<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/NCT01675947</url>
  </required_header>
  <id_info>
    <org_study_id>3368-12056</org_study_id>
    <nct_id>NCT01675947</nct_id>
    <nct_alias>NCT01664208</nct_alias>
  </id_info>
  <brief_title>Intravitreal Injections of Sirolimus in the Treatment of Geographic Atrophy</brief_title>
  <acronym>Sirolimus</acronym>
  <official_title>Multi-Center, Randomized, Single Masked Phase 2 Study of Intravitreal Injections of Sirolimus in the Treatment of Geographic Atrophy Associated With Age-Related Macular Degeneration</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Eye Institute (NEI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>The Emmes Company, LLC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Santen Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>National Eye Institute (NEI)</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will seek to enroll 50 persons who have central or non-central geographic atrophy&#xD;
      (GA) associated with age-related macular degeneration (AMD). GA in treated eye must be&#xD;
      between 0.75 disk areas (DA) and 8 DA. Eligible participants will be randomly chosen to&#xD;
      receive one of the following treatments in the study eye:&#xD;
&#xD;
        1. A 20 μL (440 μg) intravitreal (IVT) injection of sirolimus, or&#xD;
&#xD;
        2. A sham treatment (subconjunctival injection of lidocaine) Participants with two (2)&#xD;
           eligible eyes will have one eye randomly assigned to receive intravitreal sirolimus and&#xD;
           no sham in the fellow eye.&#xD;
&#xD;
      The first injection will begin at Day 0, which may occur on the date of screening/enrollment&#xD;
      or up to two weeks following screening/enrollment visit, and every month thereafter. The&#xD;
      visit schedule is as follows:&#xD;
&#xD;
        1. A clinical evaluation, including safety measures, will occur monthly.&#xD;
&#xD;
        2. Vision will be measured at the screening/enrollment visit and at 2, 3, 6, 9, 12, 18 and&#xD;
           24 months after the first injection has occurred.&#xD;
&#xD;
        3. Fundus autofluorescence will occur at screening/enrollment and at 2, 6, 12, 18 and 24&#xD;
           months after the first injection has occurred.&#xD;
&#xD;
        4. Fundus color photography and optical coherence tomography will occur at&#xD;
           screening/enrollment and at 6, 12, 18 and 24 months after the first injection has&#xD;
           occurred.&#xD;
&#xD;
      The primary goal is to evaluate whether the persons receiving the sirolimus injections show a&#xD;
      slower worsening of geographic atrophy compared to the persons receiving the sham injections.&#xD;
      A secondary goal is to evaluate the impact of sirolimus on vision compared to the sham.&#xD;
&#xD;
      NOTE: As of May 30, 2014, study injections were discontinued due to safety concerns. No&#xD;
      further enrollments will occur and follow-up will continue on all active study participants&#xD;
      on a quarterly basis. That is, on visits coinciding with 3 month intervals from date of&#xD;
      enrollment.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    On May 30, 2014, study injections were discontinued at the request of the DSMC. No further&#xD;
    recruitment will occur.&#xD;
  </why_stopped>
  <start_date>February 2012</start_date>
  <completion_date type="Anticipated">February 2016</completion_date>
  <primary_completion_date type="Actual">June 2015</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Rate of change in area of geographic atrophy</measure>
    <time_frame>Every 6 months after enrollment for 2 years</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in best-corrected visual acuity</measure>
    <time_frame>Every 6 months after enrollment for 2 years</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>Number and severity of systemic and ocular toxicities, adverse events and infections</measure>
    <time_frame>Monthly for 2 years</time_frame>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">52</enrollment>
  <condition>Geographic Atrophy</condition>
  <arm_group>
    <arm_group_label>Sirolimus</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Monthly 20 μL (440 μg) intravitreal injection of sirolimus</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Lidocaine</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>Monthly subconjunctival injection of 2% lidocaine</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sirolimus</intervention_name>
    <description>Immunosuppressive agent. Blocks the T-lymphocyte activation and smooth muscle and endothelial cell proliferation that occurs in response to antigenic and cytokine (interleukin IL-2, IL-4 and IL-15) stimulation through either Ca2+-dependent or Ca2+-independent pathways. Sirolimus arrests cell cycle progression by direct interaction with two intracellular proteins (immunophilin FK binding protein 12 (FKBP-12) and the mammalian target of rapamycin (mTOR), a multifunctional serine-threonine kinase). In cells, sirolimus binds to FKBP-12, and the resulting sirolimus-FKBP-12 complex then binds to and inhibits mTOR.</description>
    <arm_group_label>Sirolimus</arm_group_label>
    <other_name>Rapamycin, Rapamune</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lidocaine</intervention_name>
    <description>Lidocaine 2%</description>
    <arm_group_label>Lidocaine</arm_group_label>
    <other_name>Xylocaine</other_name>
    <other_name>lignocaine</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age 55 years of age or older. Prior participation in the Age-Related Eye Disease Study&#xD;
             2 (AREDS2) is not required.&#xD;
&#xD;
          -  Participant must understand and sign the protocol's informed consent document.&#xD;
&#xD;
          -  Participant must have central or non-central geographic atrophy (GA) in at least one&#xD;
             eye. GA should be at least 0.75 disk areas (DA) in size but no more than 8 disk areas&#xD;
             (DA); approximately 2.54 mm2 is 1 DA. GA is defined as one or more well-defined,&#xD;
             usually more or less circular patches of partial or complete de-pigmentation of the&#xD;
             retinal pigment epithelium (RPE), typically with exposure of underlying choroidal&#xD;
             blood vessels. Even if much of the RPE appears to be preserved and large choroidal&#xD;
             vessels are not visible, a round patch of RPE partial de-pigmentation may still be&#xD;
             classified as early GA.&#xD;
&#xD;
          -  Participant must have a steady fixation in the study eye in the foveal or parafoveal&#xD;
