<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/NCT03288987</url>
  </required_header>
  <id_info>
    <org_study_id>BEV.ARY.HR.94 (III)</org_study_id>
    <nct_id>NCT03288987</nct_id>
  </id_info>
  <brief_title>Comparing Efficacy and Safety of Stivant (AryoGen Bevacizumab) Versus Avastin in Metastatic Colorectal Cancer</brief_title>
  <official_title>A Phase III, Randomized, Two-armed, Triple Blinded, Parallel, Active Controlled Non-Inferiority Clinical Trial of Stivant (AryoGen Trastuzumab) Efficacy and Safety in Comparison to Avastin in Metastatic Colorectal Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>AryoGen Pharmed Co.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>AryoGen Pharmed Co.</source>
  <brief_summary>
    <textblock>
      This is a Phase III, randomized, two arms, double-blind (patient and assessor blinded),&#xD;
      parallel active non inferiority controlled clinical trial with a 2:1 allocation. This trial&#xD;
      was conducted to evaluate the efficacy and safety of bevacizumab (produced by AryoGen&#xD;
      Pharmed) plus FOLFIRI-3 compared with bevacizumab (Avastin®) plus FOLFIRI-3 in patients with&#xD;
      metastatic colorectal cancer (mCRC). Patients who met the following criteria could be&#xD;
      recruited to receive the mentioned intervention randomly. Inclusion criteria: male or female&#xD;
      aged 18-75 years, mCRC verified histologically, Having one or more bi-dimensionally&#xD;
      measurable lesions as defined by Response Evaluation Criteria In Solid Tumors (RECIST)&#xD;
      criteria, Was not felt to be amenable to curative resection, With an (ECOG) performance&#xD;
      status of ≤ 1, Life expectancy of longer than 3 months, Adequate organ and marrow function,&#xD;
      May have received adjuvant therapy for primary colorectal cancer provided that at least 6&#xD;
      months have elapsed from the time the adjuvant therapy was concluded and recurrent disease&#xD;
      was documented, Patients with history of hypertension must be well-controlled (blood pressure&#xD;
      less than/equal to 150/100), on a stable regimen of anti-hypertensive therapy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a Phase III, randomized, two arms, double-blind (patient and assessor blinded),&#xD;
      parallel active non inferiority controlled clinical trial with a 2:1 allocation. This trial&#xD;
      was conducted to evaluate the efficacy and safety of bevacizumab (produced by AryoGen) plus&#xD;
      FOLFIRI-3 compared with bevacizumab (Avastin®) plus FOLFIRI-3 in patients with metastatic&#xD;
      colorectal cancer (mCRC). Patients who met the following criteria could be recruited to&#xD;
      receive the mentioned intervention randomly. Inclusion criteria: male or female aged 18-75&#xD;
      years, mCRC verified histologically, Having one or more bi-dimensionally measurable lesions&#xD;
      as defined by Response Evaluation Criteria In Solid Tumors (RECIST) criteria, Was not felt to&#xD;
      be amenable to curative resection, With an (ECOG) performance status of ≤ 1, Life expectancy&#xD;
      of longer than 3 months, Adequate organ and marrow function, May have received adjuvant&#xD;
      therapy for primary colorectal cancer provided that at least 6 months have elapsed from the&#xD;
      time the adjuvant therapy was concluded and recurrent disease was documented, Patients with&#xD;
      history of hypertension must be well-controlled (blood pressure less than/equal to 150/100),&#xD;
      on a stable regimen of anti-hypertensive therapy. Exclusion criteria: Prior targeted therapy&#xD;
      for mCRC, Radiotherapy or surgery for mCRC less than 4 weeks before random assignment,&#xD;
      Undergone major surgical procedures or open biopsy within 28 days before the initiation of&#xD;
      study treatment, Experienced significant traumatic injury, within 28 days before study entry,&#xD;
      Currently using or had recently used therapeutic anticoagulants, thrombolytic therapy,&#xD;
      chronic, daily treatment with aspirin (higher than 325 mg/daily), Proteinuria exceeding&#xD;
      500mg/24 h, History or presence of central nervous system metastases, Female patients who are&#xD;
      pregnant or lactating, Patients with a history of allergic reactions attributed to compounds&#xD;
      of similar chemical or biologic composition to bevacizumab, irinotecan, 5-FU, or leucovorin,&#xD;
      Serious non-healing wound, ulcer, or active bone fracture, Myocardial infarction within 6&#xD;
      months before of study enrollment, History of stroke within 6 months before of study&#xD;
      enrollment, Unstable symptomatic arrhythmia requiring medication, Clinically significant&#xD;
      peripheral vascular disease, Uncontrolled diabetes; Serious active or uncontrolled infection,&#xD;
      Inability to comply with study and/or follow-up procedures. The primary endpoint is&#xD;
      progression-free survival and overall survival, Objective Response rate, time of treatment&#xD;
      failures, adverse events and immunogenicity will be assessed as secondary outcomes.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 4, 2016</start_date>
  <completion_date type="Actual">July 30, 2018</completion_date>
  <primary_completion_date type="Actual">July 30, 2018</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>PFS was measured from the start of chemotherapy to the date of disease progression or to the date of death if no progression whichever came first, assessed up to 12 months</time_frame>
    <description>PFS is defined as the time from the date of randomization to the first date of documentation progression (per investigator assessment) or death as a result of any cause.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Overall survival OS was defined as the time from date of randomization to date of death due to any cause</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective Response Rate</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Tumor response was defined as partial and complete responses, according to the RECIST criteria ( version 1.1). The definitions were as follows: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), decrease of at least 30% in the lesion that has the largest diameter; Objective Response Rate (ORR) = CR + PR.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Treatment Failure</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Time to treatment failure was defined as the time from the date of randomization to the date of each of the following,&#xD;
The treatment modalities did not destroy or modify the cancer cells,&#xD;
The tumor either became larger (disease progression) or stayed the same size after treatment,&#xD;
Death due to any cause,&#xD;
Discontinuation of treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of the Adverse Events</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Safety was assessed on the basis of reports of adverse events, laboratory-test results, and vital sign measurements. Adverse events were categorized According to the Common Toxicity Criteria of the National Cancer Institute, version 5.0, in which a grade of 1 indicates mild adverse events, a grade of 2 moderate adverse events, a grade of 3 serious adverse events, and a grade of 4 life-threatening adverse events</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Positive Anti-drug Antibody (ADA) Samples Among Patients (Immunogenicity)</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Anti-drug antibody assessment</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">126</enrollment>
  <condition>Metastatic Colorectal Cancer</condition>
  <arm_group>
    <arm_group_label>Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (AryoGen) 5 mg/kg will be administered every 2 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Bevacizumab + FOLFIRI-3 (Roche Bevacizumab)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (Avastin®) 5 mg/kg will be administered every 2 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bevacizumab + FOLFIRI-3</intervention_name>
