<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/NCT04443881</url>
  </required_header>
  <id_info>
    <org_study_id>ANA-COVID-GEAS</org_study_id>
    <nct_id>NCT04443881</nct_id>
  </id_info>
  <brief_title>Clinical Trial of the Use of Anakinra in Cytokine Storm Syndrome Secondary to Covid-19 (ANA-COVID-GEAS)</brief_title>
  <acronym>ANA-COVID-GEAS</acronym>
  <official_title>Clinical Trial of the Use of Anakinra in Cytokine Storm Syndrome Secondary to Covid-19. A Phase 2/3, Randomized, Open-label, Parallel Group, 2-arm, Multicenter Study Investigating the Efficacy and Safety of Intravenous Administrations of Anakinra, an Interleukin-1(IL-1) Receptor Antagonist, Added to Standard of Care, Versus Standard of Care, in Reducing Hyper-inflammation and Respiratory Distress in Patients With SARS- CoV-2 Infection</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Fundacion Miguel Servet</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Fundacion Miguel Servet</source>
  <oversight_info>
    <has_dmc>No</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>
      Phase 2/3 randomized, parallel group, 2-arm study (treatment vs. control), investigating the&#xD;
      efficacy and safety of intravenous administration of anakinra, an interleukin 1 receptor&#xD;
      antagonist ( IL-1), added to standard treatment, compared to standard treatment alone, to&#xD;
      reduce hyperinflammation and respiratory distress in patients with SARS-CoV-2 infection.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This protocol has been prepared by the Systemic Autoimmune Diseases Group (GEAS) steering&#xD;
      committee from the Spanish Society of Internal Medicine (SEMI) in response to the current&#xD;
      urgent situation that are living in Spain because of the COVID-19 pandemic. The GEAS member&#xD;
      are experts in the treatment of autoinflammatory diseases and the use of biologic drugs in&#xD;
      general, and anakinra in particular. importantly, in Spain, internal medicine physicians are&#xD;
      currently involved in the treatment of patients infected with SARS-CoV-2.&#xD;
&#xD;
      The objective of this study is to investigate new possibilities to reduce the number of&#xD;
      patients requiring mechanical ventilation. This is intended to address the most urgent need&#xD;
      to preserve the access to intense care unit support to the lower possible number of patients&#xD;
      and may potentially reduce mortality.&#xD;
&#xD;
      In December 2019, a respiratory condition caused by what was later identified as a new&#xD;
      coronavirus (SARS-CoV-2) was detected in Wuhan Province, China. In these four months, the&#xD;
      virus has spread throughout the world's population, in more than 100 countries and affecting&#xD;
      thousands of people. The WHO declared in March that we were facing a pandemic because of this&#xD;
      virus, in which Europe could now be considered the epicenter. The strict containment measures&#xD;
      implemented in China, the mass detection of the virus with subsequent isolation of cases and&#xD;
      contacts that has been carried out in countries such as Singapore, Taiwan or South Korea seem&#xD;
      to have been useful in limiting the virus´ spread. Consequently, in our country, and given&#xD;
      the extension of the infection, a state of alarm has been decreed, at least for four weeks.&#xD;
      Despite the containment measures, numerous cases are still being diagnosed every day, with an&#xD;
      approximate lethality of 3.7%, especially in those considered at risk such as patients over&#xD;
      60 years of age and with comorbidities (Report nº 17. COVID-19 situation in Spain on 27 March&#xD;
      2020. COVID-19 team. SiViES. CNE. CNM. ISCIII).&#xD;
&#xD;
      When SARS-CoV-2 infects the respiratory tract, it causes the disease called COVID-19. From&#xD;
      the point of view of the natural evolution of the disease, this can be a mild respiratory&#xD;
      syndrome, which will occur in approximately 80% of cases, or a more serious disease, with the&#xD;
      appearance of pulmonary infiltrates and in some patients a respiratory distress with rapidly&#xD;
      progressive worsening. This second phase, which is only reached by a subgroup of patients, is&#xD;
      usually seen in the interval between day 7 and day 10 of the infection from the onset of&#xD;
      symptoms. So far, there is no proven explanation for this great variability in its clinical&#xD;
      expression.&#xD;
&#xD;
      The treatment used in our country so far is based on the combination of hydroxychloroquine,&#xD;
      azithromycin and antiretrovirals (protease inhibitors, lopinavir), based on previous&#xD;
      experiences. Several clinical trials are currently underway in Spain: PanCOVID-19&#xD;
      (Azithromycin + Hydroxychloroquine + lopinavir/ritonavir), GS-US-540-5774 (Remdesivir),&#xD;
      EFC16844 (Sarilumab) and WA42380 (Tocilizumab) as well as international projects such as&#xD;
      Discovery (NCT04315948), Solidarity and REMAP-CAP which include other treatment alternatives&#xD;
      such as interferon-beta-1B or Anakinra.&#xD;
