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    Original Investigation
    January 8, 2020

    Efficacy and Safety of Lumateperone for Treatment of Schizophrenia: A Randomized Clinical Trial

    Author Affiliations
    • 1Department of Psychiatry and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York
    • 2Department of Psychiatry, Zucker Hillside Hospital, Glen Oaks, New York
    • 3Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin Berlin, Berlin, Germany
    • 4Intra-Cellular Therapies Inc, New York, New York
    • 5Now with Axsome Therapeutics Inc, New York, New York
    • 6Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York Presbyterian Hospital, New York
    • 7Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas
    JAMA Psychiatry. Published online January 8, 2020. doi:10.1001/jamapsychiatry.2019.4379
    Key Points

    Question  Does 60 mg of lumateperone tosylate (42 mg of lumateperone) significantly reduce symptoms of schizophrenia compared with placebo without relevant motor, cardiometabolic, or endocrine adverse effects?

    Findings  In this randomized clinical trial of 450 patients with acute exacerbation of schizophrenia, 42 mg of lumateperone demonstrated statistically significant differences in reducing symptoms of schizophrenia without treatment-emergent motor, cardiometabolic, or endocrine adverse effects compared with placebo.

    Meaning  Lumateperone is a potential treatment for schizophrenia and has a favorable safety profile.

    Abstract

    Importance  Individuals living with schizophrenia are affected by cardiometabolic, endocrine, and motor adverse effects of current antipsychotic medications. Lumateperone is a serotonin, dopamine, and glutamate modulator with the potential to treat schizophrenia with few adverse effects.

    Objective  To examine the efficacy and safety of lumateperone for the short-term treatment of schizophrenia.

    Design, Setting, and Participants  This randomized, double-blind, placebo-controlled, phase 3 clinical trial was conducted from November 13, 2014, to July 20, 2015, with data analyses performed from August 13 to September 15, 2015. Patients with schizophrenia who were aged 18 to 60 years and were experiencing an acute exacerbation of psychosis were enrolled from 12 clinical sites in the United States.

    Interventions  Patients were randomized 1:1:1 (150 patients in each arm) to receive lumateperone tosylate, 60 mg; lumateperone tosylate, 40 mg (equivalent to 42 or 28 mg, respectively, of the active moiety lumateperone); or placebo once daily for 4 weeks.

    Main Outcomes and Measures  The prespecified primary efficacy end point was mean change from baseline to day 28 in the Positive and Negative Syndrome Scale (PANSS) total score vs placebo. The key secondary efficacy measure was the Clinical Global Impression–Severity of Illness (CGI-S) score. The PANSS subscale scores, social function, safety, and tolerability were also assessed.

    Results  The study comprised 450 patients (mean [SD] age, 42.4 [10.2] years; 346 [77.1%] male; mean [SD] baseline PANSS score, 89.8 [10.3]; mean [SD] baseline CGI-S score, 4.8 [0.6]). In the prespecified modified intent-to-treat efficacy analysis (n = 435), 42 mg of lumateperone met the primary and key secondary efficacy objectives, demonstrating a statistically significant improvement vs placebo from baseline to day 28 on the PANSS total score (least-squares mean difference [LSMD], −4.2; 95% CI, −7.8 to −0.6; P = .02; effect size [ES], −0.3) and the CGI-S (LSMD, −0.3; 95% CI, −0.5 to −0.1; P = .003; ES, −0.4). For 28 mg of lumateperone, the LSMD from baseline to day 28 was −2.6 (95% CI, −6.2 to 1.1; P = .16; ES, −0.2) on the PANSS total score and −0.2 (95% CI, −0.5 to 0.0; P = .02; ES, −0.3) on the CGI-S. Both lumateperone doses were well tolerated without clinically significant treatment-emergent motor adverse effects or changes in cardiometabolic or endocrine factors vs placebo.

    Conclusions and Relevance  Lumateperone demonstrated efficacy for improving the symptoms of schizophrenia and had a favorable safety profile.

    Trial Registration  ClinicalTrials.gov identifier: NCT02282761

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