<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/NCT04425915</url>
  </required_header>
  <id_info>
    <org_study_id>ILBS-COVID-04</org_study_id>
    <nct_id>NCT04425915</nct_id>
  </id_info>
  <brief_title>Efficacy of Convalescent Plasma Therapy in Patients With COVID-19</brief_title>
  <official_title>Efficacy of Convalescent Plasma Therapy in Patients With COVID-19: A Randomized Control Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Institute of Liver and Biliary Sciences, India</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Institute of Liver and Biliary Sciences, India</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>
      Currently, no effective treatments are available for the COVID-19. Scientists and Researchers&#xD;
      are working on many aspects of treatment options for the development of vaccination and&#xD;
      medication to combat this life-threatening problem. Convalescent plasma from recovered&#xD;
      COVID-19 patients contains antibodies against COVID-19 which may be beneficial to severely&#xD;
      sick COVID-19 patients. Investigator have recently concluded a pilot phase II open-label RCT&#xD;
      on the efficacy of convalescent plasma in severe COVID 19 patients in which encouraging&#xD;
      results were seen. Investigator plan to further study the efficacy and safety of convalescent&#xD;
      plasma in COVID-19 severely sick patients through an RCT. Investigator will collect up to 500&#xD;
      ml Convalescent Plasma from the COVID-19 recovered persons after 14 days of clinical recovery&#xD;
      with two consecutive SARS CoV-2 negative tests by PCR at least 24 hours apart. This plasma&#xD;
      will be tested and frozen and stored. On requisition it will be thawed and sent to the&#xD;
      treating center. Two doses of 250 ml convalescent plasma each will be transfused on two&#xD;
      consecutive days to patients who fit the eligibility criteria (Severely sick COVID-19&#xD;
      patients) and are randomized to the convalescent plasma group along with the standard of care&#xD;
      and the other group will receive standard of care alone. Data will be collected to study the&#xD;
      benefits and adverse events related to convalescent plasma transfusion.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study Centres:&#xD;
&#xD;
      Institute of Liver and Biliary Sciences Sector D-1, Vasant Kunj New Delhi -110070&#xD;
&#xD;
      - Collection and testing of Convalescent Plasma&#xD;
&#xD;
      Treatment Centres&#xD;
&#xD;
      Lok Nayak Jai Prakash Hospital (LNJP)&#xD;
&#xD;
      Rajiv Gandhi Super-speciality Hospital (RGSSH)&#xD;
&#xD;
      Methodology Donor Plasmapheresis COVID-19 recovered patients will be counseled and informed&#xD;
      regarding convalescent plasma donation. The contact information of those who agree will be&#xD;
      sent to the coordinator at ILBS Blood Centre.&#xD;
&#xD;
        -  The prospective donor will be contacted and if willing to come for donation, the donor&#xD;
           will be provided conveyance if required, to come to ILBS Blood centre for Plasma&#xD;
           Donation&#xD;
&#xD;
        -  At ILBS the donor will be counseled and the doctor in-charge will explain the procedure&#xD;
           to the Donor.&#xD;
&#xD;
        -  The donor will be given a Donor Information Sheet and Informed consent will be taken on&#xD;
           the document&#xD;
&#xD;
        -  The eligibility for plasma donation will be ascertained through Medical History,&#xD;
           Physical Examination, and laboratory tests.&#xD;
&#xD;
      Donor Eligibility for Plasmapheresis&#xD;
&#xD;
        -  Virologically documented (PCR positive by nasopharyngeal swab) who is recovered and free&#xD;
           of symptoms for 14 days.&#xD;
&#xD;
        -  Has tested negative for SARS CoV 2 on two consecutive tests 24 hrs apart.&#xD;
&#xD;
        -  Fulfill all criteria of donor eligibility for donor Plasmapheresis under the Drugs &amp;&#xD;
           Cosmetics Act 1940 and Rules 1945, amended 11.03.2020&#xD;
&#xD;
        -  Females who have been pregnant may be tested for anti-HLA antibodies and eligible if&#xD;
           negative for the same.&#xD;
&#xD;
      The following Donors will be excluded&#xD;
&#xD;
        -  Do not fulfill all criteria of donor eligibility for donor Plasmapheresis under&#xD;
&#xD;
        -  the Drugs &amp; Cosmetics Act 1940 and Rules 1945, amended 11.03.2020&#xD;
&#xD;
        -  Females who have been pregnant and have not been tested for HLA antibodies or are HLA&#xD;
