Background

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.

Methods

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.

Findings

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).

Interpretation

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.

Funding

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.

中文翻译：

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社区治疗的 COVID-19 患者秋水仙碱 (COLCORONA)：3 期、随机、双盲、适应性、安慰剂对照、多中心试验

背景

有证据表明过度炎症在 COVID-19 并发症中的作用。秋水仙碱是一种口服抗炎药，对痛风、心包炎和冠心病有益。我们旨在调查秋水仙碱对 COVID-19 相关死亡或住院复合的影响。

方法

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领导。通过 PCR 检测或临床标准诊断出的 COVID-19 患者如果年龄至少为 40 岁且至少具有一项高危特征，则未在医院接受治疗的患者符合条件。随机化列表是由一位不知情的生物统计学家在计算机上生成的，并且不知情的随机化是通过一个自动交互式网络响应系统以电子方式集中和完成的。分配顺序是未分层的，使用 1:1 的比例，块模式和块大小为 6。患者被随机分配接受口服秋水仙碱（0·5 毫克，每天两次，连续 3 天，然后每天一次，连续 27 天）或匹配的安慰剂。主要疗效终点是 COVID-19 的死亡或住院复合终点。在研究结束时，97·9% 的患者的生命状态是可用的。根据意向治疗原则进行分析。COLCORONA 试验已在 ClinicalTrials.gov (NCT04322682) 注册，现在不对新参与者开放。

发现

试验招募于 2020 年 3 月 23 日开始，2020 年 12 月 22 日完成。共招募了 4488 名患者（53·9% 女性；中位年龄 54·0 岁，IQR 47·0–61·0）和 2235患者被随机分配到秋水仙碱组，2253 名患者被随机分配到安慰剂组。主要终点发生在秋水仙碱组 2235 名患者中的 104 名 (4·7%) 和安慰剂组 2253 名患者中的 131 名 (5·8%)（比值比 [OR] 0·79，95·1% CI 0 ·61-1·03；p=0·081）。在 4159 名经 PCR 确诊的 COVID-19 患者中，主要终点发生在秋水仙碱组 2075 名患者中的 96 名（4·6%）和安慰剂组 2084 名患者中的 126 名（6·0%）（OR 0· 75, 0·57–0·99；p=0·042)。秋水仙碱组 2195 名患者中的 108 名 (4·9%) 和安慰剂组 2217 名患者中的 139 名 (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 名 (2·9%) 发生肺炎，安慰剂组 2217 名患者中有 92 名 (4·1%) 发生肺炎 (p=0·021)。据报道，秋水仙碱组 2195 名患者中有 300 名 (13·7%) 和安慰剂组 2217 名患者中有 161 名 (7·3%) 腹泻（p<0·0001）。

解释

在社区治疗的患者中，包括那些没有进行强制性诊断测试的患者，秋水仙碱对 COVID-19 相关临床事件的影响没有统计学意义。在 PCR 确诊的 COVID-19 患者中，秋水仙碱导致的死亡或住院复合发生率低于安慰剂。鉴于在社区治疗的患者中缺乏预防 COVID-19 并发症的口服疗法，以及秋水仙碱对经 PCR 证实的 COVID-19 患者的益处，可以考虑将这种安全且廉价的抗炎药用于有风险的患者的并发症。尽管有这些考虑，建议在其他 PCR 阳性社区治疗患者的研究中进行复制。

资金

魁北克政府、比尔和梅琳达盖茨基金会、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、鲁丁家族基金会和慈善家索菲德马雷。