<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/NCT04403477</url>
  </required_header>
  <id_info>
    <org_study_id>BSMMU/2020/6104</org_study_id>
    <nct_id>NCT04403477</nct_id>
  </id_info>
  <brief_title>Convalescent Plasma Therapy in Severe COVID-19 Infection</brief_title>
  <official_title>Convalescent Plasma Transfusion Therapy in Severe COVID-19 Patients- a Tolerability, Efficacy and Dose-response Phase II RCT</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Dhaka Medical College</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh</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>
      As of March 18, 2020, COVID-19 cases were reported in approximately 195 countries. No&#xD;
      specific therapeutic agents or vaccines for COVID-19 are available. Several therapies, such&#xD;
      as remdesivir and favipiravir, are under investigation, but the antiviral efficacy of these&#xD;
      drugs is not yet known. The use of convalescent plasma (CP) was recommended as an empirical&#xD;
      treatment during outbreaks of Ebola virus in 2014. A protocol for treatment of Middle East&#xD;
      respiratory syndrome coronavirus (MERS-CoV) with CP was established in 2015. This approach&#xD;
      with other viral infections such as SARS-CoV, H5N1 avian influenza, and H1N1 influenza also&#xD;
      suggested that transfusion of CP was effective. In previous reports, most of the patients&#xD;
      received the CP by single transfusion. In a study involving patients with pandemic influenza&#xD;
      A(H1N1) 2009 virus infection, treatment of severe infection with CP (n = 20 patients) was&#xD;
      associated with reduced respiratory tract viral load, serum cytokine response, and mortality.&#xD;
      In another study involving 80 patients with SARS, the administration of CP was associated&#xD;
      with a higher rate of hospital discharge at day 22 from symptom onset compared with patients&#xD;
      who did not receive CP. Accordingly, these findings raise the hypothesis that use of CP&#xD;
      transfusion could be beneficial in patients infected with SARS-CoV-2. The objective of this&#xD;
      study is to describe the initial clinical experience with CP transfusion administered to&#xD;
      severe COVID-19 patients. The primary endpoint of this trial would be to assess the&#xD;
      tolerability, efficacy, and dose-response of CP in severe COVID-19 patients. The secondary&#xD;
      endpoint would be to assess the clinical and laboratory parameters after therapy, in-hospital&#xD;
      mortality, length of hospital stay, reduction in the proportion of deaths, length of ICU&#xD;
      stay, requirement of ventilator and duration of ventilator support. All RT-PCR positive cases&#xD;
      with features of severe infection will be enrolled in this study. Apheretic CP will be&#xD;
      collected from a recovered patient (consecutive two RT-PCR samples negative) between day 22&#xD;
      to 35 days of recovery and those with the antibody titre above 1:320.&#xD;
&#xD;
      This RCT will consist of three arms, a. standard care, b. standard care and 200 ml CP and c.&#xD;
      standard care and 400 ml CP as a single transfusion. Twenty (20) patients will be enrolled&#xD;
      for each arm. Randomization will be done by someone not associated with the care or&#xD;
      assessment of the patients by means of a random number table. Allocations will be concealed&#xD;
      in sequentially numbered, opaque, sealed envelopes. Clinical parameters [fever, cough,&#xD;
      dyspnea, respiratory rate, PaO2/ FiO2 level, pulse, BP, the requirement of O2, and others]&#xD;
      will be recorded before and after CP. Laboratory parameters such as complete blood count,&#xD;
      CRP, chest X-ray, SGPT, SGOT, S. Ferritin, and serum antibody titre will be measured before&#xD;
      and after transfusion. Allergic or serum sickness-like reactions will be noted and adjusted&#xD;
      with outcome. Laboratory tests including RT-PCR will be done at BSMMU virology and laboratory&#xD;
      medicine department. Apheretic plasma will be collected at the transfusion medicine&#xD;
      department of SHNIBPS hospital, ELISA, antibody titre will be done at CMBT, and patients will&#xD;
      be enrolled at DMC and MuMCH. All necessary screening tests will be done before transfusion.&#xD;
&#xD;
      Graphpad Prism v 7.0 will be used for analysis. One way ANOVA test, a non-parametric&#xD;
      Mann-Whitney test, and a Kruskal-Wallis test will be performed to compare the arms. For&#xD;
      parametric outcomes, the investigators will compare the odds ratios across the pairs.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Rationale of the Study Currently no specific treatment is available against COVID-19&#xD;
      infection. Supportive treatment along with concentrated oxygen is the only mean of treatment.&#xD;
      Researchers have already opened over 180 clinical trials of potential COVID-19 treatments for&#xD;
      recruitment, and nearly 150 could start soon. However, to date, no clinical intervention&#xD;
      trial has been completed and reported. Based on anecdotes (small case series), some of the&#xD;
      promising drugs could be azithromycin - hydroxychloroquine combination, Lopinavir/ Ritonavir,&#xD;
      Tocilizumab, Ramdisivir, Favirinapir, and others. CP transfusion is another promising option,&#xD;
      which had been tried before in SARS-CoV, MERS-CoV, and Flu and Ebola viral infection. Its&#xD;
      effectiveness against COVID-19 yet not explored. A recently published case series consists of&#xD;
      ten cases that forecast promising results. Therefore, a phase II RCT to explore the&#xD;
      tolerability, efficacy, and dose-response needs to explore urgently.&#xD;
&#xD;
      The cases started to escalate in Bangladesh and the number of confirmed cases already crossed&#xD;
      a thousand marks. Considering the cost and shortage of other above mentioned anti-viral and&#xD;
      biologics, it is inevitable that many of our patients possibly could not afford or get it.&#xD;
      However, the CP can be easily collected from the recovered patients and can easily be&#xD;
      processed to use it against active infection. This could be an effective and cheap treatment&#xD;
      option for a country like ours to face this catastrophe. Therefore conducting a phase II RCT&#xD;
      on CP transfusion is the demand of time.&#xD;
&#xD;
      Research question:&#xD;
&#xD;
      Does CP transfusion is tolerable and effective in treating severe COVID-19 patients compared&#xD;
      to standard treatment?&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      General Objective:&#xD;
&#xD;
      To assess the tolerability, efficacy, and dose-response of CP transfusion in severe COVID-19&#xD;
      patients&#xD;
&#xD;
      Specific Objectives:&#xD;
&#xD;
