<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/NCT01710839</url>
  </required_header>
  <id_info>
    <org_study_id>12246</org_study_id>
    <nct_id>NCT01710839</nct_id>
  </id_info>
  <brief_title>Widefield Angiography Guided Targeted-retinal Photocoagulation Combined With Anti VEgf Intravitreal Injections for the Treatment of Ischemic Central Retinal Vein Occlusion, Hemi Retinal Vein Occlusion, and Branch Retinal Vein Occlusion</brief_title>
  <acronym>WAVE</acronym>
  <official_title>A Phase IV Open Label Trial of the Safety, Tolerability and Efficacy of 0.5mg Ranibizumab Intravitreal Injections Combined With Wide Field Angiography Guided Panretinal Photocoagulation vs. 0.5mg Ranibizumab Intravitreal Injection Monotherapy in Subjects With Ischemic Central Retinal Vein Occlusion, Hemi Retinal Vein Occlusion, and Branch Retinal Vein Occlusion Who Incompletely Respond to at Least 2 Consecutive Intravitreal Injections in the Past 4 Months.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Charles C Wykoff, PhD, MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Genentech, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Greater Houston Retina Research</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      To see if Lucentis 0.5mg combined with Targeted Pan Retinal photocoagulation will decrease&#xD;
      the total number of intravitreal injections in a year for ischemic central retinal vein&#xD;
      occlusion, hemi-retinal vein occlusions and branch retinal vein occlusions compared to&#xD;
      standard of care&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The WAVE trial is a phase IV, open label, 12-month trial of intravitreal ranibizumab 0.5 mg&#xD;
      in patients (n=30) with ischemic CRVO, HRVO and BRVO who have been previously treated with&#xD;
      ranibizumab or any other anti-VEGF intravitreal injection therapy, who are incomplete&#xD;
      responders to 2 or more consecutive intravitreal anti-VEGF injections in the past 4 months.&#xD;
      Randomization is 1:4, 1=control, ranibizumab only, 4=treatment arm. In total, 6 subjects will&#xD;
      be randomized to control and 24 randomized to treatment arm.&#xD;
&#xD;
      Cohort 1- 24 Subjects previously treated Patients will receive 6 doses of ranibizumab 0.5 mg,&#xD;
      followed by PRN intravitreal injection of ranibizumab 0.5 mg based on pre-defined retreatment&#xD;
      criteria for up to 11 total injections.&#xD;
&#xD;
      Wide field angiography guided peripheral targeted-retinal photocoagulation (TRP), will be&#xD;
      divided into 2 sessions if needed, one at the 2 weeks post injection visit and another later&#xD;
      at M4/V7, if repeat wide field angiogram indicates areas not sufficiently treated in the&#xD;
      first TRP session&#xD;
&#xD;
      Cohort 2- 6 Subjects, previously treated patients will receive 6 doses of ranibizumab 0.5 mg,&#xD;
      followed by PRN intravitreal injection of ranibizumab 0.5 mg based on pre-defined retreatment&#xD;
      criteria for up to 11 total injections.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 2012</start_date>
  <completion_date type="Actual">October 2015</completion_date>
  <primary_completion_date type="Actual">October 2015</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
    <masking_description>Open label</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Total Number of Intravitreal Injections Over a 12 Month Period</measure>
    <time_frame>12 months</time_frame>
    <description>Assess the number of intravitreal injections over 12 months.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Visual Acuity</measure>
    <time_frame>12 month period</time_frame>
    <description>Evaluate the mean change from baseline in ETDRS best-corrected visual acuity at 12 months. The ETDRS protocol is a widely accepted international standard for macular laser photocoagulation treatment. A higher score represents better functioning.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Retinal Ischemia</measure>
    <time_frame>12 month period</time_frame>
    <description>Quantify change in area of perfused and ischemic retina.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Foveal Avascular Zone</measure>
    <time_frame>12 months</time_frame>
    <description>Assess change in foveal avascular zone area and largest diameter, measured during the early phase of the angiogram</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse Events</measure>
    <time_frame>12 months</time_frame>
    <description>Incidence and severity of adverse events (ocular and non-ocular).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neovascularization of the Iris, Optic Nerve and Elsewhere</measure>
    <time_frame>12 months</time_frame>
    <description>Percent of patients that develop neovascularization of the iris, optic nerve and/or elsewhere.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Central Foveal Outcome</measure>
    <time_frame>12 months</time_frame>
    <description>Mean change in Central Foveal Volume on High Resolution OCT.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Aqueous VEGF Levels</measure>
    <time_frame>12 Months</time_frame>
    <description>VEGF, other cytokines and ranibizumab levels in aqueous and serum samples at randomization and at the exit or early termination visit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Visual Field</measure>
    <time_frame>6 and 12 Months</time_frame>
    <description>Goldman Visual Field changes at 6 and 12 months from baseline. Goldmann perimetry is a method used to map a patient's field of vision (central and peripheral). Changes will be assessed by manual digital quantification of GVF plots.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">30</enrollment>
  <condition>Central Retinal, Hemi Retinal &amp; Brach Retinal Vein Occlusions</condition>
  <arm_group>
    <arm_group_label>Targeted Pan Retinal laser combined with 0.5mg ranibizumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Cohort 1 (n=24), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses of 0.5 mg ranibizumab followed by PRN treatment with ranibizumab 0.5 mg; after receiving the first loading dose of ranibizumab, the subject will have peripheral targeted-retinal photocoagulation (TRP) based on 200° wide field angiography with possibility of a second session of TRP at M4/M7, if non-perfusion persists based on angiogram.The 200°wide field angiography will indicate areas of peripheral ischemia which will be selectively treated, preserving areas of more perfused retina.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Ranibizumab 0.5mg</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Cohort 2 (n=6), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses followed by PRN monthly treatment with ranibizumab 0.5 mg.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>0.5mg Ranibizumab</intervention_name>
