<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/NCT04445272</url>
  </required_header>
  <id_info>
    <org_study_id>BREATH-19 (FSG011-20)</org_study_id>
    <nct_id>NCT04445272</nct_id>
  </id_info>
  <brief_title>Clinical Trial to Evaluate the Effectiveness and Safety of Tocilizumab for Treating Patients With COVID-19 Pneumonia</brief_title>
  <official_title>A Multicentre, Open-label Clinical Trial to Evaluate the Effectiveness and Safety of Intravenous Tocilizumab for Treating Patients With COVID-19 Pneumonia: the BREATH-19 Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Fundacion SEIMC-GESIDA</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Roche Pharma AG</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Dynamic Science S.L.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Fundacion SEIMC-GESIDA</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      At present, no treatment has been approved for COVID-19. However, in light of the increased&#xD;
      interest on using the anti-cytokine therapy targeting IL-6 tocilizumab in COVID-19 infected&#xD;
      patients due to its potential benefit, the Spanish Agency for Medicine and Health Products&#xD;
      (Agencia Española de Medicamentos y Productos Sanitarios, AEMPS) have initiated the&#xD;
      controlled distribution of the drug. Tocilizumab is indeed proposed as a potential treatment&#xD;
      for severe COVID-19 in Spain. Based on the positive results of tocilizumab in the treatment&#xD;
      of COVID-19 patients and the experience of tocilizumab in inducing rapid reversal of CSS in&#xD;
      other pathologies several clinical trials and observational studies are being conducted to&#xD;
      assess the effectiveness and safety of tocilizumab in COVID-19 patients. Further studies with&#xD;
      a large sample size are required to confirm the effectiveness of tocilizumab in patients with&#xD;
      COVID-19 pneumonia.&#xD;
&#xD;
      The need for the management of severe COVID-19 disease is imperative, and every effort should&#xD;
      be made to collect relevant clinical outcomes. The aim of the present study is to evaluate&#xD;
      the effectiveness of IV tocilizumab in treating patients with COVID-19 pneumonia who are&#xD;
      currently hospitalized or admitted to ICU by describing improvement of respiratory function&#xD;
      and mortality rate. This large real-world cohort therefore provides a unique opportunity to&#xD;
      study this potential medicine during the current emergency situation, and support the&#xD;
      findings from other ongoing clinical trials and observational studies, such as the&#xD;
      Roche-sponsored Phase III study that is planned to start early April.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Cytokine storm syndrome (CSS) is caused by the excessive release of cytokines during an&#xD;
      exaggerated immune response. CSS can be triggered by infections or therapeutic interventions,&#xD;
      being more severe depending on the degree and duration of immune activation. CSS is as a&#xD;
      significant on-target side-effect of chimeric antigen receptor (CAR) T-cell therapies, which&#xD;
      have been subject to assessment for the treatment of haematological malignancies. Tocilizumab&#xD;
      (intravenous, IV) is indicated for the treatment of chimeric antigen receptor CAR T&#xD;
      cell-induced severe or life-threatening CSS.&#xD;
&#xD;
      Based on the experience with tocilizumab in the CSS, and that some patients infected with&#xD;
      SARS-CoV-2 can develop CSS, leading to potentially fatal damage to lung tissue, the drug is&#xD;
      being investigated in China and Italy, and clinical trials are being conducted/planned in&#xD;
      these and several other countries. Real-word experience with tocilizumab IV have shown that&#xD;
      in a substantial proportion of COVID-19 patients with severe pneumonia, fever returned to&#xD;
      normal and respiratory function based on oxygen intake and lung opacities improved&#xD;
      remarkably. Laboratory parameters such as C-reactive protein (CRP) that seem to be increased&#xD;
      in patients infected decreased significantly with tocilizumab, and lymphocytes levels also&#xD;
      returned to normal.&#xD;
&#xD;
      All these findings have led the Spanish Agency for Medicine and Health Products (AEMPS) to&#xD;
      initiate the controlled distribution of tocilizumab IV, in light of the increased interest on&#xD;
      the anti-cytokine therapy targeting IL-6 in COVID-19 infected patients. Therefore,&#xD;
      tocilizumab might be among the therapeutic armamentarium for preventing the fatal&#xD;
      consequences of acute respiratory and multi organ failure in around 20% of the COVID-19&#xD;
      infected patients.&#xD;
&#xD;
      The aim of the present study is to evaluate the effectiveness and safety of IV tocilizumab in&#xD;
      patients with COVID-19 severe pneumonia who are currently hospitalized or admitted to ICU.&#xD;
      This large real-world cohort provides a unique opportunity to study a potential medicine&#xD;
      during the current emergency situation, and support the findings from the Roche-sponsored&#xD;
      Phase III study that is planned to start in early April.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 22, 2020</start_date>
  <completion_date type="Actual">December 23, 2020</completion_date>
  <primary_completion_date type="Actual">December 23, 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>Phase II, one-arm, open label, multicentre study</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>To calulate the time of intubation</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>Calculate the mean time of intubation</description>
  </primary_outcome>
  <primary_outcome>