        1. To identify the appropriate effective dose of CP therapy&#xD;
&#xD;
        2. To identify the efficacy of the therapy with their endpoint&#xD;
&#xD;
        3. To examine the clinical improvement after CP transfusion in severe COVID-19 patients&#xD;
&#xD;
        4. To assess the laboratory improvement after CP transfusion in severe COVID-19 patients&#xD;
&#xD;
      Study design:&#xD;
&#xD;
      Phase II RCT&#xD;
&#xD;
      Place of study:&#xD;
&#xD;
      Bangabandhu Sheikh Mujib Medical University (BSMMU), Sheikh Hasina Burn &amp; Plastic Surgery&#xD;
      Institute, Dhaka Medical College, Mugda Medical College and Centre for Medical Biotechnology&#xD;
&#xD;
      Study period:&#xD;
&#xD;
      May 2020 - October 2020 (Six months)&#xD;
&#xD;
      Study population:&#xD;
&#xD;
      COVID=19 positive patients who are diagnosed on the basis of RT-PCR at BSMMU fever clinic or&#xD;
      by any other government-designated laboratory and admitted at DMCH, MuMC, and BSMMU.&#xD;
&#xD;
      Randomization and blinding method:&#xD;
&#xD;
      Randomization will be done by someone not associated with the care or assessment of the&#xD;
      patients by means of a random number table. Allocations will be concealed in sequentially&#xD;
      numbered, opaque, sealed envelopes. In this pilot study, the CP or standard care will not be&#xD;
      blinded. However, the primary outcome (oxygen saturations, PaO2/FiO2, and BP) will be&#xD;
      recorded using an objective automated method; the study staff will not be able to influence&#xD;
      the recording of these data.&#xD;
&#xD;
      Sample size:&#xD;
&#xD;
      No similar study has been performed previously. Therefore no data are available that could be&#xD;
      used to generate a sample size calculation. This pilot study is required to provide some&#xD;
      initial data on efficacy and safety that will allow the design of a larger study.&#xD;
&#xD;
      Research instruments&#xD;
&#xD;
        1. General questionnaire for assessing socio-demographic data.&#xD;
&#xD;
        2. A checklist of clinical findings&#xD;
&#xD;
        3. A checklist of investigation findings.&#xD;
&#xD;
      Measures of Variables&#xD;
&#xD;
        1. Socio-Demographic variables&#xD;
&#xD;
             -  Age&#xD;
&#xD;
             -  Gender (Male/Female)&#xD;
&#xD;
             -  Living area (Urban/Rural)&#xD;
&#xD;
             -  Occupation&#xD;
&#xD;
        2. Clinical variables:&#xD;
&#xD;
             -  Symptoms&#xD;
&#xD;
             -  Systolic blood pressure (in mmHg)&#xD;
&#xD;
             -  Diastolic blood pressure (in mmHg)&#xD;
&#xD;
             -  Temperature&#xD;
&#xD;
             -  Respiratory rate&#xD;
&#xD;
             -  Heart rate&#xD;
&#xD;
             -  GCS&#xD;
&#xD;
        3. Laboratory variables&#xD;
&#xD;
             -  CXR&#xD;
&#xD;
             -  CBC&#xD;
&#xD;
             -  CRP&#xD;
&#xD;
             -  S. Ferritin&#xD;
&#xD;
             -  SGPT&#xD;
&#xD;
             -  SGOT&#xD;
&#xD;
             -  Antibody titre&#xD;
&#xD;
      Procedure of collection of Apheretic plasma&#xD;
&#xD;
        1. Pre-donation screening: First of all, 3 ml blood will be drawn from peripheral venous&#xD;
           site preferably from dorsum of the hand, and will be kept in EDTA tube for further&#xD;
           testing. Blood group will be confirmed by using known antisera. Screening test of 5&#xD;
           diseases (HBs Ag , Anti HCV, HIV, Syphilis, and Malaria) will be tested by the device&#xD;
           method. An automated analyzer will count complete blood count. If all things remain&#xD;
           favorable, the next step will be followed.&#xD;
&#xD;
        2. Safety assessment: Body weight and height of the donor will be measured by a&#xD;
           conventional method (standard digital weight and height scale). For preventing citrate&#xD;
           toxicity or hypocalcaemic complications (twitching, numbness, nausea, mild respiratory&#xD;
           difficulty, etc) 500 mg calcium carbonate will be given to every donor before starting&#xD;
           the procedure. Blood pressure and pulse will be monitored in every 10-minute interval&#xD;
           for precaution throughout the procedure. Weight, height, and CBC parameter will be given&#xD;
           in apheresis machine for setting up. Visible and easily palpable anti cubital vein will&#xD;
           be selected for venepuncture. Before puncturing the vein, at least 50-60 mm of Hg&#xD;
           pressure will be given above the venepuncture area for maintaining sustained pressure.&#xD;
           When everything is ready, the procedure will be started by puncturing a single needle in&#xD;
           a targeted vein.&#xD;
&#xD;
      Steps of Convalescent Plasma (CP) transfusion Before giving CP to the patient blood pressure,&#xD;
      pulse, temperature, the respiratory rate will be recorded. It can be given through the&#xD;
      central venous catheter or by peripheral channel. If peripheral venous site chosen then at&#xD;
      least 21g needle should be confirmed. Blood group and cross-matching should be confirmed&#xD;
      before starting the transfusion. When there is no chance of clerical mistake then CP&#xD;
      transfusion can be started at the rate of 100 ml/hour.&#xD;
&#xD;
      Safety Assessment:&#xD;
&#xD;
      If patient was suffering from fever then a temperature chart should be maintained. When the&#xD;
      temperature will be raised above 2 degrees Fahrenheit from the baseline then transfusion&#xD;
      should be stopped and antipyretic should be given according to the body weight. After a pause&#xD;
      of 10 minutes, transfusion can be started. If patient, feels excessive itching specific area&#xD;
      or whole over the body then Injection Chlorpheniramine maleate will be given. The steroid&#xD;
      would be preserved for managing severe respiratory distress or uncontrollable itching. Blood&#xD;
      pressure, pulse, and respiratory will be monitored every 30 minutes interval regularly.&#xD;
&#xD;
      The procedure of measuring antibody titre&#xD;
&#xD;
      SARS-CoV-2 IgG antibody titer will be tested by ELISA according to the following protocol:&#xD;
&#xD;
        1. At first the serum/plasma samples (10μL) were diluted to 1:40, 1:80, 1:160, 1:320, and&#xD;
           1:640 by serial dilution.&#xD;
&#xD;
        2. 100μl of sample diluents will be added into each well (except blank and control well)&#xD;
           which are pre-coated with SARS-CoV-2 antigens.&#xD;
&#xD;
        3. Then 10μl of specimen will be added. 100μl controls will be added to the assigned well&#xD;
           directly. All samples will be run in duplicate.&#xD;
&#xD;
        4. The plate will be covered with the plate cover and will be incubated for 30 minutes at&#xD;
           37°C.&#xD;
&#xD;
