<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/NCT04403685</url>
  </required_header>
  <id_info>
    <org_study_id>TOCIBRAS</org_study_id>
    <nct_id>NCT04403685</nct_id>
  </id_info>
  <brief_title>Safety and Efficacy of Tocilizumab in Moderate to Severe COVID-19 With Inflammatory Markers</brief_title>
  <acronym>TOCIBRAS</acronym>
  <official_title>Safety and Efficacy of Tocilizumab in Moderate to Severe COVID-19 and Increased Inflammatory Markers: a Phase III Randomized Clinical Trial (COVID-19 Coalition Brazil VI) (TOCIBRAS)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Beneficência Portuguesa de São Paulo</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Hospital do Coracao</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Hospital Israelita Albert Einstein</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Hospital Sirio-Libanes</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Hospital Alemão Oswaldo Cruz</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Brazilian Research In Intensive Care Network</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Hospital Moinhos de Vento</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Brazilian Clinical Research Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Federal University of São Paulo</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Beneficência Portuguesa de São Paulo</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The trial evaluates the efficacy and safety of Tocilizumab, which rapidly reduces the&#xD;
      inflammation process through inhibition of IL-6 in patients with moderate to severe COVID-19&#xD;
      with increased inflammatory markers. There will be two arms in the trial, one receiving the&#xD;
      best supportive care, and the other receiving it plus tocilizumab. Patients will be followed&#xD;
      until Day 29 after randomization.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Coalition VI (TOCIBRÁS) is a prospective phase III randomized controlled trial that evaluates&#xD;
      the efficacy and safety of Tocilizumab, an antibody anti-IL-6 receptor in patients with&#xD;
      moderate to severe COVID-19 with increased inflammatory markers. This is a superiority&#xD;
      open-label study with two arms. The control arm receives the best supportive care, and the&#xD;
      experimental receives it plus tocilizumab. Randomization is done centrally by REDCap 1:1.&#xD;
      Patients will be followed until Day 29 after randomization.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Safety&#xD;
  </why_stopped>
  <start_date type="Actual">May 8, 2020</start_date>
  <completion_date type="Actual">July 21, 2020</completion_date>
  <primary_completion_date type="Actual">July 8, 2020</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>
    <intervention_model_description>Prospective, randomized, superiority, open-label, controlled trial. Randomization 1:1 to best supportive care (BSC) versus Tocilizumab + BSC</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Evaluation of clinical status</measure>
    <time_frame>Day 15 of the trial</time_frame>
    <description>Evaluation of clinical status of patients on day 15 after randomization, defined by the Ordinal Scale of 7 points (score ranges from 1 to 7, with 7 being the worst score)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>All-cause mortality</measure>
    <time_frame>29 days after the randomization</time_frame>
    <description>All-cause mortality from randomization to day 28</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hospital Mortality</measure>
    <time_frame>29 days after the randomization</time_frame>
    <description>Deaths that occur during hospital admission.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Improvement of Sequential Sepsis-related Organ Failure Assessment (SOFA) scale</measure>
    <time_frame>29 days after the randomization (evaluations at D8 and D15)</time_frame>
    <description>Improvement of SOFA scale of patients at day 8, 15 and 29 after randomization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluation of clinical status</measure>
    <time_frame>29 days after the randomization (evaluations at D8 and D29)</time_frame>
    <description>Evaluation of clinical status of patients on the day 8, 22 and 29 after randomization, defined by the Ordinal Scale of 7 points (score ranges from 1 to 7, with 7 being the worst score)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ventilator free days</measure>
    <time_frame>29 days after the randomization</time_frame>
    <description>Days alive and free from mechanical ventilation since randomization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time until oxygen support independence</measure>
    <time_frame>29 days after the randomization</time_frame>
    <description>Days from randomization to independence of oxygen support</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Need of mechanical ventilation support</measure>
    <time_frame>29 days after the randomization</time_frame>
    <description>Number of patients that were not at mechanical ventilation at randomization and that required that support.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Days to mechanical ventilation support.</measure>
    <time_frame>29 days after the randomization</time_frame>
    <description>Number of days to mechanical ventilation for patients that were not receiving it at randomization.&#xD;
For patients that were not in mechanical ventilation at randomization: number of days until that support was required.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of hospitalization</measure>
    <time_frame>29 days after the randomization</time_frame>
    <description>Lenght of hospitalization stay in survivors (in days)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Other infections</measure>
    <time_frame>29 days after the randomization</time_frame>
    <description>Incidence of other infections (aside from SARS-CoV 2)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of thromboembolic events</measure>
    <time_frame>29 days after the randomization</time_frame>
    <description>Incidence of thromboembolic events in patients with COVID-19</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of adverse events</measure>
    <time_frame>29 days after the randomization (specific evaluations at D8, D15 and D29)</time_frame>
    <description>Evaluation of adverse events, as well as serious and unexpected adverse events</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Correlation of inflammatory tests and cytokines with clinical outcomes</measure>
