<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/NCT04500067</url>
  </required_header>
  <id_info>
    <org_study_id>2020-BV-BP</org_study_id>
    <nct_id>NCT04500067</nct_id>
  </id_info>
  <brief_title>Intravenous Immunoglobulin (IVIG, Bioven) Efficacy Assess for COVID-19 / SARS-CoV-2 Severe Pneumonia Complex Treatment</brief_title>
  <official_title>An Open-label Multicenter Randomized Trial to Evaluate the Efficacy of Bioven, Manufactured by Biopharma Plasma, LLC, in Complex Therapy of Patients With Pneumonia Induced by COVID-19 / SARS-CoV-2</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Biopharma Plasma LLC</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Lviv National Medical University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Vinnitsa National Medical University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Biopharma Plasma LLC</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>
      Pneumonia caused by coronavirus infection COVID-19 is characterized by a combination of&#xD;
      several dangerous factors that consistently worsen the patient's condition: viral lung damage&#xD;
      early in the disease; a sharp increase in inflammation on the background of an unbalanced&#xD;
      immune response (&quot;cytokine storm&quot;); joining a bacterial infection.&#xD;
&#xD;
      The condition of patients deteriorates significantly mostly at cytokine storm development.&#xD;
      The damaging of a large volume of lung tissue leads to develops of respiratory failure,&#xD;
      respiratory distress syndrome, or shock. Ventilatory support becomes ineffective and patients&#xD;
      die.&#xD;
&#xD;
      There are reports of the effectiveness of Human Normal Immunoglobulin for Intravenous&#xD;
      Administration (IVIG) high doses when used as part of complex therapy in patients with&#xD;
      pneumonia caused by coronavirus COVID-19. In particular, IVIG has a positive effect on&#xD;
      survival rates, overall disease course, duration of stay in the intensive care unit, and&#xD;
      ventilatory support duration.&#xD;
&#xD;
      The probable mechanism of action of high-dose IVIG therapy is considered to be a regulatory&#xD;
      effect on the immune system. Similar is the known and confirmed effectiveness of IVIG for&#xD;
      autoimmune diseases (Kavasaky disease, Guillain Barre syndrome, Chronic inflammatory&#xD;
      demyelinating polyradiculoneuropathy, Multifocal motor neuropathy).&#xD;
&#xD;
      This trial to assesses the Efficacy of IVIG (medication trade name - Bioven, manufactured by&#xD;
      Biopharma Plasma LLC) in the High Immunomodulatory Dose in Complex Treatment of Severe&#xD;
      Pneumonia Caused by COVID-19 / SARS-CoV-2&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The screening stage:&#xD;
&#xD;
      The patient or his legal representative must sign an informed consent. After signing the&#xD;
      informed consent, the screening tests&amp;procedures are performed and the compliance with the&#xD;
      inclusion / non-inclusion criteria is assessed.&#xD;
&#xD;
      For patients who have been screened and meet the inclusion criteria and do not fall under the&#xD;
      exclusion criteria, a blinded randomization procedure is provided.&#xD;
&#xD;
      Randomization is performed by the IVRS method, according to the blinded-block patient's&#xD;
      randomization table.&#xD;
&#xD;
      The clinical stage of the trial:&#xD;
&#xD;
      Begins after patient randomization. At the clinical stage, among other things, provides:&#xD;
&#xD;
        -  Determination of the individual dose of the study drug (in the study group)&#xD;
&#xD;
        -  Administration of the drug (in the study group)&#xD;
&#xD;
        -  Registration of adverse events&#xD;
&#xD;
        -  registration of information about taking antiviral drugs for the treatment of COVID-19;&#xD;
&#xD;
        -  registration of information on symptomatic therapy and administration of drugs for the&#xD;
           treatment of comorbidities;&#xD;
&#xD;
        -  measurement of vital signs (blood pressure, heart rate, respiratory rate, body&#xD;
           temperature);&#xD;
&#xD;
        -  Determination of SPO2 level&#xD;
&#xD;
        -  Determining the need for ventilation&#xD;
&#xD;
        -  Determining the need for intensive care&#xD;
&#xD;
        -  Assessment of compliance with the exclusion criteria&#xD;
&#xD;
      Patients in the Control Group will receive therapy recommended by the COVID-19 coronavirus&#xD;
      infection treatment protocol, depending on the severity of their condition according to the&#xD;
      prescribing list, which will not include immunoglobulin preparations.&#xD;
&#xD;
      Patients of the Study Group (IVIG) receive high-dose therapy with the study drug (Bioven, 10%&#xD;
      solution for infusions produced by Biopharma Plasma LLC, Ukraine). The dose is calculated by&#xD;
