Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection A Randomized Clinical Trial
Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection A Randomized Clinical Trial
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DOI：
10.1001/jamanetworkopen.2020.8857
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发表时间：
2020-04-24
影响因子：
13.8
通讯作者：
Lacerda, Marcus Vinicius Guimaraes
中科院分区：
文献类型：
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作者：
Borba, Mayla Gabriela Silva;Val, Fernando Fonseca Almeida;Lacerda, Marcus Vinicius Guimaraes
重要性对于2019冠状病毒病（COVID-19），没有推荐特定的抗病毒治疗。体外研究表明，二磷酸氯喹（CQ）的抗病毒作用需要高浓度的药物。目的评价2种剂量CQ治疗重症COVID-19患者的安全性和有效性。设计、设置和参与者这项平行、双盲、随机、IIb期临床试验于2020年3月23日至4月5日在巴西亚马逊马瑙斯的一家三级医疗机构进行，共有81名因严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）感染住院的成人患者参加。干预措施患者被分配接受高剂量CQ（即600 mg CQ，每日两次，持续10天）或低剂量CQ（即450 mg CQ，每日两次，第1天，每日一次，持续4天）。主要结果和测量主要结果是与低剂量组相比，高剂量组的致死率降低至少50%。此处提供的数据主要涉及第13天治疗期间的安全性和致死性结局。次要终点包括参与者的临床状态、实验室检查和心电图结果。结果将在第28天公布。在第0天和第4天进行病毒呼吸道分泌物RNA检测。结果在预定的440例患者中，81例患者入组（41例[50.6%]进入高剂量组，40例[49.4%]进入低剂量组）。入组患者的平均（SD）年龄为51.1（13.9）岁，大多数（60例[75.3%]）为男性。在高剂量组中观察到年龄较大（平均[SD]年龄，54.7 [13.7]岁vs 47.4 [13.3]岁）和心脏病较多（5/28 [17.9%] vs 0）。在低剂量组和高剂量组中分别有31/40（77.5%）和31/41（75.6%）例患者检测到病毒RNA。直至第13天，高剂量组的致死率为39.0%（16/41），低剂量组为15.0%（6/40）。与低剂量组（4/36 [11.1%]）相比，高剂量组QTc间期大于500毫秒的情况更多（7/37 [18.9%]）。27例患者中仅6例（22.2%）第4天呼吸道分泌物为阴性。结论和相关性本研究的初步结果表明，不应建议COVID-19重症患者使用较高剂量的CQ，因为其存在潜在的安全性风险，尤其是与阿奇霉素和奥司他韦同时使用时。这些发现不能外推到非重度COVID-19患者。
Importance There is no specific antiviral therapy recommended for coronavirus disease 2019 (COVID-19). In vitro studies indicate that the antiviral effect of chloroquine diphosphate (CQ) requires a high concentration of the drug. Objective To evaluate the safety and efficacy of 2 CQ dosages in patients with severe COVID-19. Design, Setting, and Participants This parallel, double-masked, randomized, phase IIb clinical trial with 81 adult patients who were hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was conducted from March 23 to April 5, 2020, at a tertiary care facility in Manaus, Brazilian Amazon. Interventions Patients were allocated to receive high-dosage CQ (ie, 600 mg CQ twice daily for 10 days) or low-dosage CQ (ie, 450 mg twice daily on day 1 and once daily for 4 days). Main Outcomes and Measures Primary outcome was reduction in lethality by at least 50% in the high-dosage group compared with the low-dosage group. Data presented here refer primarily to safety and lethality outcomes during treatment on day 13. Secondary end points included participant clinical status, laboratory examinations, and electrocardiogram results. Outcomes will be presented to day 28. Viral respiratory secretion RNA detection was performed on days 0 and 4. Results Out of a predefined sample size of 440 patients, 81 were enrolled (41 [50.6%] to high-dosage group and 40 [49.4%] to low-dosage group). Enrolled patients had a mean (SD) age of 51.1 (13.9) years, and most (60 [75.3%]) were men. Older age (mean [SD] age, 54.7 [13.7] years vs 47.4 [13.3] years) and more heart disease (5 of 28 [17.9%] vs 0) were seen in the high-dose group. Viral RNA was detected in 31 of 40 (77.5%) and 31 of 41 (75.6%) patients in the low-dosage and high-dosage groups, respectively. Lethality until day 13 was 39.0% in the high-dosage group (16 of 41) and 15.0% in the low-dosage group (6 of 40). The high-dosage group presented more instance of QTc interval greater than 500 milliseconds (7 of 37 [18.9%]) compared with the low-dosage group (4 of 36 [11.1%]). Respiratory secretion at day 4 was negative in only 6 of 27 patients (22.2%). Conclusions and Relevance The preliminary findings of this study suggest that the higher CQ dosage should not be recommended for critically ill patients with COVID-19 because of its potential safety hazards, especially when taken concurrently with azithromycin and oseltamivir. These findings cannot be extrapolated to patients with nonsevere COVID-19.