<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/NCT04423042</url>
  </required_header>
  <id_info>
    <org_study_id>REB20-0713</org_study_id>
    <nct_id>NCT04423042</nct_id>
  </id_info>
  <brief_title>Tocilizumab in Coronavirus-19 Positive Patients</brief_title>
  <official_title>A Nested Interventional Cohort Study to Assess the Efficacy and Safety of Adjunctive Humanized Monoclonal Interleukin-6 Receptor Blocker Tocilizumab (TCZ) Therapy to Standard of Care for the Reduction of Hyperinflammation Related Mortality in SARS-Cov2 Positive Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Calgary</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Calgary</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>
      This is a cohort study of COVID-19 patients with hyperinflammation. It aims to determine the&#xD;
      impact of adjunctive Tocilizumab (TCZ) to standard of care on the reduction of&#xD;
      hyperinflammation-related mortality in COVID-19. Patients with COVID-19 are at high risk of&#xD;
      life-threatening hyperinflammation and death. One in three COVID-19 patients admitted to ICU&#xD;
      was found to develop life-threatening hyperinflammation. The risk of death when untreated is&#xD;
      estimated to be 50-80%.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The novel coronavirus, SARS-Cov2/COVID-19, emerged in late 2019 in Wuhan, China. Quickly,&#xD;
      SARS-CoV2 spread to all corners of the globe. In March 2020, The World Health Organization&#xD;
      (WHO) declared SARS-CoV2/COVID-19 a pandemic. Individuals infected with SARS-CoV2 have a&#xD;
      varied clinical presentation, ranging from asymptomatic or mild respiratory symptoms to&#xD;
      severe involvement of the lower respiratory tract, with patients requiring mechanical&#xD;
      ventilation. A particular point of interest is how the overall severity and clinical outcomes&#xD;
      of COVID-19 patients may be associated with the excessive production of pro-inflammatory&#xD;
      cytokines, or hyperinflammation, leading to acute respiratory distress syndrome. This state&#xD;
      of hyperinflammation may be associated with increased mortality in COVID-19 patients.&#xD;
      Tocilizumab, an Interleukin-6 antagonist, may help treat COVID-19 associated&#xD;
      hyperinflammation.&#xD;
&#xD;
      This is a nested interventional cohort study of COVID-19 patients with hyperinflammation. It&#xD;
      aims to determine the impact of adjunctive Tocilizumab (TCZ) to standard of care on the&#xD;
      reduction of hyperinflammation-related mortality in COVID-19. Patients with COVID-19 are at&#xD;
      high risk of life-threatening hyperinflammation and death. One in three COVID-19 patients&#xD;
      admitted to ICU was found to develop life-threatening hyperinflammation. The risk of death&#xD;
      when untreated is estimated to be 50-80%. TCZ treatment may reduce mortality.&#xD;
&#xD;
      Primary objective: To establish that tocilizumab, in addition to standard of care, reduces&#xD;
      the 30-day mortality from hyperinflammation in COVID-19 disease significantly compared to no&#xD;
      anti-interleukin therapy plus standard of care.&#xD;
&#xD;
      Secondary objectives: To evaluate the addition of tocilizumab therapy to standard of care on&#xD;
      a number of secondary outcomes.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">July 30, 2020</start_date>
  <completion_date type="Anticipated">June 2021</completion_date>
  <primary_completion_date type="Anticipated">June 2021</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>All-cause mortality</measure>
    <time_frame>Assessed at 30 days post treatment</time_frame>
    <description>Mortality status of participants</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Ordinal Scale for evaluating subject clinical status at days 3, 8, 15, 30, 60 post treatment.</measure>
    <time_frame>Assessed at days 3, 8, 15, 30, 60 post treatment</time_frame>
    <description>Uninfected, ambulatory, hospitalized: mild disease, hospitalized: severe disease, death</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">30</enrollment>
  <condition>Covid19</condition>
  <condition>COVID-19</condition>
  <condition>Severe Acute Respiratory Syndrome Coronavirus 2</condition>
  <condition>Coronavirus</condition>
  <condition>Inflammation</condition>
  <arm_group>
    <arm_group_label>Tocilizumab Arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Tocilizumab 8 mg/kg IV up to a maximum of 800 mg with possible repetition of the same dosage within 28 hours (the optional second dose after 12 hours but before 28 hours following the first dose), based on the clinical judgement of the attending physician in consultation with the COVID-inflammation team.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>No Intervention Arm</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>No intervention arm patients will be identified from medical records, as being COVID-19 positive patients with hyperinflammation who did not receive any interleukin antagonist treatment.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Tocilizumab</intervention_name>
