What side effects are associated with this type of intervention?

Common treatments for schizophrenia, such as antipsychotic medications, often have a range of side effects. First-generation antipsychotics can cause extrapyramidal symptoms (EPS) like tremors, rigidity, and tardive dyskinesia. Second-generation antipsychotics, while generally having a lower risk of EPS, can lead to weight gain, metabolic syndrome, and increased risk of diabetes. Specific to treatments like KarXT, which involves muscarinic receptor modulation, potential side effects may include dry mouth, constipation, and blurred vision due to the peripheral muscarinic receptor antagonist component (trospium chloride). The muscarinic receptor agonist (xanomeline) may also cause gastrointestinal disturbances and increased sweating.

What prior FDA approvals exist?

The FDA has approved several antipsychotic medications for the treatment of schizophrenia, including both typical and atypical antipsychotics. Typical antipsychotics like haloperidol and chlorpromazine have been used for decades. Atypical antipsychotics, which are more commonly used today, include drugs like risperidone, olanzapine, quetiapine, and ziprasidone. These medications primarily target dopamine receptors but also affect serotonin receptors. While KarXT (xanomeline and trospium chloride) is being studied for its unique mechanism involving muscarinic receptors, there are no current FDA-approved treatments for schizophrenia that specifically use a muscarinic receptor agonist combined with a peripheral muscarinic receptor antagonist.

What other types of research exist?

Promising novel alternatives to KarXT for schizophrenia treatment in 2024 include: 1) SEP-363856, a TAAR1 agonist with potential benefits in both positive and negative symptoms; 2) Ulotaront, another TAAR1 agonist showing promise in clinical trials; 3) Lumateperone, which has a unique mechanism of action involving serotonin, dopamine, and glutamate pathways; and 4) Roluperidone, targeting negative symptoms and cognitive impairment in schizophrenia.

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KarXT for Schizophrenia

Q: What is the mechanism of action of this treatment?

Common treatments for schizophrenia include typical antipsychotics, which block dopamine D2 receptors to reduce positive symptoms, and atypical antipsychotics, which also target serotonin receptors to address both positive and negative symptoms. KarXT, an investigational treatment, combines xanomeline, a muscarinic receptor agonist that modulates neurotransmitter release, with trospium chloride, a peripheral muscarinic receptor antagonist that minimizes side effects. Understanding these mechanisms helps in tailoring treatments to individual symptom profiles and managing side effects effectively.

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 is aged ≥18 to <60 years at the time of randomization of Study KAR-012

Be older than 18 years old

Must not have

Female subject is pregnant

Any clinically significant abnormalities, including any finding(s) from ECG, or laboratory test at Visit 6, and the physical examination, vital signs, at the EOT visit of ARISE Study KAR-012 that the Investigator, in consultation with the Medical Monitor are considered to jeopardize the safety of the subject

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 5 years

Awards & highlights

Pivotal Trial

No Placebo-Only Group

Summary

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.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

Potential side effects may include digestive issues due to trospium (like constipation or dry mouth), central nervous system effects from xanomeline (such as confusion or agitation), and other common drug-related reactions.

Eligibility Criteria

Inclusion Criteria

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

Select...

I am between 18 and 59 years old.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

Select...

I am currently pregnant.

Select...

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

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 5 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 5 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 5 years for reporting.

Treatment Details

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.

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

1Treatment groups

Experimental Treatment

Group I: Drug: KarXTExperimental Treatment1 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 / 3Eligibility 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 include typical antipsychotics, which block dopamine D2 receptors to reduce positive symptoms, and atypical antipsychotics, which also target serotonin receptors to address both positive and negative symptoms. KarXT, an investigational treatment, combines xanomeline, a muscarinic receptor agonist that modulates neurotransmitter release, with trospium chloride, a peripheral muscarinic receptor antagonist that minimizes side effects. Understanding these mechanisms helps in tailoring treatments to individual symptom profiles and managing side effects 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.