Clinical trial NCT07011732: 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-1)
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: Scottsdale
country: United States
facility: Local Institution - 0098
state: Arizona
city: Scottsdale
country: United States
facility: Local Institution - 1619
state: Arizona
city: Anaheim
country: United States
facility: Local Institution - 1657
state: California
city: Costa Mesa
country: United States
facility: Local Institution - 0126
state: California
city: La Jolla
country: United States
facility: Local Institution - 0188
state: California
city: La Jolla
country: United States
facility: Local Institution - 1637
state: California
city: Pomona
country: United States
facility: Local Institution - 1662
state: California
city: Torrance
country: United States
facility: Local Institution - 0192
state: California
city: Torrance
country: United States
facility: Local Institution - 1639
state: California
city: Walnut Creek
country: United States
facility: Local Institution - 1651
state: California
city: Colorado Springs
country: United States
facility: Local Institution - 1630
state: Colorado
city: Maitland
country: United States
facility: Local Institution - 1622
state: Florida
city: Maitland
country: United States
facility: Local Institution - 1631
state: Florida
city: Miami
country: United States
facility: Local Institution - 0095
state: Florida
city: Miami
country: United States
facility: Local Institution - 1618
state: Florida
city: Miami
country: United States
facility: Local Institution - 0063
state: Florida
city: Miami
country: United States
facility: Local Institution - 1609
state: Florida
city: Miami
country: United States
facility: Local Institution - 0024
state: Florida
city: Miami
country: United States
facility: Local Institution - 1604
state: Florida
city: Ocala
country: United States
facility: Local Institution - 0058
state: Florida
city: Ocala
country: United States
facility: Local Institution - 1608
state: Florida
city: Orlando
country: United States
facility: Local Institution - 0186
state: Florida
city: Orlando
country: United States
facility: Local Institution - 1635
state: Florida
city: Port Orange
country: United States
facility: Local Institution - 0069
state: Florida
city: Port Orange
country: United States
facility: Local Institution - 1612
state: Florida
city: Savannah
country: United States
facility: Local Institution - 1661
state: Georgia
city: Boise
country: United States
facility: Local Institution - 0157
state: Idaho
city: Nampa
country: United States
facility: Local Institution - 0222
state: Idaho
city: Marrero
country: United States
facility: Local Institution - 1655
state: Louisiana
city: Gaithersburg
country: United States
facility: Local Institution - 0187
state: Maryland
city: Gaithersburg
country: United States
facility: Local Institution - 1636
state: Maryland
city: Newton
country: United States
facility: Local Institution - 0189
state: Massachusetts
city: Newton
country: United States
facility: Local Institution - 1638
state: Massachusetts
city: South Dartmouth
country: United States
facility: Local Institution - 0203
state: Massachusetts
city: South Dartmouth
country: United States
facility: Local Institution - 1642
state: Massachusetts
city: Springfield
country: United States
facility: Local Institution - 1660
state: Massachusetts
city: Troy
country: United States
facility: Local Institution - 0107
state: Michigan
city: Troy
country: United States
facility: Local Institution - 1620
state: Michigan
city: Las Vegas
country: United States
facility: Local Institution - 0221
state: Nevada
city: Las Vegas
country: United States
facility: Local Institution - 1649
state: Nevada
city: Middletown
country: United States
facility: Local Institution - 1647
state: New Jersey
city: West Long Branch
country: United States
facility: Local Institution - 0214
state: New Jersey
city: Buffalo
country: United States
facility: Local Institution - 0216
state: New York
city: Inwood
country: United States
facility: Local Institution - 0064
state: New York
city: Inwood
country: United States
