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Leflunomide treatment for patients hospitalised with COVID-19: DEFEAT-COVID randomised controlled trial

Kralj-Hans, I., Li, K., Wesek, A. , Lamorgese, A., Omar, F., Ranasinghe, K., McGee, M., Brack, K., Li, S., Aggarwal, R., Bulle, A., Kodre, A., Sharma, S., Fluck, D., John, I., Sharma, P., Belsey, J. D., Li, L. ORCID: 0000-0002-4026-0216, Seshasai, S. R. K., Li, H. L., Marczin, N. & Chen, Z. (2023). Leflunomide treatment for patients hospitalised with COVID-19: DEFEAT-COVID randomised controlled trial. BMJ Open, 13(4), article number e068179. doi: 10.1136/bmjopen-2022-068179


To evaluate the clinical efficacy and safety of leflunomide (L) added to the standard-of-care (SOC) treatment in COVID-19 patients hospitalised with moderate/critical clinical symptoms.

Prospective, open-label, multicentre, stratified, randomised clinical trial.

Five hospitals in UK and India, from September 2020 to May 2021.

Adults with PCR confirmed COVID-19 infection with moderate/critical symptoms within 15 days of onset.

Leflunomide 100 mg/day (3 days) followed by 10–20 mg/day (7 days) added to standard care.

Primary outcomes
The time to clinical improvement (TTCI) defined as two-point reduction on a clinical status scale or live discharge prior to 28 days; safety profile measured by the incidence of adverse events (AEs) within 28 days.

Eligible patients (n=214; age 56.3±14.9 years; 33% female) were randomised to SOC+L (n=104) and SOC group (n=110), stratified according to their clinical risk profile. TTCI was 7 vs 8 days in SOC+L vs SOC group (HR 1.317; 95% CI 0.980 to 1.768; p=0.070). Incidence of serious AEs was similar between the groups and none was attributed to leflunomide. In sensitivity analyses, excluding 10 patients not fulfilling the inclusion criteria and 3 who withdrew consent before leflunomide treatment, TTCI was 7 vs 8 days (HR 1.416, 95% CI 1.041 to 1.935; p=0.028), indicating a trend in favour of the intervention group. All-cause mortality rate was similar between groups, 9/104 vs 10/110. Duration of oxygen dependence was shorter in the SOC+L group being a median 6 days (IQR 4–8) compared with 7 days (IQR 5–10) in SOC group (p=0.047).

Leflunomide, added to the SOC treatment for COVID-19, was safe and well tolerated but had no major impact on clinical outcomes. It may shorten the time of oxygen dependence by 1 day and thereby improve TTCI/hospital discharge in moderately affected COVID-19 patients.

Publication Type: Article
Additional Information: © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Subjects: H Social Sciences > HN Social history and conditions. Social problems. Social reform
Q Science > QR Microbiology > QR180 Immunology
R Medicine > RA Public aspects of medicine > RA0421 Public health. Hygiene. Preventive Medicine
R Medicine > RC Internal medicine
Departments: School of Science & Technology > Engineering
SWORD Depositor:
[thumbnail of 20230421 bmjopen-2022-068179.pdf]
Text - Published Version
Available under License Creative Commons Attribution Non-commercial.

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