&#xD;
      According to recent data from the Chinese cohorts, a subgroup of patients with COVID-19 shows&#xD;
      a very marked increase in inflammatory test data, such as lymphopenia, thrombocytopenia,&#xD;
      C-reactive protein (CRP) levels, lactate dehydrogenase (LDH), IL6 (&gt; 40 pg / mL) and D-dimer&#xD;
      (&gt; 0.28 μg / L), the latter two being predictive of the development of severe pneumonia&#xD;
      (sensitivity 93.3%, specificity 96.4%). Accumulating evidence suggests that a subgroup of&#xD;
      patients with severe COVID-19 might have a cytokine storm syndrome (CSS). In this group of&#xD;
      patients in which this &quot;inflammatory profile&quot; is detected, the damage observed is not a&#xD;
      direct consequence of the viral infection (viral necrotizing pneumonia) but rather a&#xD;
      secondary hyperimmune response, mainly related to the monocyte/macrophage activation, which&#xD;
      has also been observed in autopsy studies and previously in other infections by other types&#xD;
      of coronavirus. This CSS is superimoosable to that observed in patients with secondary&#xD;
      hemophagocytic lymphohistiocytosis (sHLH), often triggered by viral infections or macrophage&#xD;
      activation syndrome (MAS), secondary to systemic and autoinflammatory autoimmune diseases.&#xD;
&#xD;
      In this group of patients there is a significant release of pro-inflammatory cytokines,&#xD;
      including interleukin (IL) -1β and IL-6. Of these, IL-1β has a greater pathogenic relevance,&#xD;
      given that it promotes the inflammatory cascade and also induces the synthesis of several&#xD;
      inflammatory genes such as IL-6 itself, IL-8, MCP-1, COX-2, IκBα, IL-1α, IL-1β and MKP-1.&#xD;
      Numerous case reports and case series have been published supporting the use of IL-1β&#xD;
      blockade in the MAS. At this time, there is some experience in the treatment of COVID-19 in&#xD;
      the subgroup of patients in the inflammatory phase with Tocilizumab (IL-6 receptor blocker),&#xD;
      but no controlled studies have been completed as yet. However, IL-6 is not a key molecule in&#xD;
      the cytokine storm that triggers MAS.&#xD;
&#xD;
      Anakinra (IL-1Ra) is a recombinant IL-1 receptor antagonist with a very short half-life of&#xD;
      4-6 hours, requiring a daily subcutaneous injection of a 100 mg dose. It has also been shown&#xD;
      to reduce levels of other pro-inflammatory cytokines (including IL-6 and IL-18) and acute&#xD;
      phase reactants such as PCR and ferritin. Therefore, it has been used in the control of&#xD;
      autoinflammatory syndromes and in patients with MAS. In addition, data have been reported&#xD;
      from a phase 3 randomized controlled trial of IL-1 blockade with anakinra in sepsis with&#xD;
      characteristics of MAS, which showed a significant improvement in the 28-day survival rate&#xD;
      (65.4% anakinra vs. 35.3% placebo), with HR for death 0.28 (0.11-0.71, p = 0.0071), with no&#xD;
      increased adverse events.&#xD;
&#xD;
      As shown by the data available in the most recent literature generated from the Chinese&#xD;
      experience, and by the most recent data made available by the different Spanish hospitals&#xD;
      responsible for the management of these patients, hyper- inflammation, caused by a cytokine&#xD;
      storm resulting from an exaggerated response of the immune system to the presence of the&#xD;
      virus (CSS-like pneumonia), is considered to represent one of the most important negative&#xD;
      prognostic factor in patients infected with SARS-CoV-2. The inclusion criteria for COVID-19&#xD;
      used in this protocol is based on the analysis of routine blood chemistry data obtained from&#xD;
      patients with SARS-CoV-2 infection. This criterion has been designed with high sensitivity&#xD;
      (&gt;90%) for patients who require ICU admission. This constitute the rationale for testing&#xD;
      drugs specifically targeted to reduce the cytokine storm.&#xD;
&#xD;
      This protocol has been prepared for the purpose of addressing the current medical emergency,&#xD;
      given the severity of the disease and the extremely high number of individuals affected. The&#xD;
      objective of this study is to investigate anakinra to reduce the number of patients requiring&#xD;
      mechanical ventilation. This is intended to address the most urgent need to preserve the&#xD;
      access to intense care unit support to the lower possible number of patients and may&#xD;
      potentially reduce mortality.&#xD;
&#xD;
      The potential applicability of the results of this clinical trial, in an extraordinary health&#xD;
      emergency such as COVID-19, is obvious. Positive results could help to define the standard&#xD;
      treatment of severe COVID-19 pneumonia and have a dramatic impact on both local and global&#xD;
      morbidity and mortality. Negative results would constitute very useful scientific evidence&#xD;
      for abandoning unfounded empirical approaches and would help redirect resources and efforts&#xD;