facility: Local Institution - 1610
state: New York
city: New Windsor
country: United States
facility: Local Institution - 1656
state: New York
city: Woodmere
country: United States
facility: Local Institution - 0206
state: New York
city: Woodmere
country: United States
facility: Local Institution - 1645
state: New York
city: Woodmere
country: United States
facility: Local Institution - 1658
state: New York
city: Monroe
country: United States
facility: Local Institution - 0017
state: North Carolina
city: Monroe
country: United States
facility: Local Institution - 1601
state: North Carolina
city: Centerville
country: United States
facility: Local Institution - 1659
state: Ohio
city: Tulsa
country: United States
facility: Local Institution - 0193
state: Oklahoma
city: Tulsa
country: United States
facility: Local Institution - 1640
state: Oklahoma
city: Columbia
country: United States
facility: Local Institution - 1652
state: South Carolina
city: Columbia
country: United States
facility: Local Institution - 1653
state: South Carolina
city: El Paso
country: United States
facility: Local Institution - 0204
state: Texas
city: El Paso
country: United States
facility: Local Institution - 1643
state: Texas
city: Salt Lake City
country: United States
facility: Local Institution - 0195
state: Utah
city: Salt Lake City
country: United States
facility: Local Institution - 1641
state: Utah
city: Bennington
country: United States
facility: Local Institution - 0212
state: Vermont
city: Bennington
country: United States
facility: Local Institution - 1646
state: Vermont
city: Seattle
country: United States
facility: Local Institution - 0205
state: Washington
city: Seattle
country: United States
facility: Local Institution - 1644
state: Washington
city: Spokane
country: United States
facility: Local Institution - 1654
state: Washington
city: La Plata
country: Argentina
facility: Local Institution - 0215
state: Buenos Aires
city: La Plata
country: Argentina
facility: Local Institution - 1001
state: Buenos Aires
city: Mar del Plata
country: Argentina
facility: Local Institution - 0217
state: Buenos Aires
city: Mar del Plata
country: Argentina
facility: Local Institution - 1002
state: Buenos Aires
city: Rosario
country: Argentina
facility: Local Institution - 1006
state: Santa Fe
city: Buenos Aires
country: Argentina
facility: Local Institution - 0218
city: Buenos Aires
country: Argentina
facility: Local Institution - 1003
city: Cordoba
country: Argentina
facility: Local Institution - 0220
city: Cordoba
country: Argentina
facility: Local Institution - 1005
city: Cordoba
country: Argentina
facility: Local Institution - 0211
city: Cordoba
country: Argentina
facility: Local Institution - 1000
city: Córdoba
country: Argentina
facility: Local Institution - 0219
city: Córdoba
country: Argentina
facility: Local Institution - 1004
city: Brasília
country: Brazil
facility: Local Institution - 0047
state: Distrito Federal
city: Brasília
country: Brazil
facility: Local Institution - 1051
state: Distrito Federal
city: Curitiba
country: Brazil
facility: Local Institution - 0049
state: Paraná
city: Curitiba
country: Brazil
facility: Local Institution - 1053
state: Paraná
city: Curitiba
country: Brazil
facility: Local Institution - 0048
state: Paraná
city: Curitiba
country: Brazil
facility: Local Institution - 1052
state: Paraná
city: Porto Alegre
country: Brazil
facility: Local Institution - 0051
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Local Institution - 1054
state: Rio Grande Do Sul
city: Sao Paulo
country: Brazil
facility: Local Institution - 1056
state: SP
city: Rio De Janeiro
country: Brazil
facility: Local Institution - 0005
city: Rio De Janeiro
country: Brazil
facility: Local Institution - 1050
city: São Paulo
country: Brazil
facility: Local Institution - 0053
city: São Paulo
country: Brazil
facility: Local Institution - 1055
city: Sofia
country: Bulgaria
facility: Local Institution - 1100
state: Sofia-Grad
city: Pleven
country: Bulgaria
facility: Local Institution - 1101
city: Razgrad
country: Bulgaria
facility: Local Institution - 1103
city: Varna
country: Bulgaria
