Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial and updated meta-analysis.
Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial and updated meta-analysis.
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DOI：
10.1016/s0140-6736(22)01109-6
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发表时间：
2022-07-30
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我们旨在评估baricitinib（Janus激酶（JAK）1-2抑制剂）用于治疗因COVID-19住院的患者的用途。这项随机、对照、开放标签、平台试验（COVID-19治疗的随机评价[RECOVERY]）正在评估英国因COVID-19住院患者的多种可能治疗方法。合格且知情同意的患者被随机分配（1：1）至仅常规标准治疗组（常规治疗组）或常规治疗加baricitinib 4 mg每日一次口服，持续10天或直至出院（baricitinib组）。主要结局是在意向治疗人群中评估的28天死亡率。进行了荟萃分析，其中包括RECOVERY试验和所有先前在COVID-19住院患者中进行的baricitinib或其他JAK抑制剂的随机对照试验的结果。RECOVERY试验已在ISRCTN（50189673）和ClinicalTrials.gov（NCT 04381936）注册，目前正在进行中。在2021年2月2日至12月29日期间，从10852名入组患者中，8156名患者被随机分配接受常规治疗加baricitinib与单独常规治疗。 随机化时，95%的患者正在接受皮质类固醇治疗，23%的患者正在接受托珠单抗治疗（另有9%的患者计划在未来24小时内使用）。总体而言，4148例接受baricitinib治疗的患者中有514例（12%）在28天内死亡，而4008例接受常规治疗的患者中有546例（14%）在28天内死亡（年龄校正率比为0.87; 95% CI为0.77 - 0.99; p= 0.028）。这13%的死亡率降低比例略低于先前8项JAK抑制剂试验（涉及3732例患者和425例死亡）的荟萃分析，其中分配至JAK抑制剂与死亡率降低43%的比例相关（率比0.57; 95%CI 0.45 - 0.72）。在对所有9项已完成的试验（涉及11888例随机分配的患者和1485例死亡）进行的更新荟萃分析中，纳入RECOVERY的结果，将其分配给baricitinib或另一种JAK抑制剂，死亡率按比例降低20%（率比0.80; 95%CI 0.72 - 0.89; p<0.0001）。 在恢复期，由于非COVID-19原因导致的死亡或感染没有显着增加，血栓形成或其他安全结果也没有显着增加。在因COVID-19住院的患者中，baricitinib显著降低了死亡风险，但获益的大小略小于先前试验的结果。迄今为止的全部随机证据表明，JAK抑制剂（主要是baricitinib）可将因COVID-19住院患者的死亡率降低约五分之一。英国研究和创新（医学研究理事会）和国家健康研究所。
We aimed to evaluate the use of baricitinib, a Janus kinase (JAK) 1–2 inhibitor, for the treatment of patients admitted to hospital with COVID-19. This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple possible treatments in patients hospitalised with COVID-19 in the UK. Eligible and consenting patients were randomly allocated (1:1) to either usual standard of care alone (usual care group) or usual care plus baricitinib 4 mg once daily by mouth for 10 days or until discharge if sooner (baricitinib group). The primary outcome was 28-day mortality assessed in the intention-to-treat population. A meta-analysis was done, which included the results from the RECOVERY trial and all previous randomised controlled trials of baricitinib or other JAK inhibitor in patients hospitalised with COVID-19. The RECOVERY trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936) and is ongoing. Between Feb 2 and Dec 29, 2021, from 10 852 enrolled, 8156 patients were randomly allocated to receive usual care plus baricitinib versus usual care alone. At randomisation, 95% of patients were receiving corticosteroids and 23% were receiving tocilizumab (with planned use within the next 24 h recorded for a further 9%). Overall, 514 (12%) of 4148 patients allocated to baricitinib versus 546 (14%) of 4008 patients allocated to usual care died within 28 days (age-adjusted rate ratio 0·87; 95% CI 0·77–0·99; p=0·028). This 13% proportional reduction in mortality was somewhat smaller than that seen in a meta-analysis of eight previous trials of a JAK inhibitor (involving 3732 patients and 425 deaths), in which allocation to a JAK inhibitor was associated with a 43% proportional reduction in mortality (rate ratio 0·57; 95% CI 0·45–0·72). Including the results from RECOVERY in an updated meta-analysis of all nine completed trials (involving 11 888 randomly assigned patients and 1485 deaths) allocation to baricitinib or another JAK inhibitor was associated with a 20% proportional reduction in mortality (rate ratio 0·80; 95% CI 0·72–0·89; p<0·0001). In RECOVERY, there was no significant excess in death or infection due to non-COVID-19 causes and no significant excess of thrombosis, or other safety outcomes. In patients hospitalised with COVID-19, baricitinib significantly reduced the risk of death but the size of benefit was somewhat smaller than that suggested by previous trials. The total randomised evidence to date suggests that JAK inhibitors (chiefly baricitinib) reduce mortality in patients hospitalised for COVID-19 by about one-fifth. UK Research and Innovation (Medical Research Council) and National Institute of Health Research.