Back to resultsSafety and Tolerability Study of Flexible Dosing of Brexpiprazole in the Treatment of Subjects With Agitation Associated With Dementia of the Alzheimer's Type
Primary Purpose
Agitation Associated With, Alzheimer's Disease, Alzheimer's Type
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Brexpiprazole, OPC-34712
Sponsored by
About this trial
This is an interventional treatment trial for Agitation Associated With focused on measuring OPC-34712, brexpiprazole, Dementia, Alzheimer's Disease, Cognitive Disorders, Agitation
Eligibility Criteria
Inclusion Criteria:
- Male and female subjects 55 to 90 years of age, inclusive, at the time of informed consent.
- Subjects who are residing at their current location for at least 14 days before screening and are expected to remain at the same location for the duration of the trial.
- Subjects with diagnosis of probable Alzheimer's disease according to NINCDS-ADRDA criteria.
- Subjects with a MMSE score of 5 to 22, inclusive, at screening and baseline visits.
- Subjects with onset of symptoms of agitation at least 2 weeks prior to the screening visit.
- Subjects with a total score greater than or equal to 4 on the agitation aggression item of the NPI-NH or NPI/NPI-NH at the screening and baseline visits.
- Subjects who require pharmacotherapy for the treatment of agitation per the investigator's judgement, after an evaluation of reversible factors (eg, pain, infection, polypharmacy) and a trial of nonpharmacological interventions.
- Subjects must have a previous MRI or CT scan of the brain, which was performed after the onset of symptoms of dementia, with findings consistent with the diagnosis of Alzheimer's disease.
Exclusion Criteria:
- Subjects with dementia or other memory impairment not due to Alzheimer's disease.
- Subjects with history of stroke, well-documented transient ischemic attack, or pulmonary or cerebral embolism.
- Subjects who currently have clinically significant neurological, hepatic, renal, metabolic, hematological, immunological, cardiovascular, pulmonary, gastrointestinal, or psychiatric disorders.
- Subjects who have been diagnosed with an Axis I disorder (DSM-IV-TR criteria).
- Subjects with uncontrolled hypertension.
- Subjects with uncontrolled insulin-dependent diabetes mellitus (IDDM)
- Subjects with epilepsy or a history of seizures.
- Subjects considered in poor general health based on the investigator's judgment.
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Placebo Comparator
Experimental
Arm Label
Placebo
Brexpiprazole (flexible dose range 0.5 to 2 mg)
Arm Description
Matching Placebo Once-Daily
Titrate up from 0.25 mg/day brexpiprazole to 1 mg/day brexpiprazole. After achieving 1 mg/day target dose may be increased or decreased based on efficacy and tolerability. Allowable flexible doses will be 0.5 mg/day, 1 mg/day, or 2 mg/day.
Outcomes
Primary Outcome Measures
Change From Baseline to Week 12/Early Termination in the Cohen-Mansfield Agitation Inventory (CMAI) Total Score
The CMAI is widely used in clinical research for evaluation of agitation associated with Alzheimer's dementia, with reliability and validity in both institutionalized and noninstitutionalized participants. It consists of 29 items, all rated on a 1 to 7 scale (1=Never and 7=Several times in an hour), with 1 being the "best" rating and 7 being the "worst" rating. The total score is the sum of ratings for all 29 items. The possible total scores range from 29 to 203. The total score will be unevaluable if less than 24 of the 29 items are recorded. If 24 to 28 of the 29 items are recorded, the total score will be the mean of the recorded items multiplied by 29 and rounded to the first decimal place. The mean change from baseline (Day 0) to week 12 in the CMAI total score is reported. Statistical comparison of interest was brexpiprazole flexible dose versus placebo, analyzed using a mixed-effect model repeated measure approach. A decrease in score indicates improvement in symptoms.
