A Study Evaluating the Efficacy of Xanomeline/Trospium (XT) on Cognitive Impairment After 24 and 52 Weeks of Treatment in Adult Participants With Schizophrenia

Exclusion Criteria18

• Be pregnant, lactating, or less than 3 months postpartum.
• Be at significant risk of committing suicide. This is defined as: participants with active suicidal ideation with some intent to act, without specific plan ("Yes" to question 4 of the Columbia-Suicide Severity Rating Scale (C-SSRS) or active suicidal ideation with specific plan and intent ("Yes" to question 5 of the C-SSRS), followed by an assessment by the treating clinician who determines it is not safe for the participant to participate in the study.
• Currently meet DSM-5 criteria for a manic episode or major depressive disorder as confirmed by the MINI.
• Currently meeting DSM-5 criteria for severe substance and/or alcohol use disorder as confirmed by the MINI (≥6 on module K for alcohol use disorder and/or ≥6 on module J for substance use disorder, unless being in early or sustained remission).
• Have a positive urine toxicology for phencyclidine, amphetamines, opiates (unless participant has a valid prescription for short-term use), cocaine, or alcohol (clinically significant alcohol use in the opinion of the Investigator). Nicotine and caffeine use is allowed. Stimulants and cannabis is allowed when used sporadically and recreationally as per the judgement of the clinician.
• Present with an intellectual disability, drug-induced psychosis, or history of clinically significant brain trauma as per the judgement of the clinician.
• Have current or past use of clozapine (used for at least 6 weeks in an effective dose range) and/or current use of a long-acting injectable antipsychotic, or anticholinergic treatment that cannot be discontinued before the baseline visit.
• Be expected to require more than the allowed psychotropic concomitant medication during the study (from baseline on). This is defined as: needing benzodiazepines of more than 2 mg lorazepam equivalent (daily), quetiapine, antidepressants, mood stabilizers or benzodiazepines at a dose exceeding the allowed threshold. If these treatments are used at the screening visit, they must be tapered down before the baseline visit.
• Have clinically significant abnormal finding on the physical examination, medical history, ECG (at screening), or clinically significant laboratory results at screening.
• Participated in any cognitive remediation/training program or completed the BACS within 4 weeks of Screening.
• Having a known allergy to xanomeline, trospium chloride or any of the ingredients of XT.
• Have current presence of clinically significant cardiovascular, pulmonary, renal, hematologic, gastrointestinal (e.g., obstructive disorders \[including conditions that may decrease GI motility, such as ulcerative colitis, intestinal atony, and myasthenia gravis\], endocrine, immunologic, dermatologic, neurologic, or oncologic disease or any other condition that, in the opinion of the investigator, would jeopardize the safety of the participant or the validity of the study results. This includes:
• a. Have history or high risk of urinary retention. 12b. All grades of hepatic impairment (mild \[Child-Pugh Class A\], moderate \[Child-Pugh Class B\], and severe \[Child-Pugh Class C\]).
• c. Elevations in hepatic transaminases at screening ≥ 2× ULN for ALT and AST and/or bilirubin \> 2 × ULN, unless in the context of Gilbert's syndrome.
• d. Have a history or high risk for narrow-angle glaucoma. 12e. Active biliary disease (e.g., symptomatic gallstones). Participants with other biliary histories are eligible and should be discussed with the sponsor.
• f. Participants with a history of bladder stones . 12g. Participants with a history of recurrent urinary tract infections. 12h. For all male participants, serum prostate-specific antigen \>10 ng/mL at screening.
• i. For male participants ≥ 45 years of age, an IPSS score of 5 (i.e, "almost always") on items 1, 3, 5, or 6, and/or for male participants ≥ 45 years of age, an IPSS score ≥ 9 for the sum of items 1, 3, 5, and 6.
• j. An eGFR of \< 60 mL/min (which indicates renal dysfunction). 12k. History of unstable hypertension or tachycardia as evidenced by a blood pressure of ≥ 160/100 mmHg at screening and/or a heart rate of ≥ 110 bpm at screening.