<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/NCT02262260</url>
  </required_header>
  <id_info>
    <org_study_id>CRFB002DTR01</org_study_id>
    <nct_id>NCT02262260</nct_id>
  </id_info>
  <brief_title>Compare Safety/Efficacy of Labeled vs Wait-Extend Regimen of Lucentis in Turkish Patients With VI Due to DME</brief_title>
  <acronym>SALUTE-D</acronym>
  <official_title>A Randomized, Open-label Non-inferiority Study to Compare Safety and Efficacy of Labeled Versus Wait and Extend Regimen of Lucentis (Ranibizumab) in Turkish Patients With Visual Impairment Due to Diabetic Macular Edema.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Novartis Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Novartis</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      To explore a more clinical feasible treatment regime with ranibizumab for DME to provide&#xD;
      satisfactory treatment effect with a lower number of visits and injections.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Diabetes mellitus (DM) is the most common endocrine disease in developed countries, with&#xD;
      prevalence estimates ranging between 2 to 5% of the world's population. Diabetic retinopathy&#xD;
      (DR) and diabetic macular edema (DME) are common microvascular complications in patients with&#xD;
      diabetes and may have a sudden and debilitating impact on visual acuity (VA), eventually&#xD;
      leading to blindness. DME is a frequent manifestation of DR and is the major cause of visual&#xD;
      loss in patients with DR. If left untreated, &gt;50% of patients lose &gt;2 lines of visual acuity&#xD;
      (VA) within 2 years. DME mostly affects the working-age population, imposing a significant&#xD;
      burden both on society and on individual patients - a burden that is expected to increase&#xD;
      with the rising prevalence of diabetes.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 12, 2014</start_date>
  <completion_date type="Actual">September 12, 2017</completion_date>
  <primary_completion_date type="Actual">September 12, 2017</primary_completion_date>
  <phase>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>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Mean Change in &quot;Best-corrected Visual Acuity&quot; at Month 12</measure>
    <time_frame>12 months</time_frame>
    <description>Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (ETDRS)-like chart while participants were in a sitting position at a testing distance of 4 meters. The range of ETDRS is 0 to 100 letters. A positive average change from baseline of BCVA indicates improvement</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Mean Change in Central Retinal Thickness (CRT)</measure>
    <time_frame>12 months</time_frame>
    <description>CRT was assessed by Optical Coherence Tomography (OCT).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Number of Injections</measure>
    <time_frame>12 months</time_frame>
    <description>Mean number of injections over a 12-month treatment period</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Number of Visits</measure>
    <time_frame>12 months</time_frame>
    <description>Mean number of visits over a 12-month treatment period</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of Patients Who Gained ≥5 Letters</measure>
    <time_frame>12 months</time_frame>
    <description>BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An increased score indicates improvement in acuity. This outcome assessed the number of participants who had improvement of ≥5 letters of visual acuity at month 12 as compared with baseline</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of Patients Who Gained ≥10 Letters</measure>
    <time_frame>12 months</time_frame>
    <description>BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An increased score indicates improvement in acuity. This outcome assessed the number of participants who had improvement of ≥10 letters of visual acuity at month 12 as compared with baseline</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of Patients Who Gained ≥15 Letters</measure>
    <time_frame>12 months</time_frame>
    <description>BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An increased score indicates improvement in acuity. This outcome assessed the number of participants who had improvement of ≥15 letters of visual acuity at month 12 as compared with baseline</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">87</enrollment>
  <condition>Diabetic Macular Edema</condition>
  <arm_group>
    <arm_group_label>Ranibizumab labeled regime arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Ranibizumab (Anti VEGF) 0.5mg treatment will be given monthly and will be continued until maximum visual acuity is achieved (the patient's visual acuity is stable for three consecutive monthly assessments performed while on ranibizumab treatment). Thereafter patients should be monitored monthly for visual acuity. Treatment will be resumed when monitoring indicates loss of visual acuity due to DME. Monthly injections should then be administered until stable visual acuity is reached again for three consecutive monthly assessments (implying a minimum of two injections). The interval between two doses should not be shorter than 1 month</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Ranibizumab wait and Extend regime arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Ranibizumab (Anti VEGF) 0.5 mg will be injected subsequently at baseline, month 1 and 2. After the three initial loading doses, patients will be called for the control visits 1 month later. If the visual acuity has reached a stable level and there is no sign of edema on OCT, patients will not receive intravitreal injection and will be called to come back 6 weeks later. The interval is increased by 2 weeks until a maximum of 8 weeks as long as the patient presents as stable regarding visual acuity, central retinal thickness and clinical findings. If there is a negative change, the interval is shortened back to 4 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Labeled regime arm</intervention_name>
