Efficacy Analysis in Healthy-Volunteer Influenza Challenge Trials: Intention To Treat.
Efficacy Analysis in Healthy-Volunteer Influenza Challenge Trials: Intention To Treat.
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健康志愿者流感挑战试验的功效分析：治疗意向。
DOI：
10.1128/aac.02018-17
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发表时间：
2018
影响因子：
4.9
通讯作者：
Memoli,MatthewJ
中科院分区：
文献类型：
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作者：
Hunsberger,Sally;Memoli,MatthewJ
Hunsberger和Memoli的评论（1）质疑了我们在II期研究中使用的流感攻毒模型中仅评价有活动性甲型流感病毒（IAV）感染证据的受试者（意向治疗感染[ITTI]人群）的病毒学终点的方法的适当性（2）。作者引用了旨在评估疾病预防或减轻携带病毒者疾病严重程度的疫苗试验。如果我们的研究是一项预防流感病毒感染的预防性研究，则这些关于感染受试者比例的问题是适当的;然而，MHAA 4549 A不是疫苗，而是一种预期用于治疗已活动性甲型流感感染的治疗药物。治疗模型旨在模拟自然感染的临床环境;因此，所有受试者在IAV接种后约24小时接受治疗。对于预防性研究，应在接种病毒之前进行治疗。充分认识到，尽管接种了疫苗，但并非所有健康受试者预期在这些激发模型中具有任何可检测的感染（3-8）。我们的目的不是证明临床疗效，而是了解药代动力学/药效学关系。这些结果不仅提供了活性证据，而且还为MHAA 4549 A剂量选择提供了信息，这是在实验室确认感染的住院患者和门诊患者中进行的大型随机盲法临床试验中评估真实临床疗效所必需的。根据研究方案预先确定ITTI选择，包括在任何给定日期具有病毒载量或血清转换证据的受试者。最合适的结局指标不是Hunsberger和Memoli（1）提出的终点感染率，而是病毒载量曲线下面积（AUC）和病毒脱落持续时间，以确定MHAA 4549 A是否可以降低感染受试者的感染程度和持续时间。这些测量包括qPCR结果和50%组织培养感染剂量（TCID 50），这是病毒负荷的两种测量方法。如果引入了任何偏倚，ITTI选择可能低估了我们治疗组的疗效，排除了那些治疗后没有继续检测到病毒感染且随后没有出现血清转化的个体。治疗研究中的ITTI选择被认为是一种标准方法，并在IAV或鼻病毒攻毒模型中确定新型抗病毒药物或免疫措施的活性证据时应用（3-8）。在Hunsberger和Memoli引用的Hayden综述中，描述了预防和治疗研究（9）。对于引用的预防性研究，报告了所有研究受试者感染的比例（3，4）。然而，在所引用的治疗研究以及后来进行的其他研究中，在评估时选择了ITTI人群，
Hunsberger and Memoli’s comment (1) challenges the appropriateness of our approach to evaluate only virological endpoints in subjects with evidence of an active influenza A virus (IAV) infection (the intention-to-treat infected [ITTI] population) in the influenza challenge model used in our phase 2 study (2). The authors have cited vaccine trials intended to assess prevention of disease or to diminish the severity of disease of those with virus on board. Had our study been a prophylactic study to prevent influenza virus infection, these concerns regarding the proportion of subjects infected would be appropriate; however, MHAA4549A was not a vaccine but rather a therapeutic intended for treatment of already-active influenza A infections. The treatment model was designed to simulate a clinical setting with natural infection; as such, all subjects were treated approximately 24 h after IAV inoculation. For a prophylactic study, the treatment would have been administered prior to inoculation with virus. It is well appreciated that despite being inoculated, not all healthy subjects are expected to have any detectable infection in these challenge models (3–8). Our intent was not to demonstrate clinical efficacy but rather to understand the pharmacokinetic/pharmacodynamic relationship. These results not only provide proof of activity but also inform MHAA4549A dose selection, which is required for assessing true clinical efficacy in larger, randomized, blind clinical trials in hospitalized-patient and outpatient populations with laboratory-confirmed infection. The ITTI selection was predefined per the study protocol and included subjects with any evidence of viral load or seroconversion on any given day. Rather than the rate of infection, the endpoint proposed by Hunsberger and Memoli (1), the most appropriate outcome measures were area under the viral-load curve (AUC) and the duration of viral shedding to determine if MHAA4549A could reduce the extent and duration of infection within the infected subjects. These measurements included both qPCR results and the 50% tissue culture infective dose (TCID50), two measures of viral burden. If any bias was introduced, ITTI selection may have underestimated the efficacy within our treatment arms by excluding those individuals who, as a result of treatment, did not go on to have detectable virus infection and did not exhibit subsequent seroconversion. ITTI selection in treatment studies is accepted as a standard approach and has been applied when determining proof of activity for novel antivirals or immune measures in IAV or rhinovirus challenge models (3–8). In the Hayden review cited by the Hunsberger and Memoli, both prophylactic and treatment studies are described (9). For the cited prophylactic studies, the proportions of all study subjects that became infected were reported (3, 4). However, in the cited treatment studies, and in additional studies conducted later, the selection of an ITTI population was applied when assessing