<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/NCT04479358</url>
  </required_header>
  <id_info>
    <org_study_id>IRB20-1179</org_study_id>
    <nct_id>NCT04479358</nct_id>
  </id_info>
  <brief_title>Low-dose Tocilizumab Versus Standard of Care in Hospitalized Patients With COVID-19</brief_title>
  <acronym>COVIDOSE-2</acronym>
  <official_title>COVIDOSE-2: A Multi-center, Randomized, Controlled Phase 2 Trial Comparing Early Administration of Low-dose Tocilizumab to Standard of Care in Hospitalized Patients With COVID-19 Pneumonitis Not Requiring Invasive Ventilation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Chicago</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Chicago</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</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>
      Tocilizumab is an effective treatment for severe coronavirus disease 2019 (Covid-19)&#xD;
      pneumonia and related inflammation. Given limited global supplies, clarification of the&#xD;
      optimal tocilizumab dose is critical. We conducted an open-label, randomized, controlled&#xD;
      trial evaluating two different dose levels of tocilizumab in Covid-19 (40mg and 120mg).&#xD;
      Randomization was stratified on remdesivir and corticosteroid at enrollment. The primary&#xD;
      outcome was the time to recovery. The key secondary outcome was 28-day mortality.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      COVID-19's high mortality may be driven by hyperinflammation. Interleukin-6 (IL-6) axis&#xD;
      therapies may reduce COVID-19 mortality. Retrospective analyses of tocilizumab in severe to&#xD;
      critical COVID-19 patients have demonstrated survival advantage and lower likelihood of&#xD;
      requiring invasive ventilation following tocilizumab administration. The majority of patients&#xD;
      have rapid resolution (i.e., within 24-72 hours following administration) of both clinical&#xD;
      and biochemical signs (fever and CRP, respectively) of hyperinflammation with only a single&#xD;
      tocilizumab dose.&#xD;
&#xD;
      The investigators hypothesized that a dose of tocilizumab significantly lower than the EMA-&#xD;
      and FDA-labeled dose (8mg/kg) as well as the emerging standard of care dose (400mg) may be&#xD;
      effective in patients with COVID-19 pneumonitis and hyperinflammation. Advantages to the&#xD;
      lower dose of tocilizumab may include lower likelihood of secondary bacterial infections as&#xD;
      well as extension of this drug's limited supply. The investigators conducted an adaptive&#xD;
      single-arm phase 2 trial (NCT04331795) evaluating clinical and biochemical response to&#xD;
      low-dose tocilizumab in patients with COVID-19 pneumonitis and hyperinflammation.&#xD;
&#xD;
      This multi-center, prospective, randomized controlled phase 2 trial -- designed as two&#xD;
      sub-studies to allow for the possible emergence of data demonstrating the clinical efficacy&#xD;
      of tocilizumab 8mg/kg or 400mg -- formally tests the clinical efficacy of low-dose&#xD;
      tocilizumab in COVID-19 pneumonia.&#xD;
&#xD;
      Sub-Study A Primary Objective A: To establish whether low-dose tocilizumab reduces the time&#xD;
      to clinical recovery in patients with COVID-19 pneumonitis and hyperinflammation, when&#xD;
      compared to a tocilizumab-free standard of care.&#xD;
&#xD;
      Hypothesis A: The investigators hypothesize that low-dose tocilizumab, when compared to a&#xD;
      tocilizumab-free standard of care, decreases the time to recovery in hospitalized,&#xD;
      non-invasively ventilated patients with COVID-19 pneumonitis and hyperinflammation by three&#xD;
      days or more.&#xD;
&#xD;
      Sub-Study B Primary Objective B: To establish whether low-dose tocilizumab is near-equivalent&#xD;
      to high-dose tocilizumab (400mg or 8 mg/kg) in reducing the time to clinical recovery in&#xD;
      patients with COVID-19 pneumonitis and hyperinflammation.&#xD;
&#xD;
      Hypothesis B: The investigators hypothesize that low-dose tocilizumab is near-equivalent to&#xD;
      high-dose tocilizumab in reducing the time to clinical recovery in hospitalized,&#xD;
      non-invasively ventilated patients with COVID-19 pneumonitis and hyperinflammation.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">September 10, 2020</start_date>
