<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/NCT02251938</url>
  </required_header>
  <id_info>
    <org_study_id>32-009</org_study_id>
    <nct_id>NCT02251938</nct_id>
  </id_info>
  <brief_title>A Phase IIIb, Multinational, Multicenter, Open-Label Extension Study Assessing the Long-Term Safety of PRN Intravitreal Injections of DE-109 in Subjects With Non-Infectious Uveitis of the Posterior Segment of the Eye Who Have Participated in the SAKURA Development Program</brief_title>
  <acronym>SPRING</acronym>
  <official_title>A Phase IIIb, Multinational, Multicenter, Open-Label Extension Study Assessing the Long-Term Safety of PRN Intravitreal Injections of DE-109 in Subjects With Non-Infectious Uveitis of the Posterior Segment of the Eye Who Have Participated in the SAKURA Development Program</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Santen Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Santen Inc.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The objective of this extension study is to evaluate the long-term safety of treatment with&#xD;
      DE-109 (440 μg) in subjects with non-infectious uveitis of the posterior segment of the eye&#xD;
      who have participated in the SAKURA development program.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a multicenter, open-label, extension study of intravitreal injections of the 440 μg&#xD;
      dose of DE-109 in subjects with non-infectious uveitis of the posterior segment who received&#xD;
      any dose of DE-109 and exited the SAKURA program under Santen Protocol 32-007, Amendment 05.&#xD;
&#xD;
      Subjects who were randomized and received at least two injections of DE-109 during the first&#xD;
      five months of the SAKURA program and obtained clinical benefit from the study medication, as&#xD;
      determined by the Investigator, may be considered for entry in this 12-month extension study.&#xD;
      The minimum time lag from last injection in the SAKURA program to entry into the current&#xD;
      protocol is 60 days.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 29, 2014</start_date>
  <completion_date type="Actual">November 27, 2017</completion_date>
  <primary_completion_date type="Actual">November 1, 2017</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change From Baseline in Best Corrected Visual Acuity (BCVA) at Month 12 in the Study Eye</measure>
    <time_frame>Day 1 (Baseline) and Month 12 or early termination visit</time_frame>
    <description>Best Corrected Visual Acuity (BCVA) measures the acuteness or clearness of best-corrected vision in ETDRS (Early Treatment of Diabetic Retinopathy Study) letters. An increase in BCVA indicates improvement in the best-corrected vision. A BCVA score of 85 ETDRS letters is equivalent to 20/20 vision, which is considered normal vision.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Mean Change From Baseline in Intraocular Pressure at Month 12 in the Study Eye</measure>
    <time_frame>Day 1 (Baseline) and Month 12 or early termination visit</time_frame>
    <description>Intraocular pressure (IOP), the fluid pressure inside the eye, was measured by applanation tonometry in millimeters mercury (mmHg) with one decimal point.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Subjects With a Shift in Choroid Status at Month 12 in the Study Eye.</measure>
    <time_frame>Day 1 (Baseline) and Month 12 or early termination visit</time_frame>
    <description>Ophthalmoscopy findings were reported as normal or abnormal.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes From Baseline in Vitreous Haze (VH) Scores at Month 12</measure>
    <time_frame>Day 1 (Baseline) and Month 12 or early termination visit</time_frame>
    <description>Vitreous Haze (VH) scores were measured using the modified Standardized Uveitis Nomenclature Photographic Scale (SUN) :&#xD;
0 No inflammation&#xD;
0.5+ Trace Inflammation (slight blurring of the optic disc margins and or loss of nerve fiber layer reflex)&#xD;
Mild blurring of the retinal vessels and optic nerve&#xD;
1.5+ Optic nerve head and posterior retina view obstruction greater than 1+ but less than 2+&#xD;
Moderate blurring of the optic nerve head&#xD;
Marked blurring of the optic nerve head&#xD;
Optic Nerve head not visible</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Subjects Who Receive Rescue Therapy.</measure>
    <time_frame>By Month12</time_frame>
    <description>Rescue therapy was defined as any treatment that would have a therapeutic effect on the uveitis in the posterior segment (e.g., systemic treatment with an immunosuppressant agent, or a corticosteroid injection in the study eye) other than intravitreal DE-109 determined by the Investigator.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Subjects With a Shift in Macula Status at Month 12 in the Study Eye.</measure>
    <time_frame>Day 1 (Baseline) and Month 12 or early termination visit</time_frame>
    <description>Ophthalmoscopy findings were reported as normal or abnormal.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Subjects With a Shift in Optic Nerve Status at Month 12 in the Study Eye.</measure>
    <time_frame>Day 1 (Baseline) and Month 12 or early termination visit</time_frame>
    <description>Ophthalmoscopy findings were reported as normal or abnormal.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Subjects With a Shift in Retina Status at Month 12 in the Study Eye.</measure>
    <time_frame>Day 1 (Baseline) and Month 12 or early termination visit</time_frame>
    <description>Ophthalmoscopy findings were reported as normal or abnormal.</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">60</enrollment>
  <condition>Non-Infectious Uveitis of the Posterior Segment of the Eye</condition>
  <arm_group>
    <arm_group_label>DE-109 Sirolimus</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>DE-109 440 μg</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>DE-109 440 μg</intervention_name>
    <description>Medium Dose</description>
    <arm_group_label>DE-109 Sirolimus</arm_group_label>
    <other_name>Sirolimus</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Participated in the SAKURA study&#xD;
&#xD;
          2. Received clinical benefit from treatment in the SAKURA study&#xD;
&#xD;
