A Study to Assess Efficacy and Safety of KarXT in Acutely Psychotic Hospitalized Adult Patients With Schizophrenia (EMERGENT-3)

NCT ID: NCT04738123

Last Updated: 2024-12-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 256 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-04-06
• Study Completion Date: 2022-12-07

Brief Summary

This is a Phase 3, randomized, double-blind, parallel-group, placebo-controlled, multicenter inpatient study to examine the efficacy and safety of KarXT in adult subjects who are acutely psychotic with a Diagnostic and Statistical Manual Fifth Edition (DSM-5) diagnosis of schizophrenia. The primary objective of the study is to assess the efficacy of KarXT (a fixed combination of xanomeline 125 mg and trospium chloride 30 mg twice daily [BID]) versus placebo in reducing Positive and Negative Syndrome Scale (PANSS) total scores in adult inpatients with a DSM-5 diagnosis of schizophrenia. The secondary objectives of the study are to evaluate improvement in disease severity and symptoms, safety and tolerability, and pharmacokinetics in adult inpatients with a DSM-5 diagnosis of schizophrenia.

Conditions

Schizophrenia; Schizophrenia; Psychosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

KarXT

Group Type: EXPERIMENTAL

Xanomeline and Trospium Chloride Capsules

Intervention Type: DRUG

Oral xanomeline 50 mg/trospium 20 mg BID on days 1-2 followed by xanomeline 100 mg/trospium 20 mg BID on days 3-7. The dose is increased to xanomeline 125 mg/trospium 30 mg BID on days 8-35 unless the subject is experiencing adverse events from the xanomeline 100 mg/ trospium 20 mg dose. Subjects who were increased to xanomeline 125 mg/trospium 30 mg will have the option to return to xanomeline 100 mg/ trospium 20 mg depending on clinical response and tolerability.

Placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo Capsules

Interventions

Xanomeline and Trospium Chloride Capsules

Oral xanomeline 50 mg/trospium 20 mg BID on days 1-2 followed by xanomeline 100 mg/trospium 20 mg BID on days 3-7. The dose is increased to xanomeline 125 mg/trospium 30 mg BID on days 8-35 unless the subject is experiencing adverse events from the xanomeline 100 mg/ trospium 20 mg dose. Subjects who were increased to xanomeline 125 mg/trospium 30 mg will have the option to return to xanomeline 100 mg/ trospium 20 mg depending on clinical response and tolerability.

Intervention Type: DRUG

Placebo

Placebo Capsules

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Subject is aged 18 to 65 years, inclusive, at screening.

2. Subject is capable of providing informed consent.

1. A signed informed consent form must be provided before any study assessments are performed.

2. Subject must be fluent (oral and written) in English or local language to consent

3. 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.

4. Subject is experiencing an acute exacerbation or relapse of psychotic symptoms, with onset less than 2 months before screening.

1. The subject requires hospitalization for this acute exacerbation or relapse of psychotic symptoms.

2. If already an inpatient at screening, has been hospitalized for less than 2 weeks for the current exacerbation at the time of screening.

5. Positive and Negative Syndrome Scale total score between 80 and 120, inclusive. Score of ≥4 (moderate or greater) for ≥2 of the following Positive Scale (P) items:

1. Item 1 (P1; delusions)

2. Item 2 (P2; conceptual disorganization)

3. Item 3 (P3; hallucinatory behavior)

4. Item 6 (P6; suspiciousness/persecution)

6. Subjects with no change (improvement) in PANSS total score between screening and baseline (Day -1) of more than 20%.

7. Subject has a CGI-S score of ≥4 at screening and baseline (Day -1) visits.

8. Subject will have been off lithium therapy for at least 2 weeks before baseline and free of all oral antipsychotic medications for at least 5 half-lives or 1 week, whichever is longer, before baseline (Day -1).

9. Subjects taking a long-acting injectable antipsychotic could not have received a dose of medication for at least 12 weeks (24 weeks for INVEGA TRINZA) before baseline visit (Day -1).

10. Subject is willing and able to be confined to an inpatient setting for the study duration, follow instructions, and comply with the protocol requirements.

