<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/NCT02218177</url>
  </required_header>
  <id_info>
    <org_study_id>VEGF wAMD cytokine study</org_study_id>
    <nct_id>NCT02218177</nct_id>
  </id_info>
  <brief_title>Intraocular Cytokines in Non-responders to Ranibizumab Treatment for Neovascular AMD</brief_title>
  <official_title>Neovascular Age-related Macular Degeneration: Intraocular Inflammatory Cytokines in the Non-responder to Ranibizumab Treatment</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Health Network, Toronto</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Health Network, Toronto</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to evaluate the level of cytokines (which are small proteins&#xD;
      important in cell signalling) in eye fluid (aqueous humour) in patients with wet age related&#xD;
      macular degeneration patients who have been treated with an injection in the eye&#xD;
      (intravitreal injection) with a drug called ranibizumab. The level of cytokines will be&#xD;
      compared between patients who have a good response to ranibizumab treatment and patients who&#xD;
      are non-responsive to ranibizumab and need other forms of therapy. This knowledge will help&#xD;
      for the future treatment and to potentially develop new medication for wet age-related&#xD;
      macular degeneration.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In the treatment of CNV (Choroidal NeoVascularization) secondary from AMD (Age Related&#xD;
      Macular Degeneration) by using ranibizumab, patients who are non-responders can be found in&#xD;
      approximately 1-10% of treatments. Thus, failure of treatment can lead to loss of vision.&#xD;
      Growth factors and cytokines, such as vascular endothelial growth factor (VEGF), pigment&#xD;
      epithelium derived factor (PEDF), interleukin 6 (IL-6) and placenta growth factor (PLGF) are&#xD;
      known to play an important role in the development of CNV angiogenesis.&#xD;
&#xD;
      The rationale for conducting this study to compare VEGF, PEDF, IL-6 and PLGF cytokine levels&#xD;
      in the aqueous humor of wet AMD and Polypoidal Choroidal Vasculopathy (PCV) patients who are&#xD;
      poor responders to anti VEGF treatment and age-matched &quot;good&quot; responders to anti VEGF.&#xD;
      Ranibizumab poor responders in AMD and PCV, who are treated with a combination of&#xD;
      PDT/ranibizumab or intravitreous injection of aflibercept (Eyelea®, Regeneron Pharmaceuticals&#xD;
      Inc. Tarrytown, NY, USA and Bayer, Basel, Switzerland) will be enrolled to the study. An&#xD;
      aqueous humor sample will be obtained when patient receives intravitreal injection treatment&#xD;
      and also at 1, 2 months follow up period. VEGF, PEDF,IL-6 and PLGF in aqueous will be&#xD;
      analyzed and used to compare between the poor response group and age matched patient with&#xD;
      good response to ranibizumab. Age, gender, visual acuity, central macular thickness by OCT,&#xD;
      lesion size and fundus autofluorescence data will be collected and used to compare between&#xD;
      these groups. Subgroup analysis of different treatment comparison with ranibizumab good&#xD;
      responder group will be evaluated. Factors associated with the non-responders of ranibizumab&#xD;
      will be analyzed.&#xD;
&#xD;
      Non-responders to ranibizumab treatment in AMD may have different levels and responses of&#xD;
      inflammatory cytokines compared to the responder group. Understanding the pathogenesis and&#xD;
      characteristic of this specific group of patients can help narrow down a specific choice of&#xD;
      treatment and prevent the reduction of visual acuity of the patient. This study also helps&#xD;
      identify factors associated to poor responders from ranibizumab treatment for wAMD.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>August 2014</start_date>
  <completion_date type="Actual">December 2016</completion_date>
  <primary_completion_date type="Actual">August 2016</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Aqueous Humour Cytokine Levels</measure>
    <time_frame>At time of Intravitreal Injection</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Demographic Data</measure>
    <time_frame>At time of appointment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of anti-VEGF injections before developing non-responder characteristics</measure>
    <time_frame>At time of appointment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>History of Previous Treatment</measure>
    <time_frame>At time of appointment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Optical Coherence Tomography (OCT) results</measure>
    <time_frame>At time of appointment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fluorescein Angiography Results and Indocyanine Green Angiography Results</measure>
    <time_frame>At time of appointment</time_frame>
  </secondary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Actual">30</enrollment>
  <condition>Age Related Macular Degeneration</condition>
  <arm_group>
    <arm_group_label>Non-responders receiving aflibercept therapy</arm_group_label>
    <description>Non-responders to ranibizumab who are now receiving aflibercept therapy</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Non-responders receiving PDT combo therapy</arm_group_label>
