A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of KarXT + KarX-EC for the Treatment of Cognitive Impairment Associated with Mild to Moderate Alzheimer’s Disease (MINDSET 1)

The primary objective of this study is to evaluate whether participants with mild to moderate Alzheimer's disease receiving KarXT plus KarX-EC demonstrate improvement in cognitive impairment and global functioning. This assessment is clinically relevant as cognitive decline and functional deterioration represent core manifestations of Alzheimer's disease that significantly impact patient independence and quality of life.

The secondary objectives include:

• Assessment of functional impairment by evaluating whether participants with mild to moderate Alzheimer's disease treated with KarXT plus KarX-EC demonstrate improvement in their ability to perform activities of daily living.

• Evaluation of behavioral symptoms, specifically examining whether participants with mild to moderate Alzheimer's disease who present with mood or behavioral disturbances experience improvement in these symptoms following treatment with KarXT plus KarX-EC.

• Evaluation of the safety and tolerability profile of KarXT plus KarX-EC in participants with mild to moderate Alzheimer's disease.

The clinical trial enrolled a total of **361 participants** diagnosed with **mild to moderate Alzheimer's Disease**. The study population consisted of both **males and females** aged between **60 and 85 years**. Participants were required to have a **Mini-Mental State Examination (MMSE)** score ranging from 12 through 22, inclusive, at the time of screening. Each participant was required to have a designated **caregiver** who maintains adequate contact of approximately 10 hours per week or more and is willing to attend all study visits. The caregiver was responsible for reporting on the participant's condition, overseeing medication and study procedure compliance, and assisting with medication administration. Participants receiving **acetylcholinesterase inhibitors (AChEIs)** and/or **memantine** were required to have been on a stable dosage for at least 12 weeks prior to screening and to maintain this stable dose throughout the study duration. The trial population was classified as a **vulnerable population**.

This is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group clinical trial designed to evaluate the efficacy and safety of KarXT combined with KarX-EC in participants with mild to moderate Alzheimer's disease. The investigational medicinal products include KarXT capsules containing xanomeline tartrate and trospium chloride, and KarX-EC capsules containing xanomeline tartrate, both administered via the oral route. Matching placebo capsules are used as comparators. The maximum treatment period is 48 weeks. The trial is sponsored by Bristol-Myers Squibb International Corporation.

The primary objective of this trial is to determine whether participants with mild to moderate Alzheimer's disease receiving KarXT combined with KarX-EC demonstrate improvement in cognitive function and global functioning compared to placebo. The primary endpoints include the change from baseline in the ADAS-Cog11 score at Week 24 and the CIBIC+ assessment at Week 24. Secondary endpoints evaluate changes from baseline in the ADCS-ADL scale at Week 24, the NPI total score at Week 24, and the occurrence of adverse events and serious adverse events, including adverse events of special interest, events leading to study intervention discontinuation, study discontinuation, or death through Week 24. Additional safety assessments include the incidence and severity of clinically significant changes in vital signs, electrocardiogram, C-SSRS, weight, and safety laboratory tests through Week 24.

Eligible participants are males and females aged between 60 and 85 years who have an MMSE score ranging from 12 through 22, inclusive, at the time of screening. Participants must have a designated caregiver who maintains adequate contact (approximately 10 hours per week or more) and is willing to attend all study visits. The caregiver is responsible for reporting on the participant's condition, overseeing medication and study procedure compliance, and assisting with medication administration. Participants receiving acetylcholinesterase inhibitors and/or memantine must have been on a stable dosage for at least 12 weeks prior to screening and agree to maintain this stable dose throughout the study duration.

The estimated recruitment start date is July 2025, and the estimated end date is March 2029. Participant involvement includes a screening visit to assess eligibility, followed by a treatment period of up to 48 weeks during which participants receive either the active investigational products or matching placebo. Follow-up visits are scheduled at regular intervals throughout the treatment period to assess efficacy and safety outcomes, including cognitive assessments, global functioning evaluations, and monitoring for adverse events and clinically significant changes in safety parameters. The end-of-study visit occurs at Week 24 for the primary efficacy assessments, with continued safety monitoring through the maximum treatment period. Conditions that may lead to early termination from the study include adverse events leading to study intervention discontinuation, adverse events leading to study discontinuation, or at the discretion of the investigator based on safety concerns or participant withdrawal of consent.

The experimental treatment regimen consists of two investigational medicinal products administered in combination. KarXT (sponsor product code BMS-986510) is a fixed-dose combination product containing two active substances: xanomeline tartrate and trospium chloride. KarXT is formulated as a capsule for oral administration. The product is manufactured by Bristol-Myers Squibb International Corporation. The maximum treatment duration is 48 weeks.

KarX-EC (sponsor product code BMS-986519) contains xanomeline tartrate as the sole active substance. This product is also formulated as a capsule for oral administration and is manufactured by Bristol-Myers Squibb International Corporation. KarX-EC is administered in combination with KarXT throughout the treatment period. The maximum treatment duration is 48 weeks.

The study includes matching placebo formulations designed to maintain blinding of treatment assignment. KarXT matching placebo and KarX-EC matching placebo are administered to participants randomized to the placebo arm. These placebo products are formulated to be indistinguishable from their respective active comparators in appearance and administration characteristics.

All investigational products are administered via the oral route. The study employs a double-blind, placebo-controlled design to evaluate the efficacy and safety of the active treatment combination (KarXT plus KarX-EC) compared to placebo in participants with cognitive impairment associated with mild to moderate Alzheimer's disease.

Efficacy will be assessed using multiple endpoints to evaluate cognitive function and global clinical status in participants with mild to moderate Alzheimer's disease. The primary efficacy parameters include the change from baseline in the Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog11) at Week 24 and the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC+) at Week 24. Secondary efficacy endpoints comprise the change from baseline in the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale at Week 24 and the change from baseline in the Neuropsychiatric Inventory (NPI) total score at Week 24. These assessments will be conducted to measure cognitive impairment, global functioning, daily living activities, and neuropsychiatric symptoms over the treatment period.