A Study to Assess the Efficacy and Safety of KarXT in Acutely Psychotic Hospitalized Chinese Adult Subjects With DSM-5 Schizophrenia

Study Overview
=================
Brief Summary
-----------------
A Phase 3, Multicenter, Two-part Study with a 5-week Double-blind Part (Randomized, Parallel-group, Placebo-controlled) followed by a 12-week Open-label Extension Part, to Evaluate the Efficacy and Safety of KarXT in Acutely Psychotic Hospitalized Chinese Adult Subjects with DSM-5 Schizophrenia

Official Title
-----------------
A Phase 3, Multicenter, Two-part Study With a 5-week Double-blind Part (Randomized, Parallel-group, Placebo-controlled) Followed by a 12-week Open-label Extension Part, to Evaluate the Efficacy and Safety of KarXT in Acutely Psychotic Hospitalized Chinese Adult Subjects With DSM-5 Schizophrenia

Conditions
-----------------
Schizophrenia

Intervention / Treatment
-----------------
* Drug: Xanomeline and Trospium Chloride Capsules
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject is Chinese national, aged 18 to 65 years, inclusive, at screening. Subject is capable of providing written informed consent. Subject has a primary diagnosis of schizophrenia established by a comprehensive psychiatric evaluation based on the DSM-5 and MINI. Subject is experiencing an acute exacerbation or relapse of psychotic symptoms, with onset less than 2 months before screening. The subject requires hospitalization for this acute exacerbation or relapse of psychotic symptoms at screen. If already an inpatient at screening, hospitalization has to be ≤2 weeks for the current exacerbation at the time of screening. PANSS total score between 80 and 120,inclusive, with a scores of ≥4 (moderate or greater) for ≥2 of the following Positive Scale (P) items: Item 1 (P1; delusions) Item 2 (P2; conceptual disorganization) Item 3 (P3; hallucinatory behavior) Item 6 (P6; suspiciousness/persecution) Subjects with no change (improvement) in PANSS total score between screening and baseline (Day -1) of more than 20%. Subject has a CGI-S score of ≥4 at screening and baseline (Day -1) visits. 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). 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). Subject is able to be confined to an inpatient setting for the duration of the 5-week double-blind part of the study, follow instructions, and comply with the protocol requirements. Body mass index of 18 to 40 kg/m2, inclusive. 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. Subject has an identified reliable informant. An informant is needed at the screening and baseline visits as well as at the end of the study for relevant assessments (site staff may act as informant while the subject is an inpatient). An informant may not be necessary if the subject has been a patient of the investigator for ≥1 year. Women of childbearing potential (WOCBP) or men whose sexual partners are WOCBP must be willing and able to adhere to the contraception guidelines. Exclusion Criteria: Any primary DSM-5 disorder other than schizophrenia within 12 months before screening (confirmed using MINI version 7.0.2 at screening). Subjects who are newly diagnosed or are experiencing their first treated episode of schizophrenia. 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. Subjects with 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 C-SSRS. Clinically significant abnormal findings on the physical examination, medical history, electrocardiogram, or clinical laboratory results at screening that, in the opinion of the investigator, would jeopardize the safety of the subject or the validity of the study results. Subjects are receiving or have recently received (within 5 half-lives or 1 week, whichever is longer, before baseline [Day -1]) oral antipsychotic medications; monoamine oxidase inhibitors; anticonvulsants (e.g., lamotrigine, valproate); tricyclic antidepressants (e.g., imipramine, desipramine); selective serotonin reuptake inhibitors; or any other psychoactive medications except for as-needed anxiolytics (e.g., lorazepam, chloral hydrate). Subjects are receiving or have recently received (within 1 week before baseline [Day -1]) metformin. Pregnant, lactating, or less than 3 months postpartum. 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. Subject has had psychiatric hospitalization(s) for more than 30 days (cumulative) during the 90 days before screening. 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 has required clozapine within the last 12 months. Subjects with prior exposure to KarXT. Subjects who experienced any significant adverse effects due to trospium chloride. Participation in another clinical study within 3 months before screening in which the subject received an experimental or investigational drug agent. Significant risk of violent or destructive behavior.

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Triple


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 8-35 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.<br>* Other names: KarXT;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo Capsules<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in PANSS total score at Week 5 | 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. | Baseline and Week 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in PANSS positive symptom score at Week 5 | 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. | Baseline and Week 5 | 
| Change from baseline in PANSS negative symptom score at Week 5 | 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. | Baseline and Week 5 | 
| Change from baseline in PANSS Negative Marder Factor score at Week 5 | The Negative Marder Factor score is derived from the PANSS and consists of the sum of 5 negative symptom items (N) and 2 general symptom items (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. | Baseline and Week 5 | 
| Change from baseline in CGI-S score at Week 5 | 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. | Baseline and Week 5 | 
| Percentage of PANSS responders (defined as a ≥30% change in PANSS total score from baseline) at Week 5 | A PANSS responder is defined as a participant with at least a 30% change in PANSS total score compared to baseline at Week 5. | Baseline and Week 5 |