           antibody positive if tested and previously transfused donors (to prevent TRALI)&#xD;
&#xD;
        -  Donors who have taken steroids during treatment for COVID-19 Donor Selection Process&#xD;
&#xD;
        -  A detailed medical history of the donor will be taken and documented&#xD;
&#xD;
        -  Physical examination ( Height, Weight, Blood Pressure, Temperature, adequate veins for&#xD;
           phlebotomy)&#xD;
&#xD;
        -  Laboratory Testing: complete Blood count, Testing for hepatitis B virus, hepatitis C&#xD;
           virus, HIV, malaria, and syphilis) by serology, blood grouping, and antibody screening.&#xD;
           Serum protein will be done in repeat donors ( Ref: D&amp;C Act and Rules)&#xD;
&#xD;
        -  Serum COVID-19 specific IgG antibody positive (with an IgG titre higher than 80).&#xD;
&#xD;
        -  All Results Evaluated &amp; Clinically Correlated The donor is deemed eligible/non-eligible&#xD;
&#xD;
      Plasmapheresis Procedure&#xD;
&#xD;
        -  Determine Volume to be collect-approx. 500 ml&#xD;
&#xD;
        -  As per the Drugs &amp; Cosmetics Act 1940 and Rules 1945, amended 11.03.2020&#xD;
&#xD;
        -  Start Donor Plasmapheresis Procedure(As per SOP)&#xD;
&#xD;
        -  Collect Convalescent Plasma The convalescent plasma will be properly labeled and frozen&#xD;
           at -80o C in a separate Deep Freezer. It will not be issued to other patients who are&#xD;
           with non-COVID.&#xD;
&#xD;
        -  Label Details: As per the Drugs &amp; Cosmetics Act 1940 and Rules 1945, amended 11.03.2020.&#xD;
&#xD;
        -  Storage condition- Below -30oC&#xD;
&#xD;
        -  Shelf life: - 1 Year&#xD;
&#xD;
      Other Sources of Convalescent Plasma:&#xD;
&#xD;
      Convalescent Plasma collected during a CP donation drive by Delhi Govt. following all rules&#xD;
      and regulations of the Drugs&amp; Cosmetics Act 1940 and Rules 1945, amended 11.03.2020 is stored&#xD;
      at ILBS and will be used in this trial.&#xD;
&#xD;
      The tests for Donors:&#xD;
&#xD;
      1. Real-time PCR for SARS-CoV-2: Nasal swab samples will be taken prior to donation and&#xD;
      tested for SARS-CoV-2 by real-time PCR method it the donor does not have two negative reports&#xD;
      24 hrs apart.&#xD;
&#xD;
      Antibody Titers of Convalescent Plasma and Patients Plasma by ELISA&#xD;
&#xD;
      For Donors:&#xD;
&#xD;
      The titre of serum neutralizing antibody which is the spike protein antibody, directed&#xD;
      against the SARS-CoV-2 RBD (receptor binding domain) proteins. The titre will be done by IgG&#xD;
      ELISA or by Rapid IgG antibody titre. The minimum titre of 80 is needed for the use of&#xD;
      convalescent in patients.&#xD;
&#xD;
      For recipients:&#xD;
&#xD;
        1. Real-time PCR for SARS-CoV-2:&#xD;
&#xD;
           Nasal swab samples will be taken prior to transfusion and tested for SARS-CoV-2 by&#xD;
           real-time PCR method. The test should be positive for eligibility of the recipient along&#xD;
           with clinical criteria for COVID-19.&#xD;
&#xD;
        2. Antibody titre: The serum of each recipient will be obtained and IgG antibody titre by&#xD;
           enzyme-linked immune-sorbent assay (ELISA) or Rapid IgG antibody method will be tested&#xD;
           one day prior to the convalescent plasma transfusion. Changes of IgG antibody titre&#xD;
           before and after convalescent plasma transfusion in patients will be studied. The serum&#xD;
           will be stored for neutralizing antibody titers by plaque reduction will be done subject&#xD;
           to availability.&#xD;
&#xD;
      Study Population:&#xD;
&#xD;
      Adult patients with severe COVID -19 infections defined as WHO Interim Guidance and the&#xD;
      Guideline of Diagnosis and Treatment of COVID-19 of National Health Commission of China&#xD;
      (version 5.0) with confirmation by real-time RT-PCR assay with severe disease i.e. meeting&#xD;
      any 2 of the following criteria&#xD;
&#xD;
        1. Patients on ventilator (in last 24 hours)&#xD;
&#xD;
        2. Respiratory distress, RR ≥30 beats/min&#xD;
&#xD;
        3. Oxygen saturation level less than 90% in resting state&#xD;
&#xD;
        4. Partial pressure of oxygen (PaO2)/oxygen concentration (FiO2) ≤ 300 mmHg&#xD;
&#xD;
        5. Lung infiltrates &gt; 50% within 24 to 48 hours&#xD;
&#xD;
      Study Design:&#xD;
&#xD;
      An open label randomized controlled trial. The study group will comprise of 400 adult&#xD;
      patients with severe COVID -19 as detailed above.&#xD;
&#xD;
      Randomization will be done in the ratio of 1:1 in with 200 patients in the treatment arm and&#xD;
