<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/NCT03034772</url>
  </required_header>
  <id_info>
    <org_study_id>16-596</org_study_id>
    <nct_id>NCT03034772</nct_id>
  </id_info>
  <brief_title>Dorzolamide-timolol in Combination With Anti-vascular Endothelial Growth Factor Injections for Wet Age-related Macular Degeneration</brief_title>
  <acronym>DAWN</acronym>
  <official_title>A Randomized Controlled Trial Comparing the Effect of Topical Dorzolamide-Timolol Versus Placebo Combined With Intravitreal Anti-Vascular Endothelial Growth Factor (VEGF) Injections in Patients With Neovascular Age-Related Macular Degeneration Who Are Incomplete Anti-VEGF Responders</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Wills Eye</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Mid Atlantic Retina</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Wills Eye</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      A previous pilot study demonstrated that commonly available glaucoma drops&#xD;
      (dorzolamide-timolol) might decrease the amount of chronic swelling in patient with wet&#xD;
      age-related macular degeneration who have been receiving anti-vascular endothelial growth&#xD;
      factor (VEGF) injections. This will be a larger study where subjects are randomly assigned to&#xD;
      receive the glaucoma drops or a placebo (artificial tears) in order to confirm whether this&#xD;
      previous finding is valid. Subjects will continue to receive the normally scheduled anti-VEGF&#xD;
      injections at regular intervals as done prior to enrollment. The only addition to the regimen&#xD;
      will be the daily use of eye drops (dorzolamide-timolol or artificial tears) twice daily for&#xD;
      the duration of the study. At the end of the study, the swelling in the retina will be&#xD;
      compared to the amount before starting the drops to see if there is any difference between&#xD;
      the group using dorzolamide-timolol versus artificial tears.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Intravitreal anti-vascular endothelial growth factor (VEGF) agents, including ranibizumab and&#xD;
      aflibercept, remain the standard of care treatment for neovascular age-related macular&#xD;
      degeneration (AMD). Various treatment modalities using these agents have been proposed,&#xD;
      including monthly, pro re nata, and treat-and-extend regimens. Despite frequent and&#xD;
      consistent treatment with anti-VEGF therapy, there is a subset of patients who are incomplete&#xD;
      responders and have persistent exudation, including intraretinal edema, subretinal fluid&#xD;
      (SRF), and/or retinal pigment epithelial detachment (PED) on spectral-domain optical&#xD;
      coherence tomography (SD-OCT). While clearance of intravitreal anti-VEGF drugs is not&#xD;
      completely understood, some studies have suggested that outflow through the anterior chamber&#xD;
      may play a role. We hypothesized that by decreasing aqueous production, outflow may also be&#xD;
      reduced which could subsequently slow the clearance of intravitreal drugs. In a prior pilot&#xD;
      study with 10 eyes of 10 patients who were incomplete responders with neovascular AMD, the&#xD;
      effect of topical dorzolamide-timolol in combination with continued intravitreal anti-VEGF&#xD;
      injections was explored. Patients were kept on the same anti-VEGF drug as well as the same&#xD;
      interval between injections for the 2 visits before enrollment and through the course of the&#xD;
      pilot study in order to minimize the chances that any changes noted might be the result of&#xD;
      altering one of these variables. The mean central subfield thickness (CST) decreased from&#xD;
      419.7 μm at enrollment to 334.1 μm at the final visit (p=0.012). Mean maximum subretinal&#xD;
      fluid (SRF) height decreased from 126.6 μm at enrollment to 56.5 μm at the final visit&#xD;
      (p=0.020). This decrease in mean CST and SRF was significant beginning at the first visit&#xD;
      after initiation of the drops. Based on this initial pilot data, dorzolamide-timolol appears&#xD;
      to be a promising adjuvant treatment in combination with anti-VEGF injections for incomplete&#xD;
      anti-VEGF responders with neovascular AMD. However, since there was no control group in the&#xD;
      pilot study, it is possible that the decreased exudation seen was a result of the continued&#xD;
      anti-VEGF therapy alone rather than an effect of the topical therapy. As a result, a&#xD;
      randomized, placebo-controlled clinical trial will be better able to assess the efficacy of&#xD;
      dorzolamide-timolol in this setting.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 8, 2017</start_date>
  <completion_date type="Actual">July 5, 2019</completion_date>
  <primary_completion_date type="Actual">February 8, 2019</primary_completion_date>
  <phase>Phase 2/Phase 3</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>
    <masking_description>Single-blind</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Mean Central Subfield Thickness (CST)</measure>
    <time_frame>Baseline and 18 weeks</time_frame>
    <description>Change in mean CST on spectral domain optical coherence tomography from baseline to the final visit</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Mean Maximum Subretinal Fluid (SRF) Height</measure>
    <time_frame>Baseline and 18 weeks</time_frame>
    <description>Change in mean maximum SRF height on spectral domain optical coherence tomography from baseline to final visit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Mean Maximum Pigment Epithelial Detachment (PED) Height</measure>
    <time_frame>Baseline and 18 weeks</time_frame>
    <description>Change in mean maximum PED height on spectral domain optical coherence tomography from baseline to final visit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Visual Acuity</measure>
