<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/NCT01661270</url>
  </required_header>
  <id_info>
    <org_study_id>EFC11338</org_study_id>
    <secondary_id>U1111-1115-7227</secondary_id>
    <nct_id>NCT01661270</nct_id>
  </id_info>
  <brief_title>A Study of Aflibercept Versus Placebo With FOLFIRI in Patients With Metastatic Colorectal Cancer Previously Treated With an Oxaliplatin Chemotherapy</brief_title>
  <acronym>AFLAME</acronym>
  <official_title>A Multinational, Randomized, Double-Blind Study of Aflibercept Versus Placebo With Irinotecan/ 5-FU Combination (FOLFIRI) in Patients With Metastatic Colorectal Cancer (MCRC) After Failure of an Oxaliplatin Based Regimen</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sanofi</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Regeneron Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Sanofi</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Primary Objective:&#xD;
&#xD;
      To evaluate the improvement in progression-free survival (PFS) of aflibercept versus placebo&#xD;
      in participants with metastatic colorectal cancer treated with FOLFIRI as second-line&#xD;
      treatment for metastatic disease.&#xD;
&#xD;
      Secondary Objectives:&#xD;
&#xD;
      To compare the overall survival (OS) in the 2 treatment arms. To compare the overall response&#xD;
      rate (ORR) in the 2 treatment arms. To assess the safety profile of the 2 treatment arms. To&#xD;
      assess immunogenicity of intravenous (IV) aflibercept in selected centers.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Screening occurred from signed informed consent to randomization (up to 21 days). A treatment&#xD;
      cycle was defined as a 2 week-period. All participants were followed during the study&#xD;
      treatment and follow-up period until death or study cut off date, which ever comes first.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>July 2012</start_date>
  <completion_date type="Actual">July 2015</completion_date>
  <primary_completion_date type="Actual">October 2014</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>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Progression-free Survival (PFS)</measure>
    <time_frame>26.7 months</time_frame>
    <description>PFS was defined as the time interval from the date of randomization to the date of first observation of either tumor progression or death due to any cause. Tumor assessment was performed by Independent Review Committee (IRC) as per response evaluation criteria in solid tumors (RECIST) version 1.0. Progression was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study or absolute increase and at least 5 mm, progression of existing non-target lesions, or presence of new lesions. PFS was calculated by Kaplan-Meier estimates.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>31.6 months</time_frame>
    <description>OS was defined as the time interval from the date of randomization to the date of death due to any cause. In the absence of confirmation of death, survival time was censored at the earliest between the last date of the participants was known to be alive and the study cut-off date. Analysis was performed by Kaplan-Meier method.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants With Objective Response</measure>
    <time_frame>26.6 months</time_frame>
    <description>Objective response rate was defined as the proportion of participants with confirmed complete response (CR) or confirmed partial response (PR), as assessed by Investigators and the IRC according to RECIST 1.0 criteria, relative to the total number of participants in the relevant analysis population. Complete Response (CR): disappearance of all target and non-target lesions and no new lesions. Partial Response (PR): At least a 30% decrease in the size of target lesions with no progression of non-target lesions and no new lesions, or, the disappearance of all target lesions but persistence of 1 or more non-target lesions not qualifying for either CR or progressive disease (PD) and no new lesions.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">332</enrollment>
  <condition>Colorectal Cancer Metastatic</condition>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo for aflibercept intravenous (IV) infusion on Day 1 of each cycle (1 cycle = 2 weeks) in combination with FOLFIRI regimen until disease progression, unacceptable toxicity or participant's refusal. FOLFIRI regimen: Irinotecan 180 mg/m^2 IV infusion and leucovorin 400 mg/m^2 IV infusion, 5-Fluorouracil IV bolus 400 mg/m^2 followed by continuous IV infusion 2400 mg/m^2.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Aflibercept</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Aflibercept 4 mg/kg IV infusion on Day 1 of each cycle (1 cycle = 2 weeks) in combination with FOLFIRI regimen until disease progression, unacceptable toxicity or participant's refusal. FOLFIRI regimen: Irinotecan 180 mg/m^2 IV infusion and leucovorin 400 mg/m^2 IV infusion, 5-Fluorouracil IV bolus 400 mg/m^2 followed by continuous IV infusion 2400 mg/m^2.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Aflibercept</intervention_name>
    <description>Pharmaceutical form: Concentrate for Solution for infusion; Route of administration: Intravenous</description>
    <arm_group_label>Aflibercept</arm_group_label>
    <other_name>AVE0005</other_name>
    <other_name>Zaltrap</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Pharmaceutical form: Concentrate for Solution for infusion; Route of administration: Intravenous</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
          -  Histological or cytological proven adenocarcinoma of the colon or rectum.&#xD;
&#xD;
          -  Metastatic disease that was not amenable to potentially curative treatment.&#xD;
&#xD;
          -  One and only one prior chemotherapeutic regimen for metastatic disease. This prior&#xD;
             chemotherapy must be an oxaliplatin containing regimen. Participants who were relapsed&#xD;
             within 6 months of completion of oxaliplatin based adjuvant chemotherapy were&#xD;