      200 patients in the control arm. Allocation concealment will be done by Sequentially Numbered&#xD;
      Opaque Sealed Envelopes (SNOSE) method.&#xD;
&#xD;
      Intervention Arm: Two doses of 250 ml Convalescent plasma from recovered COVID-19 patients +&#xD;
      Standard of Care will be given to severely sick COVID-19 patients in the treatment arm&#xD;
      Control Arm: Standard of Care will be given to severely sick COVID-19 patients in the control&#xD;
      arm Details of Standard of Care The Ministry of Health and Family Welfare has issued detailed&#xD;
      guidelines for the management of sCOVID-19 based on varying grades of severity which may be&#xD;
      periodically updated. For the management of ARDS or sepsis the respective guidelines issued&#xD;
      by ARDSNet and Surviving Sepsis campaign will be followed. Other institutional protocols for&#xD;
      supportive management will be implemented. (Ref: Guidelines on Clinical Management of&#xD;
      COVID-19. MoHFW, GoI.2020.) Monitoring and Assessment: Daily until clinical improvement&#xD;
      Adverse Effects: Will be documented Stopping rule: None (C) The expected outcome of the&#xD;
      project: Investigator expect convalescent plasma therapy to be a safe and efficacious therapy&#xD;
      based on our pilot RCT. This study will determine if there is a clinical improvement&#xD;
      /mortality benefit and further elaborate on its safety in patients with severe COVID-19&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 14, 2020</start_date>
  <completion_date type="Actual">December 15, 2020</completion_date>
  <primary_completion_date type="Actual">December 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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Efficacy of convalescent plasma in severe COVID 19 patients in time to clinical improvement (Clinical improvement: Reduction of two points in ordinal scale or live discharge from the intensive care unit, whichever is earlier)</measure>
    <time_frame>Day 28</time_frame>
    <description>The six-point scale is as follows:&#xD;
death=6;&#xD;
hospital admission for extracorporeal membrane oxygenation or mechanical ventilation=5;&#xD;
hospital admission for non-invasive ventilation or high-flow oxygen therapy=4;&#xD;
hospital admission for oxygen therapy (but not requiring high-flow or non-invasive ventilation)=3;&#xD;
hospital admission but not requiring oxygen therapy=2;&#xD;
discharged or having reached discharge criteria (defined as clinical recovery-ie, normalization of pyrexia, respiratory rate 94% on room air, and relief of cough, all maintained for at least 72 h)=1.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients in each category according to the ordinal scale</measure>
    <time_frame>48 hours</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients in each category according to the ordinal scale</measure>
    <time_frame>7 day</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients in each category according to the ordinal scale</measure>
    <time_frame>Day 14</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients in each category according to the ordinal scale</measure>
    <time_frame>Day 28</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of oxygen therapy in both groups</measure>
    <time_frame>Day 28</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of hospital stay in both groups</measure>
    <time_frame>Day 28</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients on mechanical ventilation at day 7 in both groups</measure>
    <time_frame>Day 7</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality in both groups</measure>
    <time_frame>Day 7</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality in both groups</measure>
    <time_frame>Day 28</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Intensive Care Unit stay</measure>
    <time_frame>Day 28</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of adverse effects in both groups</measure>
    <time_frame>Day 28</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Presence of antibodies against SARS-CoV-2 in serum after plasma administration</measure>
    <time_frame>Day 0</time_frame>
    <description>IgG Titres against S1, RBD antigen, and SARS CoV2 neutralizing antibody titres</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Presence of antibodies against SARS-CoV-2 in serum after plasma administration</measure>
    <time_frame>Day 3</time_frame>