    <description>Treatment will be given monthly and will be continued until maximum visual acuity is achieved (the patient's visual acuity is stable for three consecutive monthly assessments performed while on ranibizumab treatment). Thereafter patients should be monitored monthly for visual acuity. Treatment will be resumed when monitoring indicates loss of visual acuity due to DME. Monthly injections should then be administered until stable visual acuity is reached again for three consecutive monthly assessments (implying a minimum of two injections). The interval between two doses should not be shorter than 1 month.</description>
    <arm_group_label>Ranibizumab labeled regime arm</arm_group_label>
    <other_name>Arm 1</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Wait and Extend regime arm</intervention_name>
    <description>Lucentis (ranibizumab) 0.5 mg will be injected subsequently at baseline, month 1 and 2. After the three initial loading doses, patients will be called for the control visits 1 month later. If the visual acuity has reached a stable level and there is no sign of edema on OCT, patients will not receive intravitreal injection and will be called to come back 6 weeks later. The interval is increased by 2 weeks until a maximum of 8 weeks as long as the patient presents as stable regarding visual acuity, central retinal thickness and clinical findings. If there is a negative change, the interval is shortened back to 4 weeks.</description>
    <arm_group_label>Ranibizumab wait and Extend regime arm</arm_group_label>
    <other_name>Arm 2</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Written informed consent must be obtained before any assessment is performed.&#xD;
&#xD;
          -  M or F patients &gt;18 years of age who have signed an informed consent&#xD;
&#xD;
          -  Patients with Type 1 or Type 2 DM (according to ADA or WHO guidelines) with HbA1c not&#xD;
             more than 12.0% at screening (Visit 1). Patients should be on diet, exercise, and/or&#xD;
             pharmacological treatment for diabetes.&#xD;
&#xD;
          -  Patients with visual impairment due to focal or diffuse macular edema with center&#xD;
             involvement in at least one eye, as demonstrated with color fundus photography,&#xD;
             fluorescein angiography and OCT within 28 days of the baseline treatment. If both eyes&#xD;
             are eligible, the one with the worse visual acuity, as assessed at Visit 1, will be&#xD;
             selected for study treatment unless, based on medical reasons, the investigator deems&#xD;
             the other eye the more appropriate candidate for study treatment. The study eye must&#xD;
             fulfill the following criteria at Visit 1:&#xD;
&#xD;
          -  BCVA score between 78 and 39 letters, inclusively, using ETDRS-like visual acuity&#xD;
             testing charts at a testing distance of 4 meters (approximate Snellen equivalent of&#xD;
             20/32 to 20/160)&#xD;
&#xD;
          -  Decrease in vision is due to DME and not due to other causes, in the opinion of the&#xD;
             investigator&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          -  Concomitant conditions in the study eye according to defined criteria such as&#xD;
             infection, inflammation, uncontrolled glaucoma&#xD;
&#xD;
          -  Active PDR in the study eye or evidence of vitreomacular traction in either eye&#xD;
&#xD;
          -  Patients who are monocular or have a BCVA score in the non-study eye (fellow eye) £ 24&#xD;
             letters at Visit 1&#xD;
&#xD;
          -  Concomitant systemic condition according to defined criteria, eg. history of stroke,&#xD;
             uncontrolled diabetes, renal failure, unsatisfactory controlled hypertension&#xD;
&#xD;
          -  Use of other investigational drugs within 5 half-lives of enrollment, or within 30&#xD;
             days until the expected PD effect has returned to baseline, whichever is longer.&#xD;
&#xD;
          -  History of hypersensitivity to any of the study drugs or to drugs of similar chemical&#xD;
             classes.&#xD;
&#xD;
          -  History of malignancy of any organ system (other than localized basal cell carcinoma&#xD;
             of the skin), treated or untreated, within the past 5 years, regardless of whether&#xD;
             there is evidence of local recurrence or metastases.&#xD;
&#xD;
          -  Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a&#xD;
             female after conception and until the termination of gestation, confirmed by a&#xD;
             positive hCG laboratory test.&#xD;
&#xD;
          -  Women of child-bearing potential, defined as all women physiologically capable of&#xD;
             becoming pregnant, unless they are using effective methods of contraception during&#xD;
             dosing of study treatment.&#xD;
&#xD;
        Women are considered post-menopausal and not of child bearing potential if they have had 12&#xD;
        months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age&#xD;
        appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy&#xD;
        (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of&#xD;
        oophorectomy alone, only when the reproductive status of the woman has been confirmed by&#xD;
        follow up hormone level assessment is she considered not of child bearing potential.&#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>Novartis Pharmaceuticals</last_name>
    <role>Study Director</role>
    <affiliation>Novartis Pharmaceuticals</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Istanbul</city>
        <state>TUR</state>
        <zip>34098</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Adana</city>
        <zip>01330</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Ankara</city>
        <zip>06100</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Ankara</city>
        <zip>06490</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Ankara</city>
        <zip>06500</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Ankara</city>
        <zip>06590</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Izmir</city>
        <zip>35040</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Izmir</city>
        <zip>35340</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Kocaeli</city>
        <zip>41380</zip>
        <country>Turkey</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Turkey</country>
  </location_countries>
  <verification_date>March 2019</verification_date>
  <study_first_submitted>August 27, 2014</study_first_submitted>
