KarXT for Schizophrenia

(ARISE Trial)

No longer recruiting at 261 trial locations

Overseen By Haig Armen Goenjian, Site 127

Age: 18+

Sex: Any

Trial Phase: Phase 3

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 You can continue your current medications while participating

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called KarXT (Xanomeline and Trospium Chloride Capsules) to determine its effectiveness for people with schizophrenia who continue to experience symptoms despite their current medication. The study compares KarXT to a placebo to assess its impact on symptoms like delusions or hallucinations. Suitable participants are those taking certain antipsychotic medications but still struggling with symptoms. Participants must have a stable living situation and someone to assist with study activities. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants the opportunity to contribute to a potentially groundbreaking treatment.

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.

Is there any evidence suggesting that KarXT is likely to be safe for humans?

Research has shown that the combination of xanomeline and trospium chloride, known as KarXT, is generally well tolerated by people with schizophrenia. Studies have found that most side effects are mild to moderate and usually resolve on their own. These results come from trials involving participants with acute symptoms of schizophrenia. The treatment proved effective and safe for these patients, with no serious safety concerns reported. Overall, KarXT appears promising as a treatment with a unique safety profile, especially for those who do not respond well to other medications. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for schizophrenia?

Researchers are excited about KarXT for schizophrenia because it uses a unique combination of xanomeline and trospium chloride. Unlike typical antipsychotics that target dopamine receptors, KarXT targets muscarinic receptors, which may reduce symptoms without the common side effects like weight gain and sedation. This novel mechanism offers hope for a more tolerable and effective treatment option for patients who struggle with the limitations of current therapies.

What evidence suggests that KarXT might be an effective treatment for schizophrenia?

Studies have shown that KarXT, a combination of xanomeline and trospium chloride, effectively treats schizophrenia. Research indicates that it reduces severe mental symptoms such as hallucinations and delusions. In previous studies, patients experienced significant improvement in their condition with KarXT. It is generally well tolerated, with most people not experiencing serious side effects. In this trial, participants will receive either KarXT or a placebo. This treatment could offer a promising option for those with schizophrenia who aren't receiving sufficient help from their current medication. ^{1 2 4 6 7}

Who Is on the Research Team?

Bristol-Myers Squibb

Principal Investigator

Bristol-Myers Squibb

Are You a Good Fit for This Trial?

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.

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Xanomeline and Trospium Chloride Capsules

Trial Overview The 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.

How Is the Trial Designed?

Group I: Drug: KarXT Experimental Treatment 1 Intervention

Group II: Placebo Placebo Group 1 Intervention

Who Is Running the Clinical Trial?

Karuna Therapeutics

Lead Sponsor

Trials

17

Recruited

4,100+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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 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]

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]

Citations

1. jamanetwork.com jamanetwork.com/journals/jamapsychiatry/fullarticle/2818047

Efficacy and Safety of Xanomeline-Trospium Chloride in ... Conclusions and Relevance Xanomeline-trospium was efficacious and well tolerated in people with schizophrenia experiencing acute psychosis.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38691387/

Efficacy and Safety of Xanomeline-Trospium Chloride in ... Xanomeline-trospium chloride was effective in reducing symptoms of psychosis and generally well tolerated in people with schizophrenia.

3. nature.com nature.com/articles/s41537-024-00525-6

Efficacy of xanomeline and trospium chloride in ... The efficacy of xanomeline/trospium (formerly known as KarXT) for the treatment of adults with schizophrenia experiencing acute psychosis was ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0924977X24007879

Efficacy, tolerability, and safety of xanomeline-trospium ... Xanomeline-trospium is an effective treatment for schizophrenia with a unique tolerability profile, potentially addressing unmet needs.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04659161

A Study to Assess Efficacy and Safety of KarXT in Acutely ... A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms. Baseline and Week 5. Secondary Outcome Measures ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40047530/

Safety and Tolerability of Xanomeline and Trospium ... Xanomeline/trospium was generally well tolerated in people with schizophrenia. The most common AEs were mild or moderate in intensity, transient, and ...

7. nature.com nature.com/articles/s41537-022-00320-1

Safety and tolerability of KarXT (xanomeline–trospium) in a ... Despite evidence of antipsychotic efficacy in patients with psychosis associated with dementia as well as schizophrenia, the earlier clinical ...