      in another more promising direction. The expected length of time needed for recruitment is&#xD;
      3-4 weeks, depending on the epidemiological progression of the pandemic in our centers, so&#xD;
      results could be available in early May 2020.&#xD;
&#xD;
      Anakinra is a recombinant form of the human IL-Ra, r-metHuIL-1Ra, which is produced by&#xD;
      recombinant DNA technology in an E. coli expression system. Therapeutically, anakinra&#xD;
      neutralizes the biological activity of IL-1 (IL-1α and IL-1β) by competitively inhibiting its&#xD;
      binding to the IL-1RI.&#xD;
&#xD;
      Kineret (anakinra) was first approved for treatment of RA in the US in 2001 and subsequently&#xD;
      in the EU/EEA in 2002. In 2012, an sBLA on anakinra for treatment of NOMID was approved in&#xD;
      the US. Kineret is also approved for treatment of CAPS (in EU/EEA, Israel and Australia),&#xD;
      Still's disease, including SJIA and AOSD (in EU/EEA) and SJIA (in Australia).&#xD;
&#xD;
      The initial IND for anakinra was granted in 1991. The estimated cumulative exposure to&#xD;
      anakinra in completed company sponsored clinical studies up to 1 May 2018 is 6404 subject-&#xD;
      years, in 8518 subjects with various indications. Anakinra is administered s.c. at doses of&#xD;
      100 mg/day (RA) or in weight-based doses of up to 8 mg/kg/day (NOMID). In clinical studies in&#xD;
      sepsis, doses up to 2 mg/kg/hour i.v. over 72 hours were administered to &gt;500 patients and&#xD;
      were well tolerated.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 8, 2020</start_date>
  <completion_date type="Actual">March 31, 2021</completion_date>
  <primary_completion_date type="Actual">March 31, 2021</primary_completion_date>
  <phase>Phase 2/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>A phase 2/3, randomized, open label, parallel group, 2-arm, multicenter study investigating the efficacy and safety of intravenous administrations of the study drug,</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Treatment success, defined as number of patients not requiring mechanical ventilation to assess the effect of anakinra in addition to standard treatment on the need for mechanical ventilation in patients with severe COVID-19 and CSS pneumonia.</measure>
    <time_frame>Day 15</time_frame>
    <description>Treatment success, defined as number of patients not requiring mechanical ventilation by Day 15.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of patients not requiring mechanical ventilation to assess the effect of anakinra in addition to standard treatment on the need for mechanical ventilation in patients with severe COVID-19 and CSS pneumonia.</measure>
    <time_frame>Day 28</time_frame>
    <description>Number of patients not requiring mechanical ventilation</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Time to mechanical ventilation to assess the effect of anakinra in addition to standard treatment on the need for mechanical ventilation in patients with severe COVID-19 and CSS pneumonia.</measure>
    <time_frame>Up to 28 days</time_frame>
    <description>Time to mechanical ventilation</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Time to oxygen saturation normalization to assess the effect of anakinra in addition to standard treatment on the need for mechanical ventilation in patients with severe COVID-19 and CSS pneumonia.</measure>
    <time_frame>Up to 28 days</time_frame>
    <description>Time to oxygen saturation normalization</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Stay in ICU and hospitalization to assess the effect of anakinra in addition to standard treatment on the need for mechanical ventilation in patients with severe COVID-19 and CSS pneumonia.</measure>
    <time_frame>Up to 28 days</time_frame>
    <description>Stay in ICU and hospitalization</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Total mortality rate to assess the effect of anakinra in addition to standard treatment on mortality in patients with severe COVID-19 and CSS pneumonia.</measure>
    <time_frame>day 28</time_frame>
    <description>Total mortality rate</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality 48 hours, 7 days, in ICU and hospital to assess the effect of anakinra in addition to standard treatment on mortality in patients with severe COVID-19 and CSS pneumonia.</measure>
    <time_frame>48 hours, 7 days</time_frame>
    <description>Mortality 48 hours, 7 days, in ICU and hospital</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Viral clearance / viral shedding to assess the effect of anakinra in addition to standard treatment on mortality in patients with severe COVID-19 and CSS pneumonia.</measure>
    <time_frame>Up to 28 days</time_frame>
    <description>Viral clearance / viral shedding</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To assess the effect of anakinra in addition to standard treatment on mortality in patients with severe COVID-19 and CSS pneumonia.</measure>
    <time_frame>At day 28</time_frame>