  <completion_date type="Anticipated">March 1, 2025</completion_date>
  <primary_completion_date type="Anticipated">March 1, 2024</primary_completion_date>
  <phase>Phase 2</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>Two sub-studies in parallel, each of three arms (maximum).</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Time to Recovery</measure>
    <time_frame>28 days</time_frame>
    <description>Day of recovery is defined as the first day on which the patient achieves one of the following two categories from the seven-point ordinal scale: 6) Hospitalized, not requiring supplemental oxygen or ongoing medical care or 7) Not hospitalized. Time to recovery is the number of days from randomization to achievement of this status. Note that the ordinal scale is measured once daily, with the patient's worst clinical status during the 24-hour time period (0:00-23:59) being documented.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Achievement of Recovery</measure>
    <time_frame>7 days</time_frame>
    <description>This will be defined as the percentage of patients in a given arm of the study achieving one of the above two categories on the ordinal scale on day 7. Note that the ordinal scale is measured once daily, with the patient's worst clinical status during the 24-hour time period (0:00-23:59) being documented.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>28 days</time_frame>
    <description>This will be defined as the percentage of patients in a given arm of the study who are alive thirty days following randomization. Patients who are discharged to hospice will be counted as deceased on the day of discharge. Patients who are transitioned to inpatient hospice or inpatient comfort measures only will be counted as deceased on the day of transition.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hospital Length of Stay</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>This will be defined as the number of days that pass between the day of a patient's randomization and his or her discharge from the hospital.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Response: Maximum Temperature (Tmax) Response</measure>
    <time_frame>24 hours</time_frame>
    <description>Maximum temperature within 24-hour periods of time immediately prior to, immediately following, and then every 24 hours thereafter randomization. The primary endpoint is a measured Tmax in the 24-hour period immediately following randomization that is lower than the measured Tmax in the 24-hour period immediately preceding randomization.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Response: Rate of Non-Elective Invasive Mechanical Ventilation</measure>
    <time_frame>Up to 28 days</time_frame>
    <description>This will be a binary outcome defined as worsening COVID-19 disease resulting in the use of invasive mechanical ventilation during the course of the patient's COVID-19 infection.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Response: Duration of Non-Elective Invasive Mechanical Ventilation</measure>
    <time_frame>Up to 28 days</time_frame>
    <description>This will be a continuous outcome defined by the amount of time between initiation and cessation of non-elective invasive mechanical ventilation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Response: Time to Non-Elective Invasive Mechanical Ventilation</measure>
    <time_frame>Up to 28 days</time_frame>
    <description>This will be a continuous outcome defined by the amount of time between randomization and the initiation of non-elective invasive mechanical ventilation. This will be treated as a time-to-event with possible censoring.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Response: Rate of Vasopressor/Inotrope Utilization</measure>
    <time_frame>Up to 28 days</time_frame>
    <description>This will be a binary outcome defined as utilization of any vasopressor or inotropic medication.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Response: Duration of Vasopressor/Inotrope Utilization</measure>
    <time_frame>Up to 28 days</time_frame>
    <description>This will be a continuous outcome defined by the amount of time between initiation of first and cessation of last vasopressor medications.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Response: Time to Vasopressor/Inotrope Utilization</measure>
    <time_frame>Up to 28 days</time_frame>