             eligible.&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          -  Prior therapy with irinotecan.&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status &gt;1.&#xD;
&#xD;
          -  Less than 28 days elapsed from prior radiotherapy, from prior surgery and prior&#xD;
             chemotherapy to the time of randomization. Less than 42 days elapsed from prior major&#xD;
             surgery to the time to randomization.&#xD;
&#xD;
          -  Adverse events (with exception of alopecia, peripheral sensory neuropathy grade ≤ 2&#xD;
             and those listed in specific exclusion criteria) from any prior anticancer therapy of&#xD;
             grade &gt;1 (National Cancer Institute Common terminology Criteria [NCI CTCAE] v.3.0) at&#xD;
             the time of randomization.&#xD;
&#xD;
          -  Age &lt;18 years.&#xD;
&#xD;
          -  History of brain metastases, uncontrolled spinal cord compression, or carcinomatous&#xD;
             meningitis or new evidence of brain or leptomeningeal disease.&#xD;
&#xD;
          -  Other prior malignancy. Adequately treated basal cell or squamous cell skin cancer,&#xD;
             carcinoma in situ of the cervix or any other cancer from which the participants had&#xD;
             disease free for &gt; 5 years were allowed.&#xD;
&#xD;
          -  Participation in another clinical trial with an investigational drug and any&#xD;
             concurrent treatment with any investigational drug within 30 days prior to&#xD;
             randomization.&#xD;
&#xD;
          -  Any of the following within 6 months prior to randomization: myocardial infarction,&#xD;
             severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York&#xD;
             Heart Association Functional Classification (NYHA) class III or IV congestive heart&#xD;
             failure, stroke or transient ischemic attack.&#xD;
&#xD;
          -  Any of the following within 3 months prior to randomization: treatment resistant&#xD;
             peptic or duodenal ulcer disease, erosive oesophagitis or gastritis, grade 3 or 4&#xD;
             gastrointestinal bleeding/hemorrhage, gastrointestinal perforation/fistula, abdominal&#xD;
             abscess, infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism,&#xD;
             or other uncontrolled thromboembolic event.&#xD;
&#xD;
          -  Participants who had given high dose of aspirin or non steroidal anti-inflammatory&#xD;
             agents (NSAIDS) or high steroids within 4 weeks prior to randomization. The definition&#xD;
             of &quot;high dose&quot; was to be based on the investigator's judgment.&#xD;
&#xD;
          -  Occurrence of deep vein thrombosis within 4 weeks, prior to randomization.&#xD;
&#xD;
          -  Inadequate organ or bone marrow function.&#xD;
&#xD;
          -  Pregnant or breast-feeding woman. Positive serum or urine pregnancy test prior to&#xD;
             randomization. Participants with reproductive (M/F) who were not agree to use accepted&#xD;
             and effective method of contraception during the study treatment period and for at&#xD;
             least 6 months following completion of study treatment.&#xD;
&#xD;
          -  Uncontrolled hypertension.&#xD;
&#xD;
          -  Urine Protein: creatine ratio (UPCR) &gt;1 on morning spot urinalysis or proteinuria &gt;&#xD;
             500mg/24 hours.&#xD;
&#xD;
          -  Participants on anticoagulant therapy with unstable dose of warfarin and/or having an&#xD;
             out-of-therapeutic range international normalized ratio (INR) (&gt;3) within 4 weeks&#xD;
             prior to randomization.&#xD;
&#xD;
          -  Evidence of clinically significant bleeding diathesis or underlying coagulopathy.&#xD;
&#xD;
          -  Known dihydropyrimidine dehydrogenase deficiency.&#xD;
&#xD;
          -  Predisposing colonic or small bowel disorder in which the symptoms were uncontrolled&#xD;
             as indicated by baseline of &gt; 3 loose stools daily.&#xD;
&#xD;
          -  Prior history of chronic enteropathy, inflammatory enteropathy, chronic diarrhea,&#xD;
             unresolved bowel obstruction/sub-obstruction, more than hemicolectomy, extensive small&#xD;
             intestine resection with chronic diarrhea.&#xD;
&#xD;
          -  History of anaphylaxis or known intolerance to atropine sulphate or loperamide or&#xD;
             appropriate antiemetics to be administered in conjunction with FOLFIRI.&#xD;
&#xD;
          -  Treatment with concomitant anticonvulsant agents that were cytochrome P450 3A4&#xD;
             (CYP3A4) inducers (phenytoin, phenobarbital, carbamazepine), unless discontinued &gt; 7&#xD;
             days.&#xD;
&#xD;
          -  Participants with known Gilbert's syndrome.&#xD;
&#xD;
        The above information was not intended to contain all considerations relevant to a&#xD;
        participant's potential participation in a clinical trial.&#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>Clinical Sciences &amp; Operations</last_name>
    <role>Study Director</role>
    <affiliation>Sanofi</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Investigational Site Number 156003</name>
      <address>
        <city>Beijing</city>
        <zip>100071</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 156001</name>
      <address>
        <city>Beijing</city>
        <zip>100142</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 156002</name>
      <address>
        <city>Beijing</city>
        <zip>100210</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 156004</name>
      <address>
        <city>Beijing</city>
        <zip>100853</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 156016</name>
      <address>
        <city>Chengdu</city>
        <zip>610041</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 156020</name>
      <address>
        <city>Chongqing</city>
        <zip>400038</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 156021</name>
      <address>
        <city>Fuzhou</city>
        <zip>350014</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 156008</name>
      <address>
        <city>Guangzhou</city>
        <zip>510060</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 156010</name>
