<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/NCT04418427</url>
  </required_header>
  <id_info>
    <org_study_id>ADVM-022-04</org_study_id>
    <nct_id>NCT04418427</nct_id>
  </id_info>
  <brief_title>ADVM-022 Intravitreal Gene Therapy for DME</brief_title>
  <acronym>INFINITY</acronym>
  <official_title>A Phase 2, Multi-Center, Randomized, Double-Masked, Active Controlled Study of ADVM-022 (AAV.7m8-aflibercept) in Subjects With Diabetic Macular Edema [INFINITY]</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Adverum Biotechnologies, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Adverum Biotechnologies, Inc.</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      A Phase 2, Multi-Center, Randomized, Double-Masked*, Active Controlled Study of ADVM-022&#xD;
      (AAV.7m8-aflibercept) in Subjects with Diabetic Macular Edema [INFINITY]&#xD;
&#xD;
      *sponsor unmasked for enhanced safety monitoring as of May 2021&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      ADVM-022 (AAV.7m8-aflibercept) is a gene therapy product developed for the treatment of&#xD;
      serious retinal vascular diseases including Diabetic Macular Edema (DME). DME affects up to&#xD;
      10% of people with diabetes is caused by fluid accumulation in the macula and is the most&#xD;
      frequent cause of sight loss in people with diabetic retinopathy. Available therapies for&#xD;
      treating DME include laser and anti-vascular endothelial growth factor (anti-VEGF) drugs.&#xD;
      Anti-VEGFs require frequent and long-term intravitreal (IVT) injections to achieve and&#xD;
      maintain efficacy. A one-time IVT administration of ADVM-022 has the potential to treat DME&#xD;
      by providing durable expression of an anti-VEGF protein (aflibercept) to limit abnormal blood&#xD;
      vessel leakage. ADVM-022 is designed to reduce the current treatment burden which often&#xD;
      results in undertreatment, progression of disease and subsequent vision loss in patients with&#xD;
      DME.&#xD;
&#xD;
      In INFINITY, approximately 33 eligible subjects will be randomly assigned to receive one of&#xD;
      the two doses of ADVM-022, or, assigned to the control arm to receive a sham ocular injection&#xD;
      with a preceding aflibercept injection. Subjects who are assigned to receive ADVM-022 will be&#xD;
      further randomized to receive a preceding aflibercept or sham ocular injection. All subjects&#xD;
      will be assessed regularly and will receive additional aflibercept injections should DME&#xD;
      disease activity progress.&#xD;
&#xD;
      The primary objective is to assess the durability of a single intravitreal (IVT) injection of&#xD;
      ADVM-022. All subjects will be followed for 96 weeks after randomization.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 28, 2020</start_date>
  <completion_date type="Actual">November 22, 2022</completion_date>
  <primary_completion_date type="Actual">November 22, 2022</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>None (Open Label)</masking>
    <masking_description>From May 2020 through April 2021: Double-masked study Subjects, outcomes assessors and the designated masked study personnel will be masked to subject's treatment assignment throughout the study. There must be a minimum of two physicians per site to fulfill the masking requirements of the study. A masked and unmasked investigator are required to be present for administration of the preceding dose of aflibercept or sham and following dose of ADVM-022 or sham visits, thereafter only the masked investigator is required to be present.&#xD;
Starting May 2021: Open label study, study was unmasked for enhance safety monitoring.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Time to worsening of DME disease activity in the study eye.</measure>
    <time_frame>96 weeks</time_frame>
    <description>Time to worsening of DME disease activity in the study eye.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence and severity of ocular and non-ocular adverse events (AEs)</measure>
    <time_frame>96 weeks</time_frame>
    <description>Incidence and severity of ocular and non-ocular adverse events (AEs)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in central subfield thickness (CST) and macular volume over time measured by SD-OCT</measure>
    <time_frame>96 weeks</time_frame>
    <description>Change from Baseline in central subfield thickness (CST) and macular volume over time measured by SD-OCT</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in BCVA over time</measure>
    <time_frame>96 weeks</time_frame>
    <description>Change from Baseline in BCVA over time</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frequency of rescue aflibercept (2 mg IVT) in the study eye over time during the study</measure>
    <time_frame>96 weeks</time_frame>
