Comparing cotrimoxazole to standard care for the treatment of severe coronavirus (COVID-19) infection in hospitalised patients
| ISRCTN | ISRCTN85874083 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN85874083 |
| Secondary identifying numbers | CTRI/2021/02/031012 |
- Submission date
- 05/02/2021
- Registration date
- 09/02/2021
- Last edited
- 15/11/2022
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Infections and Infestations
Plain English Summary
Background and study aims
COVID-19 is a condition caused by the coronavirus (called SARS-CoV-2) that was first identified in late 2019. This virus can infect the respiratory (breathing) system. Some people do not have symptoms but can carry the virus and pass it on to others. People who have developed the condition may develop a fever and/or a continuous cough among other symptoms. This can develop into pneumonia. Pneumonia is a chest infection where the small air pockets of the lungs, called alveoli, fill with liquid and make it more difficult to breathe. At least 15-20% of those who are infected progress to severe COVID-19 disease.
In a small number of patients, there may be a misdirected immune response to the infection, causing inflammation of the lungs and respiratory failure. This response may also cause increased clotting of the blood. Currently, there is no evidence-based, specific anti-viral treatment available for COVID-19, and recommended treatment is supportive with steroids and low molecular weight heparin.
Co-trimoxazole (combination of trimethoprim and sulphamethoxazole) is an antibiotic that kills bacteria. Co-trimoxazole is effective against a wide range of bacterial infections including respiratory tract infections. It has been used for over 80 years and is well-tolerated, inexpensive, and readily available. In addition to having fighting bacterial infections, co-trimoxazole has an effect on the immune system and anti-inflammatory properties. Therefore, co-trimoxazole may be a potential treatment option severe COVID-19.
This study will investigate if starting cotrimoxazole treatment early in hospitalised COVID-19 patients could prevent the development of the disease to a critical stage.
Who can participate?
All adult patients admitted to Medical College Hospital, Kolkata with severe COVID-19 infection
What does the study involve?
Participants will be allocated to one of two groups, with an equal chance of being in either group (like tossing a coin). Participants and researchers will not have a choice in the treatment given. The first group of participants will receive the study drug, cotrimoxazole, plus standard care. They will be asked to take cotrimoxazole by mouth, three times daily, for 7 days. Treatment with drugs or procedures that the clinician responsible for the participant feels is necessary and would be part of routine clinical practice will be allowed. The other group will receive only the necessary drugs or procedures in routine clinical practice according to the best standard of care and local guidance.
What are the possible benefits and risks of participating?
All participants in this study shall have the privilege of additional (beyond routine care) closer and more intense medical attention. Co-trimoxazole is a time-tested, relatively well-tolerated drug that has been in clinical use for around five decades. Appropriate cautions shall be exercised by the investigators to guard against the known side effects of the drug. In case of any rare serious complication, urgent treatment shall be provided free of cost.
Where is the study run from?
School of Tropical Medicine, Kolkata (India)
When is the study starting and how long is it expected to run for?
October 2020 to March 2023
Who is funding the study?
Department of Health and Family Welfare, Govt of West Bengal (India)
Who is the main contact?
Prof (Dr) Bibhuti Saha
bibhuti.saha@gmail.com
Contact information
Scientific
Department of Tropical Medicine
School of Tropical Medicine
108 Chitta Ranjan Avenue
Kolkata
700073
India
| Phone | +919831296071 |
|---|---|
| bibhuti.saha@gmail.com |
Public
St. Helier Hospital
Wrythe Lane
Sutton
Sutton
SM5 1AA
United Kingdom
 ORCID ID |
0000-0002-9261-010X |
|---|---|
| Phone | +44 9800649068 |
| rehan.quadery@nhs.net |
Scientific
Department of Medicine
Medical College and Hospital
88 College Street
Kolkata
700073
India
| Phone | +91 9433044237 |
|---|---|
| udasghosh23@gmail.com |
Study information
| Study design | Single-centre randomized controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Prevention |
| Participant information sheet | ISRCTN85874083_PIS_v1.0_09Feb2021.pdf |
| Scientific title | Cotrimoxazole in hospitalised patients with severe COVID-19 infection compared to the standard of care – an investigator-initiated, randomised controlled trial |
| Study acronym | CoTroxCov |
| Study hypothesis | Use of oral cotrimoxazole in patients with severe COVID-19 can prevent ‘higher’ oxygenation requirements through non-invasive and invasive mechanical ventilation, decrease in-hospital stays, and decrease death rate |
| Ethics approval(s) | 1. Approved 09/01/2021, Institutional Ethics Committee, Medical College Kolkata (88, College St, Calcutta Medical College, College Square, Kolkata, West Bengal 700073; +919433084372; no email address available), ref: MC/KOL/IEC/NON-SPON/863/01/2021 2. Approved 14/01/2021, Clinical Research Ethics Committee (Calcutta School of Tropical Medicine, 108 Chitta Ranjan Avenue, Kolkata 700073; +919433349332; smnaser2012@gmail.com), ref: CREC-STM/2020-AS-18 |