    <measure>To calculate the time with oxygen therapy</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>Calculate the mean time with oxygen therapy</description>
  </primary_outcome>
  <primary_outcome>
    <measure>To calculate the time with Non-invasive mechanical ventilation</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>Calculate the mean time with Non-invasive mechanical ventilation</description>
  </primary_outcome>
  <primary_outcome>
    <measure>To evaluate mortality rate</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>Number of patients deaths of the total of patients included</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>To calculate respiratory function parameters</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>To calculate the mean ofPaO2/FiO2</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To calculate respiratory function parameters</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>To calculate the mean of levels of oxygen saturation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To calculate respiratory function parameters</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>To calculate the mean of SaO2/FiO2</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate radiological lung extension</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>Evaluate the lung extension of pneumonia</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate radiological evolution</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>Evaluate the type of lung affection</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To describe the duration of hospitalization and ICU use</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>Days of hospitalization in survivors and/or days at ICU throughout the study</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate the requirement of additional organ support</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>Percentage of patients with extracorporeal membrane oxygenation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate the requirement of additional organ support</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>Percentage of patients with molecular adsorbent recirculating system</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate the requirement of additional organ support</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>Percentage of patients with dialysis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate the requirement of additional organ support</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>Percentage of patients with other support therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate the effect of IV tocilizumab on the serum levels of inflammatory markers</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>Analyze the levels of IL-6</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To calculate the number of adverse events in patients with COVID-19 pneumonia treated with Tocilizumab</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>Incidence of adverse events</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To calculate the number of adverse events in patients with COVID-19 pneumonia treated with Tocilizumab</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>Incidence of adverse events by dose of Tocilizumab</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To assess time to reverse-transcriptase polymerase chain reaction (RT-PCR) virus negativity</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>To evaluate the time to RT-PCR virus negativity</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate the effect of IV tocilizumab on the serum levels of inflammatory</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>Analyze the levels of CRP</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate the effect of IV tocilizumab on the serum levels of inflammatory</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>Analyze the levels of procalcitonin (PCT)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate the effect of IV tocilizumab on the serum levels of inflammatory</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>Analyze the levels of ID-dimer</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate the effect of IV tocilizumab on the serum levels of inflammatory</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>Analyze the levels of ferritin</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To calculate the number of serious adverse events in patients with COVID-19 pneumonia treated with Tocilizumab</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>Indicende of serious adverse events</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To calculate the number of serious adverse events in patients with COVID-19 pneumonia treated with Tocilizumab</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>Indicende of serious adverse events based on dose of Tocilizumab</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To calculate the number of adverse events of special interest in patients with COVID-19 pneumonia treated with Tocilizumab</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>Indicende of adverse events of special interest based on dose of Tocilizumab</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate mortality rate</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>Number of patients deaths of the total of patients included based on dose of Tocilizumab</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate respiratory function</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>Time with intubation, oxygen therapy and Non-invasive mechanical ventilation based on dose of Tocilizumab</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate mortality rate</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>Number of patients deaths of the total of patients included based on severity of disease at the start of the study treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate mortality rate</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>Number of patients deaths of the total of patients included based on presence of cytokine storm syndrome at the start of treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate respiratory function</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>Time with intubation, oxygen therapy and Non-invasive mechanical ventilation based on severity of disease at the start of the study treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate respiratory function</measure>