        5. At the end of the incubation, each well will be washed 5 times with diluted Wash Buffer.&#xD;
&#xD;
        6. 100μl of conjugate will be added into each well except the Blank.&#xD;
&#xD;
        7. Incubation for 20 minutes at 37°C.&#xD;
&#xD;
        8. At the end of the incubation, each well will be washed 5 times with diluted Wash Buffer.&#xD;
&#xD;
        9. 50μl of Substrate Solution A and 50μl of Substrate Solution B will be added into each&#xD;
           well. Incubation for 10 minutes at 37°C avoiding light.&#xD;
&#xD;
       10. 50μl of Stop Solution will be added into each well.&#xD;
&#xD;
       11. The plate reader will be calibrated with the Blank well and the absorbance will be read&#xD;
           at 450nm.&#xD;
&#xD;
       12. The sample OD value was ≥cutoff OD value will indicate IgG antibody positive.&#xD;
&#xD;
       13. The IgG antibody titre will be determined by endpoint dilution.&#xD;
&#xD;
      Due to lack of COVID-19 plasmid in Bangladesh and global shortage, 2 ml seum will be&#xD;
      preserves from each donor and later shipped to peter Medawar building for pathogen research,&#xD;
      University of Oxford. Research collaborators in Oxford will conduct the neutralizing antibody&#xD;
      titre and the investigators will later match them with each donor. The expenses for&#xD;
      neutralizing antibody titre test will be managed by the Oxford colleagues.&#xD;
&#xD;
      Statistical analysis:&#xD;
&#xD;
      Graphpad Prism v 7.0 will be used for analysis. Demographic factors and clinical&#xD;
      characteristics will be summarized with counts (%) for categorical variables and median&#xD;
      (interquartile range [IQR]) for continuous variables, as none was expected to be normally&#xD;
      distributed. The main analysis will be carried out on an intention-to-treat basis. For the&#xD;
      primary outcome, the investigators will compare the mean between three arms using a one-way&#xD;
      ANOVA test. The investigators will also do posthoc analysis in Prism assessing (log-rank&#xD;
      Mantel-Cox test) time to sustained saturations &gt;93% and PaO2/FiO2&lt;200 mm of Hg censored&#xD;
      during enrolment, 3 days and 7 days after enrolment in a single time point. For&#xD;
      non-parametric secondary outcomes, all groups will be compared using a Kruskal-Wallis test;&#xD;
      if significant, the investigators then planned to perform pairwise comparisons with a&#xD;
      non-parametric Mann-Whitney test. For parametric outcomes, the investigators compared the&#xD;
      odds ratios across the pairs.&#xD;
&#xD;
      Facilities and procedure:&#xD;
&#xD;
      The RT-PCR and other study-related testing will be done at BSMMU. BSMMU fever clinic already&#xD;
      treated more than 1200 COVID-19 positive cases. Potential donors will be tracked from this&#xD;
      patient pool. Donors who will agree and give consent will be then sent to the Transfusion&#xD;
      medicine department of SHBPSI. 5 ml plasma will be collected and sent to the CMBT laboratory&#xD;
      for ELISA based antibody titre. If the titre fulfills the desired level (1:320 and above),&#xD;
      then 200 ml or 400 ml apheretic plasma (depending on availability and consent of the donor)&#xD;
      will be collected on the next day. 5 ml serum will be also be collected for sending into the&#xD;
      Peter Medawar Building for Pathogen Research, Oxford University for checking the neutralizing&#xD;
      antibody titre. This will be sent later and matched with the donor. The samples will be&#xD;
      shipped under the coverage of the materials transfer agreement (MTA). Dr. Fazle Rabbi&#xD;
      Chowdhury, the Co-PI of this project have the necessary permission for shipping samples&#xD;
      overseas. In the final stage, the CP will be handover to the clinical team at DMCH and MuMCH&#xD;
      as per their demand for transfusion. The clinical team will ensure the laboratory sample&#xD;
      collection before and after CP transfusion and will record the data in the case record form.&#xD;
      A laboratory medicine team of BSMMU will support the clinical team for lab testing.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">May 20, 2020</start_date>
  <completion_date type="Anticipated">October 30, 2020</completion_date>
  <primary_completion_date type="Anticipated">July 20, 2020</primary_completion_date>
  <phase>Phase 2</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>Arm-A: Standard supportive treatment; Arm-B: Standard supportive treatment + CP 200 ml; Arm C: Standard supportive treatment + CP 400 ml</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Proportion of In-hospital mortality</measure>
    <time_frame>7 days</time_frame>
    <description>% of patients died after enrolment</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Time to death</measure>
    <time_frame>7 days</time_frame>
    <description>Time to death in hours after enrolment</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Fever</measure>
    <time_frame>7 days</time_frame>
    <description>Temperature in degree Fahrenheit at Day 0, 1, 3, 7</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Respiratory distress</measure>
    <time_frame>7 days</time_frame>
    <description>Respiratory rate per minute at Day 0, 1, 3, 7</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Saturation of oxygen</measure>
    <time_frame>7 days</time_frame>
    <description>Saturation of oxygen in % at Day 0, 1, 3, 7</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood pressure</measure>
    <time_frame>7 days</time_frame>
    <description>Blood pressure in mm of Hg at Day 0, 1, 3, 7</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Oxygen requirement</measure>
    <time_frame>7 days</time_frame>
    <description>Oxygen requirements in liter/min at Day 0, 1, 3, 7</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>C-reactive Protein</measure>
    <time_frame>Day 0, 3 and 7</time_frame>
    <description>CRP level in mg/litre</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ferritin</measure>
    <time_frame>Day 0, 3 and 7</time_frame>
    <description>Serum Ferritin level in ng/ml</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>SGPT</measure>
    <time_frame>Day 0, 3 and 7</time_frame>
    <description>Serum SGPT level in I/U</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>SGOT</measure>
    <time_frame>Day 0, 3 and 7</time_frame>
    <description>Serum SGOT level in I/U</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ICU stay</measure>
    <time_frame>14 days</time_frame>
    <description>Duration of ICU stay in days</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ventilator support</measure>
    <time_frame>14 days</time_frame>
    <description>Requirement of ventilator support in hours</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hospital stay</measure>
    <time_frame>14 days</time_frame>