    <description>intravitreal injections</description>
    <arm_group_label>Ranibizumab 0.5mg</arm_group_label>
    <arm_group_label>Targeted Pan Retinal laser combined with 0.5mg ranibizumab</arm_group_label>
    <other_name>Lucentis</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Targeted Pan Retinal Photocoagulation</intervention_name>
    <description>Targeted Pan Retinal Photocoagulation based on wide field angiography</description>
    <arm_group_label>Targeted Pan Retinal laser combined with 0.5mg ranibizumab</arm_group_label>
    <other_name>PRP</other_name>
    <other_name>Pan Retinal Photocoagulation</other_name>
    <other_name>TRP</other_name>
    <other_name>Pan Laser</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age &gt; 18 years&#xD;
&#xD;
          -  Visual acuity between 20/25 and 20/800, ETDRS best corrected visual acuity&#xD;
&#xD;
          -  Ability to provide written informed consent and comply with study assessments for the&#xD;
             full duration of the study&#xD;
&#xD;
        Patients previously treated with any ITV anti-VEGF:&#xD;
&#xD;
        • With at least 2 consecutive monthly intravitreal injections of anti-VEGF medications with&#xD;
        presence of persistent or recurrent macular edema in the past 4 months&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  IOP over 30 mm Hg&#xD;
&#xD;
          -  Any previous retinal laser photocoagulation to the study eye&#xD;
&#xD;
          -  Previous intravitreal injection in the study eye of any corticosteroid treatment&#xD;
&#xD;
          -  Previous vitrectomy in study eye (posterior or anterior associated with vitreous loss&#xD;
             in cataract surgery)&#xD;
&#xD;
          -  Intracapsular cataract extraction&#xD;
&#xD;
          -  Any previous radiation treatments to head/neck that the principal or sub investigator&#xD;
             feels is clinically relevant&#xD;
&#xD;
          -  Inability to assess iris or angle neovascularization (corneal opacity precluding&#xD;
             gonioscopy)&#xD;
&#xD;
          -  Significant cardiovascular disease or cancer that would prevent follow-up visits or&#xD;
             completion of the 12 month study&#xD;
&#xD;
          -  Significant diabetic retinopathy in the fellow eye (diabetic macular edema,&#xD;
             proliferative diabetic retinopathy, or high-risk non-proliferative diabetic&#xD;
             retinopathy)&#xD;
&#xD;
          -  Participation in another simultaneous medical investigator or trial&#xD;
&#xD;
          -  Ocular disorders or concurrent disease in the study eye that may confound&#xD;
             interpretation of study results, compromise visual acuity or require medical or&#xD;
             surgical intervention, including history of retinal detachment, macular hole, or&#xD;
             choroidal neovascularization of any cause (e.g., DME, AMD, ocular histoplasmosis, or&#xD;
             pathologic myopia)&#xD;
&#xD;
          -  Structural damage to the center of the macula in the study eye prior to CRVO, HRVO and&#xD;
             BRVO likely to preclude improvement in visual acuity following the resolution of&#xD;
             macular edema, including atrophy of the retinal pigment epithelium, subretinal&#xD;
             fibrosis, laser scar(s)&#xD;
&#xD;
          -  Vitreomacular traction or clinically significant epiretinal membrane in the study eye&#xD;
             evident biomicroscopically or by OCT (vitreomacular attachment OK)&#xD;
&#xD;
          -  Infectious blepharitis, keratitis, scleritis, or conjunctivitis (in either eye) or&#xD;
             current treatment for serious systemic infection&#xD;
&#xD;
          -  Spherical equivalent of the refractive error in the study eye of more than -8 diopters&#xD;
             myopia (For patients who have had refractive or cataract surgery in the study eye,&#xD;
             preoperative spherical equivalent refractive error of more than -8 diopters myopia is&#xD;
             not allowed)&#xD;
&#xD;
          -  Uncontrolled Blood pressure: defined as systolic pressure &gt; 180mmHg and/or diastolic&#xD;
             pressure of &gt;110 mm Hg (sitting) during the screening period&#xD;
&#xD;
          -  Uncontrolled diabetes mellitus&#xD;
&#xD;
          -  Renal failure requiring dialysis or renal transplant&#xD;
&#xD;
          -  Pregnancy (positive pregnancy test) or lactation&#xD;
&#xD;
          -  Premenopausal women not using adequate contraception. The following are considered&#xD;
             effective means of contraception: surgical sterilization or use of oral&#xD;
             contraceptives, barrier contraception with either a condom or diaphragm in conjunction&#xD;
             with spermicidal gel, an IUD, or contraceptive hormone implant or patch.&#xD;
&#xD;
          -  History of other disease, metabolic dysfunction, physical examination finding, or&#xD;
             other findings giving reasonable suspicion of a disease or condition that&#xD;
             contraindicates the use an investigational drug, might affect interpretation of the&#xD;
             results of the study, or render the subject at high risk from treatment complications&#xD;
&#xD;
          -  History of allergy to fluorescein, not amenable to treatment&#xD;
&#xD;
          -  Inability to obtain fundus photographs or fluorescein angiograms of sufficient quality&#xD;
             to be analyzed by the principal investigator (PI) and/or the sub-investigator.&#xD;
&#xD;
          -  History of allergy to humanized antibodies or any component of the ranibizumab&#xD;
             formulation&#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>Charles C Wykoff, PhD, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Retina Consultants Houston</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Retina Consultants of Houston/The Medical Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Retina Consultants of Houston</name>
      <address>
        <city>Katy</city>
        <state>Texas</state>
        <zip>77494</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Retina Consultants of Houston</name>
      <address>
        <city>The Woodlands</city>
        <state>Texas</state>
        <zip>77384</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Armaly MF. Ocular pressure and visual fields. A ten-year follow-up study. Arch Ophthalmol. 1969 Jan;81(1):25-40. doi: 10.1001/archopht.1969.00990010027005. No abstract available.</citation>
    <PMID>5763217</PMID>
  </reference>
  <reference>