          3. Ability to sign informed consent and attend all study visits&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Uveitis of infectious etiology&#xD;
&#xD;
          2. Implanted device&#xD;
&#xD;
          3. Suspected or confirmed central nervous system or ocular lymphoma&#xD;
&#xD;
          4. Uncontrolled glaucoma&#xD;
&#xD;
          5. Significant ocular disease&#xD;
&#xD;
          6. Intravitreal injections in the past 60 days&#xD;
&#xD;
          7. Intraocular surgery or treatment&#xD;
&#xD;
          8. Ocular or periocular infection&#xD;
&#xD;
          9. History of herpetic infection&#xD;
&#xD;
         10. Toxoplasmosis or toxoplasmosis scar&#xD;
&#xD;
         11. Ocular malignancy&#xD;
&#xD;
         12. Vitrectomy&#xD;
&#xD;
         13. Allergy or hypersensitivity to study drug&#xD;
&#xD;
         14. Participation in other uveitis device clinical trials within 30 days&#xD;
&#xD;
         15. Any recent systemic condition/infection&#xD;
&#xD;
         16. Immunosuppressive therapy or immunocomprimised&#xD;
&#xD;
         17. Cytomegalovirus infection&#xD;
&#xD;
         18. Malignancy in remission&#xD;
&#xD;
         19. Females who are pregnant or lactating and who are not using adequate contraceptive&#xD;
&#xD;
         20. Medical marijuana or illegal drug use&#xD;
&#xD;
         21. Systemic saroidosis&#xD;
&#xD;
         22. Therapeutic radiation to the head or neck&#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>Lanita Scott, MD</last_name>
    <role>Study Director</role>
    <affiliation>Santen Inc.</affiliation>
  </overall_official>
  <location>
    <facility>
      <address>
        <city>Phoenix</city>
        <state>Arizona</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Sacramento</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Golden</city>
        <state>Colorado</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Oak Park</city>
        <state>Illinois</state>
        <zip>60304</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Jackson</city>
        <state>Michigan</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>New Brunswick</city>
        <state>New Jersey</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Palisades Park</city>
        <state>New Jersey</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>New York</city>
        <state>New York</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Orchard Park</city>
        <state>New York</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Austin</city>
        <state>Texas</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Graz</city>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Hyderabad</city>
        <state>Andhra Pradesh</state>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Aurobindo Marg</city>
        <state>New Dehli</state>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Daryaganj</city>
        <state>New Dehli</state>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Bhubaneswar</city>
        <state>Odisha</state>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Chennai</city>
        <state>Tamil Nadu</state>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Madurai</city>
        <state>Tamil Nadu</state>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Noida</city>
        <state>Uttar Pradesh</state>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Milano</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Ankara</city>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Izmir</city>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Austria</country>
    <country>France</country>
    <country>India</country>
    <country>Italy</country>
    <country>Turkey</country>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2020</verification_date>
  <study_first_submitted>September 19, 2014</study_first_submitted>
  <study_first_submitted_qc>September 25, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 29, 2014</study_first_posted>
  <results_first_submitted>October 31, 2019</results_first_submitted>
  <results_first_submitted_qc>January 31, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">February 12, 2020</results_first_posted>
  <last_update_submitted>January 31, 2020</last_update_submitted>
  <last_update_submitted_qc>January 31, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">February 12, 2020</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>Uveitis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sirolimus</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>June 30, 2014</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/38/NCT02251938/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>November 15, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/38/NCT02251938/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>DE-109 440 μg</title>
          <description>Medium dose of DE-109</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="60"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="43"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="17"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>DE-109 440 μg</title>
          <description>Medium dose of DE-109</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="60"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="43.31" spread="15.092"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="31"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="29"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="21"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="30"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Hispanic or Latino</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Not Hispanic or Latino</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="47"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Not reported</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Geographic Region</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="33"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>India</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Europe, the Middle East and Africa</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change From Baseline in Best Corrected Visual Acuity (BCVA) at Month 12 in the Study Eye</title>
