Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial.
Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial.
复制标题
DOI：
10.1016/s2213-2600(21)00222-8
复制
发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
COLCORONA Investigators
中科院分区：
文献类型：
--
作者：
Tardif JC;Bouabdallaoui N;L'Allier PL;Gaudet D;Shah B;Pillinger MH;Lopez-Sendon J;da Luz P;Verret L;Audet S;Dupuis J;Denault A;Pelletier M;Tessier PA;Samson S;Fortin D;Tardif JD;Busseuil D;Goulet E;Lacoste C;Dubois A;Joshi AY;Waters DD;Hsue P;Lepor NE;Lesage F;Sainturet N;Roy-Clavel E;Bassevitch Z;Orfanos A;Stamatescu G;Grégoire JC;Busque L;Lavallée C;Hétu PO;Paquette JS;Deftereos SG;Levesque S;Cossette M;Nozza A;Chabot-Blanchet M;Dubé MP;Guertin MC;Boivin G;COLCORONA Investigators
有证据表明，过度炎症在新冠病毒（COVID - 19）并发症中起作用。秋水仙碱是一种口服抗炎药物，对痛风、心包炎和冠心病有益。我们旨在研究秋水仙碱对新冠病毒相关死亡或住院的综合影响。
本研究是一项3期、随机、双盲、适应性、安慰剂对照、多中心试验。该研究在巴西、加拿大、希腊、南非、西班牙和美国进行，由蒙特利尔心脏研究所牵头。通过聚合酶链反应（PCR）检测或临床标准诊断为新冠病毒感染且未住院治疗的患者，若年龄至少40岁且至少有一种高危特征，则符合入组条件。随机分组列表由未设盲的生物统计学家通过计算机生成，设盲随机分组集中进行，并通过自动交互式网络应答系统以电子方式完成。分配序列未分层，采用1∶1比例，区组设计，区组大小为6。患者被随机分配接受口服秋水仙碱（0.5毫克，每天两次，持续3天，之后每天一次，持续27天）或匹配的安慰剂。主要疗效终点是新冠病毒相关的死亡或住院的综合情况。97.9%的患者在研究结束时的生命状态可获取。分析依据意向性治疗原则进行。COLCORONA试验在ClinicalTrials.gov（NCT04322682）注册，现已停止招募新参与者。
试验招募于2020年3月23日开始，并于2020年12月22日完成。共有4488名患者（53.9%为女性；中位年龄54.0岁，四分位距47.0 - 61.0）入组，2235名患者被随机分配到秋水仙碱组，2253名患者被分配到安慰剂组。秋水仙碱组2235名患者中有104人（4.7%）发生主要终点事件，安慰剂组2253名患者中有131人（5.8%）发生主要终点事件（优势比[OR]为0.79，95.1%置信区间0.61 - 1.03；p = 0.081）。在4159名经PCR确诊的新冠病毒感染患者中，秋水仙碱组2075名患者中有96人（4.6%）发生主要终点事件，安慰剂组2084名患者中有126人（6.0%）发生主要终点事件（OR为0.75，0.57 - 0.99；p = 0.042）。秋水仙碱组2195名患者中有108人（4.9%）报告了严重不良事件，安慰剂组2217名患者中有139人（6.3%）报告了严重不良事件（p = 0.051）；秋水仙碱组2195名患者中有63人（2.9%）发生肺炎，安慰剂组2217名患者中有92人（4.1%）发生肺炎（p = 0.021）。秋水仙碱组2195名患者中有300人（13.7%）报告腹泻，安慰剂组2217名患者中有161人（7.3%）报告腹泻（p < 0.0001）。
在社区治疗的患者（包括那些未进行强制性诊断检测的患者）中，秋水仙碱对新冠病毒相关临床事件的影响无统计学意义。在经PCR确诊的新冠病毒感染患者中，秋水仙碱导致的死亡或住院综合发生率低于安慰剂。鉴于社区治疗的患者缺乏用于预防新冠病毒并发症的口服疗法，且秋水仙碱对经PCR确诊的新冠病毒感染患者有益，这种安全且价格低廉的抗炎药物可考虑用于有并发症风险的患者。尽管有这些考虑，仍建议在其他经PCR确诊的社区治疗患者的研究中进行重复验证。
魁北克政府、比尔及梅琳达·盖茨基金会、美国国立卫生研究院国家心肺血液研究所、蒙特利尔心脏研究所基金会、纽约大学格罗斯曼医学院、鲁丁家族基金会以及慈善家索菲·德斯马雷。
Evidence suggests a role for excessive inflammation in COVID-19 complications. Colchicine is an oral anti-inflammatory medication beneficial in gout, pericarditis, and coronary disease. We aimed to investigate the effect of colchicine on the composite of COVID-19-related death or hospital admission. The present study is a phase 3, randomised, double-blind, adaptive, placebo-controlled, multicentre trial. The study was done in Brazil, Canada, Greece, South Africa, Spain, and the USA, and was led by the Montreal Heart Institute. Patients with COVID-19 diagnosed by PCR testing or clinical criteria who were not being treated in hospital were eligible if they were at least 40 years old and had at least one high-risk characteristic. The randomisation list was computer-generated by an unmasked