Targeting de Novo Pyrimidine Biosynthesis by Leflunomide for the Treatment of COVID-19 Virus Disease

NCT05007678 | Completed Phase 3 DMC

• 1 other identifier: 2020ZC01
• Study Type: interventional
• Target: 178
• Locations: 1 country
• Sites: 1

Brief Summary

The global COVID-19 pandemic has caused unprecedented strain on health care services around the world.The absence of specific anti-viral medications to treat the underlying infection led to a proliferation of clinical studies and trials aimed at re-purposing existing medications. Human dihydroorotate dehydrogenase (DHODH) is vital enzyme utilised by viruses to replicate in the host cell. Leflunomide, a drug that is already licenced to treat rheumatoid arthritis, is a potent inhibitor of the enzyme DHODH. Importantly, this drug has dual anti-viral and anti-inflammatory properties so it targets viral replication and suppresses host inflammatory response which plays a role at more progressive stages of infection. DEFEAT-COVID is a multi-site, international, interventional, pragmatic, parallel group design, open label, randomised CTIMP with a pilot phase that will allow to adapt procedures and assessments if required. A phase III clinical trial of leflunomide for treating COVID-19 has been registered in China, Registration number: ChiCTR2000030058). The current proposal extends the original clinical study of leflunomide in China (People's Hospital of Wuhan University) to the UK through a structured collaboration.

Conditions

COVID-19

Keywords

COVID-19; Leflunomide; Acute emergency care

Outcome Measures

Primary Outcomes (2)

• Time to clinical improvement

  TTCI is defined as the time (in days) from initiation of trial treatment (for participants in the treatment arm), or day of randomisation (for participants in the control arm), until the first occurrence of; 1. an improvement of two points on a seven-category ordinal scale of clinical status categories.All surviving patients who have not reached any TTCI ordinal level by Day 28 will be right-censored at that point. 2. live discharge from hospital.

  28 days from randomisation

• Incidence of adverse events

  All adverse events within 28 days will be recorded and incidence of serious adverse events (SAEs) and Grade 3 and 4 adverse events (AEs)\* will be reported. \*Grade 3 adverse events: Severe or medically significant but not immediately life-threatening; or hospitalisation or prolongation of hospitalisation indicated; or disabling; or limiting self-care activity of daily living. Grade 4 Life-threatening consequences; urgent intervention indicated.

  28 days from randomisation

Secondary Outcomes (14)

• Changes in virological load over time

  Days 0/1, 7,11 and 15 days post randomisation

• Time to hospital discharge

  Daily assessments during hospitalisation up to 28 days or discharge

• All-cause mortality

  From randomisation to the event within 28 days

• Duration of intensive care stay

  From randomisation to 28 days or discharge

• Duration of invasive and non-invasive ventilation

  From randomisation to discharge or 28 days

Other Outcomes (1)

• Evaluation of patient reported symptoms in follow up

  30 and 90 days after discharge

Study Arms (2)

Standard of Care

NO INTERVENTION

The usual care will be offered as per current advice on management of hospitalised patients.

leflunomide

ACTIVE COMPARATOR

Patients admitted to the hospital COVID-19 positive and within 2 weeks of symptoms' onset will be treated with loading dose of 100 mg leflunomide for 3 days, followed by 20 mg once daily. Participants with ALT/AST levels 2 times above upper limits of normal reference range will receive 10mg instead of 20mg.

Drug: leflunomide

Interventions

leflunomide DRUG

leflunomide administered orally; daily loading dose of 100mg for 3 days, followed by a daily maintenance dose 10-20mg daily, to a total course of 10 days

leflunomide

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥18 years,
• Patients with onset of symptoms \>15 days,
• Laboratory (RT-PCR) confirmed infection with 2019-nCoV.

You may not qualify if:

• Pregnant or breast feeding,
• On specific monoclonal antibodies, or other drug trial treatment for COVID-19 within one week prior to study enrolment,
• Liver function tests \>2 fold of upper limits of normal (ULN) reference levels of the respective testing assay,
• Patients with known hypersensitivity to leflunomide,
• Patients with severe immunodeficiency syndrome and hypoalbuminaemia.

Sponsors & Collaborators

• Ashford and St. Peter's Hospitals NHS Trust: lead

Study Sites (1)

Ashford and St Peters Hospital NHS Foundation Trust

Chertsey, KT16 0PZ, United Kingdom

Location

Related Publications (1)

• 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 JD, Li L, Seshasai SRK, Li HL, Marczin N, Chen Z; DEFEAT-COVID Investigators. Leflunomide treatment for patients hospitalised with COVID-19: DEFEAT-COVID randomised controlled trial. BMJ Open. 2023 Apr 13;13(4):e068179. doi: 10.1136/bmjopen-2022-068179.

  PMID: 37055207 DERIVED

MeSH Terms

Conditions

COVID-19

Interventions

Leflunomide

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Isoxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Zhong Chen, CI

  Ashford and St Peters Hospital NHS Foundation Trust

  STUDY CHAIR

• Isaac John

  Ashford and St Peters Hospital NHS Foundation Trust

  STUDY DIRECTOR

• Sharma Shashank, PI

  Ashford and St Peters Hospital NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomised

Study Record Dates

• First Submitted: July 16, 2021
• First Posted: August 16, 2021
• Study Start: September 16, 2020
• Primary Completion: July 1, 2022
• Study Completion: July 1, 2022
• Last Updated: February 27, 2023

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Within 2 years from publication of the main results
• Access Criteria: The anonymized data may be made available upon request following approval from the Trial Management Group and the Sponsor.

Locations

GB (1)