    <time_frame>through study completion, and average of 1 month</time_frame>
    <description>Time with intubation, oxygen therapy and Non-invasive mechanical ventilation based on presence of cytokine storm syndrome at the start of treatment</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">495</enrollment>
  <condition>COVID-19</condition>
  <arm_group>
    <arm_group_label>Tocilizumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will receive IV tocilizumab as per clinical practice and at the discretion of treating investigator, following the posology indicated in the SmPC, or the recommendations proposed by the Spanish Ministry of Health:&#xD;
The recommended posology by the SmPC is 8 mg per kg in patients weighing greater than or equal to 30 kg or 12 mg per kg in patients weighing less than 30 kg. If no clinical improvement in the signs and symptoms up to 3 additional doses of tocilizumab may be administered. The interval between consecutive doses should be at least 8 hours.&#xD;
The recommendations of the Spanish Ministry of Health:&#xD;
Patients more than 80 kg: first dose 600 mg; second dose 600 mg. Patients less than 80 kg: first dose 600 mg; second dose 400 mg.&#xD;
A third dose might be considered 16 to 24 hours after if: fever persists or a worsening of the laboratory parameters&#xD;
Given the exceptionality of the situation modification of doses according to the physician experience will be allowed.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tocilizumab</intervention_name>
    <description>Treatment with Tocilizumab</description>
    <arm_group_label>Tocilizumab</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Provide oral informed consent to participate in this study.&#xD;
&#xD;
          -  At least 18 years of age.&#xD;
&#xD;
          -  Diagnosed with COVID-19 pneumonia by RT-PCR.&#xD;
&#xD;
          -  Have received the first dose of tocilizumab a maximum of two days before the inclusion&#xD;
             or is candidate for tocilizumab treatment&#xD;
&#xD;
          -  Hospitalized or admitted to ICU&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  The patient has any other medical condition or is receiving concomitant medication&#xD;
             that could, in the opinion of the investigator, compromise the patient's safety or&#xD;
             collected data&#xD;
&#xD;
          -  Known severe allergic reactions to tocilizumab or other monoclonal antibodies&#xD;
&#xD;
          -  Active acute and severe infections, including tuberculosis infection&#xD;
&#xD;
          -  Pregnant or breastfeeding, or positive pregnancy test in a pre-dose examination&#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>Jose Antonio Pérez Molina</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hospital Universitario Ramón y Cajal</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hospital Universitario de Cabueñes</name>
      <address>
        <city>Gijón</city>
        <state>Asturias</state>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitari de Bellvitge</name>
      <address>
        <city>L'Hospitalet De Llobregat</city>
        <state>Barcelona</state>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Sant Joan de Déu de Manresa</name>
      <address>
        <city>Manresa</city>
        <state>Barcelona</state>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital de Mataró</name>
      <address>
        <city>Mataró</city>
        <state>Barcelona</state>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario de Galdakao</name>
      <address>
        <city>Galdakao</city>
        <state>Bizkaia</state>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Marqués Valdecilla</name>
      <address>
        <city>Santander</city>
        <state>Cantabria</state>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Público General del Tomelloso</name>
      <address>
        <city>Tomelloso</city>
        <state>Ciudad Real</state>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Jerez de la Frontera</name>
      <address>
        <city>Jerez De La Frontera</city>
        <state>Cádiz</state>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitari Son Espases</name>
      <address>
        <city>Palma De Mallorca</city>
        <state>Islas Baleares</state>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Fundación Alcorcón</name>
      <address>
        <city>Alcorcón</city>
        <state>Madrid</state>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario de Fuenlabrada</name>
      <address>
        <city>Fuenlabrada</city>
        <state>Madrid</state>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario de Getafe</name>
      <address>
        <city>Getafe</city>
        <state>Madrid</state>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Rey Juan Carlos</name>
      <address>
        <city>Móstoles</city>
        <state>Madrid</state>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Rey Juan Carlos</name>
      <address>
        <city>Móstoles</city>
        <state>Madrid</state>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Infanta Sofía</name>
      <address>
        <city>San Sebastián De Los Reyes</city>
        <state>Madrid</state>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Complejo Hospitalario de Navarra</name>
      <address>
        <city>Pamplona</city>
        <state>Navarra</state>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Nuestra Señora del Prado</name>
      <address>
        <city>Talavera De La Reina</city>
        <state>Toledo</state>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Complejo Hospitalario Universitario de Albacete</name>
      <address>
        <city>Albacete</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Infanta Cristina</name>
      <address>
        <city>Badajoz</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Clínic i Provincial Barcelona</name>
      <address>
        <city>Barcelona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital de la Santa Creu i Sant Pau</name>
      <address>
        <city>Barcelona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario de Burgos</name>
      <address>
        <city>Burgos</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Dr. Josep Trueta</name>
      <address>
        <city>Gerona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Clínico San Cecilio</name>
      <address>
        <city>Granada</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Virgen de las Nieves</name>
      <address>
        <city>Granada</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital General Universitario Gregorio Marañón</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Fundación Jiménez Díaz</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario HM Sanchinarro</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Infanta Leonor</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Ramón y Cajal</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Clínico Universitario Virgen de la Arrixaca</name>
      <address>
        <city>Murcia</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Regional Universitario de Málaga</name>
      <address>
        <city>Málaga</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Complexo Hospitalario Universitario de Ourense</name>
      <address>
        <city>Orense</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Salamanca</name>
      <address>
        <city>Salamanca</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Virgen de la Macarena</name>
      <address>
        <city>Sevilla</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Virgen del Rocío</name>
      <address>
        <city>Sevilla</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Virgen de la Salud</name>
      <address>
        <city>Toledo</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Clinico Universitario de Valencia</name>
      <address>
        <city>Valencia</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitari i Poliectenic La Fe</name>
      <address>
        <city>Valencia</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Dr. Peset</name>
      <address>
        <city>Valencia</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>
    <facility>
      <name>Hospital Universitario Miguel Servet</name>
      <address>
        <city>Zaragoza</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <reference>
    <citation>Maude SL, Barrett D, Teachey DT, Grupp SA. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J. 2014 Mar-Apr;20(2):119-22. doi: 10.1097/PPO.0000000000000035.</citation>
    <PMID>24667956</PMID>
  </reference>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>June 13, 2020</study_first_submitted>
  <study_first_submitted_qc>June 23, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 24, 2020</study_first_posted>
  <last_update_submitted>May 31, 2021</last_update_submitted>
  <last_update_submitted_qc>May 31, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">June 2, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>COVID-19</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
    <mesh_term>Pneumonia</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>November 8, 2022</submitted>
  </pending_results>
  <!-- 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/NCT04445272
org study id: BREATH-19 (FSG011-20)
nct id: NCT04445272
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
At present, no treatment has been approved for COVID-19. However, in light of the increased
      interest on using the anti-cytokine therapy targeting IL-6 tocilizumab in COVID-19 infected
      patients due to its potential benefit, the Spanish Agency for Medicine and Health Products
      (Agencia Española de Medicamentos y Productos Sanitarios, AEMPS) have initiated the
      controlled distribution of the drug. Tocilizumab is indeed proposed as a potential treatment
      for severe COVID-19 in Spain. Based on the positive results of tocilizumab in the treatment
      of COVID-19 patients and the experience of tocilizumab in inducing rapid reversal of CSS in
      other pathologies several clinical trials and observational studies are being conducted to
      assess the effectiveness and safety of tocilizumab in COVID-19 patients. Further studies with
      a large sample size are required to confirm the effectiveness of tocilizumab in patients with
      COVID-19 pneumonia.

      The need for the management of severe COVID-19 disease is imperative, and every effort should
      be made to collect relevant clinical outcomes. The aim of the present study is to evaluate
      the effectiveness of IV tocilizumab in treating patients with COVID-19 pneumonia who are
      currently hospitalized or admitted to ICU by describing improvement of respiratory function
      and mortality rate. This large real-world cohort therefore provides a unique opportunity to
      study this potential medicine during the current emergency situation, and support the
      findings from other ongoing clinical trials and observational studies, such as the
      Roche-sponsored Phase III study that is planned to start early April.