    <description>Bevacizumab 5 mg/kg will be administered at day 1 every 2 weeks. Initially, it will be administered as a 90-min infusion. If the first infusion is well tolerated, the second will be delivered as a 60-min infusion, and if the 60-min infusion is well tolerated, all subsequent infusions will be given over 30 minutes. FOLFIRI-3 regimen consists of irinotecan 100 mg/m2 over 1 hour at day 1, leucovorin 400 mg/m2 at day 1 followed by a 46 hour 5-FU continuous infusion (2000 mg/m2) and irinotecan 100 mg/m2 over 1 hour on day 3 will administer. Induction treatment was administrated every 2 weeks until disease progression, unacceptable toxicities, surgical intervention, or withdrawal of consent.</description>
    <arm_group_label>Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab)</arm_group_label>
    <arm_group_label>Bevacizumab + FOLFIRI-3 (Roche Bevacizumab)</arm_group_label>
    <other_name>FOLFIRI-3 = irinotecan + calcium folinate + 5-fluorouracil</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Are male or female aged 18-75 years at the time of signing the informed consent form.&#xD;
&#xD;
          -  Have been diagnosed as mCRC verified histologically&#xD;
&#xD;
          -  Having one or more bi-dimensionally measurable lesions as defined by Response&#xD;
             Evaluation Criteria In Solid Tumors (RECIST) criteria,&#xD;
&#xD;
          -  Was not felt to be amenable to curative resection,&#xD;
&#xD;
          -  With an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1&#xD;
&#xD;
          -  Life expectancy of longer than 3 months ( clinical assessment)&#xD;
&#xD;
          -  Adequate organ and marrow function as defined below:&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) greater than/equal to 1,500/mm3;&#xD;
&#xD;
               -  Platelets greater than/equal to 100,000/ mm3;&#xD;
&#xD;
               -  Hemoglobin greater than/equal to 9 gm/dl (may be transfused to maintain or exceed&#xD;
                  this level);&#xD;
&#xD;
               -  Total bilirubin less than/equal to 1.5 within institutional upper limit of normal&#xD;
                  (IULN);&#xD;
&#xD;
               -  Aspartate aminotransferase (AST or SGOT)/alanine aminotransferase (ALT or SGPT)&#xD;
                  less than/equal to 2.5 times IULN, or less than/equal to 5 times IULN if known&#xD;
                  liver metastases;&#xD;
&#xD;
          -  May have received adjuvant therapy for primary colorectal cancer provided that at&#xD;
             least 6 months have elapsed from the time the adjuvant therapy was concluded and&#xD;
             recurrent disease was documented&#xD;
&#xD;
          -  Patients with history of hypertension must be well-controlled (blood pressure less&#xD;
             than/equal to 150/100), on a stable regimen of anti-hypertensive therapy.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior targeted therapy for mCRC&#xD;
&#xD;
          -  Radiotherapy or surgery for mCRC less than 4 weeks before random assignment.&#xD;
&#xD;
          -  Undergone major surgical procedures or open biopsy within 28 days before the&#xD;
             initiation of study treatment&#xD;
&#xD;
          -  Experienced significant traumatic injury, within 28 days before study entry&#xD;
&#xD;
          -  Currently using or had recently used therapeutic anticoagulants, thrombolytic therapy,&#xD;
             chronic, daily treatment with aspirin (higher than 325 mg/daily). (Patients may have&#xD;
             prophylactic use of low molecular weight heparin, however therapeutic use of heparin&#xD;
             or low molecular weight heparin is not acceptable)&#xD;
&#xD;
          -  Proteinuria exceeding 500mg/24 h&#xD;
&#xD;
          -  History or presence of central nervous system metastases&#xD;
&#xD;
          -  Female patients who are pregnant or lactating&#xD;
&#xD;
          -  Patients with a history of allergic reactions attributed to compounds of similar&#xD;
             chemical or biologic composition to bevacizumab, irinotecan, 5-FU, or leucovorin&#xD;
&#xD;
          -  Serious non-healing wound, ulcer, or active bone fracture&#xD;
&#xD;
          -  Myocardial infarction within 6 months before of study enrollment;&#xD;
&#xD;
          -  History of stroke within 6 months before of study enrollment;&#xD;
&#xD;
          -  Clinically significant peripheral vascular disease;&#xD;
&#xD;
          -  Uncontrolled diabetes; Serious active or uncontrolled infection&#xD;
&#xD;
          -  Inability to comply with study and/or follow-up procedures&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Hamid Rezvani, M.D</last_name>
    <role>Principal Investigator</role>
    <affiliation>Shahid Beheshti University of Medical Sciences</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Shafa Hospital</name>
      <address>
        <city>Ahvaz</city>
        <country>Iran, Islamic Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Shahid Beheshti Hospital</name>
      <address>
        <city>Hamadān</city>
        <country>Iran, Islamic Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saba Clinic</name>
      <address>
        <city>Isfahan</city>
        <country>Iran, Islamic Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sheikh Mofid</name>
      <address>
        <city>Isfahan</city>
        <country>Iran, Islamic Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Payandeh Clinic</name>
      <address>
        <city>Kermanshah</city>
        <country>Iran, Islamic Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Shazad Clinic</name>
      <address>
        <city>Kermanshah</city>
        <country>Iran, Islamic Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Imam Reza Hospital</name>
      <address>
        <city>Mashhad</city>
        <country>Iran, Islamic Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Qaem Hospital</name>
      <address>
        <city>Mashhad</city>
        <country>Iran, Islamic Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rasool Hospital</name>
      <address>
        <city>Rasht</city>
        <country>Iran, Islamic Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Razi Hospital</name>
      <address>
        <city>Rasht</city>
        <country>Iran, Islamic Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Namazi Hospital</name>
      <address>
        <city>Shiraz</city>
        <country>Iran, Islamic Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Firoozgar Hospital</name>
      <address>
        <city>Tehran</city>
        <country>Iran, Islamic Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Imam Khomeini Hospital</name>
      <address>
        <city>Tehran</city>
        <country>Iran, Islamic Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Imam Reza Hospital (501 Artesh)</name>
      <address>
        <city>Tehran</city>
        <country>Iran, Islamic Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Masih Daneshvari Hospital</name>
      <address>
        <city>Tehran</city>
        <country>Iran, Islamic Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Masoud Internal Clinic</name>
      <address>
        <city>Tehran</city>
        <country>Iran, Islamic Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Safa najafi clinic</name>
      <address>
        <city>Tehran</city>
        <country>Iran, Islamic Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Shariati Hospital</name>
      <address>
        <city>Tehran</city>
        <country>Iran, Islamic Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sina Hospital</name>
      <address>
        <city>Tehran</city>
        <country>Iran, Islamic Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Taleqani Hospital</name>
      <address>
        <city>Tehran</city>
        <country>Iran, Islamic Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mortazavizadeh Clinic</name>
      <address>
        <city>Yazd</city>
        <country>Iran, Islamic Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Seyedshohada Hospital</name>
      <address>
        <city>Yazd</city>
        <country>Iran, Islamic Republic of</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Iran, Islamic Republic of</country>
  </location_countries>
  <link>
    <url>http://www.irct.ir/</url>
    <description>This protocol is registered according to program in Iran Registry of Clinical Trial (IRCT) with IRCT2015072517994N2 code</description>
  </link>
  <link>
    <url>http://pubmed.ncbi.nlm.nih.gov/32334845/</url>
    <description>Efficacy and Safety of Proposed Bevacizumab Biosimilar BE1040V in Patients With Metastatic Colorectal Cancer: A Phase III, Randomized, Double-blind, Noninferiority Clinical Trial</description>
