KarXT for Schizophrenia
(ARISE Trial)
Recruiting in Palo Alto (17 mi)
+239 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
Sponsor: Karuna Therapeutics
Must be taking: Atypical antipsychotics
Must not be taking: Anticholinergics
Disqualifiers: Substance use disorder, Treatment-resistant schizophrenia, Severe medical conditions, others
Stay on Your Current Meds
Pivotal Trial (Near Approval)
Prior Safety Data
Approved in 1 Jurisdiction
Trial Summary
What is the purpose of this trial?
This trial tests KarXT, a combination of two drugs, for people who haven't improved with their current treatment. KarXT aims to balance brain functions and reduce side effects. The study will look at improvements in health and daily life. KarXT has shown positive results in earlier tests.
Will I have to stop taking my current medications?
The trial requires participants to continue their current antipsychotic medications like risperidone, paliperidone, or aripiprazole. However, you may need to stop other medications that are not allowed during the study.
What data supports the effectiveness of the drug KarXT for treating schizophrenia?
Research shows that KarXT, a combination of xanomeline and trospium, significantly improved symptoms in patients with schizophrenia compared to a placebo, with a notable reduction in the Positive and Negative Syndrome Scale (PANSS) score. Additionally, it showed potential benefits for cognitive impairment in schizophrenia, especially in patients with existing cognitive issues.12345
Is KarXT safe for humans?
How is the drug KarXT different from other schizophrenia treatments?
KarXT is unique because it targets muscarinic receptors (M1 and M4) instead of the usual dopamine D2 receptors, potentially offering a new way to treat schizophrenia with fewer side effects. It combines xanomeline, which has antipsychotic effects, with trospium to reduce side effects, making it more tolerable for patients.25689
Eligibility Criteria
Adults aged 18-60 with schizophrenia, stable and not hospitalized for psychiatric issues in the last 8 weeks. They must be on certain antipsychotics without adequate symptom control, have a BMI of 18-40, and agree to use contraception if applicable. Excludes those with other primary disorders or severe substance abuse within the past year.Inclusion Criteria
I have been on the same dose of my current antipsychotic medication for at least 8 weeks.
I have been on the same dose of my schizophrenia medication for at least 8 weeks.
I've tried an antipsychotic for 6 weeks without improvement.
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Exclusion Criteria
Urine toxicology screen is positive for non-cannabis or non-benzodiazepine substances
I have previously been treated with KarXT.
I am diagnosed with schizophreniform or experiencing my first schizophrenia episode.
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Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive adjunctive KarXT or placebo for 6 weeks to assess efficacy in treating inadequately controlled symptoms of schizophrenia
6 weeks
Weekly visits (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Treatment Details
Interventions
- Xanomeline and Trospium Chloride Capsules (Acetylcholine Receptor Agonist)
Trial OverviewThe trial tests KarXT (xanomeline-trospium combo) as an add-on to current antipsychotic treatment over six weeks. It's randomized and placebo-controlled, aiming to see if it better manages schizophrenia symptoms measured by PANSS Total Score compared to a placebo.
Participant Groups
2Treatment groups
Experimental Treatment
Placebo Group
Group I: Drug: KarXTExperimental Treatment1 Intervention
Group II: PlaceboPlacebo Group1 Intervention
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Local Institution - 186Coral Gables, FL
Envision Trials LLCMiami Springs, FL
Behavioral Clinical Research , IncMiami, FL
Michigan Clinical Research Institute PCAnn Arbor, MI
More Trial Locations
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Who Is Running the Clinical Trial?
Karuna TherapeuticsLead Sponsor
References
Xanomeline-Trospium and Muscarinic Involvement in Schizophrenia. [2023]Schizophrenia is a severe mental illness that has its onset in late adolescence or early adulthood and is associated with significant dysfunction across multiple domains. The pathogenesis of schizophrenia remains unknown, but physiologic understanding of the illness has been driven by the dopamine hypothesis. However, acetylcholine (ACh) clearly plays a role with mixed results regarding effect on psychosis. Selective muscarinic M1 and M4 agonists, such as xanomeline, originally developed to aid in cognitive loss with Alzheimer's, showed promise in proof-of-concept study in 20 patients with schizophrenia. Unfortunately, tolerability problems made muscarinic agonists impractical in either condition. However, coadministration of trospium, a lipophobic, non-selective muscarinic antagonist previously used for the treatment of overactive bladder, with xanomeline resulted in a significant reduction of cholinergic adverse effects. A recent randomized, placebo-controlled study of the antipsychotic effects of this combination in 182 patients with acute psychosis revealed improved tolerability with 80% of subjects staying to the end of the 5 weeks study. At the end of the trial, the treatment group saw a -17.4 change in the positive and negative symptom scale (PANSS) score from baseline compared to a -5.9 change in the placebo arm (P < 0.001). Furthermore, the negative symptom subscore, was also superior in the active arm (P < 0.001). These early studies are exciting because they suggest that the cholinergic system may be recruited to treat a severe and disabling disorder with suboptimal treatment options. Xanomeline-trospium combination is currently in phase III studies.
