A Phase 3 Study to Evaluate the Safety and Efficacy of KarXT + KarX-EC for the Treatment of Agitation Associated With Alzheimer's Disease

Official title

A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Safety and Efficacy of KarXT + KarX-EC for the Treatment of Agitation Associated With Alzheimer's Disease (ADAGIO-2)

Overview

The purpose of this study is to evaluate the efficacy and safety of KarXT + KarX-EC in adult participants with agitation related to Alzheimer's Disease.

Interventions

• Drug Xanomeline/Trospium Chloride Capsule
  Specified dose on specified days
• Drug Xanomeline Enteric Capsule
  Specified dose on specified days
• Drug Placebo
  Specified dose on specified days

Primary outcome measures

• Change from baseline on the Cohen-Mansfield Agitation Inventory-International Psychogeriatric Association (CMAI-IPA) total score at Week 14 [Time frame: At Week 14]

Secondary outcome measures (12)

• Change from baseline on the Clinical Global Impressions-Severity (CGI-S) at Week 14 [Time frame: At Week 14]
• Change from baseline on CMAI-IPA Domains at Week 14 [Time frame: At Week 14]
• Change from baseline on CMAI Total Score at Week 14 [Time frame: At Week 14]
• Number of participants with Occurrence of Response at Week 14 [Time frame: At Week 14]
• Change from baseline on the Neuropsychiatric Inventory/Neuropsychiatric Inventory -Nursing Home (NPI/NPI-NH) Total Score at Week 14 [Time frame: At Week 14]
• Number of participants with Adverse Events (AEs) [Time frame: Up to Week 18]
• Number of participants with Treatment Emergent AEs (TEAEs) [Time frame: Up to Week 18]
• Number of participants with Serious AEs (SAEs) [Time frame: Up to Week 18]
• Number of participants with AEs leading to study drug withdrawal [Time frame: Up to Week 18]
• Number of deaths [Time frame: Up to Week 18]
• Number of participants with AEs of Special Interest (AESIs) [Time frame: Up to Week 18]
• Barnes Akathisia Rating Scale (BARS) [Time frame: Up to Week 14]

Eligibility criteria

Inclusion criteria

\- A diagnosis of Alzheimer's disease (AD) in accordance with the 2024 Alzheimer's Association criteria with one of the following confirmations of AD pathology:

i) 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.

ii) 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:

• Amyloid PET.
• Aβ42/40 ratio or pTau181/Aβ42 ratio in CSF using an HA-authorized diagnostic assay.

• Mini-Mental State Examination (MMSE) score of ≤ 24 at Screening (Visit 1).
• Have an identified caregiver who has sufficient contact (approximately 8 hours over a week) and is willing to:

i) Attend all visits and report on participant's status.

ii) Oversee participant compliance with medication and study procedures.

iii) Participate in the study assessments and provide informed consent 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).
• Cohen-Mansfield Agitation Inventory-International Psychogeriatric Association (CMAI-IPA) Total Score ≥ 30 at Screening (Visit 1) and Visit 2.

Exclusion criteria

\- Medical Conditions.

i) Agitation symptoms that are primarily attributable to a condition other than the AD causing the dementia.

ii) History of bipolar disorder, schizophrenia, or schizoaffective disorder.

iii) History of (or at high risk for) urinary retention, gastric retention, or narrow-angle glaucoma as evaluated by the Investigator.

iv) Risk of suicidal behavior during the study as determined by the Investigator's clinical assessment and/or C-SSR.

\- Prior/Concomitant Therapy.

i) 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).

A. 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.

B. Trazodone may be used as a hypnotic or for agitation if started at least 8 weeks prior to Screening (Visit 1).

Note: Mirtazapine may be used as a hypnotic if started at least 8 weeks prior to Screening (Visit 1).

\- Other protocol-defined Inclusion/Exclusion criteria apply.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 43 centers

• Chandler Clinical Trials, LLC — Chandler
• Local Institution - 2631 — Chandler
• Local Institution - 2646 — Chandler
• National Institute of Clinical Research — Garden Grove
• Local Institution - 2607 — Long Beach
• Accellacare — Long Beach
• Local Institution - 2627 — Napa
• Local Institution - 2649 — Orange
• … and 35 more centers

Ukraine · 16 centers

Center list to be confirmed — check the primary protocol.

South Korea · 10 centers

Center list to be confirmed — check the primary protocol.

United Kingdom · 10 centers

Center list to be confirmed — check the primary protocol.

Czechia · 9 centers

• AGE Centrum — Olomouc
• Neuropsychiatrie — Prague
• Institut neuropsychiatricke pece (INEP), Praha — Prague
• Neuro Health Centrum s.r.o. — Brno
• NEUROHK — Choceň
• A-SHINE s.r.o. — Pilsen
• Local Institution - 2102 — Prague
• Local Institution - 2105 — Prague
• … and 1 more center

Poland · 9 centers

Center list to be confirmed — check the primary protocol.

Hungary · 8 centers

• Local Institution - 2257 — Kalocsa
• Local Institution - 2250 — Győr
• Debreceni Egyetem Klinikai Kozpont — Debrecen
• Local Institution - 2254 — Gyöngyös
• Local Institution - 2256 — Budapest
• … and 3 more centers

Italy · 8 centers

Center list to be confirmed — check the primary protocol.

Argentina · 7 centers

• Centro Neurobiológico y de Estrés Traumático - CENydET S.R.L. — Ciudad Autonoma de Buenos Aires
• Fundacion para el Estudio y Tratamiento de Enfermedades mentales- FETEM — Buenos Aires
• Local Institution - 2004 — Buenos Aires
• Instituto Modelo de Neurología, Fundación Lennox — Córdoba
• Local Institution - 2002 — Córdoba
• Instituto Médico DAMIC — Córdoba
• Resolution Psychopharmacology Research Institute — Mendoza

France · 7 centers

• Centre Hospitalier Universitaire Toulouse - Cité de la Santé — Toulouse
• Hôpital des Charpennes - Hospices Civils de Lyon (HCL) — Villeurbanne
• Centre Hospitalier Régional Universitaire de Lille - Hôpital Roger Salengro — Lille
• Centre Hospitalier Universitaire de Limoges - Hôpital Dupuytren — Limoges
• Hopital Gui Chauliac - Chu Montpellier — Montpellier
• Centres Memoire de Ressources et de Recherche (CMRR) - Hopital Lariboisiere-Fernand-Widal — Paris
• Les Hôpitaux Universitaires de Strasbourg - Hôpital de la Robertsau — Strasbourg

Chile · 6 centers

• Biomedica Research Group — Santiago
• Local Institution - 2050 — Santiago
• Pontificia Universidad Catolica de Chile — Santiago
• Clinica Alemana — Vitacura
• Local Institution - 2055 — Viña del Mar
• Psicomed Estudios Médicos Cía Ltda — Antofagasta

Israel · 5 centers

Center list to be confirmed — check the primary protocol.

Puerto Rico · 4 centers

Center list to be confirmed — check the primary protocol.

Germany · 3 centers

• Local Institution - 2201 — Düsseldorf
• Local Institution - 2205 — Halle
• Local Institution - 2206 — Westerstede

Identifiers

NCT: NCT07011745 · CN012-0024 · 2025-520612-34 · U1111-1316-5827

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