<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/NCT04470531</url>
  </required_header>
  <id_info>
    <org_study_id>BSMMU/2020/6969</org_study_id>
    <nct_id>NCT04470531</nct_id>
  </id_info>
  <brief_title>Role of Co-trimoxazole in Severe COVID-19 Patients</brief_title>
  <official_title>Role of Co-trimoxazole in Severe COVID-19 Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Anwar Khan Mordern Medical College and Hospital, Dhaka</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Mugda Medical College and Hospital, Dhaka</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Coronavirus Disease 19 (COVID-19) is a global pandemic caused by Severe Acute Respiratory&#xD;
      Syndrome Coronavirus 2 (SARS-CoV-2). Severe disease occurs in 15% of the cases with COVID-19&#xD;
      and may progress to critical disease in only 5% of the cases with a high risk of mortality.&#xD;
      Critical disease may present as acute respiratory failure secondary to Acute Respiratory&#xD;
      Distress Syndrome (ARDS) and is caused by the body's hyper-immune response to the virus in&#xD;
      the form of a cytokine storm syndrome (CSS). There is currently no effective anti-viral&#xD;
      treatment against SARS-CoV-2 and the mainstay of treatment is supportive. Co-trimoxazole&#xD;
      (combination of trimethoprim and sulphamethoxazole in a 1:5) ratio is a Sulphur containing&#xD;
      anti-folate bactericidal antibiotic indicated for the treatment of respiratory tract&#xD;
      infections. It has been around for over 60 years and is inexpensive and readily available&#xD;
      with a good safety profile. It has a rapid onset of action with excellent bioavailability and&#xD;
      lung penetration. In addition to having antimicrobial properties co-trimoxazole have&#xD;
      immunomodulatory and anti-inflammatory properties and may be a potential treatment option for&#xD;
      cytokine storm syndrome mediated severe COVID-19.&#xD;
&#xD;
      This open-label randomized controlled trial will be conducted in the department of medicine&#xD;
      at Bangabandhu Sheikh Mujib Medical University (BSMMU), Anwar Khan Modern Medical college and&#xD;
      Mughda Medical College Hospital (DMCH), Dhaka for a duration of 6 months following approval&#xD;
      of this protocol. It will recruit at least 94 consecutive adults (18 years or older) patients&#xD;
      with clinically suspected COVID-19 and severe illness as per WHO criteria. After taking&#xD;
      informed written consent patients will be randomly assigned in a 1:1 ratio to either oral&#xD;
      co-trimoxazole in addition to standard therapy or standard therapy alone. Baseline&#xD;
      characteristics, changes in the physiological and biochemical parameters like (SpO2/FiO2&#xD;
      ratio, respiratory rate, body temperature and C - reactive protein), length of hospital stay,&#xD;
      side effects of drugs, requirement for ventilatory support (non-invasive and invasive&#xD;
      ventilation) and in-patient mortality between the two groups will be compared.&#xD;
&#xD;
      Conclusion If the results from this clinical trial demonstrate the beneficial effects of&#xD;
      co-trimoxazole in severe COVID-19 patients it could be used widely, thereby reducing the need&#xD;
      for respiratory support and potentially saving thousands of lives in developing nations with&#xD;
      limited resources where healthcare may be easily overwhelmed.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Coronavirus disease (COVID-19) caused by SARS-COV2, represents a highly transmissible and&#xD;
      potentially fatal disease that is of great global public health concern at this moment. The&#xD;
      pandemic situation in Bangladesh is also evolving rapidly with positive cases and deaths&#xD;
      increasing each day. Epidemiological changes in COVID-19 infection should be monitored taking&#xD;
      into account potential routes of transmission and subclinical infections, in addition to the&#xD;