Antipsychotic Efficacy of KarXT (Xanomeline-Trospium): Post Hoc Analysis of Positive and Negative Syndrome Scale Categorical Response Rates, Time Course of Response, and Symptom Domains of Response in a Phase 2 Study. [2022]Objective: To evaluate Positive and Negative Syndrome Scale (PANSS) categorical response rates, time course of response, and symptom subdomains of response with the combination oral agent KarXT (xanomeline-trospium) in the treatment of schizophrenia.
Xanomeline and Trospium: A Potential Fixed Drug Combination (FDC) for Schizophrenia-A Brief Review of Current Data. [2023]Xanomeline, a cholinergic agonist, was initially evaluated for the treatment of Alzheimer's disease and schizophrenia. However, drug development was stopped due to the severe cholinergic adverse effects. In recent years, xanomeline has been explored, along with trospium, a peripheral cholinergic antagonist, for schizophrenia. Xanomeline acts primarily as an M1/M4 agonist and might lead to improvement in all symptom types of schizophrenia. Due to its role as an antimuscarinic agent, trospium is expected to reduce the adverse effects of xanomeline. In initial studies, this combination seems to be promising in the treatment of schizophrenia. The most common side effects of this combination included constipation, dry mouth, and nausea. This article summarizes the present status of combination xanomeline and trospium in schizophrenia.
Xanomeline, an M(1)/M(4) preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice. [2019]Xanomeline is an M(1)/M(4) preferring muscarinic receptor agonist which decreased psychotic behaviors in patients with Alzheimer's disease, suggesting that xanomeline might be useful in the treatment of psychotic symptoms in patients with schizophrenia. The purpose of the present studies was, therefore, to compare the pharmacologic profile of xanomeline with that of known antipsychotic drugs. Electrophysiologically, xanomeline, after both acute and chronic administration in rats, inhibited A10 but not A9 dopamine cells in a manner which was blocked by the muscarinic receptor antagonist scopolamine. Behaviorally, xanomeline, like haloperidol, clozapine and olanzapine, blocked dopamine agonist-induced turning in unilateral 6-hydroxydopamine-lesioned rats, as well as apomorphine-induced climbing in mice. However, unlike the dopamine antagonist antipsychotic haloperidol, xanomeline did not produce catalepsy in rats. Moreover, xanomeline, like haloperidol, clozapine and olanzapine, inhibited conditioned avoidance responding in rats, an effect which also was blocked by scopolamine. The present results thus demonstrate that xanomeline has a pharmacologic profile which is similar to that of the atypical antipsychotics clozapine and olanzapine, thus indicating that xanomeline has the potential to be a novel approach in the treatment of psychotic symptoms in patients with schizophrenia.
Effectiveness of KarXT (xanomeline-trospium) for cognitive impairment in schizophrenia: post hoc analyses from a randomised, double-blind, placebo-controlled phase 2 study. [2023]The muscarinic receptor agonist xanomeline improved cognition in phase 2 trials in Alzheimer's disease and schizophrenia. We present data on the effect of KarXT (xanomeline-trospium) on cognition in schizophrenia from the 5-week, randomised, double-blind, placebo-controlled EMERGENT-1 trial (NCT03697252). Analyses included 125 patients with computerised Cogstate Brief Battery (CBB) subtest scores at baseline and endpoint. A post hoc subgroup analysis evaluated the effects of KarXT on cognitive performance in patients with or without clinically meaningful cognitive impairment at baseline, and a separate outlier analysis excluded patients with excessive intraindividual variability (IIV) across cognitive subdomains. ANCOVA models assessed treatment effects for completers and impairment subgroups, with or without removal of outliers. Sample-wide, cognitive improvement was numerically but not statistically greater with KarXT (n = 60) than placebo (n = 65), p = 0.16. However, post hoc analyses showed 65 patients did not exhibit clinically meaningful cognitive impairment at baseline, while eight patients had implausibly high IIV at one or both timepoints. Significant treatment effects were observed after removing outliers (KarXT n = 54, placebo n = 63; p = 0.04). Despite the small sample size, a robust (d = 0.50) and significant effect was observed among patients with cognitive impairment (KarXT n = 23, placebo n = 37; p = 0.03). These effects did not appear to be related to improvement in PANSS total scores (linear regression, R2 = 0.03). Collectively, these findings suggest that KarXT may have a separable and meaningful impact on cognition, particularly among patients with cognitive impairment.