    <time_frame>29 days after the randomization</time_frame>
    <description>Correlation of inflammatory tests and cytokines with clinical outcomes: clinical status (ordinal scale), time to oxygen support independence, ventilator free days, need of mechanical ventilation and mortality</description>
  </other_outcome>
  <other_outcome>
    <measure>Exploratory evaluation of laboratory exams during hospitalization</measure>
    <time_frame>29 days after the randomization</time_frame>
    <description>Evaluation the kinetics of hemostasia exams, inflammatory tests, cytokines, flow cytometry of blood cells, CBC, renal and liver exams</description>
  </other_outcome>
  <other_outcome>
    <measure>Evaluation of viral clearance of SARS-CoV2</measure>
    <time_frame>Day 8 and 15 after randomization</time_frame>
    <description>Evaluation of viral clearance of SARS-CoV2 using RT-PCR analysis of nasopharyngeal swab</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">129</enrollment>
  <condition>COVID</condition>
  <condition>SARS Pneumonia</condition>
  <condition>Cytokine Release Syndrome</condition>
  <arm_group>
    <arm_group_label>Tocilizumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Single-dose tocilizumab of 8 mg/kg (maximum dose of 800mg). Best supportive care.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control arm</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Best supportive care.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tocilizumab</intervention_name>
    <description>Single-dose infusion of 8 mg/kg. Maximum dose of 800 mg.</description>
    <arm_group_label>Tocilizumab</arm_group_label>
    <other_name>Actemra</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male and females with 18 years and older&#xD;
&#xD;
          -  Confirmed diagnosis of SARS-CoV 2 infection&#xD;
&#xD;
          -  More than 3 days of symptoms related to COVID-19&#xD;
&#xD;
          -  Computed tomography (or Chest X-Ray) with COVID-19 alterations&#xD;
&#xD;
          -  Both of the criteria&#xD;
&#xD;
               1. Need for oxygen supplementation to keep SPO2 &gt; 93% OR need for mechanical&#xD;
                  ventilation for less than 24 hours before the randomization&#xD;
&#xD;
               2. At least two of the following inflammatory tests above the cutoff :&#xD;
&#xD;
                    1. D-dimer &gt; 1,000 ng/mL&#xD;
&#xD;
                    2. Reactive C protein &gt; 5 mg/dL&#xD;
&#xD;
                    3. Ferritin &gt; 300 mg/dL&#xD;
&#xD;
                    4. Lactate dehydrogenase &gt; upper level limit&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Need for mechanical ventilation for 24 hours or more before the randomization&#xD;
&#xD;
          -  Hypersensitivity to tocilizumab&#xD;
&#xD;
          -  Patients without therapeutic perspective or in palliative care&#xD;
&#xD;
          -  Active non controlled infections&#xD;
&#xD;
          -  Other clinical conditions that contraindicate tocilizumab, according to the assistant&#xD;
             physician&#xD;
&#xD;
          -  Low neutrophils count (&lt; 0.5 x 109/L)&#xD;
&#xD;
          -  Low platelets count (&lt; 50 x 109/L)&#xD;
&#xD;
          -  Liver disease, cirrhosis or elevated AST or ALT above 5 times the upper level limit&#xD;
&#xD;
          -  Renal disease with estimate glomerular filtration below 30 mL/min/1.72 m2 (MDRD or&#xD;
             CKD-EPI scores)&#xD;
&#xD;
          -  Active diverticulitis&#xD;
&#xD;
          -  Breastfeeding women&#xD;
&#xD;
          -  Pregnancy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Viviane C Veiga, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Beneficência Portuguesa de Sao Paulo</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>UNIFESP</name>
      <address>
        <city>São Paulo</city>
        <state>Sao Paulo</state>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HCOR -Hospital do Coracao</name>
      <address>
        <city>Sao Paulo</city>
        <state>SP</state>
        <zip>04004030</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HAOC - Hospital Alemao Oswaldo Cruz</name>
      <address>
        <city>Sao Paulo</city>
        <zip>01323001</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Beneficência Portuguesa de Sao Paulo</name>
      <address>
        <city>Sao Paulo</city>
        <zip>01323900</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HAOC - Hospital Alemao Oswaldo Cruz - unidade Vergueiro</name>
      <address>
        <city>Sao Paulo</city>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HIAE - Hospital Israelita Albert Einstein</name>
      <address>
        <city>Sao Paulo</city>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HSL - Hospital Sírio Libanês</name>
      <address>
        <city>Sao Paulo</city>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Brazil</country>
  </location_countries>
  <verification_date>August 2020</verification_date>
  <study_first_submitted>May 24, 2020</study_first_submitted>
  <study_first_submitted_qc>May 24, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 27, 2020</study_first_posted>
  <last_update_submitted>August 22, 2020</last_update_submitted>
  <last_update_submitted_qc>August 22, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">August 26, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Beneficência Portuguesa de São Paulo</investigator_affiliation>
    <investigator_full_name>Dr Rozana Mesquita Ciconelli</investigator_full_name>
    <investigator_title>Head of research team</investigator_title>
  </responsible_party>
  <keyword>SARS-CoV 2</keyword>
  <keyword>SARS Pneumonia</keyword>
  <keyword>Tocilizumab</keyword>
  <keyword>Cytokine release syndrom</keyword>
  <keyword>Interleukin-6</keyword>
  <keyword>Hyperinflammation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pneumonia</mesh_term>
    <mesh_term>Cytokine Release Syndrome</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT04403685
org study id: TOCIBRAS
nct id: NCT04403685
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
The trial evaluates the efficacy and safety of Tocilizumab, which rapidly reduces the
      inflammation process through inhibition of IL-6 in patients with moderate to severe COVID-19
      with increased inflammatory markers. There will be two arms in the trial, one receiving the
      best supportive care, and the other receiving it plus tocilizumab. Patients will be followed
      until Day 29 after randomization.