    <citation>Boyd SR, Zachary I, Chakravarthy U, Allen GJ, Wisdom GB, Cree IA, Martin JF, Hykin PG. Correlation of increased vascular endothelial growth factor with neovascularization and permeability in ischemic central vein occlusion. Arch Ophthalmol. 2002 Dec;120(12):1644-50. doi: 10.1001/archopht.120.12.1644.</citation>
    <PMID>12470137</PMID>
  </reference>
  <reference>
    <citation>Brown DM, Campochiaro PA, Singh RP, Li Z, Gray S, Saroj N, Rundle AC, Rubio RG, Murahashi WY; CRUISE Investigators. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010 Jun;117(6):1124-1133.e1. doi: 10.1016/j.ophtha.2010.02.022. Epub 2010 Apr 9.</citation>
    <PMID>20381871</PMID>
  </reference>
  <reference>
    <citation>Campochiaro PA, Brown DM, Awh CC, Lee SY, Gray S, Saroj N, Murahashi WY, Rubio RG. Sustained benefits from ranibizumab for macular edema following central retinal vein occlusion: twelve-month outcomes of a phase III study. Ophthalmology. 2011 Oct;118(10):2041-9. doi: 10.1016/j.ophtha.2011.02.038. Epub 2011 Jun 29.</citation>
    <PMID>21715011</PMID>
  </reference>
  <reference>
    <citation>A randomized clinical trial of early panretinal photocoagulation for ischemic central vein occlusion. The Central Vein Occlusion Study Group N report. Ophthalmology. 1995 Oct;102(10):1434-44.</citation>
    <PMID>9097789</PMID>
  </reference>
  <reference>
    <citation>Natural history and clinical management of central retinal vein occlusion. The Central Vein Occlusion Study Group. Arch Ophthalmol. 1997 Apr;115(4):486-91. doi: 10.1001/archopht.1997.01100150488006. Erratum In: Arch Ophthalmol 1997 Oct;115(10):1275.</citation>
    <PMID>9109757</PMID>
  </reference>
  <reference>
    <citation>Christen WG, Glynn RJ, Manson JE, Ajani UA, Buring JE. A prospective study of cigarette smoking and risk of age-related macular degeneration in men. JAMA. 1996 Oct 9;276(14):1147-51.</citation>
    <PMID>8827967</PMID>
  </reference>
  <reference>
    <citation>Conn G, Bayne ML, Soderman DD, Kwok PW, Sullivan KA, Palisi TM, Hope DA, Thomas KA. Amino acid and cDNA sequences of a vascular endothelial cell mitogen that is homologous to platelet-derived growth factor. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2628-32. doi: 10.1073/pnas.87.7.2628.</citation>
    <PMID>2320579</PMID>
  </reference>
  <reference>
    <citation>Connolly DT, Heuvelman DM, Nelson R, Olander JV, Eppley BL, Delfino JJ, Siegel NR, Leimgruber RM, Feder J. Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest. 1989 Nov;84(5):1470-8. doi: 10.1172/JCI114322.</citation>
    <PMID>2478587</PMID>
  </reference>
  <reference>
    <citation>Connolly DT, Olander JV, Heuvelman D, Nelson R, Monsell R, Siegel N, Haymore BL, Leimgruber R, Feder J. Human vascular permeability factor. Isolation from U937 cells. J Biol Chem. 1989 Nov 25;264(33):20017-24.</citation>
    <PMID>2584205</PMID>
  </reference>
  <reference>
    <citation>de Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science. 1992 Feb 21;255(5047):989-91. doi: 10.1126/science.1312256.</citation>
    <PMID>1312256</PMID>
  </reference>
  <reference>
    <citation>Hayreh SS, Klugman MR, Podhajsky P, Kolder HE. Electroretinography in central retinal vein occlusion. Correlation of electroretinographic changes with pupillary abnormalities. Graefes Arch Clin Exp Ophthalmol. 1989;227(6):549-61. doi: 10.1007/BF02169451.</citation>
    <PMID>2483144</PMID>
  </reference>
  <verification_date>August 2017</verification_date>
  <study_first_submitted>October 17, 2012</study_first_submitted>
  <study_first_submitted_qc>October 17, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 19, 2012</study_first_posted>
  <results_first_submitted>February 22, 2017</results_first_submitted>
  <results_first_submitted_qc>February 22, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">April 11, 2017</results_first_posted>
  <last_update_submitted>August 8, 2017</last_update_submitted>
  <last_update_submitted_qc>August 8, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">September 8, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Greater Houston Retina Research</investigator_affiliation>
    <investigator_full_name>Charles C Wykoff, PhD, MD</investigator_full_name>
    <investigator_title>Deputy Director of Research</investigator_title>
  </responsible_party>
  <keyword>CRVO</keyword>
  <keyword>BRVO</keyword>
  <keyword>HRVO</keyword>
  <keyword>Macular edema</keyword>
  <keyword>vein occlusion</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Retinal Vein Occlusion</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ranibizumab</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Targeted Pan Retinal Laser Combined With 0.5mg Ranibizumab</title>
          <description>Cohort 1 (n=24), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses of 0.5 mg ranibizumab followed by PRN treatment with ranibizumab 0.5 mg; after receiving the first loading dose of ranibizumab, the subject will have peripheral targeted-retinal photocoagulation (TRP) based on 200° wide field angiography with possibility of a second session of TRP at M4/M7, if non-perfusion persists based on angiogram.The 200°wide field angiography will indicate areas of peripheral ischemia which will be selectively treated, preserving areas of more perfused retina.&#xD;
0.5mg Ranibizumab: intravitreal injections&#xD;
Targeted Pan Retinal Photocoagulation: Targeted Pan Retinal Photocoagulation based on wide field angiography</description>
        </group>
        <group group_id="P2">
          <title>Ranibizumab 0.5mg</title>
          <description>Cohort 2 (n=6), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses followed by PRN monthly treatment with ranibizumab 0.5 mg.&#xD;
0.5mg Ranibizumab: intravitreal injections</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="24"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="23"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Targeted Pan Retinal Laser Combined With 0.5mg Ranibizumab</title>
          <description>Cohort 1 (n=24), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses of 0.5 mg ranibizumab followed by PRN treatment with ranibizumab 0.5 mg; after receiving the first loading dose of ranibizumab, the subject will have peripheral targeted-retinal photocoagulation (TRP) based on 200° wide field angiography with possibility of a second session of TRP at M4/M7, if non-perfusion persists based on angiogram.The 200°wide field angiography will indicate areas of peripheral ischemia which will be selectively treated, preserving areas of more perfused retina.&#xD;
0.5mg Ranibizumab: intravitreal injections&#xD;
Targeted Pan Retinal Photocoagulation: Targeted Pan Retinal Photocoagulation based on wide field angiography</description>