11. BMI must be ≥18 and ≤40 kg/m2.

12. Subject resides in a stable living situation and is anticipated to return to that same stable living situation after discharge, in the opinion of the investigator.

13. Subject has an identified reliable informant/caregiver.

14. Women of childbearing potential, or men with sexual partners of childbearing potential, must be able and willing to use at least 1 highly effective method of contraception during the study and for 30 days after the last dose of study drug. Sperm donation is not allowed for 30 days after the final dose of study drug.

Exclusion Criteria

1. Any primary DSM-5 disorder other than schizophrenia within 12 months before screening (confirmed using MINI version 7.0.2 at screening). Symptoms of mild mood dysphoria or anxiety are allowed as long as these symptoms are not the primary focus of treatment. A screening subject with mild substance abuse disorder within the 12 months before screening must be discussed and agreed upon with the medical monitor before they can be allowed into the study.

2. Subjects who are newly diagnosed or are experiencing their first treated episode of schizophrenia.

3. History or presence of clinically significant cardiovascular, pulmonary, hepatic, 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 subject or the validity of the study results.

4. Subjects with HIV, cirrhosis, biliary duct abnormalities, hepatobiliary carcinoma, and/or active hepatic viral infections based on either medical history or liver function test results.

5. History or high risk of urinary retention, gastric retention, or narrow-angle glaucoma.

6. History of irritable bowel syndrome (with or without constipation) or serious constipation requiring treatment within the last 6 months.

7. Risk for suicidal behavior during the study as determined by the investigator's clinical assessment and Columbia-Suicide Severity Rating Scale (C-SSRS).

8. Clinically significant abnormal finding on the physical examination, medical history, ECG, or clinical laboratory results at screening.

9. Subjects cannot currently (within 5 half-lives or 1 week, whichever is longer, before baseline [Day -1]) be receiving oral antipsychotic medications; monoamine oxidase inhibitors; anticonvulsants (eg, lamotrigine, Depakote); tricyclic antidepressants (eg, imipramine, desipramine); selective serotonin reuptake inhibitors; or any other psychoactive medications except for as needed anxiolytics (eg, lorazepam, chloral hydrate).

10. Pregnant, lactating, or less than 3 months postpartum.

11. If, in the opinion of the investigator (and/or Sponsor), subject is unsuitable for enrollment in the study or subject has any finding that, in the view of the investigator (and/or Sponsor), may compromise the safety of the subject or affect his/her ability to adhere to the protocol visit schedule or fulfill visit requirements.

12. Positive test for coronavirus (COVID-19) within 2 weeks before screening and at screening.

13. Subjects with extreme concerns relating to global pandemics, such as COVID-19, that preclude study participation.

14. Subject has had psychiatric hospitalization(s) for more than 30 days (cumulative) during the 90 days before screening.

15. Subject has a history of treatment resistance to schizophrenia medications defined as failure to respond to 2 adequate courses of pharmacotherapy (a minimum of 4 weeks at an adequate dose per the label) or required clozapine within the last 12 months.

16. Subjects with prior exposure to KarXT.

17. Subjects who experienced any adverse effects due to xanomeline or trospium.

18. Participation in another clinical study in which the subject received an experimental or investigational drug agent within 3 months before screening.

19. Risk of violent or destructive behavior.

20. Current involuntary hospitalization or incarceration.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Karuna Therapeutics

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Inder Kaul, MD

Role: STUDY_DIRECTOR

Karuna Therapeutics

Locations

Pillar Clinical Research

Bentonville, Arkansas, United States

Woodland International Research Group

Little Rock, Arkansas, United States

Advanced Research Center, Inc.

Anaheim, California, United States

Clinical Innovations, Inc

Bellflower, California, United States

ProScience Research Group

Culver City, California, United States

Collaborative Neuroscience Research, LLC.

Garden Grove, California, United States

CNS Network

Long Beach, California, United States

NRC Research Institute

Orange, California, United States

Artemis Institute for Clinical Research

San Diego, California, United States

Behavioral Clinical Research, Inc.