      <address>
        <city>Hangzhou</city>
        <zip>310003</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 156011</name>
      <address>
        <city>Hangzhou</city>
        <zip>310009</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 156009</name>
      <address>
        <city>Hangzhou</city>
        <zip>310016</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 156015</name>
      <address>
        <city>Harbin</city>
        <zip>150081</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 156012</name>
      <address>
        <city>Nanjing</city>
        <zip>210002</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 156013</name>
      <address>
        <city>Nanjing</city>
        <zip>210029</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 156006</name>
      <address>
        <city>Shanghai</city>
        <zip>200032</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 156007</name>
      <address>
        <city>Shanghai</city>
        <zip>200032</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 156014</name>
      <address>
        <city>Shenyang</city>
        <zip>110001</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 156005</name>
      <address>
        <city>Tianjin</city>
        <zip>300060</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 156019</name>
      <address>
        <city>Wuhan</city>
        <zip>430022</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 156018</name>
      <address>
        <city>Wuhan</city>
        <zip>430030</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 156017</name>
      <address>
        <city>Xi'An</city>
        <zip>710032</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 344002</name>
      <address>
        <city>Hong Kong</city>
        <country>Hong Kong</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 344001</name>
      <address>
        <city>Shatin, Nt</city>
        <country>Hong Kong</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 392006</name>
      <address>
        <city>Amagasaki-Shi</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 392003</name>
      <address>
        <city>Bunkyo-Ku</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 392004</name>
      <address>
        <city>Bunkyo-Ku</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 392009</name>
      <address>
        <city>Gifu-Shi</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 392002</name>
      <address>
        <city>Kitaadachi-Gun</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 392001</name>
      <address>
        <city>Kobe-Shi</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 392005</name>
      <address>
        <city>Kochi-Shi</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 392007</name>
      <address>
        <city>Kumamoto-Shi</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 392008</name>
      <address>
        <city>Nagakute-Shi</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 392010</name>
      <address>
        <city>Takatsuki-Shi</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 702002</name>
      <address>
        <city>Singapore</city>
        <zip>119228</zip>
        <country>Singapore</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 702001</name>
      <address>
        <city>Singapore</city>
        <zip>169610</zip>
        <country>Singapore</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 158003</name>
      <address>
        <city>Taipai</city>
        <zip>10043</zip>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Investigational Site Number 158002</name>
      <address>
        <city>Taipei</city>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
    <country>Hong Kong</country>
    <country>Japan</country>
    <country>Singapore</country>
    <country>Taiwan</country>
  </location_countries>
  <verification_date>August 2016</verification_date>
  <study_first_submitted>August 7, 2012</study_first_submitted>
  <study_first_submitted_qc>August 8, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 9, 2012</study_first_posted>
  <results_first_submitted>October 22, 2015</results_first_submitted>
  <results_first_submitted_qc>October 22, 2015</results_first_submitted_qc>
  <results_first_posted type="Estimate">November 26, 2015</results_first_posted>
  <last_update_submitted>August 24, 2016</last_update_submitted>
  <last_update_submitted_qc>August 24, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 18, 2016</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>Colorectal Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aflibercept</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>The study was conducted at 37 centers in 5 countries. A total of 332 participants were randomized between 17 July 2012 and 18 March 2014.</recruitment_details>
      <pre_assignment_details>Due to treatment kit misallocation, part of the patients randomized to placebo received aflibercept for&#xD;
1/several treatment cycles and are presented as a separate group for safety evaluation.&#xD;
EOT criteria were: disease progression/death, un-tolerable toxicity, consent withdrawal/Investigator decision.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Placebo</title>
          <description>Placebo for aflibercept intravenous (IV) infusion on Day 1 of each cycle (1 cycle = 2 weeks) in combination with FOLFIRI regimen until disease progression, unacceptable toxicity or participant's refusal. FOLFIRI regimen: Irinotecan 180 mg/m^2 IV infusion and leucovorin 400 mg/m^2 IV infusion, 5-Fluorouracil IV bolus 400 mg/m^2 followed by continuous IV infusion 2400 mg/m^2.</description>
        </group>
        <group group_id="P2">
          <title>Aflibercept</title>
          <description>Aflibercept 4 mg/kg IV infusion on Day 1 of each cycle (1 cycle = 2 weeks) in combination with FOLFIRI regimen until disease progression, unacceptable toxicity or participant's refusal. FOLFIRI regimen: Irinotecan 180 mg/m^2 IV infusion and leucovorin 400 mg/m^2 IV infusion, 5-Fluorouracil IV bolus 400 mg/m^2 followed by continuous IV infusion 2400 mg/m^2.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="109"/>