  <study_first_submitted_qc>October 10, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 13, 2014</study_first_posted>
  <results_first_submitted>August 30, 2018</results_first_submitted>
  <results_first_submitted_qc>March 28, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">June 24, 2019</results_first_posted>
  <last_update_submitted>March 28, 2019</last_update_submitted>
  <last_update_submitted_qc>March 28, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">June 24, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Diabetic macular edema, DME, ranibizumab, wait and extend</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Macular Edema</mesh_term>
    <mesh_term>Edema</mesh_term>
  </condition_browse>
  <provided_document_section>
    <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>February 12, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/60/NCT02262260/SAP_000.pdf</document_url>
    </provided_document>
    <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>April 7, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/60/NCT02262260/Prot_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Labeled Regime Arm</title>
          <description>Treatment will be given monthly and will be continued until maximum visual acuity is achieved (the patient's visual acuity is stable for three consecutive monthly assessments performed while on ranibizumab treatment). Thereafter patients should be monitored monthly for visual acuity. Treatment will be resumed when monitoring indicates loss of visual acuity due to DME. Monthly injections should then be administered until stable visual acuity is reached again for three consecutive monthly assessments (implying a minimum of two injections). The interval between two doses should not be shorter than 1 month</description>
        </group>
        <group group_id="P2">
          <title>Wait and Extend Regime Arm</title>
          <description>Lucentis (ranibizumab) 0.5 mg will be injected subsequently at baseline, month 1 and 2. After the three initial loading doses, patients will be called for the control visits 1 month later. If the visual acuity has reached a stable level and there is no sign of edema on OCT, patients will not receive intravitreal injection and will be called to come back 6 weeks later. The interval is increased by 2 weeks until a maximum of 8 weeks as long as the patient presents as stable regarding visual acuity, central retinal thickness and clinical findings. If there is a negative change, the interval is shortened back to 4 weeks.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="45"/>
                <participants group_id="P2" count="42"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="34"/>
                <participants group_id="P2" count="32"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
                <participants group_id="P2" count="10"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal of consent</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Protocol deviation</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="5"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Labeled Regime Arm</title>
          <description>Treatment will be given monthly and will be continued until maximum visual acuity is achieved (the patient's visual acuity is stable for three consecutive monthly assessments performed while on ranibizumab treatment). Thereafter patients should be monitored monthly for visual acuity. Treatment will be resumed when monitoring indicates loss of visual acuity due to DME. Monthly injections should then be administered until stable visual acuity is reached again for three consecutive monthly assessments (implying a minimum of two injections). The interval between two doses should not be shorter than 1 month</description>
        </group>
        <group group_id="B2">
          <title>Wait and Extend Regime Arm</title>
          <description>Lucentis (ranibizumab) 0.5 mg will be injected subsequently at baseline, month 1 and 2. After the three initial loading doses, patients will be called for the control visits 1 month later. If the visual acuity has reached a stable level and there is no sign of edema on OCT, patients will not receive intravitreal injection and will be called to come back 6 weeks later. The interval is increased by 2 weeks until a maximum of 8 weeks as long as the patient presents as stable regarding visual acuity, central retinal thickness and clinical findings. If there is a negative change, the interval is shortened back to 4 weeks.</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="45"/>
            <count group_id="B2" value="42"/>
            <count group_id="B3" value="87"/>
          </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="45"/>
                    <count group_id="B2" value="42"/>
                    <count group_id="B3" value="87"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="61" spread="9.93"/>
                    <measurement group_id="B2" value="59.5" spread="9.68"/>
                    <measurement group_id="B3" value="60.3" spread="9.78"/>
                  </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="45"/>
                    <count group_id="B2" value="42"/>
                    <count group_id="B3" value="87"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="16"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="31"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="29"/>
                    <measurement group_id="B2" value="27"/>
                    <measurement group_id="B3" value="56"/>
                  </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_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Mean Change in &quot;Best-corrected Visual Acuity&quot; at Month 12</title>
        <description>Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (ETDRS)-like chart while participants were in a sitting position at a testing distance of 4 meters. The range of ETDRS is 0 to 100 letters. A positive average change from baseline of BCVA indicates improvement</description>
        <time_frame>12 months</time_frame>
        <population>Study completers- The patients who have completed 12 months of treatment and follow-up are defined as Study Completers.</population>
        <group_list>
          <group group_id="O1">
            <title>Labeled Regime Arm</title>
