<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/NCT04424056</url>
  </required_header>
  <id_info>
    <org_study_id>2020-23</org_study_id>
    <nct_id>NCT04424056</nct_id>
  </id_info>
  <brief_title>A Trial Using ANAKINRA, TOCILIZUMAB Alone or in Association With RUXOLITINIB in Severe Stage 2b and 3 of COVID19-associated Disease</brief_title>
  <acronym>INFLAMMACOV</acronym>
  <official_title>An Open Randomized Therapeutic Trial Using ANAKINRA, TOCILIZUMAB Alone or in Association With RUXOLITINIB in Severe Stage 2b and 3 of COVID19-associated Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assistance Publique Hopitaux De Marseille</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Assistance Publique Hopitaux De Marseille</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      COVID19-associated disease may have different clinical aspects classified in 3 stages. Some&#xD;
      patients initially presenting with a non-hypoxemic viral pneumonia (stage 2a) may evolve&#xD;
      toward a more severe stage 2b or 3 (acute respiratory distress syndrome, ARDS) around the 7th&#xD;
      or 10th day of evolution, with a severe biological inflammatory syndrome (CRP&gt;200 mg/l), and&#xD;
      some times more severe complications such as acute renal insufficiency, consumptive&#xD;
      coagulopathy or shock, requiring increasing oxygen therapy, ICU admission, invasive&#xD;
      mechanical ventilation and possibly leading to death. This detrimental evolution is due to a&#xD;
      host-derived &quot;cytokine storm&quot; with a great excess of circulating inflammatory cytokines. In&#xD;
      animal models of ARDS complicating coronavirus or influenza virus infection, the cytokine&#xD;
      storm has been linked to hyperactivation of the NLRP3 inflammasome. NLRP3 constitutes an&#xD;
      intracellular protein platform which is responsible for caspase1 activation and processing of&#xD;
      interleukin (IL)-1beta and IL-18 . IL-1b is a major proinflammatory cytokine which induces&#xD;
      IL-6, whereas IL-18 is an inducer of interferon gamma (IFNg) production by Th-1 lymphocytes.&#xD;
      A blood IL-1/IL-6 signature can be defined by increased neutrophilia and CRP concentrations,&#xD;
      whereas an IL-18/IFNg signature is characterized by severe hyperferritinemia, consumptive&#xD;
      coagulopathy and cytopenia. A majority of patients with COVID-19 infections seems to have an&#xD;
      IL-1/IL-6 signature, evolving in the more severe forms toward an IL-18/IFNg signature,&#xD;
      mimicking cytokine profiles observed in other inflammatory diseases such as Still's disease&#xD;
      or hemophagocytic syndromes. In Still's disease, therapeutic inhibition of IL-1 or IL-6 has&#xD;
      proven to be very efficient strategies. During hemophagocytic syndromes, inhibition of IFNg&#xD;
      is effective in humans notably through blockade of its receptor signalization, using the JAK&#xD;
      kinase inhibitor ruxolitinib.&#xD;
&#xD;
      Following this strategy, we propose to use biological drugs currently available for&#xD;
      inhibition of IL-1 (anakinra), IL-6 (tocilizumab) or IFNg signaling (ruxolitinib) in the&#xD;
      severe forms of COVID19-associated disease. Our hypothesis is that IL-1, IL-6 or JAK kinase&#xD;
      inhibition will allow:&#xD;
&#xD;
        1. to prevent stage 2b worsening and the need to be admitted in ICU, by decreasing&#xD;
           oxygen-requirement and systemic inflammation&#xD;
&#xD;
        2. to improve stage 3 and extremely severe stage 3, allowing invasive mechanical&#xD;
           ventilation weaning, improving multi-system organ dysfunction, leading to a faster ICU&#xD;
           exit.&#xD;
&#xD;
      We propose an open randomized therapeutic trial (1/1/1) on 216 patients with severe stage 2b&#xD;
      and 3 of the disease&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">September 1, 2020</start_date>
  <completion_date type="Anticipated">November 1, 2022</completion_date>
  <primary_completion_date type="Anticipated">September 30, 2022</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>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Ventilation free days at D28</measure>
    <time_frame>28 days</time_frame>
    <description>number of days living without mechanical ventilation at D28</description>
  </primary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">216</enrollment>
  <condition>Covid19</condition>
  <arm_group>
    <arm_group_label>Anakinra +/- Ruxolitinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Anakinra +/- Ruxolitinib&#xD;
According to clinical stage (gradual strategy):&#xD;
Stage 2b or 3 : Anakinra +/- ruxolitinib depending of evolution; Advanced stage 3 : Anakinra and Ruxolitinib</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Tocilizumab +/- Ruxolitinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Tocilizumab +/- Ruxolitinib&#xD;
According to clinical stage (gradual strategy):&#xD;
Stage 2b or 3 : Tocilizumab +/- ruxolitinib depending of evolution; Advanced stage 3: Tocilizumab +ruxolitinib</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard of care</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Treatment with drugs or procedures in routine clinical practice</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Anakinra +/- Ruxolitinib (stages 2b/3)</intervention_name>
    <description>administration of Anakinra +/- ruxolitinib, depending of evolution</description>
    <arm_group_label>Anakinra +/- Ruxolitinib</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Anakinra and Ruxolitinib (Advanced stage 3)</intervention_name>
    <description>administration of Anakinra and ruxolitinib</description>
    <arm_group_label>Anakinra +/- Ruxolitinib</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tocilizumab +/- ruxolitinib (stages 2b/3)</intervention_name>
