A Study to Assess Efficacy and Safety of KarXT for the Treatment of Psychosis Associated With Alzheimer's Disease

Study Overview
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Brief Summary
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This is a Phase 3, randomized, double-blind, placebo-controlled, parallel group study to evaluate the safety and efficacy of KarXT in male and female subjects who are aged 55 to 90 years and have mild to severe Alzheimer's Disease (AD) with moderate to severe psychosis related to AD. The primary objective of the study is to evaluate the efficacy of KarXT compared with placebo in the treatment of subjects with psychosis associated with AD as measured by the Neuropsychiatric Inventory-Clinician (NPI-C): Hallucinations and Delusions (H+D) score.

Official Title
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A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Safety and Efficacy of KarXT for the Treatment of Psychosis Associated With Alzheimer's Disease

Conditions
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Psychosis Associated With Alzheimer's Disease

Intervention / Treatment
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* Drug: KarXT
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Is a male or female aged 55 to 90 years, inclusive, at Screening. Can understand the nature of the trial and protocol requirements and provide informed consent or assent before any study assessments are performed. Meets clinical criteria for Possible AD or Probable AD. Living at the same home or residential assisted-living facility for a minimum of 6 weeks before Screening. Have an identified study partner who should have daily contact (approximately 10 hours a week or more). History of psychotic symptoms (meeting International Psychogeriatric Association criteria) (Cummings 2020) for at least 2 months prior to Screening. CGI-S scale with a score ≥ 4 at Screening and Baseline. AD subjects are required to have NPI-C: Hallucinations and Delusions (H+D) score of ≥ 6 AND meet at least 1 of the following criteria at Screening and Baseline: Moderate to severe delusions, defined as NPI-C: Delusions domain score of ≥ 2 on 2 of the 8 items OR Moderate to severe hallucinations, defined as NPI-C: Hallucinations domain score of ≥ 2 on 2 of the 7 items MMSE score of 8 to 22, inclusive, at Screening. Key Exclusion Criteria: Psychotic symptoms that are primarily attributable to a condition other than the AD causing the dementia. History of major depressive episode with psychotic features during the 12 months prior to Screening. History of bipolar disorder, schizophrenia, or schizoaffective disorder. Significant or severe medical conditions including pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, cardiovascular, or oncologic disease or any other condition that, in the opinion of the Investigator, could jeopardize the safety of the subject, ability to complete or comply with the study procedures or validity of the study results. History or high risk of urinary retention, gastric retention, or narrow-angle glaucoma as evaluated by the Investigator. Prior exposure to KarXT. History of hypersensitivity to KarXT excipients or trospium chloride. Experienced any significant adverse events (AEs) due to trospium. Participation in another clinical study in which the subject received an experimental or investigational drug within 3 months before Screening or has participated in more than 2 clinical studies in the 12 months prior to Screening.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: KarXT<br>Xanomeline and Trospium Chloride Capsules | Drug: KarXT<br>* KarXT 20/2 mg (total daily dose [TDD] 60/6 mg) KarXT 30/3 mg (TDD 90/9 mg) KarXT 40/4 mg (TDD 120/12 mg) KarXT 50/5 mg (TDD 150/15 mg) KarXT 66.7/6.67 mg (TDD 200/20 mg)<br>|
| Placebo Comparator: Placebo<br>Placebo Capsules | Drug: Placebo<br>* Placebo Capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline to End of Treatment in the Neuropsychiatric Inventory-Clinician: Hallucinations and Delusions (NPI-C: H+D) score | Neuropsychiatric Inventory-Clinician: Hallucinations and Delusions scale includes 2 domains from the NPI-C scale, namely, hallucinations and delusions. These 2 domains include the following number of items to be rated by the clinician: Hallucinations, 7 items (maximum score = 21) and Delusions, 8 items (maximum score = 24). The maximum score for the NPI-C: H+D scale is 45. Higher scores on this scale indicate worse outcomes. | Baseline and End of Treatment (up to 14 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline to End of Treatment in the Cohen-Mansfield Agitation Inventory (CMAI) score | Cohen-Mansfield Agitation Inventory (CMAI) is a caregiver's rating 29-item questionnaire used to assess the frequency of manifestations of agitated behaviors in older adults. Each item is rated on a 7-point scale ranging from 1 = never to 7 = several times per hour. Higher scores on this scale indicate worse outcomes. | Baseline and End of Treatment (up to 14 weeks) | 
| Change from Baseline to End of Treatment in the Clinical Global Impressions-Severity (CGI-S) scale | Clinical Global Impressions-Severity (CGI-S) requires the assessor to consider aspects of the psychosis (hallucinations and delusions) prior to providing a global assessment of severity. Higher scores on this scale indicate worse outcomes. | Baseline and End of Treatment (up to 14 weeks) |