Background: Successful clinical development of anti-obesity agents is aided by characterization of the placebo effect, which can be significant when lifestyle intervention (LSI) accompanies pharmacologic therapy. Understanding the time course and dynamics of the placebo effect is important when developing pharmacodynamic (PD) models that isolate drug effects. Exploratory analyses were therefore performed to examine time-dependent changes in body weight during placebo treatment with and without LSI in obese subjects.
Methods: Data were obtained from obese subjects (BMI ≥30 to ≤50 kg/m2) enrolled in the placebo arms of 2 obesity studies. In both, subjects injected placebo subcutaneously TID prior to meals for 16 weeks. Both studies included a 1-week placebo run-in prior to any LSI and a 16-week placebo treatment with or without LSI (LEARN® Program with lessons on eating, exercise, and behavioral modification) designed for weight loss. An extension to the LSI study was also performed, in which subjects received an additional 36 weeks of placebo treatment and participated in LSI designed for weight maintenance. The effect and time course of LSI on weight loss were evaluated using mean (SD) plots and boxplots of weight versus week since first dose (wsfd). The percentage of subjects achieving a 5% weight loss and the timing of subject withdrawals were also determined.
Results: A total of 748 weight measurements from 94 subjects were evaluated. The mean (SD) baseline weight was 105 (20) kg (range 72 to 162 kg). The population was 77% female and 56% of the population participated in LSI. Mean (SD) weight loss was -0.23 (0.95) kg at the end of placebo run-in. No overall reduction in body weight was observed without LSI. For subjects in the LSI program, the mean weight nadir occurred at approximately 20 to 24 weeks, followed by a consistent mean weight gain throughout the extension period. At the end of placebo treatment (Week 16), 5% weight loss was achieved in 24% of subjects utilizing LSI, versus 5% of subjects without LSI. Among subjects in the LSI group, this target was achieved in 19% at Week 52. The mean (SD) time to subject withdrawal was 18.4 (16) weeks.
Conclusions: This analysis highlights the need to consider the duration and intensity of LSI when modeling the placebo effect in obesity trials. Knowledge of the time course of placebo response, the influence of LSI, and the pattern of subject withdrawal provide an informed basis for further PD model development.
American Society for Clinical Pharmacology and Therapeutics (ASCPT), Anaheim, California, March 2007
By Brenda Cirincione, Julie Passarell, Melannie Cummings, Elizabeth Ludwig, Thaddeus H. Grasela, Amy Halseth, Mark Fineman