CX-157

Early symptomatic improvement immediately following randomization can affect signal detection in clinical trials. The impact of early improvement of the Montgomery-Asberg depression rating scale (MADRS) on eventual treatment outcome was examined in a 6-week, double-blind, placebo-controlled trial of a putative antidepressant (CX157) versus placebo in depressed subjects with major depressive disorder (MDD) who had had an inadequate response to ongoing antidepressant treatment (NCT00739908). MADRS score changes within one week after randomization directly affected treatment outcome at the study endpoint (week 6). The response and remission rates at week 6 increased significantly as the percent of MADRS score improvement increased between baseline and week 1 regardless of treatment assignment. Less MADRS improvement or actual worsening within the first week after randomization was associated with minimal overall MADRS score changes by week 6 in either treatment assignment. Alternatively, CX157 assigned subjects who had ≥30% improvement by week 1 achieved a significantly greater treatment response rate than the matched placebo group at the study endpoint (p = 0.025) that converted the lack of signal detection in the mITT population. This post-hoc analysis highlights the potent effect that early symptomatic improvement immediately following randomization can have on treatment outcome, and is particularly relevant for antidepressant drugs with rapid onset of action. The findings compel further exploration of possible moderating and mediating factors, including the experimental condition itself that can influence early response, and the need to identify "bio-types" within the population of MDD subjects.