Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT04884490 |
| Other study ID # |
BSMMU/2021/4098(A) |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
Phase 2/Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
May 15, 2021 |
| Est. completion date |
November 14, 2021 |
Study information
| Verified date |
May 2021 |
| Source |
Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Coronavirus Disease 19 (COVID-19) is a worldwide pandemic and a major global health concern
which is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The newly
emerged Coronavirus disease 2019 (COVID-19), which was first identified in Wuhan, China, has
swept through 219 countries, killing a staggering number of people. According to WHO reports,
the number of deaths had risen to 3,155,168by March 30, 2021, out of 149,910,744 confirmed
cases. In Bangladesh, the outbreak has infected over 745,322confirmed cases, with over 11,053
deaths reported. Though the patient may be asymptomatic or present with mild symptoms,
mortality is quite high in the severe form of the disease which often progresses to critical
phase presented as Acute Respiratory Distress Syndrome (ARDS). This is due to exaggerated
response of immune system to the virus termed as cytokine storm syndrome (CSS). There is
currently no effective antiviral therapy for SARS-CoV-2 and supportive care is the mainstay
of therapy. As a result we are still searching for a better therapeutic agent which will help
in treating Covid-19 cases in terms of mortality, morbidity, oxygen requirement, length of
stay in hospital. Co-trimoxazole (composed of one-part Trimethoprim and five parts
Sulfamethoxazole)is a sulphur containing anti-folate bactericidal drug which is being used
for over 60 years for various indications esp. respiratory tract infections. It is known to
have immunomodulatory and anti-inflammatory properties that may help to prevent progression
to critical phase and cytokine storm syndrome in severe COVID-19 patients. It acts rapidly
when given in high dose due to its better bioavailability and lung penetration. Low cost and
a good safety profile can make it an ideal candidate for treatment of COVID -19 in a low
resource country like Bangladesh.
Methods and materials:
This interventional double-blind place controlled randomized trial will be conducted in the
department of medicine at Bangabandhu Sheikh Mujib Medical University (BSMMU) 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 high dose co-trimoxazole in addition to standard therapy or
placebo along with standard therapy. 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 28- day mortality between the
two groups will be compared. Data will be collected from case record forms, anonymised and
stored securely in a secure online web based portal. 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. A p-value of < 0.05 will be considered to be significant. The statistical
software SPSS version 25 will be used for the analysis.
Conclusion If the results from this clinical trial demonstrate the beneficial effects of high
co-trimoxazole in patients with severe COVID-19 it could help to reduce the need for
respiratory support for thousands of patients, saving valuable lives and decrease the burden
of healthcare system in countries with limited resources.
Description:
The newly emerged Coronavirus disease 2019 (COVID-19), which was first identified in Wuhan,
China, has swept through 219 countries, killing a staggering number of people. The World
Health Organization (WHO) has declared the deadly outbreak a pandemic, with far-reaching
consequences for all people. According to WHO reports, the number of deaths had risen to
3,155,168by March 30, 2021, out of 149,910,744 confirmed cases.
The pathogen for COVID-19 has been described as the severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2), a new beta-coronavirus. Following the outbreaks of the severe
acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses
in 2003 and 2012, respectively, this strain has been the third most deadly pathogenic human
coronavirus. In Bangladesh, the outbreak has infected over 745,322confirmed cases, with over
11,053 deaths reported.
COVID-19 is spread from person to person through respiratory droplets. The disease is
characterized by respiratory symptoms, the most common of which are fever, fatigue, myalgia,
dry cough, and dyspnea.
People with co-morbidities such as diabetes, cardiovascular and cerebrovascular disorders,
cancers, and pre-existing lung diseases such as Chronic Obstructive Pulmonary Disease (COPD)
have been shown to have a greater risk of developing serious forms of the disease.
Septic shock, coagulation disorders, Acute Respiratory Distress Syndrome (ARDS), multi-organ
failure, and even death may occur in people with serious illness.
According to recent research, the SARSCoV-2 envelope spike protein receptor binding domain
binds to the angiotensin converting enzyme 2 (ACE2) receptors of the host cells, which are
mainly respiratory epithelial cells and alveolar pneumocytes type 2 (AT2).