    <description>Frequency of rescue aflibercept (2 mg IVT) in the study eye over time during the study</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of improvement in DRSS score over time</measure>
    <time_frame>96 weeks</time_frame>
    <description>Incidence of improvement in DRSS score over time</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of worsening in DRSS score over time</measure>
    <time_frame>96 weeks</time_frame>
    <description>Incidence of worsening in DRSS score over time</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Occurrence of vision threatening complication over time</measure>
    <time_frame>96 weeks</time_frame>
    <description>Occurrence of vision threatening complication over time</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of CST &lt;300 μm over time through Week 48</measure>
    <time_frame>96 weeks</time_frame>
    <description>Incidence of CST &lt;300 μm over time through Week 48</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of clinically significant findings via physical examinations, ocular examinations, imaging, and laboratory evaluation</measure>
    <time_frame>96 weeks</time_frame>
    <description>Incidence of clinically significant findings via physical examinations, ocular examinations, imaging, and laboratory evaluation</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">36</enrollment>
  <condition>Diabetic Macular Edema</condition>
  <condition>Diabetic Retinopathy</condition>
  <arm_group>
    <arm_group_label>1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>6E11 vg/eye ADVM-022 +/- aflibercept 2mg IVT</description>
  </arm_group>
  <arm_group>
    <arm_group_label>2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>2E11 vg/eye ADVM022 +/- aflibercept 2mg IVT</description>
  </arm_group>
  <arm_group>
    <arm_group_label>3</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Aflibercept 2mg IVT</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>6E11 vg/eye of ADVM-022</intervention_name>
    <description>ADVM-022 (AAV.7m8-aflibercept) is a recombinant, replication-deficient adeno-associated virus (AAV.7m8) gene therapy vector carrying a coding sequence for aflibercept</description>
    <arm_group_label>1</arm_group_label>
    <other_name>AAV.7m8-aflibercept</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>2E11 vg/eye of ADVM-022</intervention_name>
    <description>ADVM-022 (AAV.7m8-aflibercept) is a recombinant, replication-deficient adeno-associated virus (AAV.7m8) gene therapy vector carrying a coding sequence for aflibercept</description>
    <arm_group_label>2</arm_group_label>
    <other_name>AAV.7m8-aflibercept</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Aflibercept</intervention_name>
    <description>Commercially available Active Comparator</description>
    <arm_group_label>1</arm_group_label>
    <arm_group_label>2</arm_group_label>
    <arm_group_label>3</arm_group_label>
    <other_name>Eylea</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥ 18&#xD;
&#xD;
          -  Type 1 or Type 2 diabetes mellitus&#xD;
&#xD;
          -  Willing and able to provide informed consent&#xD;
&#xD;
          -  Vision impairment due to center involving diabetic macular edema&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Uncontrolled diabetes defined as HbA1C &gt;10%, or history of diabetic ketoacidosis&#xD;
             within 3 months prior to randomization; or subjects who, within the last 3 months,&#xD;
             initiated intensive insulin treatment (a pump or multiple daily injection) or plan to&#xD;
             do so in the next 3 months.&#xD;
&#xD;
          -  Acute coronary syndrome, myocardial infarction or coronary artery revascularization,&#xD;
             CVA, TIA in the last 6 months&#xD;
&#xD;
          -  Uncontrolled hypertension defined as average SBP ≥160 mmHg or an average DBP ≥100 mmHg&#xD;
&#xD;
          -  Known severe renal impairment&#xD;
&#xD;
          -  High risk Proliferative Diabetic Retinopathy&#xD;
&#xD;
          -  History of retinal disease in the study eye other than diabetic retinopathy&#xD;
&#xD;
          -  History of retinal detachment (with or without repair) in the study eye&#xD;
&#xD;
          -  History of vitrectomy, trabeculectomy, or other filtration surgery in the study eye&#xD;
&#xD;
          -  Any prior focal or grid laser photocoagulation or any prior PRP in the study eye&#xD;
&#xD;
          -  Current or planned pregnancy or breastfeeding&#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>INFINITY Medical Monitor, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Adverum Biotechnologies, Inc.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Adverum Clinical Site</name>
      <address>
        <city>Phoenix</city>
        <state>Arizona</state>