Coalition VI (TOCIBRÁS) is a prospective phase III randomized controlled trial that evaluates
      the efficacy and safety of Tocilizumab, an antibody anti-IL-6 receptor in patients with
      moderate to severe COVID-19 with increased inflammatory markers. This is a superiority
      open-label study with two arms. The control arm receives the best supportive care, and the
      experimental receives it plus tocilizumab. Randomization is done centrally by REDCap 1:1.
      Patients will be followed until Day 29 after randomization.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Prospective, randomized, superiority, open-label, controlled trial. Randomization 1:1 to best supportive care (BSC) versus Tocilizumab + BSC
primary purpose: Treatment
masking: None (Open Label)
measure: Evaluation of clinical status
time frame: Day 15 of the trial
description: Evaluation of clinical status of patients on day 15 after randomization, defined by the Ordinal Scale of 7 points (score ranges from 1 to 7, with 7 being the worst score)
measure: All-cause mortality
time frame: 29 days after the randomization
description: All-cause mortality from randomization to day 28
measure: Hospital Mortality
time frame: 29 days after the randomization
description: Deaths that occur during hospital admission.
measure: Improvement of Sequential Sepsis-related Organ Failure Assessment (SOFA) scale
time frame: 29 days after the randomization (evaluations at D8 and D15)
description: Improvement of SOFA scale of patients at day 8, 15 and 29 after randomization
measure: Evaluation of clinical status
time frame: 29 days after the randomization (evaluations at D8 and D29)
description: Evaluation of clinical status of patients on the day 8, 22 and 29 after randomization, defined by the Ordinal Scale of 7 points (score ranges from 1 to 7, with 7 being the worst score)
measure: Ventilator free days
time frame: 29 days after the randomization
description: Days alive and free from mechanical ventilation since randomization
measure: Time until oxygen support independence
time frame: 29 days after the randomization
description: Days from randomization to independence of oxygen support
measure: Need of mechanical ventilation support
time frame: 29 days after the randomization
description: Number of patients that were not at mechanical ventilation at randomization and that required that support.
measure: Days to mechanical ventilation support.
time frame: 29 days after the randomization
description: Number of days to mechanical ventilation for patients that were not receiving it at randomization.
For patients that were not in mechanical ventilation at randomization: number of days until that support was required.
measure: Duration of hospitalization
time frame: 29 days after the randomization
description: Lenght of hospitalization stay in survivors (in days)
measure: Other infections
time frame: 29 days after the randomization
description: Incidence of other infections (aside from SARS-CoV 2)
measure: Incidence of thromboembolic events
time frame: 29 days after the randomization
description: Incidence of thromboembolic events in patients with COVID-19
measure: Incidence of adverse events
time frame: 29 days after the randomization (specific evaluations at D8, D15 and D29)
description: Evaluation of adverse events, as well as serious and unexpected adverse events
measure: Correlation of inflammatory tests and cytokines with clinical outcomes
time frame: 29 days after the randomization
description: Correlation of inflammatory tests and cytokines with clinical outcomes: clinical status (ordinal scale), time to oxygen support independence, ventilator free days, need of mechanical ventilation and mortality
measure: Exploratory evaluation of laboratory exams during hospitalization
time frame: 29 days after the randomization
description: Evaluation the kinetics of hemostasia exams, inflammatory tests, cytokines, flow cytometry of blood cells, CBC, renal and liver exams
measure: Evaluation of viral clearance of SARS-CoV2
time frame: Day 8 and 15 after randomization
description: Evaluation of viral clearance of SARS-CoV2 using RT-PCR analysis of nasopharyngeal swab
arm group label: Tocilizumab
arm group type: Experimental
description: Single-dose tocilizumab of 8 mg/kg (maximum dose of 800mg). Best supportive care.
arm group label: Control arm
arm group type: No Intervention
description: Best supportive care.
intervention type: Drug
intervention name: Tocilizumab
description: Single-dose infusion of 8 mg/kg. Maximum dose of 800 mg.
arm group label: Tocilizumab
other name: Actemra
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Viviane C Veiga, MD
role: Principal Investigator
affiliation: Beneficência Portuguesa de Sao Paulo
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Brazil
responsible party type: Principal Investigator
investigator affiliation: Beneficência Portuguesa de São Paulo
investigator full name: Dr Rozana Mesquita Ciconelli
investigator title: Head of research team
mesh term: Pneumonia
mesh term: Cytokine Release Syndrome
sharing ipd: No