      body weight. Patients will also receive therapy recommended by the COVID-19 coronavirus&#xD;
      infection treatment protocol, depending on the severity of their condition according to the&#xD;
      prescribing list.&#xD;
&#xD;
      Bioven administered intravenously, at an initial rate of 0.5 - 1.0 ml/kg body weight/hour for&#xD;
      30 minutes. In the absence of any undesirable side effects, the rate of administration can be&#xD;
      gradually increased (recommended increase by 0.5 - 1.5 ml/kg body weight/hour every 10&#xD;
      minutes). According to results previously accomplished clinical studies, the maximum rate of&#xD;
      Bioven administration is up to 8.5 ml/kg body weight/hour.&#xD;
&#xD;
      Observation and completion stage:&#xD;
&#xD;
      Begins and continues from the last administration of the study drug until the discharge of&#xD;
      the patient from the hospital, but not less than 28 days from the confirmation of the&#xD;
      diagnosis of pneumonia caused by coronavirus infection COVID-19.&#xD;
&#xD;
      The following procedures are provided at the stage:&#xD;
&#xD;
        -  registration of information about taking antiviral drugs for the treatment of COVID-19;&#xD;
&#xD;
        -  registration of information on symptomatic therapy and administration of drugs for the&#xD;
           treatment of comorbidities;&#xD;
&#xD;
        -  measurement of vital signs (blood pressure, heart rate, respiratory rate, body&#xD;
           temperature);&#xD;
&#xD;
        -  determination of SPO2 level&#xD;
&#xD;
        -  registration of the results of the examination of the lungs by computed tomography (or&#xD;
           radiography)&#xD;
&#xD;
        -  taking biomaterials for laboratory research:&#xD;
&#xD;
        -  general blood test (erythrocytes, hemoglobin, expanded leukocyte formula, platelets,&#xD;
           etc.);&#xD;
&#xD;
        -  general analysis of urine;&#xD;
&#xD;
        -  biochemical analysis of blood;&#xD;
&#xD;
        -  state of the coagulation system&#xD;
&#xD;
        -  determination of inflammatory factors in the dynamics (CRP, ferritin, procalcitonin;&#xD;
           TNF-α), IL-1-beta, IL-6, complement component C3 (C3), circulating immune complexes&#xD;
           (CIC), etc.),&#xD;
&#xD;
        -  determination of IgG subclasses (G1, G2, G3, G4,);&#xD;
&#xD;
        -  Determining the need for ventilation&#xD;
&#xD;
        -  Determining the need for intensive care&#xD;
&#xD;
        -  Adverse reactions registration&#xD;
&#xD;
        -  Assessment of compliance with the exclusion criteria&#xD;
&#xD;
      The patient's condition is assessed daily till discharge; and by schedule after discharge (if&#xD;
      it happen earlier), during 28 days period after diagnosis of severe pneumonia caused by&#xD;
      coronavirus infection COVID-19 In case of death of the patient - the date and cause of death&#xD;
      are fixed. The results of the study are evaluated by endpoints.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 7, 2020</start_date>
  <completion_date type="Actual">September 15, 2020</completion_date>
  <primary_completion_date type="Actual">September 15, 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>
    <intervention_model_description>Open-label multicenter randomized controlled in parallel groups.&#xD;
Patients undergoing screening are randomized into groups in equal proportions:&#xD;
Study Group (receive IVIG Bioven with base therapy).&#xD;
Control group (receive base therapy only)&#xD;
At the stage of Data Analysis to ensure comparability of data and homogeneity of the sample, the possibility of additional comparison of groups based on the actually prescribed base therapy and other identified covariates is provided.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Period duration (in days) to clinical improvement</measure>
    <time_frame>From date post-onset of severe pneumonia to date of patient discharge or date of death, whichever came first, assessed up to 28 days</time_frame>
    <description>Number of days post-onset of severe pneumonia to the moment of normalization at least two from following primary outcomes: O2 saturation with self-breathing, respiratory movements rate with self-breathing, body temperature without antipyretics use, lymphocyte count (targeted levels set in the description each of these primary outcomes)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>O2 saturation (SPO2 percentage), with self-breathing</measure>
    <time_frame>From date post-onset of severe pneumonia to date of patient discharge or date of death, whichever came first, assessed up to 28 days</time_frame>
    <description>The target level of SPO2 percentage - 95% and above with self-breathing, is used as one of the clinical improvement criteria</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Respiratory movements rate (amount per minute), with self-breathing</measure>
