A Study to Assess Efficacy and Safety of Adjunctive KarXT in Subjects With Inadequately Controlled Symptoms of Schizophrenia

1. Any primary DSM-5 disorder other than schizophrenia within 12 months before screening (confirmed using MINI version 7.0.2 at screening)

2. The subject has a history of moderate to severe substance use disorder (other than nicotine) within the past 12 months

1. A Screening subject with mild substance use disorder within the 12 months before Screening must be discussed with the Medical Monitor before being allowed into the study

2. Subjects who test positive for cannabis at Screening may be permitted to enroll in consultation with the Medical Monitor if the subject's pattern of use is not indicative of a moderate to severe substance use disorder

3. Subject has a history of treatment-resistant schizophrenia defined as:

a. Failure to minimally respond to 2 adequate courses of antipsychotic drug (APD) pharmacotherapy Note: Failure to minimally respond is defined as persistence symptoms of moderate severity in 2 or more psychotic symptom domains or persistence of severe symptoms in 1 or more psychotic symptom domains despite adequate dose and duration (6 weeks or longer) of APD treatment.

4. History of symptom instability

a. \> 3 psychiatric hospitalizations over the last 12 months or 2 over the last 6 months

5. Current APD is other than aripiprazole, risperidone, paliperidone, or their LAI versions, ziprasidone, lurasidone, or cariprazine

6. Subjects who are diagnosed with schizophreniform disorder or are experiencing their first treated episode of schizophrenia

7. Significant or severe medical conditions including pulmonary, cardiovascular, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, or oncologic disease or any other condition that, in the opinion of the Investigator, could jeopardize the safety of the subject or the validity of the study results

1. eGFR \< 60 mL/min

2. Alanine transaminase or aspartate transaminase (AST) \> 1.5 x upper limit of normal (ULN)

3. Total bilirubin \> 1.5 x ULN (Subjects with Gilbert's syndrome can be included as long as direct bilirubin is ≤ 1.5 x ULN)

8. Subjects with human immunodeficiency virus (HIV), cirrhosis, biliary duct abnormalities, hepatobiliary carcinoma, and/or active hepatic viral infections as indicated by medical history, serologies or LFT results

9. History or high risk of urinary retention, gastric retention, or narrow-angle glaucoma as evaluated by the Investigator

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

11. Risk for suicidal behavior during the study as determined by the Investigator's clinical assessment and/or C-SSRS as confirmed by the following:

1. Answers "Yes" on items 4 or 5 (C-SSRS - ideation) with the most recent episode occurring within the 2 months before Screening or,

2. Answers "Yes" to any of the 5 items (C-SSRS behavior) with an episode occurring within the 12 months before Screening

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

13. Urine toxicology screen is positive for phencyclidine, amphetamines, opiates, cocaine, or alcohol (clinically significant alcohol use in the opinion of the Investigator)

14. Subject is currently taking, or plans to take while in the study, any prohibited concomitant medication.

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

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

17. Positive test for coronavirus (COVID-19) within 2 weeks or at Screening

18. Subjects with extreme concerns relating to global pandemics, such as COVID-19, that would obscure ratings or be expected to disrupt adherence to trial procedures

19. Unable to taper and discontinue a concomitant medication that would preclude participation in the double-blind adjunctive treatment (e.g., cannot stop anticholinergic)

20. Subjects with prior exposure to KarXT

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

22. Subjects who received investigational product as part of a clinical trial within 3 months of Screening

23. Risk of violent or destructive behavior as per Investigator's judgment that would interfere with subject's participation

24. Current involuntary hospitalization or incarcerationor on parole/probation

25. For all male subjects only, any one of the following:

1. History of bladder stones

2. History of recurrent urinary tract infections

3. Serum prostate specific antigen (PSA) \>10 ng/mL

4. An International Prostate Symptom Score (IPSS) of 5 (almost always) on either item 1, 3, 5, or 6

5. A sum of scores on IPSS items 1, 3, 5, and 6 of ≥9 Note: IPSS will be required only for male subjects ≥ 45 years of age. Subjects already enrolled in the study will have these assessments at their next clinic visit planned after re-consenting to determine current eligibility.

What this study is about