             area and media clear enough for good quality photographs.&#xD;
&#xD;
          -  Participant must have visual acuity between 20/25 and 20/200 in the study eye.&#xD;
&#xD;
          -  Female participants must be post-menopausal.&#xD;
&#xD;
          -  Male participants with female partners capable of conceiving children will be required&#xD;
             to use contraception during the study and for four months after their last sirolimus&#xD;
             injection.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Participant is in another investigational study other than AREDS2 and actively&#xD;
             receiving study therapy for geographic atrophy or choroidal neovascularization (CNV).&#xD;
&#xD;
          -  Participant is unable to comply with study procedures or follow-up visits.&#xD;
&#xD;
          -  Participant has evidence of ocular disease other than AMD in either eye that may&#xD;
             confound the outcome of the study (e.g., glaucoma, diabetic retinopathy with 10 or&#xD;
             more hemorrhages or microaneurysms, uveitis, pseudovitelliform macular degeneration,&#xD;
             moderate/severe myopia).&#xD;
&#xD;
          -  Participant has received treatment for AMD, such as macular laser, photodynamic&#xD;
             therapy (PDT) or anti-vascular endothelial growth factor (anti-VEGF) therapy&#xD;
             injection. Or the participant received an IVT injection of any agent (e.g.,&#xD;
             triamcinolone) other than an anti-VEGF agent within the last four months prior to&#xD;
             study enrollment. Vitamin supplementation for AMD is not considered an exclusionary&#xD;
             criterion.&#xD;
&#xD;
          -  Participant has had a vitrectomy.&#xD;
&#xD;
          -  Participant is expected to need ocular surgery during the course of the trial.&#xD;
&#xD;
          -  Participant has undergone lens removal in the last three months or Yttrium Aluminium&#xD;
             Garnet (YAG) laser capsulotomy within the last month.&#xD;
&#xD;
          -  Participant is on chemotherapy.&#xD;
&#xD;
          -  Participant is on immunosuppressive medication or is immunosuppressed.&#xD;
&#xD;
          -  Participant is on ocular or systemic medications known to be toxic to the lens, retina&#xD;
             or optic nerve.&#xD;
&#xD;
          -  Participant with a history of malignancy that would compromise the 2-year study&#xD;
             survival.&#xD;
&#xD;
          -  Participant with a history of ocular herpes simplex virus (HSV).&#xD;
&#xD;
          -  A condition that, in the opinion of the investigator, would preclude participation in&#xD;
             the study (e.g., unstable medical status including blood pressure and glycemic&#xD;
             control).&#xD;
&#xD;
          -  History of cancer (other than a non-melanoma skin cancer) diagnosed within the past&#xD;
             five years that could be worsened by immunosuppression. (The risk of immunosuppression&#xD;
             must be determined by an oncology consultation prior to enrollment.)&#xD;
&#xD;
          -  Ocular or periocular inflammation or infection in either eye.&#xD;
&#xD;
          -  Presence of active or inactive toxoplasmosis in the study eye.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>55 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Emily Y Chew, MD</last_name>
    <role>Study Chair</role>
    <affiliation>National Eye Institute (NEI)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Loma Linda University</name>
      <address>
        <city>Loma Linda</city>
        <state>California</state>
        <zip>92354</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of California, Davis</name>
      <address>
        <city>Sacramento</city>
        <state>California</state>
        <zip>95817</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Florida HSC</name>
      <address>
        <city>Jacksonville</city>
        <state>Florida</state>
        <zip>32209</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Emory University</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30322</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Illinois</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Elman Retina Group</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21237</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vision Research Foundation</name>
      <address>
        <city>Grand Rapids</city>
        <state>Michigan</state>
        <zip>49546</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Charlotte Eye Ear Nose &amp; Throat Associates</name>
      <address>
        <city>Charlotte</city>
        <state>North Carolina</state>
        <zip>28210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Scheie Eye Institute, University of Pennsylvania</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Palmetto Retina Center</name>
      <address>
        <city>West Columbia</city>
        <state>South Carolina</state>
        <zip>29169</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Southeastern Retina Associates, P.C.</name>
      <address>
        <city>Knoxville</city>
        <state>Tennessee</state>
        <zip>37909</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Texas Retina Associates</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75231</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Wisconsin</name>
      <address>
        <city>Madison</city>
        <state>Wisconsin</state>
        <zip>53705</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>December 2015</verification_date>
  <study_first_submitted>August 28, 2012</study_first_submitted>
  <study_first_submitted_qc>August 28, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 30, 2012</study_first_posted>
  <last_update_submitted>December 8, 2015</last_update_submitted>
  <last_update_submitted_qc>December 8, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">December 10, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Geographic Atrophy</mesh_term>
    <mesh_term>Atrophy</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sirolimus</mesh_term>
    <mesh_term>Lidocaine</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/NCT01675947
org study id: 3368-12056
nct id: NCT01675947
nct alias: NCT01664208
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
This study will seek to enroll 50 persons who have central or non-central geographic atrophy
      (GA) associated with age-related macular degeneration (AMD). GA in treated eye must be
      between 0.75 disk areas (DA) and 8 DA. Eligible participants will be randomly chosen to
      receive one of the following treatments in the study eye:

        1. A 20 μL (440 μg) intravitreal (IVT) injection of sirolimus, or

        2. A sham treatment (subconjunctival injection of lidocaine) Participants with two (2)
           eligible eyes will have one eye randomly assigned to receive intravitreal sirolimus and
           no sham in the fellow eye.

      The first injection will begin at Day 0, which may occur on the date of screening/enrollment
      or up to two weeks following screening/enrollment visit, and every month thereafter. The
      visit schedule is as follows:

        1. A clinical evaluation, including safety measures, will occur monthly.

        2. Vision will be measured at the screening/enrollment visit and at 2, 3, 6, 9, 12, 18 and
           24 months after the first injection has occurred.

        3. Fundus autofluorescence will occur at screening/enrollment and at 2, 6, 12, 18 and 24
           months after the first injection has occurred.

        4. Fundus color photography and optical coherence tomography will occur at
           screening/enrollment and at 6, 12, 18 and 24 months after the first injection has
           occurred.

      The primary goal is to evaluate whether the persons receiving the sirolimus injections show a
      slower worsening of geographic atrophy compared to the persons receiving the sham injections.
      A secondary goal is to evaluate the impact of sirolimus on vision compared to the sham.

      NOTE: As of May 30, 2014, study injections were discontinued due to safety concerns. No
      further enrollments will occur and follow-up will continue on all active study participants
      on a quarterly basis. That is, on visits coinciding with 3 month intervals from date of
      enrollment.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Participant)
measure: Rate of change in area of geographic atrophy
time frame: Every 6 months after enrollment for 2 years
measure: Change in best-corrected visual acuity
time frame: Every 6 months after enrollment for 2 years
measure: Number and severity of systemic and ocular toxicities, adverse events and infections
time frame: Monthly for 2 years
arm group label: Sirolimus
arm group type: Experimental
description: Monthly 20 μL (440 μg) intravitreal injection of sirolimus
arm group label: Lidocaine
arm group type: Sham Comparator
description: Monthly subconjunctival injection of 2% lidocaine
intervention type: Drug
intervention name: Sirolimus
description: Immunosuppressive agent. Blocks the T-lymphocyte activation and smooth muscle and endothelial cell proliferation that occurs in response to antigenic and cytokine (interleukin IL-2, IL-4 and IL-15) stimulation through either Ca2+-dependent or Ca2+-independent pathways. Sirolimus arrests cell cycle progression by direct interaction with two intracellular proteins (immunophilin FK binding protein 12 (FKBP-12) and the mammalian target of rapamycin (mTOR), a multifunctional serine-threonine kinase). In cells, sirolimus binds to FKBP-12, and the resulting sirolimus-FKBP-12 complex then binds to and inhibits mTOR.
arm group label: Sirolimus
other name: Rapamycin, Rapamune
intervention type: Drug
intervention name: Lidocaine
description: Lidocaine 2%
arm group label: Lidocaine
other name: Xylocaine
other name: lignocaine
criteria: 
gender: All
minimum age: 55 Years
maximum age: N/A
healthy volunteers: No
last name: Emily Y Chew, MD
role: Study Chair
affiliation: National Eye Institute (NEI)
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Geographic Atrophy
mesh term: Atrophy
mesh term: Sirolimus
mesh term: Lidocaine