<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/NCT02257632</url>
  </required_header>
  <id_info>
    <org_study_id>CRFB002ADE27</org_study_id>
    <nct_id>NCT02257632</nct_id>
  </id_info>
  <brief_title>Systemic Vascular Endothelial Growth Factor (VEGF) Protein Dynamics Following Intravitreal Injections of Ranibizumab Versus Aflibercept in Patients With Neovascular Age-related Macular Degeneration</brief_title>
  <acronym>TIDE AMD</acronym>
  <official_title>A Randomized, Single-blinded, Multicenter, Phase IV Study to Compare Systemic VEGF Protein Dynamics Following Monthly Intravitreal Injections of 0.5 mg Ranibizumab Versus 2 mg Aflibercept Until Study Week 12 in Patients With Neovascular (Wet) Age-related Macular Degeneration</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>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of the study was to compare the effect of intravitreal injections of ranibizumab&#xD;
      and aflibercept on systemic VEGF protein levels in treatment naïve wet neovascular&#xD;
      Age-related Macular Degeneration (wAMD) patients in a detailed time course.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      A planned study visit schedule was established at the time of baseline visit (day 1) for all&#xD;
      patients. Study assessments for patients were performed at screening visit, baseline (day 1),&#xD;
      day 2, day 8 (± 1 day to allow for flexibility in scheduling) and as of day 15 through to day&#xD;
      169 at biweekly visits.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 8, 2015</start_date>
  <completion_date type="Actual">June 8, 2017</completion_date>
  <primary_completion_date type="Actual">March 20, 2017</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Standardized Area Under the Curve (AUC) for VEGF A Levels by SIMOA (Quanterix's Single Molecule Array) Method for the Comparative Phase</measure>
    <time_frame>Baseline up to Week 12 visit (Days 1, 2, 8, 15, 29, 43, 57, 71, 85)</time_frame>
    <description>The AUC was calculated using the trapezoidal rule, where all available measurement between Day 1 and Week 12 were used. The AUC was standardized by dividing the calculated value by the number of days from first to last measurement.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Systemic VEGF-A Protein Levels From Study Week 12 to 24</measure>
    <time_frame>From study week 12 to 24 (Days 85, 99, 113, 127, 141, 155, 169)</time_frame>
    <description>Systemic VEGF-A protein levels in patients switching from monthly 2 mg aflibercept injections to monthly 0.5 mg ranibizumab compared to patients treated with monthly 0.5 mg ranibizumab from baseline (standardized area under the curve)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Systemic VEGF-A Levels From Study Week 12 to 24 (Change From Baseline)</measure>
    <time_frame>From study week 12 to 24</time_frame>
    <description>Adjustment of systemic VEGF-A levels of patients switching from aflibercept to ranibizumab to levels comparable to baseline or to levels comparable as in patients treated from baseline with ranibizumab</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">41</enrollment>
  <condition>Wet Age-Related Macular Degeneration</condition>
  <arm_group>
    <arm_group_label>Group 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>6 monthly intravitreal injections of 0.5 mg ranibizumab</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>3 monthly intravitreal injections of 2 mg aflibercept followed by 3 monthly intravitreal injections of 0.5 mg ranibizumab</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ranibizumab 0.5 mg</intervention_name>
    <description>Administered as an intravitreal injection</description>
    <arm_group_label>Group 1</arm_group_label>
    <arm_group_label>Group 2</arm_group_label>
    <other_name>Lucentis</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Aflibercept 2 mg</intervention_name>
    <description>Administered as an intravitreal injection</description>
    <arm_group_label>Group 2</arm_group_label>
    <other_name>Eylea</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Visual impairment predominantly due to neovascular AMD.&#xD;
&#xD;
          -  Active, newly diagnosed, untreated, angiographically documented, CNV lesion (i.e.&#xD;
             leakage on fluorescein angiography plus intraretinal, subretinal or sub-RPE fluid on&#xD;
             OCT) secondary to neovascular AMD in line with SmPC of ranibizumab and aflibercept&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Stroke or myocardial infarction less than 3 months prior to screening.&#xD;
&#xD;
          -  Presence of uncontrolled systolic blood pressure or diastolic blood pressure&#xD;
&#xD;
          -  Type 1 or Type 2 diabetes mellitus&#xD;
&#xD;
          -  Use of any systemic anti-VEGF drugs&#xD;
&#xD;
          -  Use of systemic or inhaled corticosteroids for at least 30 consecutive days within 3&#xD;
             months prior to screening.&#xD;
&#xD;
          -  Women who are pregnant or breast feeding or who are menstruating and capable of&#xD;
             becoming pregnant* and not practicing a medically approved method of contraception&#xD;
&#xD;
        For either eye:&#xD;
&#xD;
          -  Any active periocular or ocular infection or inflammation&#xD;
&#xD;
          -  Uncontrolled glaucoma&#xD;
&#xD;
          -  Neovascularization of the iris or neovascular glaucoma&#xD;
&#xD;
          -  History of treatment with any anti-angiogenic drugs&#xD;
&#xD;
        For study eye:&#xD;
&#xD;
          -  Atrophy or fibrosis involving the center of the fovea at the time of screening or&#xD;
             baseline.&#xD;
&#xD;
          -  Cataract (if causing significant visual impairment), planned cataract surgery during&#xD;
             the study period, vitrectomy, aphakia, glaucoma surgery, severe vitreous hemorrhage,&#xD;
             rhegmatogenous retinal detachment, proliferative retinopathy or choroidal&#xD;
             neovascularization of any other cause than wAMD&#xD;
&#xD;
          -  Irreversible structural damage within 0.5 disc diameter of the center of the macula&#xD;
&#xD;
          -  Any intraocular procedure (including cataract surgery, Yttrium-Aluminum-Garnet&#xD;
             capsulotomy) within 3 months prior to baseline or anticipated within the next 6 months&#xD;
