Clinical trial NCT07011745: A Phase 3 Study to Evaluate the Safety and Efficacy of KarXT + KarX-EC for the Treatment of Agitation Associated With Alzheimer's Disease (ADAGIO-2)
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
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Alzheimer Disease
Lead sponsor: Bristol-Myers Squibb
Sponsor class: INDUSTRY
First posted: 2025-06-10
Enrollment: 352
Sex: ALL
Minimum age (years): 55
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


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 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:.

    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).
* 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):.

  i) 1 or more aggressive behaviors occurring several times per week.

ii) 2 or more aggressive behaviors occurring once or twice per week.

iii) 3 or more aggressive behaviors occurring less than once per week.

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. 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.

Primary outcomes:
measure: Mean change from baseline on the Cohen-Mansfield Agitation Inventory-International Psychogeriatric Association (CMAI-IPA) total score at Week 14
timeFrame: At Week 14
Secondary outcomes:
measure: Mean change from baseline on the Clinical Global Impressions-Severity (CGI-S) at Week 14
timeFrame: At Week 14
measure: Mean change from baseline on the CMAI-IPA Domains at Week 14
timeFrame: At Week 14
measure: Mean change from baseline on the CMAI Total Score at Week 14
timeFrame: At Week 14
measure: Number of participants with Occurrence of Response at Week 14
timeFrame: At Week 14
measure: Mean change from baseline on the Neuropsychiatric Inventory/Neuropsychiatric Inventory -Nursing Home (NPI/NPI-NH) Total Score at Week 14
timeFrame: At Week 14
measure: Number of participants with Adverse Events (AEs)
timeFrame: Up to Week 18
measure: Number of participants with Treatment Emergent AEs (TEAEs)
timeFrame: Up to Week 18
measure: Number of participants with Serious AEs (SAEs)
timeFrame: Up to Week 18
measure: Number of participants with AEs leading to study drug withdrawal
timeFrame: Up to Week 18
measure: Number of deaths
timeFrame: Up to Week 18
measure: Number of participants with AEs of Special Interest (AESIs)
timeFrame: Up to Week 18
measure: Barnes Akathisia Rating Scale (BARS)
timeFrame: Up to Week 18
measure: Abnormal Involuntary Movement Scale (AIMS)
timeFrame: Up to Week 18
measure: Body Weight
timeFrame: Up to Week 18
measure: Body Mass Index (BMI)
timeFrame: Up to Week 18
measure: Number of participants with vital sign abnormalities
timeFrame: Up to Week 18
measure: Number of participants with clinical laboratory abnormalities
timeFrame: Up to Week 18
measure: Number of participants with electrocardiogram (ECG) abnormalities
timeFrame: Up to Week 18
measure: Number of participants with suicidal ideation as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS)
timeFrame: Up to Week 18
measure: Severity of benign prostatic hyperplasia in male participants as assessed by International Prostate Symptom Score (IPSS)
timeFrame: Up to Week 18
Other outcomes:
Locations:
city: Chandler
country: United States
facility: Local Institution - 0080
state: Arizona
city: Chandler
country: United States
facility: Local Institution - 2609
state: Arizona
city: Chandler
country: United States
facility: Local Institution - 2631
state: Arizona
city: Canoga Park
country: United States
facility: Local Institution - 0117
state: California
city: Long Beach
country: United States
facility: Local Institution - 0122
state: California
city: Long Beach
country: United States
facility: Local Institution - 2625
state: California
city: Long Beach
country: United States
facility: Local Institution - 0074
state: California
city: Long Beach
country: United States
facility: Local Institution - 2607
state: California
city: Napa
country: United States
facility: Local Institution - 2627
state: California
city: Pasadena
country: United States
facility: Local Institution - 0105
state: California
city: Pasadena
country: United States
facility: Local Institution - 2613
state: California
city: San Diego
country: United States
facility: Local Institution - 0111
state: California
city: San Diego
country: United States
facility: Local Institution - 2614
state: California
city: West Hills
country: United States
facility: Local Institution - 2620
state: California
city: Basalt
country: United States
facility: Local Institution - 0018
state: Colorado
city: Basalt
country: United States
facility: Local Institution - 2601
state: Colorado
city: Colorado Springs
country: United States
facility: Local Institution - 2635
state: Colorado
