Development of a placebo effect model combined with a dropout model for bipolar disorder

  • Wan Sun
  • Thomas P. Laughren
  • Hao Zhu
  • Guenther Hochhaus
  • Yaning Wang
Original Paper

Abstract

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.

Keywords

Bipolar disorder Placebo model Dropout Clinical trial simulation 

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Copyright information

© Springer Science+Business Media New York (outside the USA) 2013

Authors and Affiliations

  • Wan Sun
    • 1
  • Thomas P. Laughren
    • 4
  • Hao Zhu
    • 2
  • Guenther Hochhaus
    • 3
  • Yaning Wang
    • 1
  1. 1.Division of PharmacometricsOffice of Clinical Pharmacology, US Food and Drug AdministrationSilver SpringUSA
  2. 2.Division of Clinical Pharmacology 1Office of Clinical Pharmacology, US Food and Drug AdministrationSilver SpringUSA
  3. 3.Department of PharmaceuticsUniversity of FloridaGainesvilleUSA
  4. 4.Division of Psychiatry ProductsUS Food and Drug AdministrationSilver SpringUSA

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