    <description>Duration of hospital stay in days</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of Transfusion reaction</measure>
    <time_frame>24 hours</time_frame>
    <description>% of patients developed early transfusion reaction like fever, sweating, rash, abdominal pain, urticaria, vomiting, wheezing, chest tightness and hypotension</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>Covid19</condition>
  <condition>Convalescence</condition>
  <arm_group>
    <arm_group_label>Standard treatment</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Standard supportive treatment (Oxygen, Enoxaparine, antibiotic, fluid, immune modulator (Steroid) and or antiviral (favipiravir or ramdesivir or lopinavir + ritonavir)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard treatment + 200 ml plasma</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Standard supportive treatment + 200 ml apheretic convalescent plasma single transfusion</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard treatment + 400 ml plasma</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Standard supportive treatment + 400 ml apheretic convalescent plasma single transfusion</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Convalescent plasma</intervention_name>
    <description>Apheretic convalescent plasma from a COVID-19 survivor</description>
    <arm_group_label>Standard treatment + 200 ml plasma</arm_group_label>
    <arm_group_label>Standard treatment + 400 ml plasma</arm_group_label>
    <other_name>Plasma therapy</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Respiratory rate &gt; 30 breaths/min; PLUS&#xD;
&#xD;
          2. Severe respiratory distress; or SpO2 ≤ 88% on room air or PaO2/FiO2≤ 300 mm of Hg,&#xD;
             PLUS&#xD;
&#xD;
          3. Radiological evidence of bilateral lung infiltrate, AND OR&#xD;
&#xD;
          4. Systolic BP &lt; 90 mm of Hg or diastolic BP &lt;60 mm of Hg. AND OR&#xD;
&#xD;
          5. Criteria 1 to 4 AND or patient in Ventilator support&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients below18 years.&#xD;
&#xD;
          2. Pregnant women and breast-feeding mothers.&#xD;
&#xD;
          3. Previous history of allergic reaction to plasma&#xD;
&#xD;
          4. Those who will not give consent&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>16 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mohammad S Rahman, MPhil; FCPS</last_name>
    <role>Study Chair</role>
    <affiliation>Professor and Chairman of Pharmacology, BSMMU</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Mohammad S Rahman, MPhil,FCPS</last_name>
    <phone>+88 01971840757</phone>
    <email>srkhasru@gmail.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Fazle R Chowdhury, FCPS; PhD</last_name>
    <phone>+88 01916578699</phone>
    <email>mastershakil@hotmail.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Bangabandhu Sheikh Mujib Medical University</name>
      <address>
        <city>Dhaka</city>
        <zip>1200</zip>
        <country>Bangladesh</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Sayedur Rahman, MPhil; FCPS</last_name>
      <phone>+88 01971840757</phone>
      <email>srkhasru@gmail.com</email>
    </contact>
    <contact_backup>
      <last_name>Fazle R Chowdhury, FCPS;PhD</last_name>
      <phone>+88 01916578699</phone>
      <email>mastershakil@hotmail.com</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Bangladesh</country>
  </location_countries>
  <verification_date>May 2020</verification_date>
  <study_first_submitted>May 20, 2020</study_first_submitted>
  <study_first_submitted_qc>May 24, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 27, 2020</study_first_posted>
  <last_update_submitted>May 24, 2020</last_update_submitted>
  <last_update_submitted_qc>May 24, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">May 27, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh</investigator_affiliation>
    <investigator_full_name>Fazle Rabbi Chowdhury</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
    <mesh_term>Convalescence</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Data will be shared with the journal authority and make public as part of the publication</ipd_description>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_time_frame>six months</ipd_time_frame>
    <ipd_access_criteria>Available on public domain like figshare, researchgate and others</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/NCT04403477
org study id: BSMMU/2020/6104
nct id: NCT04403477
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
As of March 18, 2020, COVID-19 cases were reported in approximately 195 countries. No
      specific therapeutic agents or vaccines for COVID-19 are available. Several therapies, such
      as remdesivir and favipiravir, are under investigation, but the antiviral efficacy of these
      drugs is not yet known. The use of convalescent plasma (CP) was recommended as an empirical
      treatment during outbreaks of Ebola virus in 2014. A protocol for treatment of Middle East
      respiratory syndrome coronavirus (MERS-CoV) with CP was established in 2015. This approach
      with other viral infections such as SARS-CoV, H5N1 avian influenza, and H1N1 influenza also
      suggested that transfusion of CP was effective. In previous reports, most of the patients
      received the CP by single transfusion. In a study involving patients with pandemic influenza
      A(H1N1) 2009 virus infection, treatment of severe infection with CP (n = 20 patients) was
      associated with reduced respiratory tract viral load, serum cytokine response, and mortality.
      In another study involving 80 patients with SARS, the administration of CP was associated
      with a higher rate of hospital discharge at day 22 from symptom onset compared with patients
      who did not receive CP. Accordingly, these findings raise the hypothesis that use of CP
      transfusion could be beneficial in patients infected with SARS-CoV-2. The objective of this
      study is to describe the initial clinical experience with CP transfusion administered to
      severe COVID-19 patients. The primary endpoint of this trial would be to assess the
      tolerability, efficacy, and dose-response of CP in severe COVID-19 patients. The secondary
      endpoint would be to assess the clinical and laboratory parameters after therapy, in-hospital
      mortality, length of hospital stay, reduction in the proportion of deaths, length of ICU
      stay, requirement of ventilator and duration of ventilator support. All RT-PCR positive cases
      with features of severe infection will be enrolled in this study. Apheretic CP will be
      collected from a recovered patient (consecutive two RT-PCR samples negative) between day 22
      to 35 days of recovery and those with the antibody titre above 1:320.

      This RCT will consist of three arms, a. standard care, b. standard care and 200 ml CP and c.
      standard care and 400 ml CP as a single transfusion. Twenty (20) patients will be enrolled
      for each arm. Randomization will be done by someone not associated with the care or
      assessment of the patients by means of a random number table. Allocations will be concealed
      in sequentially numbered, opaque, sealed envelopes. Clinical parameters [fever, cough,
      dyspnea, respiratory rate, PaO2/ FiO2 level, pulse, BP, the requirement of O2, and others]
      will be recorded before and after CP. Laboratory parameters such as complete blood count,
      CRP, chest X-ray, SGPT, SGOT, S. Ferritin, and serum antibody titre will be measured before
      and after transfusion. Allergic or serum sickness-like reactions will be noted and adjusted
      with outcome. Laboratory tests including RT-PCR will be done at BSMMU virology and laboratory
      medicine department. Apheretic plasma will be collected at the transfusion medicine
      department of SHNIBPS hospital, ELISA, antibody titre will be done at CMBT, and patients will
      be enrolled at DMC and MuMCH. All necessary screening tests will be done before transfusion.

      Graphpad Prism v 7.0 will be used for analysis. One way ANOVA test, a non-parametric
      Mann-Whitney test, and a Kruskal-Wallis test will be performed to compare the arms. For
      parametric outcomes, the investigators will compare the odds ratios across the pairs.
Rationale of the Study Currently no specific treatment is available against COVID-19
      infection. Supportive treatment along with concentrated oxygen is the only mean of treatment.
      Researchers have already opened over 180 clinical trials of potential COVID-19 treatments for
      recruitment, and nearly 150 could start soon. However, to date, no clinical intervention
      trial has been completed and reported. Based on anecdotes (small case series), some of the
      promising drugs could be azithromycin - hydroxychloroquine combination, Lopinavir/ Ritonavir,
      Tocilizumab, Ramdisivir, Favirinapir, and others. CP transfusion is another promising option,
      which had been tried before in SARS-CoV, MERS-CoV, and Flu and Ebola viral infection. Its
      effectiveness against COVID-19 yet not explored. A recently published case series consists of
      ten cases that forecast promising results. Therefore, a phase II RCT to explore the
      tolerability, efficacy, and dose-response needs to explore urgently.