            <description>Treatment will be given monthly and will be continued until maximum visual acuity is achieved (the patient's visual acuity is stable for three consecutive monthly assessments performed while on ranibizumab treatment). Thereafter patients should be monitored monthly for visual acuity. Treatment will be resumed when monitoring indicates loss of visual acuity due to DME. Monthly injections should then be administered until stable visual acuity is reached again for three consecutive monthly assessments (implying a minimum of two injections). The interval between two doses should not be shorter than 1 month</description>
          </group>
          <group group_id="O2">
            <title>Wait and Extend Regime Arm</title>
            <description>Lucentis (ranibizumab) 0.5 mg will be injected subsequently at baseline, month 1 and 2. After the three initial loading doses, patients will be called for the control visits 1 month later. If the visual acuity has reached a stable level and there is no sign of edema on OCT, patients will not receive intravitreal injection and will be called to come back 6 weeks later. The interval is increased by 2 weeks until a maximum of 8 weeks as long as the patient presents as stable regarding visual acuity, central retinal thickness and clinical findings. If there is a negative change, the interval is shortened back to 4 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Change in &quot;Best-corrected Visual Acuity&quot; at Month 12</title>
          <description>Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (ETDRS)-like chart while participants were in a sitting position at a testing distance of 4 meters. The range of ETDRS is 0 to 100 letters. A positive average change from baseline of BCVA indicates improvement</description>
          <population>Study completers- The patients who have completed 12 months of treatment and follow-up are defined as Study Completers.</population>
          <units>Letters</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="32"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="76.44" spread="1.78"/>
                    <measurement group_id="O2" value="73.09" spread="1.68"/>
                  </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>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>In order to demonstrate that the &quot;wait and extend&quot; regimen of ranibizumab is non-inferior to the posology described in the prescribing information, mean change in BCVA at month 12 from the baseline visit were determined for both treatment groups, and a comparison was made between the two groups using the Independent Samples t-test.</non_inferiority_desc>
            <p_value>0.5</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Change in Central Retinal Thickness (CRT)</title>
        <description>CRT was assessed by Optical Coherence Tomography (OCT).</description>
        <time_frame>12 months</time_frame>
        <population>Study completers- The patients who have completed 12 months of treatment and follow-up are defined as Study Completers.</population>
        <group_list>
          <group group_id="O1">
            <title>Labeled Regime Arm</title>
            <description>Treatment will be given monthly and will be continued until maximum visual acuity is achieved (the patient's visual acuity is stable for three consecutive monthly assessments performed while on ranibizumab treatment). Thereafter patients should be monitored monthly for visual acuity. Treatment will be resumed when monitoring indicates loss of visual acuity due to DME. Monthly injections should then be administered until stable visual acuity is reached again for three consecutive monthly assessments (implying a minimum of two injections). The interval between two doses should not be shorter than 1 month</description>
          </group>
          <group group_id="O2">
            <title>Wait and Extend Regime Arm</title>
            <description>Lucentis (ranibizumab) 0.5 mg will be injected subsequently at baseline, month 1 and 2. After the three initial loading doses, patients will be called for the control visits 1 month later. If the visual acuity has reached a stable level and there is no sign of edema on OCT, patients will not receive intravitreal injection and will be called to come back 6 weeks later. The interval is increased by 2 weeks until a maximum of 8 weeks as long as the patient presents as stable regarding visual acuity, central retinal thickness and clinical findings. If there is a negative change, the interval is shortened back to 4 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Change in Central Retinal Thickness (CRT)</title>
          <description>CRT was assessed by Optical Coherence Tomography (OCT).</description>
          <population>Study completers- The patients who have completed 12 months of treatment and follow-up are defined as Study Completers.</population>
          <units>Micrometers</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="32"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="315.7" spread="15.07"/>
                    <measurement group_id="O2" value="348.9" spread="16.54"/>
                  </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>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>In order to demonstrate that the &quot;wait and extend&quot; regimen of ranibizumab is non-inferior to the posology described in the prescribing information, mean change in Central Retinal Thickness determined with Optical Coherence Tomography for both eyes were calculated for both groups and were compared using the Mann Whitney u test.</non_inferiority_desc>
            <p_value>0.082</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Number of Injections</title>
        <description>Mean number of injections over a 12-month treatment period</description>
        <time_frame>12 months</time_frame>
        <population>Study completers- The patients who have completed 12 months of treatment and follow-up are defined as Study Completers. Statistical analysis not performed for the injection numbers</population>
        <group_list>
          <group group_id="O1">
            <title>Labeled Regime Arm</title>
