RESUMO
Objective: In a phase 2 study, pimavanserin demonstrated efficacy as adjunctive treatment for major depressive disorder (MDD). Subsequently, two phase 3 studies (NCT03968159 in the US; NCT03999918 in Europe) were initiated to examine the efficacy and safety of adjunctive pimavanserin in subjects with MDD and inadequate response to antidepressant treatment. Studies were combined with a prespecified statistical analysis plan owing to recruitment challenges related to the COVID-19 pandemic. Experimental design: The randomized, double-blind studies enrolled 298 patients with MDD and inadequate response to current antidepressants. Patients were randomly assigned 1:1 to pimavanserin or placebo added to current antidepressant for 6 weeks. Primary endpoint was change from baseline to week 5 in the Hamilton Rating Scale for Depression, 17-item version (HAM-D-17). Principal observations: There was no effect of pimavanserin in change from baseline to week 5 in the HAM-D-17 (pimavanserin [n = 138]: least-squares mean [LSM] [standard error {SE}], -9.0 [0.58]; placebo [n = 135]: -8.1 [0.58]; mixed-effects model for repeated measures LSM [SE] difference, -0.9 [0.82], P = 0.2956). Nominal improvement with pimavanserin was observed on 2 secondary endpoints: Clinical Global Impressions-Severity scale, Karolinska Sleepiness Scale. Treatment-emergent adverse events occurred in 58.1% of pimavanserin-treated and 54.7% of placebo-treated patients. Conclusions: Adjunctive pimavanserin did not significantly improve depressive symptoms, although pimavanserin was well tolerated.