title: The double-blind variable placebo lead-in period: results from two antidepressant clinical trials.
abstract: The 1-week single-blind placebo lead-in has long been a standard in double-blind psychopharmacology clinical trials. Although a lead-in period is often necessary (e.g., to receive laboratory results before randomization), some authors have demonstrated that the standard single-blind placebo lead-in's performance was similar to having a lead-in in which placebo was not administered. The single-blind placebo lead-in did not decrease postrandomization placebo response, nor did it increase drug-placebo differences. To eliminate a higher percentage of placebo responders before randomization and to reduce potential biases in baseline ratings, the authors designed and implemented two depression studies with a double-blind variable placebo lead-in period. In these designs, both the patients and personnel at the investigative sites were blinded to the length of the placebo lead-in period and the start of the active treatment period. Approximately 28% of the patients in the double-blind placebo lead-in studies met criteria to be placebo lead-in responders, as compared with fewer than 10% from two single-blind placebo lead-in studies conducted in a similar time frame. Although all patients continued in the study (including placebo lead-in responders), the primary efficacy analysis prospectively excluded double-blind placebo lead-in responders. Analysis of postrandomization changes revealed that double-blind placebo lead-in responders, even when continuing to receive placebo treatment, maintained their response. At the study endpoint, these placebo lead-in responders had significantly lower severity scores than their counterparts who were not lead-in responders. The prospective removal of lead-in responders thus resulted in an increase in mean endpoint placebo group severity scores. This resulted in an increased drug-placebo treatment difference in one of the two studies but had no effect on the treatment difference in the other study.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. d.faries@lilly.com
authors.forename: D E
authors.initials: DE
authors.lastname: Faries
authors.forename: J H
authors.initials: JH
authors.lastname: Heiligenstein
authors.forename: G D
authors.initials: GD
authors.lastname: Tollefson
authors.forename: W Z
authors.initials: WZ
authors.lastname: Potter
mesh_terms: D000928:Antidepressive Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic / Q000379:methods* / Q000706:statistics & numerical data; D003865:Major Depressive Disorder / Q000188:drug therapy; D004311:Double-Blind Method; D006801:Humans; D010919:Placebos; D016032:Randomized Controlled Trials as Topic / Q000379:methods / Q000706:statistics & numerical data; D016037:Single-Blind Method
chemical_list: D000928:Antidepressive Agents; D010919:Placebos