Cytokine storm syndrome (CSS) is caused by the excessive release of cytokines during an
      exaggerated immune response. CSS can be triggered by infections or therapeutic interventions,
      being more severe depending on the degree and duration of immune activation. CSS is as a
      significant on-target side-effect of chimeric antigen receptor (CAR) T-cell therapies, which
      have been subject to assessment for the treatment of haematological malignancies. Tocilizumab
      (intravenous, IV) is indicated for the treatment of chimeric antigen receptor CAR T
      cell-induced severe or life-threatening CSS.

      Based on the experience with tocilizumab in the CSS, and that some patients infected with
      SARS-CoV-2 can develop CSS, leading to potentially fatal damage to lung tissue, the drug is
      being investigated in China and Italy, and clinical trials are being conducted/planned in
      these and several other countries. Real-word experience with tocilizumab IV have shown that
      in a substantial proportion of COVID-19 patients with severe pneumonia, fever returned to
      normal and respiratory function based on oxygen intake and lung opacities improved
      remarkably. Laboratory parameters such as C-reactive protein (CRP) that seem to be increased
      in patients infected decreased significantly with tocilizumab, and lymphocytes levels also
      returned to normal.

      All these findings have led the Spanish Agency for Medicine and Health Products (AEMPS) to
      initiate the controlled distribution of tocilizumab IV, in light of the increased interest on
      the anti-cytokine therapy targeting IL-6 in COVID-19 infected patients. Therefore,
      tocilizumab might be among the therapeutic armamentarium for preventing the fatal
      consequences of acute respiratory and multi organ failure in around 20% of the COVID-19
      infected patients.

      The aim of the present study is to evaluate the effectiveness and safety of IV tocilizumab in
      patients with COVID-19 severe pneumonia who are currently hospitalized or admitted to ICU.
      This large real-world cohort provides a unique opportunity to study a potential medicine
      during the current emergency situation, and support the findings from the Roche-sponsored
      Phase III study that is planned to start in early April.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Phase II, one-arm, open label, multicentre study
primary purpose: Treatment
masking: None (Open Label)
measure: To calulate the time of intubation
time frame: through study completion, and average of 1 month
description: Calculate the mean time of intubation
measure: To calculate the time with oxygen therapy
time frame: through study completion, and average of 1 month
description: Calculate the mean time with oxygen therapy
measure: To calculate the time with Non-invasive mechanical ventilation
time frame: through study completion, and average of 1 month
description: Calculate the mean time with Non-invasive mechanical ventilation
measure: To evaluate mortality rate
time frame: through study completion, and average of 1 month
description: Number of patients deaths of the total of patients included
measure: To calculate respiratory function parameters
time frame: through study completion, and average of 1 month
description: To calculate the mean ofPaO2/FiO2
measure: To calculate respiratory function parameters
time frame: through study completion, and average of 1 month
description: To calculate the mean of levels of oxygen saturation
measure: To calculate respiratory function parameters
time frame: through study completion, and average of 1 month
description: To calculate the mean of SaO2/FiO2
measure: To evaluate radiological lung extension
time frame: through study completion, and average of 1 month
description: Evaluate the lung extension of pneumonia
measure: To evaluate radiological evolution
time frame: through study completion, and average of 1 month
description: Evaluate the type of lung affection
measure: To describe the duration of hospitalization and ICU use
time frame: through study completion, and average of 1 month
description: Days of hospitalization in survivors and/or days at ICU throughout the study
measure: To evaluate the requirement of additional organ support
time frame: through study completion, and average of 1 month
description: Percentage of patients with extracorporeal membrane oxygenation
measure: To evaluate the requirement of additional organ support
time frame: through study completion, and average of 1 month
description: Percentage of patients with molecular adsorbent recirculating system
measure: To evaluate the requirement of additional organ support
time frame: through study completion, and average of 1 month
description: Percentage of patients with dialysis
measure: To evaluate the requirement of additional organ support
time frame: through study completion, and average of 1 month
description: Percentage of patients with other support therapy
measure: To evaluate the effect of IV tocilizumab on the serum levels of inflammatory markers
time frame: through study completion, and average of 1 month
description: Analyze the levels of IL-6
