CTRI Number	CTRI/2020/10/028297 [Registered on: 08/10/2020] Trial Registered Prospectively
Last Modified On:	07/10/2020
Post Graduate Thesis	No
Type of Trial	Interventional
Type of Study	Drug
Study Design	Randomized, Parallel Group Trial
Public Title of Study	Cotrimoxazole in hospitalised patients with moderate to early-severe COVID-19 infection
Scientific Title of Study	Cotrimoxazole in hospitalised patients with moderate to early-severe COVID-19 infection compared to the standard of care – an investigator-initiated, randomised controlled trial (CoTroxCov Study)
Secondary IDs if Any	Secondary ID  Registry  U1111-1259-2654  UTN
Details of Principal Investigator or overall Trial Coordinator (multi-center study) Modification(s)	Name  Dr Santanu Kumar Tripathi  Address  Room No 19 Dept of Clinical and Experimental Pharmacology School of Tropical Medicine 108, C R Avenue Room No 19 Dept of Clinical and Experimental Pharmacology School of Tropical Medicine 108, C R Avenue Kolkata WEST BENGAL 700073 India  Phone  9230566771   Fax     Email  tripathi.santanu@gmail.com
Details Contact Person Scientific Query Modification(s)	Name  Dr Santanu Kumar Tripathi  Address  Room No 19 Dept of Clinical and Experimental Pharmacology School of Tropical Medicine 108, C R Avenue Room No 19 Dept of Clinical and Experimental Pharmacology School of Tropical Medicine 108, C R Avenue Kolkata WEST BENGAL 700073 India  Phone  9230566771   Fax     Email  tripathi.santanu@gmail.com
Details Contact Person Public Query Modification(s)	Name  Dr Santanu Kumar Tripathi  Address  Room No 19 Dept of Clinical and Experimental Pharmacology School of Tropical Medicine 108, C R Avenue Room No 19 Dept of Clinical and Experimental Pharmacology School of Tropical Medicine 108, C R Avenue Kolkata WEST BENGAL 700073 India  Phone  9230566771   Fax     Email  tripathi.santanu@gmail.com
Source of Monetary or Material Support	Nil
Primary Sponsor	Name  Dept of Health and Family Welfare Government of West Bengal  Address  GN-29, Swasthya Bhawan Sector-V, Salt Lake, Kolkata, West Bengal 700091  Type of Sponsor  Other [State Government Health Department]
Details of Secondary Sponsor	Name  Address  NIL  NIL
Countries of Recruitment	India
Sites of Study	No of Sites = 1   Contact Person  Name of Site  Site Address  Phone/Fax/Email  Dr Santanu Kumar Tripathi  Medical College Hospital, Kolkata  In-Patient Department Medical College Hospital 88, College Street Kolkata West Bengal-700073 Kolkata   9230566771 tripathi.santanu@gmail.com
Details of Ethics Committee	No of Ethics Committees= 1   Name of Committee  Approval Status  Clinical Research Ethics Committee, School of Tropical Medicine, Kolkata  Approved
Regulatory Clearance Status from DCGI	Status  Not Applicable
Health Condition / Problems Studied	Health Type  Condition  Patients  Coronavirus as the cause of diseases classified elsewhere
Intervention / Comparator Agent	Type  Name  Details  Intervention  cotrimoxazole plus standard of care  Patients will receive oral cotrimoxazole 960 mg twice daily for 7 days  Comparator Agent  Routine Care  drugs or procedures in routine clinical practice according to the best standard of care as per local protocol.
