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,The Lancet Respiratory Medicine

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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
The Lancet Respiratory Medicine ( IF 38.7 ) Pub Date : 2021-07-27 , DOI: 10.1016/s2213-2600(21)00310-6
Christopher C Butler ₁ , Ly-Mee Yu ₁ , Jienchi Dorward ₂ , Oghenekome Gbinigie ₁ , Gail Hayward ₁ , Benjamin R Saville ₃ , Oliver Van Hecke ₁ , Nicholas Berry ₄ , Michelle A Detry ₄ , Christina Saunders ₄ , Mark Fitzgerald ₄ , Victoria Harris ₁ , Ratko Djukanovic ₅ , Stephan Gadola ₆ , John Kirkpatrick ₇ , Simon de Lusignan ₁ , Emma Ogburn ₁ , Philip H Evans ₈ , Nicholas P B Thomas ₉ , Mahendra G Patel ₁₀ , F D Richard Hobbs ₁ ,

Affiliation

Nuffield Department of Primary Care Health Sciences, 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 (CAPRISA), University of KwaZulu-Natal, Durban, South Africa.
Berry Consultants, Austin, TX, USA; Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN, USA.
Berry Consultants, Austin, TX, USA.
Clinical and Experimental Science, National Institute for Health Research (NIHR) Southampton Biomedical Research Centre, Faculty of Medicine, University of Southampton, Southampton, UK.
Rheumatology and Pain Medicine, Bethesda Hospital, Basel, Switzerland.
Independent Researcher, Glatton, UK.
College of Medicine and Health, University of Exeter, Exeter, UK; NIHR Clinical Research Network, NIHR, London, UK.
NIHR Clinical Research Network, NIHR, London, UK; Royal College of General Practitioners, London, UK.
Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK; School of Pharmacy and Medical Sciences, University of Bradford, Bradford, UK.

Background

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.

Methods

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.

Findings

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.

Interpretation

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.

Funding

UK Research and Innovation, Department of Health and Social Care, National Institute for Health Research.

中文翻译：

多西环素用于英国不良后果高危人群疑似 COVID-19 社区治疗（原则）：一项随机、对照、开放标签、适应性平台试验

背景

尽管缺乏临床试验证据支持强力霉素的使用，但强力霉素通常用于治疗社区中的 COVID-19 呼吸道症状。我们的目的是评估多西环素在社区中治疗不良后果高风险人群中疑似 COVID-19 的疗效。

方法

我们在英国初级保健中心开展了针对老年人 COVID-19 干预措施的全国性、开放标签、多臂、自适应平台随机试验 (PRINCIPLE)。我们纳入了 65 岁或以上，或 50 岁或以上有合并症（免疫系统减弱、心脏病、高血压、哮喘或肺部疾病、糖尿病、轻度肝损伤、中风或神经系统问题，以及自我报告的肥胖或身体-质量指数 35 kg/m ²或以上）曾因疑似 COVID-19 或在社区中 SARS-CoV-2 感染 PCR 检测呈阳性而感到不适（≤14 天）。使用响应自适应随机化将参与者随机分配到仅常规护理、常规护理加口服多西环素（第 1 天 200 毫克，然后在接下来的 6 天内每天一次 100 毫克），或常规护理加其他干预措施。本手稿中报告的干预措施是常规护理加多西环素和仅常规护理；正在对该平台试验中的其他干预措施进行评估。共同主要终点是首次自我报告康复的时间，以及与 COVID-19 相关的住院或死亡，这两项都是在随机化后 28 天内测量的，并按意向治疗进行了分析。该试验正在进行中，并已在 ISRCTN 注册，86534580。

发现

试验于 2020 年 4 月 2 日开始。多西环素的随机分组于 2020 年 7 月 24 日开始，并于 2020 年 12 月 14 日停止，因为达到了预先指定的无效标准；在这些日期之间，有 2689 名参与者被随机分配入组。其中，2508 名 (93·3%) 参与者提供了随访数据并被纳入主要分析：780 名 (31·1%) 在常规护理加多西环素组，948 名在常规护理组 (37·8 %), 780 (31·1%) 在常规护理加其他干预组。在随机分配到常规护理加多西环素组和仅常规护理组的 1792 名参与者中，平均年龄为 61·1 岁 (SD 7·9)；999 (55·7%) 名参与者为女性，790 (44·1%) 名参与者为男性。在初级分析模型中，对比10·1 [8·7 至 11·7] 天，风险比 1·04 [95% BCI 0·93 至 1·17]）。首次自我报告恢复的中位时间估计获益为 0·5 天 [95% BCI -0·99 至 2·04]，具有临床意义的获益（定义为≥1·5 天）的概率为 0·5 10. 与 COVID-19 相关的住院或死亡发生在常规护理加多西环素组的 41 名参与者（粗百分比 5·3%）和仅常规护理组的 43 名参与者（4·5%）（估计的绝对百分比差异 -0·5 % [95% BCI -2·6 至 1·4]); 常规治疗加多西环素组有 5 例死亡 (0·6%)，仅常规治疗组有 2 例 (0·2%)。