    <description>Frequency and severity of AEs: Treatment-emergent severe fatal and life-threatening serious adverse events (SAEs), Adverse events leading to premature discontinuation of study treatment, Anaphylactic/anaphylactoid reactions, Anakinra treatment group: Severe neutropenia, Treatment-emergent laboratory abnormalities.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Change in IL-6 to assess the effect of anakinra on IL-6, ferritin, and selected biomarkers relevant for hyperinflammation, MAS and cytokine storm change from baseline.</measure>
    <time_frame>During 28 days</time_frame>
    <description>Change (improvement) in IL-6</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in ferritin to assess the effect of anakinra</measure>
    <time_frame>During 28 days</time_frame>
    <description>Change (improvement) in ferritin</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in D-dimer to assess the effect of anakinra</measure>
    <time_frame>During 28 days</time_frame>
    <description>Change (improvement) in D-dimer</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in TGs to assess the effect of anakinra</measure>
    <time_frame>During 28 days</time_frame>
    <description>Change (improvement) in TGs</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in lymphopenia to assess the effect of anakinra</measure>
    <time_frame>During 28 days</time_frame>
    <description>Change (improvement) in lymphopenia</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in CRP to assess the effect of anakinra</measure>
    <time_frame>During 28 days</time_frame>
    <description>Change (improvement) in CRP</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in ESR to assess the effect of anakinra</measure>
    <time_frame>During 28 days</time_frame>
    <description>Change (improvement) in ESR</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in LDH to assess the effect of anakinra</measure>
    <time_frame>During 28 days</time_frame>
    <description>Change (improvement) in LDH</description>
  </other_outcome>
  <other_outcome>
    <measure>Time to defervescence to assess the effect of anakinra</measure>
    <time_frame>During 28 days</time_frame>
    <description>Time to defervescence (fever end)</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">179</enrollment>
  <condition>COVID-19 Pnemonia</condition>
  <arm_group>
    <arm_group_label>Anakinra Arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Standard of care plus Anakinra (100mg) administered as 4-times daily i.v. infusions for a maximun of 15 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control Arm</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Standard of care</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Anakinra 149 MG/ML Prefilled Syringe [Kineret]</intervention_name>
    <description>Anakinra (100 mg/ 6 hours) i.v infusión during 15 days</description>
    <arm_group_label>Anakinra Arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  Inclusion Criteria:&#xD;
&#xD;
               -  Age 18-80 years.&#xD;
&#xD;
               -  Severe pneumonia COVID-19 defined as:&#xD;
&#xD;
               -  Nasopharyngeal smear with RCP positive for SARS-CoV-2&#xD;
&#xD;
               -  X-Rays (or other technique) pulmonary infiltrates compatible with pneumonia.&#xD;
&#xD;
               -  1 or more of the following criteria:&#xD;
&#xD;
               -  Ambient air oxygen saturation &lt;= 94% measured with a pulse oximeter.&#xD;
&#xD;
               -  Pa:FiO2 (partial pressure O2/fraction of inspired O2) &lt;=300.&#xD;
&#xD;
               -  Sa:FiO2 (O2 saturation measured with pulse oximeter/ fraction of inspired O2)&#xD;
                  &lt;=350.&#xD;
&#xD;
               -  High suspicion of CSS that could resemble MAS-like: represented by IL-6 values &gt;&#xD;
                  40 pg/mL and/or ferritin &gt;500 ug/L and/or PCR &gt; 30 mg/L (rationale: ≥ 5 upper&#xD;
                  normal limit) and/or LDH &gt;300 UI/L. We have chosen these parameters because they&#xD;
                  are implemented in all the participating hospitals, they are a reflection of the&#xD;
                  cytokine storm and they have also been significant in terms of predicting&#xD;
                  mortality in patients with COVID-19 (9).&#xD;
&#xD;
               -  Written informed consent. The protocol will be explained to the patient in front&#xD;
                  of a nurse who will act as a legal witness by signing the document on behalf of&#xD;
                  the patient.&#xD;
&#xD;
          -  Exclusion Criteria:&#xD;
&#xD;
               -  Need for oro-tracheal intubation and/or invasive mechanical ventilation at the&#xD;
                  start of the study.&#xD;
&#xD;
               -  AST/ALT with values greater than 5 times normal levels.&#xD;
&#xD;
               -  Neutrophils &lt; 1.500 cell/mmc.&#xD;
&#xD;
               -  Platelets &lt; 50.000 cell/mmc.&#xD;
&#xD;
               -  Sepsis or pneumonia documented by other pathogens than SARS-CoV-2.&#xD;
&#xD;
               -  Existence of any life-threatening comorbidity or any other medical condition&#xD;
                  that, in the investigator's opinion, makes the patient unsuitable for inclusion.&#xD;
