Randomised Multi-arm Trial of Ruxolitinib (RUX) and Fostamatinib (FOS) for COVID-19 Pneumonia
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 185
- 试验地点
- 5
- 主要终点
- Progression from mild to severe COVID-19 pneumonia within 14 days in hospitalised patients
研究概览
简要总结
The Multi-arm trial of Inflammatory Signal Inhibitors for COVID-19 (MATIS) study is a two-stage, open-label, randomised controlled trial assessing the efficacy of ruxolitinib (RUX) and fostamatinib (FOS) individually, compared to standard of care in the treatment of COVID-19 pneumonia. The primary outcome is the proportion of hospitalised patients progressing from mild or moderate to severe COVID-19 pneumonia. Patients are treated for 14 days and will receive follow-up assessment at 7, 14 and 28 days after the first study dose. Patients with mild or moderate COVID-19 pneumonia will be recruited. Initially, n=171 (57 per arm) patients will be recruited in Stage 1. Following interim analysis to assess the efficacy and safety of the treatments, approximately n=285 (95 per arm) will be recruited during Stage 2.
详细描述
COVID-19 pneumonia is characterised by respiratory and multi-organ failure in the context of marked systemic inflammation. It is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV2) infection. The hallmark of severe disease is hypoxia and a radiological pattern of acute lung injury that shares features with Acute Respiratory Distress Syndrome (ARDS). Early features of COVID-19 result from host viral response and typically include symptoms such as fever and dry cough. Later features, typically occurring beyond 7 days, are characterised by marked and progressive systemic inflammation, identified by elevations in a plethora of inflammatory molecules such as C-reactive protein, ferritin and IL6. In a subset of patients, hyperinflammatory responses drive acute lung injury and may result in catastrophic multi-organ failure and death.
The aetiology of COVID-19 induced ARDS is incompletely understood but appears to be associated with lung inflammation effected by a monocytic and neutrophilic infiltration, elevated cytokine levels and tissue damage. Elevations in circulating inflammatory molecules are associated with poor prognosis. In particular, the COVID-19 hyperinflammatory response syndrome is associated thrombotic complications which are postulated to drive cardiac dysfunction and microvascular thrombi, suggested by elevations in troponin and D-dimer, respectively. Similar hyperinflammatory responses are also seen in macrophage activation syndromes such as haemophagocytic lymphohistiocytosis, or in the cytokine release syndrome associated with chimeric antigen receptor T cell therapy. Further, preliminary data from China and Italy have shown immediate resolution of symptoms using anti-interleukin-6 agents (anti-IL6) therapy and Janus kinase inhibitors (JAK)/signal transducer and activator of transcription (STAT) inhibitors in patients with severe disease. There may be an early window of opportunity to treat the COVID-19 hyperinflammatory syndrome before acute lung injury leads to organ failure.
There are currently no approved treatments for COVID-19 pneumonia. This is a protocol for a randomised controlled, multi-arm trial of early intervention with inflammatory signal inhibitors.
Study purpose
A number of therapeutic interventions targeting inflammatory signalling might reduce the severity of the inflammatory response phase resulting in amelioration of the lung damage thereby averting respiratory failure and the need for mechanical ventilation. This trial aims to evaluate the efficacy of two inhibitors of key signalling pathways using drugs which are already licensed for use in other clinical indications.
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
- Single (Outcomes Assessor)
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
- •Patients age ≥ 18 years at screening
- •Patients with mild or moderate C19 pneumonia, defined as Grade 3 or 4 severity by the WHO COVID-19 Ordinal Scale by
- •Patients meeting criteria: Hospitalization AND SARS-CoV2 infection (clinically suspected* or laboratory-confirmed) AND Radiological change consistent with COVID-19 disease
- •C-reactive protein (CRP) greater than or equal to 30mg/L
- •Informed consent from patient or personal or professional representative
- •No medical history that might, in the opinion of the responsible clinician, put the patient at significant risk if he/she were to participate in the trial
- •Agreement to abstain from sexual intercourse or use contraception that is >99% effective for all participants of childbearing potential for 42 days after the last dose of study drug. For male participants, agreement to abstain from sperm donation for 42 days after the last dose of study drug.
- •Able to read English. Non-English speakers will be able to join the study. If patients are unable to understand verbal or written information in English - hospital translation services will be requested at the participating site for the participant where possible.
排除标准
- •Requiring either invasive or non-invasive ventilation including CPAP or high flow nasal oxygen at any point after hospital admission and before baseline not related to a pre-existing condition (e.g. obstructive sleep apnoea)
- •Grade ≥ 5 severity on the modified WHO COVID-19 Ordinal Scale, viz. O2 saturation < 90% on ≥ 60% inspired oxygen at baseline; non-invasive ventilation; or invasive mechanical ventilation at any point since hospital admission.
- •In the opinion of the investigator, progression to death is inevitable within the next 24 hours, irrespective of the provision of therapy
- •Known severe allergic reactions to the investigational agents
- •Child Pugh B or C grade hepatic dysfunction
- •Use of drugs within the preceding 14 days that are known to interact with any study treatment (FOS or RUX), as listed in the Summary of Product Characteristics
- •Pregnant or breast feeding
- •Any medical condition or concomitant medication that in the opinion of the investigator would compromise subjects' safety or compliance with study procedures.
- •Any medical condition which in the opinion of the principal investigator would compromise the scientific integrity of the study
- •Pregnant or breast feeding
研究组 & 干预措施
Standard of care
干预措施: Standard of care (Other)
Fostamatinib
干预措施: Fostamatinib (Drug)
Ruxolitinib
干预措施: Ruxolitinib (Drug)
结局指标
主要结局
Progression from mild to severe COVID-19 pneumonia within 14 days in hospitalised patients
时间窗: Day 14
Patients are recruited at a WHO COVID-19 Severity Score of 3 and 4 and the primary endpoint is the comparison of patients whose COVID-19 pneumonia progresses to a severity score ≥ 5 on the modified WHO Ordinal Scale. Specifically, the primary endpoint is met when the following are recorded within 14 days: * Death * Requirement for invasive ventilation * Requirement for non-invasive ventilation including CPAP or high flow nasal oxygen * O2 saturation \< 90% on ≥60% inspired oxygen
次要结局
- Mortality(Day 28)
- Invasive ventilation(Day 28)
- Non-invasive ventilation including CPAP and high flow nasal oxygen(Day 28)
- Renal replacement therapy(Day 28)
- Venous Thromboembolism(Day 28)
- Serum Creatinine(Day 28)
- Length of stay(Day 28)
- Serious Adverse Events(Day 28)
- Serious Adverse Reactions(Day 28)
- Treatment discontinuation(Day 14)
- Change in severity from the modified WHO COVID-19 ordinal scale(Day 28)
- C-Reactive protein(Day 28)
- lactate dehydrogenase(Da 28)
- ferritin(Da 28)
- d-dimer(Day 28)