Doxycycline for community treatment of suspected COVID-19 in people at high risk of adverse outcomes in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial.
Doxycycline for community treatment of suspected COVID-19 in people at high risk of adverse outcomes in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial.
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对疑似COVID-19的社区治疗的强力霉素在英国有不良结果的高风险（原则）：一项随机，控制，开放标签，适应性平台试验。
DOI：
10.1016/s2213-2600(21)00310-6
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发表时间：
2021-09
期刊：
影响因子：
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通讯作者：
PRINCIPLE Trial Collaborative Group
中科院分区：
文献类型：
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作者：
Butler CC;Yu LM;Dorward J;Gbinigie O;Hayward G;Saville BR;Van Hecke O;Berry N;Detry MA;Saunders C;Fitzgerald M;Harris V;Djukanovic R;Gadola S;Kirkpatrick J;de Lusignan S;Ogburn E;Evans PH;Thomas NPB;Patel MG;Hobbs FDR;PRINCIPLE Trial Collaborative Group
多西环素经常用于治疗社区中的COVID-19呼吸道症状，尽管缺乏临床试验证据支持其使用。我们的目的是评估多西环素在社区中治疗疑似COVID-19不良后果高风险人群的疗效。我们在英国的初级保健中心进行了一项全国性、开放标签、多组、适应性平台的老年人COVID-19干预措施随机试验（PRINCIPLE）。我们纳入了65岁或以上，或50岁或以上合并症的患者（免疫系统减弱、心脏病、高血压、哮喘或肺病、糖尿病、轻度肝损害、中风或神经问题，以及自我报告的肥胖或体重指数≥ 35 kg/m2），在社区中因疑似COVID-19或SARS-CoV-2感染PCR检测阳性而感到不适（≤14天）的人。使用反应适应性随机化将参与者随机分配至仅常规护理、常规护理加口服强力霉素（第1天200 mg，然后100 mg，每天一次，持续6天）或常规护理加其他干预措施。本手稿中报告的干预措施为常规护理加强力霉素和仅常规护理;本平台试验中其他干预措施的评价正在进行中。共同主要终点是至首次自我报告恢复的时间，以及与COVID-19相关的住院或死亡时间，均在随机化后28天内测量，并按意向治疗进行分析。审判于2020年4月2日开始。2020年7月24日开始多西环素随机化，2020年12月14日停止，因为符合预先规定的无效标准; 2689名受试者入组并在这些日期之间进行随机化。其中，2508例（93.3%）参与者提供了随访数据，并被纳入主要分析：常规护理加多西环素组780例（31.1%），仅常规护理组948例（37.8%），常规护理加其他干预组780例（31.1%）。在1792名参与者中，随机分配到常规护理加多西环素组和仅常规护理组，平均年龄为61.1岁（SD 7.9）; 999名（55.7%）参与者为女性，790名（44.1%）为男性。在主要分析模型中，常规护理加多西环素组和仅常规护理组之间首次自我报告恢复的中位时间几乎没有差异（9.6 [95%贝叶斯可信区间[BCI] 8.3至11.0]天vs 10.1 [8.7至11.7]天，风险比1.04 [95% BCI 0.93至1.17]）。至首次自我报告恢复的中位时间的估计获益为0.5天[95%BCI − 0.99至2.04]，具有临床意义的获益概率（定义为≥ 1.5天）为0.10。41人发生与COVID-19相关的住院或死亡（粗百分比5.3%）的参与者在常规护理加强力霉素组和43（4.5%）的参与者在常规护理组（估计绝对百分比差异− 0.5%[95%BCI − 2.6至1.4]）;常规护理加强力霉素组有5例死亡（0.6%），仅常规护理组有2例死亡（0.2%）。在英国社区的疑似COVID-19患者中，这些患者的不良结局风险较高，使用多西环素治疗与COVID-19相关的恢复或住院或死亡时间的临床意义减少无关，不应用作COVID-19的常规治疗。英国研究和创新，卫生和社会保健部，国家卫生研究所。
Doxycycline is often used for treating COVID-19 respiratory symptoms in the community despite an absence of evidence from clinical trials to support its use. We aimed to assess the efficacy of doxycycline to treat suspected COVID-19 in the community among people at high risk of adverse outcomes. We did a national, open-label, multi-arm, adaptive platform randomised trial of interventions against COVID-19 in older people (PRINCIPLE) across primary care centres in the UK. We included people aged 65 years or older, or 50 years or older with comorbidities (weakened immune system, heart disease, hypertension, asthma or lung disease, diabetes, mild hepatic impairment, stroke or neurological problem, and self-reported obesity or body-mass index of 35 kg/m2 or greater), who had been unwell (for ≤14 days) with suspected COVID-19 or a positive PCR test for SARS-CoV-2 infection in the community. Participants were randomly assigned using response adaptive randomisation to usual care only, usual care plus oral doxycycline (200 mg on day 1, then 100 mg once daily for the following 6 days), or usual care plus other interventions. The interventions reported in this manuscript are usual care plus doxycycline and usual care only; evaluations of other interventions in this platform trial are ongoing. The coprimary endpoints were time to first self-reported recovery, and hospitalisation or death related to COVID-19, both measured over 28 days from randomisation and analysed by intention to treat. This trial is ongoing and is registered with ISRCTN, 86534580. The trial opened on April 2, 2020. Randomisation to doxycycline began on July 24, 2020, and was stopped on Dec 14, 2020, because the prespecified futility criterion was met; 2689 participants were enrolled and randomised between these dates. Of these, 2508 (93·3%) participants contributed follow-up data and were included in the primary analysis: 780 (31·1%) in the usual care plus doxycycline group, 948 in the usual care only group (37·8%), and 780 (31·1%) in the usual care plus other interventions group. Among the 1792 participants randomly assigned to the usual care plus doxycycline and usual care only groups, the mean age was 61·1 years (SD 7·9); 999 (55·7%) participants were female and 790 (44·1%) were male. In the primary analysis model, there was little evidence of difference in median time to first self-reported recovery between the usual care plus doxycycline group and the usual care only group (9·6 [95% Bayesian Credible Interval [BCI] 8·3 to 11·0] days vs 10·1 [8·7 to 11·7] days, hazard ratio 1·04 [95% BCI 0·93 to 1·17]). The estimated benefit in median time to first self-reported recovery was 0·5 days [95% BCI −0·99 to 2·04] and the probability of a clinically meaningful benefit (defined as ≥1·5 days) was 0·10. Hospitalisation or death related to COVID-19 occurred in 41 (crude percentage 5·3%) participants in the usual care plus doxycycline group and 43 (4·5%) in the usual care only group (estimated absolute percentage difference −0·5% [95% BCI −2·6 to 1·4]); there were five deaths (0·6%) in the usual care plus doxycycline group and two (0·2%) in the usual care only group. In patients with suspected COVID-19 in the community in the UK, who were at high risk of adverse outcomes, treatment with doxycycline was not associated with clinically meaningful reductions in time to recovery or hospital admissions or deaths related to COVID-19, and should not be used as a routine treatment for COVID-19. UK Research and Innovation, Department of Health and Social Care, National Institute for Health Research.