  </link>
  <verification_date>September 2020</verification_date>
  <study_first_submitted>September 18, 2017</study_first_submitted>
  <study_first_submitted_qc>September 18, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 20, 2017</study_first_posted>
  <results_first_submitted>September 15, 2020</results_first_submitted>
  <results_first_submitted_qc>December 30, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">January 22, 2021</results_first_posted>
  <last_update_submitted>December 30, 2020</last_update_submitted>
  <last_update_submitted_qc>December 30, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">January 22, 2021</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>Leucovorin</mesh_term>
    <mesh_term>Bevacizumab</mesh_term>
    <mesh_term>Fluorouracil</mesh_term>
    <mesh_term>Irinotecan</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>July 3, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/87/NCT03288987/SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Study Protocol and Informed Consent Form</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>April 3, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/87/NCT03288987/Prot_ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab)</title>
          <description>Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (AryoGen) 5 mg/kg will be administered every 2 weeks.&#xD;
Bevacizumab + FOLFIRI-3: Bevacizumab 5 mg/kg will be administered at day 1 every 2 weeks. Initially, it will be administered as a 90-min infusion. If the first infusion is well tolerated, the second will be delivered as a 60-min infusion, and if the 60-min infusion is well tolerated, all subsequent infusions will be given over 30 minutes. FOLFIRI-3 regimen consists of irinotecan 100 mg/m2 over 1 hour at day 1, leucovorin 400 mg/m2 at day 1 followed by a 46 hour 5-FU continuous infusion (2000 mg/m2) and irinotecan 100 mg/m2 over 1 hour on day 3 will administer. Induction treatment was administrated every 2 weeks until disease progression, unacceptable toxicities, surgical intervention, or withdrawal of consent.</description>
        </group>
        <group group_id="P2">
          <title>Bevacizumab + FOLFIRI-3 (Roche Bevacizumab)</title>
          <description>Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (Avastin®) 5 mg/kg will be administered every 2 weeks.&#xD;
Bevacizumab + FOLFIRI-3: Bevacizumab 5 mg/kg will be administered at day 1 every 2 weeks. Initially, it will be administered as a 90-min infusion. If the first infusion is well tolerated, the second will be delivered as a 60-min infusion, and if the 60-min infusion is well tolerated, all subsequent infusions will be given over 30 minutes. FOLFIRI-3 regimen consists of irinotecan 100 mg/m2 over 1 hour at day 1, leucovorin 400 mg/m2 at day 1 followed by a 46 hour 5-FU continuous infusion (2000 mg/m2) and irinotecan 100 mg/m2 over 1 hour on day 3 will administer. Induction treatment was administrated every 2 weeks until disease progression, unacceptable toxicities, surgical intervention, or withdrawal of consent.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="82"/>
                <participants group_id="P2" count="44"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Patients Receiving Medication</title>
              <participants_list>
                <participants group_id="P1" count="80"/>
                <participants group_id="P2" count="44"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="72">Per protocol population</participants>
                <participants group_id="P2" count="40">Per protocol population</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab)</title>
          <description>Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (AryoGen) 5 mg/kg will be administered every 2 weeks.&#xD;
Bevacizumab + FOLFIRI-3: Bevacizumab 5 mg/kg will be administered at day 1 every 2 weeks. Initially, it will be administered as a 90-min infusion. If the first infusion is well tolerated, the second will be delivered as a 60-min infusion, and if the 60-min infusion is well tolerated, all subsequent infusions will be given over 30 minutes. FOLFIRI-3 regimen consists of irinotecan 100 mg/m2 over 1 hour at day 1, leucovorin 400 mg/m2 at day 1 followed by a 46 hour 5-FU continuous infusion (2000 mg/m2) and irinotecan 100 mg/m2 over 1 hour on day 3 will administer. Induction treatment was administrated every 2 weeks until disease progression, unacceptable toxicities, surgical intervention, or withdrawal of consent.</description>
        </group>
        <group group_id="B2">
          <title>Bevacizumab + FOLFIRI-3 (Roche Bevacizumab)</title>
          <description>Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (Avastin®) 5 mg/kg will be administered every 2 weeks.&#xD;
Bevacizumab + FOLFIRI-3: Bevacizumab 5 mg/kg will be administered at day 1 every 2 weeks. Initially, it will be administered as a 90-min infusion. If the first infusion is well tolerated, the second will be delivered as a 60-min infusion, and if the 60-min infusion is well tolerated, all subsequent infusions will be given over 30 minutes. FOLFIRI-3 regimen consists of irinotecan 100 mg/m2 over 1 hour at day 1, leucovorin 400 mg/m2 at day 1 followed by a 46 hour 5-FU continuous infusion (2000 mg/m2) and irinotecan 100 mg/m2 over 1 hour on day 3 will administer. Induction treatment was administrated every 2 weeks until disease progression, unacceptable toxicities, surgical intervention, or withdrawal of consent.</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="82"/>
            <count group_id="B2" value="44"/>
            <count group_id="B3" value="126"/>
          </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="56.26" spread="11.94"/>
                    <measurement group_id="B2" value="56.27" spread="13.12"/>
                    <measurement group_id="B3" value="56.26" spread="12.31"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="31"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="46"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="51"/>
                    <measurement group_id="B2" value="29"/>
                    <measurement group_id="B3" value="80"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="82"/>
                    <measurement group_id="B2" value="44"/>
                    <measurement group_id="B3" value="126"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Progression Free Survival (PFS)</title>
        <description>PFS is defined as the time from the date of randomization to the first date of documentation progression (per investigator assessment) or death as a result of any cause.</description>
        <time_frame>PFS was measured from the start of chemotherapy to the date of disease progression or to the date of death if no progression whichever came first, assessed up to 12 months</time_frame>
        <population>The population assessable for PFS was per protocol.</population>
        <group_list>
          <group group_id="O1">
            <title>Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab)</title>
            <description>Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (AryoGen) 5 mg/kg will be administered every 2 weeks.&#xD;
Bevacizumab + FOLFIRI-3: Bevacizumab 5 mg/kg will be administered at day 1 every 2 weeks. Initially, it will be administered as a 90-min infusion. If the first infusion is well tolerated, the second will be delivered as a 60-min infusion, and if the 60-min infusion is well tolerated, all subsequent infusions will be given over 30 minutes. FOLFIRI-3 regimen consists of irinotecan 100 mg/m2 over 1 hour at day 1, leucovorin 400 mg/m2 at day 1 followed by a 46 hour 5-FU continuous infusion (2000 mg/m2) and irinotecan 100 mg/m2 over 1 hour on day 3 will administer. Induction treatment was administrated every 2 weeks until disease progression, unacceptable toxicities, surgical intervention, or withdrawal of consent.</description>
          </group>
          <group group_id="O2">
            <title>Bevacizumab + FOLFIRI-3 (Roche Bevacizumab)</title>
            <description>Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (Avastin®) 5 mg/kg will be administered every 2 weeks.&#xD;