             following baseline.&#xD;
&#xD;
          -  Use of intravitreal or topical ocular corticosteroids administered for at least 30&#xD;
             consecutive days within 3 months prior to screening.&#xD;
&#xD;
        For fellow eye&#xD;
&#xD;
        - Retinal or choroidal neovascularization or macula edema of any cause&#xD;
&#xD;
        Other protocol-defined inclusion/exclusion criteria may apply.&#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>Koeln</city>
        <zip>50924</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Marburg</city>
        <zip>35039</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>München</city>
        <zip>80336</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>München</city>
        <zip>81675</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Osnabrück</city>
        <zip>49076</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Regensburg</city>
        <zip>93042</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>October 2, 2014</study_first_submitted>
  <study_first_submitted_qc>October 2, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 6, 2014</study_first_posted>
  <results_first_submitted>June 5, 2018</results_first_submitted>
  <results_first_submitted_qc>January 31, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">May 7, 2019</results_first_posted>
  <last_update_submitted>January 31, 2019</last_update_submitted>
  <last_update_submitted_qc>January 31, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">May 7, 2019</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>Macular Degeneration</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ranibizumab</mesh_term>
    <mesh_term>Aflibercept</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <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>April 27, 2015</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/32/NCT02257632/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 10, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/32/NCT02257632/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>The study included adult patients with active, newly diagnosed, and untreated wAMD. A total of 40 patients were treated at 6 study sites across Germany. Patients were treated in an outpatient setting.</recruitment_details>
      <pre_assignment_details>At Screening, the eligibility criteria were performed.&#xD;
.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Ranibizumab</title>
          <description>6 monthly intravitreal injections of 0.5 mg ranibizumab</description>
        </group>
        <group group_id="P2">
          <title>Aflibercept and Ranibizumab</title>
          <description>3 monthly intravitreal injections of 2 mg aflibercept followed by 3 monthly intravitreal injections of 0.5 mg ranibizumab</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="19"/>
                <participants group_id="P2" count="22"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Full Analysis Set (FAS)</title>
              <participants_list>
                <participants group_id="P1" count="19"/>
                <participants group_id="P2" count="21"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Safety Set (SAF)</title>
              <participants_list>
                <participants group_id="P1" count="19"/>
                <participants group_id="P2" count="21"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Per-Protocol Set (PPS)</title>
              <participants_list>
                <participants group_id="P1" count="17"/>
                <participants group_id="P2" count="20"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="18"/>
                <participants group_id="P2" count="19"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Full Analysis Set (FAS)</population>
      <group_list>
        <group group_id="B1">
          <title>Ranibizumab</title>
          <description>6 monthly intravitreal injections of 0.5 mg ranibizumab</description>
        </group>
        <group group_id="B2">
          <title>Aflibercept and Ranibizumab</title>
          <description>3 monthly intravitreal injections of 2 mg aflibercept followed by 3 monthly intravitreal injections of 0.5 mg ranibizumab</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="19"/>
            <count group_id="B2" value="21"/>
            <count group_id="B3" value="40"/>
          </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="74.3" spread="5.50"/>
                    <measurement group_id="B2" value="75.4" spread="8.94"/>
                    <measurement group_id="B3" value="74.9" spread="7.43"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex/Gender, Customized</title>
          <population>Full Analysis Set (FAS)</population>
          <units>Participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Female</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="21"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Male</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="19"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Caucasian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="19"/>
                    <measurement group_id="B2" value="21"/>
                    <measurement group_id="B3" value="40"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Standardized Area Under the Curve (AUC) for VEGF A Levels by SIMOA (Quanterix's Single Molecule Array) Method for the Comparative Phase</title>
        <description>The AUC was calculated using the trapezoidal rule, where all available measurement between Day 1 and Week 12 were used. The AUC was standardized by dividing the calculated value by the number of days from first to last measurement.</description>
        <time_frame>Baseline up to Week 12 visit (Days 1, 2, 8, 15, 29, 43, 57, 71, 85)</time_frame>
        <population>Per-Protocol Set (PPS)</population>
        <group_list>
          <group group_id="O1">
            <title>Ranibizumab</title>
            <description>6 monthly intravitreal injections of 0.5 mg ranibizumab</description>
          </group>
          <group group_id="O2">
            <title>Aflibercept and Ranibizumab</title>
            <description>3 monthly intravitreal injections of 2 mg aflibercept followed by 3 monthly intravitreal injections of 0.5 mg ranibizumab</description>
