Aims: Existing evidence from clinical trial data suggests that a positive placebo effect occurs in overactive bladder (OAB) patients (1). Researchers also confirmed that the placebo response in OAB clinical trials was substantial by a meta-analysis based on the change from baseline (CFB) outcomes at the end of the study period (2). However, the time course of the placebo response in OAB clinical trials has not been systematically investigated via model-based analysis. The aim of this study is to describe the time course of the placebo effect in OAB and quantitatively investigate the covariates for the placebo response.
Methods: We conducted a search of public data sources including new drug application (NDA) materials which had been published online for the study-level micturition frequency (MF) to develop the placebo effect model. Mean patient age, mean male proportion, baseline MF, and ethnicity (non-Japanese or Japanese) were tested as covariates. The parameter estimation was performed using NONMEM 7 (Level 1.2, ICON Development Solutions, Ellicott City, MD, USA) with the FOCE-I method.
Results: There were 17 clinical studies for anti-cholinergic (anti-muscarinic) agents and a beta-3 adrenergic agonist with 3,580 placebo-arm patients. The exponential models rather than linear ones adequately described the time course of placebo effect with the typical value of the maximum placebo effect (Pmax) of approx. 2 MF reduction/day. Ethnicity (non-Japanese or Japanese) was detected as a covariate on the rate constant for onset of the placebo effect with objective function value (OFV) reduction of 7.6, which had already been suggested in clinical studies of fesoterodine, one of the anti-muscarinic agents.
Conclusion: The placebo effect in the OAB clinical trials is adequately described by an exponential model over time. The developed model could be the useful tool for the drug effect evaluation.
1. Mangera A, Chapple CR, Kopp ZS, Plested M. The placebo effect in overactive bladder syndrome. Nat Rev Urol. 2011;8(9):495-503.
2. Lee S, Malhotra B, Creanga D, Carlsson M, Glue P. A meta-analysis of the placebo response in antimuscarinic drug trials for overactive bladder. BMC Med Res Methodol. 2009;9:55.