Oral GS-5806 Activity in a Respiratory Syncytial Virus Challenge Study
Oral GS-5806 Activity in a Respiratory Syncytial Virus Challenge Study
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DOI：
10.1056/nejmoa1401184
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发表时间：
2014-08-21
影响因子：
158.5
通讯作者：
Chien, Jason W.
中科院分区：
文献类型：
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作者：
DeVincenzo, John P.;Whitley, Richard J.;Chien, Jason W.
背景呼吸道合胞病毒(RSV)是导致婴儿住院的常见原因，越来越多地被认为是导致相当大的发病率和死亡率的原因。目前还没有公认的抗病毒治疗方法。方法我们对口服RSV进入抑制剂GS-5806进行了一项双盲、安慰剂对照研究，研究对象是接受鼻腔内RSV临床挑战毒株的健康成年人。参与者被监测了12天。在RSV感染阳性检测时或接种后5天，以最先发生的为准，参与者被随机分配到七个连续队列中的一个接受GS-5806或安慰剂治疗。第1~4组首剂GS-5806 50 mg，随后每日25 mg；第5组首剂50 mg，以后2天每日25 mg；第6组100 mg；第7组首剂10 mg，以后4天每日5 mg。第5、6和7组的剂量选择是在对第1至第4组的数据进行中期分析后进行的。主要终点是病毒载量的曲线下面积(AUC)，该曲线下面积在第一次接种后至接种后第12天进行评估。次要终点是粘液重量和症状评分。结果在感染呼吸道合胞病毒的1至4个队列中的54名参与者中，积极治疗与较低的病毒载量(调整后平均为250.7对数10菌斑形成单位当量x每毫升小时；P<；0.001)、较低的粘液总重量(平均6.9g对15.1g；P=0.03)以及症状评分较基线的变化有关(调整后平均为-20.2x小时对204.9小时；P=0.005)。第5、6和7组的结果相似。接受GS-5806治疗的参与者中更常见的不良事件包括中性粒细胞数量减少和丙氨酸氨基转移酶水平升高。结论在一项针对健康成年人的挑战性研究中，GS-5806治疗降低了病毒载量和临床疾病的严重性。(由Gilead Sciences提供资金；ClinicalTrials.gov编号，NCT01756482。)
BACKGROUNDRespiratory syncytial virus (RSV) is a common cause of infant hospitalizations and is increasingly recognized as a cause of considerable morbidity and mortality. No accepted antiviral treatment exists.METHODSWe conducted a double-blind, placebo-controlled study of GS-5806, an oral RSV-entry inhibitor, in healthy adults who received a clinical challenge strain of RSV intranasally. Participants were monitored for 12 days. At the time of a positive test for RSV infection or 5 days after inoculation, whichever occurred first, participants were randomly assigned to receive GS-5806 or placebo in one of seven sequential cohorts. Cohorts 1 to 4 received a first dose of 50 mg of GS-5806 and then 25 mg daily for the next 4 days, cohort 5 received a first dose of 50 mg and then 25 mg daily for the next 2 days, cohort 6 received one 100-mg dose, and cohort 7 received a first dose of 10 mg and then 5 mg daily for the next 4 days. Dose selection for cohorts 5, 6, and 7 occurred after an interim analysis of data for cohorts 1 to 4. The primary end point was the area under the curve (AUC) for the viral load, which was assessed after administration of the first dose through the 12th day after inoculation. Secondary end points were mucus weight and symptom scores.RESULTSAmong the 54 participants in cohorts 1 to 4 who were infected with RSV, active treatment was associated with a lower viral load (adjusted mean, 250.7 vs. 757.7 log 10 plaque-forming-unit equivalents [PFUe] x hours per milliliter; P< 0.001), lower total mucus weight (mean, 6.9 g vs. 15.1 g; P = 0.03), and a lower AUC for the change from baseline in symptom scores (adjusted mean, -20.2 vs. 204.9 x hours; P = 0.005). The results were similar in cohorts 5, 6, and 7. Adverse events, including low neutrophil counts and increased levels of alanine aminotransferase, were more common among participants receiving GS-5806.CONCLUSIONSTreatment with GS-5806 reduced the viral load and the severity of clinical disease in a challenge study of healthy adults. (Funded by Gilead Sciences; ClinicalTrials.gov number, NCT01756482.)