Secondary Outcome Measures
Change in the Clinical Global Impression Severity of Illness (CGI-S) Score, as Related to Symptoms of Agitation
The severity of agitation for each participant was rated using the CGI-S. The investigator (or designee) answered the following question: "Considering your total clinical experience with this particular population, how mentally ill (as related to agitation) was the participant at the observation period?" Response choices were 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants. The score 0 (= not assessed) was set to missing. The CGI-S was therefore a 7-point scale (1-7). The primary analysis used a mixed-effect model repeated measure approach.
Full Information
NCT ID
NCT01922258
First Posted
August 12, 2013
Last Updated
November 4, 2020
Sponsor
Otsuka Pharmaceutical Development & Commercialization, Inc.
Collaborators
H. Lundbeck A/S
1. Study Identification
Unique Protocol Identification Number
NCT01922258
Brief Title
Safety and Tolerability Study of Flexible Dosing of Brexpiprazole in the Treatment of Subjects With Agitation Associated With Dementia of the Alzheimer's Type
Official Title
A Phase 3, 12-week, Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy, Safety, and Tolerability of Flexible Dosing of Brexpiprazole (OPC-34712) in the Treatment of Subjects With Agitation Associated With Dementia of the Alzheimer's Type
Study Type
Interventional
2. Study Status
Record Verification Date
November 2020
Overall Recruitment Status
Completed
Study Start Date
September 2013 (Actual)
Primary Completion Date
March 2017 (Actual)
Study Completion Date
March 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Otsuka Pharmaceutical Development & Commercialization, Inc.
Collaborators
H. Lundbeck A/S
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
To compare the efficacy of flexible dosing of brexpiprazole with placebo in subjects with agitation associated with dementia of the Alzheimer's type
Detailed Description
Behavioral symptoms, such as agitation, are core features in subjects with Alzheimer's disease and related dementias and develop in the majority of dementia subjects. The presence of agitation in subjects with Alzheimer's disease places a significant burden not only on subjects and their caregivers but also on the healthcare system.
This is a trial designed to assess the safety and efficacy of flexible dosing of brexpiprazole in the treatment of subjects with agitation associated with dementia of the Alzheimer's type. The trial consists of a 12-week double-blind treatment period with a 30-day follow-up. The trial population will include male and female subjects between 55 and 90 years of age (inclusive) with a diagnosis of probable Alzheimer's disease, who are residing either in an institutionalized setting or in a non-institutionalized setting where the subject is not living alone.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Agitation Associated With, Alzheimer's Disease, Alzheimer's Type, Mental Disorder, Nervous System Diseases
Keywords
OPC-34712, brexpiprazole, Dementia, Alzheimer's Disease, Cognitive Disorders, Agitation
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
270 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Matching Placebo Once-Daily
Arm Title
Brexpiprazole (flexible dose range 0.5 to 2 mg)
Arm Type
Experimental
Arm Description
Titrate up from 0.25 mg/day brexpiprazole to 1 mg/day brexpiprazole. After achieving 1 mg/day target dose may be increased or decreased based on efficacy and tolerability. Allowable flexible doses will be 0.5 mg/day, 1 mg/day, or 2 mg/day.
Intervention Type
Drug
Intervention Name(s)
Brexpiprazole, OPC-34712
Intervention Description
Flexible dose of 0.5 to 2 mg/day or placebo tablets for up to 12 weeks
Primary Outcome Measure Information:
Title
Change From Baseline to Week 12/Early Termination in the Cohen-Mansfield Agitation Inventory (CMAI) Total Score
Description
The CMAI is widely used in clinical research for evaluation of agitation associated with Alzheimer's dementia, with reliability and validity in both institutionalized and noninstitutionalized participants. It consists of 29 items, all rated on a 1 to 7 scale (1=Never and 7=Several times in an hour), with 1 being the "best" rating and 7 being the "worst" rating. The total score is the sum of ratings for all 29 items. The possible total scores range from 29 to 203. The total score will be unevaluable if less than 24 of the 29 items are recorded. If 24 to 28 of the 29 items are recorded, the total score will be the mean of the recorded items multiplied by 29 and rounded to the first decimal place. The mean change from baseline (Day 0) to week 12 in the CMAI total score is reported. Statistical comparison of interest was brexpiprazole flexible dose versus placebo, analyzed using a mixed-effect model repeated measure approach. A decrease in score indicates improvement in symptoms.