        <description>Best Corrected Visual Acuity (BCVA) measures the acuteness or clearness of best-corrected vision in ETDRS (Early Treatment of Diabetic Retinopathy Study) letters. An increase in BCVA indicates improvement in the best-corrected vision. A BCVA score of 85 ETDRS letters is equivalent to 20/20 vision, which is considered normal vision.</description>
        <time_frame>Day 1 (Baseline) and Month 12 or early termination visit</time_frame>
        <group_list>
          <group group_id="O1">
            <title>DE-109 440 μg</title>
            <description>Medium dose of DE-109</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Best Corrected Visual Acuity (BCVA) at Month 12 in the Study Eye</title>
          <description>Best Corrected Visual Acuity (BCVA) measures the acuteness or clearness of best-corrected vision in ETDRS (Early Treatment of Diabetic Retinopathy Study) letters. An increase in BCVA indicates improvement in the best-corrected vision. A BCVA score of 85 ETDRS letters is equivalent to 20/20 vision, which is considered normal vision.</description>
          <units>ETDRS Letters</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="43"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.1" spread="11.35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Mean Change From Baseline in Intraocular Pressure at Month 12 in the Study Eye</title>
        <description>Intraocular pressure (IOP), the fluid pressure inside the eye, was measured by applanation tonometry in millimeters mercury (mmHg) with one decimal point.</description>
        <time_frame>Day 1 (Baseline) and Month 12 or early termination visit</time_frame>
        <group_list>
          <group group_id="O1">
            <title>DE-109 440 μg</title>
            <description>Medium dose of DE-109</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Change From Baseline in Intraocular Pressure at Month 12 in the Study Eye</title>
          <description>Intraocular pressure (IOP), the fluid pressure inside the eye, was measured by applanation tonometry in millimeters mercury (mmHg) with one decimal point.</description>
          <units>mmHg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="43"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.3" spread="4.16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Subjects With a Shift in Choroid Status at Month 12 in the Study Eye.</title>
        <description>Ophthalmoscopy findings were reported as normal or abnormal.</description>
        <time_frame>Day 1 (Baseline) and Month 12 or early termination visit</time_frame>
        <group_list>
          <group group_id="O1">
            <title>DE-109 440 μg</title>
            <description>Medium dose of DE-109</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Subjects With a Shift in Choroid Status at Month 12 in the Study Eye.</title>
          <description>Ophthalmoscopy findings were reported as normal or abnormal.</description>
          <units>Subjects</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="43"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Normal to Normal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="36"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Normal to Abnormal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Abnormal to Normal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Abnormal to Abnormal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Changes From Baseline in Vitreous Haze (VH) Scores at Month 12</title>
        <description>Vitreous Haze (VH) scores were measured using the modified Standardized Uveitis Nomenclature Photographic Scale (SUN) :&#xD;
0 No inflammation&#xD;
0.5+ Trace Inflammation (slight blurring of the optic disc margins and or loss of nerve fiber layer reflex)&#xD;
Mild blurring of the retinal vessels and optic nerve&#xD;
1.5+ Optic nerve head and posterior retina view obstruction greater than 1+ but less than 2+&#xD;
Moderate blurring of the optic nerve head&#xD;
Marked blurring of the optic nerve head&#xD;
Optic Nerve head not visible</description>
        <time_frame>Day 1 (Baseline) and Month 12 or early termination visit</time_frame>
        <group_list>
          <group group_id="O1">
            <title>DE-109 440 μg</title>
            <description>Medium dose of DE-109</description>
          </group>
        </group_list>
        <measure>
          <title>Changes From Baseline in Vitreous Haze (VH) Scores at Month 12</title>
          <description>Vitreous Haze (VH) scores were measured using the modified Standardized Uveitis Nomenclature Photographic Scale (SUN) :&#xD;
0 No inflammation&#xD;
0.5+ Trace Inflammation (slight blurring of the optic disc margins and or loss of nerve fiber layer reflex)&#xD;
Mild blurring of the retinal vessels and optic nerve&#xD;
1.5+ Optic nerve head and posterior retina view obstruction greater than 1+ but less than 2+&#xD;
Moderate blurring of the optic nerve head&#xD;
Marked blurring of the optic nerve head&#xD;
Optic Nerve head not visible</description>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="43"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.09" spread="0.847"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Subjects Who Receive Rescue Therapy.</title>
        <description>Rescue therapy was defined as any treatment that would have a therapeutic effect on the uveitis in the posterior segment (e.g., systemic treatment with an immunosuppressant agent, or a corticosteroid injection in the study eye) other than intravitreal DE-109 determined by the Investigator.</description>
        <time_frame>By Month12</time_frame>
        <group_list>
          <group group_id="O1">
            <title>DE-109 440 μg</title>
            <description>Medium dose of DE-109</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Subjects Who Receive Rescue Therapy.</title>
          <description>Rescue therapy was defined as any treatment that would have a therapeutic effect on the uveitis in the posterior segment (e.g., systemic treatment with an immunosuppressant agent, or a corticosteroid injection in the study eye) other than intravitreal DE-109 determined by the Investigator.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="60"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Subjects With a Shift in Macula Status at Month 12 in the Study Eye.</title>