      The cases started to escalate in Bangladesh and the number of confirmed cases already crossed
      a thousand marks. Considering the cost and shortage of other above mentioned anti-viral and
      biologics, it is inevitable that many of our patients possibly could not afford or get it.
      However, the CP can be easily collected from the recovered patients and can easily be
      processed to use it against active infection. This could be an effective and cheap treatment
      option for a country like ours to face this catastrophe. Therefore conducting a phase II RCT
      on CP transfusion is the demand of time.

      Research question:

      Does CP transfusion is tolerable and effective in treating severe COVID-19 patients compared
      to standard treatment?

      Objectives:

      General Objective:

      To assess the tolerability, efficacy, and dose-response of CP transfusion in severe COVID-19
      patients

      Specific Objectives:

        1. To identify the appropriate effective dose of CP therapy

        2. To identify the efficacy of the therapy with their endpoint

        3. To examine the clinical improvement after CP transfusion in severe COVID-19 patients

        4. To assess the laboratory improvement after CP transfusion in severe COVID-19 patients

      Study design:

      Phase II RCT

      Place of study:

      Bangabandhu Sheikh Mujib Medical University (BSMMU), Sheikh Hasina Burn & Plastic Surgery
      Institute, Dhaka Medical College, Mugda Medical College and Centre for Medical Biotechnology

      Study period:

      May 2020 - October 2020 (Six months)

      Study population:

      COVID=19 positive patients who are diagnosed on the basis of RT-PCR at BSMMU fever clinic or
      by any other government-designated laboratory and admitted at DMCH, MuMC, and BSMMU.

      Randomization and blinding method:

      Randomization will be done by someone not associated with the care or assessment of the
      patients by means of a random number table. Allocations will be concealed in sequentially
      numbered, opaque, sealed envelopes. In this pilot study, the CP or standard care will not be
      blinded. However, the primary outcome (oxygen saturations, PaO2/FiO2, and BP) will be
      recorded using an objective automated method; the study staff will not be able to influence
      the recording of these data.

      Sample size:

      No similar study has been performed previously. Therefore no data are available that could be
      used to generate a sample size calculation. This pilot study is required to provide some
      initial data on efficacy and safety that will allow the design of a larger study.

