A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of Adjunctive Pimavanserin in Patients With Major Depressive Disorder and an Inadequate Response to Therapy (CLARITY)

Abstract

Objective: Pimavanserin is a 5-hydroxytryptamine2A antagonist/inverse receptor agonist. In this Phase 2 study, we studied the efficacy and safety of pimavanserin as adjunctive therapy in patients with major depressive disorder (MDD). Methods: This was a multicenter, randomized, double-blind, placebo-controlled study in patients with DSM-5–defined MDD and an inadequate response to a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI). Using a 2-stage sequential parallel-comparison design, patients were initially randomized in a 3:1 ratio to placebo or pimavanserin added to ongoing SSRI or SNRI therapy; at 5 weeks, placebo non-responders were re-randomized to placebo or pimavanserin for an additional 5 weeks. Key endpoints were change from baseline to the end of each stage for the HAMD-17 total score and Sheehan Disability Score (SDS) score. Results: Between December 2016 and October 2018, 207 patients were randomized. For the prespecified pooled SPCD analyses of Stages 1 and 2, the LS mean (standard error) difference for the HAMD-17 total was (-1.7 (0.85), p=0.039) and the SDS was (-0.8 (0.29), p=0.004). At Week 5 of Stage 1, LS mean (standard error) difference for pimavanserin vs. placebo was significant for changes on the HAMD-17 (-4.0 [1.09], p=0.0003) and SDS (-1.2 [0.40], p=0.0036) with effect sizes of 0.626 and 0.498, respectively. Early and sustained separation of pimavanserin from placebo (p<0.05) occurred at 1 week. Most common AEs with pimavanserin were dry mouth, nausea, and headache. Conclusion: Pimavanserin demonstrated robust efficacy in patients with MDD and an inadequate response to an SSRI/SNRI. Tolerability was consistent with previous experience.