Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial.
Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial.
复制标题
DOI：
10.1016/s2213-2600(21)00331-3
复制
发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
COV-BARRIER Study Group
中科院分区：
文献类型：
--
作者：
Marconi VC;Ramanan AV;de Bono S;Kartman CE;Krishnan V;Liao R;Piruzeli MLB;Goldman JD;Alatorre-Alexander J;de Cassia Pellegrini R;Estrada V;Som M;Cardoso A;Chakladar S;Crowe B;Reis P;Zhang X;Adams DH;Ely EW;COV-BARRIER Study Group
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。本研究评估巴西替尼联合标准护理治疗住院成人COVID-19的疗效和安全性。在这项三期双盲、随机、安慰剂对照试验中，参与者来自亚洲、欧洲、北美和南美12个国家的101个中心。接受标准治疗的COVID-19住院成人被随机分配（1:1），每天接受一次baricitinib （4mg）或匹配的安慰剂，长达14天。标准治疗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进展到高流量供氧、无创通气、有创机械通气或在第28天死亡的比例。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；在意向治疗人群中对两者进行了评估。安全性分析是在安全人群中进行的，安全人群定义为所有随机分配的参与者，他们接受了至少一剂研究药物，并且在第一次基线后访问之前没有丢失随访。本研究已在ClinicalTrials.gov注册，编号NCT04421027。在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baricitinib组（n=764）或安慰剂组（n=761）。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%）接受地塞米松治疗；287名（18.9%）参与者接受瑞德西韦治疗。总体而言，接受巴比替尼治疗的受试者中有27.8%和接受安慰剂治疗的受试者中有30.5%进展到主要终点（优势比为0.85 [95% CI 0.67至1.08],p= 0.18），绝对风险差异为- 2.7个百分点（95% CI - 7.3至1.9）。baricitinib组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]；名义p= 0.0018），死亡率相对降低38.2%；每20名接受巴西替尼治疗的参与者可预防1例额外死亡。baricitinib组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）。严重不良事件的发生频率（baricitinib组750例中的110例[15%]vs安慰剂组752例中的135例[18%]）、严重感染（64例[9%]vs 74例[10%]）和静脉血栓栓塞事件（20例[3%]vs 19例[3%]）在两组之间相似。虽然总体上疾病进展频率没有显著降低，但baricitinib加标准治疗（包括地塞米松）与单独标准治疗具有相似的安全性，并且与COVID-19住院成人死亡率降低相关。礼来公司。摘要的法文、日文、葡萄牙文、俄文和西班牙文译本见补充材料一节。
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. 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. 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. 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. Eli Lilly and Company. For the French, Japanese, Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.