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,The Lancet

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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
The Lancet ( IF 98.4 ) Pub Date : 2021-08-10 , DOI: 10.1016/s0140-6736(21)01744-x
Ly-Mee Yu ₁ , Mona Bafadhel ₂ , Jienchi Dorward ₃ , Gail Hayward ₁ , Benjamin R Saville ₄ , Oghenekome Gbinigie ₁ , Oliver Van Hecke ₁ , Emma Ogburn ₁ , Philip H Evans ₅ , Nicholas P B Thomas ₆ , Mahendra G Patel ₁ , Duncan Richards ₇ , Nicholas Berry ₈ , Michelle A Detry ₈ , Christina Saunders ₈ , Mark Fitzgerald ₈ , Victoria Harris ₁ , Milensu Shanyinde ₁ , Simon de Lusignan ₁ , Monique I Andersson ₂ , Peter J Barnes ₉ , Richard E K Russell ₂ , Dan V Nicolau ₁₀ , Sanjay Ramakrishnan ₁₁ , F D Richard Hobbs ₁ , Christopher C Butler ₁ ,

Affiliation

Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK; Centre for the AIDS Programme of Research in South Africa, University of KwaZulu-Natal, Durban, South Africa.
Berry Consultants, Austin, TX, USA; Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN, USA.
College of Medicine and Health, University of Exeter, Exeter, UK; National Institute for Health Research Clinical Research Network, National Institute for Health Research, London, UK.
National Institute for Health Research Clinical Research Network, National Institute for Health Research, London, UK; Royal College of General Practitioners, London, UK.
Oxford Clinical Trials Research Unit, Botnar Research Centre, University of Oxford, Oxford, UK.
Berry Consultants, Austin, TX, USA.
National Heart and Lung Institute, Imperial College, London, UK.
Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; UQ Centre for Clinical Research, University of Queensland, Brisbane, QLD, Australia.
National Institute for Health Research Oxford Biomedical Research Centre, Oxford, UK.

Background

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.

Methods

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.

Findings

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).

Interpretation

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.

Funding

National Institute of Health Research and United Kingdom Research Innovation.

中文翻译：

英国社区并发症高危人群吸入布地奈德治疗 COVID-19（原理）：一项随机、对照、开放标签、适应性平台试验

背景

之前的一项疗效试验发现，未入院的患者可从吸入布地奈德治疗 COVID-19 中获益，但对高危人群的有效性尚不清楚。我们的目的是确定吸入布地奈德是否会减少社区并发症高风险人群的康复时间以及与 COVID-19 相关的住院或死亡。

方法

PRINCIPLE 是一项多中心、开放标签、多臂、随机、受控、自适应平台试验，在英国的中央试验中心和初级保健中心远程进行。符合资格的参与者年龄为 65 岁或以上，或 50 岁或以上，患有合并症，并且因疑似 COVID-19 不适长达 14 天但未入院。参与者被随机分配至常规护理、常规护理加吸入布地奈德（800 μg，每天两次，持续 14 天）或常规护理加其他干预措施，并随访 28 天。参与者了解小组分配。共同主要终点是使用贝叶斯模型进行分析的 28 天内首次自我报告的与 COVID-19 相关的康复和入院或死亡的时间。主要分析人群包括从平台试验开始直至布地奈德组结束期间所有符合条件的 SARS-CoV-2 阳性参与者，随机分配至布地奈德、常规护理和其他干预措施。该试验已在 ISRCTN 注册中心 (ISRCTN86534580) 注册并正在进行中。

发现

该试验于2020年4月2日开始入组，从2020年11月27日起随机分配至布地奈德，直至2021年3月31日达到预定的恢复时间优势标准。 4700 名参与者被随机分配接受布地奈德 (n=1073)、单独常规护理 (n=1988) 或其他治疗 (n=1639)。主要分析模型包括 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。与常规护理组（11·8 天）相比，布地奈德组首次自我报告的恢复时间有大约 2·94 天（95% 贝叶斯可信区间 [BCI] 1·19 至 5·12）的优势[95% BCI 10·0 至 14·1] vs 14·7 天 [12·3 至 18·0]；风险比 1·21 [95% BCI 1·08 至 1·36]），概率为优越性大于0·999，满足预先设定的优越性阈值0·99。对于入院或死亡结局，布地奈德组的估计发生率为 6·8%（95% BCI 4·1 至 10·2），而常规护理组的估计发生率为 8·8%（5·5 至 12·7）组（估计绝对差异 2·0% [95% BCI –0·2 至 4·5]；比值比 0·75 [95% BCI 0·55 至 1·03]），优越性概率 0·963 ，低于预先指定的优势阈值 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（与 COVID-19 无关的入院）。