Inclusion Criteria	Age From  18.00 Year(s) Age To  65.00 Year(s) Gender  Both  Details  a. Adult individuals, age >18 and <65 years b. COVID-19 infection documented by a positive RT-PCR test c. Hospitalised patients with moderate to early-severe COVID-19 infection, characterized by fever (at the time of screening or when admitted), oxygen saturation ≤ 94% on air at rest and requiring supplemental oxygen through mask or nasal cannula/catheter d. Clinical/radiological evidence of interstitial pneumonia requiring admission (optional) e. Informed verbal consent under urgent conditions, documented in the electronically
ExclusionCriteria	Details  a. Patients who require invasive or non-invasive (including CPAP and high flow nasal cannula) ventilation at the time of inclusion. b. AST/ALT values >5 fold the ULN. c. Documented impairment of renal function d. Absolute neutrophil count below 500 cells/mm3 e. Absolute platelet count below 50,000 cells/mm3 f. Documented sepsis or high suspicion of superimposed severe bacterial or fungal infection g. Comorbidities or concomitant medications likely to be incompatible for cotrimoxazole use h. Pregnancy or lactation. i. History of cotrimoxazole hypersensitivity j. Patients participating in another clinical trial for SARS-CoV-2 infection
Method of Generating Random Sequence	Random Number Table
Method of Concealment	Not Applicable
Blinding/Masking	Not Applicable
Primary Outcome	Outcome  TimePoints  a. Mean change in clinical status assessment using the 7-point ordinal scale at day 7 after randomisation compared to baseline b. Duration of hospitalisation: Days from the date of enrolment to the date of discharge c. Number of in-patient deaths   Till Discharge
Secondary Outcome	Outcome  TimePoints  1. Changes in body temperature, respiratory rate, CRP, SpO2 2. Incidence of serious and non-serious adverse events   Till Discharge
Target Sample Size	Total Sample Size="200" Sample Size from India="200"
Phase of Trial	Phase 2
Date of First Enrollment (India)	26/10/2020
Date of First Enrollment (Global)	No Date Specified
Estimated Duration of Trial	Years="0" Months="6" Days="0"
Recruitment Status of Trial (Global) Modification(s)	Not Applicable
Recruitment Status of Trial (India)	Not Yet Recruiting
Publication Details Modification(s)	NIL
Brief Summary	COVID-19, caused by SARS-CoV-2, is a highly transmissible disease that has caused a global pandemic.  The disease is mostly self-limiting with milder form of infection, but at least 15-20% of those who are infected progress to severe disease. The case fatality, albeit at a low rate not exceeding 1-2%, is attributed to a misdirected hyperimmune response to the infection leading to a cytokine release syndrome or cytokine storm.  The cytokine-mediated inflammation of the lung alveolar bed may result in ARDS and acute respiratory failure. Further, cytokine-induced hypercoagulability adds to the injury. With no evidence-based, specific anti-viral treatment yet available, the mainstay of therapy is supportive with steroids and low molecular weight heparin. Co-trimoxazole (combination of trimethoprim and sulphamethoxazole in a 1:5 ratio is an anti-folate bactericidal agent effective against a wide range of systemic bacterial infections including respiratory tract infections. It has been around for over 80 years and is inexpensive and readily available with a generally good safety profile. It has a rapid onset of action with excellent bioavailability and lung penetration. In addition to having antimicrobial properties co-trimoxazole has immunomodulatory and anti-inflammatory properties and may be a potential treatment option for cytokine storm syndrome mediated severe COVID-19. Cotrimoxazole acts on peripheral blood mononuclear cells and suppress TNFa secretion at clinically achievable concentrations.  Cotrimoxazole reduces systemic inflammation in HIV infection by altering the gut microbiome and immune activation.  Such immunomodulatory and anti-inflammatory properties of cotrimoxazole may account for it’s potential use in rheumatoid arthritis, The benefit of using cotrimoxazole in fibrotic lung disease has been reported by several researcher groups. Against this backdrop, it is not surprising to witness off-label use of cotrimoxazole in Covid-19. It is believed, during the Covid-19 disease process, mitochondrial injury of host cells occurs leading to release of damage associated molecular patterns (DAMPs). These DAMPs stimulate formyl peptide receptors (FPRs) present on the surface of neutrophils and monocytes, leading to release of intracellular and extracellular reactive oxygen species (ROS), which then drive the cytokine storm. Cotrimoxazole is reported to block the FPRs and thus may prove beneficial by decreasing neutrophil recruitment, generation of ROS and production of pro-inflammatory cytokines. The few attempts to study if cotrimoxazole therapy could prompt favourable outcome in Covid-19 have been quite promising.  In view of the above, we contemplate to undertake a randomized controlled trial in order to investigate if oral cotrimoxazole therapy instituted early in hospitalised Covid-19 patients could prevent transition of the disease to a severe or critical stage. Study Hypothesis: Our hypothesis is that use of oral cotrimoxazole in early stages (window of opportunity) of COVID-19 moderate to early-severe pneumonia can prevent ‘higher’ oxygenation requirements through non-invasive and invasive mechanical ventilation, and decrease in-hospital stays as well as death rate.