measure: To calculate the number of adverse events in patients with COVID-19 pneumonia treated with Tocilizumab
time frame: through study completion, and average of 1 month
description: Incidence of adverse events
measure: To calculate the number of adverse events in patients with COVID-19 pneumonia treated with Tocilizumab
time frame: through study completion, and average of 1 month
description: Incidence of adverse events by dose of Tocilizumab
measure: To assess time to reverse-transcriptase polymerase chain reaction (RT-PCR) virus negativity
time frame: through study completion, and average of 1 month
description: To evaluate the time to RT-PCR virus negativity
measure: To evaluate the effect of IV tocilizumab on the serum levels of inflammatory
time frame: through study completion, and average of 1 month
description: Analyze the levels of CRP
measure: To evaluate the effect of IV tocilizumab on the serum levels of inflammatory
time frame: through study completion, and average of 1 month
description: Analyze the levels of procalcitonin (PCT)
measure: To evaluate the effect of IV tocilizumab on the serum levels of inflammatory
time frame: through study completion, and average of 1 month
description: Analyze the levels of ID-dimer
measure: To evaluate the effect of IV tocilizumab on the serum levels of inflammatory
time frame: through study completion, and average of 1 month
description: Analyze the levels of ferritin
measure: To calculate the number of serious adverse events in patients with COVID-19 pneumonia treated with Tocilizumab
time frame: through study completion, and average of 1 month
description: Indicende of serious adverse events
measure: To calculate the number of serious adverse events in patients with COVID-19 pneumonia treated with Tocilizumab
time frame: through study completion, and average of 1 month
description: Indicende of serious adverse events based on dose of Tocilizumab
measure: To calculate the number of adverse events of special interest in patients with COVID-19 pneumonia treated with Tocilizumab
time frame: through study completion, and average of 1 month
description: Indicende of adverse events of special interest based on dose of Tocilizumab
measure: To evaluate mortality rate
time frame: through study completion, and average of 1 month
description: Number of patients deaths of the total of patients included based on dose of Tocilizumab
measure: To evaluate respiratory function
time frame: through study completion, and average of 1 month
description: Time with intubation, oxygen therapy and Non-invasive mechanical ventilation based on dose of Tocilizumab
measure: To evaluate mortality rate
time frame: through study completion, and average of 1 month
description: Number of patients deaths of the total of patients included based on severity of disease at the start of the study treatment
measure: To evaluate mortality rate
time frame: through study completion, and average of 1 month
description: Number of patients deaths of the total of patients included based on presence of cytokine storm syndrome at the start of treatment
measure: To evaluate respiratory function
time frame: through study completion, and average of 1 month
description: Time with intubation, oxygen therapy and Non-invasive mechanical ventilation based on severity of disease at the start of the study treatment
measure: To evaluate respiratory function
time frame: through study completion, and average of 1 month
description: Time with intubation, oxygen therapy and Non-invasive mechanical ventilation based on presence of cytokine storm syndrome at the start of treatment
arm group label: Tocilizumab
arm group type: Experimental
description: Patients will receive IV tocilizumab as per clinical practice and at the discretion of treating investigator, following the posology indicated in the SmPC, or the recommendations proposed by the Spanish Ministry of Health:
The recommended posology by the SmPC is 8 mg per kg in patients weighing greater than or equal to 30 kg or 12 mg per kg in patients weighing less than 30 kg. If no clinical improvement in the signs and symptoms up to 3 additional doses of tocilizumab may be administered. The interval between consecutive doses should be at least 8 hours.
The recommendations of the Spanish Ministry of Health:
Patients more than 80 kg: first dose 600 mg; second dose 600 mg. Patients less than 80 kg: first dose 600 mg; second dose 400 mg.
A third dose might be considered 16 to 24 hours after if: fever persists or a worsening of the laboratory parameters
Given the exceptionality of the situation modification of doses according to the physician experience will be allowed.
intervention type: Drug
intervention name: Tocilizumab
description: Treatment with Tocilizumab
arm group label: Tocilizumab
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Jose Antonio Pérez Molina
role: Principal Investigator
affiliation: Hospital Universitario Ramón y Cajal
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country: Spain
citation: Maude SL, Barrett D, Teachey DT, Grupp SA. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J. 2014 Mar-Apr;20(2):119-22. doi: 10.1097/PPO.0000000000000035.
PMID: 24667956
responsible party type: Sponsor
mesh term: COVID-19
mesh term: Pneumonia
sharing ipd: No
submitted: November 8, 2022