Xanomeline + Trospium for Schizophrenia

Recruiting at 6 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Collaborative Neuroscience Research, LLC

Must be taking: Atypical antipsychotics

Must not be taking: Tricyclics, Paroxetine, Antispasmodics, Antihistamines

Disqualifiers: Substance use disorder, Cardiovascular disease, Hepatic impairment, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

100 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

Participants must stop taking their current atypical antipsychotic (AP) medication to switch to the trial medication. However, they can continue taking other non-prohibited psychotropic medications that are not secondary AP treatments.

What data supports the effectiveness of the drug Xanomeline/Trospium for treating schizophrenia?

Research shows that the combination of xanomeline and trospium significantly improved symptoms in patients with schizophrenia, with a notable reduction in symptom scores compared to a placebo. This combination also reduced the side effects that xanomeline alone previously caused, making it a promising treatment option. ^{1 2 3 4 5}

Is the combination of Xanomeline and Trospium safe for humans?

The combination of Xanomeline and Trospium has been studied for schizophrenia, and while it shows promise, common side effects include constipation, dry mouth, and nausea. Trospium helps reduce the adverse effects of Xanomeline, making the combination more tolerable in initial studies. ^{1 2 3 5 6}

How is the drug Xanomeline-Trospium unique for treating schizophrenia?

Xanomeline-Trospium is unique because it combines xanomeline, which targets specific brain receptors (M1/M4 muscarinic receptors) without affecting dopamine, with trospium, which reduces side effects by blocking peripheral receptors. This combination may improve symptoms of schizophrenia with fewer side effects compared to traditional antipsychotics that primarily target dopamine. ^{1 2 3 4 5}

What is the purpose of this trial?

The study design is a de-escalation of current atypical AP treatment to X/T at a maintenance dose of X/T established either at 100 mg xanomeline/20 mg trospium chloride BID (total daily dose 200 mg xanomeline/40 mg trospium chloride) or 125 mg xanomeline/30 mg trospium chloride BID (total daily dose 250 mg xanomeline/60 mg trospium chloride) based on participants' clinical response and/or tolerability. While the package insert for X/T provides guidance for clinicians on dosing, this study is designed to assess how transitioning will occur in the "real world" situation.

Eligibility Criteria

This trial is for individuals with schizophrenia who are currently on atypical antipsychotic medications. Participants will switch to a new treatment involving Xanomeline/Trospium, and their response and tolerance to the medication will be monitored.

Inclusion Criteria

Participant has not required psychiatric hospitalization, acute crisis intervention, or other increase in level of care due to symptom exacerbation within 12 weeks of Screening and is psychiatrically stable in the opinion of the Investigator

Individuals of childbearing potential (IOCBP) must be willing and able to adhere to the contraception guidelines as defined in Appendix 1

Participant is willing and able, in the opinion of the Investigator, to discontinue all secondary AP medications prior to Baseline visit

Exclusion Criteria

Pregnant, breastfeeding, or less than 3 months postpartum

Participant has a history of moderate to severe alcohol use disorder or a substance use disorder within the past 6 months or a positive urine drug screen for a substance other than cannabis at Screening or Baseline

History or presence of clinically significant cardiovascular, pulmonary, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, or oncologic disease or any other condition that, in the opinion of the Investigator, would jeopardize the safety of the participant or the validity of the study results

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2 weeks

Pre-switch Baseline

Baseline visit before switching from atypical AP treatment to X/T

Treatment

Participants undergo an 8-week open-label treatment phase with X/T

8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

1-2 weeks

Treatment Details

Interventions

• Xanomeline/Trospium

Trial Overview The study tests how patients with schizophrenia transition from their current atypical antipsychotic treatments to a maintenance dose of Xanomeline/Trospium Chloride. The process aims to reflect real-world conditions in an 8-week open-label setup.

Participant Groups

Group I: slower transition Experimental Treatment 1 Intervention

slower transition arm will reduce the atypical AP treatment at a rate of 25% of the initial treatment over a 4-week period

Group II: accelerated transition Experimental Treatment 1 Intervention

accelerated transition arm will reduce the atypical AP treatment at a rate of 50% of the initial treatment over a 2-week period,

Who Is Running the Clinical Trial?

Collaborative Neuroscience Research, LLC

Lead Sponsor

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Findings from Research

Xanomeline, a cholinergic agonist, shows potential for improving symptoms of schizophrenia, particularly when combined with trospium, a peripheral cholinergic antagonist that may help mitigate xanomeline's adverse effects.

Initial studies of the xanomeline and trospium combination indicate promise in treating schizophrenia, with common side effects including constipation, dry mouth, and nausea, suggesting a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Xanomeline and Trospium: A Potential Fixed Drug Combination (FDC) for Schizophrenia-A Brief Review of Current Data. Singh, A.[2023]

In a 5-week study involving 170 patients with schizophrenia, the combination treatment KarXT (xanomeline-trospium) showed significantly higher response rates compared to placebo, with 59% of patients achieving at least a 20% reduction in symptoms by week 2.

KarXT demonstrated early and sustained improvements across all symptom domains of schizophrenia, including positive and negative symptoms, with significant effects observed as early as 2 weeks into treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Weiden, PJ., Breier, A., Kavanagh, S., et al.[2022]

A combination of xanomeline and trospium showed improved tolerability and significant antipsychotic effects in a randomized study of 182 patients with acute psychosis, with a notable reduction in symptoms as measured by the PANSS score.

The study suggests that targeting the cholinergic system may offer a new treatment avenue for schizophrenia, as the combination therapy demonstrated superior efficacy in reducing both positive and negative symptoms compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Xanomeline-Trospium and Muscarinic Involvement in Schizophrenia. Kidambi, N., Elsayed, OH., El-Mallakh, RS.[2023]

Xanomeline, a muscarinic receptor agonist, has shown promise in reducing psychotic behaviors in Alzheimer's patients and may be effective for treating psychotic symptoms in schizophrenia, as it shares a similar pharmacologic profile with atypical antipsychotics like clozapine and olanzapine.

Unlike traditional dopamine antagonist antipsychotics such as haloperidol, xanomeline does not induce catalepsy in rats, suggesting it may have a better safety profile while still effectively managing psychotic symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Xanomeline, an M(1)/M(4) preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice. Shannon, HE., Rasmussen, K., Bymaster, FP., et al.[2019]

Second-generation antipsychotic long-acting injections (SGA-LAIs) generally have safety profiles similar to their oral counterparts, but they also present new safety concerns, such as the risk of postinjection syndrome and worsening psychosis, particularly with olanzapine-LAI.

The review highlighted serious risks associated with risperidone-LAI and paliperidone palmitate, including worsening psychotic symptoms and a concerning link to increased suicide rates, emphasizing the need for further research to clarify these safety signals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse effects associated with second-generation antipsychotic long-acting injection treatment: a comprehensive systematic review. Gentile, S.[2018]

References

1. United States pubmed.ncbi.nlm.nih.gov

Xanomeline and Trospium: A Potential Fixed Drug Combination (FDC) for Schizophrenia-A Brief Review of Current Data. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

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]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Xanomeline-Trospium and Muscarinic Involvement in Schizophrenia. [2023]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Xanomeline, an M(1)/M(4) preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Adverse effects associated with second-generation antipsychotic long-acting injection treatment: a comprehensive systematic review. [2018]