      adaptation, evolution, and virus spread among humans and possible intermediate animals and&#xD;
      reservoirs. But till today there is no specific management to deal with this highly deadly&#xD;
      viral infection. Howeverthere are few drugs which might cause some beneficial effects in the&#xD;
      recovery of the patient. Cotrimoxazole is a time tested antibiotic which has been in clinical&#xD;
      use for 60 years with anti-bacterial action against a wide range of organism. In addition to&#xD;
      the antimicrobial effects, co-trimoxazole has anti-inflammatory and immunomodulatory effects.&#xD;
      Co-trimoxazole has previously been shown to exert anti-cytokine effect by inhibiting&#xD;
      interleukin 1, 6 (IL-1, IL-6) and Tumour Necrosis Factor α (TNF α) which are the major&#xD;
      cytokines identified in patients with severe COVID-19. As in some case reports this has shown&#xD;
      significant clinical improvement in ARDS, so there is a possibility, that cotrimoxazole might&#xD;
      have also role in improving the clinical outcome in COVID-19 patients especially in moderate&#xD;
      to severe cases. As till today there is no specific treatment for COVID-19 infections, if&#xD;
      cotrimoxazole ifs found to be effective this will bring a great benefit to the target&#xD;
      populations. Beside this, cotrimoxazole is a very cheap drug in comparison to other ones this&#xD;
      will also be of great economical benefit in taking cares of the general population. As there&#xD;
      is no such study published about the role of cotrimoxazole in COVID-19 patients, this study&#xD;
      will generate a new information which bring a great benefit in battling with the COVID-19&#xD;
      infection.&#xD;
&#xD;
      Research Question:&#xD;
&#xD;
      What is the outcome of co-trimoxazole in severe COVID-19 patients?&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      General Objectives To assess the clinical outcome of co-trimoxazolein patients with severe&#xD;
      COVID-19&#xD;
&#xD;
      Specific Objectives:&#xD;
&#xD;
      To assess length of stay who are treated with co-trimoxazole in addition to standard&#xD;
      treatment versus standard treatment alone.&#xD;
&#xD;
      To find out side effects (rash.itching. dizziness, headache, nausea,vomiting, diarrhea, sore&#xD;
      throat, unusual bruising or bleeding, yellowing of the skin or eye discolorations, joint or&#xD;
      muscle pain,red or purple skin.etc) of drugs who are treated with co-trimoxazole in addition&#xD;
      to standard treatment versus standard treatment alone.&#xD;
&#xD;
      To find out requirement for ventilator support (non-invasive and invasive ventilation) who&#xD;
      are treated with co-trimoxazole in addition to standard treatment versus standard treatment&#xD;
      alone.&#xD;
&#xD;
      To assess the mortality in patients with severe COVID-19 who are treated with co-trimoxazole&#xD;
      in addition to standard treatment versus standard treatment alone.&#xD;
&#xD;
      Study design:Open-label randomized controlled trial Study duration: Six months.&#xD;
&#xD;
      Study Population:&#xD;
&#xD;
      Patients presenting to participating hospitals in Bangladesh with symptoms ofCOVID-19 will be&#xD;
      assessed for eligibility.&#xD;
&#xD;
      Inclusion criteria&#xD;
&#xD;
        1. Diagnosed COVID-19 patients ( RT-PCR positive for COVID-19)&#xD;
&#xD;
        2. Age &gt; 18 years&#xD;
&#xD;
        3. Hypoxic respiratory failure (saturation &lt;90% on air at rest or increasing oxygen&#xD;
           requirement)&#xD;
&#xD;
        4. Chest examination findings of bilateral crackles on auscultation or chest x-ray showing&#xD;
           bilateral infiltrates&#xD;
&#xD;
        5. C-Reactive Protein &gt; 50mg/L&#xD;
&#xD;
      Exclusion criteria&#xD;
&#xD;
        1. Multi-organ failure&#xD;
&#xD;
        2. Severe ARDS (requiring ventilator support on presentation in the form of invasive or&#xD;
           non-invasive ventilation)&#xD;
&#xD;
        3. Septic Shock&#xD;
&#xD;
        4. Severe liver disease&#xD;
&#xD;
        5. Acute Kidney Injury (where GFR&lt; 15 and plasma-sulfamethoxazoleconcentration cannot be&#xD;
           monitored)&#xD;
&#xD;
        6. Drug allergy/intolerance to co-trimoxazole / Sulphar sensitivity&#xD;
&#xD;
        7. Pregnancy&#xD;
&#xD;
        8. Already receiving Tocilizumab or convalescent therapy Sampling procedure:This RCT will&#xD;
           consist of two arms, experimental group and control group.Randomized (1:1) case:&#xD;
           control, (non-blinded) trial.&#xD;
&#xD;
             1. control group will receive standard treatment,&#xD;
&#xD;
             2. experimental group will recivestandard care and oral co-triamoxazole. Forty-seven&#xD;
                (47) patients will be enrolled for each arm. Randomization will be done by a random&#xD;
                number table. Allocations will be in sequentially numbered.&#xD;
&#xD;
      Treatment protocol Eligible patients will be received either to oral co-trimoxazole +&#xD;
      standard therapy or standard therapy alone. (According to institution /national protocol)&#xD;
&#xD;
      The following treatments are recommended as standard therapy:&#xD;
&#xD;
        1. Antibiotics for secondary bacterial infection as per institutional guidelines&#xD;
&#xD;
        2. Supplemental oxygen (to keep saturations between 90% to 96%)&#xD;
&#xD;
        3. Intravenous hydration (to maintain euvolumia)&#xD;
&#xD;
        4. Thrombo-prophylaxis as per local guidelines&#xD;
&#xD;
        5. Paracetamol (oral or I/V 1gram QDS as required or regular)&#xD;
&#xD;
        6. To consider steroids if indicated (i.e. acute exacerbation of COPD or acute severe&#xD;
           asthma) NOTE: The dose of co-trimoxazoleis 960 mg (trimethoprim 160mg +&#xD;
           sulphamethoxazole 800mg) twice daily for 7 days orally.&#xD;
&#xD;
      sample size: 94&#xD;
&#xD;
      Research instrument:&#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 Variable:&#xD;
&#xD;
      Data collection required for both groups (co-trimoxazole + standard therapyand standard&#xD;
      therapy alone)&#xD;
&#xD;
        1. Age&#xD;
&#xD;
        2. Sex&#xD;
&#xD;
        3. Ethnicity&#xD;
&#xD;
        4. Past medical history - Hypertension, use of ACEI or ARB, DM, IHD, COPD, CKD, Obesity&#xD;
           (BMI) andCancer&#xD;
&#xD;
        5. Presenting symptoms (dry cough, productive cough, fever, sore throat, myalgia, lethargy,&#xD;
           headache, breathlessness, nausea, diarrhoea and any other)&#xD;
&#xD;
        6. Baseline observations on dayof initiating treatment (Day 0): oxygen saturation(SpO2),&#xD;
           fraction of inspired oxygen (FiO2) , SpO2/FiO2 ratio, respiratory rate, body&#xD;
           temperature, neutrophil-lymphocyte ratio, C-Reactive Protein&amp;findings of bilateral&#xD;
           infiltrates on chest-x-ray.&#xD;
&#xD;
        7. Follow-up observations after randomization on Day 1,2,3,4 and 5 for SpO2/FiO2 ratio,&#xD;
           respiratory rate,body temperature and C-Reactive Protein&#xD;
&#xD;
        8. Length of stay (in days)&#xD;
&#xD;
        9. Use of ventilator support (invasive or non-invasive ventilation)&#xD;
&#xD;
       10. Side effects of drugs&#xD;
&#xD;
       11. In-patient mortality Primary end points&#xD;
&#xD;
      1. Length of stay in hospital (in days) 2. In-patient mortality&#xD;
&#xD;
      Secondary end points&#xD;
&#xD;
        1. Change in observations after randomization on Day 1,2,3,4 and 5 for SpO2/FiO2 ratio,&#xD;
           respiratory rate, body temperature and C-Reactive Protein&#xD;
&#xD;
        2. Use of ventilator support (invasive or non-invasive ventilation)&#xD;
&#xD;
        3. Side effects of drugs co-trimoxazole&#xD;
&#xD;
      Data Collection procedure:&#xD;
&#xD;
      Pre-designed case record form (CRF) will be used for collecting data, which will also contain&#xD;
      the result of the study. The information collected in the CRF will be reviewed and&#xD;
      inconsistencies will be investigated and clarified. Data from case record forms will be&#xD;
      anonymised and stored securely in a secure online web-based portal.&#xD;
&#xD;
      Statistical analysis: Statistical analysis will be performed using t-test or Mann -Whitney U&#xD;
      test or Wilcoxon signed rank test for continuous variables and Chi- square test or Fisher's&#xD;
      exact test for categorical variables. Survival will be assessed by the Kaplan-Meier method.&#xD;
      Comparisons between two groups will be performed using the log-rank test and Hazard&#xD;
      regression test.A p-value of &lt; 0.05 will be considered to be significant. The statistical&#xD;
      software SPSS version 25 will be used for the analysis.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">July 12, 2020</start_date>
  <completion_date type="Anticipated">January 30, 2021</completion_date>
  <primary_completion_date type="Anticipated">October 12, 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 :control group will receive standard treatment, Arm B: experimental group will receive standard care and oral co-triamoxazole</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Length of stay in hospital (in days)</measure>
    <time_frame>14 days</time_frame>
    <description>Duration of hospital stay in days</description>
  </primary_outcome>
  <primary_outcome>
    <measure>In-patient mortality</measure>
    <time_frame>14 days</time_frame>
    <description>% of patients died after enrollment</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>SpO2/FiO2 ratio</measure>
    <time_frame>Day 1,2,3,4 and 5</time_frame>
    <description>ratio of Saturation of oxygen in % and Fraction of inspired oxygen</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>respiratory rate</measure>
    <time_frame>Day 1,2,3,4 and 5</time_frame>
    <description>Respiratory rate per minute</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>C-reactive Protein</measure>
    <time_frame>Day 1,2,3,4 and 5</time_frame>
    <description>CRP level in mg/litre</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fever</measure>
    <time_frame>Day 1,2,3,4 and 5</time_frame>
    <description>Temperature in degree Fahrenheit</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>Proportion of drug adverse reaction</measure>
    <time_frame>24 hours</time_frame>
    <description>% of patients developed early reaction like fever, rash, abdominal pain, urticaria, vomiting, wheezing, chest tightness</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">94</enrollment>
  <condition>Covid19</condition>
  <condition>Severe COVID-19 Patients</condition>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Arm A :No Intervention/control: Standard treatment&#xD;
Antibiotics for secondary bacterial infection as per institutional guidelines&#xD;
Supplemental oxygen (to keep saturations between 90% to 96%)&#xD;
Intravenous hydration (to maintain euvolumia)&#xD;
Thrombo-prophylaxis as per local guidelines&#xD;
Paracetamol (oral or I/V 1gram QDS as required or regular)&#xD;
To consider steroids if indicated (i.e. acute exacerbation of COPD or acute severe asthma)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>intervention /experimental</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Arm B: Experimental Arm received oral co-trimoxazole + standard therapy&#xD;
The following treatments are recommended as standard therapy:&#xD;
Antibiotics for secondary bacterial infection as per institutional guidelines&#xD;
Supplemental oxygen (to keep saturations between 90% to 96%)&#xD;
Intravenous hydration (to maintain euvolumia)&#xD;
Thrombo-prophylaxis as per local guidelines&#xD;
Paracetamol (oral or I/V 1gram QDS as required or regular)&#xD;
To consider steroids if indicated (i.e. acute exacerbation of COPD or acute severe asthma)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>oral co-trimoxazole</intervention_name>
    <description>oral co-trimoxazole + standard therapy</description>
    <arm_group_label>intervention /experimental</arm_group_label>
    <other_name>co-trimoxazole</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Diagnosed COVID-19 patients ( RT-PCR positive for COVID-19)&#xD;
&#xD;
          2. Age &gt; 18 years&#xD;
&#xD;
          3. Hypoxic respiratory failure (saturation &lt;90% on air at rest or increasing oxygen&#xD;
             requirement)&#xD;
&#xD;
          4. Chest examination findings of bilateral crackles on auscultation or chest x-ray&#xD;
             showing bilateral infiltrates&#xD;
&#xD;
          5. C-Reactive Protein &gt; 50mg/L&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Multi-organ failure&#xD;
&#xD;
          2. Severe ARDS (requiring ventilator support on presentation in the form of invasive or&#xD;
             non-invasive ventilation)&#xD;
&#xD;
          3. Septic Shock&#xD;
&#xD;
          4. Severe liver disease&#xD;
&#xD;
          5. Acute Kidney Injury (where GFR&lt; 15 and plasma-sulfamethoxazoleconcentration cannot be&#xD;
             monitored)&#xD;
&#xD;
          6. Drug allergy/intolerance to co-trimoxazole / Sulphar sensitivity&#xD;
&#xD;
          7. Pregnancy&#xD;
&#xD;
          8. Already receiving Tocilizumab or convalescent therapy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Shohael Arafat</last_name>
    <role>Study Chair</role>
    <affiliation>ICMJE</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Shohael Arafat, FCPS</last_name>
    <phone>01732330313</phone>
    <email>arafat2001@gmail.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Rehan Quadery</last_name>
    <email>arafat2001@gmail.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>Shohael Arafat, FCPS</last_name>
      <phone>01732330313</phone>
      <email>arafat2001@gmail.com</email>
    </contact>
    <contact_backup>
      <last_name>Rehan Quadery</last_name>
    </contact_backup>
  </location>
  <location_countries>
    <country>Bangladesh</country>
  </location_countries>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>July 11, 2020</study_first_submitted>
  <study_first_submitted_qc>July 13, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 14, 2020</study_first_posted>
  <last_update_submitted>July 15, 2020</last_update_submitted>
  <last_update_submitted_qc>July 15, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 16, 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>Prof. Dr. Shohael Mahmud Arafat</investigator_full_name>
    <investigator_title>Chairman and professor of internal medicine</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Trimethoprim, Sulfamethoxazole Drug Combination</mesh_term>
  </intervention_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/NCT04470531
org study id: BSMMU/2020/6969
nct id: NCT04470531
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
Coronavirus Disease 19 (COVID-19) is a global pandemic caused by Severe Acute Respiratory
      Syndrome Coronavirus 2 (SARS-CoV-2). Severe disease occurs in 15% of the cases with COVID-19
      and may progress to critical disease in only 5% of the cases with a high risk of mortality.
      Critical disease may present as acute respiratory failure secondary to Acute Respiratory
      Distress Syndrome (ARDS) and is caused by the body's hyper-immune response to the virus in
      the form of a cytokine storm syndrome (CSS). There is currently no effective anti-viral
      treatment against SARS-CoV-2 and the mainstay of treatment is supportive. Co-trimoxazole
      (combination of trimethoprim and sulphamethoxazole in a 1:5) ratio is a Sulphur containing
      anti-folate bactericidal antibiotic indicated for the treatment of respiratory tract
      infections. It has been around for over 60 years and is inexpensive and readily available
      with a good safety profile. It has a rapid onset of action with excellent bioavailability and
      lung penetration. In addition to having antimicrobial properties co-trimoxazole have
      immunomodulatory and anti-inflammatory properties and may be a potential treatment option for
      cytokine storm syndrome mediated severe COVID-19.