    <description>administration of Tocilizumab +/- ruxolitinib, depending of evolution</description>
    <arm_group_label>Tocilizumab +/- Ruxolitinib</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tocilizumab and Ruxolitinib (Advanced stage 3)</intervention_name>
    <description>administration of Tocilizumab and Ruxolitinib</description>
    <arm_group_label>Tocilizumab +/- Ruxolitinib</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Standard of care</intervention_name>
    <description>Treatment with drugs or procedures in routine clinical practice</description>
    <arm_group_label>Standard of care</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients older than 18 year up to 75 year-old maximum&#xD;
&#xD;
          -  Eligible for resuscitation care in UCI&#xD;
&#xD;
          -  with proven infection with COVID-19, using at least one positive pharyngeal polymerase&#xD;
             chain reaction (PCR) test&#xD;
&#xD;
          -  COVID19 infection pneumonia at&#xD;
&#xD;
               -  Stage 2b: Hypoxemic pneumonia (respiratory rate &gt;30/min, Sat O2&lt;90 mm Hg in&#xD;
                  ambient air) associated with a marked biological inflammatory syndrome&#xD;
                  (CRP&gt;150mg/l) - or Stage 3: ARDS defined by a mechanically ventilated patient&#xD;
                  with a PaO2/FiO2 ratio &lt; 300 for more than 24 hours.&#xD;
&#xD;
               -  or Advanced Stage 3: moderate to severe ARDS (PaO2/FiO2 &lt; 200 to PEEP of at least&#xD;
                  8 cmH2O) on invasive mechanical ventilation associated with another organ failure&#xD;
                  or syndrome among : 1) Shock with norepinephrine dosage &gt; 3 mg/hour, 2) Acute&#xD;
                  renal oligo-anuric failure or requiring extra-renal lavage, 3) Hepatocellular&#xD;
                  failure or coagulopathy with factor V &lt; 50%, 4) Myocarditis causing acute heart&#xD;
                  failure and/or shock. , 5) Hemophagocytic syndrome, 6) Hyperferritinemia &gt; 5000&#xD;
                  ng/mL&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients younger than 18 or older than 75 year-old,&#xD;
&#xD;
          -  Pregnant or breastfeeding woman&#xD;
&#xD;
          -  Patient for whom measures of therapeutic limitations have been issued (non-admission&#xD;
             to intensive care unit)&#xD;
&#xD;
          -  Patients treated with immunosuppressant/immunomodulators (Not only the concomitant&#xD;
             administration of the following drugs prohibited in the protocol: other JAK&#xD;
             inhibitors, corticosteroids, IL6 inhibitors).&#xD;
&#xD;
          -  Patient already included in another interventional therapeutic trial&#xD;
&#xD;
          -  Use of chronic oral corticosteroids &gt; 10 mg prednisone equivalent per day for&#xD;
             non-COVID-19 related disease&#xD;
&#xD;
          -  Uncontrolled autoimmune disease&#xD;
&#xD;
          -  Patients with active, suspected or known active systemic bacterial, viral (excluding&#xD;
             COVID-19) or fungal infections that are not controlled (not only HIV, HBV or HCV&#xD;
             infection and untreated bacterial or mycotic infection)&#xD;
&#xD;
          -  Patients with severe pre-existing uncontrolled organ dysfunction (heart, liver or&#xD;
             kidney failure) not related to COVID-19&#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_contact>
    <last_name>Gilles Kaplanski, MD</last_name>
    <email>gilles.kaplanski@ap-hm.fr</email>
  </overall_contact>
  <location>
    <facility>
      <name>Assistance Publique Hôpitaux de Marseille</name>
      <address>
        <city>Marseille</city>
        <zip>13005</zip>
        <country>France</country>
      </address>
    </facility>
    <contact>
      <last_name>Gilles Kaplanski</last_name>
      <email>gilles.kaplanski@ap-hm.fr</email>
    </contact>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>June 8, 2020</study_first_submitted>
  <study_first_submitted_qc>June 8, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 9, 2020</study_first_posted>
  <last_update_submitted>June 19, 2020</last_update_submitted>
  <last_update_submitted_qc>June 19, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 23, 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>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Interleukin 1 Receptor Antagonist Protein</mesh_term>
  </intervention_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/NCT04424056
org study id: 2020-23
nct id: NCT04424056
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
COVID19-associated disease may have different clinical aspects classified in 3 stages. Some
      patients initially presenting with a non-hypoxemic viral pneumonia (stage 2a) may evolve
      toward a more severe stage 2b or 3 (acute respiratory distress syndrome, ARDS) around the 7th
      or 10th day of evolution, with a severe biological inflammatory syndrome (CRP>200 mg/l), and
      some times more severe complications such as acute renal insufficiency, consumptive
      coagulopathy or shock, requiring increasing oxygen therapy, ICU admission, invasive
      mechanical ventilation and possibly leading to death. This detrimental evolution is due to a
      host-derived "cytokine storm" with a great excess of circulating inflammatory cytokines. In
      animal models of ARDS complicating coronavirus or influenza virus infection, the cytokine
      storm has been linked to hyperactivation of the NLRP3 inflammasome. NLRP3 constitutes an
      intracellular protein platform which is responsible for caspase1 activation and processing of
      interleukin (IL)-1beta and IL-18 . IL-1b is a major proinflammatory cytokine which induces
      IL-6, whereas IL-18 is an inducer of interferon gamma (IFNg) production by Th-1 lymphocytes.