facility: Local Institution - 1102
city: Hamilton
country: Canada
facility: Local Institution - 0185
state: Ontario
city: Hamilton
country: Canada
facility: Local Institution - 1153
state: Ontario
city: Toronto
country: Canada
facility: Local Institution - 0183
state: Ontario
city: Toronto
country: Canada
facility: Local Institution - 1151
state: Ontario
city: Toronto
country: Canada
facility: Local Institution - 0194
state: Ontario
city: Toronto
country: Canada
facility: Local Institution - 1154
state: Ontario
city: Whitby
country: Canada
facility: Local Institution - 0184
state: Ontario
city: Whitby
country: Canada
facility: Local Institution - 1152
state: Ontario
city: Montreal
country: Canada
facility: Local Institution - 0182
state: Quebec
city: Montreal
country: Canada
facility: Local Institution - 1150
state: Quebec
city: Zagreb
country: Croatia
facility: Local Institution - 1550
state: Grad Zagreb
city: Zagreb
country: Croatia
facility: Local Institution - 1553
state: Grad Zagreb
city: Rijeka
country: Croatia
facility: Local Institution - 1554
city: Split
country: Croatia
facility: Local Institution - 1551
city: Varazdin
country: Croatia
facility: Local Institution - 1552
city: Patras
country: Greece
facility: Local Institution - 0201
state: Achaïa
city: Patras
country: Greece
facility: Local Institution - 1200
state: Achaḯa
city: Athens
country: Greece
facility: Local Institution - 0210
state: Attiki
city: Athens
country: Greece
facility: Local Institution - 1205
state: Attiki
city: Athens
country: Greece
facility: Local Institution - 0207
state: Attiki
city: Athens
country: Greece
facility: Local Institution - 1202
state: Attiki
city: Athens
country: Greece
facility: Local Institution - 0213
city: Athens
country: Greece
facility: Local Institution - 1206
city: Athens
country: Greece
facility: Local Institution - 0208
city: Athens
country: Greece
facility: Local Institution - 1203
city: Athens
country: Greece
facility: Local Institution - 1207
city: Ioannina
country: Greece
facility: Local Institution - 0202
city: Ioannina
country: Greece
facility: Local Institution - 1201
city: Thessaloniki
country: Greece
facility: Local Institution - 0209
city: Thessaloniki
country: Greece
facility: Local Institution - 1204
city: Hyderabad
country: India
facility: Local Institution - 1251
state: Andhra Pradesh
city: Hyderabad
country: India
facility: Local Institution - 1252
state: Telangana
city: Varanasi
country: India
facility: Local Institution - 1254
state: Uttar Pradesh
city: Kolkata
country: India
facility: Local Institution - 1250
state: West Bengal
city: New Delhi
country: India
facility: Local Institution - 1253
city: Hadano
country: Japan
facility: Local Institution - 0167
state: Kanagawa
city: Hadano
country: Japan
facility: Local Institution - 1301
state: Kanagawa
city: Kawasaki
country: Japan
facility: Local Institution - 0191
state: Kanagawa
city: Kawasaki
country: Japan
facility: Local Institution - 1307
state: Kanagawa
city: Sakai
country: Japan
facility: Local Institution - 0170
state: Osaka
city: Sakai
country: Japan
facility: Local Institution - 1304
state: Osaka
city: Karatsu-shi
country: Japan
facility: Local Institution - 0166
state: Saga-Ken
city: Karatsu-shi
country: Japan
facility: Local Institution - 1300
state: Saga-Ken
city: Kanzaki-Gun Yoshinogari-Cho
country: Japan
facility: Local Institution - 0169
state: Saga
city: Kanzaki-Gun Yoshinogari-Cho
country: Japan
facility: Local Institution - 1303
state: Saga
city: Bunkyo-ku
country: Japan
facility: Local Institution - 0171
state: Tokyo
city: Bunkyo-ku
country: Japan
facility: Local Institution - 1305
state: Tokyo
city: Fukuoka
country: Japan
facility: Local Institution - 0168
city: Fukuoka
country: Japan
facility: Local Institution - 1302
city: Okayama
country: Japan
facility: Local Institution - 0190
city: Okayama
country: Japan
facility: Local Institution - 1306
city: Saltillo
country: Mexico
facility: Local Institution - 1355
state: Coahuila
city: Ciudad de México
country: Mexico
facility: Local Institution - 0148
state: Distrito Federal
city: Ciudad de México
