TY - JOUR
T1 - A phase 2, randomized, double-blind, placebo-controlled ST of adjunctive pimavanserin in patients with major depressive disorder and an inadequate response to therapy (CLARITY)
AU - Fava, Maurizio
AU - Dirks, Bryan
AU - Freeman, Marlene P.
AU - Papakostas, George I.
AU - Shelton, Richard C.
AU - Thase, Michael E.
AU - Trivedi, Madhukar H.
AU - Liu, Keith
AU - Stankovic, Srdjan
N1 - Funding Information:
editorial assistance of Richard S. Perry, PharmD, Neuropsychopharmacol. 2018;28(4):445–456.PubMed CrossRef Department of Health, Education, and Welfare; in the preparation of this manuscript, which was Marek GJ, Carpenter LL, McDougle CJ, et al. Public Health Service; Alcohol, Drug Abuse, and supported by ACADIA Pharmaceuticals Inc, San Synergistic action of 5-HT2A antagonists and Mental Health Administration; 1976:534–537.
Funding Information:
(for lectures or consultancy) from Abbott, ACADIA, Alkermes, Asopharma Centroamerica y Caribe, AstraZeneca, Avanir, Bristol-Myers Squibb, Brainsway, Cephalon, Dey, Eli Lilly, Evotec, Forest, GlaxoSmithKline, Inflabloc, Grunbiotics, Jazz, H. Lundbeck, Medichem, Meiji Seika, Novartis, Otsuka, Pamlab, Pfizer, Pharma Trade, Pierre Fabre, Ridge Diagnostics, Shire, Sunovion, Takeda, Theracos, Titan, and Wyeth; and has received research support (paid to hospital) from AstraZeneca, Bristol-Myers Squibb, Forest, NIMH, Neuralstem*, Pamlab, Pfizer, Ridge Diagnostics (formerly known as Precision Human Biolaboratories), Sunovion, Tal Medical, and Theracos. He served (not currently) on the speakers bureau for Bristol-Myers Squibb and Pfizer. (*Asterisk denotes activity undertaken on behalf of Massachusetts General Hospital.) Dr Shelton has received grants from National Institutes of Health (NIH), Patient-Centered Outcomes Research Institute, ACADIA, Alkermes, Allergan, Avanir, Cerecor, Genomind, Intracellular Therapies, Janssen, Myriad Genetics, Navitor, NeuroRx, Novartis, Otsuka, Nestle’ Health, Novartis, and Takeda and has received consulting fees from ACADIA, Allergan, Cerecor, Clintara, Janssen, Lundbeck, Medtronic, MSI Methylation Sciences, Naurex, Nestle Health, Pfizer, and Takeda. In the past 3 years, Dr Thase has received advisory/consultant fees from ACADIA, Akili, Alkermes, Allergan (Forest, Naurex), Cerecor, Fabre-Kramer, Gerson Lehrman Group, Guidepoint Global, Johnson & Johnson (Janssen, Ortho-McNeil), H. Lundbeck, Moksha8, Nestlé (Pamlab), Neuralstem, Novartis, Otsuka, Pfizer, Sage, and Sunovion; has received grant support from ACADIA, Agency for Healthcare Research and Quality, Alkermes, Allergan (Forest, Naurex), AssureRx Health, Avanir, Axsome, Intracellular Therapies, Janssen, Johnson & Johnson (Janssen, Ortho-McNeil), NIH/NIMH, Otsuka, Patient-Centered Outcomes Research Institute, and Takeda; and has received royalties from American Psychiatric Foundation, Guilford Publications, Herald House, and W.W. Norton & Company. His spouse is employed by Peloton Advantage, which does business with most major pharmaceutical companies. Dr Trivedi has received advisor/consultant and received fees from Alkermes, AstraZeneca, Cerecor, Eli Lilly, Lundbeck, Naurex, Neuronetics, Otsuka, Pamlab, Pfizer Inc, Shire, and Takeda. and has received grants/research support from NIMH and NIDA. Drs Dirks, Liu, and Stankovic are employees of ACADIA Pharmaceuticals Inc, San Diego, California. Funding/support: This study was supported by ACADIA Pharmaceuticals Inc, San Diego, California. Role of the sponsor: The funder of the study had a role in study design, data analysis, data interpretation, and writing of the report. Disclaimer: Dr Freeman, JCP Editor in Chief, was not involved in the editorial review or decision to publish this article. Previous presentation: Presented at the 2019 American Psychiatric Association Annual Meeting, May 18–22, 2019, San Francisco, California.