      Research instruments

        1. General questionnaire for assessing socio-demographic data.

        2. A checklist of clinical findings

        3. A checklist of investigation findings.

      Measures of Variables

        1. Socio-Demographic variables

             -  Age

             -  Gender (Male/Female)

             -  Living area (Urban/Rural)

             -  Occupation

        2. Clinical variables:

             -  Symptoms

             -  Systolic blood pressure (in mmHg)

             -  Diastolic blood pressure (in mmHg)

             -  Temperature

             -  Respiratory rate

             -  Heart rate

             -  GCS

        3. Laboratory variables

             -  CXR

             -  CBC

             -  CRP

             -  S. Ferritin

             -  SGPT

             -  SGOT

             -  Antibody titre

      Procedure of collection of Apheretic plasma

        1. Pre-donation screening: First of all, 3 ml blood will be drawn from peripheral venous
           site preferably from dorsum of the hand, and will be kept in EDTA tube for further
           testing. Blood group will be confirmed by using known antisera. Screening test of 5
           diseases (HBs Ag , Anti HCV, HIV, Syphilis, and Malaria) will be tested by the device
           method. An automated analyzer will count complete blood count. If all things remain
           favorable, the next step will be followed.

        2. Safety assessment: Body weight and height of the donor will be measured by a
           conventional method (standard digital weight and height scale). For preventing citrate
           toxicity or hypocalcaemic complications (twitching, numbness, nausea, mild respiratory
           difficulty, etc) 500 mg calcium carbonate will be given to every donor before starting
           the procedure. Blood pressure and pulse will be monitored in every 10-minute interval
           for precaution throughout the procedure. Weight, height, and CBC parameter will be given
           in apheresis machine for setting up. Visible and easily palpable anti cubital vein will
           be selected for venepuncture. Before puncturing the vein, at least 50-60 mm of Hg
           pressure will be given above the venepuncture area for maintaining sustained pressure.
           When everything is ready, the procedure will be started by puncturing a single needle in
           a targeted vein.

      Steps of Convalescent Plasma (CP) transfusion Before giving CP to the patient blood pressure,
      pulse, temperature, the respiratory rate will be recorded. It can be given through the
      central venous catheter or by peripheral channel. If peripheral venous site chosen then at
      least 21g needle should be confirmed. Blood group and cross-matching should be confirmed
      before starting the transfusion. When there is no chance of clerical mistake then CP
      transfusion can be started at the rate of 100 ml/hour.

      Safety Assessment:

      If patient was suffering from fever then a temperature chart should be maintained. When the
      temperature will be raised above 2 degrees Fahrenheit from the baseline then transfusion
      should be stopped and antipyretic should be given according to the body weight. After a pause
      of 10 minutes, transfusion can be started. If patient, feels excessive itching specific area
      or whole over the body then Injection Chlorpheniramine maleate will be given. The steroid
      would be preserved for managing severe respiratory distress or uncontrollable itching. Blood
      pressure, pulse, and respiratory will be monitored every 30 minutes interval regularly.

      The procedure of measuring antibody titre

      SARS-CoV-2 IgG antibody titer will be tested by ELISA according to the following protocol:

        1. At first the serum/plasma samples (10μL) were diluted to 1:40, 1:80, 1:160, 1:320, and
           1:640 by serial dilution.

        2. 100μl of sample diluents will be added into each well (except blank and control well)
           which are pre-coated with SARS-CoV-2 antigens.

        3. Then 10μl of specimen will be added. 100μl controls will be added to the assigned well
           directly. All samples will be run in duplicate.

        4. The plate will be covered with the plate cover and will be incubated for 30 minutes at
           37°C.

        5. At the end of the incubation, each well will be washed 5 times with diluted Wash Buffer.

        6. 100μl of conjugate will be added into each well except the Blank.

        7. Incubation for 20 minutes at 37°C.

        8. At the end of the incubation, each well will be washed 5 times with diluted Wash Buffer.

        9. 50μl of Substrate Solution A and 50μl of Substrate Solution B will be added into each
           well. Incubation for 10 minutes at 37°C avoiding light.

       10. 50μl of Stop Solution will be added into each well.

       11. The plate reader will be calibrated with the Blank well and the absorbance will be read
           at 450nm.

       12. The sample OD value was ≥cutoff OD value will indicate IgG antibody positive.

       13. The IgG antibody titre will be determined by endpoint dilution.

      Due to lack of COVID-19 plasmid in Bangladesh and global shortage, 2 ml seum will be
      preserves from each donor and later shipped to peter Medawar building for pathogen research,
      University of Oxford. Research collaborators in Oxford will conduct the neutralizing antibody
      titre and the investigators will later match them with each donor. The expenses for
      neutralizing antibody titre test will be managed by the Oxford colleagues.

      Statistical analysis:

      Graphpad Prism v 7.0 will be used for analysis. Demographic factors and clinical
      characteristics will be summarized with counts (%) for categorical variables and median
      (interquartile range [IQR]) for continuous variables, as none was expected to be normally
      distributed. The main analysis will be carried out on an intention-to-treat basis. For the
      primary outcome, the investigators will compare the mean between three arms using a one-way
      ANOVA test. The investigators will also do posthoc analysis in Prism assessing (log-rank
      Mantel-Cox test) time to sustained saturations >93% and PaO2/FiO2<200 mm of Hg censored
      during enrolment, 3 days and 7 days after enrolment in a single time point. For
      non-parametric secondary outcomes, all groups will be compared using a Kruskal-Wallis test;
      if significant, the investigators then planned to perform pairwise comparisons with a
      non-parametric Mann-Whitney test. For parametric outcomes, the investigators compared the
      odds ratios across the pairs.