            <description>Treatment will be given monthly and will be continued until maximum visual acuity is achieved (the patient's visual acuity is stable for three consecutive monthly assessments performed while on ranibizumab treatment). Thereafter patients should be monitored monthly for visual acuity. Treatment will be resumed when monitoring indicates loss of visual acuity due to DME. Monthly injections should then be administered until stable visual acuity is reached again for three consecutive monthly assessments (implying a minimum of two injections). The interval between two doses should not be shorter than 1 month</description>
          </group>
          <group group_id="O2">
            <title>Wait and Extend Regime Arm</title>
            <description>Lucentis (ranibizumab) 0.5 mg will be injected subsequently at baseline, month 1 and 2. After the three initial loading doses, patients will be called for the control visits 1 month later. If the visual acuity has reached a stable level and there is no sign of edema on OCT, patients will not receive intravitreal injection and will be called to come back 6 weeks later. The interval is increased by 2 weeks until a maximum of 8 weeks as long as the patient presents as stable regarding visual acuity, central retinal thickness and clinical findings. If there is a negative change, the interval is shortened back to 4 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Number of Injections</title>
          <description>Mean number of injections over a 12-month treatment period</description>
          <population>Study completers- The patients who have completed 12 months of treatment and follow-up are defined as Study Completers. Statistical analysis not performed for the injection numbers</population>
          <units>Injections</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="32"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.4" spread="0.44"/>
                    <measurement group_id="O2" value="7.5" spread="0.44"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Number of Visits</title>
        <description>Mean number of visits over a 12-month treatment period</description>
        <time_frame>12 months</time_frame>
        <population>Study completers- The patients who have completed 12 months of treatment and follow-up are defined as Study Completers. Statistical analysis not performed to compare visits</population>
        <group_list>
          <group group_id="O1">
            <title>Labeled Regime Arm</title>
            <description>Treatment will be given monthly and will be continued until maximum visual acuity is achieved (the patient's visual acuity is stable for three consecutive monthly assessments performed while on ranibizumab treatment). Thereafter patients should be monitored monthly for visual acuity. Treatment will be resumed when monitoring indicates loss of visual acuity due to DME. Monthly injections should then be administered until stable visual acuity is reached again for three consecutive monthly assessments (implying a minimum of two injections). The interval between two doses should not be shorter than 1 month</description>
          </group>
          <group group_id="O2">
            <title>Wait and Extend Regime Arm</title>
            <description>Lucentis (ranibizumab) 0.5 mg will be injected subsequently at baseline, month 1 and 2. After the three initial loading doses, patients will be called for the control visits 1 month later. If the visual acuity has reached a stable level and there is no sign of edema on OCT, patients will not receive intravitreal injection and will be called to come back 6 weeks later. The interval is increased by 2 weeks until a maximum of 8 weeks as long as the patient presents as stable regarding visual acuity, central retinal thickness and clinical findings. If there is a negative change, the interval is shortened back to 4 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Number of Visits</title>
          <description>Mean number of visits over a 12-month treatment period</description>
          <population>Study completers- The patients who have completed 12 months of treatment and follow-up are defined as Study Completers. Statistical analysis not performed to compare visits</population>
          <units>Number of visits</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="32"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11.2" spread="0.19"/>
                    <measurement group_id="O2" value="10.2" spread="0.24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Proportion of Patients Who Gained ≥5 Letters</title>
        <description>BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An increased score indicates improvement in acuity. This outcome assessed the number of participants who had improvement of ≥5 letters of visual acuity at month 12 as compared with baseline</description>
        <time_frame>12 months</time_frame>
        <population>Study completers- The patients who have completed 12 months of treatment and follow-up are defined as Study Completers</population>
        <group_list>
          <group group_id="O1">
            <title>Labeled Regime Arm</title>
            <description>Treatment will be given monthly and will be continued until maximum visual acuity is achieved (the patient's visual acuity is stable for three consecutive monthly assessments performed while on ranibizumab treatment). Thereafter patients should be monitored monthly for visual acuity. Treatment will be resumed when monitoring indicates loss of visual acuity due to DME. Monthly injections should then be administered until stable visual acuity is reached again for three consecutive monthly assessments (implying a minimum of two injections). The interval between two doses should not be shorter than 1 month</description>
          </group>
          <group group_id="O2">
            <title>Wait and Extend Regime Arm</title>
            <description>Lucentis (ranibizumab) 0.5 mg will be injected subsequently at baseline, month 1 and 2. After the three initial loading doses, patients will be called for the control visits 1 month later. If the visual acuity has reached a stable level and there is no sign of edema on OCT, patients will not receive intravitreal injection and will be called to come back 6 weeks later. The interval is increased by 2 weeks until a maximum of 8 weeks as long as the patient presents as stable regarding visual acuity, central retinal thickness and clinical findings. If there is a negative change, the interval is shortened back to 4 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Proportion of Patients Who Gained ≥5 Letters</title>