city: Norwalk
country: United States
facility: Local Institution - 2632
state: Connecticut
city: Bonita Springs
country: United States
facility: Local Institution - 0019
state: Florida
city: Bonita Springs
country: United States
facility: Local Institution - 2602
state: Florida
city: Hialeah
country: United States
facility: Local Institution - 2626
state: Florida
city: Homestead
country: United States
facility: Local Institution - 0034
state: Florida
city: Homestead
country: United States
facility: Local Institution - 2606
state: Florida
city: Maitland
country: United States
facility: Local Institution - 0121
state: Florida
city: Maitland
country: United States
facility: Local Institution - 2624
state: Florida
city: Miami
country: United States
facility: Local Institution - 2633
state: Florida
city: Orlando
country: United States
facility: Local Institution - 2634
state: Florida
city: Tampa
country: United States
facility: Local Institution - 0118
state: Florida
city: Tampa
country: United States
facility: Local Institution - 2621
state: Florida
city: Atlanta
country: United States
facility: Local Institution - 0082
state: Georgia
city: Atlanta
country: United States
facility: Local Institution - 2611
state: Georgia
city: Worcester
country: United States
facility: Local Institution - 0112
state: Massachusetts
city: Worcester
country: United States
facility: Local Institution - 2615
state: Massachusetts
city: Ann Arbor
country: United States
facility: Local Institution - 0115
state: Michigan
city: Ann Arbor
country: United States
facility: Local Institution - 2618
state: Michigan
city: Saint Paul
country: United States
facility: Local Institution - 2630
state: Minnesota
city: Hattiesburg
country: United States
facility: Local Institution - 2629
state: Mississippi
city: Ozark
country: United States
facility: Local Institution - 0021
state: Missouri
city: Ozark
country: United States
facility: Local Institution - 2603
state: Missouri
city: Las Vegas
country: United States
facility: Local Institution - 2628
state: Nevada
city: Staten Island
country: United States
facility: Local Institution - 0116
state: New York
city: Staten Island
country: United States
facility: Local Institution - 2619
state: New York
city: Morehead City
country: United States
facility: Local Institution - 0075
state: North Carolina
city: Morehead City
country: United States
facility: Local Institution - 2608
state: North Carolina
city: Blue Ash
country: United States
facility: Local Institution - 0114
state: Ohio
city: Blue Ash
country: United States
facility: Local Institution - 2617
state: Ohio
city: Milan
country: United States
facility: Local Institution - 0028
state: Tennessee
city: Carrollton
country: United States
facility: Local Institution - 0113
state: Texas
city: Carrollton
country: United States
facility: Local Institution - 2616
state: Texas
city: Cypress
country: United States
facility: Local Institution - 0033
state: Texas
city: Cypress
country: United States
facility: Local Institution - 2605
state: Texas
city: Mesquite
country: United States
facility: Local Institution - 0119
state: Texas
city: Mesquite
country: United States
facility: Local Institution - 2622
state: Texas
city: San Antonio
country: United States
facility: Local Institution - 0120
state: Texas
city: San Antonio
country: United States
facility: Local Institution - 2623
state: Texas
city: Bountiful
country: United States
facility: Local Institution - 0104
state: Utah
city: Bountiful
country: United States
facility: Local Institution - 2612
state: Utah
city: Milwaukee
country: United States
facility: Local Institution - 0081
state: Wisconsin
city: Milwaukee
country: United States
facility: Local Institution - 2610
state: Wisconsin
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: Local Institution - 0129
state: Buenos Aires
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: Local Institution - 2005
state: Buenos Aires
city: Buenos Aires
country: Argentina
facility: Local Institution - 0130
state: Ciudad Autonoma De Buenos Aires
city: Buenos Aires
country: Argentina
facility: Local Institution - 2006
state: Ciudad Autonoma De Buenos Aires
city: Buenos Aires
country: Argentina
facility: Local Institution - 0128
city: Buenos Aires
country: Argentina
facility: Local Institution - 2004
city: Cordoba
country: Argentina
facility: Local Institution - 0123
city: Cordoba
country: Argentina
facility: Local Institution - 2000
city: Córdoba
country: Argentina
facility: Local Institution - 0126
city: Córdoba
country: Argentina
facility: Local Institution - 2002
city: Córdoba
country: Argentina
facility: Local Institution - 0127
city: Córdoba
country: Argentina
facility: Local Institution - 2003