    <description>This will be a continuous outcome defined by the amount of time between randomization and the initiation of any vasopressor or inotropic medication. This will be treated as a time-to-event with possible censoring.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Response: Duration of Increased Supplemental Oxygen from Baseline</measure>
    <time_frame>28 days</time_frame>
    <description>This will be an ordinal outcome defined by the number of days counted from randomization over which the participant requires supplemental oxygen in excess over his/her baseline supplemental oxygen requirement. The supplemental oxygen requirement is defined as the highest liters-per-minute flow of supplemental oxygen required by the patient each day over the course of the hospitalization.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biochemical Response: C-reactive Protein Response Rate</measure>
    <time_frame>24 hours</time_frame>
    <description>This will be a binary outcome defined as the presence or absence of a decline in CRP of ≥ 25% from baseline CRP in the 27 +/- 3 hours after tocilizumab administration, as compared to pre-treatment baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety: Rate of Secondary Infection</measure>
    <time_frame>28 days</time_frame>
    <description>This will be defined as the percentage of patients in a study arm who develop serious non-COVID-19 viral, bacterial, or fungal infections (e.g., bloodstream infection, hospital-acquired pneumonia, ventilator-associated pneumonia, opportunistic infection) following randomization and up to the 28-day assessment of overall survival.</description>
  </secondary_outcome>
  <number_of_arms>6</number_of_arms>
  <enrollment type="Actual">75</enrollment>
  <condition>COVID-19</condition>
  <arm_group>
    <arm_group_label>Sub-study A, Tocilizumab-Free Standard of Care</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive no tocilizumab.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sub-study A, Tocilizumab 40mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive tocilizumab 40mg.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sub-study A, Tocilizumab 120mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive tocilizumab 120mg.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sub-study B, Tocilizumab 400mg or 8mg/kg Standard of Care</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab dose (400mg or 8mgkg).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sub-study B, Tocilizumab 40mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab 40mg.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sub-study B, Tocilizumab 120mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab 120mg.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tocilizumab</intervention_name>
    <description>Tocilizumab 40mg</description>
    <arm_group_label>Sub-study A, Tocilizumab 40mg</arm_group_label>
    <arm_group_label>Sub-study B, Tocilizumab 40mg</arm_group_label>
    <other_name>Tocilizumab 40mg</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tocilizumab</intervention_name>
    <description>Tocilizumab 120mg</description>
    <arm_group_label>Sub-study A, Tocilizumab 120mg</arm_group_label>
    <arm_group_label>Sub-study B, Tocilizumab 120mg</arm_group_label>
    <other_name>Tocilizumab 120mg</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Standard of Care</intervention_name>
    <description>Tocilizumab-Free Standard of Care</description>
    <arm_group_label>Sub-study A, Tocilizumab-Free Standard of Care</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Standard of Care</intervention_name>
    <description>Tocilizumab 400mg or 8mg/kg</description>
    <arm_group_label>Sub-study B, Tocilizumab 400mg or 8mg/kg Standard of Care</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adults ≥ 18 years of age&#xD;
&#xD;
          -  Approval from the patient's primary inpatient service&#xD;
&#xD;
          -  Hospitalized&#xD;
&#xD;
          -  Fever, documented in electronic medical record and defined as: T ≥ 38 degrees C by any&#xD;
             conventional clinical method (forehead, tympanic, oral, axillary, rectal)&#xD;
&#xD;
          -  Positive test for active SARS-CoV-2 infection&#xD;
&#xD;
          -  Radiographic evidence of infiltrates on chest radiograph (CXR) or computed tomography&#xD;
