Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19: The TOGETHER Randomized Clinical Trial.
Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19: The TOGETHER Randomized Clinical Trial.
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DOI：
10.1001/jamanetworkopen.2021.6468
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发表时间：
2021-04-01
影响因子：
13.8
通讯作者：
TOGETHER Investigators
中科院分区：
文献类型：
--
作者：
Reis G;Moreira Silva EADS;Medeiros Silva DC;Thabane L;Singh G;Park JJH;Forrest JI;Harari O;Quirino Dos Santos CV;Guimarães de Almeida APF;Figueiredo Neto AD;Savassi LCM;Milagres AC;Teixeira MM;Simplicio MIC;Ribeiro LB;Oliveira R;Mills EJ;TOGETHER Investigators
作为9天疗程的羟氯喹或洛比那韦-利托那韦能否阻止新冠肺炎患者因新冠肺炎而住院？在这项包括685名患者的试验中，接受羟氯喹或洛匹那韦-利托那韦治疗的患者与接受安慰剂治疗的患者相比，与新冠肺炎相关的住院率没有显著差异。这些发现可能会为新冠肺炎针对新冠肺炎患者的门诊治疗指南提供参考，并表明在疫情大流行期间，可以在低收入环境下成功完成大规模的新冠肺炎药物门诊临床试验。这项随机临床试验检验了羟氯喹或洛比那韦-利托那韦对减少早期有症状的新冠肺炎高危门诊患者的住院率是否有效。需要关于羟氯喹或洛比那韦-利托那韦在发展中国家治疗新冠肺炎高危门诊患者的疗效的数据。目的：确定羟氯喹或洛比那韦-利托那韦是否能减少门诊中早期有症状的新冠肺炎高危患者的住院时间。这项随机临床试验是在巴西进行的。最近被诊断为SARS-CoV-2感染的呼吸道症状的成年人在2020年6月2日至9月30日期间登记。计划的样本量为1476名患者，计划在500名患者入选后进行中期分析。这项试验在对685名患者进行无效性中期分析后停止。统计分析于2020年12月进行。患者随机分为羟氯喹(800 mg负荷量，然后每天400 mg，共9天)、洛匹那韦-利托那韦(每12小时负荷量分别为800 mg和200 mg，随后分别为400 mg和100 mg，每12小时一次)或安慰剂。主要结果是随机分组后90天评估与新冠肺炎相关的住院和死亡情况。新冠肺炎相关住院用COX比例风险模型进行分析。该试验包括以下次要结果：全因住院、病毒清除、症状缓解和不良事件。在685名参与者中，632人(92.3%)自认为是混血，377人(55.0%)是女性，年龄中位数(范围)为53岁(18-94岁)。共有214名参与者被随机分配到羟氯喹、244名洛比那韦-利托那韦和227名安慰剂。在第一次中期分析中，数据安全监测委员会建议停止羟氯喹和洛匹那韦-利托那韦两组的注册，因为这是无效的。因新冠肺炎住院的患者比例，羟氯喹组为3.7%(8名参与者)，洛匹那韦-利托那韦组为5.7%(14名参与者)，安慰剂组为4.8%(11名参与者)。我们发现，新冠肺炎相关住院的干预措施之间没有显著差异(羟氯喹：危险比[HR]，0.76[95%CI，0.30-1.88]；洛匹那韦-利托那韦：HR，1.16[95%CI，0.53-2.56]；以及第14天病毒清除的二次结局(羟氯喹：优势比[OR]，0.91[95%CI，0.82-1.02]；洛匹那韦-利托那韦：OR，1.04[95%CI，0.94-1.16])。在试验结束时，有3例死亡记录，1例在安慰剂组，2例在洛比那韦-利托那韦干预组。在这项随机临床试验中，羟氯喹和洛匹那韦-利托那韦都没有显示出在减少新冠肺炎相关住院或其他次要临床结果方面有任何显著益处。这项试验表明，即使在新冠肺炎大流行期间，也可以在低收入环境中实施权宜之计的临床试验。ClinicalTrials.gov标识：NCT04403100
Does hydroxychloroquine or lopinavir-ritonavir, administered as a 9-day course, prevent COVID-19–associated hospitalization in patients with COVID-19? In this trial that included 685 patients, rates of COVID-19–associated hospitalization in patients treated with hydroxychloroquine or lopinavir-ritonavir were not significantly different compared with those who received placebo. These findings may inform COVID-19 treatment guidelines for outpatients with COVID-19 and demonstrate that large-scale outpatient clinical trials of repurposed drugs can be successfully completed in low-income settings during the pandemic. This randomized clinical trial examines whether hydroxychloroquine or lopinavir-ritonavir is effective for reducing hospitalization among high-risk outpatients with early symptomatic COVID-19. Data on the efficacy of hydroxychloroquine or lopinavir-ritonavir for the treatment of high-risk outpatients with COVID-19 in developing countries are needed. To determine whether hydroxychloroquine or lopinavir-ritonavir reduces hospitalization among high-risk patients with early symptomatic COVID-19 in an outpatient setting. This randomized clinical trial was conducted in Brazil. Recently symptomatic adults diagnosed with respiratory symptoms from SARS-CoV-2 infection were enrolled between June 2 and September 30, 