Hollywood, Florida, United States

Larkin Behavioral Health Services

Hollywood, Florida, United States

Atlanta Center for Medical Research

Atlanta, Georgia, United States

iResearch Atlanta, LLC

Decatur, Georgia, United States

AMITA Health Center for Psychiatric Research

Chicago, Illinois, United States

Uptown Research Institute

Chicago, Illinois, United States

AMITA Health Center for Psychiatric Research

Hoffman Estates, Illinois, United States

Hassman Research Institute

Berlin, New Jersey, United States

Hassman Research Institute

Marlton, New Jersey, United States

Community Clinical Research, Inc.

Austin, Texas, United States

InSite Clinical Research, LLC

DeSoto, Texas, United States

Dnipropetrovsk Regional Clinical Hospital named after I.I. Mechnikov

Dnipro, , Ukraine

Institute of Neurology, Psychiatry and Narcology of the National Academy of Medical Sciences of Ukraine

Kharkiv, , Ukraine

Regional Clinical Psychiatric Hospital No. 3, Adult Psychiatric Department No. 3

Kharkiv, , Ukraine

Regional Clinical Psychiatric Hospital No. 3, Psychiatric Department for First Episode Psychosis

Kharkiv, , Ukraine

Kherson Regional Institution of Mental Care

Kherson, , Ukraine

Kyiv City Psychoneurological Hospital #2

Kyiv, , Ukraine

Kyiv Regional Medical Incorporation "Psychiatry", Center for Novel Treatment and Rehabilitation of Psychotic Disorders

Kyiv, , Ukraine

Lviv Regional Clinical Psychiatric Hospital, Department #20

Lviv, , Ukraine

Lviv Regional Clinical Psychiatric Hospital, Department #25

Lviv, , Ukraine

Regional Institution of Mental Psychiatric Care of the Poltava Regional Council

Poltava, , Ukraine

Cherkasy Regional Psychiatric Hospital of Cherkasy Regional Council

Smila, , Ukraine

M.I. Pyrogov Vinnytsya National Medical University

Vinnytsia, , Ukraine

Countries

United States; Ukraine

References

Yeung PP, Breier A, Zhu H, Kaul I, Marcus RN. Xanomeline and Trospium Chloride for the Treatment of Agitation Associated With Schizophrenia: PANSS-Excited Component Results From 3 Randomized, Double-Blind, Placebo-Controlled EMERGENT Trials. J Clin Psychiatry. 2025 Mar 24;86(2):24m15668. doi: 10.4088/JCP.24m15668.

Reference Type: DERIVED

PMID: 40215379 (View on PubMed)

Citrome L, Neugebauer NM, Meli AA, Kando J. Xanomeline and Trospium Chloride Versus Placebo for the Treatment of Schizophrenia: A Post Hoc Analysis of Number Needed to Treat, Number Needed to Harm, and Likelihood to Be Helped or Harmed. Neuropsychiatr Dis Treat. 2025 Apr 5;21:761-773. doi: 10.2147/NDT.S503494. eCollection 2025.

Reference Type: DERIVED

PMID: 40212458 (View on PubMed)

Kaul I, Claxton A, Sawchak S, Sauder C, Brannan SK, Raj E, Ruan S, Konis G, Brown D, Cutler AJ, Marcus R. Safety and Tolerability of Xanomeline and Trospium Chloride in Schizophrenia: Pooled Results From the 5-Week, Randomized, Double-Blind, Placebo-Controlled EMERGENT Trials. J Clin Psychiatry. 2025 Feb 26;86(1):24m15497. doi: 10.4088/JCP.24m15497.

Reference Type: DERIVED

PMID: 40047530 (View on PubMed)

Kaul I, Sawchak S, Walling DP, Tamminga CA, Breier A, Zhu H, Miller AC, Paul SM, Brannan SK. Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia: A Randomized Clinical Trial. JAMA Psychiatry. 2024 Aug 1;81(8):749-756. doi: 10.1001/jamapsychiatry.2024.0785.

Reference Type: DERIVED

PMID: 38691387 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

KAR-009

Identifier Type: -

Identifier Source: org_study_id