<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/NCT04459325</url>
  </required_header>
  <id_info>
    <org_study_id>DRN-ALI-III</org_study_id>
    <secondary_id>#216 eff date 27.05.2020</secondary_id>
    <nct_id>NCT04459325</nct_id>
  </id_info>
  <brief_title>Tigerase® Efficacy and Safety as Part of Complex Therapy in Patients With COVID-19</brief_title>
  <official_title>A Prospective Open-label Study of the Tigerase® Efficacy and Safety as Part of Complex Therapy in Patients With COVID-19</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>AO GENERIUM</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>AO GENERIUM</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>
      It is a multicenter, open-label, randomized, parallel-group study of the efficacy and safety&#xD;
      of Tigerase® (GENERIUM JSC, Russia) with standard therapy versus standard therapy in patients&#xD;
      with COVID-19.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      COVID-19 (Coronavirus disease-19) is an acute respiratory infectious disease caused by&#xD;
      SARS-CoV-2 coronavirus. The spread of the disease quickly developed to the global pandemic in&#xD;
      March-April 2020, and was characterized by acute respiratory distress syndrome (ARDS) in&#xD;
      10-15% of cases, which leads to a high frequency of hospitalization in the intensive care&#xD;
      unit and high mortality. The search for effective treatment and reducing the severity of&#xD;
      COVID-19 is a priority in the development of medical science.&#xD;
&#xD;
      One of the key processes of the innate immune system are neutrophil extracellular traps&#xD;
      (NET), formed by neutrophils when they eject their DNA from the cytoplasm. NET is most often&#xD;
      described as a mechanism for capturing bacteria in order to limit their spread. In addition,&#xD;
      NET also plays a role in antiviral immunity. In particular, viral infections lung damage is&#xD;
      at least partially due to NET.&#xD;
&#xD;
      This suggests that drug disruption of NET in COVID-19 is promising. DNase preparations, and&#xD;
      in particular Tigerase®, are safe and effective for the treatment of cystic fibrosis and can&#xD;
      serve as a NET destruction agent in patient with COVID-19.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 1, 2020</start_date>
  <completion_date type="Actual">July 20, 2020</completion_date>
  <primary_completion_date type="Actual">July 20, 2020</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>The proportion of patients with mechanical ventilation</measure>
    <time_frame>Day 8</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Category change on WHO Ordinal Scale for Clinical Improvement</measure>
    <time_frame>Day 8</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>The proportion of patients with mechanical ventilation</measure>
    <time_frame>Day 28</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Category change on WHO Ordinal Scale for Clinical Improvement</measure>
    <time_frame>Day 28</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients surviving 28 days after inclusion in the study</measure>
    <time_frame>Day 28</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of days of oxygen therapy during the treatment period</measure>
    <time_frame>Day 8</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in C-reactive protein level</measure>
    <time_frame>Days 3, 5, 8</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in oxygenation index</measure>
    <time_frame>Days 3, 5, 8</time_frame>
    <description>PaO2 / FiO2, FiO2 = fraction of oxygen in inhaled air,% PaO2 = partial pressure of oxygen in arterial blood, mm Hg</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in SpO2/FiO2 index</measure>
    <time_frame>Days 1, 2, 3, 4, 5, 6, 7, 8</time_frame>
    <description>SpO2 / FiO2, FiO2 = fraction of oxygen in inhaled air,% SpO2 = hemoglobin oxygen saturation, %</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in ferritin level</measure>
    <time_frame>Days 3, 5, 8</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in D-dimer level</measure>
    <time_frame>Days 3, 5, 8</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in neutrophil-leucocyte ratio</measure>
    <time_frame>Days 3, 5, 8</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in leucocyte-C-reactive protein ratio</measure>
    <time_frame>Days 3, 5, 8</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in the level of relative (%) number of lymphocytes of the general blood test</measure>
    <time_frame>Days 3, 5, 8</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">100</enrollment>
  <condition>COVID-19</condition>
  <condition>Coronavirus Disease 2019</condition>
  <arm_group>
    <arm_group_label>Study drug and best available care</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Best available care and Tigerase®/nebulised dornase alfa [2.5 mg BID] for 7 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group (best available care)</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Patients will receive the usual care in accordance with good practice.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Tigerase® and best available care</intervention_name>
    <description>Nebulised dornase alfa [2.5 mg BID] for 7 days</description>
    <arm_group_label>Study drug and best available care</arm_group_label>
    <other_name>Dornase Alfa Inhalation Solution and best available care</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Best available care</intervention_name>
    <description>Patients will receive the usual care in accordance with good practice.</description>
    <arm_group_label>Control group (best available care)</arm_group_label>
    <other_name>Standard of care</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Written informed consent for participation in the study&#xD;
