Peginterferon lambda for the treatment of outpatients with COVID-19: a phase 2, placebo-controlled randomised trial.
Peginterferon lambda for the treatment of outpatients with COVID-19: a phase 2, placebo-controlled randomised trial.
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DOI：
10.1016/s2213-2600(20)30566-x
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发表时间：
2021-05
期刊：
影响因子：
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通讯作者：
Hansen BE
中科院分区：
文献类型：
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作者：
Feld JJ;Kandel C;Biondi MJ;Kozak RA;Zahoor MA;Lemieux C;Borgia SM;Boggild AK;Powis J;McCready J;Tan DHS;Chan T;Coburn B;Kumar D;Humar A;Chan A;O'Neil B;Noureldin S;Booth J;Hong R;Smookler D;Aleyadeh W;Patel A;Barber B;Casey J;Hiebert R;Mistry H;Choong I;Hislop C;Santer DM;Lorne Tyrrell D;Glenn JS;Gehring AJ;Janssen HLA;Hansen BE
迄今为止，只有单克隆抗体被证明对COVID-19门诊患者有效。干扰素λ-1是一种III型干扰素，参与先天性抗病毒反应，具有抗呼吸道病原体的活性。我们的目的是研究聚乙二醇干扰素λ治疗轻中度COVID-19门诊患者的安全性和有效性。在这项双盲、安慰剂对照试验中，实验室确诊的COVID-19门诊患者在症状发作或首次拭子阳性（如果无症状）的7天内被随机分配接受单次皮下注射聚乙二醇干扰素λ 180 μg或安慰剂。使用计算机生成的随机化列表将受试者随机分配（1：1），该列表使用随机化时间表创建，分为四个区组。给药时，研究护士收到一个密封的不透明信封，信封上有治疗分配编号。主要终点是注射后第7天严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）RNA阴性的患者比例，按照意向治疗原则进行χ2检验分析。使用双变量logistic回归对主要终点进行预先设定的分析，根据基线病毒载量进行调整。审判现已结束。本试验注册于ClinicalTrials.gov，NCT 04354259。在2020年5月18日至9月4日期间，我们每组招募了30名患者。从第3天开始，接受聚乙二醇干扰素λ治疗的患者SARS-CoV-2 RNA的下降幅度大于安慰剂组，第7天的差异为2.42 log拷贝/mL（p= 0.0041）。到第7天，聚乙二醇干扰素λ组有24名（80%）参与者的病毒载量检测不到，而安慰剂组有19名（63%）（p= 0.15）。在控制了基线病毒载量后，聚乙二醇干扰素λ组患者在第7天检测不到病毒的可能性高于安慰剂组（比值比[OR] 4.12 [95%CI 1.15 - 16.73; p= 0.029）。在基线病毒载量高于106拷贝/mL的患者中，聚乙二醇干扰素λ组19例患者中有15例（79%）在第7天检测不到病毒，而安慰剂组16例患者中有6例（38%）检测不到病毒（OR 6.25 [95%CI 1.49 - 31.06]; p= 0.012）。聚乙二醇干扰素λ耐受性良好，两组之间的不良事件相似，轻度和一过性转氨酶升高，聚乙二醇干扰素λ组中更常见的浓度升高。两个个体达到3级增加的阈值，每组各一个，没有报告其他3级或4级实验室不良事件。聚乙二醇干扰素λ加速了COVID-19门诊患者的病毒下降，增加了第7天病毒清除的患者比例，特别是在基线病毒载量高的患者中。聚乙二醇干扰素λ具有预防临床恶化和缩短病毒脱落持续时间的潜力。多伦多COVID-19行动倡议，多伦多大学，和安大略省第一个COVID-19快速研究基金，多伦多综合和西部医院基金会。
To date, only monoclonal antibodies have been shown to be effective for outpatients with COVID-19. Interferon lambda-1 is a type III interferon involved in innate antiviral responses with activity against respiratory pathogens. We aimed to investigate the safety and efficacy of peginterferon lambda in the treatment of outpatients with mild-to-moderate COVID-19. In this double-blind, placebo-controlled trial, outpatients with laboratory-confirmed COVID-19 were randomly assigned to a single subcutaneous injection of peginterferon lambda 180 μg or placebo within 7 days of symptom onset or first positive swab if asymptomatic. Participants were randomly assigned (1:1) using a computer-generated randomisation list created with a randomisation schedule in blocks of four. At the time of administration, study nurses received a sealed opaque envelope with the treatment allocation number. The primary endpoint was the proportion of patients who were negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA on day 7 after the injection, analysed by a χ2 test following an intention-to-treat principle. Prespecified analysis of the primary endpoint, adjusted for baseline viral load, using bivariate logistic regression was done. The trial is now complete. This trial is registered with ClinicalTrials.gov, NCT04354259. Between May 18, and Sept 4, 2020, we recruited 30 patients per group. The decline in SARS-CoV-2 RNA was greater in those treated with peginterferon lambda than placebo from day 3 onwards, with a difference of 2·42 log copies per mL at day 7 (p=0·0041). By day 7, 24 (80%) participants in the peginterferon lambda group had an undetectable viral load, compared with 19 (63%) in the placebo group (p=0·15). After controlling for baseline viral load, patients in the peginterferon lambda group were more likely to have undetectable virus by day 7 than were those in the placebo group (odds ratio [OR] 4·12 [95% CI 1·15–16·73; p=0·029). Of those with baseline viral load above 106 copies per mL, 15 (79%) of 19 patients in the peginterferon lambda group had undetectable virus on day 7, compared with six (38%) of 16 in the placebo group (OR 6·25 [95% CI 1·49–31·06]; p=0·012). Peginterferon lambda was well tolerated, and adverse events were similar between groups with mild and transient aminotransferase, concentration increases more frequently observed in the peginterferon lambda group. Two individuals met the threshold of grade 3 increase, one in each group, and no other grade 3 or 4 laboratory adverse events were reported. Peginterferon lambda accelerated viral decline in outpatients with COVID-19, increasing the proportion of patients with viral clearance by day 7, particularly in those with high baseline viral load. Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding. The Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.