| Condition | Hospitalized patients with severe COVID-19 (SARS-CoV-2 infection) |
| Intervention | Current intervention as of 14/11/2022: Randomisation to treatment arms cotrimoxazole plus standard of care or standard of care ony in a 1:1 ratio will be performed using an internet-based randomisation tool. The intervention group, cotrimoxazole plus standard of care, will receive oral cotrimoxazole 960 mg three times daily for 7 days. Treatment with drugs or procedures in routine clinical practice that the clinician responsible for the patient deems necessary is allowed. The control group will receive drugs or procedures in routine clinical practice according to the best standard of care as per local protocol. _____ Previous intervention: Randomisation to treatment arms cotrimoxazole plus standard of care or standard of care ony in a 2:1 ratio will be performed using an internet-based randomisation tool. The intervention group, cotrimoxazole plus standard of care, will receive oral cotrimoxazole 960 mg three times daily for 7 days. Treatment with drugs or procedures in routine clinical practice that the clinician responsible for the patient deems necessary is allowed. The control group will receive drugs or procedures in routine clinical practice according to the best standard of care as per local protocol. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | cotrimoxazole |
| Primary outcome measure | Current primary outcome measure as of 15/11/2022: Number of in-patient deaths measured from patient records between baseline and hospital discharge or death _____ Previous primary outcome measure: 1.Clinical status, the number of patients requiring escalation of care to non-invasive ventilation (CPAP and HFNC) and invasive ventilation measured using the 7-point ordinal scale (scored from 1 to 7 as follows: 1= death; 2= hospitalised, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3= hospitalised, requiring non-invasive ventilation or high flow oxygen devices; 4= hospitalised, requiring supplemental oxygen; 5= hospitalised, not requiring supplemental oxygen, but in need of ongoing medical care (COVID-19 related or otherwise), 6= hospitalised, not requiring supplemental oxygen and no longer requires ongoing medical care (independent); or 7= not hospitalised) between baseline and hospital discharge or death 2. Duration of hospitalisation measured from patient records between baseline and hospital discharge or death 3. Number of in-patient deaths measured from patient records between baseline and hospital discharge or death |
| Secondary outcome measures | Current secondary outcome measures as of 15/11/2022: 1. Clinical status, the number of patients requiring escalation of care to non-invasive ventilation (CPAP and HFNC) and invasive ventilation measured using the 7-point ordinal scale (scored from 1 to 7 as follows: 1= death; 2= hospitalised, requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3= hospitalised, requiring non-invasive ventilation or high flow oxygen devices; 4= hospitalised, requiring supplemental oxygen; 5= hospitalised, not requiring supplemental oxygen, but in need of ongoing medical care (COVID-19 related or otherwise), 6= hospitalised, not requiring supplemental oxygen and no longer requires ongoing medical care (independent); or 7= not hospitalised) between baseline and hospital discharge or death 2. Time to recovery measured from patient records between baseline and hospital discharge or death 1. Changes in COVID-19 severity measured using the following at baseline, 3, and 7 days: 1.1. Body temperature measured using a thermometer 1.2. Respiratory rate measured using manual method 1.3. Serum levels of C-reactive protein (CRP) measured from blood samples 1.4. Oxygen saturation measured using a pulse oximeter 2. Incidence of serious and non-serious adverse events measured from patient records between baseline and hospital discharge or death _____ Previous secondary outcome measures: 1. Changes in COVID-19 severity measured using the following at baseline, 3, and 7 days: 1.1. Body temperature measured using a thermometer 1.2. Respiratory rate measured using manual method 1.3. Serum levels of C-reactive protein (CRP) measured from blood samples 1.4. Oxygen saturation measured using a pulse oximeter 2. Incidence of serious and non-serious adverse events measured from patient records between baseline and hospital discharge or death |
| Overall study start date | 01/10/2020 |
| Overall study end date | 01/03/2023 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 110 |
| Participant inclusion criteria | Current inclusion criteria as of 14/11/2022: 1. Adult male or female individuals, age ≥18 years and ≤70 years 2. Patients giving written informed consent to participate in the study (i.e. GCS 15/15: conscious, alert, and oriented) 3. COVID-19 documented by a positive RT-PCR test/Rapid Antigen Test 4. Hospitalised patients with severe COVID-19, requiring supplemental oxygen through a non-re-Breath mask between 10-15 l/min maintaining saturations between 92-96% for up to 30 h and between 94-98% for the first 6 h 5. Clinical/radiological evidence of interstitial pneumonia requiring admission (optional) _____ Previous inclusion criteria as of 13/05/2021: 1. Adult male or female individuals, age ≥18 years and ≤65 years 2. Patients giving written informed consent to participate in the study (i.e. GCS 15/15: conscious, alert, and