        </group>
        <group group_id="B2">
          <title>Ranibizumab 0.5mg</title>
          <description>Cohort 2 (n=6), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses followed by PRN monthly treatment with ranibizumab 0.5 mg.&#xD;
0.5mg Ranibizumab: intravitreal injections</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="24"/>
            <count group_id="B2" value="6"/>
            <count group_id="B3" value="30"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="64.1" lower_limit="43" upper_limit="80"/>
                    <measurement group_id="B2" value="63.8" lower_limit="56" upper_limit="77"/>
                    <measurement group_id="B3" value="64.1" lower_limit="43" upper_limit="80"/>
                  </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="11"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>RVO Subtype</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>CRVO</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>BRVO</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>HRVO</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Prior Anti-VEGF Injections</title>
          <units>injections</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="10.2" lower_limit="2" upper_limit="34"/>
                    <measurement group_id="B2" value="10.0" lower_limit="2" upper_limit="41"/>
                    <measurement group_id="B3" value="10.1" lower_limit="2" upper_limit="41"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>ETDRS BCVA Letters</title>
          <description>Visual function of the study eye was assessed using the ETDRS protocol, which is a widely accepted international standard for macular laser photocoagulation treatment. A higher score represents better functioning.</description>
          <units>ETDRS BCVA Letters</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="51.7" lower_limit="7" upper_limit="77"/>
                    <measurement group_id="B2" value="55.3" lower_limit="29" upper_limit="71"/>
                    <measurement group_id="B3" value="52.4" lower_limit="7" upper_limit="77"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Central Retinal Thickness</title>
          <units>micrometers</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="525" lower_limit="224" upper_limit="1240"/>
                    <measurement group_id="B2" value="471" lower_limit="272" upper_limit="910"/>
                    <measurement group_id="B3" value="514" lower_limit="224" upper_limit="1240"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Total Number of Intravitreal Injections Over a 12 Month Period</title>
        <description>Assess the number of intravitreal injections over 12 months.</description>
        <time_frame>12 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Targeted Pan Retinal Laser Combined With 0.5mg Ranibizumab</title>
            <description>Cohort 1 (n=24), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses of 0.5 mg ranibizumab followed by PRN treatment with ranibizumab 0.5 mg; after receiving the first loading dose of ranibizumab, the subject will have peripheral targeted-retinal photocoagulation (TRP) based on 200° wide field angiography with possibility of a second session of TRP at M4/M7, if non-perfusion persists based on angiogram.The 200°wide field angiography will indicate areas of peripheral ischemia which will be selectively treated, preserving areas of more perfused retina.&#xD;
0.5mg Ranibizumab: intravitreal injections&#xD;
Targeted Pan Retinal Photocoagulation: Targeted Pan Retinal Photocoagulation based on wide field angiography</description>
          </group>
          <group group_id="O2">
            <title>Ranibizumab 0.5mg</title>
            <description>Cohort 2 (n=6), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses followed by PRN monthly treatment with ranibizumab 0.5 mg.&#xD;
0.5mg Ranibizumab: intravitreal injections</description>
          </group>
        </group_list>
        <measure>
          <title>Total Number of Intravitreal Injections Over a 12 Month Period</title>
          <description>Assess the number of intravitreal injections over 12 months.</description>
          <units>injections</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.7" lower_limit="5" upper_limit="12"/>
                    <measurement group_id="O2" value="9.5" lower_limit="7" upper_limit="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Visual Acuity</title>
        <description>Evaluate the mean change from baseline in ETDRS best-corrected visual acuity at 12 months. The ETDRS protocol is a widely accepted international standard for macular laser photocoagulation treatment. A higher score represents better functioning.</description>
        <time_frame>12 month period</time_frame>
        <population>1 patient withdrew from the study before month 12</population>
        <group_list>
          <group group_id="O1">
            <title>Targeted Pan Retinal Laser Combined With 0.5mg Ranibizumab</title>
            <description>Cohort 1 (n=24), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses of 0.5 mg ranibizumab followed by PRN treatment with ranibizumab 0.5 mg; after receiving the first loading dose of ranibizumab, the subject will have peripheral targeted-retinal photocoagulation (TRP) based on 200° wide field angiography with possibility of a second session of TRP at M4/M7, if non-perfusion persists based on angiogram.The 200°wide field angiography will indicate areas of peripheral ischemia which will be selectively treated, preserving areas of more perfused retina.&#xD;
0.5mg Ranibizumab: intravitreal injections&#xD;
Targeted Pan Retinal Photocoagulation: Targeted Pan Retinal Photocoagulation based on wide field angiography</description>
          </group>
          <group group_id="O2">
            <title>Ranibizumab 0.5mg</title>
            <description>Cohort 2 (n=6), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses followed by PRN monthly treatment with ranibizumab 0.5 mg.&#xD;
0.5mg Ranibizumab: intravitreal injections</description>
          </group>
        </group_list>
        <measure>
          <title>Visual Acuity</title>
          <description>Evaluate the mean change from baseline in ETDRS best-corrected visual acuity at 12 months. The ETDRS protocol is a widely accepted international standard for macular laser photocoagulation treatment. A higher score represents better functioning.</description>
          <population>1 patient withdrew from the study before month 12</population>
          <units>ETDRS BCVA Letters</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="23"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14.9" spread="3.4"/>