Bevacizumab + FOLFIRI-3: Bevacizumab 5 mg/kg will be administered at day 1 every 2 weeks. Initially, it will be administered as a 90-min infusion. If the first infusion is well tolerated, the second will be delivered as a 60-min infusion, and if the 60-min infusion is well tolerated, all subsequent infusions will be given over 30 minutes. FOLFIRI-3 regimen consists of irinotecan 100 mg/m2 over 1 hour at day 1, leucovorin 400 mg/m2 at day 1 followed by a 46 hour 5-FU continuous infusion (2000 mg/m2) and irinotecan 100 mg/m2 over 1 hour on day 3 will administer. Induction treatment was administrated every 2 weeks until disease progression, unacceptable toxicities, surgical intervention, or withdrawal of consent.</description>
          </group>
        </group_list>
        <measure>
          <title>Progression Free Survival (PFS)</title>
          <description>PFS is defined as the time from the date of randomization to the first date of documentation progression (per investigator assessment) or death as a result of any cause.</description>
          <population>The population assessable for PFS was per protocol.</population>
          <units>Day</units>
          <param>Median</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="72"/>
                <count group_id="O2" value="40"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="232" spread="NA">The median has been obtained from the KM (SPSS) using the 50th percentile and the standard error from the 45th percentile. However, it was not possible to compute the standard error (45th percentile) for AryoGen Bevacizumab because the data from the survival function did not reach the 45th percentile. This was possible for the Bevacizumab of Roche. Data should be seen in the publication of study results.</measurement>
                    <measurement group_id="O2" value="210" spread="12.21"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>Noninferiority was declared by comparing the 90% CI for the hazard ratio (HR) of the AryoGen Pharmed Bevacizumab to the reference product (Roche Bevacizumab) to the point-estimate margin and was based on the synthesis method.</non_inferiority_desc>
            <p_value>0.47</p_value>
            <method>Regression, Cox</method>
            <method_desc>Upper limit of CI is lower than the noninferiority margin (1.44).</method_desc>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>0.79</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.46</ci_lower_limit>
            <ci_upper_limit>1.35</ci_upper_limit>
            <estimate_desc>The 90 % CI based on synthesis method is (0.45,1.38). In HR calculation, the AryoGen Pharmed Bevacizumab to Roche Bevacizumab was reported. (reference group was Roche Bevacizumab)</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival (OS)</title>
        <description>Overall survival OS was defined as the time from date of randomization to date of death due to any cause</description>
        <time_frame>Up to 12 months</time_frame>
        <population>ITT population was used in this outcome analysis. The probability of overall survival in this study was higher than 50% in one year, so the calculation of median was not applicant.&#xD;
The number of death in both arms is reported.</population>
        <group_list>
          <group group_id="O1">
            <title>Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab)</title>
            <description>Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (AryoGen) 5 mg/kg will be administered every 2 weeks.&#xD;
Bevacizumab + FOLFIRI-3: Bevacizumab 5 mg/kg will be administered at day 1 every 2 weeks. Initially, it will be administered as a 90-min infusion. If the first infusion is well tolerated, the second will be delivered as a 60-min infusion, and if the 60-min infusion is well tolerated, all subsequent infusions will be given over 30 minutes. FOLFIRI-3 regimen consists of irinotecan 100 mg/m2 over 1 hour at day 1, leucovorin 400 mg/m2 at day 1 followed by a 46 hour 5-FU continuous infusion (2000 mg/m2) and irinotecan 100 mg/m2 over 1 hour on day 3 will administer. Induction treatment was administrated every 2 weeks until disease progression, unacceptable toxicities, surgical intervention, or withdrawal of consent.</description>
          </group>
          <group group_id="O2">
            <title>Bevacizumab + FOLFIRI-3 (Roche Bevacizumab)</title>
            <description>Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (Avastin®) 5 mg/kg will be administered every 2 weeks.&#xD;
Bevacizumab + FOLFIRI-3: Bevacizumab 5 mg/kg will be administered at day 1 every 2 weeks. Initially, it will be administered as a 90-min infusion. If the first infusion is well tolerated, the second will be delivered as a 60-min infusion, and if the 60-min infusion is well tolerated, all subsequent infusions will be given over 30 minutes. FOLFIRI-3 regimen consists of irinotecan 100 mg/m2 over 1 hour at day 1, leucovorin 400 mg/m2 at day 1 followed by a 46 hour 5-FU continuous infusion (2000 mg/m2) and irinotecan 100 mg/m2 over 1 hour on day 3 will administer. Induction treatment was administrated every 2 weeks until disease progression, unacceptable toxicities, surgical intervention, or withdrawal of consent.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival (OS)</title>
          <description>Overall survival OS was defined as the time from date of randomization to date of death due to any cause</description>
          <population>ITT population was used in this outcome analysis. The probability of overall survival in this study was higher than 50% in one year, so the calculation of median was not applicant.&#xD;
The number of death in both arms is reported.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="82"/>
                <count group_id="O2" value="44"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="30"/>
                    <measurement group_id="O2" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.99</p_value>
            <method>Regression, Cox</method>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>0.99</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.55</ci_lower_limit>
            <ci_upper_limit>1.80</ci_upper_limit>
            <estimate_desc>In HR calculation, the AryoGen Pharmed Bevacizumab to Roche Bevacizumab was reported. (reference group was Roche Bevacizumab)</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Objective Response Rate</title>
        <description>Tumor response was defined as partial and complete responses, according to the RECIST criteria ( version 1.1). The definitions were as follows: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), decrease of at least 30% in the lesion that has the largest diameter; Objective Response Rate (ORR) = CR + PR.</description>
        <time_frame>Up to 12 months</time_frame>
        <population>Both baseline imaging and imaging at the time of withdrawal, could not be gathered in all patients. So ORR could be reported in the mentioned population in each treatment group.</population>
        <group_list>
          <group group_id="O1">
            <title>Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab)</title>
            <description>Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (AryoGen) 5 mg/kg will be administered every 2 weeks.&#xD;
Bevacizumab + FOLFIRI-3: Bevacizumab 5 mg/kg will be administered at day 1 every 2 weeks. Initially, it will be administered as a 90-min infusion. If the first infusion is well tolerated, the second will be delivered as a 60-min infusion, and if the 60-min infusion is well tolerated, all subsequent infusions will be given over 30 minutes. FOLFIRI-3 regimen consists of irinotecan 100 mg/m2 over 1 hour at day 1, leucovorin 400 mg/m2 at day 1 followed by a 46 hour 5-FU continuous infusion (2000 mg/m2) and irinotecan 100 mg/m2 over 1 hour on day 3 will administer. Induction treatment was administrated every 2 weeks until disease progression, unacceptable toxicities, surgical intervention, or withdrawal of consent.</description>
          </group>
          <group group_id="O2">
            <title>Bevacizumab + FOLFIRI-3 (Roche Bevacizumab)</title>
            <description>Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (Avastin®) 5 mg/kg will be administered every 2 weeks.&#xD;