          </group>
        </group_list>
        <measure>
          <title>Standardized Area Under the Curve (AUC) for VEGF A Levels by SIMOA (Quanterix's Single Molecule Array) Method for the Comparative Phase</title>
          <description>The AUC was calculated using the trapezoidal rule, where all available measurement between Day 1 and Week 12 were used. The AUC was standardized by dividing the calculated value by the number of days from first to last measurement.</description>
          <population>Per-Protocol Set (PPS)</population>
          <units>pg/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
                <count group_id="O2" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="18.78" spread="8.460"/>
                    <measurement group_id="O2" value="33.95" spread="7.659"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&lt;0.0001</p_value>
            <p_value_desc>missing Baseline VEGF-A level covariate values were imputed by the mean value of non-missing Baseline VEGF-A level from all other patients</p_value_desc>
            <method>ANCOVA</method>
            <method_desc>including treatment group and center as fixed effect factors and Baseline VEGF-A as a covariate</method_desc>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-14.98</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-19.64</ci_lower_limit>
            <ci_upper_limit>-10.32</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Systemic VEGF-A Protein Levels From Study Week 12 to 24</title>
        <description>Systemic VEGF-A protein levels in patients switching from monthly 2 mg aflibercept injections to monthly 0.5 mg ranibizumab compared to patients treated with monthly 0.5 mg ranibizumab from baseline (standardized area under the curve)</description>
        <time_frame>From study week 12 to 24 (Days 85, 99, 113, 127, 141, 155, 169)</time_frame>
        <population>Per-Protocol Set (PPS)</population>
        <group_list>
          <group group_id="O1">
            <title>Ranibizumab</title>
            <description>6 monthly intravitreal injections of 0.5 mg ranibizumab</description>
          </group>
          <group group_id="O2">
            <title>Aflibercept and Ranibizumab</title>
            <description>3 monthly intravitreal injections of 2 mg aflibercept followed by 3 monthly intravitreal injections of 0.5 mg ranibizumab</description>
          </group>
        </group_list>
        <measure>
          <title>Systemic VEGF-A Protein Levels From Study Week 12 to 24</title>
          <description>Systemic VEGF-A protein levels in patients switching from monthly 2 mg aflibercept injections to monthly 0.5 mg ranibizumab compared to patients treated with monthly 0.5 mg ranibizumab from baseline (standardized area under the curve)</description>
          <population>Per-Protocol Set (PPS)</population>
          <units>pg/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
                <count group_id="O2" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="17.93" spread="5.316"/>
                    <measurement group_id="O2" value="29.07" spread="7.863"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&lt; 0.0001</p_value>
            <p_value_desc>missing Baseline VEGF-A level covariate values were imputed by the mean value of non-missing Baseline VEGF-A level from all the patients with values</p_value_desc>
            <method>ANCOVA</method>
            <method_desc>including treatment group and center as fixed effect factors and Baseline VEGF-A as a covariate</method_desc>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-11.46</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-15.98</ci_lower_limit>
            <ci_upper_limit>-6.94</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Systemic VEGF-A Levels From Study Week 12 to 24 (Change From Baseline)</title>
        <description>Adjustment of systemic VEGF-A levels of patients switching from aflibercept to ranibizumab to levels comparable to baseline or to levels comparable as in patients treated from baseline with ranibizumab</description>
        <time_frame>From study week 12 to 24</time_frame>
        <population>Per-Protocol Set (PPS) Number of participants analyzed at each time point represents patients with a value for both baseline and the specific post-baseline visit</population>
        <group_list>
          <group group_id="O1">
            <title>Ranibizumab</title>
            <description>6 monthly intravitreal injections of 0.5 mg ranibizumab</description>
          </group>
          <group group_id="O2">
            <title>Aflibercept and Ranibizumab</title>
            <description>3 monthly intravitreal injections of 2 mg aflibercept followed by 3 monthly intravitreal injections of 0.5 mg ranibizumab</description>
          </group>
        </group_list>
        <measure>
          <title>Systemic VEGF-A Levels From Study Week 12 to 24 (Change From Baseline)</title>
          <description>Adjustment of systemic VEGF-A levels of patients switching from aflibercept to ranibizumab to levels comparable to baseline or to levels comparable as in patients treated from baseline with ranibizumab</description>
          <population>Per-Protocol Set (PPS) Number of participants analyzed at each time point represents patients with a value for both baseline and the specific post-baseline visit</population>
          <units>pg/ml</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="17"/>
                <count group_id="O2" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Change from Baseline at Week 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="16"/>
                    <count group_id="O2" value="17"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.37" spread="5.369"/>
                    <measurement group_id="O2" value="23.73" spread="13.700"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change from Baseline at Week 14</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="16"/>
                    <count group_id="O2" value="17"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.00" spread="6.128"/>
                    <measurement group_id="O2" value="21.93" spread="15.638"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change from Baseline at Week 16</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="15"/>