    <description>patients who are non-responders to ranibizumab who have been switched to combination photodynamic therapy (PDT)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Responders to ranibizumab</arm_group_label>
    <description>Patients who are responders to ranibizumab and are continuing monthly injections.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Aflibercept</intervention_name>
    <description>anti-VEGF treatment for wet age related macular degeneration</description>
    <arm_group_label>Non-responders receiving aflibercept therapy</arm_group_label>
    <other_name>Eylea (R)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ranibizumab</intervention_name>
    <description>anti-VEGF treatment for wet age related macular degeneration</description>
    <arm_group_label>Responders to ranibizumab</arm_group_label>
    <other_name>Lucentis</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Combination Photodynamic Therapy</intervention_name>
    <description>Use of cold laser with an intravitreal injection of dexamethasone to treat wet age related macular degeneration</description>
    <arm_group_label>Non-responders receiving PDT combo therapy</arm_group_label>
  </intervention>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Aqueous Humour from Eye&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Study patients in the treatment group will be those greater than 50 years old, with age&#xD;
        related macular degeneration, who are non-responder/ resistance to ranibizumab treatment.&#xD;
        Control group will include patients who are responders to ranibizumab treatment.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age 50 years or more&#xD;
&#xD;
          -  Ranibizumab resistance/poor responder patients in all AMD entities (typical AMD, PCV&#xD;
             and RAP) who will be treated with intravitreous ranibizumab in combination with&#xD;
             verteporfin photodynamic therapy&#xD;
&#xD;
          -  Ranibizumab resistance/poor responder patients in all AMD entity (typical AMD, PCV and&#xD;
             RAP) who will be treated with intravitreous aflibercept injection&#xD;
&#xD;
          -  AMD patient who is good response to the treatment of ranibizumab (control group)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any evidence of good response in treatment of ranibizumab,&#xD;
&#xD;
          -  Uncooperative patients to intravitreal treatment&#xD;
&#xD;
          -  Patients who have clinically active ocular inflammation&#xD;
&#xD;
          -  Patients who have previous PDT treatment within 6 months&#xD;
&#xD;
          -  Patient who previously have ocular treatment of immunosuppressive agent within 3&#xD;
             months&#xD;
&#xD;
          -  Patient who previously have ocular treatment of steroid with in 3 months&#xD;
&#xD;
          -  Patients who are currently on systemic treatment of anti-VEGF medication or&#xD;
             immunosuppressive agents.&#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>Wai-Ching Lam, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Toronto Western Hospital, University Health Network, University of Toronto</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Toronto Western Hospital</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M2N4H3</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>October 2018</verification_date>
  <study_first_submitted>August 13, 2014</study_first_submitted>
  <study_first_submitted_qc>August 13, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 18, 2014</study_first_posted>
  <last_update_submitted>October 9, 2018</last_update_submitted>
  <last_update_submitted_qc>October 9, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">October 11, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University Health Network, Toronto</investigator_affiliation>
    <investigator_full_name>Wai-Ching Lam</investigator_full_name>
    <investigator_title>Professor University of Toronto, Residency Program Director Dept. of Ophthalmology, Continuing Medical Education Director Dept. of Ophthalmology</investigator_title>
  </responsible_party>
  <keyword>wet Age Related Macular Degeneration</keyword>
  <keyword>Ranibizumab</keyword>
  <keyword>Aflibercept</keyword>
  <keyword>Combination Photodynamic Therapy</keyword>
  <keyword>Cytokine analysis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Macular Degeneration</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ranibizumab</mesh_term>
    <mesh_term>Aflibercept</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02218177
org study id: VEGF wAMD cytokine study
nct id: NCT02218177
lead sponsor: 
has dmc: No
The purpose of this study is to evaluate the level of cytokines (which are small proteins
      important in cell signalling) in eye fluid (aqueous humour) in patients with wet age related
      macular degeneration patients who have been treated with an injection in the eye
      (intravitreal injection) with a drug called ranibizumab. The level of cytokines will be
      compared between patients who have a good response to ranibizumab treatment and patients who
      are non-responsive to ranibizumab and need other forms of therapy. This knowledge will help
      for the future treatment and to potentially develop new medication for wet age-related
      macular degeneration.