             (CT)&#xD;
&#xD;
          -  Ability to provide written informed consent on the part of the subject or, in the&#xD;
             absence of decisional capacity of the subject, an appropriate surrogate (e.g. a&#xD;
             legally authorized representative).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Concurrent use of invasive mechanical ventilation&#xD;
&#xD;
          -  Concurrent use of vasopressor or inotropic medications&#xD;
&#xD;
          -  Previous receipt of tocilizumab or another anti-IL6R or IL-6 inhibitor in the year&#xD;
             prior.&#xD;
&#xD;
          -  Known history of hypersensitivity to tocilizumab.&#xD;
&#xD;
          -  Diagnosis of end-stage liver disease or listed for liver transplant.&#xD;
&#xD;
          -  Elevation of AST or ALT in excess of 10 times the upper limit of normal.&#xD;
&#xD;
          -  Neutropenia (Absolute neutrophil count &lt; 500/uL).&#xD;
&#xD;
          -  Thrombocytopenia (Platelets &lt; 50,000/uL).&#xD;
&#xD;
          -  On active therapy with a Bruton's tyrosine kinase-targeted agent, which include the&#xD;
             following:&#xD;
&#xD;
          -  Acalabrutinib&#xD;
&#xD;
          -  Ibrutinib&#xD;
&#xD;
          -  Zanubrutinib&#xD;
&#xD;
          -  On active therapy with a JAK2-targeted agent, which include the following:&#xD;
&#xD;
          -  Tofacitinib&#xD;
&#xD;
          -  Baricitinib&#xD;
&#xD;
          -  Upadacitinib&#xD;
&#xD;
          -  Ruxolitinib&#xD;
&#xD;
          -  Any of the following biologic immunosuppressive agent (and any biosimilar versions&#xD;
             thereof) administered in the past 6 months or less::&#xD;
&#xD;
          -  Abatacept&#xD;
&#xD;
          -  Adalimumab&#xD;
&#xD;
          -  Alemtuzumab&#xD;
&#xD;
          -  Atezolizumab&#xD;
&#xD;
          -  Belimumab&#xD;
&#xD;
          -  Blinatumomab&#xD;
&#xD;
          -  Brentuximab&#xD;
&#xD;
          -  Certolizumab&#xD;
&#xD;
          -  Daratumumab&#xD;
&#xD;
          -  Durvalumab&#xD;
&#xD;
          -  Eculizumab&#xD;
&#xD;
          -  Elotuzumab&#xD;
&#xD;
          -  Etanercept&#xD;
&#xD;
          -  Gemtuzumab&#xD;
&#xD;
          -  Golimumab&#xD;
&#xD;
          -  Ibritumomab&#xD;
&#xD;
          -  Infliximab&#xD;
&#xD;
          -  Inotuzumab&#xD;
&#xD;
          -  Ipilimumab&#xD;
&#xD;
          -  Ixekizumab&#xD;
&#xD;
          -  Moxetumomab&#xD;
&#xD;
          -  Nivolumab&#xD;
&#xD;
          -  Obinutuzumab&#xD;
&#xD;
          -  Ocrelizumab&#xD;
&#xD;
          -  Ofatumumab&#xD;
&#xD;
          -  Pembrolizumab&#xD;
&#xD;
          -  Polatuzumab&#xD;
&#xD;
          -  Rituximab&#xD;
&#xD;
          -  Rituximab&#xD;
&#xD;
          -  Sarilumab&#xD;
&#xD;
          -  Secukinumab&#xD;
&#xD;
          -  Tocilizumab&#xD;
&#xD;
          -  Tositumumab&#xD;
&#xD;
          -  Tremelimumab&#xD;
&#xD;
          -  Urelumab&#xD;
&#xD;
          -  Ustekinumab&#xD;
&#xD;
          -  History of bone marrow transplantation (including chimeric antigen receptor T-cell) or&#xD;
             solid organ transplant&#xD;
&#xD;
          -  Known history of Hepatitis B or Hepatitis C (patients who have completed&#xD;
             curative-intent anti-HCV treatments are not excluded from trial)&#xD;
&#xD;
          -  Positive result on hepatitis B or C screening&#xD;
&#xD;
          -  Known history of mycobacterium tuberculosis infection at risk for reactivation&#xD;
&#xD;
          -  Known history of gastrointestinal perforation&#xD;
&#xD;
          -  Active diverticulitis&#xD;
&#xD;
          -  Multi-organ failure as determined by primary treating physicians&#xD;
&#xD;
          -  Any other documented serious, active infection besides COVID-19 - including but not&#xD;
             limited to: lobar pneumonia consistent with bacterial infection, bacteremia,&#xD;
             culture-negative endocarditis, or current mycobacterial infection - at the discretion&#xD;
             of primary treating physicians&#xD;
&#xD;
          -  Pregnant patients or nursing mothers&#xD;
&#xD;
          -  Patients who are unable to discontinue scheduled antipyretic medications, either as&#xD;
             monotherapy (e.g., acetaminophen or ibuprofen [aspirin is acceptable]) or as part of&#xD;
             combination therapy (e.g., hydrocodone/acetaminophen, aspirin/acetaminophen/caffeine&#xD;
             [Excedrin®])&#xD;