          <description>BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An increased score indicates improvement in acuity. This outcome assessed the number of participants who had improvement of ≥5 letters of visual acuity at month 12 as compared with baseline</description>
          <population>Study completers- The patients who have completed 12 months of treatment and follow-up are defined as Study Completers</population>
          <units>Participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="32"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="29"/>
                    <measurement group_id="O2" value="22"/>
                  </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>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>Comparison was made between the two groups using the Independent Samples t-test.</non_inferiority_desc>
            <p_value>0.095</p_value>
            <method>Chi-squared</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Proportion of Patients Who Gained ≥10 Letters</title>
        <description>BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An increased score indicates improvement in acuity. This outcome assessed the number of participants who had improvement of ≥10 letters of visual acuity at month 12 as compared with baseline</description>
        <time_frame>12 months</time_frame>
        <population>Study completers- The patients who have completed 12 months of treatment and follow-up are defined as Study Completers</population>
        <group_list>
          <group group_id="O1">
            <title>Labeled Regime Arm</title>
            <description>Treatment will be given monthly and will be continued until maximum visual acuity is achieved (the patient's visual acuity is stable for three consecutive monthly assessments performed while on ranibizumab treatment). Thereafter patients should be monitored monthly for visual acuity. Treatment will be resumed when monitoring indicates loss of visual acuity due to DME. Monthly injections should then be administered until stable visual acuity is reached again for three consecutive monthly assessments (implying a minimum of two injections). The interval between two doses should not be shorter than 1 month</description>
          </group>
          <group group_id="O2">
            <title>Wait and Extend Regime Arm</title>
            <description>Lucentis (ranibizumab) 0.5 mg will be injected subsequently at baseline, month 1 and 2. After the three initial loading doses, patients will be called for the control visits 1 month later. If the visual acuity has reached a stable level and there is no sign of edema on OCT, patients will not receive intravitreal injection and will be called to come back 6 weeks later. The interval is increased by 2 weeks until a maximum of 8 weeks as long as the patient presents as stable regarding visual acuity, central retinal thickness and clinical findings. If there is a negative change, the interval is shortened back to 4 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Proportion of Patients Who Gained ≥10 Letters</title>
          <description>BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An increased score indicates improvement in acuity. This outcome assessed the number of participants who had improvement of ≥10 letters of visual acuity at month 12 as compared with baseline</description>
          <population>Study completers- The patients who have completed 12 months of treatment and follow-up are defined as Study Completers</population>
          <units>Participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="32"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="23"/>
                    <measurement group_id="O2" value="15"/>
                  </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>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>comparison was made between the two groups using the Independent Samples t-test.</non_inferiority_desc>
            <p_value>0.072</p_value>
            <method>Chi-squared</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Proportion of Patients Who Gained ≥15 Letters</title>
        <description>BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An increased score indicates improvement in acuity. This outcome assessed the number of participants who had improvement of ≥15 letters of visual acuity at month 12 as compared with baseline</description>
        <time_frame>12 months</time_frame>
        <population>Study completers- The patients who have completed 12 months of treatment and follow-up are defined as Study Completers</population>
        <group_list>
          <group group_id="O1">
            <title>Labeled Regime Arm</title>
            <description>Treatment will be given monthly and will be continued until maximum visual acuity is achieved (the patient's visual acuity is stable for three consecutive monthly assessments performed while on ranibizumab treatment). Thereafter patients should be monitored monthly for visual acuity. Treatment will be resumed when monitoring indicates loss of visual acuity due to DME. Monthly injections should then be administered until stable visual acuity is reached again for three consecutive monthly assessments (implying a minimum of two injections). The interval between two doses should not be shorter than 1 month</description>
          </group>
          <group group_id="O2">
            <title>Wait and Extend Regime Arm</title>
            <description>Lucentis (ranibizumab) 0.5 mg will be injected subsequently at baseline, month 1 and 2. After the three initial loading doses, patients will be called for the control visits 1 month later. If the visual acuity has reached a stable level and there is no sign of edema on OCT, patients will not receive intravitreal injection and will be called to come back 6 weeks later. The interval is increased by 2 weeks until a maximum of 8 weeks as long as the patient presents as stable regarding visual acuity, central retinal thickness and clinical findings. If there is a negative change, the interval is shortened back to 4 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Proportion of Patients Who Gained ≥15 Letters</title>
