Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial.
Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial.
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DOI：
10.1016/s0140-6736(21)01744-x
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发表时间：
2021-09-04
期刊：
影响因子：
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通讯作者：
PRINCIPLE Trial Collaborative Group
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文献类型：
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作者：
Yu LM;Bafadhel M;Dorward J;Hayward G;Saville BR;Gbinigie O;Van Hecke O;Ogburn E;Evans PH;Thomas NPB;Patel MG;Richards D;Berry N;Detry MA;Saunders C;Fitzgerald M;Harris V;Shanyinde M;de Lusignan S;Andersson MI;Barnes PJ;Russell REK;Nicolau DV Jr;Ramakrishnan S;Hobbs FDR;Butler CC;PRINCIPLE Trial Collaborative Group
之前的一项疗效试验发现，吸入布地奈德对未入院的患者的新冠肺炎有好处，但对高危人群的有效性尚不清楚。我们的目标是确定吸入布地奈德是否减少社区并发症高危人群的康复时间和与新冠肺炎相关的入院或死亡。Print是一项多中心、开放标签、多臂、随机、受控、适应性的平台试验，在英国的一个中央试验地点和初级保健中心远程进行。符合条件的参与者年龄为65岁或以上，或50岁或以上，患有合并症，疑似新冠肺炎患者身体不适长达14天，但未住院。参与者被随机分配到常规护理、常规护理加吸入布地奈德(每天两次800μg，连续14天)或常规护理加其他干预措施，并随访28天。参与者意识到了小组分配。采用贝叶斯模型进行分析，得出与新冠肺炎相关的首次自我报告康复时间和28天内入院或死亡的相关指标。主要分析人群包括所有符合条件的SARS-CoV-2阳性参与者，从平台试验开始到布地奈德组关闭，随机分配到布地奈德、日常护理和其他干预措施。这项试验在ISRCTN登记处登记(ISRCTN86534580)，目前正在进行中。该试验于2020年4月2日开始招募，从2020年11月27日开始随机服用布地奈德，直到2021年3月31日，达到了预先指定的恢复优势时间标准。4700名参与者被随机分配到布地奈德组(n=1073)、单独常规护理组(n=1988)或其他治疗组(n=1639)。初步分析模型包括2530名SARS-CoV-2阳性参与者，其中布地奈德组787人，常规护理组1069人，接受其他治疗的974人。布地奈德组首次自我报告的恢复时间估计为2.94天(95%贝叶斯可信区间[BCI]1·19至5·12)，与常规护理组相比(11.8天[95%BCI 10.0至14.1]对14.7天[12.3至18.0]；风险比1.21[95%BCI 1.08至1.36])，优势概率大于0.999，达到预先指定的优势阈值0.99。在住院或死亡结局方面，布地奈德组的估计率为6.8%(95%BCI 4.1~10.2)，而普通护理组为8.8%(5.5~12.7)(估计绝对差值2.0%[95%BCI-0.2~4.5]；优势比0·75[95%BCI 0.55~1.03])，优势概率为0.963，低于预先设定的优势阈值0.975。布地奈德组的两名参与者和常规护理组的四名参与者发生了严重的不良事件(住院与新冠肺炎无关)。对于社区中并发症风险较高的新冠肺炎患者，吸入布地奈德可缩短康复时间，并有可能减少住院或死亡(尽管我们的结果没有达到优势阈值)。国家卫生研究所和英国研究创新研究所。
A previous efficacy trial found benefit from inhaled budesonide for COVID-19 in patients not admitted to hospital, but effectiveness in high-risk individuals is unknown. We aimed to establish whether inhaled budesonide reduces time to recovery and COVID-19-related hospital admissions or deaths among people at high risk of complications in the community. PRINCIPLE is a multicentre, open-label, multi-arm, randomised, controlled, adaptive platform trial done remotely from a central trial site and at primary care centres in the UK. Eligible participants were aged 65 years or older or 50 years or older with comorbidities, and unwell for up to 14 days with suspected COVID-19 but not admitted to hospital. Participants were randomly assigned to usual care, usual care plus inhaled budesonide (800 μg twice daily for 14 days), or usual care plus other interventions, and followed up for 28 days. Participants were aware of group assignment. The coprimary endpoints are time to first self-reported recovery and hospital admission or death related to COVID-19, within 28 days, analysed using Bayesian models. The primary analysis population included all eligible SARS-CoV-2-positive participants randomly assigned to budesonide, usual care, and other interventions, from the start of the platform trial until the budesonide group was closed. This trial is registered at the ISRCTN registry (ISRCTN86534580) and is ongoing. The trial began enrolment on April 2, 2020, with randomisation to budesonide from Nov 27, 2020, until March 31, 2021, when the prespecified time to recovery superiority criterion was met. 4700 participants were randomly assigned to budesonide (n=1073), usual care alone (n=1988), or other treatments (n=1639). The primary analysis model includes 2530 SARS-CoV-2-positive participants, with 787 in the budesonide group, 1069 in the usual care group, and 974 receiving other treatments. There was a benefit in time to first self-reported recovery of an estimated 2·94 days (95% Bayesian credible interval [BCI] 1·19 to 5·12) in the budesonide group versus the usual care group (11·8 days [95% BCI 10·0 to 14·1] vs 14·7 days [12·3 to 18·0]; hazard ratio 1·21 [95% BCI 1·08 to 1·36]), with a probability of superiority greater than 0·999, meeting the prespecified superiority threshold of 0·99. For the hospital admission or death outcome, the estimated rate was 6·8% (95% BCI 4·1 to 10·2) in the budesonide group versus 8·8% (5·5 to 12·7) in the usual care group (estimated absolute difference 2·0% [95% BCI –0·2 to 4·5]; odds ratio 0·75 [95% BCI 0·55 to 1·03]), with a probability of superiority 0·963, below the prespecified superiority threshold of 0·975. Two participants in the budesonide group and four in the usual care group had serious adverse events (hospital admissions unrelated to COVID-19). Inhaled budesonide improves time to recovery, with a chance of also reducing hospital admissions or deaths (although our results did not meet the superiority threshold), in people with COVID-19 in the community who are at higher risk of complications. National Institute of Health Research and United Kingdom Research Innovation.