Bevacizumab + FOLFIRI-3: Bevacizumab 5 mg/kg will be administered at day 1 every 2 weeks. Initially, it will be administered as a 90-min infusion. If the first infusion is well tolerated, the second will be delivered as a 60-min infusion, and if the 60-min infusion is well tolerated, all subsequent infusions will be given over 30 minutes. FOLFIRI-3 regimen consists of irinotecan 100 mg/m2 over 1 hour at day 1, leucovorin 400 mg/m2 at day 1 followed by a 46 hour 5-FU continuous infusion (2000 mg/m2) and irinotecan 100 mg/m2 over 1 hour on day 3 will administer. Induction treatment was administrated every 2 weeks until disease progression, unacceptable toxicities, surgical intervention, or withdrawal of consent.</description>
          </group>
        </group_list>
        <measure>
          <title>Objective Response Rate</title>
          <description>Tumor response was defined as partial and complete responses, according to the RECIST criteria ( version 1.1). The definitions were as follows: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), decrease of at least 30% in the lesion that has the largest diameter; Objective Response Rate (ORR) = CR + PR.</description>
          <population>Both baseline imaging and imaging at the time of withdrawal, could not be gathered in all patients. So ORR could be reported in the mentioned population in each treatment group.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="42"/>
                <count group_id="O2" value="23"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="17"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.17</p_value>
            <method>Fisher's Exact Test</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time to Treatment Failure</title>
        <description>Time to treatment failure was defined as the time from the date of randomization to the date of each of the following,&#xD;
The treatment modalities did not destroy or modify the cancer cells,&#xD;
The tumor either became larger (disease progression) or stayed the same size after treatment,&#xD;
Death due to any cause,&#xD;
Discontinuation of treatment</description>
        <time_frame>Up to 12 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab)</title>
            <description>Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (AryoGen) 5 mg/kg will be administered every 2 weeks.&#xD;
Bevacizumab + FOLFIRI-3: Bevacizumab 5 mg/kg will be administered at day 1 every 2 weeks. Initially, it will be administered as a 90-min infusion. If the first infusion is well tolerated, the second will be delivered as a 60-min infusion, and if the 60-min infusion is well tolerated, all subsequent infusions will be given over 30 minutes. FOLFIRI-3 regimen consists of irinotecan 100 mg/m2 over 1 hour at day 1, leucovorin 400 mg/m2 at day 1 followed by a 46 hour 5-FU continuous infusion (2000 mg/m2) and irinotecan 100 mg/m2 over 1 hour on day 3 will administer. Induction treatment was administrated every 2 weeks until disease progression, unacceptable toxicities, surgical intervention, or withdrawal of consent.</description>
          </group>
          <group group_id="O2">
            <title>Bevacizumab + FOLFIRI-3 (Roche Bevacizumab)</title>
            <description>Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (Avastin®) 5 mg/kg will be administered every 2 weeks.&#xD;
Bevacizumab + FOLFIRI-3: Bevacizumab 5 mg/kg will be administered at day 1 every 2 weeks. Initially, it will be administered as a 90-min infusion. If the first infusion is well tolerated, the second will be delivered as a 60-min infusion, and if the 60-min infusion is well tolerated, all subsequent infusions will be given over 30 minutes. FOLFIRI-3 regimen consists of irinotecan 100 mg/m2 over 1 hour at day 1, leucovorin 400 mg/m2 at day 1 followed by a 46 hour 5-FU continuous infusion (2000 mg/m2) and irinotecan 100 mg/m2 over 1 hour on day 3 will administer. Induction treatment was administrated every 2 weeks until disease progression, unacceptable toxicities, surgical intervention, or withdrawal of consent.</description>
          </group>
        </group_list>
        <measure>
          <title>Time to Treatment Failure</title>
          <description>Time to treatment failure was defined as the time from the date of randomization to the date of each of the following,&#xD;
The treatment modalities did not destroy or modify the cancer cells,&#xD;
The tumor either became larger (disease progression) or stayed the same size after treatment,&#xD;
Death due to any cause,&#xD;
Discontinuation of treatment</description>
          <units>Day</units>
          <param>Median</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="80"/>
                <count group_id="O2" value="44"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="73" spread="9.39"/>
                    <measurement group_id="O2" value="73" spread="9.12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.59</p_value>
            <method>Regression, Cox</method>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>1.11</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.76</ci_lower_limit>
            <ci_upper_limit>1.61</ci_upper_limit>
            <estimate_desc>In HR calculation, the AryoGen Pharmed Bevacizumab to Roche Bevacizumab was reported. (reference group was Roche Bevacizumab)</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Incidence of the Adverse Events</title>
        <description>Safety was assessed on the basis of reports of adverse events, laboratory-test results, and vital sign measurements. Adverse events were categorized According to the Common Toxicity Criteria of the National Cancer Institute, version 5.0, in which a grade of 1 indicates mild adverse events, a grade of 2 moderate adverse events, a grade of 3 serious adverse events, and a grade of 4 life-threatening adverse events</description>
        <time_frame>Up to 12 months</time_frame>
        <population>A total of 124 patients were analyzed for AEs. since two patients did not receive study medication and were not included in the safety population.</population>
        <group_list>
          <group group_id="O1">
            <title>Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab)</title>
            <description>Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (AryoGen) 5 mg/kg will be administered every 2 weeks.&#xD;
Bevacizumab + FOLFIRI-3: Bevacizumab 5 mg/kg will be administered at day 1 every 2 weeks. Initially, it will be administered as a 90-min infusion. If the first infusion is well tolerated, the second will be delivered as a 60-min infusion, and if the 60-min infusion is well tolerated, all subsequent infusions will be given over 30 minutes. FOLFIRI-3 regimen consists of irinotecan 100 mg/m2 over 1 hour at day 1, leucovorin 400 mg/m2 at day 1 followed by a 46 hour 5-FU continuous infusion (2000 mg/m2) and irinotecan 100 mg/m2 over 1 hour on day 3 will administer. Induction treatment was administrated every 2 weeks until disease progression, unacceptable toxicities, surgical intervention, or withdrawal of consent.</description>
          </group>
          <group group_id="O2">
            <title>Bevacizumab + FOLFIRI-3 (Roche Bevacizumab)</title>
            <description>Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (Avastin®) 5 mg/kg will be administered every 2 weeks.&#xD;
Bevacizumab + FOLFIRI-3: Bevacizumab 5 mg/kg will be administered at day 1 every 2 weeks. Initially, it will be administered as a 90-min infusion. If the first infusion is well tolerated, the second will be delivered as a 60-min infusion, and if the 60-min infusion is well tolerated, all subsequent infusions will be given over 30 minutes. FOLFIRI-3 regimen consists of irinotecan 100 mg/m2 over 1 hour at day 1, leucovorin 400 mg/m2 at day 1 followed by a 46 hour 5-FU continuous infusion (2000 mg/m2) and irinotecan 100 mg/m2 over 1 hour on day 3 will administer. Induction treatment was administrated every 2 weeks until disease progression, unacceptable toxicities, surgical intervention, or withdrawal of consent.</description>
          </group>
        </group_list>
        <measure>
          <title>Incidence of the Adverse Events</title>
          <description>Safety was assessed on the basis of reports of adverse events, laboratory-test results, and vital sign measurements. Adverse events were categorized According to the Common Toxicity Criteria of the National Cancer Institute, version 5.0, in which a grade of 1 indicates mild adverse events, a grade of 2 moderate adverse events, a grade of 3 serious adverse events, and a grade of 4 life-threatening adverse events</description>
