Background

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.

Methods

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.

Findings

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.

Interpretation

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.

Funding

UK Research and Innovation (Medical Research Council) and National Institute of Health Research.

中文翻译：

---

巴瑞克替尼治疗住院的 COVID-19 患者（恢复）：一项随机、对照、开放标签的平台试验和更新的荟萃分析

背景

我们的目的是评估巴瑞克替尼（一种 Janus 激酶 (JAK) 1-2 抑制剂）在治疗住院的 COVID-19 患者中的用途。

方法

这项随机、对照、开放标签的平台试验（COVID-19 治疗的随机评估 [RECOVERY]）正在评估在英国住院的 COVID-19 患者的多种可能的治疗方法。符合条件且同意的患者被随机分配 (1:1) 至单独常规标准护理组（常规护理组）或常规护理加巴瑞克替尼 4 mg，每天口服一次，持续 10 天，或直至出院（如果较早出院）（巴瑞克替尼组）。主要结局是意向治疗人群的 28 天死亡率评估。进行了一项荟萃分析，其中包括 RECOVERY 试验以及之前所有针对 COVID-19 住院患者使用巴瑞替尼或其他 JAK 抑制剂的随机对照试验的结果。RECOVERY 试验已在 ISRCTN (50189673) 和 ClinicalTrials.gov (NCT04381​​936) 注册，并且正在进行中。

发现

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巴瑞克替尼与单独接受常规治疗。随机分组时，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（另外 9% 的患者计划在接下来的 24 小时内使用）。总体而言，分配至巴瑞替尼治疗的 4148 名患者中有 514 名患者 (12%) 在 28 天内死亡，而分配至常规治疗的 4008 名患者中有 546 名患者 (14%) 在 28 天内死亡（年龄调整比率 0·87；95% CI 0·77–0·99） ；p=0·028)。这 13% 的死亡率下降比例略小于之前 8 项 JAK 抑制剂试验（涉及 3732 名患者和 425 例死亡）的荟萃分析中所见的结果，其中分配给 JAK 抑制剂与 43% 的死亡率下降相关死亡率（比率 0·57；95% CI 0·45–0·72）。将 RECOVERY 的结果纳入所有 9 项已完成试验（涉及 11 888 名随机分配的患者和 1485 名死亡患者）的更新荟萃分析中，分配给巴瑞替尼或另一种 JAK 抑制剂与死亡率按比例降低 20% 相关（比率 0·80） ；95% CI 0·72–0·89；p<0·0001）。在恢复阶段，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。

解释

在因 COVID-19 住院的患者中，巴瑞克替尼显着降低了死亡风险，但获益程度略小于之前试验所建议的水平。迄今为止的全部随机证据表明，JAK 抑制剂（主要是巴瑞替尼）可将因 COVID-19 住院的患者死亡率降低约五分之一。

资金

英国研究与创新（医学研究委员会）和国家健康研究所。