                    <measurement group_id="O2" value="10.7" spread="4.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Retinal Ischemia</title>
        <description>Quantify change in area of perfused and ischemic retina.</description>
        <time_frame>12 month period</time_frame>
        <population>Analysis of this outcome measure is still in progress. Data will be reported when the analysis is completed.</population>
        <group_list>
          <group group_id="O1">
            <title>Targeted Pan Retinal Laser Combined With 0.5mg Ranibizumab</title>
            <description>Cohort 1 (n=24), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses of 0.5 mg ranibizumab followed by PRN treatment with ranibizumab 0.5 mg; after receiving the first loading dose of ranibizumab, the subject will have peripheral targeted-retinal photocoagulation (TRP) based on 200° wide field angiography with possibility of a second session of TRP at M4/M7, if non-perfusion persists based on angiogram.The 200°wide field angiography will indicate areas of peripheral ischemia which will be selectively treated, preserving areas of more perfused retina.&#xD;
0.5mg Ranibizumab: intravitreal injections&#xD;
Targeted Pan Retinal Photocoagulation: Targeted Pan Retinal Photocoagulation based on wide field angiography</description>
          </group>
          <group group_id="O2">
            <title>Ranibizumab 0.5mg</title>
            <description>Cohort 2 (n=6), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses followed by PRN monthly treatment with ranibizumab 0.5 mg.&#xD;
0.5mg Ranibizumab: intravitreal injections</description>
          </group>
        </group_list>
        <measure>
          <title>Retinal Ischemia</title>
          <description>Quantify change in area of perfused and ischemic retina.</description>
          <population>Analysis of this outcome measure is still in progress. Data will be reported when the analysis is completed.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Foveal Avascular Zone</title>
        <description>Assess change in foveal avascular zone area and largest diameter, measured during the early phase of the angiogram</description>
        <time_frame>12 months</time_frame>
        <population>Analysis of this outcome measure is still in progress. Data will be reported when the analysis is completed.</population>
        <group_list>
          <group group_id="O1">
            <title>Targeted Pan Retinal Laser Combined With 0.5mg Ranibizumab</title>
            <description>Cohort 1 (n=24), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses of 0.5 mg ranibizumab followed by PRN treatment with ranibizumab 0.5 mg; after receiving the first loading dose of ranibizumab, the subject will have peripheral targeted-retinal photocoagulation (TRP) based on 200° wide field angiography with possibility of a second session of TRP at M4/M7, if non-perfusion persists based on angiogram.The 200°wide field angiography will indicate areas of peripheral ischemia which will be selectively treated, preserving areas of more perfused retina.&#xD;
0.5mg Ranibizumab: intravitreal injections&#xD;
Targeted Pan Retinal Photocoagulation: Targeted Pan Retinal Photocoagulation based on wide field angiography</description>
          </group>
          <group group_id="O2">
            <title>Ranibizumab 0.5mg</title>
            <description>Cohort 2 (n=6), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses followed by PRN monthly treatment with ranibizumab 0.5 mg.&#xD;
0.5mg Ranibizumab: intravitreal injections</description>
          </group>
        </group_list>
        <measure>
          <title>Foveal Avascular Zone</title>
          <description>Assess change in foveal avascular zone area and largest diameter, measured during the early phase of the angiogram</description>
          <population>Analysis of this outcome measure is still in progress. Data will be reported when the analysis is completed.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Adverse Events</title>
        <description>Incidence and severity of adverse events (ocular and non-ocular).</description>
        <time_frame>12 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Targeted Pan Retinal Laser Combined With 0.5mg Ranibizumab</title>
            <description>Cohort 1 (n=24), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses of 0.5 mg ranibizumab followed by PRN treatment with ranibizumab 0.5 mg; after receiving the first loading dose of ranibizumab, the subject will have peripheral targeted-retinal photocoagulation (TRP) based on 200° wide field angiography with possibility of a second session of TRP at M4/M7, if non-perfusion persists based on angiogram.The 200°wide field angiography will indicate areas of peripheral ischemia which will be selectively treated, preserving areas of more perfused retina.&#xD;
0.5mg Ranibizumab: intravitreal injections&#xD;
Targeted Pan Retinal Photocoagulation: Targeted Pan Retinal Photocoagulation based on wide field angiography</description>
          </group>
          <group group_id="O2">
            <title>Ranibizumab 0.5mg</title>
            <description>Cohort 2 (n=6), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses followed by PRN monthly treatment with ranibizumab 0.5 mg.&#xD;
0.5mg Ranibizumab: intravitreal injections</description>
          </group>
        </group_list>
        <measure>
          <title>Adverse Events</title>
          <description>Incidence and severity of adverse events (ocular and non-ocular).</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Notable Ocular Events</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="17"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Serious Non-Ocular Events</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Neovascularization of the Iris, Optic Nerve and Elsewhere</title>
        <description>Percent of patients that develop neovascularization of the iris, optic nerve and/or elsewhere.</description>
        <time_frame>12 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Targeted Pan Retinal Laser Combined With 0.5mg Ranibizumab</title>
            <description>Cohort 1 (n=24), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses of 0.5 mg ranibizumab followed by PRN treatment with ranibizumab 0.5 mg; after receiving the first loading dose of ranibizumab, the subject will have peripheral targeted-retinal photocoagulation (TRP) based on 200° wide field angiography with possibility of a second session of TRP at M4/M7, if non-perfusion persists based on angiogram.The 200°wide field angiography will indicate areas of peripheral ischemia which will be selectively treated, preserving areas of more perfused retina.&#xD;