biostatistician, and masked randomisation was centralised and done electronically through an automated interactive web-response system. The allocation sequence was unstratified and used a 1:1 ratio with a blocking schema and block sizes of six. Patients were randomly assigned to receive orally administered colchicine (0·5 mg twice per day for 3 days and then once per day for 27 days thereafter) or matching placebo. The primary efficacy endpoint was the composite of death or hospital admission for COVID-19. Vital status at the end of the study was available for 97·9% of patients. The analyses were done according to the intention-to-treat principle. The COLCORONA trial is registered with ClinicalTrials.gov (NCT04322682) and is now closed to new participants. Trial enrolment began in March 23, 2020, and was completed in Dec 22, 2020. A total of 4488 patients (53·9% women; median age 54·0 years, IQR 47·0–61·0) were enrolled and 2235 patients were randomly assigned to colchicine and 2253 to placebo. The primary endpoint occurred in 104 (4·7%) of 2235 patients in the colchicine group and 131 (5·8%) of 2253 patients in the placebo group (odds ratio [OR] 0·79, 95·1% CI 0·61–1·03; p=0·081). Among the 4159 patients with PCR-confirmed COVID-19, the primary endpoint occurred in 96 (4·6%) of 2075 patients in the colchicine group and 126 (6·0%) of 2084 patients in the placebo group (OR 0·75, 0·57–0·99; p=0·042). Serious adverse events were reported in 108 (4·9%) of 2195 patients in the colchicine group and 139 (6·3%) of 2217 patients in the placebo group (p=0·051); pneumonia occurred in 63 (2·9%) of 2195 patients in the colchicine group and 92 (4·1%) of 2217 patients in the placebo group (p=0·021). Diarrhoea was reported in 300 (13·7%) of 2195 patients in the colchicine group and 161 (7·3%) of 2217 patients in the placebo group (p<0·0001). In community-treated patients including those without a mandatory diagnostic test, the effect of colchicine on COVID-19-related clinical events was not statistically significant. Among patients with PCR-confirmed COVID-19, colchicine led to a lower rate of the composite of death or hospital admission than placebo. Given the absence of orally administered therapies to prevent COVID-19 complications in community-treated patients and the benefit of colchicine in patients with PCR-proven COVID-19, this safe and inexpensive anti-inflammatory agent could be considered for use in those at risk of complications. Notwithstanding these considerations, replication in other studies of PCR-positive community-treated patients is recommended. The Government of Quebec, the Bill & Melinda Gates Foundation, the National Heart, Lung, and Blood Institute of the US National Institutes of Health, the Montreal Heart Institute Foundation, the NYU Grossman School of Medicine, the Rudin Family Foundation, and philanthropist Sophie Desmarais.