        <description>Ophthalmoscopy findings were reported as normal or abnormal.</description>
        <time_frame>Day 1 (Baseline) and Month 12 or early termination visit</time_frame>
        <group_list>
          <group group_id="O1">
            <title>DE-109 440 μg</title>
            <description>Medium dose of DE-109</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Subjects With a Shift in Macula Status at Month 12 in the Study Eye.</title>
          <description>Ophthalmoscopy findings were reported as normal or abnormal.</description>
          <units>Subjects</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="43"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Normal to Normal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Normal to Abnormal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Abnormal to Normal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Abnormal to Abnormal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Subjects With a Shift in Optic Nerve Status at Month 12 in the Study Eye.</title>
        <description>Ophthalmoscopy findings were reported as normal or abnormal.</description>
        <time_frame>Day 1 (Baseline) and Month 12 or early termination visit</time_frame>
        <group_list>
          <group group_id="O1">
            <title>DE-109 440 μg</title>
            <description>Medium dose of DE-109</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Subjects With a Shift in Optic Nerve Status at Month 12 in the Study Eye.</title>
          <description>Ophthalmoscopy findings were reported as normal or abnormal.</description>
          <units>Subjects</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="43"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Normal to Normal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="39"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Normal to Abnormal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Abnormal to Normal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Abnormal to Abnormal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Subjects With a Shift in Retina Status at Month 12 in the Study Eye.</title>
        <description>Ophthalmoscopy findings were reported as normal or abnormal.</description>
        <time_frame>Day 1 (Baseline) and Month 12 or early termination visit</time_frame>
        <group_list>
          <group group_id="O1">
            <title>DE-109 440 μg</title>
            <description>Medium dose of DE-109</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Subjects With a Shift in Retina Status at Month 12 in the Study Eye.</title>
          <description>Ophthalmoscopy findings were reported as normal or abnormal.</description>
          <units>Subjects</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="43"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Normal to Normal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="34"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Normal to Abnormal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Abnormal to Normal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Abnormal to Abnormal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>An on-study Adverse Events (AEs) were collected after the date of the written informed consent until the Last Study Visit at Month 12 or early termination visit.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>DE-109 440 μg</title>
          <description>Medium dose of DE-109&#xD;
DE-109: Medium Dose of DE-109</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (16.0)</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <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="60"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Cataract</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Visual Acuity Reduced</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Vitreous Hemorrhage</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Cellulitis Gangrenous</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Procedural Complication</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Intraocular Pressure Increased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Pathological Fracture</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Lung Adenocarcinoma Metastatic</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Cerebrovascular Accident</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Trigeminal Neuralgia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Arterial Occlusive Disease</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA (16.0)</default_vocab>
        <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="35" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Uveitis</sub_title>
                <counts group_id="E1" events="16" subjects_affected="8" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Cystoid Macular Oedema</sub_title>
                <counts group_id="E1" events="9" subjects_affected="6" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Intermediate Uvei</sub_title>
                <counts group_id="E1" events="12" subjects_affected="6" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Iridocyclitis</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Macular Fibrosis</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Intraocular Pressure Increased</sub_title>
                <counts group_id="E1" events="9" subjects_affected="7" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Intraocular Pressure Decreased</sub_title>
                <counts group_id="E1" events="5" subjects_affected="3" subjects_at_risk="60"/>
              </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 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>R&amp;D Quality Manager</name_or_title>
      <organization>Santen Inc</organization>
      <phone>+1 415 268 9199</phone>
      <email>evelyn.chikere@santen.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/NCT02251938
org study id: 32-009
nct id: NCT02251938
lead sponsor: 
has dmc: No
The objective of this extension study is to evaluate the long-term safety of treatment with
      DE-109 (440 μg) in subjects with non-infectious uveitis of the posterior segment of the eye
      who have participated in the SAKURA development program.