      Facilities and procedure:

      The RT-PCR and other study-related testing will be done at BSMMU. BSMMU fever clinic already
      treated more than 1200 COVID-19 positive cases. Potential donors will be tracked from this
      patient pool. Donors who will agree and give consent will be then sent to the Transfusion
      medicine department of SHBPSI. 5 ml plasma will be collected and sent to the CMBT laboratory
      for ELISA based antibody titre. If the titre fulfills the desired level (1:320 and above),
      then 200 ml or 400 ml apheretic plasma (depending on availability and consent of the donor)
      will be collected on the next day. 5 ml serum will be also be collected for sending into the
      Peter Medawar Building for Pathogen Research, Oxford University for checking the neutralizing
      antibody titre. This will be sent later and matched with the donor. The samples will be
      shipped under the coverage of the materials transfer agreement (MTA). Dr. Fazle Rabbi
      Chowdhury, the Co-PI of this project have the necessary permission for shipping samples
      overseas. In the final stage, the CP will be handover to the clinical team at DMCH and MuMCH
      as per their demand for transfusion. The clinical team will ensure the laboratory sample
      collection before and after CP transfusion and will record the data in the case record form.
      A laboratory medicine team of BSMMU will support the clinical team for lab testing.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Arm-A: Standard supportive treatment; Arm-B: Standard supportive treatment + CP 200 ml; Arm C: Standard supportive treatment + CP 400 ml
primary purpose: Treatment
masking: None (Open Label)
measure: Proportion of In-hospital mortality
time frame: 7 days
description: % of patients died after enrolment
measure: Time to death
time frame: 7 days
description: Time to death in hours after enrolment
measure: Fever
time frame: 7 days
description: Temperature in degree Fahrenheit at Day 0, 1, 3, 7
measure: Respiratory distress
time frame: 7 days
description: Respiratory rate per minute at Day 0, 1, 3, 7
measure: Saturation of oxygen
time frame: 7 days
description: Saturation of oxygen in % at Day 0, 1, 3, 7
measure: Blood pressure
time frame: 7 days
description: Blood pressure in mm of Hg at Day 0, 1, 3, 7
measure: Oxygen requirement
time frame: 7 days
description: Oxygen requirements in liter/min at Day 0, 1, 3, 7
measure: C-reactive Protein
time frame: Day 0, 3 and 7
description: CRP level in mg/litre
measure: Ferritin
time frame: Day 0, 3 and 7
description: Serum Ferritin level in ng/ml
measure: SGPT
time frame: Day 0, 3 and 7
description: Serum SGPT level in I/U
measure: SGOT
time frame: Day 0, 3 and 7
description: Serum SGOT level in I/U
measure: ICU stay
time frame: 14 days
description: Duration of ICU stay in days
measure: Ventilator support
time frame: 14 days
description: Requirement of ventilator support in hours
measure: Hospital stay
time frame: 14 days
description: Duration of hospital stay in days
measure: Proportion of Transfusion reaction
time frame: 24 hours
description: % of patients developed early transfusion reaction like fever, sweating, rash, abdominal pain, urticaria, vomiting, wheezing, chest tightness and hypotension
arm group label: Standard treatment
arm group type: No Intervention
description: Standard supportive treatment (Oxygen, Enoxaparine, antibiotic, fluid, immune modulator (Steroid) and or antiviral (favipiravir or ramdesivir or lopinavir + ritonavir)
arm group label: Standard treatment + 200 ml plasma
arm group type: Experimental
description: Standard supportive treatment + 200 ml apheretic convalescent plasma single transfusion
arm group label: Standard treatment + 400 ml plasma
arm group type: Experimental
description: Standard supportive treatment + 400 ml apheretic convalescent plasma single transfusion
intervention type: Biological
intervention name: Convalescent plasma
description: Apheretic convalescent plasma from a COVID-19 survivor
arm group label: Standard treatment + 200 ml plasma
arm group label: Standard treatment + 400 ml plasma
other name: Plasma therapy
criteria: 
gender: All
minimum age: 16 Years
maximum age: N/A
healthy volunteers: No
last name: Mohammad S Rahman, MPhil; FCPS
role: Study Chair
affiliation: Professor and Chairman of Pharmacology, BSMMU
last name: Mohammad S Rahman, MPhil,FCPS
phone: +88 01971840757
email: srkhasru@gmail.com
last name: Fazle R Chowdhury, FCPS; PhD
phone: +88 01916578699
email: mastershakil@hotmail.com
facility: 
status: Recruiting
contact: 
contact backup: 
country: Bangladesh
responsible party type: Principal Investigator
investigator affiliation: Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
investigator full name: Fazle Rabbi Chowdhury
investigator title: Assistant Professor
mesh term: COVID-19
mesh term: Convalescence
sharing ipd: Yes
ipd description: Data will be shared with the journal authority and make public as part of the publication
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd time frame: six months
ipd access criteria: Available on public domain like figshare, researchgate and others