                    <count group_id="O2" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.01" spread="4.675"/>
                    <measurement group_id="O2" value="19.26" spread="16.432"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change from Baseline at Week 18</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="14"/>
                    <count group_id="O2" value="14"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.99" spread="5.582"/>
                    <measurement group_id="O2" value="11.61" spread="10.844"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change from Baseline at Week 20</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="15"/>
                    <count group_id="O2" value="16"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.62" spread="6.460"/>
                    <measurement group_id="O2" value="4.84" spread="11.065"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change from Baseline at Week 22</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="14"/>
                    <count group_id="O2" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.66" spread="8.109"/>
                    <measurement group_id="O2" value="2.45" spread="8.543"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change from Baseline at Week 24</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="13"/>
                    <count group_id="O2" value="14"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.18" spread="3.664"/>
                    <measurement group_id="O2" value="0.96" spread="9.553"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>28 weeks</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Ranibizumab (Up to Month 3)</title>
          <description>3 monthly intravitreal injections of 0.5 mg ranibizumab</description>
        </group>
        <group group_id="E2">
          <title>Ranibizumab (After Month 3)</title>
          <description>3 monthly intravitreal injections of 0.5 mg ranibizumab</description>
        </group>
        <group group_id="E3">
          <title>Aflibercept and Ranibizumab (Up to Month 3 - Aflibercept)</title>
          <description>3 monthly intravitreal injections of 2 mg aflibercept (AEs reported that started before switching to ranibizumab)</description>
        </group>
        <group group_id="E4">
          <title>Aflibercept and Ranibizumab (After Month 3 - Ranibizumab)</title>
          <description>3 monthly intravitreal injections of 0.5 mg ranibizumab (AEs reported that started on or after switching to ranibizumab)</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (20.0)</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="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="3" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Cardiac failure congestive</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Optic nerve cupping</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Retinal pigment epithelial tear</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Bone cyst</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Benign lung neoplasm</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>3</frequency_threshold>
        <default_vocab>MedDRA (20.0)</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="14" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="17" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="17" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Aortic valve disease</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Aortic valve incompetence</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Cardiac discomfort</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Cardiac fibrillation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Cardiovascular disorder</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Mitral valve incompetence</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Sinus bradycardia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Tricuspid valve incompetence</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="21"/>
              </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="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Thyroid mass</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Anterior chamber cell</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Blepharitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Choroidal neovascularisation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Conjunctival erosion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Conjunctival haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Conjunctival hyperaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Corneal erosion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Dry eye</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Eye discharge</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Eye pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Eyelid oedema</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Foreign body sensation in eyes</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Lacrimation increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Macular fibrosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Metamorphopsia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Ocular discomfort</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Pinguecula</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Retinal fibrosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Retinal scar</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Subretinal fluid</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Vision blurred</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Visual acuity reduced</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Visual impairment</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Vitreous detachment</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Vitreous floaters</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="21"/>