      This open-label randomized controlled trial will be conducted in the department of medicine
      at Bangabandhu Sheikh Mujib Medical University (BSMMU), Anwar Khan Modern Medical college and
      Mughda Medical College Hospital (DMCH), Dhaka for a duration of 6 months following approval
      of this protocol. It will recruit at least 94 consecutive adults (18 years or older) patients
      with clinically suspected COVID-19 and severe illness as per WHO criteria. After taking
      informed written consent patients will be randomly assigned in a 1:1 ratio to either oral
      co-trimoxazole in addition to standard therapy or standard therapy alone. Baseline
      characteristics, changes in the physiological and biochemical parameters like (SpO2/FiO2
      ratio, respiratory rate, body temperature and C - reactive protein), length of hospital stay,
      side effects of drugs, requirement for ventilatory support (non-invasive and invasive
      ventilation) and in-patient mortality between the two groups will be compared.

      Conclusion If the results from this clinical trial demonstrate the beneficial effects of
      co-trimoxazole in severe COVID-19 patients it could be used widely, thereby reducing the need
      for respiratory support and potentially saving thousands of lives in developing nations with
      limited resources where healthcare may be easily overwhelmed.
Coronavirus disease (COVID-19) caused by SARS-COV2, represents a highly transmissible and
      potentially fatal disease that is of great global public health concern at this moment. The
      pandemic situation in Bangladesh is also evolving rapidly with positive cases and deaths
      increasing each day. Epidemiological changes in COVID-19 infection should be monitored taking
      into account potential routes of transmission and subclinical infections, in addition to the
      adaptation, evolution, and virus spread among humans and possible intermediate animals and
      reservoirs. But till today there is no specific management to deal with this highly deadly
      viral infection. Howeverthere are few drugs which might cause some beneficial effects in the
      recovery of the patient. Cotrimoxazole is a time tested antibiotic which has been in clinical
      use for 60 years with anti-bacterial action against a wide range of organism. In addition to
      the antimicrobial effects, co-trimoxazole has anti-inflammatory and immunomodulatory effects.
      Co-trimoxazole has previously been shown to exert anti-cytokine effect by inhibiting
      interleukin 1, 6 (IL-1, IL-6) and Tumour Necrosis Factor α (TNF α) which are the major
      cytokines identified in patients with severe COVID-19. As in some case reports this has shown
      significant clinical improvement in ARDS, so there is a possibility, that cotrimoxazole might
      have also role in improving the clinical outcome in COVID-19 patients especially in moderate
      to severe cases. As till today there is no specific treatment for COVID-19 infections, if
      cotrimoxazole ifs found to be effective this will bring a great benefit to the target
      populations. Beside this, cotrimoxazole is a very cheap drug in comparison to other ones this
      will also be of great economical benefit in taking cares of the general population. As there
      is no such study published about the role of cotrimoxazole in COVID-19 patients, this study
      will generate a new information which bring a great benefit in battling with the COVID-19
      infection.