&#xD;
               -  Inability to obtain informed consent.&#xD;
&#xD;
               -  Positivity for HBV, HCV or tuberculin test serology.&#xD;
&#xD;
               -  Pregnancy.&#xD;
&#xD;
               -  Use of other previous or concomitant biological treatments. Patients in&#xD;
                  concomitant treatment with other biologicals that may interfere will be excluded:&#xD;
                  tocilizumab, canakinumab, TNFalfa inhibitors, JAKiinibs&#xD;
&#xD;
               -  Severe renal dysfunction (estimated glomerular filtration rate ≤ 30 ml / min /&#xD;
                  1.73 m2) or receive continuous renal replacement therapy, hemodialysis or&#xD;
                  peritoneal dialysis.&#xD;
&#xD;
               -  Uncontrolled hypertension (sitting systolic blood pressure &gt; 180 mmHg or&#xD;
                  diastolic blood pressure &gt; 110 mmHg).&#xD;
&#xD;
               -  Administration of plasma from convalescent patients who have recovered from&#xD;
                  SARS-CoV-2 infection.&#xD;
&#xD;
               -  History of hypersensitivity or allergy to any component of the study drug.&#xD;
&#xD;
               -  Enrollment in another concurrent intervention clinical trial, or intake of an&#xD;
                  investigational medication within three months or 5 half-lives prior to inclusion&#xD;
                  in this study, if deemed to interfere with the objectives of this study as&#xD;
                  assessed by the investigator.&#xD;
&#xD;
               -  Predictable inability to cooperate with given instructions or study procedures.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Patricia Fanlo Mateo, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Complejo Hospitalario de Navarra</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hospital Universitario Miguel Servet</name>
      <address>
        <city>Zaragoza</city>
        <state>Aragón</state>
        <zip>50009</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario de Cabueñes</name>
      <address>
        <city>Gijón</city>
        <state>Asturias</state>
        <zip>33394</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Clinic</name>
      <address>
        <city>Barcelona</city>
        <state>Cataluña</state>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Vall d´Hebron</name>
      <address>
        <city>Barcelona</city>
        <state>Cataluña</state>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Complexo Hospitalario Universitario de Santiago</name>
      <address>
        <city>Santiago De Compostela</city>
        <state>Galicia</state>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Son Espases</name>
      <address>
        <city>Palma De Mallorca</city>
        <state>Mallorca</state>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Complejo Hospitalario de Navarra</name>
      <address>
        <city>Pamplona</city>
        <state>Navarra</state>
        <zip>31008</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario La Paz</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Ramon y Cajal</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario y Politecnico La Fe</name>
      <address>
        <city>Valencia</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Complejo Hospitalario Universitario de Vigo</name>
      <address>
        <city>Vigo</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Clínico Universitario Lozano Blesa</name>
      <address>
        <city>Zaragoza</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <verification_date>May 2021</verification_date>
  <study_first_submitted>June 18, 2020</study_first_submitted>
  <study_first_submitted_qc>June 20, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 23, 2020</study_first_posted>
  <last_update_submitted>May 27, 2021</last_update_submitted>
  <last_update_submitted_qc>May 27, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">June 1, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Covid-19 disease</keyword>
  <keyword>pneumonia</keyword>
  <keyword>Cytokine Storm Sindrome</keyword>
  <keyword>Anti IL-1</keyword>
  <keyword>Anakinra</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
    <mesh_term>Cytokine Release Syndrome</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>
    <ipd_description>All collected IPD will be available for exploitation in future research projects. This statement also includes the availability of the study protocol, the statistical analysis plan, the informed consent form, the clinical study report and the analytic code.</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/NCT04443881
org study id: ANA-COVID-GEAS
nct id: NCT04443881
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
Phase 2/3 randomized, parallel group, 2-arm study (treatment vs. control), investigating the
      efficacy and safety of intravenous administration of anakinra, an interleukin 1 receptor
      antagonist ( IL-1), added to standard treatment, compared to standard treatment alone, to
      reduce hyperinflammation and respiratory distress in patients with SARS-CoV-2 infection.