The virus then induces lysis of the infected cells, causing the release of proinflammatory
cytokines such as interleukin (IL) IL1, IL2, IL6, IL 7, interferon gamma, macrophage
inflammatory proteins, tumor necrosis factor alpha, and others, initiating the host's
inflammatory immune response.
A cytokine storm syndrome (CSS) develops in patients with severe forms of the disease as a
result of the host's excessive immune response combined with continued lysis of the infected
cells. Damage Associated Molecular Patterns (DAMPs) released after mitochondrial injury in
host cells stimulate Formyl Peptide Receptors (FPRs) on the outer surface of neutrophils and
monocytes' cell membranes, causing their recruitment to the lungs. FPRs cause the release of
Reactive Oxygen Species (ROS) in the tissue when stimulated, which leads to the release of
even more cytokines.
This causes extensive tissue damage, causing mild respiratory symptoms like dry cough and
fever to quickly progress into Acute Respiratory Distress Syndrome, followed by multiple
organ failure in susceptible patients.
A large, randomized clinical trial involving more than 6400 hospitalized patients with
Covid-19 showed that dexamethasone significantly reduced 30-day mortality (17% reduction);
benefit was limited to patients who required oxygen supplementation and appeared greater in
patients receiving mechanical ventilation.10 Consequently, dexamethasone (or potentially
other glucocorticoids) is now considered the standard of care for patients with severe
Covid-19. Data from a randomized, placebo-controlled trial involving more than 1000 patients
with severe Covid-19 showed that the antiviral agent remdesivir reduced time to clinical
recovery; the benefit appeared greatest in patients who were receiving supplemental oxygen
but were not intubated.11The combination of dexamethasone and remdesivir is increasingly used
clinically, but its benefit has not been shown in randomized clinical trials. Tocilizumab, an
interleukin-6 inhibitor, did not significantly reduce disease progression.
Therefore in managing severe Covid-19 patients physicians are still searching for better
options. The key to managing severe COVID-19 is to prevent this cytokine storm from
occurring, as well as to ensure that there are no secondary bacterial infections in the
patient's already compromised lungs.
Cotrimoxazole is a common antibiotic used to treat a variety of illnesses, including urinary
and respiratory tract infections and opportunistic pneumocystis pneumonia, and toxoplasmosis
in HIV/AIDS patients. Being composed of one-part Trimethoprim and five parts
Sulfamethoxazole, Cotrimoxazole is a low-cost drug with good effectiveness and a low risk of
side effects.
Many studies have shown that Cotrimoxazole has immunomodulatory and anti-inflammatory
properties. In the ARROW trial, plasma pro-inflammatory markers like C reactive protein (CRP)
and Interleukin 6 were found to be lower in continuous Cotrimoxazole prophylaxis, implying
that it has anti-inflammatory and immunomodulatory properties.
Cotrimoxazole has been shown to block FPRs, preventing the recruitment of inflammatory cells,
the release of cytokines, and the production of reactive oxygen species (ROS) in damaged
tissue.
Cotrimoxazole has also been shown to be effective in lowering pro-inflammatory cytokines such
as IL-1, 2, 6, 8, and Tumor Necrosis Factor - α.
This could prevent the clinically serious COVID-19 from progressing to ARDS by preventing the
imminent CSS. In addition, the drug is very effective in treating nosocomial and
opportunistic infections. This could also help to prevent COVID from progressing to ARDS by
avoiding secondary bacterial infection.
A comparative study involving 44 cases, suggested that adding oral Trimethoprim or
Cotrimoxazole reduces acute lung injury in patients with severe COVID-19, resulting in
decreased need for ventilatory support and improved outcomes. These drugs have no direct
antiviral properties, but they may help to prevent ARDS. The positive effects were noticeable
within hours of the first dose, owing to their high absorption and lung penetration.
Another study involving 201 patients shown a significant reduction in mortality, intubation
rate, length of hospital and critical care stay and inflammatory markers in the patients
treated with Cotrimoxazole along with standard treatment compared to the patients treated
with standard treatment alone. A higher dose of Cotrimoxazole was used in this study with
excellent safety profile.
A randomized control trial with Cotrimoxazole in patients with severe COVID-19 is underway in
India and results are awaited (Clinical Trials Registration-India ID CTRI/2020/10/028297).
