Evaluation of the Safety and Efficacy of Trospium Chloride and Xanomeline Tartrate in Treating Agitation in Alzheimer's Disease: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study
- Trial ID
- 2025-520613-31-00
- Protocol
- CN012-0023
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the efficacy of KarXT + KarX-EC compared to a placebo in managing agitation associated with Alzheimer’s disease, as assessed by the Cohen-Mansfield Agitation Inventory – International Psychogeriatric Association scale. The secondary objective includes evaluating efficacy using the Clinical Global Impressions – Severity score.
Participants
The study involves a total of 251 patients. The population includes both males and females, characterized as a vulnerable group. Participants must have a confirmed diagnosis of Alzheimer’s disease based on specific pathological criteria, such as amyloid positron emission tomography or specific biomarkers in the cerebrospinal fluid or plasma. Inclusion requires a Mini-Mental State Examination score between 5 and 22 and a documented history of agitation. Specific clinical thresholds must be met, including an NPI/NPI-NH Agitation/Aggression score of 4 or greater, a CGI-S score of 4 or greater, and specific frequency criteria for aggressive behaviors as measured by the Cohen-Mansfield Agitation Inventory – International Psychogeriatric Association. Additionally, the presence of a dedicated caregiver is required to oversee medication compliance and study procedures.
Plans and Procedures
This Phase 3, randomized, double-blind, placebo-controlled, parallel group study is designed to evaluate the safety and efficacy of KarXT and KarX-EC in the treatment of agitation associated with Alzheimer’s disease. The primary objective is to demonstrate efficacy compared to a placebo using the Cohen-Mansfield Agitation Inventory – International Psychogeriatric Association (CMAI-IPA) scale. The study sequence includes a screening visit (Visit 1) to assess eligibility through measures such as the Mini-Mental State Examination (MMSE), clinical assessments of agitation, and diagnostic confirmation of Alzheimer's disease pathology. Following screening, a baseline visit (Visit 2) is conducted. Participants will undergo treatment monitoring through to the end of treatment. The estimated recruitment period is scheduled from October 30, 2025, to November 8, 2028.
Treatment
The experimental medication KarXT is an oral capsule containing trospium chloride and xanomeline tartrate, administered at a dosage of 9999 mg.
The experimental medication KarX-EC is an oral capsule containing xanomeline tartrate, administered at a dosage of 9999 mg.
The control groups consist of KarXT matching Placebo and KarX-EC matching Placebo, which are used as a placebo in this study regarding the treatment of agitation associated with Alzheimer's disease.
Efficacy
The efficacy of the intervention for the treatment of agitation associated with Alzheimer’s disease is evaluated through specific primary and secondary endpoints. The primary endpoint is the change from baseline to the end of treatment in the total score of the Cohen-Mansfield Agitation Inventory – International Psychogeriatric Association (CMAI-IPA) compared with placebo.
Secondary efficacy assessment includes the change from baseline to the end of treatment on the Clinical Global Impression-Severity (CGI-S) scale as it relates specifically to agitation compared with placebo.
Inclusion and Exclusion Criteria
Inclusion Criteria
- A diagnosis of Alzheimer’s disease (AD) in accordance with the 2024 Alzheimer’s Association criteria with one of the the following confirmations of AD pathology: - Historical evidence of AD diagnosis with amyloid positron emission tomography (PET), Aβ42/40 ratio in CSF, pTau181/Aβ42 ratio in CSF or pTau217/Aβ42 ratio in plasma using an Health Authority (HA)-authorized diagnostic assay. - If no historical evidence available: A. A plasma biomarker will be assessed for eligibility if allowed per regulatory requirements. The test cutoff(s) will be based on diagnostic use approval. B. If a plasma biomarker assay cannot be used or if the assay result is inconclusive, conduct one the following: o Amyloid PET o Aβ42/40 ratio or pTau181/Aβ42 ratio in CSF using an HA-authorized diagnostic assay
- Mini-Mental State Examination (MMSE) score of 5 to 22, inclusive, at Screening (Visit 1)
- Have one identified caregiver who should have sufficient contact (approximately 10 hours a week or more) and is willing to: Attend all visits and report on participant’s status Oversee participant compliance with medication and study procedures Participate in the study assessments and provide IC to participate in the study
- History of agitation that meets the International Psychogeriatric Association (IPA) consensus definition for agitation in cognitive disorders with onset at least two weeks prior to Screening (Visit 1).
- AD participants are required to have NPI/NPI-NH Agitation/Aggression score ≥ 4 at Screening (Visit 1) and Baseline (Visit 2).
- CGI-S ≥ 4, as related to agitation, at Screening (Visit 1) and Baseline (Visit 2)
- At least 1 of the following 3 criteria must be established from the CMAI-IPA at Screening (Visit 1) and Baseline (Visit 2; CMAI-IPA Physical/Verbal Aggression Positivity): 1 or more aggressive behaviors occurring several times per week 2 or more aggressive behaviors occurring once or twice per week 3 or more aggressive behaviors occurring less than once per week
Exclusion Criteria
- Medical Conditions Agitation symptoms that are primarily attributable to a condition other than the AD causing the dementia History of bipolar disorder, schizophrenia, or schizoaffective disorder History of (or at high risk for) urinary retention, gastric retention, or narrow-angle glaucoma as evaluated by the Investigator Risk of suicidal behavior during the study as determined by the Investigator’s clinical assessment and/or C-SSR
- Prior/Concomitant Therapy - Recent history of receiving monoamine oxidase inhibitors, anticonvulsants (eg, lamotrigine, divalproex), mood stabilizers (eg, lithium), tricyclic antidepressants (eg, imipramine, desipramine), or any other psychoactive medications except for as needed anxiolytics (eg, lorazepam) Selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors taken at a stable dose for at least 8 weeks prior to Screening (Visit 1) may be permitted Mirtazapine or trazodone may be used as a hypnotic if started at least 8 weeks prior to Screening (Visit 1)
- Other protocol-defined Inclusion/Exclusion criteria apply.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Recruiting | 30 Oct 2025 | 10 |
 Croatia | Recruiting | 30 Oct 2025 | 13 |
 Greece | Recruiting | 30 Oct 2025 | 18 |
 Portugal | Recruiting | 30 Oct 2025 | 8 |
 Romania | Recruiting | 30 Oct 2025 | 25 |
 Spain | Recruiting | 30 Oct 2025 | 29 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
KarX-EC | Test | CAPSULE | ORAL | 9999 | 9999 | PRD12408417 |
KarX-EC | Test | CAPSULE | ORAL | 9999 | 9999 | PRD12408422 |
KarXT | Test | CAPSULE | ORAL | 9999 | 9999 | PRD12404377 |
KarXT matching Placebo | Placebo | N/A | — | — | — | N/A |
KarX-EC matching Placebo | Placebo | N/A | — | — | — | N/A |
KarXT | Test | CAPSULE | ORAL | 9999 | 9999 | PRD12404386 |
KarX-EC | Test | CAPSULE | ORAL | 9999 | 9999 | PRD12408431 |
KarXT | Test | CAPSULE | ORAL | 9999 | 9999 | PRD12404394 |
KarX-EC | Test | CAPSULE | ORAL | 9999 | 9999 | PRD12408423 |
KarXT | Test | CAPSULE | ORAL | 9999 | 9999 | PRD12404368 |