This protocol has been prepared by the Systemic Autoimmune Diseases Group (GEAS) steering
      committee from the Spanish Society of Internal Medicine (SEMI) in response to the current
      urgent situation that are living in Spain because of the COVID-19 pandemic. The GEAS member
      are experts in the treatment of autoinflammatory diseases and the use of biologic drugs in
      general, and anakinra in particular. importantly, in Spain, internal medicine physicians are
      currently involved in the treatment of patients infected with SARS-CoV-2.

      The objective of this study is to investigate new possibilities to reduce the number of
      patients requiring mechanical ventilation. This is intended to address the most urgent need
      to preserve the access to intense care unit support to the lower possible number of patients
      and may potentially reduce mortality.

      In December 2019, a respiratory condition caused by what was later identified as a new
      coronavirus (SARS-CoV-2) was detected in Wuhan Province, China. In these four months, the
      virus has spread throughout the world's population, in more than 100 countries and affecting
      thousands of people. The WHO declared in March that we were facing a pandemic because of this
      virus, in which Europe could now be considered the epicenter. The strict containment measures
      implemented in China, the mass detection of the virus with subsequent isolation of cases and
      contacts that has been carried out in countries such as Singapore, Taiwan or South Korea seem
      to have been useful in limiting the virus´ spread. Consequently, in our country, and given
      the extension of the infection, a state of alarm has been decreed, at least for four weeks.
      Despite the containment measures, numerous cases are still being diagnosed every day, with an
      approximate lethality of 3.7%, especially in those considered at risk such as patients over
      60 years of age and with comorbidities (Report nº 17. COVID-19 situation in Spain on 27 March
      2020. COVID-19 team. SiViES. CNE. CNM. ISCIII).

      When SARS-CoV-2 infects the respiratory tract, it causes the disease called COVID-19. From
      the point of view of the natural evolution of the disease, this can be a mild respiratory
      syndrome, which will occur in approximately 80% of cases, or a more serious disease, with the
      appearance of pulmonary infiltrates and in some patients a respiratory distress with rapidly
      progressive worsening. This second phase, which is only reached by a subgroup of patients, is
      usually seen in the interval between day 7 and day 10 of the infection from the onset of
      symptoms. So far, there is no proven explanation for this great variability in its clinical
      expression.

      The treatment used in our country so far is based on the combination of hydroxychloroquine,
      azithromycin and antiretrovirals (protease inhibitors, lopinavir), based on previous
      experiences. Several clinical trials are currently underway in Spain: PanCOVID-19
      (Azithromycin + Hydroxychloroquine + lopinavir/ritonavir), GS-US-540-5774 (Remdesivir),
      EFC16844 (Sarilumab) and WA42380 (Tocilizumab) as well as international projects such as
      Discovery (NCT04315948), Solidarity and REMAP-CAP which include other treatment alternatives
      such as interferon-beta-1B or Anakinra.

      According to recent data from the Chinese cohorts, a subgroup of patients with COVID-19 shows
      a very marked increase in inflammatory test data, such as lymphopenia, thrombocytopenia,
      C-reactive protein (CRP) levels, lactate dehydrogenase (LDH), IL6 (> 40 pg / mL) and D-dimer
      (> 0.28 μg / L), the latter two being predictive of the development of severe pneumonia
      (sensitivity 93.3%, specificity 96.4%). Accumulating evidence suggests that a subgroup of
      patients with severe COVID-19 might have a cytokine storm syndrome (CSS). In this group of
      patients in which this "inflammatory profile" is detected, the damage observed is not a
      direct consequence of the viral infection (viral necrotizing pneumonia) but rather a
      secondary hyperimmune response, mainly related to the monocyte/macrophage activation, which
      has also been observed in autopsy studies and previously in other infections by other types
      of coronavirus. This CSS is superimoosable to that observed in patients with secondary
      hemophagocytic lymphohistiocytosis (sHLH), often triggered by viral infections or macrophage
      activation syndrome (MAS), secondary to systemic and autoinflammatory autoimmune diseases.

