An Open-label Study to Assess the Long-term Safety, Tolerability, and Efficacy of KarXT in Adult Patients With Schizophrenia (EMERGENT-5)

Study Overview
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Brief Summary
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This is a Phase 3, multicenter, 56-week, outpatient, open-label (OL) study to evaluate the long-term safety, tolerability, and efficacy of KarXT in de novo subjects with Diagnostic and Statistical Manual-Fifth Edition (DSM-5) schizophrenia. In this OL study, all subjects will receive KarXT (a fixed combination of xanomeline 125 mg and trospium chloride 30 mg twice daily [BID]) for up to 52 weeks. The primary objective of the study is to assess the long-term safety and tolerability of KarXT in subjects with a DSM-5 diagnosis of schizophrenia. The secondary objective of this study is to assess the long-term efficacy and characterize the pharmacokinetics of xanomeline and trospium after administration of KarXT.

Official Title
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An Open-label Study to Assess the Long-term Safety, Tolerability, and Efficacy of KarXT in De Novo Subjects With DSM-5 Schizophrenia

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: Xanomeline and Trospium Chloride Capsules


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is aged 18 to 65 years at screening. Subject is capable of providing informed consent. A signed informed consent form (ICF) must be provided before any study assessments are performed. Subject must be fluent in (oral and written) the language of the ICGF to consent. Subject has a primary diagnosis of schizophrenia established by a comprehensive psychiatric evaluation based on the DSM-5 (American Psychiatric Association 2013) criteria and confirmed by Mini International Neuropsychiatric Interview for Schizophrenia and Psychotic Disorder Studies (MINI) version 7.0.2. Subject has not required psychiatric hospitalization, acute crisis intervention, or other increase in level of care due to symptom exacerbation within 8 weeks of screening and is psychiatrically stable in the opinion of the investigator. PANSS total score ≤ 80 at screening and Baseline Visit B (Day 0). Clinical Global Impression - Severity (CGI-S) score of ≤ 4 at screening and Baseline Visit B (Day 0). At the time of screening, or at any time within the 30 days prior to screening, the subject must have received an oral antipsychotic medication daily at a dose and frequency consistent with the drug label. In the opinion of the investigator, it is clinically appropriate for the subject to discontinue current antipsychotic therapy and initiate experimental treatment with KarXT. Subject is willing and able, in the opinion of the investigator, to discontinue all antipsychotic medications prior to baseline visit. Subject has an identified reliable informant willing to be able to address some questions related to certain study visits, if needed. An informant may not be necessary if the subject has been the patient of the investigator for ≥1 year. At Day 0, subject will have been off lithium therapy for at least 2 weeks and must have discontinued all oral antipsychotic medications. Subjects taking a long-acting injectable antipsychotic could not have received a dose of medication for at least 12 weeks (24 weeks for paliperidone palmitate) before Day 0. Body mass index must be ≥ 18 and ≤ 40 kg/m2. Subject resides in a stable living situation and is anticipated to remain in a stable living situation for the duration of study enrollment, in the opinion of the investigator. Women of childbearing potential or men with sexual partners of childbearing potential must be willing and able to use at least 1 highly effective method of contraception during the study and for at least 30 days after the last dose of KarXT. Sperm donation is not allowed for 30 days after the final dose of KarXT. Exclusion Criteria: Any primary DSM-5 disorder other than schizophrenia within 12 months before screening (confirmed using MINI version 7.0.2 at screening). Subject has a history of moderate to severe alcohol use disorder or a substance (other than nicotine or caffeine) use disorder within the past 12 months or a positive urine drug screen (UDS) for a substance other than cannabis at screening or baseline. 