    <description>IgG Titres against S1, RBD antigen, and SARS CoV2 neutralizing antibody titres</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Presence of antibodies against SARS-CoV-2 in serum after plasma administration</measure>
    <time_frame>Day 7</time_frame>
    <description>IgG Titres against S1, RBD antigen, and SARS CoV2 neutralizing antibody titres</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Presence of antibodies against SARS-CoV-2 in serum after plasma administration</measure>
    <time_frame>Day 14</time_frame>
    <description>IgG Titres against S1, RBD antigen, and SARS CoV2 neutralizing antibody titres</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Cytokines in both groups</measure>
    <time_frame>Day 28</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in acute phase reactants in both groups</measure>
    <time_frame>Day 28</time_frame>
    <description>Serum ferritin</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation of the titers in COVID-19 convalescent plasma donors with duration of illness, the severity of symptoms, duration of hospital stay, drugs used in therapy, duration between recovery, and donation.</measure>
    <time_frame>Day 28</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">400</enrollment>
  <condition>COVID</condition>
  <arm_group>
    <arm_group_label>Convalescent Plasma with Standard of Care</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Two doses of 250 ml Convalescent plasma from recovered COVID-19 patients + Standard of Care will be given to severely sick COVID-19 patients in the treatment arm</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard of Care</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>The Ministry of Health and Family Welfare has issued detailed guidelines for the management of sCOVID-19 based on varying grades of severity which may be periodically updated. For the management of ARDS or sepsis the respective guidelines issued by ARDSNet and Surviving Sepsis campaign will be followed. Other institutional protocols for supportive management will be implemented. (Ref: Guidelines on Clinical Management of COVID-19. MoHFW, GoI.2020.)</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Convalescent Plasma</intervention_name>
    <description>Dose-250 ml Frequency - 2 doses on consecutive days Duration -Start by day 3 of symptom onset (of severe COVID-19 as in inclusion criteria) in eligible patients</description>
    <arm_group_label>Convalescent Plasma with Standard of Care</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Standard of Care</intervention_name>
    <description>The Ministry of Health and Family Welfare has issued detailed guidelines for the management of sCOVID-19 based on varying grades of severity which may be periodically updated. For the management of ARDS or sepsis the respective guidelines issued by ARDSNet and Surviving Sepsis campaign will be followed. Other institutional protocols for supportive management will be implemented. (Ref: Guidelines on Clinical Management of COVID-19. MoHFW, GoI.2020.)</description>
    <arm_group_label>Convalescent Plasma with Standard of Care</arm_group_label>
    <arm_group_label>Standard of Care</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Recipient Inclusion Criteria:&#xD;
&#xD;
        - Patients with severe COVID-19 will be considered for randomization and will be transfused&#xD;
        convalescent plasma within 3 days of symptom onset (Severe COVID-19) Severe COVID -19&#xD;
        defined by WHO Interim Guidance and the Guideline of Diagnosis and Treatment of COVID-19 of&#xD;
        National Health Commission of China (version 5.0) along with confirmation by real-time&#xD;
        RT-PCR assay with severe disease i.e. meeting any 2 of the following criteria-&#xD;
&#xD;
          -  Patients on ventilator (in last 24 hours)&#xD;
&#xD;
          -  Respiratory distress, RR ≥30 beats/min&#xD;
&#xD;
          -  Oxygen saturation level less than 90 % in resting state&#xD;
&#xD;
          -  Partial pressure of oxygen (PaO2)/oxygen concentration (FiO2) ≤ 300 mmHg&#xD;
&#xD;
          -  Lung infiltrates &gt; 50% within 24 to 48 hours&#xD;
&#xD;
        Recipient Exclusion Criteria:&#xD;
&#xD;
          -  Patient/ family members who do not give consent to participate in the study.&#xD;
&#xD;
          -  Patients with age less than 18 years&#xD;
&#xD;
          -  Patients presenting with multi-organ failure&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Individuals with HIV and Viral Hepatitis and Cancer&#xD;
&#xD;
          -  Extremely moribund patients with an expected life expectancy of less than 24 hours&#xD;
&#xD;
