diabetic retinopathy.

      Fluorescein angiography (FA) was the method used to assess changes in macular perfusion after
      anti-VEGF injections in most of the studies. Despite its clinical usefulness, however, FA is
      known to have documented risks. Optical coherence tomography angiography (OCTA) is a new
      noninvasive method of acquiring high-resolution images of the retinal vasculature that can be
      utilized in the treatment of retinal disease without the need for dye injection. It allows
      the visualization of the superficial and deep retinal capillary layers separately and the
      construction of microvascular flow maps.

      Several studies have proved the reliability of OCTA in detecting and quantifying macular
      ischemia in diabetics.

      In this study, investigators aim to evaluate the effect of repeated intravitreal injections
      of different Anti-VEGF agents on the perfusion of different capillary layers in the macula of
      diabetic patients using OCTA.
This is a prospective interventional study to evaluate the effect of repeated intravitreal
      injections of Anti-VEGF on macular perfusion in diabetic patients using optical coherence
      tomography angiography (OCTA).

      Each patient will receive a detailed ophthalmologic examination including measurement of BCVA
      as well as applanation tonometry, undilated and dilated slit-lamp biomicroscopic examination
      and indirect fundus examination.

      Duration of diabetes and its control through HbA1C measurement will be recorded for each
      patient.

      Type 1 and 2 diabetic patients found to have BCVA worse than 6/6 and clinical evidence of
      macular edema will undergo SD OCT and FA.

      Patients with center involved macula edema detected by SD OCT will be included in the study
      and will undergo baseline macular OCTA.

      These patients will then undergo intravitreal injections of Anti-VEGF monthly for 3 months
      then OCTA will be repeated to evaluate changes in macular perfusion and SD OCT will be
      repeated to assess retinal thickness. Patients with center involving macular edema on SD-OCT
      after the first 3 injections will continue to receive intravitreal Anti-VEGF injections
      monthly until the edema subsides or the study duration ends. These patients then undergo a
      final macular OCTA for perfusion evaluation and SD OCT for thickness assessment.

      OCTA will be performed with an Avanti RTVue XR system (Optovue, Inc., Fremont, CA, USA). Area
      of FAZ and capillary density at each capillary layer will be calculated before and after
      interventions using the OCTA machine software and ImageJ software.