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 Subject has human immunodeficiency virus (HIV), cirrhosis, biliary duct abnormalities, hepatobiliary carcinoma, and/or active hepatic viral infections based on either medical history or liver function test results. History or high risk of urinary retention, gastric retention, or narrow-angle glaucoma History of irritable bowel syndrome (with or without constipation) or serious constipation requiring treatment within the last 6 months Risk for suicidal behavior during the study as determined by the investigator's clinical assessment and Columbia-Suicide Severity Rating Scale (C-SSRS). Clinically significant abnormal finding from the physical examination, medical history, ECG, or clinical laboratory results at screening. Subjects cannot currently (within 5 half-lives before Day 0) be receiving monoamine oxidase inhibitors, anticonvulsants, tricyclic antidepressants, centrally active anticholinergics, or any other psychoactive medications other than daily antipsychotic maintenance therapy. As-needed anxiolytics and/or sleep aids are permitted. Selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors taken at stable dose may be permitted. 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) within the past 12 months or having received clozapine within the past 3 years Pregnant, lactating, or less than 3 months postpartum. 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. Subjects has tested positive for coronavirus disease 2019 (COVID-19) within 2 weeks of screening. Subject has extreme concerns relating to global pandemics, such as COVID-19, that preclude study participation. Subject has had psychiatric hospitalization(s) for more than 30 days (cumulative) within the 6 months before screening. Subject has prior exposure to KarXT. Risk of violent or destructive behavior. Current involuntary hospitalization or incarceration.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KarXT<br> | Drug: Xanomeline and Trospium Chloride Capsules<br>* 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 8-364 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. Re-escalation to 125/30 BID or re-titration in cases in which the subject has been off KarXT for a longer period of time (at least a week) is allowed and will require a discussion between the principal investigator and the medical monitor.<br>* Other names: KarXT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events (TEAEs) | The number and percentage of participants with TEAEs will be determined | From initial dose through 7 days after the final dose (up to 53 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of serious TEAEs | The number and percentage of participants with serious TEAEs will be determined | From initial dose through 7 days after the final dose (up to 53 weeks) | 
| Incidence of TEAEs leading to withdrawal | The number and percentage of participants with TEAEs leading to withdrawal will be determined | From initial dose through 7 days after the final dose (up to 53 weeks) | 
| Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Week 52 | The PANSS is a medical scale used for measuring symptom severity of participants with schizophrenia. The PANSS rating form contains 7 positive symptom scales, 7 negative system scales, and 16 general psychopathology symptom scales. Participants are rated from 1 to 7 on each symptom scale. The total score is the sum of all scales with a minimum score of 30 and a maximum score of 210. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms. | Week 52 | 
| Change From Baseline in PANSS Positive Score at Week 52 | For positive symptoms in schizophrenia, participants are rated from 1 to 7 on each symptom scale, with a minimum score of 7 and a maximum score of 49. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms. | Week 52 | 
| Change From Baseline in PANSS Negative Score at Week 52 | For negative symptoms in schizophrenia, participants are rated from 1 to 7 on each symptom scale, with a minimum score of 7 and a maximum score of 49. A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms. | Week 52 | 
| Change From Baseline in PANSS Negative Marder Factor Score | The Negative Marder Factor score is derived from the PANSS and consists of the sum of 5 negative scales (N) and 2 general scales (G) (N1. Blunted affect; N2. Emotional withdrawal; N3. Poor rapport; N4. Passive/apathetic social withdrawal; N6. Lack of spontaneity; G7. Motor retardation; and G16. Active social avoidance), with a minimum score of 7 and a maximum score of 49. | Week 52 | 
| Change From Baseline in Clinical Global Impression - Severity (CGI-S) Score at Week 52 | The CGI-S modified asked the clinician 1 question: Considering your total clinical experience, how mentally ill is the participant at this time? The clinician's answer rated on the following 7-point scale: 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill participants. | Week 52 | 
| Percentage of PANSS responders (a 30% change in PANSS total score) at Week 52 | A PANSS responder is defined as a participant with at least a 30% change in PANSS total score compared to baseline at Week 52. | Week 52 |