Randomized Double-Blind Placebo-Controlled Trial on the Safety and Efficacy of Imatinib for Hospitalized Adults With COVID-19
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 21
- 试验地点
- 1
- 主要终点
- The proportion of patients with a two-point change using the 8-category ordinal scale
研究概览
简要总结
This study is a randomized Double-Blind Placebo-Controlled Trial on the Safety and Efficacy of Imatinib for Hospitalized Adults with COVID-19
详细描述
Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and at present with no approved or proven antiviral treatment.
Imatinib is a tyrosine kinase inhibitor that has been approved for treatment of many hematologic and solid neoplasm. Imatinib is a weak base that compared to the extracellular compartment is enriched over 1000-fold in the lysosome within several hours as a result of its lysosomotropic property. Imatinib as a weak base accumulates in lysosomes resulting in some antiviral activities by lysosomal alkalization required for virus/cell fusion.
Imatinib demonstrates in vitro activity against SARS-CoV viruses. Imatinib inhibit SARS-CoV and MERS-CoV with micromolar EC50s (range, 9.8 to 17.6 μM) with low toxicity. The mechanism of action studies suggested that ABL-1 tyrosine kinase regulates budding or release of poxviruses and Ebola virus, demonstrating that the c-ABL-1 kinase signaling pathways play an important role in the egress of these viruses. It is also reported that kinase signaling may also be important for replication of two members of the Coronaviridae family, SARS-CoV and MERS-CoV. In vivo studies performed in the mouse model of vaccinia virus infection showed that imatinib was effective in blocking dissemination of the virus.
Imatinib has anti-inflammatory activity including its effectiveness in a "two-hit" murine model of acute lung injury (ALI) caused by combined lipopolysaccharide (LPS) and ventilator-induced lung injury (VILI). Imatinib significantly decreased bronchoalveolar lavage protein, total cells, neutrophils, and TNFα levels in mice exposed to LPS plus VILI, indicating that it attenuates ALI in this clinically relevant model. In another experiment, imatinib attenuated ALI when given 4 hours after LPS, suggesting potential efficacy when given after the onset of injury. Overall, these results strongly suggest the therapeutic potential of imatinib against inflammatory vascular leak and a potential role of imatinib combination therapy for patients with acute respiratory distress syndrome (ARDS) on mechanical ventilation.
The investigators hypothesize that addition of imatinib to the best conventional care (BCC) improves the outcome of hospitalized adult patients with COVID-19. This hypothesis is on the bases of 1) intralysosomal entrapment of imatinib will increase endosomal pH and effectively decrease SARS-CoV-2/cell fusion, 2) kinase inhibitory activity of imatinib will interfere with budding/release or replication of SARS-CoV-2, and 3) because of the critical role of mechanical ventilation in the care of patients with ARDS, imatinib will have a significant clinical impact for patients with severe COVID-19 infection in Intensive Care Unit (ICU).
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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Imatinib
Imatinib oral 400 mg daily for 14 days.
干预措施: Imatinib (Drug)
Placebo
Placebo oral for 14 days
干预措施: Placebo oral tablet (Drug)
结局指标
主要结局
The proportion of patients with a two-point change using the 8-category ordinal scale
时间窗: Day 14 from baseline
The ordinal scale is an evaluation of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 5) Hospitalized, requiring supplemental oxygen; 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 8) Death.
次要结局
- All-Cause mortality(Day 28 and Day 60 post baseline)
- Hospitalization(Up to 60 days post baseline)
- Duration of ICU stay(Up to 60 days post baseline)
- SARS-CoV-2 negative(Up to 60 days post baseline)
- Duration of ECMO or invasive mechanical ventilation(Up to 60 days post baseline)
- Time to a 2-point clinical change(Up to 60 days post baseline)
- Negative oropharyngeal or nasopharyngeal swab(Up to 28 days post baseline)
- Serious adverse events (SAEs)(Up to 60 days post baseline)
- Discontinuation due to adverse events(Up to 60 days post baseline)