          <population>A total of 124 patients were analyzed for AEs. since two patients did not receive study medication and were not included in the safety population.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="80"/>
                <count group_id="O2" value="44"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="76"/>
                    <measurement group_id="O2" value="44"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>&gt;0.05</p_value>
            <method>Fisher's Exact Test</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Positive Anti-drug Antibody (ADA) Samples Among Patients (Immunogenicity)</title>
        <description>Anti-drug antibody assessment</description>
        <time_frame>Up to 12 months</time_frame>
        <population>Positive ADA was reported in two patients.</population>
        <group_list>
          <group group_id="O1">
            <title>Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab)</title>
            <description>Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (AryoGen) 5 mg/kg will be administered every 2 weeks.&#xD;
Bevacizumab + FOLFIRI-3: Bevacizumab 5 mg/kg will be administered at day 1 every 2 weeks. Initially, it will be administered as a 90-min infusion. If the first infusion is well tolerated, the second will be delivered as a 60-min infusion, and if the 60-min infusion is well tolerated, all subsequent infusions will be given over 30 minutes. FOLFIRI-3 regimen consists of irinotecan 100 mg/m2 over 1 hour at day 1, leucovorin 400 mg/m2 at day 1 followed by a 46 hour 5-FU continuous infusion (2000 mg/m2) and irinotecan 100 mg/m2 over 1 hour on day 3 will administer. Induction treatment was administrated every 2 weeks until disease progression, unacceptable toxicities, surgical intervention, or withdrawal of consent.</description>
          </group>
          <group group_id="O2">
            <title>Bevacizumab + FOLFIRI-3 (Roche Bevacizumab)</title>
            <description>Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (Avastin®) 5 mg/kg will be administered every 2 weeks.&#xD;
Bevacizumab + FOLFIRI-3: Bevacizumab 5 mg/kg will be administered at day 1 every 2 weeks. Initially, it will be administered as a 90-min infusion. If the first infusion is well tolerated, the second will be delivered as a 60-min infusion, and if the 60-min infusion is well tolerated, all subsequent infusions will be given over 30 minutes. FOLFIRI-3 regimen consists of irinotecan 100 mg/m2 over 1 hour at day 1, leucovorin 400 mg/m2 at day 1 followed by a 46 hour 5-FU continuous infusion (2000 mg/m2) and irinotecan 100 mg/m2 over 1 hour on day 3 will administer. Induction treatment was administrated every 2 weeks until disease progression, unacceptable toxicities, surgical intervention, or withdrawal of consent.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Positive Anti-drug Antibody (ADA) Samples Among Patients (Immunogenicity)</title>
          <description>Anti-drug antibody assessment</description>
          <population>Positive ADA was reported in two patients.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="82"/>
                <count group_id="O2" value="44"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Up to 12 months</time_frame>
      <desc>The Safety Population included patients who received at least one dose of the investigational medicines. The different definition of the ITT (all patients who were randomized) should explain the inconsistency across the All-cause Mortality ( ITT population: 82 patients in the group treated with Bevacizumab AryoGen and 44 patients in the group Bevacizumab Roche) and SAE/ Other AE (Safety Population: 80 patients in the group Bevacizumab AryoGen and 44 patients in the group Bevacizumab Roche).</desc>
      <group_list>
        <group group_id="E1">
          <title>Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab)</title>
          <description>Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (AryoGen) 5 mg/kg will be administered every 2 weeks.&#xD;
Bevacizumab + FOLFIRI-3: Bevacizumab 5 mg/kg will be administered at day 1 every 2 weeks. Initially, it will be administered as a 90-min infusion. If the first infusion is well tolerated, the second will be delivered as a 60-min infusion, and if the 60-min infusion is well tolerated, all subsequent infusions will be given over 30 minutes. FOLFIRI-3 regimen consists of irinotecan 100 mg/m2 over 1 hour at day 1, leucovorin 400 mg/m2 at day 1 followed by a 46 hour 5-FU continuous infusion (2000 mg/m2) and irinotecan 100 mg/m2 over 1 hour on day 3 will administer. Induction treatment was administrated every 2 weeks until disease progression, unacceptable toxicities, surgical intervention, or withdrawal of consent.</description>
        </group>
        <group group_id="E2">
          <title>Bevacizumab + FOLFIRI-3 (Roche Bevacizumab)</title>
          <description>Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (Avastin®) 5 mg/kg will be administered every 2 weeks.&#xD;
Bevacizumab + FOLFIRI-3: Bevacizumab 5 mg/kg will be administered at day 1 every 2 weeks. Initially, it will be administered as a 90-min infusion. If the first infusion is well tolerated, the second will be delivered as a 60-min infusion, and if the 60-min infusion is well tolerated, all subsequent infusions will be given over 30 minutes. FOLFIRI-3 regimen consists of irinotecan 100 mg/m2 over 1 hour at day 1, leucovorin 400 mg/m2 at day 1 followed by a 46 hour 5-FU continuous infusion (2000 mg/m2) and irinotecan 100 mg/m2 over 1 hour on day 3 will administer. Induction treatment was administrated every 2 weeks until disease progression, unacceptable toxicities, surgical intervention, or withdrawal of consent.</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="30" subjects_at_risk="82"/>
                <counts group_id="E2" subjects_affected="17" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="31" subjects_at_risk="80"/>
                <counts group_id="E2" subjects_affected="17" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Myocardial infarction</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Gastrointestinal haemorrhage</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Peritonitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Disease progression</sub_title>
                <counts group_id="E1" events="25" subjects_affected="25" subjects_at_risk="80"/>
                <counts group_id="E2" events="15" subjects_affected="15" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Perforation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Abdominal infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="80"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Opioid abuse</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute kidney injury</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Embolism</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <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="75" subjects_at_risk="80"/>
                <counts group_id="E2" subjects_affected="42" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" events="131" subjects_affected="62" subjects_at_risk="80"/>
                <counts group_id="E2" events="76" subjects_affected="37" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Leukopenia</sub_title>
                <counts group_id="E1" events="42" subjects_affected="22" subjects_at_risk="80"/>
                <counts group_id="E2" events="25" subjects_affected="19" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" events="46" subjects_affected="25" subjects_at_risk="80"/>
                <counts group_id="E2" events="26" subjects_affected="15" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Thrombocytopenia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="80"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Bradycardia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Chest pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Palpitations</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Tachycardia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Vertigo</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Diabetic foot</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Hyperglycaemia</sub_title>