                <participants group_id="P2" count="223"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="26">Met end of treatment (EOT) criteria.</participants>
                <participants group_id="P2" count="47">Met EOT criteria</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>Disease Progression</title>
              <participants_list>
                <participants group_id="P1" count="67">Met EOT criteria</participants>
                <participants group_id="P2" count="118">Met EOT criteria</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="1">Met EOT criteria</participants>
                <participants group_id="P2" count="8">Met EOT criteria</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>Participant's Request</title>
              <participants_list>
                <participants group_id="P1" count="15">Met EOT criteria</participants>
                <participants group_id="P2" count="48">Met EOT criteria</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>Other Reasons</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="109">Treatment until disease progression/death, toxicity, consent withdrawal or Investigator's decision.</participants>
                <participants group_id="P2" count="223">Treatment until disease progression/death, toxicity, consent withdrawal or Investigator's decision.</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Placebo</title>
          <description>Placebo for IV infusion on Day 1 of each cycle (1 cycle = 2 weeks) in combination with FOLFIRI regimen until disease progression, unacceptable toxicity or participant's refusal. FOLFIRI regimen: Irinotecan 180 mg/m^2 IV infusion and leucovorin 400 mg/m^2 IV infusion, 5-Fluorouracil IV bolus 400 mg/m^2 followed by continuous IV infusion 2400 mg/m^2.</description>
        </group>
        <group group_id="B2">
          <title>Aflibercept</title>
          <description>Aflibercept 4 mg/kg IV infusion on Day 1 of each cycle (1 cycle = 2 weeks) in combination with FOLFIRI regimen until disease progression, unacceptable toxicity or participant's refusal. FOLFIRI regimen: Irinotecan 180 mg/m^2 IV infusion and leucovorin 400 mg/m^2 IV infusion, 5-Fluorouracil IV bolus 400 mg/m^2 followed by continuous IV infusion 2400 mg/m^2.</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="109"/>
            <count group_id="B2" value="223"/>
            <count group_id="B3" value="332"/>
          </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="53.0" spread="11.3"/>
                    <measurement group_id="B2" value="55.1" spread="10.9"/>
                    <measurement group_id="B3" value="54.4" spread="11.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="46"/>
                    <measurement group_id="B2" value="95"/>
                    <measurement group_id="B3" value="141"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="63"/>
                    <measurement group_id="B2" value="128"/>
                    <measurement group_id="B3" value="191"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Progression-free Survival (PFS)</title>
        <description>PFS was defined as the time interval from the date of randomization to the date of first observation of either tumor progression or death due to any cause. Tumor assessment was performed by Independent Review Committee (IRC) as per response evaluation criteria in solid tumors (RECIST) version 1.0. Progression was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study or absolute increase and at least 5 mm, progression of existing non-target lesions, or presence of new lesions. PFS was calculated by Kaplan-Meier estimates.</description>
        <time_frame>26.7 months</time_frame>
        <population>Intent-to-Treat (ITT) population included all randomized participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Placebo for IV infusion on Day 1 of each cycle (1 cycle = 2 weeks) in combination with FOLFIRI regimen until disease progression, unacceptable toxicity or participant's refusal. FOLFIRI regimen: Irinotecan 180 mg/m^2 IV infusion and leucovorin 400 mg/m^2 IV infusion, 5-Fluorouracil IV bolus 400 mg/m^2 followed by continuous IV infusion 2400 mg/m^2.</description>
          </group>
          <group group_id="O2">
            <title>Aflibercept</title>
            <description>Aflibercept 4 mg/kg IV infusion on Day 1 of each cycle (1 cycle = 2 weeks) in combination with FOLFIRI regimen until disease progression, unacceptable toxicity or participant's refusal. FOLFIRI regimen: Irinotecan 180 mg/m^2 IV infusion and leucovorin 400 mg/m^2 IV infusion, 5-Fluorouracil IV bolus 400 mg/m^2 followed by continuous IV infusion 2400 mg/m^2.</description>
          </group>
        </group_list>
        <measure>
          <title>Progression-free Survival (PFS)</title>
          <description>PFS was defined as the time interval from the date of randomization to the date of first observation of either tumor progression or death due to any cause. Tumor assessment was performed by Independent Review Committee (IRC) as per response evaluation criteria in solid tumors (RECIST) version 1.0. Progression was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study or absolute increase and at least 5 mm, progression of existing non-target lesions, or presence of new lesions. PFS was calculated by Kaplan-Meier estimates.</description>
          <population>Intent-to-Treat (ITT) population included all randomized participants.</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="109"/>
                <count group_id="O2" value="223"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.59" lower_limit="4.632" upper_limit="6.111"/>
                    <measurement group_id="O2" value="6.93" lower_limit="6.045" upper_limit="7.655"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival (OS)</title>
        <description>OS was defined as the time interval from the date of randomization to the date of death due to any cause. In the absence of confirmation of death, survival time was censored at the earliest between the last date of the participants was known to be alive and the study cut-off date. Analysis was performed by Kaplan-Meier method.</description>