          -  Hemodynamic instability requiring vasopressors&#xD;
&#xD;
          -  Previous history of allergy to plasma&#xD;
&#xD;
          -  Cirrhosis&#xD;
&#xD;
          -  Severe renal impairment with GFR&lt; 30ml/min or recipients of RRT, peritoneal dialysis&#xD;
&#xD;
          -  Patients with uncontrolled diabetes mellitus, hypertension, arrhythmias and unstable&#xD;
             Angina&#xD;
&#xD;
        Donor Inclusion Criteria for Plasmapheresis&#xD;
&#xD;
          -  Virologically documented (PCR positive by nasopharyngeal swab) who is recovered and&#xD;
             free of symptoms for 14 days.&#xD;
&#xD;
          -  Has tested negative for SARS CoV 2 on two consecutive tests 24 hrs apart.&#xD;
&#xD;
          -  Fulfill all criteria of donor eligibility for donor Plasmapheresis under the Drugs &amp;&#xD;
             Cosmetics Act 1940 and Rules 1945, amended 11.03.2020&#xD;
&#xD;
          -  Females who have been pregnant may be tested for anti-HLA antibodies and eligible if&#xD;
             negative for the same.&#xD;
&#xD;
        Donors Exclusion Criteria:&#xD;
&#xD;
          -  Do not fulfill all criteria of donor eligibility for donor Plasmapheresis under&#xD;
&#xD;
          -  the Drugs &amp; Cosmetics Act 1940 and Rules 1945, amended 11.03.2020&#xD;
&#xD;
          -  Females who have been pregnant and have not been tested for HLA antibodies or are HLA&#xD;
             antibody positive if tested and previously transfused donors (to prevent TRALI)&#xD;
&#xD;
          -  Donors who have taken steroids during treatment for COVID-19&#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>Maulana Azad Medical College</name>
      <address>
        <city>New Delhi</city>
        <state>Delhi</state>
        <zip>110006</zip>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institute of Liver &amp; Biliary Sciences</name>
      <address>
        <city>New Delhi</city>
        <state>Delhi</state>
        <zip>110070</zip>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rajiv Gandhi Super Speciality Hospital</name>
      <address>
        <city>New Delhi</city>
        <state>Delhi</state>
        <zip>110093</zip>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>India</country>
  </location_countries>
  <verification_date>June 2021</verification_date>
  <study_first_submitted>June 7, 2020</study_first_submitted>
  <study_first_submitted_qc>June 10, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 11, 2020</study_first_posted>
  <last_update_submitted>October 6, 2021</last_update_submitted>
  <last_update_submitted_qc>October 6, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">October 14, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Analytic Code</ipd_info_type>
    <ipd_time_frame>After publication till 5 years</ipd_time_frame>
    <ipd_access_criteria>It will be available for researcher scientist &amp; government agencies.</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/NCT04425915
org study id: ILBS-COVID-04
nct id: NCT04425915
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Currently, no effective treatments are available for the COVID-19. Scientists and Researchers
      are working on many aspects of treatment options for the development of vaccination and
      medication to combat this life-threatening problem. Convalescent plasma from recovered
      COVID-19 patients contains antibodies against COVID-19 which may be beneficial to severely
      sick COVID-19 patients. Investigator have recently concluded a pilot phase II open-label RCT
      on the efficacy of convalescent plasma in severe COVID 19 patients in which encouraging
      results were seen. Investigator plan to further study the efficacy and safety of convalescent
      plasma in COVID-19 severely sick patients through an RCT. Investigator will collect up to 500
      ml Convalescent Plasma from the COVID-19 recovered persons after 14 days of clinical recovery
      with two consecutive SARS CoV-2 negative tests by PCR at least 24 hours apart. This plasma
      will be tested and frozen and stored. On requisition it will be thawed and sent to the
      treating center. Two doses of 250 ml convalescent plasma each will be transfused on two
      consecutive days to patients who fit the eligibility criteria (Severely sick COVID-19
      patients) and are randomized to the convalescent plasma group along with the standard of care
      and the other group will receive standard of care alone. Data will be collected to study the
      benefits and adverse events related to convalescent plasma transfusion.
Study Centres:

      Institute of Liver and Biliary Sciences Sector D-1, Vasant Kunj New Delhi -110070

      - Collection and testing of Convalescent Plasma

      Treatment Centres

      Lok Nayak Jai Prakash Hospital (LNJP)

      Rajiv Gandhi Super-speciality Hospital (RGSSH)

      Methodology Donor Plasmapheresis COVID-19 recovered patients will be counseled and informed
      regarding convalescent plasma donation. The contact information of those who agree will be
      sent to the coordinator at ILBS Blood Centre.

        -  The prospective donor will be contacted and if willing to come for donation, the donor
           will be provided conveyance if required, to come to ILBS Blood centre for Plasma
           Donation

        -  At ILBS the donor will be counseled and the doctor in-charge will explain the procedure
           to the Donor.

        -  The donor will be given a Donor Information Sheet and Informed consent will be taken on
           the document

        -  The eligibility for plasma donation will be ascertained through Medical History,
           Physical Examination, and laboratory tests.

      Donor Eligibility for Plasmapheresis

        -  Virologically documented (PCR positive by nasopharyngeal swab) who is recovered and free
           of symptoms for 14 days.

        -  Has tested negative for SARS CoV 2 on two consecutive tests 24 hrs apart.

        -  Fulfill all criteria of donor eligibility for donor Plasmapheresis under the Drugs &
           Cosmetics Act 1940 and Rules 1945, amended 11.03.2020

        -  Females who have been pregnant may be tested for anti-HLA antibodies and eligible if
           negative for the same.

      The following Donors will be excluded

        -  Do not fulfill all criteria of donor eligibility for donor Plasmapheresis under

        -  the Drugs & Cosmetics Act 1940 and Rules 1945, amended 11.03.2020

        -  Females who have been pregnant and have not been tested for HLA antibodies or are HLA
           antibody positive if tested and previously transfused donors (to prevent TRALI)

        -  Donors who have taken steroids during treatment for COVID-19 Donor Selection Process

        -  A detailed medical history of the donor will be taken and documented

        -  Physical examination ( Height, Weight, Blood Pressure, Temperature, adequate veins for
           phlebotomy)

        -  Laboratory Testing: complete Blood count, Testing for hepatitis B virus, hepatitis C
           virus, HIV, malaria, and syphilis) by serology, blood grouping, and antibody screening.
           Serum protein will be done in repeat donors ( Ref: D&C Act and Rules)

        -  Serum COVID-19 specific IgG antibody positive (with an IgG titre higher than 80).

        -  All Results Evaluated & Clinically Correlated The donor is deemed eligible/non-eligible

      Plasmapheresis Procedure

        -  Determine Volume to be collect-approx. 500 ml

        -  As per the Drugs & Cosmetics Act 1940 and Rules 1945, amended 11.03.2020

        -  Start Donor Plasmapheresis Procedure(As per SOP)

        -  Collect Convalescent Plasma The convalescent plasma will be properly labeled and frozen
           at -80o C in a separate Deep Freezer. It will not be issued to other patients who are
           with non-COVID.

        -  Label Details: As per the Drugs & Cosmetics Act 1940 and Rules 1945, amended 11.03.2020.