                <counts group_id="E1" events="67" subjects_affected="43" subjects_at_risk="80"/>
                <counts group_id="E2" events="50" subjects_affected="28" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal discomfort</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Abdominal distension</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="11" subjects_affected="10" subjects_at_risk="80"/>
                <counts group_id="E2" events="4" subjects_affected="3" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Abdominal pain lower</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Aphthous ulcer</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Ascites</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="10" subjects_affected="6" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" events="8" subjects_affected="7" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Dyschezia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="80"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Haematochezia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Mouth ulceration</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="80"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="27" subjects_affected="14" subjects_at_risk="80"/>
                <counts group_id="E2" events="7" subjects_affected="6" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Proctalgia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Rectal haemorrhage</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="80"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="8" subjects_affected="7" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Asthenia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Drug intolerance</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Hypothermia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Influenza like illness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="80"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Xerosis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Jaundice</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="33" subjects_affected="22" subjects_at_risk="80"/>
                <counts group_id="E2" events="13" subjects_affected="9" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" events="34" subjects_affected="24" subjects_at_risk="80"/>
                <counts group_id="E2" events="14" subjects_affected="9" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" events="16" subjects_affected="10" subjects_at_risk="80"/>
                <counts group_id="E2" events="9" subjects_affected="9" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Blood creatinine increased</sub_title>
                <counts group_id="E1" events="10" subjects_affected="5" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Hepatic enzyme increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>International normalised ratio increased</sub_title>
                <counts group_id="E1" events="36" subjects_affected="20" subjects_at_risk="80"/>
                <counts group_id="E2" events="15" subjects_affected="11" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Lymphocyte count abnormal</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="80"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="13" subjects_affected="11" subjects_at_risk="80"/>
                <counts group_id="E2" events="5" subjects_affected="3" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="10" subjects_affected="10" subjects_at_risk="80"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Weight decreased</sub_title>
                <counts group_id="E1" events="10" subjects_affected="9" subjects_at_risk="80"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>White blood cells urine positive</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="80"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Hyperkalaemia</sub_title>
                <counts group_id="E1" events="6" subjects_affected="5" subjects_at_risk="80"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Hypernatraemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Hypokalaemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="80"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Hyponatraemia</sub_title>
                <counts group_id="E1" events="9" subjects_affected="8" subjects_at_risk="80"/>
                <counts group_id="E2" events="12" subjects_affected="9" subjects_at_risk="44"/>
              </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" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="80"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Dysphonia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="80"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Neuralgia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="80"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Tachyphrenia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="80"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Haematuria</sub_title>
                <counts group_id="E1" events="25" subjects_affected="13" subjects_at_risk="80"/>
                <counts group_id="E2" events="8" subjects_affected="7" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Polyuria</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="80"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Proteinuria</sub_title>
                <counts group_id="E1" events="32" subjects_affected="18" subjects_at_risk="80"/>
                <counts group_id="E2" events="15" subjects_affected="12" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Breast pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="80"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Bradypnoea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="80"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="80"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Tachypnoea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Wheezing</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Acne</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="80"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Skin wound</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Arteritis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="80"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Haemorrhoids</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="19" subjects_affected="11" subjects_at_risk="80"/>
                <counts group_id="E2" events="8" subjects_affected="5" subjects_at_risk="44"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="80"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="44"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Nasim Anjidani (Director of Medical- Clinical Trials)</name_or_title>
      <organization>Aryogen</organization>
      <phone>009809125477964</phone>
      <email>anjidani.n@orchidpharmed.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/NCT03288987
org study id: BEV.ARY.HR.94 (III)
nct id: NCT03288987
lead sponsor: 
This is a Phase III, randomized, two arms, double-blind (patient and assessor blinded),
      parallel active non inferiority controlled clinical trial with a 2:1 allocation. This trial
      was conducted to evaluate the efficacy and safety of bevacizumab (produced by AryoGen
      Pharmed) plus FOLFIRI-3 compared with bevacizumab (Avastin®) plus FOLFIRI-3 in patients with
      metastatic colorectal cancer (mCRC). Patients who met the following criteria could be
      recruited to receive the mentioned intervention randomly. Inclusion criteria: male or female
      aged 18-75 years, mCRC verified histologically, Having one or more bi-dimensionally
      measurable lesions as defined by Response Evaluation Criteria In Solid Tumors (RECIST)
      criteria, Was not felt to be amenable to curative resection, With an (ECOG) performance
      status of ≤ 1, Life expectancy of longer than 3 months, Adequate organ and marrow function,
      May have received adjuvant therapy for primary colorectal cancer provided that at least 6
      months have elapsed from the time the adjuvant therapy was concluded and recurrent disease
      was documented, Patients with history of hypertension must be well-controlled (blood pressure
      less than/equal to 150/100), on a stable regimen of anti-hypertensive therapy.