        <time_frame>31.6 months</time_frame>
        <population>ITT population.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Placebo for IV infusion on Day 1 of each cycle (1 cycle = 2 weeks) in combination with FOLFIRI regimen until disease progression, unacceptable toxicity or participant's refusal. FOLFIRI regimen: Irinotecan 180 mg/m^2 IV infusion and leucovorin 400 mg/m^2 IV infusion, 5-Fluorouracil IV bolus 400 mg/m^2 followed by continuous IV infusion 2400 mg/m^2.</description>
          </group>
          <group group_id="O2">
            <title>Aflibercept</title>
            <description>Aflibercept 4 mg/kg IV infusion on Day 1 of each cycle (1 cycle = 2 weeks) in combination with FOLFIRI regimen until disease progression, unacceptable toxicity or participant's refusal. FOLFIRI regimen: Irinotecan 180 mg/m^2 IV infusion and leucovorin 400 mg/m^2 IV infusion, 5-Fluorouracil IV bolus 400 mg/m^2 followed by continuous IV infusion 2400 mg/m^2.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival (OS)</title>
          <description>OS was defined as the time interval from the date of randomization to the date of death due to any cause. In the absence of confirmation of death, survival time was censored at the earliest between the last date of the participants was known to be alive and the study cut-off date. Analysis was performed by Kaplan-Meier method.</description>
          <population>ITT population.</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="109"/>
                <count group_id="O2" value="233"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11.93" lower_limit="10.086" upper_limit="14.292"/>
                    <measurement group_id="O2" value="14.59" lower_limit="13.175" upper_limit="16.460"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants With Objective Response</title>
        <description>Objective response rate was defined as the proportion of participants with confirmed complete response (CR) or confirmed partial response (PR), as assessed by Investigators and the IRC according to RECIST 1.0 criteria, relative to the total number of participants in the relevant analysis population. Complete Response (CR): disappearance of all target and non-target lesions and no new lesions. Partial Response (PR): At least a 30% decrease in the size of target lesions with no progression of non-target lesions and no new lesions, or, the disappearance of all target lesions but persistence of 1 or more non-target lesions not qualifying for either CR or progressive disease (PD) and no new lesions.</description>
        <time_frame>26.6 months</time_frame>
        <population>ITT population.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Placebo for IV infusion on Day 1 of each cycle (1 cycle = 2 weeks) in combination with FOLFIRI regimen until disease progression, unacceptable toxicity or participant's refusal. FOLFIRI regimen: Irinotecan 180 mg/m^2 IV infusion and leucovorin 400 mg/m^2 IV infusion, 5-Fluorouracil IV bolus 400 mg/m^2 followed by continuous IV infusion 2400 mg/m^2.</description>
          </group>
          <group group_id="O2">
            <title>Aflibercept</title>
            <description>Aflibercept 4 mg/kg IV infusion on Day 1 of each cycle (1 cycle = 2 weeks) in combination with FOLFIRI regimen until disease progression, unacceptable toxicity or participant's refusal. FOLFIRI regimen: Irinotecan 180 mg/m^2 IV infusion and leucovorin 400 mg/m^2 IV infusion, 5-Fluorouracil IV bolus 400 mg/m^2 followed by continuous IV infusion 2400 mg/m^2.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With Objective Response</title>
          <description>Objective response rate was defined as the proportion of participants with confirmed complete response (CR) or confirmed partial response (PR), as assessed by Investigators and the IRC according to RECIST 1.0 criteria, relative to the total number of participants in the relevant analysis population. Complete Response (CR): disappearance of all target and non-target lesions and no new lesions. Partial Response (PR): At least a 30% decrease in the size of target lesions with no progression of non-target lesions and no new lesions, or, the disappearance of all target lesions but persistence of 1 or more non-target lesions not qualifying for either CR or progressive disease (PD) and no new lesions.</description>
          <population>ITT population.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="109"/>
                <count group_id="O2" value="233"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.7" lower_limit="NA" upper_limit="NA">Insufficient number of participants for the CI to be calculated</measurement>
                    <measurement group_id="O2" value="18.4" lower_limit="13.3" upper_limit="23.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>All AE collected from signature of informed consent upto resolution/stabilization/death regardless of seriousness/relationship to IMP.After cutoff date for OS,only ongoing AE &amp; SAE were followed until resolution,stabilization/2 follow-ups(about 4 months).</time_frame>
      <desc>Reported AEs were treatment-emergent AEs that developed/worsened during 'on-treatment period' (from first dose of Aflibercept to 30 days of follow-up visit). Safety population (subset of ITT population): all participants who received at least one dose of study drug. Due to operational treatment error, 3 arms were reported for safety analysis.</desc>
      <group_list>
        <group group_id="E1">
          <title>Placebo Only</title>
          <description>Placebo for IV infusion on Day 1 of each cycle (1 cycle = 2 weeks) in combination with FOLFIRI regimen until disease progression, unacceptable toxicity or participant's refusal. FOLFIRI regimen: Irinotecan 180 mg/m^2 IV infusion and leucovorin 400 mg/m^2 IV infusion, 5-Fluorouracil IV bolus 400 mg/m^2 followed by continuous IV infusion 2400 mg/m^2.</description>
        </group>
        <group group_id="E2">
          <title>Aflibercept Only</title>
