Background

Baricitinib is an oral selective Janus kinase 1/2 inhibitor with known anti-inflammatory properties. This study evaluates the efficacy and safety of baricitinib in combination with standard of care for the treatment of hospitalised adults with COVID-19.

Methods

In this phase 3, double-blind, randomised, placebo-controlled trial, participants were enrolled from 101 centres across 12 countries in Asia, Europe, North America, and South America. Hospitalised adults with COVID-19 receiving standard of care were randomly assigned (1:1) to receive once-daily baricitinib (4 mg) or matched placebo for up to 14 days. Standard of care included systemic corticosteroids, such as dexamethasone, and antivirals, including remdesivir. The composite primary endpoint was the proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28, assessed in the intention-to-treat population. All-cause mortality by day 28 was a key secondary endpoint, and all-cause mortality by day 60 was an exploratory endpoint; both were assessed in the intention-to-treat population. Safety analyses were done in the safety population defined as all randomly allocated participants who received at least one dose of study drug and who were not lost to follow-up before the first post-baseline visit. This study is registered with ClinicalTrials.gov, NCT04421027.

Findings

Between June 11, 2020, and Jan 15, 2021, 1525 participants were randomly assigned to the baricitinib group (n=764) or the placebo group (n=761). 1204 (79·3%) of 1518 participants with available data were receiving systemic corticosteroids at baseline, of whom 1099 (91·3%) were on dexamethasone; 287 (18·9%) participants were receiving remdesivir. Overall, 27·8% of participants receiving baricitinib and 30·5% receiving placebo progressed to meet the primary endpoint (odds ratio 0·85 [95% CI 0·67 to 1·08], p=0·18), with an absolute risk difference of −2·7 percentage points (95% CI −7·3 to 1·9). The 28-day all-cause mortality was 8% (n=62) for baricitinib and 13% (n=100) for placebo (hazard ratio [HR] 0·57 [95% CI 0·41–0·78]; nominal p=0·0018), a 38·2% relative reduction in mortality; one additional death was prevented per 20 baricitinib-treated participants. The 60-day all-cause mortality was 10% (n=79) for baricitinib and 15% (n=116) for placebo (HR 0·62 [95% CI 0·47–0·83]; p=0·0050). The frequencies of serious adverse events (110 [15%] of 750 in the baricitinib group vs 135 [18%] of 752 in the placebo group), serious infections (64 [9%] vs 74 [10%]), and venous thromboembolic events (20 [3%] vs 19 [3%]) were similar between the two groups.

Interpretation

Although there was no significant reduction in the frequency of disease progression overall, treatment with baricitinib in addition to standard of care (including dexamethasone) had a similar safety profile to that of standard of care alone, and was associated with reduced mortality in hospitalised adults with COVID-19.

Funding

Eli Lilly and Company.

Translations

For the French, Japanese, Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.

中文翻译：

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baricitinib 治疗住院成人 COVID-19 (COV-BARRIER) 的疗效和安全性：一项随机、双盲、平行组、安慰剂对照的 3 期试验

背景

Baricitinib 是一种口服选择性 Janus 激酶 1/2 抑制剂，具有已知的抗炎特性。本研究评估了巴瑞克替尼结合标准护理治疗 COVID-19 住院成人的疗效和安全性。

方法

在这个双盲、随机、安慰剂对照的第 3 阶段试验中，参与者来自亚洲、欧洲、北美和南美 12 个国家的 101 个中心。接受标准护理的 COVID-19 住院成人被随机分配 (1:1) 接受每日一次的巴瑞克替尼 (4 mg) 或匹配的安慰剂，最长持续 14 天。护理标准包括全身性皮质类固醇，如地塞米松和抗病毒药物，包括瑞德西韦。复合主要终点是在意向治疗人群中评估的第 28 天时进展为高流量氧气、无创通气、有创机械通气或死亡的比例。第 28 天的全因死亡率是一个关键的次要终点，第 60 天的全因死亡率是一个探索性终点；两者均在意向治疗人群中进行了评估。安全性分析是在安全性人群中进行的，安全性人群定义为接受至少一剂研究药物且在第一次基线后访视前未失访的所有随机分配的参与者。本研究已在 ClinicalTrials.gov 注册，NCT04421027。

发现

2020 年 6 月 11 日至 2021 年 1 月 15 日期间，1525 名参与者被随机分配到巴瑞克替尼组（n=764）或安慰剂组（n=761）。在有可用数据的 1518 名参与者中，有 1204 名 (79·3%) 在基线时接受全身性皮质类固醇治疗，其中 1099 名 (91·3%) 使用地塞米松；287 名 (18·9%) 参与者正在接受瑞德西韦治疗。总体而言，27·8% 接受巴瑞克替尼的参与者和 30·5% 接受安慰剂的参与者进展达到主要终点（比值比 0·85 [95% CI 0·67 至 1·08]，p=0·18），其中绝对风险差异为 -2·7 个百分点（95% CI -7·3 至 1·9）。baricitinib 组的 28 天全因死亡率为 8% (n=62)，安慰剂组为 13% (n=100)（风险比 [HR] 0·57 [95% CI 0·41–0·78]；标称 p=0·0018)，死亡率相对降低 38·2%；每 20 名接受巴瑞克替尼治疗的参与者可避免 1 例死亡。巴瑞克替尼的 60 天全因死亡率为 10% (n=79)，安慰剂组为 15% (n=116)（HR 0·62 [95% CI 0·47–0·83]；p=0· 0050）。严重不良事件的频率（baricitinib 组 750 例中的​​ 110 例 [15%]vs安慰剂组 752 人中的 135 人 [18%]）、严重感染（64 人 [9%] 人与74 人 [10%]）和静脉血栓栓塞事件（20 人 [3%]人与19 人 [3%]）两组。

解释

尽管整体疾病进展频率没有显着降低，但在标准护理（包括地塞米松）之外使用巴瑞克替尼治疗与单独使用标准护理具有相似的安全性，并且与住院成人的死亡率降低相关2019冠状病毒病。

资金

礼来公司。

翻译

对于摘要的法语、日语、葡萄牙语、俄语和西班牙语翻译，请参阅补充材料部分。