&#xD;
          -  CRP &lt; 40 mg/L&#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>Pankti D Reid, MD, MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Chicago</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Chicago Medicine</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60637</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Strohbehn GW, Reid PD, Ratain MJ. Applied Clinical Pharmacology in a Crisis: Interleukin-6 Axis Blockade and COVID-19. Clin Pharmacol Ther. 2020 Sep;108(3):425-427. doi: 10.1002/cpt.1931. Epub 2020 Jul 4.</citation>
    <PMID>32488861</PMID>
  </reference>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>July 13, 2020</study_first_submitted>
  <study_first_submitted_qc>July 18, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 21, 2020</study_first_posted>
  <last_update_submitted>May 11, 2023</last_update_submitted>
  <last_update_submitted_qc>May 11, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 15, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>COVID-19</keyword>
  <keyword>Tocilizumab</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Individual participant data that underlie the results of this article, after de-identification. Sharing period will be 1 month after data are published and available indefinitely thereafter. Researchers who provide methodologically sound proposals for the purposes of achieving stated aims in their proposal will be eligible for data-sharing.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Analytic Code</ipd_info_type>
    <ipd_time_frame>From 1 month following publication of data. Available indefinitely thereafter.</ipd_time_frame>
    <ipd_access_criteria>Proposals will need to be sent to study principal investigators. Requestors will need to sign a data access request form. Link to be determined.</ipd_access_criteria>
  </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/NCT04479358
org study id: IRB20-1179
nct id: NCT04479358
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
Tocilizumab is an effective treatment for severe coronavirus disease 2019 (Covid-19)
      pneumonia and related inflammation. Given limited global supplies, clarification of the
      optimal tocilizumab dose is critical. We conducted an open-label, randomized, controlled
      trial evaluating two different dose levels of tocilizumab in Covid-19 (40mg and 120mg).
      Randomization was stratified on remdesivir and corticosteroid at enrollment. The primary
      outcome was the time to recovery. The key secondary outcome was 28-day mortality.
COVID-19's high mortality may be driven by hyperinflammation. Interleukin-6 (IL-6) axis
      therapies may reduce COVID-19 mortality. Retrospective analyses of tocilizumab in severe to
      critical COVID-19 patients have demonstrated survival advantage and lower likelihood of
      requiring invasive ventilation following tocilizumab administration. The majority of patients
      have rapid resolution (i.e., within 24-72 hours following administration) of both clinical
      and biochemical signs (fever and CRP, respectively) of hyperinflammation with only a single
      tocilizumab dose.

      The investigators hypothesized that a dose of tocilizumab significantly lower than the EMA-
      and FDA-labeled dose (8mg/kg) as well as the emerging standard of care dose (400mg) may be
      effective in patients with COVID-19 pneumonitis and hyperinflammation. Advantages to the
      lower dose of tocilizumab may include lower likelihood of secondary bacterial infections as
      well as extension of this drug's limited supply. The investigators conducted an adaptive
      single-arm phase 2 trial (NCT04331795) evaluating clinical and biochemical response to
      low-dose tocilizumab in patients with COVID-19 pneumonitis and hyperinflammation.

      This multi-center, prospective, randomized controlled phase 2 trial -- designed as two
      sub-studies to allow for the possible emergence of data demonstrating the clinical efficacy
      of tocilizumab 8mg/kg or 400mg -- formally tests the clinical efficacy of low-dose
      tocilizumab in COVID-19 pneumonia.

      Sub-Study A Primary Objective A: To establish whether low-dose tocilizumab reduces the time
      to clinical recovery in patients with COVID-19 pneumonitis and hyperinflammation, when
      compared to a tocilizumab-free standard of care.