    <description>Tocilizumab binds to both soluble and membrane-bound interleukin-6 receptors and has been shown to inhibit interleukin 6-mediated signalling.</description>
    <arm_group_label>Tocilizumab Arm</arm_group_label>
    <other_name>Actemra</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age ≥ 18 years&#xD;
&#xD;
          2. All genders&#xD;
&#xD;
          3. Hospitalization for suspected or confirmed SARS-CoV2 infection. COVID-19 diagnosis&#xD;
             defined as positive on reverse-transcriptase polymerase chain reaction, with&#xD;
             provincial laboratory confirmation.&#xD;
&#xD;
          4. Signs of hyperinflammation (cytokine release syndrome) defined by the presence of any&#xD;
             of the following:&#xD;
&#xD;
             i. Elevated C-reactive protein (≥70 mg/dl and/or rising since last 24h not due to&#xD;
             bacterial infection), ii. Ferritin (&gt;700 mcg/L and/or rising since last 24h),&#xD;
&#xD;
          5. Anti-interleukin treatment indication as per hyperinflammation team&#xD;
&#xD;
          6. Informed consent for participation in the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Goal of Care C (palliative care)&#xD;
&#xD;
          2. Known hypersensitivity to TCZ or its components&#xD;
&#xD;
          3. Current systemic immunosuppressive therapy; anti-interleukin 1 or anti-interleukin 6&#xD;
             treatment&#xD;
&#xD;
          4. Known active bacterial or fungal infections or other clinical conditions that&#xD;
             contraindicate TCZ and cannot be treated or resolved according to the physician's&#xD;
             judgment&#xD;
&#xD;
          5. Current or history of bowel perforation or diverticulitis&#xD;
&#xD;
          6. Suspicion of active or latent tuberculosis&#xD;
&#xD;
          7. Pregnant or breastfeeding patient&#xD;
&#xD;
          8. Patients with known prior liver disease&#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>Susanne Benseler, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Calgary</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Jacinda R Larson, PhD</last_name>
    <phone>4039555537</phone>
    <email>jacinda.larson@albertahealthservices.ca</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Namneet Sandhu, MPH</last_name>
    <email>namneet.sandhu@ucalgary.ca</email>
  </overall_contact_backup>
  <link>
    <url>https://www.rochecanada.com/PMs/Actemra/Actemra_PM_E.pdf</url>
    <description>Hoffmann-La Roche Limited. Product Monograph, ACTEMRA® tocilizumab.</description>
  </link>
  <reference>
    <citation>Xu X, Han M, Li T, Sun W, Wang D, Fu B, Zhou Y, Zheng X, Yang Y, Li X, Zhang X, Pan A, Wei H. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A. 2020 May 19;117(20):10970-10975. doi: 10.1073/pnas.2005615117. Epub 2020 Apr 29.</citation>
    <PMID>32350134</PMID>
  </reference>
  <reference>
    <citation>Alzghari SK, Acuna VS. Supportive Treatment with Tocilizumab for COVID-19: A Systematic Review. J Clin Virol. 2020 Jun;127:104380. doi: 10.1016/j.jcv.2020.104380. Epub 2020 Apr 21. No abstract available.</citation>
    <PMID>32353761</PMID>
  </reference>
  <reference>
    <citation>Zhang C, Wu Z, Li JW, Zhao H, Wang GQ. Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality. Int J Antimicrob Agents. 2020 May;55(5):105954. doi: 10.1016/j.ijantimicag.2020.105954. Epub 2020 Mar 29.</citation>
    <PMID>32234467</PMID>
  </reference>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>June 5, 2020</study_first_submitted>
  <study_first_submitted_qc>June 5, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 9, 2020</study_first_posted>
  <last_update_submitted>July 20, 2020</last_update_submitted>
  <last_update_submitted_qc>July 20, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 22, 2020</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>COVID-19</mesh_term>
    <mesh_term>Coronavirus Infections</mesh_term>
    <mesh_term>Severe Acute Respiratory Syndrome</mesh_term>
    <mesh_term>Inflammation</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Results will be rapidly published.</ipd_description>
  </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/NCT04423042
org study id: REB20-0713
nct id: NCT04423042
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
This is a cohort study of COVID-19 patients with hyperinflammation. It aims to determine the
      impact of adjunctive Tocilizumab (TCZ) to standard of care on the reduction of
      hyperinflammation-related mortality in COVID-19. Patients with COVID-19 are at high risk of
      life-threatening hyperinflammation and death. One in three COVID-19 patients admitted to ICU
      was found to develop life-threatening hyperinflammation. The risk of death when untreated is
      estimated to be 50-80%.
