Marostica Eleonora, Russu Alberto, Yang Shuying, De Nicolao Giuseppe, Zamuner Stefano, Beerahee Misba
Department of Industrial and Information Engineering, University of Pavia, Via Ferrata 1, 27100 , Pavia, Italy,
J Pharmacokinet Pharmacodyn. 2014 Dec;41(6):553-69. doi: 10.1007/s10928-014-9373-1. Epub 2014 Aug 15.
Asthma is an obstructive lung disease where the mechanism of disease progression is not fully understood hence motivating the use of empirical models to describe the evolution of the patient's health state. With reference to placebo response, measured in terms of FEV1 (Forced Expiratory Volume in 1 s), a range of empirical models taken from the literature were compared at a single trial level. In particular, eleven GSK trials lasting 12 weeks in mild-to-moderate asthma were used for the modelling of longitudinal placebo responses. Then, the chosen exponential model was used to carry out an individual participant data meta-analysis on eleven trials. A covariate analysis was also performed to find relevant covariates in asthma to be accounted for in the meta-analysis model. Age, gender, and height were found statistically significant (e.g. the taller the patients the higher the FEV1, the older the patients the lower the FEV1, and females have lower FEV1). By truncating each trial at week 4, the predictive properties of the meta-analysis model were also investigated, showing its ability to predict long-term FEV1 response from truncated trials. Summarizing, the study suggests that: (i) the exponential model effectively describes the placebo response; (ii) the meta-analysis approach may prove helpful to simulate new trials as well as to reduce trial duration in view of its predictive properties; (iii) the inclusion of available covariates within the meta-analysis model provides a reduction of the inter-individual variability.
哮喘是一种阻塞性肺部疾病，其疾病进展机制尚未完全明确，因此促使人们使用经验模型来描述患者健康状态的演变。关于以第1秒用力呼气量（FEV1）衡量的安慰剂反应，在单个试验层面比较了一系列从文献中获取的经验模型。具体而言，使用了11项针对轻至中度哮喘患者、为期12周的葛兰素史克（GSK）试验来模拟纵向安慰剂反应。然后，使用选定的指数模型对11项试验进行个体参与者数据荟萃分析。还进行了协变量分析，以找出荟萃分析模型中需要考虑的哮喘相关协变量。发现年龄、性别和身高具有统计学意义（例如，患者越高，FEV1越高；患者年龄越大，FEV1越低；女性的FEV1较低）。通过在第4周截断每个试验，还研究了荟萃分析模型的预测特性，结果显示该模型能够从截断试验中预测长期FEV1反应。总之，该研究表明：（i）指数模型有效地描述了安慰剂反应；（ii）鉴于其预测特性，荟萃分析方法可能有助于模拟新试验并缩短试验持续时间；（iii）在荟萃分析模型中纳入可用协变量可减少个体间变异性。