Funding Information:
Submitted: May 24, 2019; accepted August 19, 2019. Published online: September 24, 2019. Author contributions: All authors had full access to all of the data in the study and had full responsibility for the content of the manuscript for publication. The corresponding author was responsible for the final review and had final responsibility for the decision to submit for publication. Potential conflicts of interest: Dr Freeman has received advisory/consulting fees from Alkermes, Otsuka, Janssen, Sage, JDS Therapeutics, and Sunovion; took part in an independent data safety and monitoring committee for Janssen (Johnson & Johnson); has performed medical editing for the Global Organization for EPA and DHA Omega-3 newsletter; has received research support through Massachusetts General Hospital (MGH) from National Pregnancy Registry for Atypical Antipsychotics, Alkermes, AstraZeneca, Otsuka, Forest/Actavis, Ortho-McNeil Janssen, and Sunovion; has received other research support from Takeda and JayMac; and as an employee of MGH, works with the MGH Clinical Trials Network and Institute, which has had research funding from multiple pharmaceutical companies and National Institute of Mental Health (NIMH). Dr Fava has received research support from Abbott, ACADIA, Alkermes, American Cyanamid, Aspect Medical Systems, AstraZeneca, Avanir, Axsome Therapeutics, Biohaven, BioResearch, BrainCells, Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon, Cerecor, Clarus Funds, Clintara, Covance, Covidien, Eli Lilly, EnVivo, Euthymics Bioscience, Forest, FORUM, Ganeden Biotech, GlaxoSmithKline, Harvard Clinical Research Institute, Hoffman-LaRoche, Icon Clinical Research, i3 Innovus/Ingenix, Janssen, Jed Foundation, Johnson & Johnson, Lichtwer Pharma, Lorex, Lundbeck, Marinus, MedAvante, Methylation Sciences, National Alliance for Research on Schizophrenia and Depression, National Center for Complementary and Alternative Medicine, National Coordinating Center for Integrated Medicine, National Institute of Drug Abuse (NIDA), NIMH, Neuralstem, NeuroRx, Novartis, Organon, Otsuka, Pamlab, Pfizer; Pharmacia-Upjohn, Pharmaceutical Research Associates; Pharmavite, PharmoRx Therapeutics, Photothera, Reckitt Benckiser, Roche Pharmaceuticals, RCT Logic (formerly Clinical Trials Solutions), Sanofi-Aventis US, Shire, Solvay, Stanley Medical Research Institute, Synthelabo, Taisho, Takeda, Tal Medical, VistaGen, and Wyeth-Ayerst; has received advisory board/consultant fees from Abbott, ACADIA, Affectis, Alkermes, Amarin, Aspect Medical Systems, AstraZeneca, Auspex, Avanir, Axsome Therapeutics, Bayer, Best Practice Project Management, Biogen, BioMarin, Biovail, Boehringer Ingelheim, Boston Pharmaceuticals, BrainCells, Bristol-Myers Squibb, CeNeRx BioPharma, Cephalon, Cerecor, CNS Response, Compellis, Cypress, DiagnoSearch Life Sciences (P), Dainippon Sumitomo, Dov, Edgemont, Eisai, Eli Lilly, EnVivo,
Publisher Copyright:
© 2019 Physicians Postgraduate Press, Inc.
PY - 2019
Y1 - 2019
N2 - Objective: Pimavanserin is a 5-hydroxytryptamine-2A antagonist and inverse receptor agonist. This phase 2 study examined 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 nonresponders were re-randomized to placebo or pimavanserin for an additional 5 weeks. Key endpoints were change from baseline to the end of each stage in 17-item Hamilton Depression Rating Scale (HDRS-17) total score and Sheehan Disability Scale (SDS) score. Results: Between December 2016 and October 2018, 207 patients were randomized. For the prespecified pooled Sequential Parallel Comparison Design analyses of Stages 1 and 2, the least squares (LS) mean (SE) difference for the HDRS-17 total score was −1.7 (0.85) (P=.039) and for the SDS score was −0.8 (0.29) (P=.004). At week 5 of Stage 1, LS mean (SE) difference for pimavanserin versus placebo was significant for changes on the HDRS-17 (−4.0 [1.09], P=.0003) and SDS (−1.2 [0.40], P=.0036) with effect sizes of 0.626 and 0.498, respectively. Early and sustained separation of pimavanserin from placebo (P<.05) occurred at 1 week. The most common adverse events with pimavanserin were dry mouth, nausea, and headache. Conclusions: Pimavanserin demonstrated robust efficacy in patients with MDD and an inadequate response to an SSRI or SNRI. Tolerability was consistent with previous experience.
AB - Objective: Pimavanserin is a 5-hydroxytryptamine-2A antagonist and inverse receptor agonist. This phase 2 study examined 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 nonresponders were re-randomized to placebo or pimavanserin for an additional 5 weeks. Key endpoints were change from baseline to the end of each stage in 17-item Hamilton Depression Rating Scale (HDRS-17) total score and Sheehan Disability Scale (SDS) score. Results: Between December 2016 and October 2018, 207 patients were randomized. For the prespecified pooled Sequential Parallel Comparison Design analyses of Stages 1 and 2, the least squares (LS) mean (SE) difference for the HDRS-17 total score was −1.7 (0.85) (P=.039) and for the SDS score was −0.8 (0.29) (P=.004). At week 5 of Stage 1, LS mean (SE) difference for pimavanserin versus placebo was significant for changes on the HDRS-17 (−4.0 [1.09], P=.0003) and SDS (−1.2 [0.40], P=.0036) with effect sizes of 0.626 and 0.498, respectively. Early and sustained separation of pimavanserin from placebo (P<.05) occurred at 1 week. The most common adverse events with pimavanserin were dry mouth, nausea, and headache. Conclusions: Pimavanserin demonstrated robust efficacy in patients with MDD and an inadequate response to an SSRI or SNRI. Tolerability was consistent with previous experience.
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U2 - 10.4088/JCP.19m12928
DO - 10.4088/JCP.19m12928
M3 - Article
C2 - 31556975
AN - SCOPUS:85072662408
SN - 0160-6689
VL - 80
JO - Journal of Clinical Psychiatry
JF - Journal of Clinical Psychiatry
IS - 6
M1 - 19m12928
ER -