oriented) 3. COVID-19 documented by a positive RT-PCR test/Rapid Antigen Test 4. Hospitalised patients with severe COVID-19, requiring supplemental oxygen through a non-re-Breath mask between 10-15 l/min maintaining saturations between 92-96% for up to 30 h and between 94-98% for the first 6 h 5. Clinical/radiological evidence of interstitial pneumonia requiring admission (optional) _____ Previous inclusion criteria: 1. Aged between 18 and 65 years 2. COVID-19 infection documented by a positive RT-PCR test 3. Hospitalised with severe COVID-19 infection, characterized by fever (at the time of screening or when admitted) and requiring supplemental oxygen through non-rebreather mask between 10 and 15 l/ min 4. Clinical/radiological evidence of interstitial pneumonia requiring admission (optional) 5. Informed written consent given |
| Participant exclusion criteria | Current exclusion criteria as of 13/05/2021: 1. Patients who require invasive or non-invasive (including CPAP and high flow nasal cannula). ventilation at the time of inclusion 2. AST/ALT values >5 fold the upper normal limit 3. Impairment of renal function( creatinine clearance<30ml/min/m²) 4. Absolute neutrophil count below 500 cells/mm³ 5. Absolute platelet count below 50,000 cells/mm³ 6. Documented sepsis or high clinical suspicion of superimposed severe bacterial or fungal infection 7. Concomitant acute medical emergencies, such as AMI, acute pericarditis, PE, stroke, acute Surgical and orthopaedic emergencies like acute abdomen and fractured neck of femur etc. 8. Comobidities or concomitant medications likely to be incompatible for cotrimoxazole use pregnancy or lactation 9. History of cotrimoxazole hypersensitivity 10. Patients participating in another clinical trial for SARS-CoV-2 infection _____ Previous exclusion criteria: 1. Require invasive or non-invasive (including CPAP and high flow nasal cannula) ventilation at the time of inclusion 2. Aspartate transaminase (AST)/alanine transaminase (ALT) ratio >5 times the ULN 3. Documented impairment of renal function 4. Absolute neutrophil count <500 cells/mm³ 5. Absolute platelet count <50,000 cells/mm³ 6. Documented sepsis or high suspicion of superimposed severe bacterial or fungal infection 7. Comorbidities or concomitant medications likely to be incompatible for cotrimoxazole use 8. Pregnancy or lactation 9. History of cotrimoxazole hypersensitivity 10. Participating in another clinical trial for SARS-CoV-2 infection |
| Recruitment start date | 15/02/2021 |
| Recruitment end date | 01/09/2022 |
Locations
Countries of recruitment
- India
Study participating centres
Calcutta Medical College
College Square
Kolkata
700073
India
108, Chitta Ranjan Avenue
Kolkata
700073
India
Sponsor information
Government
108 Chitta Ranjan Avenue
Kolkata
700073
India
| Phone | +919831234802 |
|---|---|
| directorstm18@gmail.com | |
| Website | http://www.stmkolkata.org/ |
Funders
Funder type
Government
Government organisation / Local government
- Location
- India
Results and Publications
| Intention to publish date | 01/09/2023 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Other |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal |
| IPD sharing plan | The datasets generated and/or analysed during the current study during this study will be included in the subsequent results publication |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Participant information sheet | version v1.0 | 09/02/2021 | 01/03/2021 | No | Yes |
| Protocol file | version v2.0 | 24/12/2020 | 01/03/2021 | No | No |
Additional files
- ISRCTN85874083_PIS_v1.0_09Feb2021.pdf
- Uploaded 01/03/2021
- ISRCTN85874083_PROTOCOL_v2.0_24Dec2020.pdf
- Uploaded 01/03/2021
Editorial Notes
15/11/2022: The following changes have been made:
1. The primary outcome measure has been updated.
2. The secondary outcome measures have been updated.
14/11/2022: The following changes have been made:
1. The intervention has been updated.
2. The inclusion criteria have been updated.
3. The target number of participants has been changed from 200 to 110 and the total target enrolment has been changed from 200 to 110.
20/04/2022: The following changes were made to the trial record:
1. The overall end date was changed from 01/09/2022 to 01/03/2023.
2. The intention to publish date was changed from 01/10/2021 to 01/09/2023.
3. The plain English summary was updated to reflect these changes.
07/02/2022: The following changes have been made:
1. The recruitment end date has been changed from 28/02/2022 to 01/09/2022.
2. The overall trial end date has been changed from 28/02/2022 to 01/09/2022 and the plain English summary has been updated to reflect this change.
12/10/2021: The overall trial end date has been changed from 01/10/2021 to 28/02/2022 and the plain English summary has been updated to reflect this change.
26/08/2021: The recruitment end date has been changed from 31/08/2021 to 28/02/2022.
13/05/2021: The following changes were made to the trial record:
1. The inclusion criteria were changed.
2. The exclusion criteria were changed.
12/05/2021: The recruitment end date was changed from 15/05/2021 to 31/08/2021.
25/03/2021: Internal review.
01/03/2021: The following changes have been made:
1. Uploaded protocol version 2.0, 24 December 2020 (not peer reviewed) as an additional file.
2. Uploaded participant information sheet as an additional file.
09/02/2021: Trial’s existence confirmed by the Institutional Ethics Committee, Medical College Kolkata.