country: Mexico
facility: Local Institution - 1356
state: Distrito Federal
city: Monterrey
country: Mexico
facility: Local Institution - 0141
state: Nuevo León
city: Monterrey
country: Mexico
facility: Local Institution - 1350
state: Nuevo León
city: Mexico City
country: Mexico
facility: Local Institution - 0224
city: Mexico City
country: Mexico
facility: Local Institution - 1361
city: Mexico City
country: Mexico
facility: Local Institution - 0226
city: Mexico City
country: Mexico
facility: Local Institution - 1363
city: Mexico City
country: Mexico
facility: Local Institution - 0223
city: Mexico City
country: Mexico
facility: Local Institution - 1360
city: San Luis Potosi
country: Mexico
facility: Local Institution - 0225
city: San Luis Potosi
country: Mexico
facility: Local Institution - 1362
city: Tlalnepantla de Baz
country: Mexico
facility: Local Institution - 1352
city: Coimbra
country: Portugal
facility: Local Institution - 0197
city: Coimbra
country: Portugal
facility: Local Institution - 1401
city: Guimaraes
country: Portugal
facility: Local Institution - 0198
city: Guimaraes
country: Portugal
facility: Local Institution - 1402
city: Lisboa
country: Portugal
facility: Local Institution - 0200
city: Lisboa
country: Portugal
facility: Local Institution - 1404
city: Senhora da Hora
country: Portugal
facility: Local Institution - 0199
city: Senhora da Hora
country: Portugal
facility: Local Institution - 1403
city: Torres Vedras
country: Portugal
facility: Local Institution - 0196
city: Torres Vedras
country: Portugal
facility: Local Institution - 1400
city: San Juan
country: Puerto Rico
facility: Local Institution - 0011
city: Bucharest
country: Romania
facility: Local Institution - 1459
state: București
city: Bucuresti
country: Romania
facility: Local Institution - 1450
state: București
city: Bucuresti
country: Romania
facility: Local Institution - 1452
state: București
city: Bucuresti
country: Romania
facility: Local Institution - 1453
state: București
city: Bucuresti
country: Romania
facility: Local Institution - 1454
state: București
city: Bucuresti
country: Romania
facility: Local Institution - 1455
state: București
city: Bucuresti
country: Romania
facility: Local Institution - 1456
state: București
city: Bucuresti
country: Romania
facility: Local Institution - 1458
state: București
city: Bucuresti
country: Romania
facility: Local Institution - 1451
city: Constanta
country: Romania
facility: Local Institution - 1461
city: Iasi
country: Romania
facility: Local Institution - 1457
city: Sanpetru /Brasov
country: Romania
facility: Local Institution - 1460
city: Sibiu
country: Romania
facility: Local Institution - 1462
city: Getxo
country: Spain
facility: Local Institution - 1510
state: Bizkaia
city: Elche (alicante)
country: Spain
facility: Local Institution - 0181
city: Elche (alicante)
country: Spain
facility: Local Institution - 1509
city: Madrid
country: Spain
facility: Local Institution - 0180
city: Madrid
country: Spain
facility: Local Institution - 1508
city: Madrid
country: Spain
facility: Local Institution - 0177
city: Madrid
country: Spain
facility: Local Institution - 1505
city: Malaga
country: Spain
facility: Local Institution - 0174
city: Malaga
country: Spain
facility: Local Institution - 1502
city: Pamplona
country: Spain
facility: Local Institution - 0179
city: Pamplona
country: Spain
facility: Local Institution - 1507
city: Salamanca
country: Spain
facility: Local Institution - 0172
city: Salamanca
country: Spain
facility: Local Institution - 1500
city: Sevilla
country: Spain
facility: Local Institution - 0175
city: Sevilla
country: Spain
facility: Local Institution - 1503
city: Terrassa
country: Spain
facility: Local Institution - 0176
city: Terrassa
country: Spain
facility: Local Institution - 1504
city: Valladolid
country: Spain
facility: Local Institution - 0178
city: Valladolid
country: Spain
facility: Local Institution - 1506
city: Zaragoza
country: Spain
facility: Local Institution - 0173
city: Zaragoza
country: Spain
facility: Local Institution - 1501
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References: