Role of Co-trimoxazole in Severe COVID-19 Patients
Role of Co-trimoxazole in Severe COVID-19 Patients
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.
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