      Hypothesis A: The investigators hypothesize that low-dose tocilizumab, when compared to a
      tocilizumab-free standard of care, decreases the time to recovery in hospitalized,
      non-invasively ventilated patients with COVID-19 pneumonitis and hyperinflammation by three
      days or more.

      Sub-Study B Primary Objective B: To establish whether low-dose tocilizumab is near-equivalent
      to high-dose tocilizumab (400mg or 8 mg/kg) in reducing the time to clinical recovery in
      patients with COVID-19 pneumonitis and hyperinflammation.

      Hypothesis B: The investigators hypothesize that low-dose tocilizumab is near-equivalent to
      high-dose tocilizumab in reducing the time to clinical recovery in hospitalized,
      non-invasively ventilated patients with COVID-19 pneumonitis and hyperinflammation.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Two sub-studies in parallel, each of three arms (maximum).
primary purpose: Treatment
masking: None (Open Label)
measure: Time to Recovery
time frame: 28 days
description: Day of recovery is defined as the first day on which the patient achieves one of the following two categories from the seven-point ordinal scale: 6) Hospitalized, not requiring supplemental oxygen or ongoing medical care or 7) Not hospitalized. Time to recovery is the number of days from randomization to achievement of this status. Note that the ordinal scale is measured once daily, with the patient's worst clinical status during the 24-hour time period (0:00-23:59) being documented.
measure: Achievement of Recovery
time frame: 7 days
description: This will be defined as the percentage of patients in a given arm of the study achieving one of the above two categories on the ordinal scale on day 7. Note that the ordinal scale is measured once daily, with the patient's worst clinical status during the 24-hour time period (0:00-23:59) being documented.
measure: Overall Survival
time frame: 28 days
description: This will be defined as the percentage of patients in a given arm of the study who are alive thirty days following randomization. Patients who are discharged to hospice will be counted as deceased on the day of discharge. Patients who are transitioned to inpatient hospice or inpatient comfort measures only will be counted as deceased on the day of transition.
measure: Hospital Length of Stay
time frame: Up to 1 year
description: This will be defined as the number of days that pass between the day of a patient's randomization and his or her discharge from the hospital.
measure: Clinical Response: Maximum Temperature (Tmax) Response
time frame: 24 hours
description: Maximum temperature within 24-hour periods of time immediately prior to, immediately following, and then every 24 hours thereafter randomization. The primary endpoint is a measured Tmax in the 24-hour period immediately following randomization that is lower than the measured Tmax in the 24-hour period immediately preceding randomization.
measure: Clinical Response: Rate of Non-Elective Invasive Mechanical Ventilation
time frame: Up to 28 days
description: This will be a binary outcome defined as worsening COVID-19 disease resulting in the use of invasive mechanical ventilation during the course of the patient's COVID-19 infection.
measure: Clinical Response: Duration of Non-Elective Invasive Mechanical Ventilation
time frame: Up to 28 days
description: This will be a continuous outcome defined by the amount of time between initiation and cessation of non-elective invasive mechanical ventilation.
measure: Clinical Response: Time to Non-Elective Invasive Mechanical Ventilation
time frame: Up to 28 days
description: This will be a continuous outcome defined by the amount of time between randomization and the initiation of non-elective invasive mechanical ventilation. This will be treated as a time-to-event with possible censoring.
measure: Clinical Response: Rate of Vasopressor/Inotrope Utilization
time frame: Up to 28 days
description: This will be a binary outcome defined as utilization of any vasopressor or inotropic medication.
measure: Clinical Response: Duration of Vasopressor/Inotrope Utilization
time frame: Up to 28 days
description: This will be a continuous outcome defined by the amount of time between initiation of first and cessation of last vasopressor medications.
measure: Clinical Response: Time to Vasopressor/Inotrope Utilization
time frame: Up to 28 days
description: This will be a continuous outcome defined by the amount of time between randomization and the initiation of any vasopressor or inotropic medication. This will be treated as a time-to-event with possible censoring.