The novel coronavirus, SARS-Cov2/COVID-19, emerged in late 2019 in Wuhan, China. Quickly,
      SARS-CoV2 spread to all corners of the globe. In March 2020, The World Health Organization
      (WHO) declared SARS-CoV2/COVID-19 a pandemic. Individuals infected with SARS-CoV2 have a
      varied clinical presentation, ranging from asymptomatic or mild respiratory symptoms to
      severe involvement of the lower respiratory tract, with patients requiring mechanical
      ventilation. A particular point of interest is how the overall severity and clinical outcomes
      of COVID-19 patients may be associated with the excessive production of pro-inflammatory
      cytokines, or hyperinflammation, leading to acute respiratory distress syndrome. This state
      of hyperinflammation may be associated with increased mortality in COVID-19 patients.
      Tocilizumab, an Interleukin-6 antagonist, may help treat COVID-19 associated
      hyperinflammation.

      This is a nested interventional cohort study of COVID-19 patients with hyperinflammation. It
      aims to determine the impact of adjunctive Tocilizumab (TCZ) to standard of care on the
      reduction of hyperinflammation-related mortality in COVID-19. Patients with COVID-19 are at
      high risk of life-threatening hyperinflammation and death. One in three COVID-19 patients
      admitted to ICU was found to develop life-threatening hyperinflammation. The risk of death
      when untreated is estimated to be 50-80%. TCZ treatment may reduce mortality.

      Primary objective: To establish that tocilizumab, in addition to standard of care, reduces
      the 30-day mortality from hyperinflammation in COVID-19 disease significantly compared to no
      anti-interleukin therapy plus standard of care.

      Secondary objectives: To evaluate the addition of tocilizumab therapy to standard of care on
      a number of secondary outcomes.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: All-cause mortality
time frame: Assessed at 30 days post treatment
description: Mortality status of participants
measure: Ordinal Scale for evaluating subject clinical status at days 3, 8, 15, 30, 60 post treatment.
time frame: Assessed at days 3, 8, 15, 30, 60 post treatment
description: Uninfected, ambulatory, hospitalized: mild disease, hospitalized: severe disease, death
arm group label: Tocilizumab Arm
arm group type: Experimental
description: Tocilizumab 8 mg/kg IV up to a maximum of 800 mg with possible repetition of the same dosage within 28 hours (the optional second dose after 12 hours but before 28 hours following the first dose), based on the clinical judgement of the attending physician in consultation with the COVID-inflammation team.
arm group label: No Intervention Arm
arm group type: No Intervention
description: No intervention arm patients will be identified from medical records, as being COVID-19 positive patients with hyperinflammation who did not receive any interleukin antagonist treatment.
intervention type: Biological
intervention name: Tocilizumab
description: Tocilizumab binds to both soluble and membrane-bound interleukin-6 receptors and has been shown to inhibit interleukin 6-mediated signalling.
arm group label: Tocilizumab Arm
other name: Actemra
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Susanne Benseler, MD PhD
role: Principal Investigator
affiliation: University of Calgary
last name: Jacinda R Larson, PhD
phone: 4039555537
email: jacinda.larson@albertahealthservices.ca
last name: Namneet Sandhu, MPH
email: namneet.sandhu@ucalgary.ca
url: https://www.rochecanada.com/PMs/Actemra/Actemra_PM_E.pdf
description: Hoffmann-La Roche Limited. Product Monograph, ACTEMRA® tocilizumab.
citation: Xu X, Han M, Li T, Sun W, Wang D, Fu B, Zhou Y, Zheng X, Yang Y, Li X, Zhang X, Pan A, Wei H. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A. 2020 May 19;117(20):10970-10975. doi: 10.1073/pnas.2005615117. Epub 2020 Apr 29.
PMID: 32350134
citation: Alzghari SK, Acuna VS. Supportive Treatment with Tocilizumab for COVID-19: A Systematic Review. J Clin Virol. 2020 Jun;127:104380. doi: 10.1016/j.jcv.2020.104380. Epub 2020 Apr 21. No abstract available.
PMID: 32353761
citation: Zhang C, Wu Z, Li JW, Zhao H, Wang GQ. Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality. Int J Antimicrob Agents. 2020 May;55(5):105954. doi: 10.1016/j.ijantimicag.2020.105954. Epub 2020 Mar 29.
PMID: 32234467
responsible party type: Sponsor
mesh term: COVID-19
mesh term: Coronavirus Infections
mesh term: Severe Acute Respiratory Syndrome
mesh term: Inflammation
sharing ipd: No
ipd description: Results will be rapidly published.