0.5mg Ranibizumab: intravitreal injections&#xD;
Targeted Pan Retinal Photocoagulation: Targeted Pan Retinal Photocoagulation based on wide field angiography</description>
          </group>
          <group group_id="O2">
            <title>Ranibizumab 0.5mg</title>
            <description>Cohort 2 (n=6), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses followed by PRN monthly treatment with ranibizumab 0.5 mg.&#xD;
0.5mg Ranibizumab: intravitreal injections</description>
          </group>
        </group_list>
        <measure>
          <title>Neovascularization of the Iris, Optic Nerve and Elsewhere</title>
          <description>Percent of patients that develop neovascularization of the iris, optic nerve and/or elsewhere.</description>
          <units>percentage of patients</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.33"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Central Foveal Outcome</title>
        <description>Mean change in Central Foveal Volume on High Resolution OCT.</description>
        <time_frame>12 months</time_frame>
        <population>1 patient withdrew from the study before month 12</population>
        <group_list>
          <group group_id="O1">
            <title>Targeted Pan Retinal Laser Combined With 0.5mg Ranibizumab</title>
            <description>Cohort 1 (n=24), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses of 0.5 mg ranibizumab followed by PRN treatment with ranibizumab 0.5 mg; after receiving the first loading dose of ranibizumab, the subject will have peripheral targeted-retinal photocoagulation (TRP) based on 200° wide field angiography with possibility of a second session of TRP at M4/M7, if non-perfusion persists based on angiogram.The 200°wide field angiography will indicate areas of peripheral ischemia which will be selectively treated, preserving areas of more perfused retina.&#xD;
0.5mg Ranibizumab: intravitreal injections&#xD;
Targeted Pan Retinal Photocoagulation: Targeted Pan Retinal Photocoagulation based on wide field angiography</description>
          </group>
          <group group_id="O2">
            <title>Ranibizumab 0.5mg</title>
            <description>Cohort 2 (n=6), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses followed by PRN monthly treatment with ranibizumab 0.5 mg.&#xD;
0.5mg Ranibizumab: intravitreal injections</description>
          </group>
        </group_list>
        <measure>
          <title>Central Foveal Outcome</title>
          <description>Mean change in Central Foveal Volume on High Resolution OCT.</description>
          <population>1 patient withdrew from the study before month 12</population>
          <units>cubic millimeters</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="23"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.15" spread=".21"/>
                    <measurement group_id="O2" value="-0.15" spread=".20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Aqueous VEGF Levels</title>
        <description>VEGF, other cytokines and ranibizumab levels in aqueous and serum samples at randomization and at the exit or early termination visit.</description>
        <time_frame>12 Months</time_frame>
        <population>Analysis of this outcome measure is still in progress. Data will be reported when the analysis is completed.</population>
        <group_list>
          <group group_id="O1">
            <title>Targeted Pan Retinal Laser Combined With 0.5mg Ranibizumab</title>
            <description>Cohort 1 (n=24), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses of 0.5 mg ranibizumab followed by PRN treatment with ranibizumab 0.5 mg; after receiving the first loading dose of ranibizumab, the subject will have peripheral targeted-retinal photocoagulation (TRP) based on 200° wide field angiography with possibility of a second session of TRP at M4/M7, if non-perfusion persists based on angiogram.The 200°wide field angiography will indicate areas of peripheral ischemia which will be selectively treated, preserving areas of more perfused retina.&#xD;
0.5mg Ranibizumab: intravitreal injections&#xD;
Targeted Pan Retinal Photocoagulation: Targeted Pan Retinal Photocoagulation based on wide field angiography</description>
          </group>
          <group group_id="O2">
            <title>Ranibizumab 0.5mg</title>
            <description>Cohort 2 (n=6), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses followed by PRN monthly treatment with ranibizumab 0.5 mg.&#xD;
0.5mg Ranibizumab: intravitreal injections</description>
          </group>
        </group_list>
        <measure>
          <title>Aqueous VEGF Levels</title>
          <description>VEGF, other cytokines and ranibizumab levels in aqueous and serum samples at randomization and at the exit or early termination visit.</description>
          <population>Analysis of this outcome measure is still in progress. Data will be reported when the analysis is completed.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Visual Field</title>
        <description>Goldman Visual Field changes at 6 and 12 months from baseline. Goldmann perimetry is a method used to map a patient's field of vision (central and peripheral). Changes will be assessed by manual digital quantification of GVF plots.</description>
        <time_frame>6 and 12 Months</time_frame>
        <population>Patients who completed GVF testing at baseline, M6, and M12 with adequate fixation and cooperation during testing were included in GVF analyses (n=14)</population>
        <group_list>
          <group group_id="O1">
            <title>Targeted Pan Retinal Laser Combined With 0.5mg Ranibizumab</title>
            <description>Cohort 1 (n=24), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses of 0.5 mg ranibizumab followed by PRN treatment with ranibizumab 0.5 mg; after receiving the first loading dose of ranibizumab, the subject will have peripheral targeted-retinal photocoagulation (TRP) based on 200° wide field angiography with possibility of a second session of TRP at M4/M7, if non-perfusion persists based on angiogram.The 200°wide field angiography will indicate areas of peripheral ischemia which will be selectively treated, preserving areas of more perfused retina.&#xD;
0.5mg Ranibizumab: intravitreal injections&#xD;
Targeted Pan Retinal Photocoagulation: Targeted Pan Retinal Photocoagulation based on wide field angiography</description>
          </group>
          <group group_id="O2">
            <title>Ranibizumab 0.5mg</title>
            <description>Cohort 2 (n=6), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses followed by PRN monthly treatment with ranibizumab 0.5 mg.&#xD;
0.5mg Ranibizumab: intravitreal injections</description>
          </group>