Evidence of trospium's ability to mitigate cholinergic adverse events related to xanomeline: phase 1 study results. [2023]Label="RATIONALE" NlmCategory="BACKGROUND">The M1/M4 preferring muscarinic receptor agonist xanomeline demonstrated antipsychotic and procognitive effects in patients with Alzheimer's disease or schizophrenia in prior studies, but further clinical development was limited by cholinergic adverse events (AEs). KarXT combines xanomeline with the peripherally restricted muscarinic receptor antagonist trospium with the goal of improving tolerability and is in clinical development for schizophrenia and other neuropsychiatric disorders.
Site-independent confirmation of primary site-based PANSS ratings in a schizophrenia trial. [2022]Blinded, site-independent (remote) ratings from audio-digital recordings of site-based Positive and Negative Syndrome Scale (PANSS) interviews were obtained in a 5-week, randomized, double-blinded study assessing the safety, tolerability, and efficacy of KarXT (a fixed combination of xanomeline and trospium chloride) in hospitalized adults with schizophrenia experiencing an acute exacerbation of psychosis (EMERGENT-1; ClinicalTrials.gov identifier: NCT3697252). The blinded site-independent raters had no knowledge of site location, study visit, drug vs. placebo assignment, or any treatment emergent adverse events (TEAEs). Concordance analyses of 561 paired site-based and site-independent PANSS ratings across all visits revealed a high correlation (ICC = 0.775). Paired scoring differences were positively correlated with the PANSS total score (Spearman's rho = 0.37, p
Muscarinic M1 and M4 receptor agonists for schizophrenia: promising candidates for the therapeutic arsenal. [2023]Successful phase 3 trials of KarXT in people with schizophrenia herald a new era of treating the disorder with drugs that do not target the dopamine D2 receptor. The active component of KarXT is xanomeline, a muscarinic (CHRM) M1 and M4 agonist, making muscarinic receptors a viable target for treating schizophrenia.
Safety and tolerability of KarXT (xanomeline-trospium) in a phase 2, randomized, double-blind, placebo-controlled study in patients with schizophrenia. [2022]KarXT combines xanomeline, an M1/M4 preferring muscarinic agonist with no direct D2 receptor antagonism, with the peripherally restricted anticholinergic trospium. In EMERGENT-1 (NCT03697252), a 5-week, randomized, double-blind, placebo-controlled, phase 2 study in inpatients with schizophrenia, KarXT met the primary efficacy endpoint, numerous secondary endpoints, and was generally well tolerated. Here, we conducted additional post hoc analyses of safety and tolerability data of KarXT from EMERGENT-1 with a particular focus on adverse events (AEs) that may be associated with muscarinic receptor agonism (nausea or vomiting) or antagonism (dry mouth or constipation). A total of 179 patients received at least one dose of either KarXT (n = 89) or placebo (n = 90) and were included in the analyses. KarXT was associated with a low overall AE burden. The majority of procholinergic and anticholinergic AEs with KarXT were mild, occurred in the first 1-2 weeks of treatment, and were transient with a median duration ranging from 1 day for vomiting to 13 days for dry mouth. No patients in either treatment group discontinued the study due to any procholinergic or anticholinergic AEs. Incidence of somnolence/sedation AEs with KarXT were low and similar to those in the placebo group. KarXT was associated with no significant or clinically relevant changes in body weight, metabolic parameters, or vital signs. KarXT was generally well tolerated with an AE profile consistent with the activity of xanomeline-trospium at muscarinic receptors.