A Study to Assess Efficacy and Safety of KarXT in Acutely Psychotic Hospitalized Adult Patients With Schizophrenia (EMERGENT-2)

Inclusion Criteria:

1. Subject is aged 18 to 65 years, inclusive, at screening.
2. Subject is capable of providing informed consent.
3. A signed informed consent form must be provided before any study assessments areperformed.
4. Subject must be fluent (oral and written) in English to consent
5. Subject has a primary diagnosis of schizophrenia established by a comprehensivepsychiatric evaluation based on the DSM-5 criteria and confirmed by Mini InternationalNeuropsychiatric Interview for Schizophrenia and Psychotic Disorder Studies (MINI)version 7.0.2.
6. Subject is experiencing an acute exacerbation or relapse of psychotic symptoms, withonset less than 2 months before screening.
7. The subject requires hospitalization for this acute exacerbation or relapse ofpsychotic symptoms.
8. If already an inpatient at screening, has been hospitalized for less than 2 weeksfor the current exacerbation at the time of screening.
9. Positive and Negative Syndrome Scale total score between 80 and 120, inclusive. Scoreof ≥4 (moderate or greater) for ≥2 of the following Positive Scale (P) items:
10. Item 1 (P1; delusions)
11. Item 2 (P2; conceptual disorganization)
12. Item 3 (P3; hallucinatory behavior)
13. Item 6 (P6; suspiciousness/persecution)
14. Subjects with no change (improvement) in PANSS total score between screening andbaseline (Day -1) of more than 20%.
15. Subject has a CGI-S score of ≥4 at screening and baseline (Day -1) visits.
16. Subject will have been off lithium therapy for at least 2 weeks before baseline andfree of all oral antipsychotic medications for at least 5 half-lives or 1 week,whichever is longer, before baseline (Day -1).
17. Subjects taking a long-acting injectable antipsychotic could not have received a doseof medication for at least 12 weeks (24 weeks for INVEGA TRINZA) before baseline visit (Day -1).
18. Subject is willing and able to be confined to an inpatient setting for the studyduration, follow instructions, and comply with the protocol requirements.
19. BMI must be ≥18 and ≤40 kg/m2.
20. Subject resides in a stable living situation and is anticipated to return to that samestable living situation after discharge, in the opinion of the investigator.
21. Subject has an identified reliable informant.
22. Women of childbearing potential, or men with sexual partners of childbearingpotential, must be able and willing to use at least 1 highly effective method ofcontraception 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 oranxiety 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 beforescreening must be discussed and agreed upon with the medical monitor before they canbe allowed into the study.
2. Subjects who are newly diagnosed or are experiencing their first treated episode ofschizophrenia.
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 theinvestigator, would jeopardize the safety of the subject or the validity of the studyresults.
4. Subjects with HIV, cirrhosis, biliary duct abnormalities, hepatobiliary carcinoma,and/or active hepatic viral infections based on either medical history or liverfunction test results.
5. History or high risk of urinary retention, gastric retention, or narrow-angleglaucoma.
6. History of irritable bowel syndrome (with or without constipation) or seriousconstipation requiring treatment within the last 6 months.
7. Risk for suicidal behavior during the study as determined by the investigator'sclinical 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, beforebaseline [Day -1]) be receiving oral antipsychotic medications; monoamine oxidaseinhibitors; anticonvulsants (eg, lamotrigine, Depakote); tricyclic antidepressants (eg, imipramine, desipramine); selective serotonin reuptake inhibitors; or any otherpsychoactive medications except for as needed anxiolytics (eg, lorazepam, chloralhydrate).
10. Pregnant, lactating, or less than 3 months postpartum.
11. If, in the opinion of the investigator (and/or Sponsor), subject is unsuitable forenrollment in the study or subject has any finding that, in the view of theinvestigator (and/or Sponsor), may compromise the safety of the subject or affecthis/her ability to adhere to the protocol visit schedule or fulfill visitrequirements.
12. Positive test for coronavirus (COVID-19) within 2 weeks before screening and atscreening.
13. Subjects with extreme concerns relating to global pandemics, such as COVID-19, thatpreclude 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 asfailure to respond to 2 adequate courses of pharmacotherapy (a minimum of 4 weeks atan 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 experimentalor investigational drug agent within 3 months before screening.
19. Risk of violent or destructive behavior.
20. Current involuntary hospitalization or incarceration.