        </group_list>
        <measure>
          <title>Visual Field</title>
          <description>Goldman Visual Field changes at 6 and 12 months from baseline. Goldmann perimetry is a method used to map a patient's field of vision (central and peripheral). Changes will be assessed by manual digital quantification of GVF plots.</description>
          <population>Patients who completed GVF testing at baseline, M6, and M12 with adequate fixation and cooperation during testing were included in GVF analyses (n=14)</population>
          <units>square degrees</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
                <count group_id="O2" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Month 6</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1269" spread="180"/>
                    <measurement group_id="O2" value="102" spread="423"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Month 12</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1628" spread="353"/>
                    <measurement group_id="O2" value="-1875" spread="326"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>12 months</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Targeted Pan Retinal Laser Combined With 0.5mg Ranibizumab</title>
          <description>Cohort 1 (n=24), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses of 0.5 mg ranibizumab followed by PRN treatment with ranibizumab 0.5 mg; after receiving the first loading dose of ranibizumab, the subject will have peripheral targeted-retinal photocoagulation (TRP) based on 200° wide field angiography with possibility of a second session of TRP at M4/M7, if non-perfusion persists based on angiogram.The 200°wide field angiography will indicate areas of peripheral ischemia which will be selectively treated, preserving areas of more perfused retina.&#xD;
0.5mg Ranibizumab: intravitreal injections&#xD;
Targeted Pan Retinal Photocoagulation: Targeted Pan Retinal Photocoagulation based on wide field angiography</description>
        </group>
        <group group_id="E2">
          <title>Ranibizumab 0.5mg</title>
          <description>Cohort 2 (n=6), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses followed by PRN monthly treatment with ranibizumab 0.5 mg.&#xD;
0.5mg Ranibizumab: intravitreal injections</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Bradycardia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hemorrhoids with rectal bleeding</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>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="17" subjects_at_risk="24"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Glaucoma suspect</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Cataract progression</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Visual distortion</sub_title>
                <counts group_id="E1" events="8" subjects_affected="8" subjects_at_risk="24"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Posterior vitreous detachment</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Vitreous hemorrhage</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Epiretinal membrane</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </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>Charles C Wykoff, PhD, MD</name_or_title>
      <organization>Retina Consultants of Houston</organization>
      <phone>713-524-3434</phone>
      <email>ccwmd@houstonretina.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/NCT01710839
org study id: 12246
nct id: NCT01710839
lead sponsor: 
collaborator: 
has dmc: No
To see if Lucentis 0.5mg combined with Targeted Pan Retinal photocoagulation will decrease
      the total number of intravitreal injections in a year for ischemic central retinal vein
      occlusion, hemi-retinal vein occlusions and branch retinal vein occlusions compared to
      standard of care
The WAVE trial is a phase IV, open label, 12-month trial of intravitreal ranibizumab 0.5 mg
      in patients (n=30) with ischemic CRVO, HRVO and BRVO who have been previously treated with
      ranibizumab or any other anti-VEGF intravitreal injection therapy, who are incomplete
      responders to 2 or more consecutive intravitreal anti-VEGF injections in the past 4 months.
      Randomization is 1:4, 1=control, ranibizumab only, 4=treatment arm. In total, 6 subjects will
      be randomized to control and 24 randomized to treatment arm.

      Cohort 1- 24 Subjects previously treated Patients will receive 6 doses of ranibizumab 0.5 mg,
      followed by PRN intravitreal injection of ranibizumab 0.5 mg based on pre-defined retreatment
      criteria for up to 11 total injections.

      Wide field angiography guided peripheral targeted-retinal photocoagulation (TRP), will be
      divided into 2 sessions if needed, one at the 2 weeks post injection visit and another later
      at M4/V7, if repeat wide field angiogram indicates areas not sufficiently treated in the
      first TRP session

      Cohort 2- 6 Subjects, previously treated patients will receive 6 doses of ranibizumab 0.5 mg,
      followed by PRN intravitreal injection of ranibizumab 0.5 mg based on pre-defined retreatment
      criteria for up to 11 total injections.
allocation: Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
masking description: Open label
measure: Total Number of Intravitreal Injections Over a 12 Month Period
time frame: 12 months
description: Assess the number of intravitreal injections over 12 months.
measure: Visual Acuity
time frame: 12 month period
description: Evaluate the mean change from baseline in ETDRS best-corrected visual acuity at 12 months. The ETDRS protocol is a widely accepted international standard for macular laser photocoagulation treatment. A higher score represents better functioning.
measure: Retinal Ischemia
time frame: 12 month period
description: Quantify change in area of perfused and ischemic retina.
measure: Foveal Avascular Zone
time frame: 12 months
description: Assess change in foveal avascular zone area and largest diameter, measured during the early phase of the angiogram
measure: Adverse Events
time frame: 12 months
description: Incidence and severity of adverse events (ocular and non-ocular).
measure: Neovascularization of the Iris, Optic Nerve and Elsewhere
time frame: 12 months
description: Percent of patients that develop neovascularization of the iris, optic nerve and/or elsewhere.
measure: Central Foveal Outcome
time frame: 12 months
description: Mean change in Central Foveal Volume on High Resolution OCT.
measure: Aqueous VEGF Levels
time frame: 12 Months
description: VEGF, other cytokines and ranibizumab levels in aqueous and serum samples at randomization and at the exit or early termination visit.