          <description>BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An increased score indicates improvement in acuity. This outcome assessed the number of participants who had improvement of ≥15 letters of visual acuity at month 12 as compared with baseline</description>
          <population>Study completers- The patients who have completed 12 months of treatment and follow-up are defined as Study Completers</population>
          <units>Participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="32"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12"/>
                    <measurement group_id="O2" value="10"/>
                  </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>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>comparison was made between the two groups using the Independent Samples t-test</non_inferiority_desc>
            <p_value>0.466</p_value>
            <method>Chi-squared</method>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>12 month study</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Labeled Treatment Arm</title>
          <description>Treatment will be given monthly and will be continued until maximum visual acuity is achieved (the patient's visual acuity is stable for three consecutive monthly assessments performed while on ranibizumab treatment). Thereafter patients should be monitored monthly for visual acuity. Treatment will be resumed when monitoring indicates loss of visual acuity due to DME. Monthly injections should then be administered until stable visual acuity is reached again for three consecutive monthly assessments (implying a minimum of two injections). The interval between two doses should not be shorter than 1 month</description>
        </group>
        <group group_id="E2">
          <title>Wait and Extend Regimen Arm</title>
          <description>Lucentis (ranibizumab) 0.5 mg will be injected subsequently at baseline, month 1 and 2. After the three initial loading doses, patients will be called for the control visits 1 month later. If the visual acuity has reached a stable level and there is no sign of edema on OCT, patients will not receive intravitreal injection and will be called to come back 6 weeks later. The interval is increased by 2 weeks until a maximum of 8 weeks as long as the patient presents as stable regarding visual acuity, central retinal thickness and clinical findings. If there is a negative change, the interval is shortened back to 4 weeks.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (21.0)</default_vocab>
        <default_assessment>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="1" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Angina pectoris</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Coronary artery disease</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Myocardial infarction</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Vitreous hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Cholecystitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Cholelithiasis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Subdural haematoma</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Diabetes mellitus inadequate control</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Breast cancer</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Gallbladder neoplasm</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Cerebrovascular accident</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Proteinuria</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Renal failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Diabetic foot</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>1</frequency_threshold>
        <default_vocab>MedDRA (21.0)</default_vocab>
        <default_assessment>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="12" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Iron deficiency anaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Angina pectoris</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Vertigo</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Dry eye</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Eye haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Itchy eyes</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Ocular hyperemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Vitreoretinal traction syndrome</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Vitreous hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Vitreous opacity</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Gastric spasm</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Gastritis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Ocular hyperemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Gall bladder stone</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Gallbladder inflammation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Hepatic steatosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Adenovirus infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Eye infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Foot infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Influenza</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Increased intraocular pressure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Vitamin D deficiency</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Gallbladder papillary adenocarcinoma</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Tinnitus</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Impaired renal function</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Renal cyst</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="45"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="42"/>
              </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>The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Study Director</name_or_title>
      <organization>Novartis Pharmaceuticals</organization>
      <phone>862-778-8300</phone>
      <email>novartis.email@novartis.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/NCT02262260
org study id: CRFB002DTR01
nct id: NCT02262260
lead sponsor: 
has dmc: No
To explore a more clinical feasible treatment regime with ranibizumab for DME to provide
      satisfactory treatment effect with a lower number of visits and injections.
