Targeting de Novo Pyrimidine Biosynthesis by Leflunomide as a Novel Concept for the Treatment of Corona Virus Disease 2019 (COVID-19)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 178
- 试验地点
- 1
- 主要终点
- Incidence of adverse events
研究概览
简要总结
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.
详细描述
Leflunomide is a potent inhibitor of the enzyme DHODH and is already licenced to treat rheumatoid arthritis. Importantly, this drug has dual anti-viral and anti-inflammatory properties which is advantageous in COVID-19 infected patients, as more progressive stages of the disease involve augmented responses from the host inflammatory mechanisms leading to serious complications and death.
Based on the current understanding of the pathogenesis of COVID-19 infection and its spectrum of clinical manifestation it is evident that a significant proportion of those infected develop pneumonia, systemic inflammatory response and cardiovascular complications with high morbidity and mortality. The progression from initial mild symptoms (usually fever, fatigue and cough) to severe pneumonia requiring oxygen support or mechanical ventilation often takes one to two weeks after the onset of symptoms. The progression leading to a such deterioration is thought to be related to the kinetics of viral replication culminating in an exaggerated surge in inflammatory mediator release, called "cytokine storm".
Host-targeting antiviral (HTA) strategies have many advantages to fight against a broad spectrum of viruses compared to direct-acting antiviral drugs. These include blocking the viral replication and overcoming the potential of viral mutagenesis simultaneously.
Concept The quest for optimal HTA strategies enabled the investigators to identify a crucial enzyme called human dihydroorotate dehydrogenase (DHODH) that limits pyrimidine synthesis. This is a vital metabolic process utilised by viruses for replication.
In preclinical models of cell and animal infection by SARS-CoV-2 the DHODH inhibitors exhibited multiple actions including attenuation of viral genome replication, suppression of the inflammatory reaction and the release of pro-inflammatory cytokines and chemokine. These drugs also offered protection against mortality in mice when administered at later stages of infection when direct acting antivirals offered no survival benefit. The hypothesis is that DHODH inhibitors may have the advantage in treatment of COVID-19 disease even at its advanced stage compared to the drugs with either standalone anti-viral or anti-inflammatory properties.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥18 years,
- •Patients with onset of symptoms >15 days,
- •Laboratory (RT-PCR) confirmed infection with 2019-nCoV.
排除标准
- •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.
研究组 & 干预措施
leflunomide
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.
干预措施: leflunomide (Drug)
结局指标
主要结局
Incidence of adverse events
时间窗: 28 days from randomisation
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.
Time to clinical improvement
时间窗: 28 days from randomisation
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.
次要结局
- Time to hospital discharge(Daily assessments during hospitalisation up to 28 days or discharge)
- Incidence of re-intubation(From randomisation to 28 days or discharge)
- Evaluation of surrogate of inflammation and lung recovery(Daily measurements from randomisation to discharge or 28 days)
- Incidence of acute kidney injury(From randomisation to discharge or 28 days)
- Need for renal replacement therapy(From randomisation to discharge or 28 days)
- Characterisation of biomarkers including high sensitivity CRP, ferritin, procalcitonin, troponin, BNP, creatinine and kidney biomarkers.(Daily measurements during hospitalisation to 28 days or discharge)
- All-cause mortality(From randomisation to the event within 28 days)
- Degree of acute lung injury(At baseline, 15 and 28 days or discharge)
- Changes in virological load over time(Days 0/1, 7,11 and 15 days post randomisation)
- Incidence of inotropic/vasoactive support(From randomisation to discharge or 28 days)
- Duration of invasive and non-invasive ventilation(From randomisation to discharge or 28 days)
- Duration of intensive care stay(From randomisation to 28 days or discharge)
- Incidence of tracheostomy(From randomisation to 28 days or discharge)
- Changes in cytokine profile including pro- and anti-inflammatory cytokines(Days 0, 1, 3 and 11)