              </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="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Gastrooesophageal reflux disease</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fibrosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Influenza like illness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Injection site pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Sensation of foreign body</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Hypersensitivity</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Bronchitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Conjunctivitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Gastroenteritis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Herpes simplex</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Hordeolum</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Influenza</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Rhinitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Viral upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="4" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Hand fracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Laceration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood pressure increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Body temperature increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Electrocardiogram abnormal</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Gamma-glutamyltransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Haemoglobin E present</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Intraocular pressure increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Mean cell haemoglobin concentration increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Mean cell haemoglobin increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hypercholesterolaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Hyperglycaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Iron deficiency</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Fibromyalgia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Intervertebral disc protrusion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Muscular weakness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Spinal column stenosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Spinal osteoarthritis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Basal cell carcinoma</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Burning sensation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Monoparesis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Sciatica</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Chronic kidney disease</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Bronchial wall thickening</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Oropharyngeal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Pulmonary embolism</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Actinic keratosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Hyperhidrosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Melanosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Photosensitivity reaction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Sebaceous gland disorder</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Jaw operation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="21"/>
              </event>
              <event>
                <sub_title>Intermittent claudication</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="19"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="21"/>
              </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 (ie, data from all sites) in the clinical trial.</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/NCT02257632
org study id: CRFB002ADE27
nct id: NCT02257632
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The purpose of the study was to compare the effect of intravitreal injections of ranibizumab
      and aflibercept on systemic VEGF protein levels in treatment naïve wet neovascular
      Age-related Macular Degeneration (wAMD) patients in a detailed time course.
A planned study visit schedule was established at the time of baseline visit (day 1) for all
      patients. Study assessments for patients were performed at screening visit, baseline (day 1),
      day 2, day 8 (± 1 day to allow for flexibility in scheduling) and as of day 15 through to day
      169 at biweekly visits.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Participant)
measure: Standardized Area Under the Curve (AUC) for VEGF A Levels by SIMOA (Quanterix's Single Molecule Array) Method for the Comparative Phase
time frame: Baseline up to Week 12 visit (Days 1, 2, 8, 15, 29, 43, 57, 71, 85)
description: The AUC was calculated using the trapezoidal rule, where all available measurement between Day 1 and Week 12 were used. The AUC was standardized by dividing the calculated value by the number of days from first to last measurement.
measure: Systemic VEGF-A Protein Levels From Study Week 12 to 24
time frame: From study week 12 to 24 (Days 85, 99, 113, 127, 141, 155, 169)
description: Systemic VEGF-A protein levels in patients switching from monthly 2 mg aflibercept injections to monthly 0.5 mg ranibizumab compared to patients treated with monthly 0.5 mg ranibizumab from baseline (standardized area under the curve)
measure: Systemic VEGF-A Levels From Study Week 12 to 24 (Change From Baseline)
time frame: From study week 12 to 24
description: Adjustment of systemic VEGF-A levels of patients switching from aflibercept to ranibizumab to levels comparable to baseline or to levels comparable as in patients treated from baseline with ranibizumab
arm group label: Group 1
arm group type: Experimental
description: 6 monthly intravitreal injections of 0.5 mg ranibizumab
arm group label: Group 2
arm group type: Experimental
description: 3 monthly intravitreal injections of 2 mg aflibercept followed by 3 monthly intravitreal injections of 0.5 mg ranibizumab
intervention type: Drug
intervention name: Ranibizumab 0.5 mg
description: Administered as an intravitreal injection
arm group label: Group 1
arm group label: Group 2
other name: Lucentis
intervention type: Drug
intervention name: Aflibercept 2 mg
description: Administered as an intravitreal injection
arm group label: Group 2
other name: Eylea
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: 
country: Germany
responsible party type: Sponsor
mesh term: Macular Degeneration
mesh term: Ranibizumab
mesh term: Aflibercept
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 