Diabetes mellitus (DM) is the most common endocrine disease in developed countries, with
      prevalence estimates ranging between 2 to 5% of the world's population. Diabetic retinopathy
      (DR) and diabetic macular edema (DME) are common microvascular complications in patients with
      diabetes and may have a sudden and debilitating impact on visual acuity (VA), eventually
      leading to blindness. DME is a frequent manifestation of DR and is the major cause of visual
      loss in patients with DR. If left untreated, >50% of patients lose >2 lines of visual acuity
      (VA) within 2 years. DME mostly affects the working-age population, imposing a significant
      burden both on society and on individual patients - a burden that is expected to increase
      with the rising prevalence of diabetes.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Mean Change in "Best-corrected Visual Acuity" at Month 12
time frame: 12 months
description: Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (ETDRS)-like chart while participants were in a sitting position at a testing distance of 4 meters. The range of ETDRS is 0 to 100 letters. A positive average change from baseline of BCVA indicates improvement
measure: Mean Change in Central Retinal Thickness (CRT)
time frame: 12 months
description: CRT was assessed by Optical Coherence Tomography (OCT).
measure: Mean Number of Injections
time frame: 12 months
description: Mean number of injections over a 12-month treatment period
measure: Mean Number of Visits
time frame: 12 months
description: Mean number of visits over a 12-month treatment period
measure: Proportion of Patients Who Gained ≥5 Letters
time frame: 12 months
description: BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An increased score indicates improvement in acuity. This outcome assessed the number of participants who had improvement of ≥5 letters of visual acuity at month 12 as compared with baseline
measure: Proportion of Patients Who Gained ≥10 Letters
time frame: 12 months
description: BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An increased score indicates improvement in acuity. This outcome assessed the number of participants who had improvement of ≥10 letters of visual acuity at month 12 as compared with baseline
measure: Proportion of Patients Who Gained ≥15 Letters
time frame: 12 months
description: BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An increased score indicates improvement in acuity. This outcome assessed the number of participants who had improvement of ≥15 letters of visual acuity at month 12 as compared with baseline
arm group label: Ranibizumab labeled regime arm
arm group type: Experimental
description: Ranibizumab (Anti VEGF) 0.5mg treatment will be given monthly and will be continued until maximum visual acuity is achieved (the patient's visual acuity is stable for three consecutive monthly assessments performed while on ranibizumab treatment). Thereafter patients should be monitored monthly for visual acuity. Treatment will be resumed when monitoring indicates loss of visual acuity due to DME. Monthly injections should then be administered until stable visual acuity is reached again for three consecutive monthly assessments (implying a minimum of two injections). The interval between two doses should not be shorter than 1 month
arm group label: Ranibizumab wait and Extend regime arm
arm group type: Experimental
description: Ranibizumab (Anti VEGF) 0.5 mg will be injected subsequently at baseline, month 1 and 2. After the three initial loading doses, patients will be called for the control visits 1 month later. If the visual acuity has reached a stable level and there is no sign of edema on OCT, patients will not receive intravitreal injection and will be called to come back 6 weeks later. The interval is increased by 2 weeks until a maximum of 8 weeks as long as the patient presents as stable regarding visual acuity, central retinal thickness and clinical findings. If there is a negative change, the interval is shortened back to 4 weeks.
intervention type: Drug
intervention name: Labeled regime arm
description: Treatment will be given monthly and will be continued until maximum visual acuity is achieved (the patient's visual acuity is stable for three consecutive monthly assessments performed while on ranibizumab treatment). Thereafter patients should be monitored monthly for visual acuity. Treatment will be resumed when monitoring indicates loss of visual acuity due to DME. Monthly injections should then be administered until stable visual acuity is reached again for three consecutive monthly assessments (implying a minimum of two injections). The interval between two doses should not be shorter than 1 month.
arm group label: Ranibizumab labeled regime arm
other name: Arm 1
intervention type: Drug
intervention name: Wait and Extend regime arm
description: Lucentis (ranibizumab) 0.5 mg will be injected subsequently at baseline, month 1 and 2. After the three initial loading doses, patients will be called for the control visits 1 month later. If the visual acuity has reached a stable level and there is no sign of edema on OCT, patients will not receive intravitreal injection and will be called to come back 6 weeks later. The interval is increased by 2 weeks until a maximum of 8 weeks as long as the patient presents as stable regarding visual acuity, central retinal thickness and clinical findings. If there is a negative change, the interval is shortened back to 4 weeks.
arm group label: Ranibizumab wait and Extend regime arm
other name: Arm 2
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Novartis Pharmaceuticals
role: Study Director
affiliation: Novartis Pharmaceuticals
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Turkey
responsible party type: Sponsor
mesh term: Macular Edema
mesh term: Edema
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 