          <description>Aflibercept 4 mg/kg IV infusion on Day 1 of each cycle (1 cycle = 2 weeks) in combination with FOLFIRI regimen until disease progression, unacceptable toxicity or participant's refusal. FOLFIRI regimen: Irinotecan 180 mg/m^2 IV infusion and leucovorin 400 mg/m^2 IV infusion, 5-Fluorouracil IV bolus 400 mg/m^2 followed by continuous IV infusion 2400 mg/m^2.</description>
        </group>
        <group group_id="E3">
          <title>Mixed Administration (Placebo and Aflibercept)</title>
          <description>Participants who were originally randomized to receive either Placebo or Aflibercept, actually received both the treatment (Placebo and Aflibercept).</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA-18.0</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="30" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="43" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Thrombocytopenia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Bone marrow failure</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Acute left ventricular failure</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Acute coronary syndrome</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Acute myocardial infarction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Angina pectoris</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Cardiopulmonary failure</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Gastrointestinal haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Intestinal obstruction</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Abdominal mass</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Ileus</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Intestinal perforation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Lower gastrointestinal haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Ascites</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Colitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Mouth ulceration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Oesophageal varices haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Rectal perforation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Small intestinal obstruction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Stomatitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Hepatic function abnormal</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Liver injury</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Bile duct stone</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Cholecystitis chronic</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Gallbladder perforation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Anal abscess</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Fungal skin infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Hepatitis B</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Peritonitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Catheter site abscess</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Gastroenteritis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Herpes zoster</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Lobar pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Lung abscess</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Neutropenic sepsis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Traumatic intracranial haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Blood alkaline phosphatase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Blood lactate dehydrogenase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperammonaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Hypoglycaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Musculoskeletal chest pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Lymphangiosis carcinomatosa</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Cerebral infarction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Peroneal nerve palsy</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Posterior reversible encephalopathy syndrome</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Cerebral ischaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Loss of consciousness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Completed suicide</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </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="33"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Calculus urinary</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Bladder outlet obstruction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Haematuria</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Vaginal fistula</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Female genital tract fistula</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Genital rash</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Pulmonary embolism</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Interstitial lung disease</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Pneumothorax</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Oropharyngeal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Subcutaneous emphysema</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Deep vein thrombosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Subclavian vein thrombosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Venous thrombosis limb</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA-18.0</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="32" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="109" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="188" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="22" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="68" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="135" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Leukopenia</sub_title>