measure: Clinical Response: Duration of Increased Supplemental Oxygen from Baseline
time frame: 28 days
description: This will be an ordinal outcome defined by the number of days counted from randomization over which the participant requires supplemental oxygen in excess over his/her baseline supplemental oxygen requirement. The supplemental oxygen requirement is defined as the highest liters-per-minute flow of supplemental oxygen required by the patient each day over the course of the hospitalization.
measure: Biochemical Response: C-reactive Protein Response Rate
time frame: 24 hours
description: This will be a binary outcome defined as the presence or absence of a decline in CRP of ≥ 25% from baseline CRP in the 27 +/- 3 hours after tocilizumab administration, as compared to pre-treatment baseline.
measure: Safety: Rate of Secondary Infection
time frame: 28 days
description: This will be defined as the percentage of patients in a study arm who develop serious non-COVID-19 viral, bacterial, or fungal infections (e.g., bloodstream infection, hospital-acquired pneumonia, ventilator-associated pneumonia, opportunistic infection) following randomization and up to the 28-day assessment of overall survival.
arm group label: Sub-study A, Tocilizumab-Free Standard of Care
arm group type: Active Comparator
description: Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive no tocilizumab.
arm group label: Sub-study A, Tocilizumab 40mg
arm group type: Experimental
description: Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive tocilizumab 40mg.
arm group label: Sub-study A, Tocilizumab 120mg
arm group type: Experimental
description: Patient assigned to Sub-study A by primary treating physicians. Patient enrolled on trial sub-study A and randomized to receive tocilizumab 120mg.
arm group label: Sub-study B, Tocilizumab 400mg or 8mg/kg Standard of Care
arm group type: Active Comparator
description: Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab dose (400mg or 8mgkg).
arm group label: Sub-study B, Tocilizumab 40mg
arm group type: Experimental
description: Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab 40mg.
arm group label: Sub-study B, Tocilizumab 120mg
arm group type: Experimental
description: Patient assigned to Sub-study B by primary treating physicians. Patient enrolled on trial sub-study B and randomized to receive standard of care tocilizumab 120mg.
intervention type: Drug
intervention name: Tocilizumab
description: Tocilizumab 40mg
arm group label: Sub-study A, Tocilizumab 40mg
arm group label: Sub-study B, Tocilizumab 40mg
other name: Tocilizumab 40mg
intervention type: Drug
intervention name: Tocilizumab
description: Tocilizumab 120mg
arm group label: Sub-study A, Tocilizumab 120mg
arm group label: Sub-study B, Tocilizumab 120mg
other name: Tocilizumab 120mg
intervention type: Other
intervention name: Standard of Care
description: Tocilizumab-Free Standard of Care
arm group label: Sub-study A, Tocilizumab-Free Standard of Care
intervention type: Other
intervention name: Standard of Care
description: Tocilizumab 400mg or 8mg/kg
arm group label: Sub-study B, Tocilizumab 400mg or 8mg/kg Standard of Care
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Pankti D Reid, MD, MPH
role: Principal Investigator
affiliation: University of Chicago
facility: 
country: United States
citation: Strohbehn GW, Reid PD, Ratain MJ. Applied Clinical Pharmacology in a Crisis: Interleukin-6 Axis Blockade and COVID-19. Clin Pharmacol Ther. 2020 Sep;108(3):425-427. doi: 10.1002/cpt.1931. Epub 2020 Jul 4.
PMID: 32488861
responsible party type: Sponsor
mesh term: COVID-19
sharing ipd: Yes
ipd description: Individual participant data that underlie the results of this article, after de-identification. Sharing period will be 1 month after data are published and available indefinitely thereafter. Researchers who provide methodologically sound proposals for the purposes of achieving stated aims in their proposal will be eligible for data-sharing.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Analytic Code
ipd time frame: From 1 month following publication of data. Available indefinitely thereafter.
ipd access criteria: Proposals will need to be sent to study principal investigators. Requestors will need to sign a data access request form. Link to be determined.