        <zip>85014</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Adverum Clinical Site</name>
      <address>
        <city>Bakersfield</city>
        <state>California</state>
        <zip>93309</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Adverum Clinical Site</name>
      <address>
        <city>Beverly Hills</city>
        <state>California</state>
        <zip>90211</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Adverum Clinical Site</name>
      <address>
        <city>Golden</city>
        <state>Colorado</state>
        <zip>80401</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Adverum Clinical Site</name>
      <address>
        <city>Deerfield Beach</city>
        <state>Florida</state>
        <zip>33064</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Adverum Clinical Site</name>
      <address>
        <city>Reno</city>
        <state>Nevada</state>
        <zip>89502</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Adverum Clinical Site</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19107</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Adverum Clinical Site</name>
      <address>
        <city>West Columbia</city>
        <state>South Carolina</state>
        <zip>29169</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Adverum Clinical Site</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37203</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Adverum Clinical Site</name>
      <address>
        <city>Abilene</city>
        <state>Texas</state>
        <zip>79606</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Adverum Clinical Site</name>
      <address>
        <city>Austin</city>
        <state>Texas</state>
        <zip>78705</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Adverum Clinical Site</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Adverum Clinical Site</name>
      <address>
        <city>The Woodlands</city>
        <state>Texas</state>
        <zip>77384</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Adverum Clinical Site</name>
      <address>
        <city>Arecibo</city>
        <zip>00612</zip>
        <country>Puerto Rico</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Puerto Rico</country>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>May 28, 2020</study_first_submitted>
  <study_first_submitted_qc>June 3, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 5, 2020</study_first_posted>
  <last_update_submitted>August 6, 2023</last_update_submitted>
  <last_update_submitted_qc>August 6, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 8, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>ADVM-022</keyword>
  <keyword>ADVM-022-04</keyword>
  <keyword>AAV.7m8</keyword>
  <keyword>Anti-VEGF therapy</keyword>
  <keyword>Blindness</keyword>
  <keyword>INFINITY</keyword>
  <keyword>Gene therapy</keyword>
  <keyword>Aflibercept (Eylea)</keyword>
  <keyword>Retinal Diseases</keyword>
  <keyword>Eye Diseases</keyword>
  <keyword>AAV Vector</keyword>
  <keyword>Adverum</keyword>
  <keyword>DME</keyword>
  <keyword>Diabetic macular edema</keyword>
  <keyword>Diabetic eye disease</keyword>
  <keyword>Diabetic retinopathy</keyword>
  <keyword>DR</keyword>
  <keyword>AAV.7m8-aflibercept</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Macular Edema</mesh_term>
    <mesh_term>Retinal Diseases</mesh_term>
    <mesh_term>Diabetic Retinopathy</mesh_term>
    <mesh_term>Edema</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <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/NCT04418427
org study id: ADVM-022-04
nct id: NCT04418427
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
A Phase 2, Multi-Center, Randomized, Double-Masked*, Active Controlled Study of ADVM-022
      (AAV.7m8-aflibercept) in Subjects with Diabetic Macular Edema [INFINITY]

      *sponsor unmasked for enhanced safety monitoring as of May 2021
ADVM-022 (AAV.7m8-aflibercept) is a gene therapy product developed for the treatment of
      serious retinal vascular diseases including Diabetic Macular Edema (DME). DME affects up to
      10% of people with diabetes is caused by fluid accumulation in the macula and is the most
      frequent cause of sight loss in people with diabetic retinopathy. Available therapies for
      treating DME include laser and anti-vascular endothelial growth factor (anti-VEGF) drugs.
      Anti-VEGFs require frequent and long-term intravitreal (IVT) injections to achieve and
      maintain efficacy. A one-time IVT administration of ADVM-022 has the potential to treat DME
      by providing durable expression of an anti-VEGF protein (aflibercept) to limit abnormal blood
      vessel leakage. ADVM-022 is designed to reduce the current treatment burden which often
      results in undertreatment, progression of disease and subsequent vision loss in patients with
      DME.

      In INFINITY, approximately 33 eligible subjects will be randomly assigned to receive one of
      the two doses of ADVM-022, or, assigned to the control arm to receive a sham ocular injection
      with a preceding aflibercept injection. Subjects who are assigned to receive ADVM-022 will be
      further randomized to receive a preceding aflibercept or sham ocular injection. All subjects
      will be assessed regularly and will receive additional aflibercept injections should DME
      disease activity progress.

      The primary objective is to assess the durability of a single intravitreal (IVT) injection of
      ADVM-022. All subjects will be followed for 96 weeks after randomization.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
masking description: From May 2020 through April 2021: Double-masked study Subjects, outcomes assessors and the designated masked study personnel will be masked to subject's treatment assignment throughout the study. There must be a minimum of two physicians per site to fulfill the masking requirements of the study. A masked and unmasked investigator are required to be present for administration of the preceding dose of aflibercept or sham and following dose of ADVM-022 or sham visits, thereafter only the masked investigator is required to be present.
Starting May 2021: Open label study, study was unmasked for enhance safety monitoring.
measure: Time to worsening of DME disease activity in the study eye.
time frame: 96 weeks
description: Time to worsening of DME disease activity in the study eye.
measure: Incidence and severity of ocular and non-ocular adverse events (AEs)
time frame: 96 weeks
description: Incidence and severity of ocular and non-ocular adverse events (AEs)
measure: Change from Baseline in central subfield thickness (CST) and macular volume over time measured by SD-OCT
time frame: 96 weeks
description: Change from Baseline in central subfield thickness (CST) and macular volume over time measured by SD-OCT
measure: Change from Baseline in BCVA over time
time frame: 96 weeks
description: Change from Baseline in BCVA over time
measure: Frequency of rescue aflibercept (2 mg IVT) in the study eye over time during the study
time frame: 96 weeks
description: Frequency of rescue aflibercept (2 mg IVT) in the study eye over time during the study
measure: Incidence of improvement in DRSS score over time
time frame: 96 weeks
description: Incidence of improvement in DRSS score over time
measure: Incidence of worsening in DRSS score over time
time frame: 96 weeks
description: Incidence of worsening in DRSS score over time
measure: Occurrence of vision threatening complication over time
time frame: 96 weeks
description: Occurrence of vision threatening complication over time
measure: Incidence of CST <300 μm over time through Week 48
time frame: 96 weeks
description: Incidence of CST <300 μm over time through Week 48
measure: Incidence of clinically significant findings via physical examinations, ocular examinations, imaging, and laboratory evaluation
time frame: 96 weeks
description: Incidence of clinically significant findings via physical examinations, ocular examinations, imaging, and laboratory evaluation
arm group label: 1
arm group type: Experimental
description: 6E11 vg/eye ADVM-022 +/- aflibercept 2mg IVT
arm group label: 2
arm group type: Experimental
description: 2E11 vg/eye ADVM022 +/- aflibercept 2mg IVT
arm group label: 3
arm group type: Active Comparator
description: Aflibercept 2mg IVT
intervention type: Biological
intervention name: 6E11 vg/eye of ADVM-022
description: ADVM-022 (AAV.7m8-aflibercept) is a recombinant, replication-deficient adeno-associated virus (AAV.7m8) gene therapy vector carrying a coding sequence for aflibercept
arm group label: 1
other name: AAV.7m8-aflibercept
intervention type: Biological
intervention name: 2E11 vg/eye of ADVM-022
description: ADVM-022 (AAV.7m8-aflibercept) is a recombinant, replication-deficient adeno-associated virus (AAV.7m8) gene therapy vector carrying a coding sequence for aflibercept
arm group label: 2
other name: AAV.7m8-aflibercept
intervention type: Biological
intervention name: Aflibercept
description: Commercially available Active Comparator
arm group label: 1
arm group label: 2
arm group label: 3
other name: Eylea
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: INFINITY Medical Monitor, MD
role: Study Chair
affiliation: Adverum Biotechnologies, Inc.
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Puerto Rico
country: United States
responsible party type: Sponsor
mesh term: Macular Edema
mesh term: Retinal Diseases
mesh term: Diabetic Retinopathy
mesh term: Edema
mesh term: Aflibercept