      In this group of patients there is a significant release of pro-inflammatory cytokines,
      including interleukin (IL) -1β and IL-6. Of these, IL-1β has a greater pathogenic relevance,
      given that it promotes the inflammatory cascade and also induces the synthesis of several
      inflammatory genes such as IL-6 itself, IL-8, MCP-1, COX-2, IκBα, IL-1α, IL-1β and MKP-1.
      Numerous case reports and case series have been published supporting the use of IL-1β
      blockade in the MAS. At this time, there is some experience in the treatment of COVID-19 in
      the subgroup of patients in the inflammatory phase with Tocilizumab (IL-6 receptor blocker),
      but no controlled studies have been completed as yet. However, IL-6 is not a key molecule in
      the cytokine storm that triggers MAS.

      Anakinra (IL-1Ra) is a recombinant IL-1 receptor antagonist with a very short half-life of
      4-6 hours, requiring a daily subcutaneous injection of a 100 mg dose. It has also been shown
      to reduce levels of other pro-inflammatory cytokines (including IL-6 and IL-18) and acute
      phase reactants such as PCR and ferritin. Therefore, it has been used in the control of
      autoinflammatory syndromes and in patients with MAS. In addition, data have been reported
      from a phase 3 randomized controlled trial of IL-1 blockade with anakinra in sepsis with
      characteristics of MAS, which showed a significant improvement in the 28-day survival rate
      (65.4% anakinra vs. 35.3% placebo), with HR for death 0.28 (0.11-0.71, p = 0.0071), with no
      increased adverse events.

      As shown by the data available in the most recent literature generated from the Chinese
      experience, and by the most recent data made available by the different Spanish hospitals
      responsible for the management of these patients, hyper- inflammation, caused by a cytokine
      storm resulting from an exaggerated response of the immune system to the presence of the
      virus (CSS-like pneumonia), is considered to represent one of the most important negative
      prognostic factor in patients infected with SARS-CoV-2. The inclusion criteria for COVID-19
      used in this protocol is based on the analysis of routine blood chemistry data obtained from
      patients with SARS-CoV-2 infection. This criterion has been designed with high sensitivity
      (>90%) for patients who require ICU admission. This constitute the rationale for testing
      drugs specifically targeted to reduce the cytokine storm.

      This protocol has been prepared for the purpose of addressing the current medical emergency,
      given the severity of the disease and the extremely high number of individuals affected. The
      objective of this study is to investigate anakinra to reduce the number of patients requiring
      mechanical ventilation. This is intended to address the most urgent need to preserve the
      access to intense care unit support to the lower possible number of patients and may
      potentially reduce mortality.

      The potential applicability of the results of this clinical trial, in an extraordinary health
      emergency such as COVID-19, is obvious. Positive results could help to define the standard
      treatment of severe COVID-19 pneumonia and have a dramatic impact on both local and global
      morbidity and mortality. Negative results would constitute very useful scientific evidence
      for abandoning unfounded empirical approaches and would help redirect resources and efforts
      in another more promising direction. The expected length of time needed for recruitment is
      3-4 weeks, depending on the epidemiological progression of the pandemic in our centers, so
      results could be available in early May 2020.

      Anakinra is a recombinant form of the human IL-Ra, r-metHuIL-1Ra, which is produced by
      recombinant DNA technology in an E. coli expression system. Therapeutically, anakinra
      neutralizes the biological activity of IL-1 (IL-1α and IL-1β) by competitively inhibiting its
      binding to the IL-1RI.

      Kineret (anakinra) was first approved for treatment of RA in the US in 2001 and subsequently
      in the EU/EEA in 2002. In 2012, an sBLA on anakinra for treatment of NOMID was approved in
      the US. Kineret is also approved for treatment of CAPS (in EU/EEA, Israel and Australia),
      Still's disease, including SJIA and AOSD (in EU/EEA) and SJIA (in Australia).

      The initial IND for anakinra was granted in 1991. The estimated cumulative exposure to
      anakinra in completed company sponsored clinical studies up to 1 May 2018 is 6404 subject-
      years, in 8518 subjects with various indications. Anakinra is administered s.c. at doses of
      100 mg/day (RA) or in weight-based doses of up to 8 mg/kg/day (NOMID). In clinical studies in
      sepsis, doses up to 2 mg/kg/hour i.v. over 72 hours were administered to >500 patients and
      were well tolerated.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: A phase 2/3, randomized, open label, parallel group, 2-arm, multicenter study investigating the efficacy and safety of intravenous administrations of the study drug,
primary purpose: Treatment
masking: None (Open Label)
measure: Treatment success, defined as number of patients not requiring mechanical ventilation to assess the effect of anakinra in addition to standard treatment on the need for mechanical ventilation in patients with severe COVID-19 and CSS pneumonia.