city: Mendoza
country: Argentina
facility: Local Institution - 0124
city: Mendoza
country: Argentina
facility: Local Institution - 2001
city: Santiago
country: Chile
facility: Local Institution - 2051
state: Metropolitana
city: Santiago
country: Chile
facility: Local Institution - 2052
state: Metropolitana
city: Santiago
country: Chile
facility: Local Institution - 0131
state: Región Metropolitana De Santiago
city: Santiago
country: Chile
facility: Local Institution - 2050
state: Región Metropolitana De Santiago
city: Vitacura
country: Chile
facility: Local Institution - 2054
state: Santiago
city: Vina del Mar
country: Chile
facility: Local Institution - 2055
state: Valparaiso
city: Antofagasta
country: Chile
facility: Local Institution - 2053
city: Brno
country: Czechia
facility: Local Institution - 2103
state: Jihomoravský Kraj
city: Olomouc
country: Czechia
facility: Local Institution - 2107
state: Olomoucký Kraj
city: Prague
country: Czechia
facility: Local Institution - 2100
state: Praha 6
city: Praha
country: Czechia
facility: Local Institution - 2106
state: Praha 8
city: Chocen
country: Czechia
facility: Local Institution - 2101
city: Plzeň
country: Czechia
facility: Local Institution - 2104
city: Prague
country: Czechia
facility: Local Institution - 2102
city: Praha 10
country: Czechia
facility: Local Institution - 2105
city: Rychnov nad Kneznou
country: Czechia
facility: Local Institution - 2108
city: Toulouse
country: France
facility: Local Institution - 0024
state: Haute-Garonne
city: Toulouse
country: France
facility: Local Institution - 2150
state: Haute-Garonne
city: Villeurbanne
country: France
facility: Local Institution - 0025
state: Rhône
city: Villeurbanne
country: France
facility: Local Institution - 2151
state: Rhône
city: Lille
country: France
facility: Local Institution - 0027
city: Lille
country: France
facility: Local Institution - 2153
city: Limoges
country: France
facility: Local Institution - 0028
city: Limoges
country: France
facility: Local Institution - 2156
city: Paris
country: France
facility: Local Institution - 0026
city: Paris
country: France
facility: Local Institution - 2152
city: Strasbourg Cedex
country: France
facility: Local Institution - 0029
city: Strasbourg Cedex
country: France
facility: Local Institution - 2155
city: Erbach
country: Germany
facility: Local Institution - 0093
state: Hessen
city: Erbach
country: Germany
facility: Local Institution - 2203
state: Hessen
city: Böblingen
country: Germany
facility: Local Institution - 0090
city: Düsseldorf
country: Germany
facility: Local Institution - 0091
city: Düsseldorf
country: Germany
facility: Local Institution - 2201
city: Frankfurt am Main
country: Germany
facility: Local Institution - 0092
city: Halle /Saale
country: Germany
facility: Local Institution - 0095
city: Halle /Saale
country: Germany
facility: Local Institution - 2205
city: Kirrberger Strasse 1
country: Germany
facility: Local Institution - 0094
city: Westerstede
country: Germany
facility: Local Institution - 0096
city: Westerstede
country: Germany
facility: Local Institution - 2206
city: Kalocsa
country: Hungary
facility: Local Institution - 2257
state: Bács-Kiskun
city: Győr
country: Hungary
facility: Local Institution - 2250
state: Győr-Moson-Sopron
city: Gyöngyös
country: Hungary
facility: Local Institution - 2254
state: Heves
city: Budapest
country: Hungary
facility: Local Institution - 2256
city: Budapest
country: Hungary
facility: Local Institution - 2255
city: Budapest
country: Hungary
facility: Local Institution - 2251
city: Budapest
country: Hungary
facility: Local Institution - 2253
city: Debrecen
country: Hungary
facility: Local Institution - 2252
city: Rishon Le'Tzion
country: Israel
facility: Local Institution - 2304
state: Central
city: Petch Tikva
country: Israel
facility: Local Institution - 0109
state: IL
city: Petch Tikva
country: Israel
facility: Local Institution - 2302
state: IL
city: Jerusalem
country: Israel
facility: Local Institution - 0108
city: Jerusalem
country: Israel
facility: Local Institution - 2301
city: Netanya
country: Israel
facility: Local Institution - 2303
city: Ramat Gan
country: Israel
facility: Local Institution - 0107
city: Ramat Gan
country: Israel
facility: Local Institution - 2300
city: Ramat-Gan
country: Israel
facility: Local Institution - 2305
city: Napoli
country: Italy
facility: Local Institution - 0098
state: Campania
city: Napoli
country: Italy
facility: Local Institution - 2351
state: Campania
city: Roma
country: Italy
facility: Local Institution - 0101
state: Lazio
city: Roma
country: Italy
facility: Local Institution - 2354
state: Lazio
city: Roma
country: Italy
facility: Local Institution - 0099
state: Lazio
city: Roma
country: Italy