    <time_frame>From date post-onset of severe pneumonia to date of patient discharge or date of death, whichever came first, assessed up to 28 days</time_frame>
    <description>The target level of respiratory movements - 28 per minute or less with self-breathing, is used as one of the clinical improvement criteria</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Body temperature without antipyretics use</measure>
    <time_frame>From date post-onset of severe pneumonia to date of patient discharge or date of death, whichever came first, assessed up to 28 days</time_frame>
    <description>Measured in degrees Celsius. Fever absence (body temperature no more 37 degrees Celsius) during at least 24 hours without antipyretics, is used as one of the clinical improvement criteria.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Lymphocyte count</measure>
    <time_frame>From date post-onset of severe pneumonia to date of patient discharge or date of death, whichever came first, assessed up to 28 days</time_frame>
    <description>The target level 1000 cells / mm3 and above is used as one of the clinical improvement criteria (applicable for patients with lymphocytes count lower 1000 cells / mm3 at screening moment)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time from the onset of the disease to discharge, in days</measure>
    <time_frame>28 days</time_frame>
    <description>Period duration (in days)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of the need for ventilatory support, in days</measure>
    <time_frame>28 days</time_frame>
    <description>Number of days with ventilatory support</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of the need for intensive care, in days</measure>
    <time_frame>28 days</time_frame>
    <description>Number of days in the intensive care unit</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of need for oxygenation in days (SPO2 ≤ 93% with self-breathing)</measure>
    <time_frame>28 days</time_frame>
    <description>Number of days with necessery of oxygenation support</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The C-reactive protein (CRP) level</measure>
    <time_frame>Day 0 (screening), day 5, day 14, day 28</time_frame>
    <description>Measuring the analyte concentration in plasma (mg/L)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The tumor necrozis factor alpha (TNF-α) level</measure>
    <time_frame>Day 0 (screening), day 5, day 14, day 28</time_frame>
    <description>Measuring the analyte concentration in plasma (pg/mL)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The interleukin-1β (IL-1β) level</measure>
    <time_frame>Day 0 (screening), day 5, day 14, day 28</time_frame>
    <description>Measuring the analyte concentration in plasma (pg/mL)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The interleukin-6 (IL-6) level</measure>
    <time_frame>Day 0 (screening), day 5, day 14, day 28</time_frame>
    <description>Measuring the analyte concentration in plasma (pg/mL)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The D-dimer level</measure>
    <time_frame>Day 0 (screening), day 5, day 14, day 28</time_frame>
    <description>Measuring the analyte concentration in plasma (µg FEU/mL)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The Complement (C3 component) level</measure>
    <time_frame>Day 0 (screening), day 5, day 14, day 28</time_frame>
    <description>Measuring the analyte concentration in plasma (g/L)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The Circulating immune complexes level</measure>
    <time_frame>Day 0 (screening), day 5, day 14, day 28</time_frame>
    <description>Measuring the analyte concentration in plasma (U/mL)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The ferritin level</measure>
    <time_frame>Day 0 (screening), day 5, day 14, day 28</time_frame>
    <description>Analyte concentration in plasma (ng/mL)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The procalcitonin level</measure>
    <time_frame>Day 0 (screening), day 5, day 14, day 28</time_frame>
    <description>Analyte concentration in plasma (ng/mL)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>IgG subtypes</measure>
    <time_frame>Day 0 (screening), day 5, day 14, day 28</time_frame>
    <description>The IgG-subtypes (IgG1-IgG4) concentration in plasma (mg/dL)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Survival assessment for a 28-day follow-up period since the onset of severe pneumonia</measure>
    <time_frame>28 days</time_frame>
    <description>Survivealance estimation</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Frequency of side effects</measure>
    <time_frame>28 days</time_frame>
    <description>Number of participants with adverse reactions related by investigational drug as assessed by CTCАЕ v 4.0</description>
  </other_outcome>
  <other_outcome>
    <measure>Frequency of serious side effects</measure>
    <time_frame>28 days</time_frame>
    <description>Number of participants with serious adverse reactions related by investigational drug as assessed by CTCАЕ v 4.0</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">76</enrollment>
  <condition>Covid19</condition>
  <condition>Pneumonia</condition>
  <arm_group>
    <arm_group_label>Study Group (IVIG)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive IVIG (trade name - Bioven) with base therapy</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Patients receive base therapy only</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>IVIG</intervention_name>
    <description>Patients in the study group receive the drug Bioven, 10% solution for infusions produced by LLC Biopharma Plasma 0,8-1,0 g/kg once a day for 2 days (total course dose - 1.6-2.0 g/kg) as well as base treatment recommended by the protocol of COVID-19 coronavirus infection treatment depending on the severity of their condition according to the prescription sheet.</description>
    <arm_group_label>Study Group (IVIG)</arm_group_label>
    <other_name>Human normal immunoglobulin for intravenous administration</other_name>
    <other_name>Bioven</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Men and women 18 years of age and older;&#xD;
&#xD;
          -  COVID-19 documentary confirmed by PCR lab test;&#xD;
&#xD;
          -  severe pneumonia caused by COVID-19 according to the criteria below:&#xD;
&#xD;
               -  - fever or suspicion of respiratory infection;&#xD;
&#xD;
               -  - the number of respiratory movements 30 per 1 min and above;&#xD;
&#xD;
               -  - severe respiratory failure or SpO2 &lt;90% with spontaneous breathing indoors;&#xD;
&#xD;
               -  - the presence of foci of inflammation in the lungs according to the results of&#xD;
                  computed tomography, which is documented.&#xD;
&#xD;
               -  or if any of the conditions listed below have developed on the background of&#xD;
                  previously diagnosed coronavirus pneumonia:&#xD;
&#xD;
                    -  - severe respiratory failure required mechanical ventilation (ALV);&#xD;
&#xD;
                    -  - acute respiratory distress syndrome according to WHO diagnostic criteria&#xD;
                       (development within one week after the manifestation of disease clinical&#xD;
                       symptoms or emergence of new ones or deterioration of respiratory syndromes.&#xD;
                       Chest visualization (lung X-ray, CT or ultrasound); bilateral opacities not&#xD;
                       fully explaining the gravity of condition or lung collapse or nodules);&#xD;
&#xD;
                    -  - sepsis according to WHO diagnostic criteria (life-threatening organ&#xD;
                       dysfunction caused by disturbance of host reaction to suspected or proven&#xD;
                       infection. The features of organ dysfunction include the following: mental&#xD;
                       change, labored or shallow breathing, low oxygenation, oliguria or anuria,&#xD;
                       rapid heart palpitation, weak pulse, cold extremities or low blood pressure,&#xD;
                       skin blotching or lab-proven coagulopathy, thrombocytopenia, acidosis, high&#xD;
                       level of lactic acid or hyperbilirubinemia);&#xD;
&#xD;
                    -  - endotoxic shock according to WHO diagnostic criteria (persisting&#xD;
                       hypotension despite extensive resuscitation requiring vasoconstrictors for&#xD;
                       maintaining mean arterial pressure ≥ 65 mmHg and serum lactate level &gt; 2&#xD;
                       mmol/l);&#xD;
&#xD;
          -  the signed patient's informed consent to participation in the trial;&#xD;
&#xD;
          -  the negative pregnancy test (for female patients of reproductive age), readiness to&#xD;
             use reliable contraception methods during the whole duration of the trial.&#xD;
&#xD;
          -  the ability, according to the researcher, to follow all requirements of the research&#xD;
             protocol.&#xD;
&#xD;
          -  this study allows you to take into account the results of examinations related to the&#xD;
             disease, conducted within 10 days before signing the Informed Consent. Such data are&#xD;
             transferred from the primary documentation to the CRF.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  known intolerance to plasma or immunoglobulin drugs;&#xD;
&#xD;
          -  drug allergy or hypersensitization to immunoglobulin drugs;&#xD;
&#xD;
          -  any known counter-indication to immunoglobulin drugs according to the instruction for&#xD;
             medical application of the tested drug;&#xD;
&#xD;
          -  pneumonia not associated with COVID-19 infection;&#xD;
&#xD;
          -  pregnancy, lactation period;&#xD;
&#xD;
          -  any clinically significant impairment of liver function (elevation of serum&#xD;
             transaminase levels more than 3 times the upper limit of normal);&#xD;
&#xD;
          -  serum creatinine levels more than 2 times the upper limit of normal for a given age&#xD;
             and gender;&#xD;
&#xD;
          -  established diagnosis of primary immunodeficiency;&#xD;
&#xD;
          -  verified HIV-infection;&#xD;
&#xD;
          -  immune diseases (blood immune diseases, rheumatic diseases, nephritis, etc.)&#xD;
&#xD;
          -  severe cardiovascular failure (Stage III);&#xD;
&#xD;
          -  mental illness in anamnesis;&#xD;
&#xD;
          -  the need for prescribing medicines or procedures that are incompatible with the&#xD;
             administration of the drug within the scope of this study: monoclonal antybodies;&#xD;
&#xD;
          -  known drug addiction;&#xD;
&#xD;
          -  participation in any other clinical trial presently or within the last 30 days.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Site 08 - &quot;Central City Clinical Hospital of Ivano-Frankivsk City Council&quot;</name>
      <address>
        <city>Ivano-Frankivs'k</city>
        <state>Ivano-Frankivs'k Region</state>
        <zip>76018</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site 02 - &quot;Bila Tserkva City Hospital №3&quot;</name>
      <address>
        <city>Bila Tserkva</city>
        <state>Kyiv Region</state>
        <zip>09112</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site 03 - &quot;Lviv Regional Infectious Diseases Clinical Hospital&quot;</name>
      <address>
        <city>Lviv</city>
        <state>Lviv Region</state>
        <zip>79010</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site 04 - &quot;City Clinical Infectious Diseases Hospital&quot;, Odesa</name>
      <address>
        <city>Odesa</city>
        <state>Odesa Region</state>
        <zip>65021</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site 07 - &quot;Ternopil City Municipal Ambulance Hospital&quot;</name>
      <address>
        <city>Ternopil'</city>
        <state>Ternopil' Region</state>
        <zip>46006</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site 06 - &quot;Vinnytsia City Clinical Hospital №1&quot;</name>
      <address>
        <city>Vinnitsia</city>
        <state>Vinnitsia Region</state>
        <zip>21021</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site 09 - &quot;Volyn Regional Clinical Hospital&quot;</name>
      <address>
        <city>Luts'k</city>
        <state>Volyn Region</state>
        <zip>43000</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site 01 - &quot;Kyiv City Clinical Hospital №17&quot;</name>
      <address>
        <city>Kyiv</city>
        <zip>03110</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Site 05 - &quot;Kyiv City Clinical Hospital №4&quot;</name>
      <address>
        <city>Kyiv</city>
        <zip>03110</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Ukraine</country>
  </location_countries>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>July 15, 2020</study_first_submitted>
  <study_first_submitted_qc>August 4, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 5, 2020</study_first_posted>
  <last_update_submitted>October 12, 2020</last_update_submitted>
  <last_update_submitted_qc>October 12, 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>Pneumonia</keyword>
  <keyword>COVID-19</keyword>
  <keyword>SARS-CoV-2</keyword>
  <keyword>IVIG</keyword>
  <keyword>Immunoglobulin for Intravenous Administration</keyword>
  <keyword>Bioven</keyword>
  <keyword>Coronavirus</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>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Immunoglobulins</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>After completion of the trial, results will be published. Access to parts CSR planned after the release of scientific publications</ipd_description>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_time_frame>After trial result publication 3 months later</ipd_time_frame>
    <ipd_access_criteria>For specialists in medicine, pharmacy, scientists</ipd_access_criteria>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04500067
org study id: 2020-BV-BP
nct id: NCT04500067
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Pneumonia caused by coronavirus infection COVID-19 is characterized by a combination of
      several dangerous factors that consistently worsen the patient's condition: viral lung damage
      early in the disease; a sharp increase in inflammation on the background of an unbalanced
      immune response ("cytokine storm"); joining a bacterial infection.

      The condition of patients deteriorates significantly mostly at cytokine storm development.
      The damaging of a large volume of lung tissue leads to develops of respiratory failure,
      respiratory distress syndrome, or shock. Ventilatory support becomes ineffective and patients
      die.

      There are reports of the effectiveness of Human Normal Immunoglobulin for Intravenous
      Administration (IVIG) high doses when used as part of complex therapy in patients with
      pneumonia caused by coronavirus COVID-19. In particular, IVIG has a positive effect on
      survival rates, overall disease course, duration of stay in the intensive care unit, and
      ventilatory support duration.

      The probable mechanism of action of high-dose IVIG therapy is considered to be a regulatory
      effect on the immune system. Similar is the known and confirmed effectiveness of IVIG for
      autoimmune diseases (Kavasaky disease, Guillain Barre syndrome, Chronic inflammatory
      demyelinating polyradiculoneuropathy, Multifocal motor neuropathy).

      This trial to assesses the Efficacy of IVIG (medication trade name - Bioven, manufactured by
      Biopharma Plasma LLC) in the High Immunomodulatory Dose in Complex Treatment of Severe
      Pneumonia Caused by COVID-19 / SARS-CoV-2
The screening stage:

      The patient or his legal representative must sign an informed consent. After signing the
      informed consent, the screening tests&procedures are performed and the compliance with the
      inclusion / non-inclusion criteria is assessed.

      For patients who have been screened and meet the inclusion criteria and do not fall under the
      exclusion criteria, a blinded randomization procedure is provided.

      Randomization is performed by the IVRS method, according to the blinded-block patient's
      randomization table.

      The clinical stage of the trial:

      Begins after patient randomization. At the clinical stage, among other things, provides:

        -  Determination of the individual dose of the study drug (in the study group)

        -  Administration of the drug (in the study group)

        -  Registration of adverse events

        -  registration of information about taking antiviral drugs for the treatment of COVID-19;

        -  registration of information on symptomatic therapy and administration of drugs for the
           treatment of comorbidities;

        -  measurement of vital signs (blood pressure, heart rate, respiratory rate, body
           temperature);

        -  Determination of SPO2 level

        -  Determining the need for ventilation

        -  Determining the need for intensive care

        -  Assessment of compliance with the exclusion criteria

      Patients in the Control Group will receive therapy recommended by the COVID-19 coronavirus
      infection treatment protocol, depending on the severity of their condition according to the
      prescribing list, which will not include immunoglobulin preparations.

      Patients of the Study Group (IVIG) receive high-dose therapy with the study drug (Bioven, 10%
      solution for infusions produced by Biopharma Plasma LLC, Ukraine). The dose is calculated by
      body weight. Patients will also receive therapy recommended by the COVID-19 coronavirus
      infection treatment protocol, depending on the severity of their condition according to the
      prescribing list.

      Bioven administered intravenously, at an initial rate of 0.5 - 1.0 ml/kg body weight/hour for
      30 minutes. In the absence of any undesirable side effects, the rate of administration can be
      gradually increased (recommended increase by 0.5 - 1.5 ml/kg body weight/hour every 10
      minutes). According to results previously accomplished clinical studies, the maximum rate of
      Bioven administration is up to 8.5 ml/kg body weight/hour.

      Observation and completion stage:

      Begins and continues from the last administration of the study drug until the discharge of
      the patient from the hospital, but not less than 28 days from the confirmation of the
      diagnosis of pneumonia caused by coronavirus infection COVID-19.

      The following procedures are provided at the stage:

        -  registration of information about taking antiviral drugs for the treatment of COVID-19;

        -  registration of information on symptomatic therapy and administration of drugs for the
           treatment of comorbidities;

        -  measurement of vital signs (blood pressure, heart rate, respiratory rate, body
           temperature);

        -  determination of SPO2 level

        -  registration of the results of the examination of the lungs by computed tomography (or
           radiography)

        -  taking biomaterials for laboratory research:

        -  general blood test (erythrocytes, hemoglobin, expanded leukocyte formula, platelets,
           etc.);

        -  general analysis of urine;

        -  biochemical analysis of blood;

        -  state of the coagulation system

        -  determination of inflammatory factors in the dynamics (CRP, ferritin, procalcitonin;
           TNF-α), IL-1-beta, IL-6, complement component C3 (C3), circulating immune complexes
           (CIC), etc.),

        -  determination of IgG subclasses (G1, G2, G3, G4,);