measure: Visual Field
time frame: 6 and 12 Months
description: Goldman Visual Field changes at 6 and 12 months from baseline. Goldmann perimetry is a method used to map a patient's field of vision (central and peripheral). Changes will be assessed by manual digital quantification of GVF plots.
arm group label: Targeted Pan Retinal laser combined with 0.5mg ranibizumab
arm group type: Experimental
description: Cohort 1 (n=24), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses of 0.5 mg ranibizumab followed by PRN treatment with ranibizumab 0.5 mg; after receiving the first loading dose of ranibizumab, the subject will have peripheral targeted-retinal photocoagulation (TRP) based on 200° wide field angiography with possibility of a second session of TRP at M4/M7, if non-perfusion persists based on angiogram.The 200°wide field angiography will indicate areas of peripheral ischemia which will be selectively treated, preserving areas of more perfused retina.
arm group label: Ranibizumab 0.5mg
arm group type: Active Comparator
description: Cohort 2 (n=6), previously treated with at least 2 consecutive or more intravitreal injections of any anti-VEGF agent with persistent or recurrent macular edema will receive 6 loading doses followed by PRN monthly treatment with ranibizumab 0.5 mg.
intervention type: Drug
intervention name: 0.5mg Ranibizumab
description: intravitreal injections
arm group label: Ranibizumab 0.5mg
arm group label: Targeted Pan Retinal laser combined with 0.5mg ranibizumab
other name: Lucentis
intervention type: Procedure
intervention name: Targeted Pan Retinal Photocoagulation
description: Targeted Pan Retinal Photocoagulation based on wide field angiography
arm group label: Targeted Pan Retinal laser combined with 0.5mg ranibizumab
other name: PRP
other name: Pan Retinal Photocoagulation
other name: TRP
other name: Pan Laser
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Charles C Wykoff, PhD, MD
role: Principal Investigator
affiliation: Retina Consultants Houston
facility: 
facility: 
facility: 
country: United States
citation: Armaly MF. Ocular pressure and visual fields. A ten-year follow-up study. Arch Ophthalmol. 1969 Jan;81(1):25-40. doi: 10.1001/archopht.1969.00990010027005. No abstract available.
PMID: 5763217
citation: Boyd SR, Zachary I, Chakravarthy U, Allen GJ, Wisdom GB, Cree IA, Martin JF, Hykin PG. Correlation of increased vascular endothelial growth factor with neovascularization and permeability in ischemic central vein occlusion. Arch Ophthalmol. 2002 Dec;120(12):1644-50. doi: 10.1001/archopht.120.12.1644.
PMID: 12470137
citation: Brown DM, Campochiaro PA, Singh RP, Li Z, Gray S, Saroj N, Rundle AC, Rubio RG, Murahashi WY; CRUISE Investigators. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010 Jun;117(6):1124-1133.e1. doi: 10.1016/j.ophtha.2010.02.022. Epub 2010 Apr 9.
PMID: 20381871
citation: Campochiaro PA, Brown DM, Awh CC, Lee SY, Gray S, Saroj N, Murahashi WY, Rubio RG. Sustained benefits from ranibizumab for macular edema following central retinal vein occlusion: twelve-month outcomes of a phase III study. Ophthalmology. 2011 Oct;118(10):2041-9. doi: 10.1016/j.ophtha.2011.02.038. Epub 2011 Jun 29.
PMID: 21715011
citation: A randomized clinical trial of early panretinal photocoagulation for ischemic central vein occlusion. The Central Vein Occlusion Study Group N report. Ophthalmology. 1995 Oct;102(10):1434-44.
PMID: 9097789
citation: Natural history and clinical management of central retinal vein occlusion. The Central Vein Occlusion Study Group. Arch Ophthalmol. 1997 Apr;115(4):486-91. doi: 10.1001/archopht.1997.01100150488006. Erratum In: Arch Ophthalmol 1997 Oct;115(10):1275.
PMID: 9109757
citation: Christen WG, Glynn RJ, Manson JE, Ajani UA, Buring JE. A prospective study of cigarette smoking and risk of age-related macular degeneration in men. JAMA. 1996 Oct 9;276(14):1147-51.
PMID: 8827967
citation: Conn G, Bayne ML, Soderman DD, Kwok PW, Sullivan KA, Palisi TM, Hope DA, Thomas KA. Amino acid and cDNA sequences of a vascular endothelial cell mitogen that is homologous to platelet-derived growth factor. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2628-32. doi: 10.1073/pnas.87.7.2628.
PMID: 2320579
citation: Connolly DT, Heuvelman DM, Nelson R, Olander JV, Eppley BL, Delfino JJ, Siegel NR, Leimgruber RM, Feder J. Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest. 1989 Nov;84(5):1470-8. doi: 10.1172/JCI114322.
PMID: 2478587
citation: Connolly DT, Olander JV, Heuvelman D, Nelson R, Monsell R, Siegel N, Haymore BL, Leimgruber R, Feder J. Human vascular permeability factor. Isolation from U937 cells. J Biol Chem. 1989 Nov 25;264(33):20017-24.
PMID: 2584205
citation: de Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science. 1992 Feb 21;255(5047):989-91. doi: 10.1126/science.1312256.
PMID: 1312256
citation: Hayreh SS, Klugman MR, Podhajsky P, Kolder HE. Electroretinography in central retinal vein occlusion. Correlation of electroretinographic changes with pupillary abnormalities. Graefes Arch Clin Exp Ophthalmol. 1989;227(6):549-61. doi: 10.1007/BF02169451.
PMID: 2483144
responsible party type: Sponsor-Investigator
investigator affiliation: Greater Houston Retina Research
investigator full name: Charles C Wykoff, PhD, MD
investigator title: Deputy Director of Research
mesh term: Retinal Vein Occlusion
mesh term: Ranibizumab
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 