facility: Local Institution - 2352
state: Lazio
city: Milano
country: Italy
facility: Local Institution - 0100
state: Lombardia
city: Milano
country: Italy
facility: Local Institution - 2353
state: Lombardia
city: Pisa
country: Italy
facility: Local Institution - 0097
state: PI
city: Pisa
country: Italy
facility: Local Institution - 2350
state: PI
city: Brescia
country: Italy
facility: Local Institution - 0103
city: Brescia
country: Italy
facility: Local Institution - 2356
city: Isernia
country: Italy
facility: Local Institution - 0102
city: Isernia
country: Italy
facility: Local Institution - 2355
city: Roma
country: Italy
facility: Local Institution - 0125
city: Roma
country: Italy
facility: Local Institution - 2357
city: Incheon
country: Korea, Republic of
facility: Local Institution - 0002
state: Incheon Gwang'yeogsi
city: Incheon
country: Korea, Republic of
facility: Local Institution - 2401
state: Incheon Gwang'yeogsi
city: Seoul
country: Korea, Republic of
facility: Local Institution - 0008
state: Seoul-teukbyeolsi [Seoul]
city: Seoul
country: Korea, Republic of
facility: Local Institution - 2407
state: Seoul-teukbyeolsi [Seoul]
city: Seoul
country: Korea, Republic of
facility: Local Institution - 0004
state: Seoul-teukbyeolsi [Seoul]
city: Seoul
country: Korea, Republic of
facility: Local Institution - 2403
state: Seoul-teukbyeolsi [Seoul]
city: Seoul
country: Korea, Republic of
facility: Local Institution - 0007
state: Seoul-teukbyeolsi [Seoul]
city: Seoul
country: Korea, Republic of
facility: Local Institution - 2406
state: Seoul-teukbyeolsi [Seoul]
city: Deagu
country: Korea, Republic of
facility: Local Institution - 0001
state: Taegu-Kwangyǒkshi
city: Deagu
country: Korea, Republic of
facility: Local Institution - 2400
state: Taegu-Kwangyǒkshi
city: Incheon
country: Korea, Republic of
facility: Local Institution - 2409
city: Seoul
country: Korea, Republic of
facility: Local Institution - 0003
city: Seoul
country: Korea, Republic of
facility: Local Institution - 2402
city: Seoul
country: Korea, Republic of
facility: Local Institution - 0009
city: Seoul
country: Korea, Republic of
facility: Local Institution - 2408
city: Seoul
country: Korea, Republic of
facility: Local Institution - 0006
city: Seoul
country: Korea, Republic of
facility: Local Institution - 2405
city: Seoul
country: Korea, Republic of
facility: Local Institution - 0005
city: Seoul
country: Korea, Republic of
facility: Local Institution - 2404
city: Bydgoszcz
country: Poland
facility: Local Institution - 2454
state: Kujawsko-pomorskie
city: Lublin
country: Poland
facility: Local Institution - 0137
state: Lubelskie
city: Katowice
country: Poland
facility: Local Institution - 2455
city: Lublin
country: Poland
facility: Local Institution - 2451
city: Lublin
country: Poland
facility: Local Institution - 2452
city: Poznan
country: Poland
facility: Local Institution - 0106
city: Poznan
country: Poland
facility: Local Institution - 2450
city: Sochaczew
country: Poland
facility: Local Institution - 2453
city: Chorzów
country: Poland
facility: Local Institution - 2456
state: Śląskie
city: Bayamon
country: Puerto Rico
facility: Local Institution - 0016
city: London
country: United Kingdom
facility: Local Institution - 0011
state: Greater London
city: London
country: United Kingdom
facility: Local Institution - 2501
state: Greater London
city: Chertsey
country: United Kingdom
facility: Local Institution - 0023
state: Surrey
city: Chertsey
country: United Kingdom
facility: Local Institution - 2508
state: Surrey
city: Cambridge
country: United Kingdom
facility: Local Institution - 0012
city: Cambridge
country: United Kingdom
facility: Local Institution - 2502
city: London
country: United Kingdom
facility: Local Institution - 0010
city: London
country: United Kingdom
facility: Local Institution - 2500
city: Motherwell
country: United Kingdom
facility: Local Institution - 2510
city: Preston
country: United Kingdom
facility: Local Institution - 0015
city: Preston
country: United Kingdom
facility: Local Institution - 2505
city: Redruth
country: United Kingdom
facility: Local Institution - 0017
city: Redruth
country: United Kingdom
facility: Local Institution - 2507
city: Sheffield
country: United Kingdom
facility: Local Institution - 0014
city: Sheffield
country: United Kingdom
facility: Local Institution - 2504
city: Stafford
country: United Kingdom
facility: Local Institution - 0016
city: Stafford
country: United Kingdom
facility: Local Institution - 2509
city: Wolverhampton
country: United Kingdom
facility: Local Institution - 0013
city: Wolverhampton
country: United Kingdom
facility: Local Institution - 2503
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References: