KarXT for Schizophrenia

Recruiting in Palo Alto (17 mi)

+299 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Karuna Therapeutics

Must be taking: Antipsychotics

Disqualifiers: Suicidal behavior, Pregnant, Urinary retention, others

Stay on Your Current Meds

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This trial tests the safety and tolerability of KarXT, a combination of two drugs, in schizophrenia patients who haven't responded well to their current treatments. KarXT aims to improve symptoms and manage side effects better than existing medications. KarXT (xanomeline plus trospium) is an emerging treatment for schizophrenia, showing promise in managing total, positive, and negative symptoms.

Will I have to stop taking my current medications?

No, you will not have to stop taking your current antipsychotic medication. Participants are required to stay on the same antipsychotic drug and dose they were using in the previous 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, as measured by a reduction in the Positive and Negative Syndrome Scale (PANSS) score. Additionally, it showed promise in improving cognitive function, particularly in patients with cognitive impairment. ^{1 2 3 4 5}

Is KarXT safe for humans?

KarXT, a combination of xanomeline and trospium, has been studied for safety in humans. While xanomeline alone caused severe side effects, combining it with trospium seems to reduce these effects. Common side effects of KarXT include constipation, dry mouth, and nausea. ^{1 2 5 6 7}

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. ^{1 5 7 8 9}

Research Team

Bristol-Myers Squibb

Principal Investigator

Bristol-Myers Squibb

Eligibility Criteria

This trial is for adults aged 18-60 with schizophrenia who haven't responded well to current antipsychotic treatments. Participants must have completed the ARISE Study, be in a stable living situation, and have a reliable informant. Women of childbearing age must use contraception.

Inclusion Criteria

Subject resides in a stable living situation, in the opinion of the Investigator

I can sign a consent form before any tests are done.

Subject has identified a reliable informant/caregiver willing and able to assist with study activities as needed throughout the subject's participation in the study. The informant can complete the study visits assessments via phone (as per local regulations). In Bulgaria, the informant must be physically present at all study visits

Exclusion Criteria

Risk for suicidal behavior during the study as determined by the Investigator's clinical assessment and/or Columbia-Suicide Severity Rating Scale (C-SSRS) as confirmed by the following: Subject answers 'Yes' to 'suicidal ideation' Item 4 (active suicidal ideation with some intent to act, without a specific plan) or Item 5 (active suicidal ideation with a specific plan and intent) on the C-SSRS. Non-suicidal self-injurious behavior is not exclusionary

I am currently pregnant.

I don't have any health issues that could make the trial unsafe for me.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive adjunctive KarXT for long-term safety and tolerability assessment

52 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension

Participants continue receiving adjunctive KarXT to assess long-term safety and tolerability

52 weeks

Treatment Details

Interventions

• Xanomeline and Trospium Chloride Capsules (Muscarinic Agonist/Antagonist)

Trial Overview The study tests long-term safety and tolerability of KarXT (xanomeline and trospium chloride capsules) as an add-on treatment for schizophrenia over 52 weeks. It's open-label, meaning everyone knows they're getting the drug, not a placebo.

Participant Groups

Group I: Drug: KarXT Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Karuna Therapeutics

Lead Sponsor

Trials

17

Recruited

4,100+

Findings from Research

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]

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]

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]

In a 5-week trial involving 125 patients with schizophrenia, KarXT (xanomeline-trospium) showed a significant improvement in cognitive performance among those with clinically meaningful cognitive impairment, with a robust effect size of 0.50.

When outliers were removed, KarXT demonstrated a statistically significant cognitive benefit compared to placebo (p=0.04), suggesting that it may effectively enhance cognition independently of overall symptom improvement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of KarXT (xanomeline-trospium) for cognitive impairment in schizophrenia: post hoc analyses from a randomised, double-blind, placebo-controlled phase 2 study. Sauder, C., Allen, LA., Baker, E., et al.[2023]

In a 5-week randomized, double-blind study involving 148 hospitalized adults with schizophrenia, KarXT (a combination of xanomeline and trospium chloride) showed significantly greater improvement in symptoms compared to placebo, as measured by the Positive and Negative Syndrome Scale (PANSS).

The study utilized blinded, site-independent ratings from audio recordings of PANSS interviews, which confirmed the efficacy of KarXT and demonstrated a high correlation with site-based ratings, suggesting this method could enhance the reliability of clinical assessments in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Site-independent confirmation of primary site-based PANSS ratings in a schizophrenia trial. Targum, SD., Murphy, C., Breier, A., et al.[2022]

In a phase 1 clinical trial with 68 healthy volunteers, the combination of xanomeline and trospium (KarXT) significantly reduced cholinergic adverse events by 46% compared to xanomeline alone, improving tolerability.

KarXT also showed a better safety profile, with no cases of syncope and lower rates of postural dizziness compared to xanomeline alone, while maintaining xanomeline's pharmacokinetic profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evidence of trospium's ability to mitigate cholinergic adverse events related to xanomeline: phase 1 study results. Breier, A., Brannan, SK., Paul, SM., et al.[2023]

In a 5-week phase 2 study involving 179 patients with schizophrenia, KarXT demonstrated significant efficacy and was generally well tolerated, with a low overall burden of adverse events (AEs).

Most AEs related to muscarinic receptor activity were mild and transient, with no patients discontinuing treatment due to these side effects, indicating a favorable safety profile for KarXT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of KarXT (xanomeline-trospium) in a phase 2, randomized, double-blind, placebo-controlled study in patients with schizophrenia. Correll, CU., Angelov, AS., Miller, AC., et al.[2022]

KarXT, which contains xanomeline, targets muscarinic M1 and M4 receptors instead of the traditional dopamine D2 receptor, showing promise in treating schizophrenia based on successful phase 3 trials.

The effectiveness of muscarinic receptor activation may vary among individuals with schizophrenia, suggesting the need for personalized treatment approaches to identify those who would benefit most from this type of therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Muscarinic M1 and M4 receptor agonists for schizophrenia: promising candidates for the therapeutic arsenal. Dean, B.[2023]

References

1. 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]

2. 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]

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

Effectiveness of KarXT (xanomeline-trospium) for cognitive impairment in schizophrenia: post hoc analyses from a randomised, double-blind, placebo-controlled phase 2 study. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Site-independent confirmation of primary site-based PANSS ratings in a schizophrenia trial. [2022]

7. Germany pubmed.ncbi.nlm.nih.gov

Evidence of trospium's ability to mitigate cholinergic adverse events related to xanomeline: phase 1 study results. [2023]

8. Germany pubmed.ncbi.nlm.nih.gov

Safety and tolerability of KarXT (xanomeline-trospium) in a phase 2, randomized, double-blind, placebo-controlled study in patients with schizophrenia. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Muscarinic M1 and M4 receptor agonists for schizophrenia: promising candidates for the therapeutic arsenal. [2023]