The double-blind variable placebo lead-in period: Results from two antidepressant clinical trials

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 ofte n necessary (e.g., to receive laboratory results before randomization), som e 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 admi nistered. The single-blind placebo lead-in did not decrease postrandomizati on placebo response, nor did it increase drug-placebo differences. To elimi nate a higher percentage of placebo responders before randomization and to reduce potential biases in baseline ratings, the authors designed and imple mented two depression studies with a double-blind variable placebo lead-in period. In these designs, both the patients and personnel at the investigat ive 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 co ntinued in the study (including placebo lead-in responders), the primary ef ficacy analysis prospectively excluded double-blind placebo lead-in respond ers. Analysis of postrandomization changes revealed that double-blind place bo lead-in responders, even when continuing to receive placebo treatment, m aintained their response. At the study endpoint, these placebo lead-in resp onders 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.