What is the mechanism of action of this treatment?

Common treatments for schizophrenia primarily include typical and atypical antipsychotics, which work by blocking dopamine receptors to reduce psychotic symptoms. However, newer treatments like KarXT, which combines xanomeline (a muscarinic receptor agonist) and trospium chloride (a muscarinic receptor antagonist), target muscarinic receptors. This approach aims to modulate neurotransmitter systems differently, potentially offering benefits in symptom control and side effect profiles. For schizophrenia patients, these mechanisms are crucial as they can lead to improved symptom management and better overall functioning, addressing both positive and negative symptoms more effectively.

What side effects are associated with this type of intervention?

Common treatments for schizophrenia, particularly those targeting muscarinic receptors like KarXT, can have various side effects. Xanomeline, a muscarinic receptor agonist, may cause gastrointestinal issues, increased sweating, and salivation. Trospium chloride, a muscarinic receptor antagonist, can lead to dry mouth, constipation, and urinary retention. Atypical antipsychotics, often used in schizophrenia treatment, are associated with weight gain, metabolic syndrome, sedation, and extrapyramidal symptoms. Combining these treatments aims to balance efficacy with manageable side effects.

What prior FDA approvals exist?

The FDA has approved several antipsychotic medications for the treatment of schizophrenia, primarily focusing on atypical antipsychotics such as olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole. These drugs primarily target dopamine and serotonin receptors to manage symptoms. While KarXT (xanomeline and trospium chloride) is being studied for its unique mechanism involving muscarinic receptors, most FDA-approved treatments do not specifically target these receptors. Instead, they focus on modulating neurotransmitter pathways to alleviate both positive and negative symptoms of schizophrenia.

What other types of research exist?

Promising novel alternatives to KarXT for schizophrenia patients include: 1) NDMC analogue <b13f</b, which demonstrates antipsychotic activity similar to clozapine with potential procognitive benefits when combined with a peripherally acting anticholinergic compound. 2) Brexpiprazole, an adjunctive treatment that has shown efficacy in patients with major depressive disorder and may offer benefits for schizophrenia. 3) VU6001192, a selective negative allosteric modulator of mGlu2, which could provide a new approach to managing schizophrenia symptoms.

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KarXT for Schizophrenia (ARISE Trial)

Phase 3

Recruiting

Research Sponsored by Karuna Therapeutics

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Subject has a primary diagnosis of schizophrenia established by a comprehensive psychiatric evaluation based on the DSM-5 criteria and confirmed by Mini International Neuropsychiatric Interview for Schizophrenia and Psychotic Disorder Studies (MINI) version 7.0.2

Subject is currently being treated with monotherapy risperidone, paliperidone, aripiprazole, ziprasidone or lurasidone and has been taking this treatment with the same dosing regimen for at least 8 weeks at the time of Screening (supported by documentation)

Timeline

Screening 30 days

Treatment 7 weeks

Follow Up week 6

Awards & highlights

Pivotal Trial

Summary

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.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

Potential side effects are not detailed but may include typical reactions associated with anticholinergic drugs like xanomeline and trospium such as dry mouth, constipation, blurred vision, urinary retention; plus any specific risks related to their combination.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I have been diagnosed with schizophrenia by a psychiatrist.

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I have been on the same dose of my schizophrenia medication for at least 8 weeks.

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I've tried an antipsychotic for 6 weeks without improvement.

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I am between 18 and 59 years old.

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

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I have been diagnosed with schizophrenia by a detailed psychiatric evaluation.

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I have been on the same dose of my current antipsychotic medication for at least 8 weeks.

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I have tried an antipsychotic for 6 weeks without improvement.

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I am using or willing to use effective birth control if I can have children.

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I have been diagnosed with schizophrenia by a detailed psychiatric evaluation.

Timeline

Screening ~ 30 days9 visits

Treatment ~ 7 weeks0 visits

Follow Up ~ week 6

Screening ~ 30 days

Treatment ~ 7 weeks

Follow Up ~week 6

This trial's timeline: 30 days for screening, 7 weeks for treatment, and week 6 for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Week 6

Secondary study objectives

Change from Baseline in Clinical Global Impression-Severity (CGI-S) at Week 6

Change from Baseline in Personal Social Performance (PSP) at Week 6

Change from Baseline in Positive and Negative Syndrome Scale (PANSS) Marder Negative symptom factor score at Week 6

+2 more

Side effects data

From 2022 Phase 3 trial • 252 Patients • NCT04659161

21%

Constipation

19%

Dyspepsia

19%

Nausea

14%

Vomiting

13%

Headache

10%

Hypertension

Dizziness

Abdominal discomfort

Gastrooesophageal reflux disease

Diarrhoea

Anxiety

Dry mouth

Somnolence

Vision blurred

Abdominal pain

Heart rate increased

Orthostatic hypotension

Insomnia

Suicidal ideation

Agitation

Salivary hypersecretion

Back pain

Psychotic disorder

Toothache

100%

80%

60%

40%

20%

Study treatment Arm

KarXT

Placebo

Awards & Highlights

Pivotal Trial

The final step before approval, pivotal trials feature drugs that have already shown basic safety & efficacy.

Trial Design

2Treatment groups

Experimental Treatment

Placebo Group

Group I: Drug: KarXTExperimental Treatment1 Intervention

Group II: PlaceboPlacebo Group1 Intervention

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Xanomeline and Trospium Chloride Capsules

2021

Completed Phase 3

~1410

0 / 15Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for schizophrenia primarily include typical and atypical antipsychotics, which work by blocking dopamine receptors to reduce psychotic symptoms. However, newer treatments like KarXT, which combines xanomeline (a muscarinic receptor agonist) and trospium chloride (a muscarinic receptor antagonist), target muscarinic receptors. This approach aims to modulate neurotransmitter systems differently, potentially offering benefits in symptom control and side effect profiles. For schizophrenia patients, these mechanisms are crucial as they can lead to improved symptom management and better overall functioning, addressing both positive and negative symptoms more effectively.

Clinical Effectiveness of Muscarinic Receptor-Targeted Interventions in Neuropsychiatric Disorders: A Systematic Review.Proof of mechanism and target engagement of glutamatergic drugs for the treatment of schizophrenia: RCTs of pomaglumetad and TS-134 on ketamine-induced psychotic symptoms and pharmacoBOLD in healthy volunteers.The muscarinic agonist xanomeline increases monoamine release and immediate early gene expression in the rat prefrontal cortex.