Targeting muscarinic receptors in schizophrenia treatment: Novel antipsychotic xanomeline/trospium chloride

Table 1 An overview of clinical trials in schizophrenia patients listed in the ClinicalTrials.gov registry up to January 19, 2025

ClinicalTrials.gov ID, other study IDs	Official title	Phase	Status	Duration of treatment	Start date	Completion date
NCT03697252[44], EMERGENT-1, KAR-004	A phase 2, randomized, double-blinded study to assess the safety, tolerability, and efficacy of KarXT in hospitalized adults with DSM-5 schizophrenia	2	Completed	5 weeks	September 18, 2018	September 04, 2019
NCT04659161[45], EMERGENT-2, KAR-007	A phase 3, randomized, double-blind, parallel-group, placebo-controlled, multicenter study to evaluate the efficacy and safety of KarXT in acutely psychotic hospitalized adults with DSM-5 schizophrenia	3	Completed	5 weeks	December 16, 2020	May 24, 2022
NCT04738123[46], EMERGENT-3, KAR-009	A phase 3, randomized, double-blind, parallel-group, placebo-controlled, multicenter study to evaluate the efficacy and safety of KarXT in acutely psychotic hospitalized adults with DSM-5 schizophrenia	3	Completed	5 weeks	April 06, 2021	December 07, 2022
NCT04659174[48], EMERGENT-4, KAR-008	An open-label extension study to assess the long-term safety, tolerability, and efficacy of KarXT in subjects with DSM-5 schizophrenia	3	Completed	52 weeks	February 01, 2021	October 03, 2023
NCT04820309[49], EMERGENT-5, KAR-011	An open-label study to assess the long-term safety, tolerability, and efficacy of KarXT in de novo subjects with DSM-5 schizophrenia	3	Completed	52 weeks	June 02, 2021	May 24, 2024
NCT05643170[51], PENNANT, KAR-014	A multi-center, open-label study to assess the effectiveness, long-term safety, tolerability, and durability of effect of KarXT in patients with DSM-5 diagnosis of schizophrenia	3	Terminated (company's business decision)	3 years	November 08, 2022	March 08, 2023
NCT05919823[50], UNITE-001	A phase 3, multicenter, two-part study with a 5-week double-blind part (randomized, parallel-group, placebo-controlled) followed by a 12-week open-label extension part, to evaluate the efficacy and safety of KarXT in acutely psychotic hospitalized Chinese adult subjects with DSM-5 schizophrenia	3	Recruiting	5 weeks (double-blind) + 12 weeks (open-label)	May 29, 2023	May 2025 (estimated)
NCT05145413[52], ARISE, KAR-012	A phase 3, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of adjunctive KarXT in subjects with inadequately controlled symptoms of schizophrenia	3	Recruiting	6 weeks	November 12, 2021	February 28, 2025 (estimated)
NCT05304767[53], KAR-013	An open-label extension study to assess the long-term safety and tolerability of adjunctive KarXT in subjects with inadequately controlled symptoms of schizophrenia	3	Recruiting	52 weeks	March 07, 2022	February 27, 2026 (estimated)

KarXT: Xanomeline/trospium chloride; DSM-5: Diagnostic and Statistical Manual of Mental Disorders, fifth edition.

Table 2 Key findings on the effects based on the positive and negative syndrome scale scores from completed 5-week clinical trials

Variable	EMERGENT-1[43]		EMERGENT-2[14]		EMERGENT-3[47]
	KarXT vs placebo	P value	KarXT vs placebo	P value	KarXT vs placebo	P value
Number of patients (modified intention-to-treat population)	83 vs 87	-	117 vs 119	-	114 vs 120	-
Least-squares mean change from baseline in PANSS total score (points)	-17.4 vs -5.9	< 0.001	-21.2 vs -11.6	< 0.0001	-20.6 vs -12.2	< 0.0001
Least-squares mean change from baseline in PANSS positive symptom subscore (points)	-5.6 vs -2.4	< 0.001	-6.8 vs -3.9	< 0.0001	-7.1 vs -3.6	< 0.0001
Least-squares mean change from baseline in PANSS negative symptom subscore (points)	-3.2 vs -0.9	< 0.001	-3.4 vs -1.6	0.0055	-2.7 vs -1.8	0.1224
Least-squares mean change from baseline in PANSS Marder negative symptom subscore (points)	-3.9 vs -1.3	< 0.001	-4.2 vs -2.0	0.0022	-3.5 vs -2.7	0.1957

Studies included patients aged 18-60 years (EMERGENT-1) or up to 65 years (EMERGENT-2 and EMERGENT-3) with a primary diagnosis of schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders, fifth edition, experiencing an acute exacerbation or relapse of psychosis requiring hospitalization with onset within 2 months before screening. Participants were required to be free of antipsychotic medication for a specified period before the baseline assessment: In EMERGENT-1, at least two weeks for oral antipsychotics or 1.5 injection cycles for long-acting injectables (LAI); and in EMERGENT-2 and EMERGENT-3, at least five half-lives or one week (whichever was longer) for oral antipsychotics, or at least 12 weeks for LAI (24 weeks for paliperidone palmitate). KarXT: Xanomeline/trospium chloride; PANSS: Positive and Negative Syndrome Scale.