        -  Determining the need for ventilation

        -  Determining the need for intensive care

        -  Adverse reactions registration

        -  Assessment of compliance with the exclusion criteria

      The patient's condition is assessed daily till discharge; and by schedule after discharge (if
      it happen earlier), during 28 days period after diagnosis of severe pneumonia caused by
      coronavirus infection COVID-19 In case of death of the patient - the date and cause of death
      are fixed. The results of the study are evaluated by endpoints.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Open-label multicenter randomized controlled in parallel groups.
Patients undergoing screening are randomized into groups in equal proportions:
Study Group (receive IVIG Bioven with base therapy).
Control group (receive base therapy only)
At the stage of Data Analysis to ensure comparability of data and homogeneity of the sample, the possibility of additional comparison of groups based on the actually prescribed base therapy and other identified covariates is provided.
primary purpose: Treatment
masking: None (Open Label)
measure: Period duration (in days) to clinical improvement
time frame: From date post-onset of severe pneumonia to date of patient discharge or date of death, whichever came first, assessed up to 28 days
description: Number of days post-onset of severe pneumonia to the moment of normalization at least two from following primary outcomes: O2 saturation with self-breathing, respiratory movements rate with self-breathing, body temperature without antipyretics use, lymphocyte count (targeted levels set in the description each of these primary outcomes)
measure: O2 saturation (SPO2 percentage), with self-breathing
time frame: From date post-onset of severe pneumonia to date of patient discharge or date of death, whichever came first, assessed up to 28 days
description: The target level of SPO2 percentage - 95% and above with self-breathing, is used as one of the clinical improvement criteria
measure: Respiratory movements rate (amount per minute), with self-breathing
time frame: From date post-onset of severe pneumonia to date of patient discharge or date of death, whichever came first, assessed up to 28 days
description: The target level of respiratory movements - 28 per minute or less with self-breathing, is used as one of the clinical improvement criteria
measure: Body temperature without antipyretics use
time frame: From date post-onset of severe pneumonia to date of patient discharge or date of death, whichever came first, assessed up to 28 days
description: Measured in degrees Celsius. Fever absence (body temperature no more 37 degrees Celsius) during at least 24 hours without antipyretics, is used as one of the clinical improvement criteria.
measure: Lymphocyte count
time frame: From date post-onset of severe pneumonia to date of patient discharge or date of death, whichever came first, assessed up to 28 days
description: The target level 1000 cells / mm3 and above is used as one of the clinical improvement criteria (applicable for patients with lymphocytes count lower 1000 cells / mm3 at screening moment)
measure: Time from the onset of the disease to discharge, in days
time frame: 28 days
description: Period duration (in days)
measure: Duration of the need for ventilatory support, in days
time frame: 28 days
description: Number of days with ventilatory support
measure: Duration of the need for intensive care, in days
time frame: 28 days
description: Number of days in the intensive care unit
measure: Duration of need for oxygenation in days (SPO2 ≤ 93% with self-breathing)
time frame: 28 days
description: Number of days with necessery of oxygenation support
measure: The C-reactive protein (CRP) level
time frame: Day 0 (screening), day 5, day 14, day 28
description: Measuring the analyte concentration in plasma (mg/L)
measure: The tumor necrozis factor alpha (TNF-α) level
time frame: Day 0 (screening), day 5, day 14, day 28
description: Measuring the analyte concentration in plasma (pg/mL)
measure: The interleukin-1β (IL-1β) level
time frame: Day 0 (screening), day 5, day 14, day 28
description: Measuring the analyte concentration in plasma (pg/mL)
measure: The interleukin-6 (IL-6) level
time frame: Day 0 (screening), day 5, day 14, day 28
description: Measuring the analyte concentration in plasma (pg/mL)
measure: The D-dimer level
time frame: Day 0 (screening), day 5, day 14, day 28
description: Measuring the analyte concentration in plasma (µg FEU/mL)
measure: The Complement (C3 component) level
time frame: Day 0 (screening), day 5, day 14, day 28
description: Measuring the analyte concentration in plasma (g/L)
measure: The Circulating immune complexes level
time frame: Day 0 (screening), day 5, day 14, day 28
description: Measuring the analyte concentration in plasma (U/mL)
measure: The ferritin level
time frame: Day 0 (screening), day 5, day 14, day 28
description: Analyte concentration in plasma (ng/mL)
measure: The procalcitonin level
time frame: Day 0 (screening), day 5, day 14, day 28
description: Analyte concentration in plasma (ng/mL)
measure: IgG subtypes
time frame: Day 0 (screening), day 5, day 14, day 28
description: The IgG-subtypes (IgG1-IgG4) concentration in plasma (mg/dL)
measure: Survival assessment for a 28-day follow-up period since the onset of severe pneumonia
time frame: 28 days
description: Survivealance estimation
measure: Frequency of side effects
time frame: 28 days
description: Number of participants with adverse reactions related by investigational drug as assessed by CTCАЕ v 4.0
measure: Frequency of serious side effects
time frame: 28 days
description: Number of participants with serious adverse reactions related by investigational drug as assessed by CTCАЕ v 4.0
arm group label: Study Group (IVIG)
arm group type: Experimental
description: Patients receive IVIG (trade name - Bioven) with base therapy
arm group label: Control group
arm group type: No Intervention
description: Patients receive base therapy only
intervention type: Drug
intervention name: IVIG
description: Patients in the study group receive the drug Bioven, 10% solution for infusions produced by LLC Biopharma Plasma 0,8-1,0 g/kg once a day for 2 days (total course dose - 1.6-2.0 g/kg) as well as base treatment recommended by the protocol of COVID-19 coronavirus infection treatment depending on the severity of their condition according to the prescription sheet.
arm group label: Study Group (IVIG)
other name: Human normal immunoglobulin for intravenous administration
other name: Bioven
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
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country: Ukraine
responsible party type: Sponsor
mesh term: COVID-19
mesh term: Pneumonia
mesh term: Immunoglobulins
sharing ipd: Yes
ipd description: After completion of the trial, results will be published. Access to parts CSR planned after the release of scientific publications
ipd info type: Clinical Study Report (CSR)
ipd time frame: After trial result publication 3 months later
ipd access criteria: For specialists in medicine, pharmacy, scientists