      A blood IL-1/IL-6 signature can be defined by increased neutrophilia and CRP concentrations,
      whereas an IL-18/IFNg signature is characterized by severe hyperferritinemia, consumptive
      coagulopathy and cytopenia. A majority of patients with COVID-19 infections seems to have an
      IL-1/IL-6 signature, evolving in the more severe forms toward an IL-18/IFNg signature,
      mimicking cytokine profiles observed in other inflammatory diseases such as Still's disease
      or hemophagocytic syndromes. In Still's disease, therapeutic inhibition of IL-1 or IL-6 has
      proven to be very efficient strategies. During hemophagocytic syndromes, inhibition of IFNg
      is effective in humans notably through blockade of its receptor signalization, using the JAK
      kinase inhibitor ruxolitinib.

      Following this strategy, we propose to use biological drugs currently available for
      inhibition of IL-1 (anakinra), IL-6 (tocilizumab) or IFNg signaling (ruxolitinib) in the
      severe forms of COVID19-associated disease. Our hypothesis is that IL-1, IL-6 or JAK kinase
      inhibition will allow:

        1. to prevent stage 2b worsening and the need to be admitted in ICU, by decreasing
           oxygen-requirement and systemic inflammation

        2. to improve stage 3 and extremely severe stage 3, allowing invasive mechanical
           ventilation weaning, improving multi-system organ dysfunction, leading to a faster ICU
           exit.

      We propose an open randomized therapeutic trial (1/1/1) on 216 patients with severe stage 2b
      and 3 of the disease
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Ventilation free days at D28
time frame: 28 days
description: number of days living without mechanical ventilation at D28
arm group label: Anakinra +/- Ruxolitinib
arm group type: Experimental
description: Anakinra +/- Ruxolitinib
According to clinical stage (gradual strategy):
Stage 2b or 3 : Anakinra +/- ruxolitinib depending of evolution; Advanced stage 3 : Anakinra and Ruxolitinib
arm group label: Tocilizumab +/- Ruxolitinib
arm group type: Experimental
description: Tocilizumab +/- Ruxolitinib
According to clinical stage (gradual strategy):
Stage 2b or 3 : Tocilizumab +/- ruxolitinib depending of evolution; Advanced stage 3: Tocilizumab +ruxolitinib
arm group label: Standard of care
arm group type: Active Comparator
description: Treatment with drugs or procedures in routine clinical practice
intervention type: Drug
intervention name: Anakinra +/- Ruxolitinib (stages 2b/3)
description: administration of Anakinra +/- ruxolitinib, depending of evolution
arm group label: Anakinra +/- Ruxolitinib
intervention type: Drug
intervention name: Anakinra and Ruxolitinib (Advanced stage 3)
description: administration of Anakinra and ruxolitinib
arm group label: Anakinra +/- Ruxolitinib
intervention type: Drug
intervention name: Tocilizumab +/- ruxolitinib (stages 2b/3)
description: administration of Tocilizumab +/- ruxolitinib, depending of evolution
arm group label: Tocilizumab +/- Ruxolitinib
intervention type: Drug
intervention name: Tocilizumab and Ruxolitinib (Advanced stage 3)
description: administration of Tocilizumab and Ruxolitinib
arm group label: Tocilizumab +/- Ruxolitinib
intervention type: Other
intervention name: Standard of care
description: Treatment with drugs or procedures in routine clinical practice
arm group label: Standard of care
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Gilles Kaplanski, MD
email: gilles.kaplanski@ap-hm.fr
facility: 
contact: 
country: France
responsible party type: Sponsor
mesh term: COVID-19
mesh term: Interleukin 1 Receptor Antagonist Protein
sharing ipd: No