      All statistical analyses will be done using IBM SPSS v20.0 statistical software (IBM
      Corporation, NY, USA). Descriptive statistics will be calculated, and the data will be
      summarized as mean ± SD for numerical data, and as frequencies and percentages for
      categorical data.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: FAZ Area Change
time frame: At baseline and after 3-6 consecutive monthly injections.
description: Effect of repeated intravitreal Anti-VEGF injections on Foveal Avascular Zone (FAZ) area measured using the freehand tool of ImageJ
measure: Macular Capillary Density Change at Full Retinal Thickness
time frame: At baseline and after 3-6 consecutive monthly injections.
description: Effect of repeated intravitreal Anti-VEGF injections on macular capillary density using the change in the skeletonized vascular density and fractal dimension measured by ImageJ
measure: BCVA Change
time frame: At baseline and after 3-6 consecutive monthly injections.
description: Correlation of BCVA change with degree of capillary non-perfusion before and after injections
arm group label: Bevacizumab group
arm group type: Experimental
description: Monthly intravitreal injection of 2.5 mg of Bevacizumab for at least 3 consecutive months. This is followed by treat and extend regimen after resolution of macular edema.
intervention type: Drug
intervention name: Bevacizumab
description: Repeated intravitreal injections of Bevacizumab monthly
arm group label: Bevacizumab group
other name: Avastin
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Khaled E El Rakhawy, PhD
role: Study Director
affiliation: Cairo University
last name: Karim A Raafat, PhD
role: Study Director
affiliation: Cairo University
last name: Ahmed AA Abdel Kader, PhD
role: Study Chair
affiliation: Cairo University
last name: Ayman GA Elnahry, MSc
role: Principal Investigator
affiliation: Cairo University
facility: 
country: Egypt
citation: Ajlan RS, Silva PS, Sun JK. Vascular Endothelial Growth Factor and Diabetic Retinal Disease. Semin Ophthalmol. 2016;31(1-2):40-8. doi: 10.3109/08820538.2015.1114833.
PMID: 26959128
citation: Michaelides M, Kaines A, Hamilton RD, Fraser-Bell S, Rajendram R, Quhill F, Boos CJ, Xing W, Egan C, Peto T, Bunce C, Leslie RD, Hykin PG. A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study) 12-month data: report 2. Ophthalmology. 2010 Jun;117(6):1078-1086.e2. doi: 10.1016/j.ophtha.2010.03.045. Epub 2010 Apr 22.
PMID: 20416952
citation: Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol. 1985 Dec;103(12):1796-806.
PMID: 2866759
citation: Avery RL. Regression of retinal and iris neovascularization after intravitreal bevacizumab (Avastin) treatment. Retina. 2006 Mar;26(3):352-4. doi: 10.1097/00006982-200603000-00016. No abstract available.
PMID: 16508438
citation: Chapman JA, Beckey C. Pegaptanib: a novel approach to ocular neovascularization. Ann Pharmacother. 2006 Jul-Aug;40(7-8):1322-6. doi: 10.1345/aph.1G604. Epub 2006 Jul 18.
PMID: 16849623
citation: Zhang X, Bao S, Hambly BD, Gillies MC. Vascular endothelial growth factor-A: a multifunctional molecular player in diabetic retinopathy. Int J Biochem Cell Biol. 2009 Dec;41(12):2368-71. doi: 10.1016/j.biocel.2009.07.011. Epub 2009 Jul 29.
PMID: 19646547
citation: Hwang TS, Gao SS, Liu L, Lauer AK, Bailey ST, Flaxel CJ, Wilson DJ, Huang D, Jia Y. Automated Quantification of Capillary Nonperfusion Using Optical Coherence Tomography Angiography in Diabetic Retinopathy. JAMA Ophthalmol. 2016 Apr;134(4):367-73. doi: 10.1001/jamaophthalmol.2015.5658.
PMID: 26795548
citation: Bradley PD, Sim DA, Keane PA, Cardoso J, Agrawal R, Tufail A, Egan CA. The Evaluation of Diabetic Macular Ischemia Using Optical Coherence Tomography Angiography. Invest Ophthalmol Vis Sci. 2016 Feb;57(2):626-31. doi: 10.1167/iovs.15-18034.
PMID: 26903223
citation: Freiberg FJ, Pfau M, Wons J, Wirth MA, Becker MD, Michels S. Optical coherence tomography angiography of the foveal avascular zone in diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol. 2016 Jun;254(6):1051-8. doi: 10.1007/s00417-015-3148-2. Epub 2015 Sep 4.
PMID: 26338819
citation: Spaide RF, Klancnik JM Jr, Cooney MJ. Retinal vascular layers imaged by fluorescein angiography and optical coherence tomography angiography. JAMA Ophthalmol. 2015 Jan;133(1):45-50. doi: 10.1001/jamaophthalmol.2014.3616.
PMID: 25317632
citation: Yannuzzi LA, Rohrer KT, Tindel LJ, Sobel RS, Costanza MA, Shields W, Zang E. Fluorescein angiography complication survey. Ophthalmology. 1986 May;93(5):611-7. doi: 10.1016/s0161-6420(86)33697-2.
PMID: 3523356
citation: Bonnin P, Pournaras JA, Lazrak Z, Cohen SY, Legargasson JF, Gaudric A, Levy BI, Massin P. Ultrasound assessment of short-term ocular vascular effects of intravitreal injection of bevacizumab (Avastin((R)) ) in neovascular age-related macular degeneration. Acta Ophthalmol. 2010 Sep;88(6):641-5. doi: 10.1111/j.1755-3768.2009.01526.x.
PMID: 19563370
citation: Papadopoulou DN, Mendrinos E, Mangioris G, Donati G, Pournaras CJ. Intravitreal ranibizumab may induce retinal arteriolar vasoconstriction in patients with neovascular age-related macular degeneration. Ophthalmology. 2009 Sep;116(9):1755-61. doi: 10.1016/j.ophtha.2009.03.017. Epub 2009 Jun 27.
PMID: 19560206
citation: Manousaridis K, Talks J. Macular ischaemia: a contraindication for anti-VEGF treatment in retinal vascular disease? Br J Ophthalmol. 2012 Feb;96(2):179-84. doi: 10.1136/bjophthalmol-2011-301087.
PMID: 22250209
citation: Nguyen QD, Brown DM, Marcus DM, Boyer DS, Patel S, Feiner L, Gibson A, Sy J, Rundle AC, Hopkins JJ, Rubio RG, Ehrlich JS; RISE and RIDE Research Group. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012 Apr;119(4):789-801. doi: 10.1016/j.ophtha.2011.12.039. Epub 2012 Feb 11.
PMID: 22330964
citation: Mitchell P, Bandello F, Schmidt-Erfurth U, Lang GE, Massin P, Schlingemann RO, Sutter F, Simader C, Burian G, Gerstner O, Weichselberger A; RESTORE study group. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011 Apr;118(4):615-25. doi: 10.1016/j.ophtha.2011.01.031.
PMID: 21459215
responsible party type: Principal Investigator
investigator affiliation: Cairo University
investigator full name: Ayman Gehad Elnahry
investigator title: Clinical Demonstrator
mesh term: Macular Edema
mesh term: Macular Degeneration
mesh term: Bevacizumab
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 