This is a multicenter, open-label, extension study of intravitreal injections of the 440 μg
      dose of DE-109 in subjects with non-infectious uveitis of the posterior segment who received
      any dose of DE-109 and exited the SAKURA program under Santen Protocol 32-007, Amendment 05.

      Subjects who were randomized and received at least two injections of DE-109 during the first
      five months of the SAKURA program and obtained clinical benefit from the study medication, as
      determined by the Investigator, may be considered for entry in this 12-month extension study.
      The minimum time lag from last injection in the SAKURA program to entry into the current
      protocol is 60 days.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change From Baseline in Best Corrected Visual Acuity (BCVA) at Month 12 in the Study Eye
time frame: Day 1 (Baseline) and Month 12 or early termination visit
description: Best Corrected Visual Acuity (BCVA) measures the acuteness or clearness of best-corrected vision in ETDRS (Early Treatment of Diabetic Retinopathy Study) letters. An increase in BCVA indicates improvement in the best-corrected vision. A BCVA score of 85 ETDRS letters is equivalent to 20/20 vision, which is considered normal vision.
measure: Mean Change From Baseline in Intraocular Pressure at Month 12 in the Study Eye
time frame: Day 1 (Baseline) and Month 12 or early termination visit
description: Intraocular pressure (IOP), the fluid pressure inside the eye, was measured by applanation tonometry in millimeters mercury (mmHg) with one decimal point.
measure: Number of Subjects With a Shift in Choroid Status at Month 12 in the Study Eye.
time frame: Day 1 (Baseline) and Month 12 or early termination visit
description: Ophthalmoscopy findings were reported as normal or abnormal.
measure: Changes From Baseline in Vitreous Haze (VH) Scores at Month 12
time frame: Day 1 (Baseline) and Month 12 or early termination visit
description: Vitreous Haze (VH) scores were measured using the modified Standardized Uveitis Nomenclature Photographic Scale (SUN) :
0 No inflammation
0.5+ Trace Inflammation (slight blurring of the optic disc margins and or loss of nerve fiber layer reflex)
Mild blurring of the retinal vessels and optic nerve
1.5+ Optic nerve head and posterior retina view obstruction greater than 1+ but less than 2+
Moderate blurring of the optic nerve head
Marked blurring of the optic nerve head
Optic Nerve head not visible
measure: Number of Subjects Who Receive Rescue Therapy.
time frame: By Month12
description: Rescue therapy was defined as any treatment that would have a therapeutic effect on the uveitis in the posterior segment (e.g., systemic treatment with an immunosuppressant agent, or a corticosteroid injection in the study eye) other than intravitreal DE-109 determined by the Investigator.
measure: Number of Subjects With a Shift in Macula Status at Month 12 in the Study Eye.
time frame: Day 1 (Baseline) and Month 12 or early termination visit
description: Ophthalmoscopy findings were reported as normal or abnormal.
measure: Number of Subjects With a Shift in Optic Nerve Status at Month 12 in the Study Eye.
time frame: Day 1 (Baseline) and Month 12 or early termination visit
description: Ophthalmoscopy findings were reported as normal or abnormal.
measure: Number of Subjects With a Shift in Retina Status at Month 12 in the Study Eye.
time frame: Day 1 (Baseline) and Month 12 or early termination visit
description: Ophthalmoscopy findings were reported as normal or abnormal.
arm group label: DE-109 Sirolimus
arm group type: Experimental
description: DE-109 440 μg
intervention type: Drug
intervention name: DE-109 440 μg
description: Medium Dose
arm group label: DE-109 Sirolimus
other name: Sirolimus
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Lanita Scott, MD
role: Study Director
affiliation: Santen Inc.
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Austria
country: France
country: India
country: Italy
country: Turkey
country: United States
responsible party type: Sponsor
mesh term: Uveitis
mesh term: Sirolimus
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 