Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial.
Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial.
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DOI：
10.1016/s2214-109x(21)00448-4
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发表时间：
2022-01
期刊：
影响因子：
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通讯作者：
TOGETHER investigators
中科院分区：
文献类型：
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作者：
Reis G;Dos Santos Moreira-Silva EA;Silva DCM;Thabane L;Milagres AC;Ferreira TS;Dos Santos CVQ;de Souza Campos VH;Nogueira AMR;de Almeida APFG;Callegari ED;de Figueiredo Neto AD;Savassi LCM;Simplicio MIC;Ribeiro LB;Oliveira R;Harari O;Forrest JI;Ruton H;Sprague S;McKay P;Glushchenko AV;Rayner CR;Lenze EJ;Reiersen AM;Guyatt GH;Mills EJ;TOGETHER investigators
最近的证据表明氟伏沙明对COVID-19具有潜在的治疗作用。在针对急性症状性COVID-19患者的TOGETHER试验中，我们旨在评估氟伏沙明与安慰剂相比在预防住院治疗（定义为在COVID-19紧急情况下滞留或因COVID-19转移到三级医院）方面的疗效。这项安慰剂对照、随机、适应性平台试验在确诊为SARS-CoV-2阳性的高危症状性巴西成年人中进行，包括来自巴西11个临床中心的合格患者，这些患者具有进展为严重疾病的已知风险因素。患者被随机分配（1：1）至氟伏沙明（100 mg，每日两次，持续10天）或安慰剂组（或本文未报告的其他治疗组）。试验团队、研究中心工作人员和患者均对治疗分配设盲。我们的主要结局是住院治疗的复合终点，定义为在基于意向治疗的随机分配后28天内，在COVID-19紧急情况下保留或因COVID-19转移到三级医院。改良的意向治疗探讨了在主要结局事件发生前接受至少24小时治疗的患者，以及根据方案分析探索了具有高水平依从性（>80%）的患者。我们使用贝叶斯分析框架来建立干预与安慰剂相比的效果沿着成功概率。该试验在ClinicalTrials.gov（NCT 04727424）上注册，目前正在进行中。研究小组筛选了9803名潜在的参与者。该试验于2020年6月2日启动，当前方案报告从2021年1月20日至8月5日随机分配至氟伏沙明，当时试验组因优效性而停止。741名患者被分配到氟伏沙明组，756名患者被分配到安慰剂组。参与者的平均年龄为50岁（范围18-102岁）; 58%为女性。与安慰剂组相比，氟伏沙明组在COVID-19紧急情况下观察超过6小时或因COVID-19转移到三级医院的患者比例较低（741例中的79例[11%] vs 756例中的119例[16%]）;相对风险[RR] 0·68; 95%贝叶斯可信区间[95%BCI]：0.52 - 0.88），优效性概率为99.8%，超过预定优效性阈值97.6%（风险差异5.0%）。在复合主要结局事件中，87%为住院。改良意向治疗分析的主要结局结果相似（RR 0.69，95%BCI 0.53 - 0.90），符合方案分析的主要结局结果较大（RR 0.34，95%BCI 0.21 - 0.54）。在主要意向治疗分析中，氟伏沙明组有17例死亡，安慰剂组有25例死亡（比值比[OR] 0.68，95%CI：0.36 - 1.27）。在符合方案人群中，氟伏沙明组有1例死亡，安慰剂组有12例死亡（OR 0.09; 95% CI 0.01 - 0.47）。我们发现氟伏沙明组和安慰剂组患者治疗后出现的不良事件数量无显著差异。在早期诊断为COVID-19的高风险门诊患者中使用氟伏沙明（100 mg，每日两次，持续10天）治疗，减少了住院（定义为在COVID-19紧急情况下滞留或转移到三级医院）的需求。FastGrants和雨水慈善基金会。摘要的葡萄牙语翻译见补充材料部分。
Recent evidence indicates a potential therapeutic role of fluvoxamine for COVID-19. In the TOGETHER trial for acutely symptomatic patients with COVID-19, we aimed to assess the efficacy of fluvoxamine versus placebo in preventing hospitalisation defined as either retention in a COVID-19 emergency setting or transfer to a tertiary hospital due to COVID-19. This placebo-controlled, randomised, adaptive platform trial done among high-risk symptomatic Brazilian adults confirmed positive for SARS-CoV-2 included eligible patients from 11 clinical sites in Brazil with a known risk factor for progression to severe disease. Patients were randomly assigned (1:1) to either fluvoxamine (100 mg twice daily for 10 days) or placebo (or other treatment groups not reported here). The trial team, site staff, and patients were masked to treatment allocation. Our primary outcome was a composite endpoint of hospitalisation defined as either retention in a COVID-19 emergency setting or transfer to tertiary hospital due to COVID-19 up to 28 days post-random assignment on the basis of intention to treat. Modified intention to treat explored patients receiving at least 24 h of treatment before a primary outcome event and per-protocol analysis explored patients with a high level adherence (>80%). We used a Bayesian analytic framework to establish the effects along with probability of success of intervention compared with placebo. The trial is registered at ClinicalTrials.gov (NCT04727424) and is ongoing. The study team screened 9803 potential participants for this trial. The trial was initiated on June 2, 2020, with the current protocol reporting randomisation to fluvoxamine from Jan 20 to Aug 5, 2021, when the trial arms were stopped for superiority. 741 patients were allocated to fluvoxamine and 756 to placebo. The average age of participants was 50 years (range 18–102 years); 58% were female. The proportion of patients observed in a COVID-19 emergency setting for more than 6 h or transferred to a teritary hospital due to COVID-19 was lower for the fluvoxamine group compared with placebo (79 [11%] of 741 vs 119 [16%] of 756); relative risk [RR] 0·68; 95% Bayesian credible interval [95% BCI]: 0·52–0·88), with a probability of superiority of 99·8% surpassing the prespecified superiority threshold of 97·6% (risk difference 5·0%). Of the composite primary outcome events, 87% were hospitalisations. Findings for the primary outcome were similar for the modified intention-to-treat analysis (RR 0·69, 95% BCI 0·53–0·90) and larger in the per-protocol analysis (RR 0·34, 95% BCI, 0·21–0·54). There were 17 deaths in the fluvoxamine group and 25 deaths in the placebo group in the primary intention-to-treat analysis (odds ratio [OR] 0·68, 95% CI: 0·36–1·27). There was one death in the fluvoxamine group and 12 in the placebo group for the per-protocol population (OR 0·09; 95% CI 0·01–0·47). We found no significant differences in number of treatment emergent adverse events among patients in the fluvoxamine and placebo groups. Treatment with fluvoxamine (100 mg twice daily for 10 days) among high-risk outpatients with early diagnosed COVID-19 reduced the need for hospitalisation defined as retention in a COVID-19 emergency setting or transfer to a tertiary hospital. FastGrants and The Rainwater Charitable Foundation. For the Portuguese translation of the abstract see Supplementary Materials section.