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. 2024 Nov 2;10(1):102.
doi: 10.1038/s41537-024-00525-6.

Efficacy of xanomeline and trospium chloride in schizophrenia: pooled results from three 5-week, randomized, double-blind, placebo-controlled, EMERGENT trials

Inder Kaul  1 , Sharon Sawchak  1 , Amy Claxton  1 , Colin Sauder  1 , Howard H Hassman  2 , Rishi Kakar  3 , David P Walling  4 , Leslie Citrome  5 , Haiyuan Zhu  1 , Andrew C Miller  1 , Stephen K Brannan  6
Affiliations

Efficacy of xanomeline and trospium chloride in schizophrenia: pooled results from three 5-week, randomized, double-blind, placebo-controlled, EMERGENT trials

Inder Kaul et al. Schizophrenia (Heidelb). .

Erratum in

Abstract

In the 5-week, randomized, double-blind, placebo-controlled EMERGENT-1 (NCT03697252), EMERGENT-2 (NCT04659161), and EMERGENT-3 (NCT04738123) trials, xanomeline and trospium chloride (formerly known as KarXT) significantly improved symptoms of schizophrenia and was generally well tolerated. We pooled data from the EMERGENT trials to further characterize the efficacy of xanomeline/trospium and provide sufficient statistical power to analyze responses in participant subgroups. In pooled analyses, xanomeline/trospium significantly improved Positive and Negative Syndrome Scale (PANSS) total score at week 5 versus placebo (least squares mean difference, -9.9; 95% confidence interval, -12.4, -7.3; p < 0.0001; Cohen's d effect size, 0.65). PANSS subscale and Clinical Global Impression-Severity scores also improved significantly with xanomeline/trospium versus placebo. Subgroup analyses consistently favored xanomeline/trospium over placebo regardless of differences in participant age, sex, race, body mass index, and baseline PANSS total score. These results add to existing evidence demonstrating robust and reliable improvements in symptoms with xanomeline/trospium across a broad spectrum of people with schizophrenia.

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Conflict of interest statement

I.K., S.S., A.C., C.S., and H.Z. are employees of Karuna Therapeutics, a Bristol Myers Squibb company. A.C.M and S.K.B. are consultants of Karuna Therapeutics, a Bristol Myers Squibb company. H.H.H. was a principal investigator for the EMERGENT-1 and EMERGENT-2 trials. R.K. was a principal investigator for the EMERGENT-2 trial. L.C. is a consultant for AbbVie/Allergan, Acadia, Adamas, Alkermes, Angelini, Astellas, Avanir, Axsome, Biogen, BioXcel, Boehringer Ingelheim, Cadent Therapeutics, Cerevel, Clinilabs, COMPASS, Delpor, Eisai, Enteris BioPharma, HLS Therapeutics, Idorsia, INmune Bio, Impel, Intra-Cellular Therapies, Janssen, Karuna, Lundbeck, Luye, Lyndra, MapLight, Marvin, Medavante-ProPhase, Merck, Mitsubishi-Tanabe Pharma, Neumora, Neurocrine, Neurelis, Noema, Novartis, Noven, Otsuka, Ovid, Praxis, Recordati, Relmada, Reviva, Sage, Sumitomo/Sunovion, Supernus, Teva, University of Arizona, Vanda, Wells Fargo, and one-off ad hoc consulting for individuals/entities conducting marketing, commercial, or scientific scoping research; is a speaker for AbbVie/Allergan, Acadia, Alkermes, Angelini, Axsome, BioXcel, Eisai, Idorsia, Intra-Cellular Therapies, Janssen, Lundbeck, Neurocrine, Noven, Otsuka, Recordati, Sage, Sunovion, Takeda, Teva, and CME activities organized by medical education companies such as Medscape, NACCME, NEI, Vindico, and universities and professional organizations/societies; owns stocks (small number of shares of common stock) in Bristol-Myers Squibb, Eli Lilly, J & J, Merck, and Pfizer purchased >10 years ago, and stock options: Reviva; receives royalties/publishing income from Taylor & Francis (Editor-in-Chief, Current Medical Research and Opinion, 2022-date), Wiley (Editor-in-Chief, International Journal of Clinical Practice, through end 2019), UpToDate (reviewer), Springer Healthcare (book), Elsevier (Topic Editor, Psychiatry, Clinical Therapeutics). D.P.W. has received research support from AbbVie, Acadia, Alkermes, Allergan, Avanir, BMS, Cerevel, Indivior, IntraCellular, J & J RPD, Karuna, Lupin, Lundbeck, Neurocrine, Novartis, Noven, Pfizer, Roche, Sage, Sunovion, and Takeda; and has received research support and served as a consultant for Biogen, Boehringer Ingelheim, Janssen, Lyndra, and Otsuka.

Figures

Fig. 1
Fig. 1. Participant disposition.
aThe safety population included all participants who received ≥1 dose of trial drug. bThe modified intent-to-treat population, used for all efficacy analyses, included all participants randomized who received ≥1 dose of trial drug, had a baseline Positive and Negative Syndrome Scale (PANSS) assessment, and had ≥1 postbaseline PANSS assessment. X/T xanomeline/trospium.
Fig. 2
Fig. 2. Pooled PANSS scores change from baseline.
A PANSS total score. B PANSS positive subscale score. C PANSS negative subscale score. D PANSS Marder negative factor score. Values are LSM ± SE. LS mean difference vs. placebo: *p < 0.05; **p < 0.01; ****p < 0.0001. SE standard error, LSM least squares mean, PANSS Positive and Negative Syndrome Scale, X/T xanomeline/trospium.
Fig. 3
Fig. 3. CGI-S score change from baseline.
LS mean difference xanomeline/trospium vs. placebo: ****p < 0.0001. CGI-S Clinical Global Improvement‒Severity, LS least squares, PANSS Positive and Negative Syndrome Scale, SEM standard error of the mean, X/T xanomeline/trospium.
Fig. 4
Fig. 4. PANSS categorical response rates at week 5.
**p < 0.01. ****p < 0.0001. PANSS categorical response rates based on floor-adjusted total score (total score minus 30). PANSS Positive and Negative Syndrome Scale, X/T xanomeline/trospium.
Fig. 5
Fig. 5. Proportion of participants achieving improvement in CGI-S scores at week 5.
***p < 0.001. ****p < 0.0001. CGI-S Clinical Global Impression–Severity, X/T xanomeline/trospium.
Fig. 6
Fig. 6. Change in CGI-S score distribution from baseline at week 5a.
A CGI-S score distribution at baseline. B CGI-S score distribution at week 5. aCGI-S scores were available at week 5 for 244 participants in the xanomeline/trospium group and 263 participants in the placebo group. CGI-S Clinical Global Impression–Severity, X/T xanomeline/trospium.
Fig. 7
Fig. 7. Subgroup analysis of xanomeline/trospium effect on PANSS total score.
BMI body mass index, CI confidence interval, LSM least squares mean, PANSS Positive and Negative Syndrome Scale, X/T xanomeline/trospium.
See this image and copyright information in PMC

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