This is a Phase III, randomized, two arms, double-blind (patient and assessor blinded),
      parallel active non inferiority controlled clinical trial with a 2:1 allocation. This trial
      was conducted to evaluate the efficacy and safety of bevacizumab (produced by AryoGen) plus
      FOLFIRI-3 compared with bevacizumab (Avastin®) plus FOLFIRI-3 in patients with metastatic
      colorectal cancer (mCRC). Patients who met the following criteria could be recruited to
      receive the mentioned intervention randomly. Inclusion criteria: male or female aged 18-75
      years, mCRC verified histologically, Having one or more bi-dimensionally measurable lesions
      as defined by Response Evaluation Criteria In Solid Tumors (RECIST) criteria, Was not felt to
      be amenable to curative resection, With an (ECOG) performance status of ≤ 1, Life expectancy
      of longer than 3 months, Adequate organ and marrow function, May have received adjuvant
      therapy for primary colorectal cancer provided that at least 6 months have elapsed from the
      time the adjuvant therapy was concluded and recurrent disease was documented, Patients with
      history of hypertension must be well-controlled (blood pressure less than/equal to 150/100),
      on a stable regimen of anti-hypertensive therapy. Exclusion criteria: Prior targeted therapy
      for mCRC, Radiotherapy or surgery for mCRC less than 4 weeks before random assignment,
      Undergone major surgical procedures or open biopsy within 28 days before the initiation of
      study treatment, Experienced significant traumatic injury, within 28 days before study entry,
      Currently using or had recently used therapeutic anticoagulants, thrombolytic therapy,
      chronic, daily treatment with aspirin (higher than 325 mg/daily), Proteinuria exceeding
      500mg/24 h, History or presence of central nervous system metastases, Female patients who are
      pregnant or lactating, Patients with a history of allergic reactions attributed to compounds
      of similar chemical or biologic composition to bevacizumab, irinotecan, 5-FU, or leucovorin,
      Serious non-healing wound, ulcer, or active bone fracture, Myocardial infarction within 6
      months before of study enrollment, History of stroke within 6 months before of study
      enrollment, Unstable symptomatic arrhythmia requiring medication, Clinically significant
      peripheral vascular disease, Uncontrolled diabetes; Serious active or uncontrolled infection,
      Inability to comply with study and/or follow-up procedures. The primary endpoint is
      progression-free survival and overall survival, Objective Response rate, time of treatment
      failures, adverse events and immunogenicity will be assessed as secondary outcomes.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Progression Free Survival (PFS)
time frame: PFS was measured from the start of chemotherapy to the date of disease progression or to the date of death if no progression whichever came first, assessed up to 12 months
description: PFS is defined as the time from the date of randomization to the first date of documentation progression (per investigator assessment) or death as a result of any cause.
measure: Overall Survival (OS)
time frame: Up to 12 months
description: Overall survival OS was defined as the time from date of randomization to date of death due to any cause
measure: Objective Response Rate
time frame: Up to 12 months
description: Tumor response was defined as partial and complete responses, according to the RECIST criteria ( version 1.1). The definitions were as follows: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), decrease of at least 30% in the lesion that has the largest diameter; Objective Response Rate (ORR) = CR + PR.
measure: Time to Treatment Failure
time frame: Up to 12 months
description: Time to treatment failure was defined as the time from the date of randomization to the date of each of the following,
The treatment modalities did not destroy or modify the cancer cells,
The tumor either became larger (disease progression) or stayed the same size after treatment,
Death due to any cause,
Discontinuation of treatment
measure: Incidence of the Adverse Events
time frame: Up to 12 months
description: Safety was assessed on the basis of reports of adverse events, laboratory-test results, and vital sign measurements. Adverse events were categorized According to the Common Toxicity Criteria of the National Cancer Institute, version 5.0, in which a grade of 1 indicates mild adverse events, a grade of 2 moderate adverse events, a grade of 3 serious adverse events, and a grade of 4 life-threatening adverse events
measure: Number of Positive Anti-drug Antibody (ADA) Samples Among Patients (Immunogenicity)
time frame: Up to 12 months
description: Anti-drug antibody assessment
arm group label: Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab)
arm group type: Experimental
description: Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (AryoGen) 5 mg/kg will be administered every 2 weeks.
arm group label: Bevacizumab + FOLFIRI-3 (Roche Bevacizumab)
arm group type: Active Comparator
description: Bevacizumab+FOLFIRI-3 (irinotecan, leucovorin, and 5-FU). Bevacizumab (Avastin®) 5 mg/kg will be administered every 2 weeks.
intervention type: Drug
intervention name: Bevacizumab + FOLFIRI-3
description: Bevacizumab 5 mg/kg will be administered at day 1 every 2 weeks. Initially, it will be administered as a 90-min infusion. If the first infusion is well tolerated, the second will be delivered as a 60-min infusion, and if the 60-min infusion is well tolerated, all subsequent infusions will be given over 30 minutes. FOLFIRI-3 regimen consists of irinotecan 100 mg/m2 over 1 hour at day 1, leucovorin 400 mg/m2 at day 1 followed by a 46 hour 5-FU continuous infusion (2000 mg/m2) and irinotecan 100 mg/m2 over 1 hour on day 3 will administer. Induction treatment was administrated every 2 weeks until disease progression, unacceptable toxicities, surgical intervention, or withdrawal of consent.
arm group label: Bevacizumab + FOLFIRI-3 (AryoGen Pharmed Bevacizumab)
arm group label: Bevacizumab + FOLFIRI-3 (Roche Bevacizumab)
other name: FOLFIRI-3 = irinotecan + calcium folinate + 5-fluorouracil
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Hamid Rezvani, M.D
role: Principal Investigator
affiliation: Shahid Beheshti University of Medical Sciences
facility: 
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country: Iran, Islamic Republic of
url: http://www.irct.ir/
description: This protocol is registered according to program in Iran Registry of Clinical Trial (IRCT) with IRCT2015072517994N2 code
url: http://pubmed.ncbi.nlm.nih.gov/32334845/
description: Efficacy and Safety of Proposed Bevacizumab Biosimilar BE1040V in Patients With Metastatic Colorectal Cancer: A Phase III, Randomized, Double-blind, Noninferiority Clinical Trial
responsible party type: Sponsor
mesh term: Colorectal Neoplasms
mesh term: Leucovorin
mesh term: Bevacizumab
mesh term: Fluorouracil
mesh term: Irinotecan
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 