&#xD;
          2. Men and women aged ≥18 years&#xD;
&#xD;
          3. Laboratory-confirmed diagnosis of coronavirus infection caused by COVID19, moderate&#xD;
             severity *&#xD;
&#xD;
             *Criteria for moderate flow (just one point) Mandatory Criterion&#xD;
&#xD;
               -  Pneumonia Additional criteria (used to characterize the disease and are not&#xD;
                  required to determine the severity)&#xD;
&#xD;
               -  Fever above 38 ° C&#xD;
&#xD;
               -  respiratory rate more than 22 / min&#xD;
&#xD;
               -  Shortness of breath during physical exertion&#xD;
&#xD;
               -  SpO2 &lt;95%&#xD;
&#xD;
               -  С-reactive protein (CRP) of serum more than 10 mg / l&#xD;
&#xD;
          4. Patients with pneumonia with a stable level of hemoglobin saturation by oxygen (&gt; 93%)&#xD;
             on oxygen support and / or receiving respiratory support of non-invasive mechanical&#xD;
             ventilation&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Individual intolerance or hypersensitivity to the active or any of the excipients of&#xD;
             the drug Tigerase®&#xD;
&#xD;
          2. The need for invasive mechanical ventilation at the time of inclusion of the patient&#xD;
&#xD;
          3. Patients severe condition (one of the following characteristics):&#xD;
&#xD;
               -  Respiratory distress syndrome with respiratory rate ≥30 per minute&#xD;
&#xD;
               -  Saturation of hemoglobin with oxygen ≤93% with oxygen support&#xD;
&#xD;
          4. Patient participate in any clinical trials and / or taking the experimental drug&#xD;
             within 30 days before inclusion this trial&#xD;
&#xD;
          5. Severe competitive respiratory system diseases (bronchial asthma, chronic obstructive&#xD;
             pulmonary disease - COPD, cystic fibrosis, interstitial lung disease)&#xD;
&#xD;
          6. Positive results of laboratory testing for HIV and hepatitis B and C&#xD;
&#xD;
          7. Life expectancy less than 12 months without COVID-19&#xD;
&#xD;
          8. Other diseases and conditions, significant laboratory or instrumental deviation,&#xD;
             which, according to investigator opinion, may impact the results of the study, limit&#xD;
             the patient's participation in the trial or create an unreasonable risk for the&#xD;
             patient&#xD;
&#xD;
          9. Patient's unwillingness or disability to comply with the recommendations prescribed by&#xD;
             protocol, as well as any concomitant medical or serious mental conditions that render&#xD;
             the patient unsuitable for participation in the study, limit the legitimacy of&#xD;
             obtaining informed consent or may affect the patient's ability to participate in the&#xD;
             study (including disability to use a nebulizer)&#xD;
&#xD;
         10. Positive pregnancy test in women&#xD;
&#xD;
         11. The period of breastfeeding in women&#xD;
&#xD;
         12. Refusal of male patients and female patients with preserved reproductive function to&#xD;
             use adequate methods of contraception throughout the study and for at least 30 days&#xD;
             after the end of therapy with the studied drug&#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>Oksana A. Markova, MD</last_name>
    <role>Study Chair</role>
    <affiliation>AO GENERIUM</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>City Clinical Hospital #15</name>
      <address>
        <city>Moscow</city>
        <zip>111539</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>I.M. Sechenov First Moscow State Medical University (Sechenov University)</name>
      <address>
        <city>Moscow</city>
        <zip>119991</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>City Clinical Hospital #51</name>
      <address>
        <city>Moscow</city>
        <zip>121309</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>City Clinical Hospital #52</name>
      <address>
        <city>Moscow</city>
        <zip>123182</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>N.V. Sklifosovsky Scientific Research Institute of First Aid</name>
      <address>
        <city>Moscow</city>
        <zip>129090</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Siberian State Medical University (SibMed)</name>
      <address>
        <city>Moscow</city>
        <zip>634050</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Russian Federation</country>
  </location_countries>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>July 3, 2020</study_first_submitted>
  <study_first_submitted_qc>July 3, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 7, 2020</study_first_posted>
  <last_update_submitted>October 13, 2020</last_update_submitted>
  <last_update_submitted_qc>October 13, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">October 14, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>COVID-19</keyword>
  <keyword>Coronavirus Infections</keyword>
  <keyword>Coronaviridae Infections</keyword>
  <keyword>Dornase alfa</keyword>
  <keyword>Virus Diseases</keyword>
  <keyword>Acute lung injury</keyword>
  <keyword>Acute respiratory distress syndrome</keyword>
  <keyword>Respiratory Insufficiency</keyword>
  <keyword>Respiratory Tract Diseases</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
    <mesh_term>Coronavirus Infections</mesh_term>
  </condition_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/NCT04459325
org study id: DRN-ALI-III
secondary id: #216 eff date 27.05.2020
nct id: NCT04459325
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
It is a multicenter, open-label, randomized, parallel-group study of the efficacy and safety
      of Tigerase® (GENERIUM JSC, Russia) with standard therapy versus standard therapy in patients
      with COVID-19.
COVID-19 (Coronavirus disease-19) is an acute respiratory infectious disease caused by
      SARS-CoV-2 coronavirus. The spread of the disease quickly developed to the global pandemic in
      March-April 2020, and was characterized by acute respiratory distress syndrome (ARDS) in
      10-15% of cases, which leads to a high frequency of hospitalization in the intensive care
      unit and high mortality. The search for effective treatment and reducing the severity of
      COVID-19 is a priority in the development of medical science.

      One of the key processes of the innate immune system are neutrophil extracellular traps
      (NET), formed by neutrophils when they eject their DNA from the cytoplasm. NET is most often
      described as a mechanism for capturing bacteria in order to limit their spread. In addition,
      NET also plays a role in antiviral immunity. In particular, viral infections lung damage is
      at least partially due to NET.

      This suggests that drug disruption of NET in COVID-19 is promising. DNase preparations, and
      in particular Tigerase®, are safe and effective for the treatment of cystic fibrosis and can
      serve as a NET destruction agent in patient with COVID-19.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: The proportion of patients with mechanical ventilation
time frame: Day 8
measure: Category change on WHO Ordinal Scale for Clinical Improvement
time frame: Day 8
measure: The proportion of patients with mechanical ventilation
time frame: Day 28
measure: Category change on WHO Ordinal Scale for Clinical Improvement
time frame: Day 28
measure: Proportion of patients surviving 28 days after inclusion in the study
time frame: Day 28
measure: Number of days of oxygen therapy during the treatment period
time frame: Day 8
measure: Change in C-reactive protein level
time frame: Days 3, 5, 8
measure: Change in oxygenation index
time frame: Days 3, 5, 8
description: PaO2 / FiO2, FiO2 = fraction of oxygen in inhaled air,% PaO2 = partial pressure of oxygen in arterial blood, mm Hg
measure: Change in SpO2/FiO2 index
time frame: Days 1, 2, 3, 4, 5, 6, 7, 8
description: SpO2 / FiO2, FiO2 = fraction of oxygen in inhaled air,% SpO2 = hemoglobin oxygen saturation, %
measure: Change in ferritin level
time frame: Days 3, 5, 8
measure: Change in D-dimer level
time frame: Days 3, 5, 8
measure: Change in neutrophil-leucocyte ratio
time frame: Days 3, 5, 8
measure: Change in leucocyte-C-reactive protein ratio
time frame: Days 3, 5, 8
measure: Change in the level of relative (%) number of lymphocytes of the general blood test
time frame: Days 3, 5, 8
arm group label: Study drug and best available care
arm group type: Experimental
description: Best available care and Tigerase®/nebulised dornase alfa [2.5 mg BID] for 7 days
arm group label: Control group (best available care)
arm group type: Other
description: Patients will receive the usual care in accordance with good practice.
intervention type: Biological
intervention name: Tigerase® and best available care
description: Nebulised dornase alfa [2.5 mg BID] for 7 days
arm group label: Study drug and best available care
other name: Dornase Alfa Inhalation Solution and best available care
intervention type: Other
intervention name: Best available care
description: Patients will receive the usual care in accordance with good practice.
arm group label: Control group (best available care)
other name: Standard of care
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Oksana A. Markova, MD
role: Study Chair
affiliation: AO GENERIUM
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Russian Federation
responsible party type: Sponsor
mesh term: COVID-19
mesh term: Coronavirus Infections
sharing ipd: No