      Research Question:

      What is the outcome of co-trimoxazole in severe COVID-19 patients?

      Objectives:

      General Objectives To assess the clinical outcome of co-trimoxazolein patients with severe
      COVID-19

      Specific Objectives:

      To assess length of stay who are treated with co-trimoxazole in addition to standard
      treatment versus standard treatment alone.

      To find out side effects (rash.itching. dizziness, headache, nausea,vomiting, diarrhea, sore
      throat, unusual bruising or bleeding, yellowing of the skin or eye discolorations, joint or
      muscle pain,red or purple skin.etc) of drugs who are treated with co-trimoxazole in addition
      to standard treatment versus standard treatment alone.

      To find out requirement for ventilator support (non-invasive and invasive ventilation) who
      are treated with co-trimoxazole in addition to standard treatment versus standard treatment
      alone.

      To assess the mortality in patients with severe COVID-19 who are treated with co-trimoxazole
      in addition to standard treatment versus standard treatment alone.

      Study design:Open-label randomized controlled trial Study duration: Six months.

      Study Population:

      Patients presenting to participating hospitals in Bangladesh with symptoms ofCOVID-19 will be
      assessed for eligibility.

      Inclusion criteria

        1. Diagnosed COVID-19 patients ( RT-PCR positive for COVID-19)

        2. Age > 18 years

        3. Hypoxic respiratory failure (saturation <90% on air at rest or increasing oxygen
           requirement)

        4. Chest examination findings of bilateral crackles on auscultation or chest x-ray showing
           bilateral infiltrates

        5. C-Reactive Protein > 50mg/L

      Exclusion criteria

        1. Multi-organ failure

        2. Severe ARDS (requiring ventilator support on presentation in the form of invasive or
           non-invasive ventilation)

        3. Septic Shock

        4. Severe liver disease

        5. Acute Kidney Injury (where GFR< 15 and plasma-sulfamethoxazoleconcentration cannot be
           monitored)

        6. Drug allergy/intolerance to co-trimoxazole / Sulphar sensitivity

        7. Pregnancy

        8. Already receiving Tocilizumab or convalescent therapy Sampling procedure:This RCT will
           consist of two arms, experimental group and control group.Randomized (1:1) case:
           control, (non-blinded) trial.

             1. control group will receive standard treatment,

             2. experimental group will recivestandard care and oral co-triamoxazole. Forty-seven
                (47) patients will be enrolled for each arm. Randomization will be done by a random
                number table. Allocations will be in sequentially numbered.

      Treatment protocol Eligible patients will be received either to oral co-trimoxazole +
      standard therapy or standard therapy alone. (According to institution /national protocol)

      The following treatments are recommended as standard therapy:

        1. Antibiotics for secondary bacterial infection as per institutional guidelines

        2. Supplemental oxygen (to keep saturations between 90% to 96%)

        3. Intravenous hydration (to maintain euvolumia)

        4. Thrombo-prophylaxis as per local guidelines

        5. Paracetamol (oral or I/V 1gram QDS as required or regular)

        6. To consider steroids if indicated (i.e. acute exacerbation of COPD or acute severe
           asthma) NOTE: The dose of co-trimoxazoleis 960 mg (trimethoprim 160mg +
           sulphamethoxazole 800mg) twice daily for 7 days orally.

      sample size: 94

      Research instrument:

        1. General questionnaire for assessing socio-demographic data.

        2. A checklist of clinical findings

        3. A checklist of investigation findings.

      Measures Variable:

      Data collection required for both groups (co-trimoxazole + standard therapyand standard
      therapy alone)

        1. Age

        2. Sex

        3. Ethnicity

        4. Past medical history - Hypertension, use of ACEI or ARB, DM, IHD, COPD, CKD, Obesity
           (BMI) andCancer

        5. Presenting symptoms (dry cough, productive cough, fever, sore throat, myalgia, lethargy,
           headache, breathlessness, nausea, diarrhoea and any other)

        6. Baseline observations on dayof initiating treatment (Day 0): oxygen saturation(SpO2),
           fraction of inspired oxygen (FiO2) , SpO2/FiO2 ratio, respiratory rate, body
           temperature, neutrophil-lymphocyte ratio, C-Reactive Protein&findings of bilateral
           infiltrates on chest-x-ray.