Another randomized control trial is currently underway led by the author and team where a
lower dose of Cotrimoxazole is being used (ClinicalTrials.gov Identifier NCT04470531).20 High
dose Co-trimoxazole may have a potential role to play in preventing the exaggerated immune
response in the form of cytokine storm syndrome in patients with severe COVID-19 by its
anti-inflammatory and immunomodulatory effect.
RATIONALE:
Corona virus disease (COVID-19), caused by SARS-COV2, is a highly transmissible and
potentially deadly disease that is currently causing widespread concern in the global public
health community. Bangladesh's pandemic situation is also rapidly changing, with positive
cases and deaths rising by the day. There is no specific management for this highly lethal
viral infection as of yet. However, there are a few medications that may have a positive
impact on the patient's recovery. But large randomized controlled trials investigating the
efficacy of those agents have not found much promising result specially when it comes to
mortality benefit and cost effectiveness. We are still in need of better therapeutics to
combat this pandemic situation. Co-trimoxazole is a tried-and-true antibiotic that has been
used in clinical practice for over 60 years and is effective against a wide range of
bacteria. Co-trimoxazole also has anti-inflammatory, and immunomodulatory properties in
addition to its antimicrobial properties. In previous studies Co-trimoxazole has shown to
exert anti-cytokine effect by inhibiting interleukin 1, 6 (IL-1, IL-6) and Tumour Necrosis
Factor α (TNF α). These are the major cytokines identified in patients with severe COVID-19.
Because Cotrimoxazole has been shown to improve clinical outcomes in ARDS patients in some
case reports, there is a chance that it may help improve clinical outcomes in COVID-19
patients. The efficacy of a variety of old and new therapeutic agents is being studied all
over the world in order to effectively prevent the life-threatening conditions linked to
COVID-19. Because of its immunomodulatory effect, low cost, and good safety profile,
co-trimoxazole may be an ideal candidate to investigate. If this agent can be found to reduce
the oxygen demand or shorten the length of stay in hospital of severe Covid-19 patients it
will definitely have a positive impact in the era of pandemic in resource constraint setting
like Bangladesh. This research will provide new data on the safety and effectiveness of
high-dose Co-trimoxazole, which will hopefully aid in developing an effective treatment
protocol for COVID-19 infection.
Research Question:
Is there any beneficial role of high dose co-trimoxazole in patients with severe COVID-19?
Objectives:
General Objectives To compare the role of high dose co-trimoxazole in severeCOVID-19 patients
in addition to standard treatment versus standard treatment along with placebo.
Specific Objectives:
To compare the baseline characteristics in severe covid 19 patients.
To compare the length of stay who are treated with high dose co-trimoxazole in addition to
standard treatment versus standard treatment along with placebo.
To compare the requirement for oxygen support through high flow nasal cannula who are treated
with high dose co-trimoxazole in addition to standard treatment versus standard treatment
along with placebo.
To compare the requirement for ventilatory support (non-invasive and invasive ventilation)
who are treated with high dose co-trimoxazole in addition to standard treatment versus
standard treatment along with placebo.
To assess the mortality in patients with severe COVID-19 who are treated with high dose
co-trimoxazole in addition to standard treatment versus standard treatment along with
placebo.
To assess the changes in the physiological and biochemical parameters who are treated with
co-trimoxazole in addition to standard treatment versus standard treatment along with
placebo.
To find out side effects of drugs who are treated with high dose co-trimoxazole in addition
to standard treatment versus standard treatment along with placebo.
Methods and procedure:
Study design: Single-centre interventional double-blind placebo controlled randomized trial.
Study duration: Six months. Place of study: Medicine department (Covid Unit) of Bangabandhu
Sheikh Mujib Medical University (BSMMU) Period of Study: Six months following approval of the
protocol Sampling technique: Random sampling followed by patients will be assigned in a 1:1
ratio to either oral high dose co-trimoxazole in addition to standard therapy or standard
therapy along with placebo
Sample Size:
In order to provide reasonable estimates for the power calculation in the current trial, we
used data from a recent COVID-19 study that showed decrease in length of stay by about
25%.Based on similar change with the current intervention we estimated that a total of 94
participants would be needed to detect a significant difference with over 90% power. We will
conduct an interim power analysis to test these assumptions, using data from 50 individuals,
and adjust sample size if power is lower than anticipated.
At least total 94 study population will be included for the study.