                <counts group_id="E1" subjects_affected="20" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="59" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="84" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Thrombocytopenia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="22" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="24" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="12" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="22" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="61" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="110" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="14" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="60" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="122" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="22" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="56" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="107" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Stomatitis</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="27" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="60" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="19" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="42" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="14" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="35" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Abdominal distension</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="13" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="11" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Mouth ulceration</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="11" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="29" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="15" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Gastrointestinal haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Proctalgia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Toothache</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Rectal discharge</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="37" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="84" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="15" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="33" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Asthenia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="24" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Chest discomfort</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="11" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="19" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="14" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="11" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="19" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Weight decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="27" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="21" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Blood pressure increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>White blood cell count decreased</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="16" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Haemoglobin decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="15" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="42" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="90" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Hypokalaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="15" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="11" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="14" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="17" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="17" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Cholinergic syndrome</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="11" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Hypoaesthesia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Neuropathy peripheral</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="10" subjects_at_risk="188"/>
              </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="33"/>
                <counts group_id="E2" subjects_affected="19" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="37" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Haematuria</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="30" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="38" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="13" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="18" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Dysphonia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="13" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="26" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Productive cough</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Oropharyngeal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="11" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="13" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Hyperhidrosis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="10" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Palmar-plantar erythrodysaesthesia syndrome</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="11" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="43" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Pigmentation disorder</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Skin hyperpigmentation</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="13" subjects_at_risk="188"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="10" subjects_at_risk="188"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E2" subjects_affected="43" subjects_at_risk="111"/>
                <counts group_id="E3" subjects_affected="65" subjects_at_risk="188"/>
              </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>If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Trial Transparency Team</name_or_title>
      <organization>Sanofi</organization>
      <email>Contact-US@sanofi.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/NCT01661270
org study id: EFC11338
secondary id: U1111-1115-7227
nct id: NCT01661270
lead sponsor: 
collaborator: 
has dmc: Yes
Primary Objective:

      To evaluate the improvement in progression-free survival (PFS) of aflibercept versus placebo
      in participants with metastatic colorectal cancer treated with FOLFIRI as second-line
      treatment for metastatic disease.