        7. Follow-up observations after randomization on Day 1,2,3,4 and 5 for SpO2/FiO2 ratio,
           respiratory rate,body temperature and C-Reactive Protein

        8. Length of stay (in days)

        9. Use of ventilator support (invasive or non-invasive ventilation)

       10. Side effects of drugs

       11. In-patient mortality Primary end points

      1. Length of stay in hospital (in days) 2. In-patient mortality

      Secondary end points

        1. Change in observations after randomization on Day 1,2,3,4 and 5 for SpO2/FiO2 ratio,
           respiratory rate, body temperature and C-Reactive Protein

        2. Use of ventilator support (invasive or non-invasive ventilation)

        3. Side effects of drugs co-trimoxazole

      Data Collection procedure:

      Pre-designed case record form (CRF) will be used for collecting data, which will also contain
      the result of the study. The information collected in the CRF will be reviewed and
      inconsistencies will be investigated and clarified. Data from case record forms will be
      anonymised and stored securely in a secure online web-based portal.

      Statistical analysis: Statistical analysis will be performed using t-test or Mann -Whitney U
      test or Wilcoxon signed rank test for continuous variables and Chi- square test or Fisher's
      exact test for categorical variables. Survival will be assessed by the Kaplan-Meier method.
      Comparisons between two groups will be performed using the log-rank test and Hazard
      regression test.A p-value of < 0.05 will be considered to be significant. The statistical
      software SPSS version 25 will be used for the analysis.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Arm A :control group will receive standard treatment, Arm B: experimental group will receive standard care and oral co-triamoxazole
primary purpose: Treatment
masking: None (Open Label)
measure: Length of stay in hospital (in days)
time frame: 14 days
description: Duration of hospital stay in days
measure: In-patient mortality
time frame: 14 days
description: % of patients died after enrollment
measure: SpO2/FiO2 ratio
time frame: Day 1,2,3,4 and 5
description: ratio of Saturation of oxygen in % and Fraction of inspired oxygen
measure: respiratory rate
time frame: Day 1,2,3,4 and 5
description: Respiratory rate per minute
measure: C-reactive Protein
time frame: Day 1,2,3,4 and 5
description: CRP level in mg/litre
measure: Fever
time frame: Day 1,2,3,4 and 5
description: Temperature in degree Fahrenheit
measure: Ventilator support
time frame: 14 days
description: Requirement of ventilator support in hours
measure: Proportion of drug adverse reaction
time frame: 24 hours
description: % of patients developed early reaction like fever, rash, abdominal pain, urticaria, vomiting, wheezing, chest tightness
arm group label: Control
arm group type: No Intervention
description: Arm A :No Intervention/control: Standard treatment
Antibiotics for secondary bacterial infection as per institutional guidelines
Supplemental oxygen (to keep saturations between 90% to 96%)
Intravenous hydration (to maintain euvolumia)
Thrombo-prophylaxis as per local guidelines
Paracetamol (oral or I/V 1gram QDS as required or regular)
To consider steroids if indicated (i.e. acute exacerbation of COPD or acute severe asthma)
arm group label: intervention /experimental
arm group type: Experimental
description: Arm B: Experimental Arm received oral co-trimoxazole + standard therapy
The following treatments are recommended as standard therapy:
Antibiotics for secondary bacterial infection as per institutional guidelines
Supplemental oxygen (to keep saturations between 90% to 96%)
Intravenous hydration (to maintain euvolumia)
Thrombo-prophylaxis as per local guidelines
Paracetamol (oral or I/V 1gram QDS as required or regular)
To consider steroids if indicated (i.e. acute exacerbation of COPD or acute severe asthma)
intervention type: Drug
intervention name: oral co-trimoxazole
description: oral co-trimoxazole + standard therapy
arm group label: intervention /experimental
other name: co-trimoxazole
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Shohael Arafat
role: Study Chair
affiliation: ICMJE
last name: Shohael Arafat, FCPS
phone: 01732330313
email: arafat2001@gmail.com
last name: Rehan Quadery
email: arafat2001@gmail.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: Prof. Dr. Shohael Mahmud Arafat
investigator title: Chairman and professor of internal medicine
mesh term: COVID-19
mesh term: Trimethoprim, Sulfamethoxazole Drug Combination
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