        -  Storage condition- Below -30oC

        -  Shelf life: - 1 Year

      Other Sources of Convalescent Plasma:

      Convalescent Plasma collected during a CP donation drive by Delhi Govt. following all rules
      and regulations of the Drugs& Cosmetics Act 1940 and Rules 1945, amended 11.03.2020 is stored
      at ILBS and will be used in this trial.

      The tests for Donors:

      1. Real-time PCR for SARS-CoV-2: Nasal swab samples will be taken prior to donation and
      tested for SARS-CoV-2 by real-time PCR method it the donor does not have two negative reports
      24 hrs apart.

      Antibody Titers of Convalescent Plasma and Patients Plasma by ELISA

      For Donors:

      The titre of serum neutralizing antibody which is the spike protein antibody, directed
      against the SARS-CoV-2 RBD (receptor binding domain) proteins. The titre will be done by IgG
      ELISA or by Rapid IgG antibody titre. The minimum titre of 80 is needed for the use of
      convalescent in patients.

      For recipients:

        1. Real-time PCR for SARS-CoV-2:

           Nasal swab samples will be taken prior to transfusion and tested for SARS-CoV-2 by
           real-time PCR method. The test should be positive for eligibility of the recipient along
           with clinical criteria for COVID-19.

        2. Antibody titre: The serum of each recipient will be obtained and IgG antibody titre by
           enzyme-linked immune-sorbent assay (ELISA) or Rapid IgG antibody method will be tested
           one day prior to the convalescent plasma transfusion. Changes of IgG antibody titre
           before and after convalescent plasma transfusion in patients will be studied. The serum
           will be stored for neutralizing antibody titers by plaque reduction will be done subject
           to availability.

      Study Population:

      Adult patients with severe COVID -19 infections defined as WHO Interim Guidance and the
      Guideline of Diagnosis and Treatment of COVID-19 of National Health Commission of China
      (version 5.0) with confirmation by real-time RT-PCR assay with severe disease i.e. meeting
      any 2 of the following criteria

        1. Patients on ventilator (in last 24 hours)

        2. Respiratory distress, RR ≥30 beats/min

        3. Oxygen saturation level less than 90% in resting state

        4. Partial pressure of oxygen (PaO2)/oxygen concentration (FiO2) ≤ 300 mmHg

        5. Lung infiltrates > 50% within 24 to 48 hours

      Study Design:

      An open label randomized controlled trial. The study group will comprise of 400 adult
      patients with severe COVID -19 as detailed above.

      Randomization will be done in the ratio of 1:1 in with 200 patients in the treatment arm and
      200 patients in the control arm. Allocation concealment will be done by Sequentially Numbered
      Opaque Sealed Envelopes (SNOSE) method.