      Secondary Objectives:

      To compare the overall survival (OS) in the 2 treatment arms. To compare the overall response
      rate (ORR) in the 2 treatment arms. To assess the safety profile of the 2 treatment arms. To
      assess immunogenicity of intravenous (IV) aflibercept in selected centers.
Screening occurred from signed informed consent to randomization (up to 21 days). A treatment
      cycle was defined as a 2 week-period. All participants were followed during the study
      treatment and follow-up period until death or study cut off date, which ever comes first.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Progression-free Survival (PFS)
time frame: 26.7 months
description: PFS was defined as the time interval from the date of randomization to the date of first observation of either tumor progression or death due to any cause. Tumor assessment was performed by Independent Review Committee (IRC) as per response evaluation criteria in solid tumors (RECIST) version 1.0. Progression was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study or absolute increase and at least 5 mm, progression of existing non-target lesions, or presence of new lesions. PFS was calculated by Kaplan-Meier estimates.
measure: Overall Survival (OS)
time frame: 31.6 months
description: OS was defined as the time interval from the date of randomization to the date of death due to any cause. In the absence of confirmation of death, survival time was censored at the earliest between the last date of the participants was known to be alive and the study cut-off date. Analysis was performed by Kaplan-Meier method.
measure: Percentage of Participants With Objective Response
time frame: 26.6 months
description: Objective response rate was defined as the proportion of participants with confirmed complete response (CR) or confirmed partial response (PR), as assessed by Investigators and the IRC according to RECIST 1.0 criteria, relative to the total number of participants in the relevant analysis population. Complete Response (CR): disappearance of all target and non-target lesions and no new lesions. Partial Response (PR): At least a 30% decrease in the size of target lesions with no progression of non-target lesions and no new lesions, or, the disappearance of all target lesions but persistence of 1 or more non-target lesions not qualifying for either CR or progressive disease (PD) and no new lesions.
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo for aflibercept intravenous (IV) infusion on Day 1 of each cycle (1 cycle = 2 weeks) in combination with FOLFIRI regimen until disease progression, unacceptable toxicity or participant's refusal. FOLFIRI regimen: Irinotecan 180 mg/m^2 IV infusion and leucovorin 400 mg/m^2 IV infusion, 5-Fluorouracil IV bolus 400 mg/m^2 followed by continuous IV infusion 2400 mg/m^2.
arm group label: Aflibercept
arm group type: Experimental
description: Aflibercept 4 mg/kg IV infusion on Day 1 of each cycle (1 cycle = 2 weeks) in combination with FOLFIRI regimen until disease progression, unacceptable toxicity or participant's refusal. FOLFIRI regimen: Irinotecan 180 mg/m^2 IV infusion and leucovorin 400 mg/m^2 IV infusion, 5-Fluorouracil IV bolus 400 mg/m^2 followed by continuous IV infusion 2400 mg/m^2.
intervention type: Drug
intervention name: Aflibercept
description: Pharmaceutical form: Concentrate for Solution for infusion; Route of administration: Intravenous
arm group label: Aflibercept
other name: AVE0005
other name: Zaltrap
intervention type: Drug
intervention name: Placebo
description: Pharmaceutical form: Concentrate for Solution for infusion; Route of administration: Intravenous
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Clinical Sciences & Operations
role: Study Director
affiliation: Sanofi
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country: China
country: Hong Kong
country: Japan
country: Singapore
country: Taiwan
responsible party type: Sponsor
mesh term: Colorectal Neoplasms
mesh term: Aflibercept
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 