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

Abstract

Objective: 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.

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

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

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

Intervention: 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.

Results: 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).

Conclusion: 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.

Trial registration numbers: EudraCT Number: 2020-002952-18, NCT05007678.

Keywords: COVID-19; INFECTIOUS DISEASES; Respiratory infections.

Figure 1

Randomisation, treatment assignment and follow-up of study participants. Immunotherapy included tocilizumab, bevacizumab and interferon alpha and beta. ITT, intention to treat; SOC, standard of care.

Figure 2

Time to clinical improvement of two points on a clinical status scale or discharge prior 28 days in a stratified ITT analysis (primary outcome). Patients who died were censored at the time their death occurred, while all surviving patients who did not reach TTCI criteria by day 28 were right censored at that point. Most of the patients were discharged within the first 10 days of admission. ITT, intention to treat; SOC, standard of care; TTCI, time to clinical improvement.

Figure 3

Cumulative all-cause mortality (A) oxygen dependence (B) by 28 days. SOC, standard of care.

Figure 4

Mean changes in log10 viral load (copies/mL) from baseline. Error bars represent SE. Numbers in the bars represent the number of samples available for measurements. SOC, standard of care.