Role of Co-trimoxazole in Severe COVID-19 Patients

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.