Evaluation of KarXT (Trospium Chloride, Xanomeline Tartrate) for Treating Psychosis in Alzheimer's Disease: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this Phase 3, randomized, double-blind, placebo-controlled study is to evaluate the **efficacy** of KarXT compared with placebo in the treatment of **psychosis** associated with Alzheimer's Disease (AD). This is measured by the Neuropsychiatric Inventory-Clinician (NPI-C) focusing on Hallucinations and Delusions (H+D) scores. The clinical relevance of this objective lies in addressing the significant challenge of managing psychosis in AD, which can severely impact patient quality of life and caregiver burden.

Secondary objectives include evaluating the efficacy of KarXT compared with placebo in the treatment of **agitation** in participants with psychosis associated with AD, as measured by the Cohen-Mansfield Agitation Inventory (CMAI). This is clinically important as agitation is a common and distressing symptom in AD, often leading to increased healthcare utilization and caregiver stress.

The clinical trial involves a total of **256 participants** diagnosed with **psychosis associated with Alzheimer's disease**. The study population includes both male and female subjects, aged between **55 and 90 years**. Participants were selected based on specific criteria, including a diagnosis of possible or probable Alzheimer's disease, confirmed by a magnetic resonance imaging (MRI) or computed tomography (CT) scan to exclude other central nervous system diseases. The trial population is characterized by a history of psychotic symptoms for at least two months prior to screening. The study does not specify particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, given the age range and health condition of the participants.

The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled, parallel group study designed to evaluate the safety and efficacy of KarXT for the treatment of **psychosis associated with Alzheimer's disease**. The trial aims to compare the efficacy of KarXT with a placebo, focusing on changes in the Neuropsychiatric Inventory-Clinician (NPI-C) Hallucinations and Delusions (H+D) score from baseline to the end of treatment. The trial is expected to commence recruitment on March 31, 2025, and conclude by February 27, 2026.

Participants will be randomly assigned to receive either KarXT, which contains the active substances **trospium chloride** and **xanomeline tartrate**, or a placebo. The pharmaceutical form of KarXT is a capsule, administered orally. The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess the final outcomes. The primary endpoint is the change in the NPI-C H+D score, while secondary endpoints include changes in the Cohen-Mansfield Agitation Inventory (CMAI) total score.

Participants will be involved in the study for the duration of the treatment period, which is determined by the trial protocol. Inclusion criteria require participants to be aged 55-90 years, diagnosed with possible or probable Alzheimer's disease, and have a history of psychotic symptoms for at least two months prior to the screening visit. Conditions that may lead to early termination from the study include the development of any exclusion criteria or adverse events that compromise participant safety. The trial is not classified as a low-intervention study, and it adheres to rigorous scientific and ethical standards to ensure the validity and reliability of the results.

The clinical trial involves the administration of the experimental medication **KarXT**, which is formulated as a **capsule**. The active substances in KarXT are **trospium chloride** and **xanomeline tartrate**, both of which are of chemical origin. The medication is produced by Karuna Therapeutics Inc. and is administered orally. The dosage of KarXT varies across different formulations, with a maximum daily dose ranging from 609,996 mg to 20,099,920 mg. The maximum total dose is capped at 9,999 mg, and the treatment period extends up to 9,999 days. The trial does not involve a pediatric formulation, and the medication is not classified as an orphan drug.

In addition to the experimental medication, a **placebo** is used as a comparator treatment in this study. The placebo is not associated with any active substances and does not have a specified pharmaceutical form. It serves as a control to evaluate the efficacy and safety of KarXT in treating psychosis associated with Alzheimer's disease. The placebo is administered in a manner consistent with the experimental treatment to maintain the double-blind nature of the trial.

The efficacy of KarXT in the treatment of **psychosis associated with Alzheimer's disease** will be assessed in a Phase 3, randomized, double-blind, placebo-controlled, parallel group study. The primary endpoint for evaluating efficacy is the change from baseline to the end of treatment in the Neuropsychiatric Inventory-Clinician (NPI-C): Hallucinations and Delusions (H+D) score. This score is a validated measure used to assess the severity of hallucinations and delusions in participants. Secondary endpoints include the change from baseline to the end of treatment in the Cohen-Mansfield Agitation Inventory (CMAI) total score, which evaluates the level of agitation in participants.

Participants will be assessed at various timepoints throughout the study to monitor changes in these scores. The trial will involve the administration of KarXT in capsule form, containing the active substances **trospium chloride** and **xanomeline tartrate**, with a maximum daily dose specified. The study is designed to ensure rigorous data collection and analysis, adhering to the highest standards of clinical research to determine the efficacy of the treatment in the specified patient population.