2020. The planned sample size was 1476 patients, with interim analyses planned after 500 patients were enrolled. The trial was stopped after the interim analysis for futility with a sample size of 685 patients. Statistical analysis was performed in December 2020. Patients were randomly assigned to hydroxychloroquine (800 mg loading dose, then 400 mg daily for 9 days), lopinavir-ritonavir (loading dose of 800 mg and 200 mg, respectively, every 12 hours followed by 400 mg and 100 mg, respectively, every 12 hours for the next 9 days), or placebo. The primary outcomes were COVID-19–associated hospitalization and death assessed at 90 days after randomization. COVID-19–associated hospitalization was analyzed with a Cox proportional hazards model. The trial included the following secondary outcomes: all-cause hospitalization, viral clearance, symptom resolution, and adverse events. Of 685 participants, 632 (92.3%) self-identified as mixed-race, 377 (55.0%) were women, and the median (range) age was 53 (18-94) years. A total of 214 participants were randomized to hydroxychloroquine; 244, lopinavir-ritonavir; and 227, placebo. At first interim analysis, the data safety monitoring board recommended stopping enrollment of both hydroxychloroquine and lopinavir-ritonavir groups because of futility. The proportion of patients hospitalized for COVID-19 was 3.7% (8 participants) in the hydroxychloroquine group, 5.7% (14 participants) in the lopinavir-ritonavir group, and 4.8% (11 participants) in the placebo group. We found no significant differences between interventions for COVID-19–associated hospitalization (hydroxychloroquine: hazard ratio [HR], 0.76 [95% CI, 0.30-1.88]; lopinavir-ritonavir: HR, 1.16 [95% CI, 0.53-2.56] as well as for the secondary outcome of viral clearance through day 14 (hydroxychloroquine: odds ratio [OR], 0.91 [95% CI, 0.82-1.02]; lopinavir-ritonavir: OR, 1.04 [95% CI, 0.94-1.16]). At the end of the trial, there were 3 fatalities recorded, 1 in the placebo group and 2 in the lopinavir-ritonavir intervention group. In this randomized clinical trial, neither hydroxychloroquine nor lopinavir-ritonavir showed any significant benefit for decreasing COVID-19–associated hospitalization or other secondary clinical outcomes. This trial suggests that expedient clinical trials can be implemented in low-income settings even during the COVID-19 pandemic. ClinicalTrials.gov Identifier: NCT04403100
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DOI：
10.1056/nejmoa2022926
发表时间：
2020-11-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
RECOVERY Collaborative Group;Horby P;Mafham M;Linsell L;Bell JL;Staplin N;Emberson JR;Wiselka M;Ustianowski A;Elmahi E;Prudon B;Whitehouse T;Felton T;Williams J;Faccenda J;Underwood J;Baillie JK;Chappell LC;Faust SN;Jaki T;Jeffery K;Lim WS;Montgomery A;Rowan K;Tarning J;Watson JA;White NJ;Juszczak E;Haynes R;Landray MJ
通讯作者：
Landray MJ
影响因子：
9.4
作者：
Lieberman, Joshua A.;Pepper, Gregory;Greninger, Alexander L.
通讯作者：
Greninger, Alexander L.
影响因子：
158.5
作者：
Boulware, David R.;Pullen, Matthew F.;Hullsiek, Kathy H.
通讯作者：
Hullsiek, Kathy H.
影响因子：
7.2
作者：
Barrett, B;Brown, R;Alt, J
通讯作者：
Alt, J
影响因子：
168.9
作者：
Huang, Chaolin;Wang, Yeming;Cao, Bin
通讯作者：
Cao, Bin