time frame: Day 15
description: Treatment success, defined as number of patients not requiring mechanical ventilation by Day 15.
measure: Number of patients not requiring mechanical ventilation to assess the effect of anakinra in addition to standard treatment on the need for mechanical ventilation in patients with severe COVID-19 and CSS pneumonia.
time frame: Day 28
description: Number of patients not requiring mechanical ventilation
measure: Time to mechanical ventilation to assess the effect of anakinra in addition to standard treatment on the need for mechanical ventilation in patients with severe COVID-19 and CSS pneumonia.
time frame: Up to 28 days
description: Time to mechanical ventilation
measure: Time to oxygen saturation normalization to assess the effect of anakinra in addition to standard treatment on the need for mechanical ventilation in patients with severe COVID-19 and CSS pneumonia.
time frame: Up to 28 days
description: Time to oxygen saturation normalization
measure: Stay in ICU and hospitalization to assess the effect of anakinra in addition to standard treatment on the need for mechanical ventilation in patients with severe COVID-19 and CSS pneumonia.
time frame: Up to 28 days
description: Stay in ICU and hospitalization
measure: Total mortality rate to assess the effect of anakinra in addition to standard treatment on mortality in patients with severe COVID-19 and CSS pneumonia.
time frame: day 28
description: Total mortality rate
measure: Mortality 48 hours, 7 days, in ICU and hospital to assess the effect of anakinra in addition to standard treatment on mortality in patients with severe COVID-19 and CSS pneumonia.
time frame: 48 hours, 7 days
description: Mortality 48 hours, 7 days, in ICU and hospital
measure: Viral clearance / viral shedding to assess the effect of anakinra in addition to standard treatment on mortality in patients with severe COVID-19 and CSS pneumonia.
time frame: Up to 28 days
description: Viral clearance / viral shedding
measure: To assess the effect of anakinra in addition to standard treatment on mortality in patients with severe COVID-19 and CSS pneumonia.
time frame: At day 28
description: Frequency and severity of AEs: Treatment-emergent severe fatal and life-threatening serious adverse events (SAEs), Adverse events leading to premature discontinuation of study treatment, Anaphylactic/anaphylactoid reactions, Anakinra treatment group: Severe neutropenia, Treatment-emergent laboratory abnormalities.
measure: Change in IL-6 to assess the effect of anakinra on IL-6, ferritin, and selected biomarkers relevant for hyperinflammation, MAS and cytokine storm change from baseline.
time frame: During 28 days
description: Change (improvement) in IL-6
measure: Change in ferritin to assess the effect of anakinra
time frame: During 28 days
description: Change (improvement) in ferritin
measure: Change in D-dimer to assess the effect of anakinra
time frame: During 28 days
description: Change (improvement) in D-dimer
measure: Change in TGs to assess the effect of anakinra
time frame: During 28 days
description: Change (improvement) in TGs
measure: Change in lymphopenia to assess the effect of anakinra
time frame: During 28 days
description: Change (improvement) in lymphopenia
measure: Change in CRP to assess the effect of anakinra
time frame: During 28 days
description: Change (improvement) in CRP
measure: Change in ESR to assess the effect of anakinra
time frame: During 28 days
description: Change (improvement) in ESR
measure: Change in LDH to assess the effect of anakinra
time frame: During 28 days
description: Change (improvement) in LDH
measure: Time to defervescence to assess the effect of anakinra
time frame: During 28 days
description: Time to defervescence (fever end)
arm group label: Anakinra Arm
arm group type: Experimental
description: Standard of care plus Anakinra (100mg) administered as 4-times daily i.v. infusions for a maximun of 15 days
arm group label: Control Arm
arm group type: No Intervention
description: Standard of care
intervention type: Drug
intervention name: Anakinra 149 MG/ML Prefilled Syringe [Kineret]
description: Anakinra (100 mg/ 6 hours) i.v infusión during 15 days
arm group label: Anakinra Arm
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Patricia Fanlo Mateo, PhD
role: Principal Investigator
affiliation: Complejo Hospitalario de Navarra
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country: Spain
responsible party type: Sponsor
mesh term: COVID-19
mesh term: Cytokine Release Syndrome
mesh term: Interleukin 1 Receptor Antagonist Protein
sharing ipd: No
ipd description: All collected IPD will be available for exploitation in future research projects. This statement also includes the availability of the study protocol, the statistical analysis plan, the informed consent form, the clinical study report and the analytic code.