PMID- 37055207
OWN - NLM
STAT- MEDLINE
DCOM- 20230417
LR  - 20230423
IS  - 2044-6055 (Electronic)
IS  - 2044-6055 (Linking)
VI  - 13
IP  - 4
DP  - 2023 Apr 13
TI  - Leflunomide treatment for patients hospitalised with COVID-19: DEFEAT-COVID 
      randomised controlled trial.
PG  - e068179
LID - 10.1136/bmjopen-2022-068179 [doi]
LID - e068179
AB  - 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.
CI  - (c) 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.
FAU - Kralj-Hans, Ines
AU  - Kralj-Hans I
AUID- ORCID: 0000-0001-7401-6281
AD  - Ashford and Saint Peter's Hospitals NHS Trust, Chertsey, UK i.kralj-hans@nhs.net.
FAU - Li, Kuo
AU  - Li K
AD  - Imperial College, London, UK.
FAU - Wesek, Adrian
AU  - Wesek A
AD  - Imperial College, London, UK.
FAU - Lamorgese, Alexia
AU  - Lamorgese A
AD  - JB Medical Ltd, Sudbury, UK.
FAU - Omar, Fatima
AU  - Omar F
AD  - Ashford and Saint Peter's Hospitals NHS Trust, Chertsey, UK.
FAU - Ranasinghe, Kapila
AU  - Ranasinghe K
AD  - Ashford and Saint Peter's Hospitals NHS Trust, Chertsey, UK.
FAU - McGee, Megan
AU  - McGee M
AD  - Ashford and Saint Peter's Hospitals NHS Trust, Chertsey, UK.
FAU - Brack, Kieran
AU  - Brack K
AD  - Ashford and Saint Peter's Hospitals NHS Trust, Chertsey, UK.
FAU - Li, Shiliang
AU  - Li S
AD  - East China University of Science and Technology, Shanghai, China.
FAU - Aggarwal, Ritesh
AU  - Aggarwal R
AD  - Max Hospital, Delhi, India.
FAU - Bulle, Ajay
AU  - Bulle A
AD  - Meditrina Institute of Medical Science, Nagpur, India.
FAU - Kodre, Aparna
AU  - Kodre A
AD  - Noble Hospital, Pune, India.
FAU - Sharma, Shashank
AU  - Sharma S
AD  - St Peters Hospital Emergency Department, Ashford and Saint Peter's Hospitals NHS 
      Trust, Chertsey, UK.
FAU - Fluck, David
AU  - Fluck D
AD  - Cardiology, Ashford and Saint Peter's Hospitals NHS Trust, Chertsey, UK.
FAU - John, Isaac
AU  - John I
AD  - Ashford and Saint Peter's Hospitals NHS Trust, Chertsey, UK.
FAU - Sharma, Pankaj
AU  - Sharma P
AD  - Royal Holloway University of London, Egham, UK.
FAU - Belsey, Jonathan D
AU  - Belsey JD
AD  - JB Medical Ltd, Sudbury, UK.
FAU - Li, Ling
AU  - Li L
AUID- ORCID: 0000-0002-4026-0216
AD  - Department of Engineering, City University, London, UK.
FAU - Seshasai, Sreenivasa Rao Kondapally
AU  - Seshasai SRK
AD  - St George's University Hospitals NHS Foundation Trust, London, UK.
FAU - Li, Hong Lin
AU  - Li HL
AD  - Shanghai Key Laboratory of New Drug Design, Shanghai, China.
FAU - Marczin, Nandor
AU  - Marczin N
AD  - Imperial College, London, UK.
FAU - Chen, Zhong
AU  - Chen Z
AD  - Ashford and Saint Peter's Hospitals NHS Trust, Chertsey, UK.
CN  - DEFEAT-COVID Investigators
LA  - eng
SI  - ClinicalTrials.gov/NCT05007678
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20230413
PL  - England
TA  - BMJ Open
JT  - BMJ open
JID - 101552874
RN  - G162GK9U4W (Leflunomide)
RN  - ICJ93X8X90 (canertinib dihydrochloride)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - Adult
MH  - Humans
MH  - Female
MH  - Middle Aged
MH  - Aged
MH  - Male
MH  - *COVID-19
MH  - Leflunomide/therapeutic use
MH  - SARS-CoV-2
MH  - Prospective Studies
MH  - Treatment Outcome
MH  - Oxygen
PMC - PMC10105917
OTO - NOTNLM
OT  - COVID-19
OT  - INFECTIOUS DISEASES
OT  - Respiratory infections
COIS- Competing interests: None declared.
FIR - Sharma, Shashank
IR  - Sharma S
FIR - McGee, Megan
IR  - McGee M
FIR - Brack, Kieran
IR  - Brack K
FIR - Aquino, Maia
IR  - Aquino M
FIR - Pereira, Rita
IR  - Pereira R
FIR - Frost, Vicky
IR  - Frost V
FIR - Gibson, Kirsty
IR  - Gibson K
FIR - Croft, Maria
IR  - Croft M
FIR - Omar, Fatima
IR  - Omar F
FIR - Ranasinghe, Kapila
IR  - Ranasinghe K
FIR - Mahendran, Siva
IR  - Mahendran S
FIR - Joseph, Anna
IR  - Joseph A
FIR - Grout, Maggie
IR  - Grout M
FIR - Dewan, Arun
IR  - Dewan A
FIR - Aggarwal, Ritesh
IR  - Aggarwal R
FIR - Bulle, Ajay
IR  - Bulle A
FIR - Kodre, Aparna
IR  - Kodre A
EDAT- 2023/04/14 06:00
MHDA- 2023/04/17 06:41
PMCR- 2023/04/13
CRDT- 2023/04/13 21:42
PHST- 2023/04/17 06:41 [medline]
PHST- 2023/04/13 21:42 [entrez]
PHST- 2023/04/14 06:00 [pubmed]
PHST- 2023/04/13 00:00 [pmc-release]
AID - bmjopen-2022-068179 [pii]
AID - 10.1136/bmjopen-2022-068179 [doi]
PST - epublish
SO  - BMJ Open. 2023 Apr 13;13(4):e068179. doi: 10.1136/bmjopen-2022-068179.