In the treatment of CNV (Choroidal NeoVascularization) secondary from AMD (Age Related
      Macular Degeneration) by using ranibizumab, patients who are non-responders can be found in
      approximately 1-10% of treatments. Thus, failure of treatment can lead to loss of vision.
      Growth factors and cytokines, such as vascular endothelial growth factor (VEGF), pigment
      epithelium derived factor (PEDF), interleukin 6 (IL-6) and placenta growth factor (PLGF) are
      known to play an important role in the development of CNV angiogenesis.

      The rationale for conducting this study to compare VEGF, PEDF, IL-6 and PLGF cytokine levels
      in the aqueous humor of wet AMD and Polypoidal Choroidal Vasculopathy (PCV) patients who are
      poor responders to anti VEGF treatment and age-matched "good" responders to anti VEGF.
      Ranibizumab poor responders in AMD and PCV, who are treated with a combination of
      PDT/ranibizumab or intravitreous injection of aflibercept (Eyelea®, Regeneron Pharmaceuticals
      Inc. Tarrytown, NY, USA and Bayer, Basel, Switzerland) will be enrolled to the study. An
      aqueous humor sample will be obtained when patient receives intravitreal injection treatment
      and also at 1, 2 months follow up period. VEGF, PEDF,IL-6 and PLGF in aqueous will be
      analyzed and used to compare between the poor response group and age matched patient with
      good response to ranibizumab. Age, gender, visual acuity, central macular thickness by OCT,
      lesion size and fundus autofluorescence data will be collected and used to compare between
      these groups. Subgroup analysis of different treatment comparison with ranibizumab good
      responder group will be evaluated. Factors associated with the non-responders of ranibizumab
      will be analyzed.

      Non-responders to ranibizumab treatment in AMD may have different levels and responses of
      inflammatory cytokines compared to the responder group. Understanding the pathogenesis and
      characteristic of this specific group of patients can help narrow down a specific choice of
      treatment and prevent the reduction of visual acuity of the patient. This study also helps
      identify factors associated to poor responders from ranibizumab treatment for wAMD.
observational model: Case-Control
time perspective: Prospective
measure: Aqueous Humour Cytokine Levels
time frame: At time of Intravitreal Injection
measure: Demographic Data
time frame: At time of appointment
measure: Number of anti-VEGF injections before developing non-responder characteristics
time frame: At time of appointment
measure: History of Previous Treatment
time frame: At time of appointment
measure: Optical Coherence Tomography (OCT) results
time frame: At time of appointment
measure: Fluorescein Angiography Results and Indocyanine Green Angiography Results
time frame: At time of appointment
arm group label: Non-responders receiving aflibercept therapy
description: Non-responders to ranibizumab who are now receiving aflibercept therapy
arm group label: Non-responders receiving PDT combo therapy
description: patients who are non-responders to ranibizumab who have been switched to combination photodynamic therapy (PDT)
arm group label: Responders to ranibizumab
description: Patients who are responders to ranibizumab and are continuing monthly injections.
intervention type: Drug
intervention name: Aflibercept
description: anti-VEGF treatment for wet age related macular degeneration
arm group label: Non-responders receiving aflibercept therapy
other name: Eylea (R)
intervention type: Drug
intervention name: Ranibizumab
description: anti-VEGF treatment for wet age related macular degeneration
arm group label: Responders to ranibizumab
other name: Lucentis
intervention type: Procedure
intervention name: Combination Photodynamic Therapy
description: Use of cold laser with an intravitreal injection of dexamethasone to treat wet age related macular degeneration
arm group label: Non-responders receiving PDT combo therapy
Aqueous Humour from Eye
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Wai-Ching Lam, MD
role: Principal Investigator
affiliation: Toronto Western Hospital, University Health Network, University of Toronto
facility: 
country: Canada
responsible party type: Principal Investigator
investigator affiliation: University Health Network, Toronto
investigator full name: Wai-Ching Lam
investigator title: Professor University of Toronto, Residency Program Director Dept. of Ophthalmology, Continuing Medical Education Director Dept. of Ophthalmology
mesh term: Macular Degeneration
mesh term: Ranibizumab
mesh term: Aflibercept