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)

Fava, MaurizioDirks, BryanShelton, Richard C.Thase, Michael E.Trivedi, Madhukar H.Liu, KeithStankovic, SrdjanFreeman, MarlenePapakostas, George2022-07-282019-09-24Fava, Maurizio, Bryan Dirks, Marlene P. Freeman, George I. Papakostas, Richard C. Shelton, Michael E. Thase, Madhukar H. Trivedi, Keith Liu, and Srdjan Stankovic. 2019. 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). The Journal of Clinical Psychiatry 80, no. 6.1555-2101https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37372914Objective: 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.en-USA Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of Adjunctive Pimavanserin in Patients With Major Depressive Disorder and an Inadequate Response to Therapy (CLARITY)Journal Article2022-07-2810.4088/jcp.19m12928