    <time_frame>Baseline and 18 weeks</time_frame>
    <description>Change in mean best available visual acuity from baseline to final visit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Mean Intraocular Pressure (IOP)</measure>
    <time_frame>Baseline and 18 weeks</time_frame>
    <description>Change in mean IOP from baseline to final visit.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">52</enrollment>
  <condition>Neovascular Age-related Macular Degeneration</condition>
  <condition>Wet Macular Degeneration</condition>
  <arm_group>
    <arm_group_label>Dorzolamide-timolol</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Topical dorzolamide-timolol twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Artificial tears</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Topical artificial tears twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dorzolamide-timolol</intervention_name>
    <description>Topical eye drop (active comparator) used twice daily for study duration</description>
    <arm_group_label>Dorzolamide-timolol</arm_group_label>
    <other_name>Cosopt</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Artificial tears</intervention_name>
    <description>Topical eye drop (placebo comparator) used twice daily for study duration</description>
    <arm_group_label>Artificial tears</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Active choroidal neovascularization (CNV) due to AMD.&#xD;
&#xD;
          2. Prior treatment with at least 4 injections of anti-VEGF agents in the past 6 months&#xD;
             and persistent intraretinal and/or subretinal fluid on SD-OCT at each visit during&#xD;
             this period.&#xD;
&#xD;
          3. Baseline CST ≥ 270 µm on SD-OCT automated retinal thickness map.&#xD;
&#xD;
          4. Injection of the same anti-VEGF agent at each of the two visits immediately preceding&#xD;
             study enrollment.&#xD;
&#xD;
          5. Time interval of 5 weeks (± 1 week) between visits for at least two visits immediately&#xD;
             preceding study enrollment.&#xD;
&#xD;
          6. Subjects of either gender aged ≥ 45 years.&#xD;
&#xD;
          7. Provide written informed consent&#xD;
&#xD;
          8. Ability to comply with study and follow-up procedures and return for study visits.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. History of uveitis.&#xD;
&#xD;
          2. Presence of intraocular inflammation, significant epiretinal membrane (causing&#xD;
             distortion of macular anatomy per investigator discretion), significant vitreomacular&#xD;
             traction (per investigator discretion), macular hole, or vitreous hemorrhage.&#xD;
&#xD;
          3. Any ophthalmic surgery within previous 6 months, including cataract extraction.&#xD;
&#xD;
          4. Any history of vitrectomy or glaucoma surgery (e.g., trabeculectomy, tube shunt).&#xD;
&#xD;
          5. Current prescription eye drop usage (e.g., glaucoma drops, corticosteroid drops,&#xD;
             etc.).&#xD;
&#xD;
          6. Any contraindication for topical use of a beta-blocker (e.g., bradycardia,&#xD;
             decompensated heart failure, chronic obstructive pulmonary disease, reactive airway&#xD;
             disease, asthma, etc.).&#xD;
&#xD;
          7. Any history of sulfonamide allergy.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>45 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jason Hsu, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Wills Eye</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Palo Alto Medical Foundation</name>
      <address>
        <city>Palo Alto</city>
        <state>California</state>
        <zip>94301</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ophthalmic Consultants of Boston</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Associated Retinal Consultants</name>
      <address>
        <city>Royal Oak</city>
        <state>Michigan</state>
        <zip>48073</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mid Atlantic Retina- Wills Eye Institute</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19107</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Retina Consultants of Houston</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Sridhar J, Hsu J, Shahlaee A, Garg SJ, Spirn MJ, Fineman MS, Vander J. Topical Dorzolamide-Timolol With Intravitreous Anti-Vascular Endothelial Growth Factor for Neovascular Age-Related Macular Degeneration. JAMA Ophthalmol. 2016 Apr;134(4):437-43. doi: 10.1001/jamaophthalmol.2016.0045.</citation>
    <PMID>26914218</PMID>
  </reference>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>January 25, 2017</study_first_submitted>
  <study_first_submitted_qc>January 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 27, 2017</study_first_posted>
  <results_first_submitted>May 24, 2020</results_first_submitted>
  <results_first_submitted_qc>June 5, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">June 19, 2020</results_first_posted>
  <last_update_submitted>June 5, 2020</last_update_submitted>
  <last_update_submitted_qc>June 5, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 19, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Wills Eye</investigator_affiliation>
    <investigator_full_name>Jason Hsu, MD</investigator_full_name>
    <investigator_title>Co-director of Retina Research</investigator_title>
  </responsible_party>
  <keyword>neovascular</keyword>
  <keyword>wet</keyword>
  <keyword>age-related</keyword>
  <keyword>macular degeneration</keyword>
  <keyword>dorzolamide</keyword>
  <keyword>timolol</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Macular Degeneration</mesh_term>
    <mesh_term>Wet Macular Degeneration</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Timolol</mesh_term>
    <mesh_term>Dorzolamide</mesh_term>
    <mesh_term>Lubricant Eye Drops</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>February 4, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/72/NCT03034772/Prot_SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>Since multiple centers were enrolling simultaneously, two more patients then anticipated were randomized</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Dorzolamide-timolol</title>
          <description>Topical dorzolamide-timolol twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals.&#xD;
Dorzolamide-timolol: Topical eye drop (active comparator) used twice daily for study duration</description>
        </group>
        <group group_id="P2">
          <title>Artificial Tears</title>
          <description>Topical artificial tears twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals.&#xD;
Artificial tears: Topical eye drop (placebo comparator) used twice daily for study duration</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="27"/>
                <participants group_id="P2" count="25"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="27"/>
                <participants group_id="P2" count="23"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Dorzolamide-timolol</title>
          <description>Topical dorzolamide-timolol twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals.&#xD;
Dorzolamide-timolol: Topical eye drop (active comparator) used twice daily for study duration</description>
        </group>
        <group group_id="B2">
          <title>Artificial Tears</title>
          <description>Topical artificial tears twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals.&#xD;
Artificial tears: Topical eye drop (placebo comparator) used twice daily for study duration</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="27"/>
            <count group_id="B2" value="23"/>
            <count group_id="B3" value="50"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="27"/>
                    <count group_id="B2" value="23"/>
                    <count group_id="B3" value="50"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="79.7" spread="7.5"/>
                    <measurement group_id="B2" value="77.5" spread="6.3"/>
                    <measurement group_id="B3" value="78.4" spread="7"/>
                  </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>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="27"/>
                    <count group_id="B2" value="23"/>
                    <count group_id="B3" value="50"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                    <measurement group_id="B2" value="16"/>
                    <measurement group_id="B3" value="34"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race and Ethnicity Not Collected</title>
          <population>Race and Ethnicity were not collected from any participant.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                    <count group_id="B2" value="0"/>
                    <count group_id="B3" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="27"/>
                    <count group_id="B2" value="23"/>
                    <count group_id="B3" value="50"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="27"/>
                    <measurement group_id="B2" value="23"/>
                    <measurement group_id="B3" value="50"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Intravitreal anti-vascular endothelial growth factor agent used</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="27"/>
                    <count group_id="B2" value="23"/>
                    <count group_id="B3" value="50"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Aflibercept</title>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="14"/>
                    <measurement group_id="B3" value="27"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Ranibizumab</title>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Number of prior anti-vascular endothelial growth factor (VEGF) injections</title>
          <units>injections</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="27"/>
                    <count group_id="B2" value="23"/>
                    <count group_id="B3" value="50"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="20" spread="15.6"/>
                    <measurement group_id="B2" value="21.1" spread="11.6"/>
                    <measurement group_id="B3" value="20.5" spread="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Injection interval before enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="27"/>
                    <count group_id="B2" value="23"/>
                    <count group_id="B3" value="50"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Every 4 weeks</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="29"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Every 5 weeks</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Every 6 weeks</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Visual Acuity (logarithm of the minimum angle of resolution, logMAR)</title>
          <units>logMAR</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="27"/>
                    <count group_id="B2" value="23"/>
                    <count group_id="B3" value="50"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0.37" spread="0.31"/>
                    <measurement group_id="B2" value="0.348" spread="0.19"/>
                    <measurement group_id="B3" value="0.361" spread="0.26"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Intraocular Pressure</title>
          <units>mm Hg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="27"/>
                    <count group_id="B2" value="23"/>
                    <count group_id="B3" value="50"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="14.37" spread="2.9"/>
                    <measurement group_id="B2" value="14.22" spread="3.1"/>
                    <measurement group_id="B3" value="14.3" spread="2.95"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Baseline Optical Coherence Tomography (OCT) Measurements</title>
          <units>microns</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <title>Central subfield thickness</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="27"/>
                    <count group_id="B2" value="23"/>
                    <count group_id="B3" value="50"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="348.3" spread="75.5"/>
                    <measurement group_id="B2" value="321.3" spread="80.5"/>
                    <measurement group_id="B3" value="335.9" spread="78.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Maximum pigment epithelial detachment height</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="27"/>
                    <count group_id="B2" value="23"/>
                    <count group_id="B3" value="50"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="230.2" spread="116.4"/>
                    <measurement group_id="B2" value="178.9" spread="111"/>
                    <measurement group_id="B3" value="206.1" spread="115.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Maximum subretinal fluid height</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="27"/>
                    <count group_id="B2" value="23"/>
                    <count group_id="B3" value="50"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="103.15" spread="68.5"/>
                    <measurement group_id="B2" value="90" spread="70.5"/>
                    <measurement group_id="B3" value="96.98" spread="69.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in Mean Central Subfield Thickness (CST)</title>
        <description>Change in mean CST on spectral domain optical coherence tomography from baseline to the final visit</description>
        <time_frame>Baseline and 18 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dorzolamide-timolol</title>
            <description>Topical dorzolamide-timolol twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals.&#xD;
Dorzolamide-timolol: Topical eye drop (active comparator) used twice daily for study duration</description>
          </group>
          <group group_id="O2">
            <title>Artificial Tears</title>
            <description>Topical artificial tears twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals.&#xD;
Artificial tears: Topical eye drop (placebo comparator) used twice daily for study duration</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Mean Central Subfield Thickness (CST)</title>
          <description>Change in mean CST on spectral domain optical coherence tomography from baseline to the final visit</description>
          <units>microns</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="27"/>
                <count group_id="O2" value="23"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-36.6" spread="54"/>
                    <measurement group_id="O2" value="1.7" spread="52.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.04</p_value>
            <method>ANCOVA</method>
            <method_desc>Mean difference between the 2 groups derived using analysis of covariance, with the baseline value and type of anti-VEGF drug used as covariates.</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Mean Maximum Subretinal Fluid (SRF) Height</title>
        <description>Change in mean maximum SRF height on spectral domain optical coherence tomography from baseline to final visit.</description>
        <time_frame>Baseline and 18 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dorzolamide-timolol</title>
            <description>Topical dorzolamide-timolol twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals.&#xD;
Dorzolamide-timolol: Topical eye drop (active comparator) used twice daily for study duration</description>
          </group>
          <group group_id="O2">
            <title>Artificial Tears</title>
            <description>Topical artificial tears twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals.&#xD;
Artificial tears: Topical eye drop (placebo comparator) used twice daily for study duration</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Mean Maximum Subretinal Fluid (SRF) Height</title>
          <description>Change in mean maximum SRF height on spectral domain optical coherence tomography from baseline to final visit.</description>
          <units>microns</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="27"/>
                <count group_id="O2" value="23"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-49.4" spread="55"/>
                    <measurement group_id="O2" value="-22.2" spread="56"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.11</p_value>
            <method>ANCOVA</method>
            <method_desc>Mean difference between the 2 groups derived using analysis of covariance, with the baseline value and type of anti-VEGF drug used as covariates.</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Mean Maximum Pigment Epithelial Detachment (PED) Height</title>
        <description>Change in mean maximum PED height on spectral domain optical coherence tomography from baseline to final visit.</description>
        <time_frame>Baseline and 18 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dorzolamide-timolol</title>
            <description>Topical dorzolamide-timolol twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals.&#xD;
Dorzolamide-timolol: Topical eye drop (active comparator) used twice daily for study duration</description>
          </group>
          <group group_id="O2">
            <title>Artificial Tears</title>
            <description>Topical artificial tears twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals.&#xD;
Artificial tears: Topical eye drop (placebo comparator) used twice daily for study duration</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Mean Maximum Pigment Epithelial Detachment (PED) Height</title>
          <description>Change in mean maximum PED height on spectral domain optical coherence tomography from baseline to final visit.</description>
          <units>microns</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="27"/>
                <count group_id="O2" value="23"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-39.1" spread="65"/>
                    <measurement group_id="O2" value="1.1" spread="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.01</p_value>
            <method>ANCOVA</method>
            <method_desc>Mean difference between the 2 groups derived using analysis of covariance, with the baseline value and type of anti-VEGF drug used as covariates.</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Visual Acuity</title>
        <description>Change in mean best available visual acuity from baseline to final visit.</description>
        <time_frame>Baseline and 18 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dorzolamide-timolol</title>
            <description>Topical dorzolamide-timolol twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals.&#xD;
Dorzolamide-timolol: Topical eye drop (active comparator) used twice daily for study duration</description>
          </group>
          <group group_id="O2">
            <title>Artificial Tears</title>
            <description>Topical artificial tears twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals.&#xD;
Artificial tears: Topical eye drop (placebo comparator) used twice daily for study duration</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Visual Acuity</title>
          <description>Change in mean best available visual acuity from baseline to final visit.</description>
          <units>logMAR</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="27"/>
                <count group_id="O2" value="23"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.031" spread="0.15"/>
                    <measurement group_id="O2" value="0.018" spread="0.16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.78</p_value>
            <method>ANCOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Mean Intraocular Pressure (IOP)</title>
        <description>Change in mean IOP from baseline to final visit.</description>
        <time_frame>Baseline and 18 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dorzolamide-timolol</title>
            <description>Topical dorzolamide-timolol twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals.&#xD;
Dorzolamide-timolol: Topical eye drop (active comparator) used twice daily for study duration</description>
          </group>
          <group group_id="O2">
            <title>Artificial Tears</title>
            <description>Topical artificial tears twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals.&#xD;
Artificial tears: Topical eye drop (placebo comparator) used twice daily for study duration</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Mean Intraocular Pressure (IOP)</title>
          <description>Change in mean IOP from baseline to final visit.</description>
          <units>mm Hg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="27"/>
                <count group_id="O2" value="23"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.81" spread="3.8"/>
                    <measurement group_id="O2" value="-0.78" spread="2.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.24</p_value>
            <method>ANCOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>20 months</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Dorzolamide-timolol</title>
          <description>Topical dorzolamide-timolol twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals.&#xD;
Dorzolamide-timolol: Topical eye drop (active comparator) used twice daily for study duration</description>
        </group>
        <group group_id="E2">
          <title>Artificial Tears</title>
          <description>Topical artificial tears twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals.&#xD;
Artificial tears: Topical eye drop (placebo comparator) used twice daily for study duration</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="25"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Eyelid edema</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="25"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT 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>Jason Hsu, MD</name_or_title>
      <organization>Wills Eye Physicians, Mid Atlantic Retina</organization>
      <phone>215-928-3092</phone>
      <email>research@midatlanticretina.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/NCT03034772
org study id: 16-596
nct id: NCT03034772
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
A previous pilot study demonstrated that commonly available glaucoma drops
      (dorzolamide-timolol) might decrease the amount of chronic swelling in patient with wet
      age-related macular degeneration who have been receiving anti-vascular endothelial growth
      factor (VEGF) injections. This will be a larger study where subjects are randomly assigned to
      receive the glaucoma drops or a placebo (artificial tears) in order to confirm whether this
      previous finding is valid. Subjects will continue to receive the normally scheduled anti-VEGF
      injections at regular intervals as done prior to enrollment. The only addition to the regimen
      will be the daily use of eye drops (dorzolamide-timolol or artificial tears) twice daily for
      the duration of the study. At the end of the study, the swelling in the retina will be
      compared to the amount before starting the drops to see if there is any difference between
      the group using dorzolamide-timolol versus artificial tears.
Intravitreal anti-vascular endothelial growth factor (VEGF) agents, including ranibizumab and
      aflibercept, remain the standard of care treatment for neovascular age-related macular
      degeneration (AMD). Various treatment modalities using these agents have been proposed,
      including monthly, pro re nata, and treat-and-extend regimens. Despite frequent and
      consistent treatment with anti-VEGF therapy, there is a subset of patients who are incomplete
      responders and have persistent exudation, including intraretinal edema, subretinal fluid
      (SRF), and/or retinal pigment epithelial detachment (PED) on spectral-domain optical
      coherence tomography (SD-OCT). While clearance of intravitreal anti-VEGF drugs is not
      completely understood, some studies have suggested that outflow through the anterior chamber
      may play a role. We hypothesized that by decreasing aqueous production, outflow may also be
      reduced which could subsequently slow the clearance of intravitreal drugs. In a prior pilot
      study with 10 eyes of 10 patients who were incomplete responders with neovascular AMD, the
      effect of topical dorzolamide-timolol in combination with continued intravitreal anti-VEGF
      injections was explored. Patients were kept on the same anti-VEGF drug as well as the same
      interval between injections for the 2 visits before enrollment and through the course of the
      pilot study in order to minimize the chances that any changes noted might be the result of
      altering one of these variables. The mean central subfield thickness (CST) decreased from
      419.7 μm at enrollment to 334.1 μm at the final visit (p=0.012). Mean maximum subretinal
      fluid (SRF) height decreased from 126.6 μm at enrollment to 56.5 μm at the final visit
      (p=0.020). This decrease in mean CST and SRF was significant beginning at the first visit
      after initiation of the drops. Based on this initial pilot data, dorzolamide-timolol appears
      to be a promising adjuvant treatment in combination with anti-VEGF injections for incomplete
      anti-VEGF responders with neovascular AMD. However, since there was no control group in the
      pilot study, it is possible that the decreased exudation seen was a result of the continued
      anti-VEGF therapy alone rather than an effect of the topical therapy. As a result, a
      randomized, placebo-controlled clinical trial will be better able to assess the efficacy of
      dorzolamide-timolol in this setting.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Participant)
masking description: Single-blind
measure: Change in Mean Central Subfield Thickness (CST)
time frame: Baseline and 18 weeks
description: Change in mean CST on spectral domain optical coherence tomography from baseline to the final visit
measure: Change in Mean Maximum Subretinal Fluid (SRF) Height
time frame: Baseline and 18 weeks
description: Change in mean maximum SRF height on spectral domain optical coherence tomography from baseline to final visit.
measure: Change in Mean Maximum Pigment Epithelial Detachment (PED) Height
time frame: Baseline and 18 weeks
description: Change in mean maximum PED height on spectral domain optical coherence tomography from baseline to final visit.
measure: Change in Visual Acuity
time frame: Baseline and 18 weeks
description: Change in mean best available visual acuity from baseline to final visit.
measure: Change in Mean Intraocular Pressure (IOP)
time frame: Baseline and 18 weeks
description: Change in mean IOP from baseline to final visit.
arm group label: Dorzolamide-timolol
arm group type: Active Comparator
description: Topical dorzolamide-timolol twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals.
arm group label: Artificial tears
arm group type: Placebo Comparator
description: Topical artificial tears twice daily for the study duration. All patients will continue to receive intravitreal anti-VEGF injections at regularly scheduled intervals.
intervention type: Drug
intervention name: Dorzolamide-timolol
description: Topical eye drop (active comparator) used twice daily for study duration
arm group label: Dorzolamide-timolol
other name: Cosopt
intervention type: Other
intervention name: Artificial tears
description: Topical eye drop (placebo comparator) used twice daily for study duration
arm group label: Artificial tears
criteria: 
gender: All
minimum age: 45 Years
maximum age: N/A
healthy volunteers: No
last name: Jason Hsu, MD
role: Principal Investigator
affiliation: Wills Eye
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
citation: Sridhar J, Hsu J, Shahlaee A, Garg SJ, Spirn MJ, Fineman MS, Vander J. Topical Dorzolamide-Timolol With Intravitreous Anti-Vascular Endothelial Growth Factor for Neovascular Age-Related Macular Degeneration. JAMA Ophthalmol. 2016 Apr;134(4):437-43. doi: 10.1001/jamaophthalmol.2016.0045.
PMID: 26914218
responsible party type: Principal Investigator
investigator affiliation: Wills Eye
investigator full name: Jason Hsu, MD
investigator title: Co-director of Retina Research
mesh term: Macular Degeneration
mesh term: Wet Macular Degeneration
mesh term: Timolol
mesh term: Dorzolamide
mesh term: Lubricant Eye Drops
sharing ipd: No
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