Division of Pharmacometrics, Office of Clinical Pharmacology, US Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
J Pharmacokinet Pharmacodyn. 2013 Jun;40(3):359-68. doi: 10.1007/s10928-013-9305-5. Epub 2013 Mar 2.
The aim of this study was to develop a placebo model for bipolar disorder to help optimize clinical trial designs for studies targeting manic episodes in bipolar disorder. A bipolar disease database was built based on individual longitudinal data collected from over 3,000 patients in 11 clinical trials for 5 approved bipolar drugs. An empirical placebo effect model with an exponential decay process plus a linear progression process was developed to quantify the time course of the Young Mania Rating Scale total score based on only placebo data from the database. In order to describe the dropout pattern during the trials, a parametric survival model was developed and the Weibull distribution was identified to be the best distribution to describe the data. Based on the likelihood ratio test, it was found that patients with higher baseline score, slower disease improvement and more rapid disease progression tended to dropout earlier, and the trial features such as trial starting year and trial site were also significant covariates for dropout. A combination of the placebo effect model and the dropout model was applied to simulate new clinical trials through Monte-Carlo simulation. Both the placebo effect model and dropout model described the observed data reasonably well based on various diagnostic plots. The joint placebo response and dropout models can serve as a tool to simulate the most likely level of placebo response with the expected dropout pattern to help design a new clinical trial.
本研究旨在为双相情感障碍开发一种安慰剂模型，以帮助优化针对双相情感障碍躁狂发作的临床试验设计。基于来自 11 项 5 种已批准的双相情感障碍药物临床试验的 3000 多名患者的个体纵向数据，建立了一个双相情感障碍数据库。为了定量描述 Young Mania Rating Scale 总分随时间的变化，开发了一个具有指数衰减过程和线性进展过程的经验安慰剂效应模型，该模型仅基于数据库中的安慰剂数据。为了描述试验期间的脱落模式，开发了一个参数生存模型，并确定威布尔分布是描述数据的最佳分布。基于似然比检验，发现基线得分较高、疾病改善较慢和疾病进展较快的患者往往较早脱落，并且试验特征，如试验开始年份和试验地点，也是脱落的重要协变量。将安慰剂效应模型和脱落模型相结合，通过蒙特卡罗模拟应用于新的临床试验。安慰剂效应模型和脱落模型都能根据各种诊断图合理地描述观察到的数据。联合安慰剂反应和脱落模型可作为一种工具，模拟最有可能的安慰剂反应水平和预期的脱落模式，以帮助设计新的临床试验。