      Intervention Arm: Two doses of 250 ml Convalescent plasma from recovered COVID-19 patients +
      Standard of Care will be given to severely sick COVID-19 patients in the treatment arm
      Control Arm: Standard of Care will be given to severely sick COVID-19 patients in the control
      arm Details of Standard of Care The Ministry of Health and Family Welfare has issued detailed
      guidelines for the management of sCOVID-19 based on varying grades of severity which may be
      periodically updated. For the management of ARDS or sepsis the respective guidelines issued
      by ARDSNet and Surviving Sepsis campaign will be followed. Other institutional protocols for
      supportive management will be implemented. (Ref: Guidelines on Clinical Management of
      COVID-19. MoHFW, GoI.2020.) Monitoring and Assessment: Daily until clinical improvement
      Adverse Effects: Will be documented Stopping rule: None (C) The expected outcome of the
      project: Investigator expect convalescent plasma therapy to be a safe and efficacious therapy
      based on our pilot RCT. This study will determine if there is a clinical improvement
      /mortality benefit and further elaborate on its safety in patients with severe COVID-19
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Efficacy of convalescent plasma in severe COVID 19 patients in time to clinical improvement (Clinical improvement: Reduction of two points in ordinal scale or live discharge from the intensive care unit, whichever is earlier)
time frame: Day 28
description: The six-point scale is as follows:
death=6;
hospital admission for extracorporeal membrane oxygenation or mechanical ventilation=5;
hospital admission for non-invasive ventilation or high-flow oxygen therapy=4;
hospital admission for oxygen therapy (but not requiring high-flow or non-invasive ventilation)=3;
hospital admission but not requiring oxygen therapy=2;
discharged or having reached discharge criteria (defined as clinical recovery-ie, normalization of pyrexia, respiratory rate 94% on room air, and relief of cough, all maintained for at least 72 h)=1.
measure: Proportion of patients in each category according to the ordinal scale
time frame: 48 hours
measure: Proportion of patients in each category according to the ordinal scale
time frame: 7 day
measure: Proportion of patients in each category according to the ordinal scale
time frame: Day 14
measure: Proportion of patients in each category according to the ordinal scale
time frame: Day 28
measure: Duration of oxygen therapy in both groups
time frame: Day 28
measure: Duration of hospital stay in both groups
time frame: Day 28
measure: Proportion of patients on mechanical ventilation at day 7 in both groups
time frame: Day 7
measure: Mortality in both groups
time frame: Day 7
measure: Mortality in both groups
time frame: Day 28
measure: Duration of Intensive Care Unit stay
time frame: Day 28
measure: Incidence of adverse effects in both groups
time frame: Day 28
measure: Presence of antibodies against SARS-CoV-2 in serum after plasma administration
time frame: Day 0
description: IgG Titres against S1, RBD antigen, and SARS CoV2 neutralizing antibody titres
measure: Presence of antibodies against SARS-CoV-2 in serum after plasma administration
time frame: Day 3
description: IgG Titres against S1, RBD antigen, and SARS CoV2 neutralizing antibody titres
measure: Presence of antibodies against SARS-CoV-2 in serum after plasma administration
time frame: Day 7
description: IgG Titres against S1, RBD antigen, and SARS CoV2 neutralizing antibody titres
measure: Presence of antibodies against SARS-CoV-2 in serum after plasma administration
time frame: Day 14
description: IgG Titres against S1, RBD antigen, and SARS CoV2 neutralizing antibody titres
measure: Change in Cytokines in both groups
time frame: Day 28
measure: Change in acute phase reactants in both groups
time frame: Day 28
description: Serum ferritin
measure: Correlation of the titers in COVID-19 convalescent plasma donors with duration of illness, the severity of symptoms, duration of hospital stay, drugs used in therapy, duration between recovery, and donation.
time frame: Day 28
arm group label: Convalescent Plasma with Standard of Care
arm group type: Experimental
description: Two doses of 250 ml Convalescent plasma from recovered COVID-19 patients + Standard of Care will be given to severely sick COVID-19 patients in the treatment arm
arm group label: Standard of Care
arm group type: Active Comparator
description: The Ministry of Health and Family Welfare has issued detailed guidelines for the management of sCOVID-19 based on varying grades of severity which may be periodically updated. For the management of ARDS or sepsis the respective guidelines issued by ARDSNet and Surviving Sepsis campaign will be followed. Other institutional protocols for supportive management will be implemented. (Ref: Guidelines on Clinical Management of COVID-19. MoHFW, GoI.2020.)
intervention type: Biological
intervention name: Convalescent Plasma
description: Dose-250 ml Frequency - 2 doses on consecutive days Duration -Start by day 3 of symptom onset (of severe COVID-19 as in inclusion criteria) in eligible patients
arm group label: Convalescent Plasma with Standard of Care
intervention type: Other
intervention name: Standard of Care
description: The Ministry of Health and Family Welfare has issued detailed guidelines for the management of sCOVID-19 based on varying grades of severity which may be periodically updated. For the management of ARDS or sepsis the respective guidelines issued by ARDSNet and Surviving Sepsis campaign will be followed. Other institutional protocols for supportive management will be implemented. (Ref: Guidelines on Clinical Management of COVID-19. MoHFW, GoI.2020.)
arm group label: Convalescent Plasma with Standard of Care
arm group label: Standard of Care
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
facility: 
facility: 
country: India
responsible party type: Sponsor
sharing ipd: Yes
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Analytic Code
ipd time frame: After publication till 5 years
ipd access criteria: It will be available for researcher scientist & government agencies.