Time Frame
From screening to week 12/early termination
Secondary Outcome Measure Information:
Title
Change in the Clinical Global Impression Severity of Illness (CGI-S) Score, as Related to Symptoms of Agitation
Description
The severity of agitation for each participant was rated using the CGI-S. The investigator (or designee) answered the following question: "Considering your total clinical experience with this particular population, how mentally ill (as related to agitation) was the participant at the observation period?" Response choices were 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants. The score 0 (= not assessed) was set to missing. The CGI-S was therefore a 7-point scale (1-7). The primary analysis used a mixed-effect model repeated measure approach.
Time Frame
From screening to week 12/early termination
10. Eligibility
Sex
All
Minimum Age & Unit of Time
55 Years
Maximum Age & Unit of Time
90 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Male and female subjects 55 to 90 years of age, inclusive, at the time of informed consent.
Subjects who are residing at their current location for at least 14 days before screening and are expected to remain at the same location for the duration of the trial.
Subjects with diagnosis of probable Alzheimer's disease according to NINCDS-ADRDA criteria.
Subjects with a MMSE score of 5 to 22, inclusive, at screening and baseline visits.
Subjects with onset of symptoms of agitation at least 2 weeks prior to the screening visit.
Subjects with a total score greater than or equal to 4 on the agitation aggression item of the NPI-NH or NPI/NPI-NH at the screening and baseline visits.
Subjects who require pharmacotherapy for the treatment of agitation per the investigator's judgement, after an evaluation of reversible factors (eg, pain, infection, polypharmacy) and a trial of nonpharmacological interventions.
Subjects must have a previous MRI or CT scan of the brain, which was performed after the onset of symptoms of dementia, with findings consistent with the diagnosis of Alzheimer's disease.
Exclusion Criteria:
Subjects with dementia or other memory impairment not due to Alzheimer's disease.
Subjects with history of stroke, well-documented transient ischemic attack, or pulmonary or cerebral embolism.
Subjects who currently have clinically significant neurological, hepatic, renal, metabolic, hematological, immunological, cardiovascular, pulmonary, gastrointestinal, or psychiatric disorders.
Subjects who have been diagnosed with an Axis I disorder (DSM-IV-TR criteria).
Subjects with uncontrolled hypertension.
Subjects with uncontrolled insulin-dependent diabetes mellitus (IDDM)
Subjects with epilepsy or a history of seizures.
Subjects considered in poor general health based on the investigator's judgment.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Eva Koheygi, MD
Organizational Affiliation
Otsuka Pharmaceutical Development and Commercialization, Inc.
Official's Role
Study Director
Facility Information:
City
Imperial
State/Province
California
ZIP/Postal Code
92251
Country
United States
City
Lakewood
State/Province
California
ZIP/Postal Code
08755
Country
United States
City
Long Beach
State/Province
California
ZIP/Postal Code
90806
Country
United States
City
Long Beach
State/Province
California
ZIP/Postal Code
90822
Country
United States
City
Panorama City
State/Province
California
ZIP/Postal Code
91402
Country
United States
City
Universal City
State/Province
California
ZIP/Postal Code
91950
Country
United States
City
Denver
State/Province
Colorado
ZIP/Postal Code
80209
Country
United States
City
Bradenton
State/Province
Florida
ZIP/Postal Code
34205
Country
United States
City
Miami
State/Province
Florida
ZIP/Postal Code
33142
Country
United States
City
Miami
State/Province
Florida
ZIP/Postal Code
33165
Country
United States
City
Miami
State/Province
Florida
ZIP/Postal Code
33176
Country
United States
City
Orange City
State/Province
Florida
ZIP/Postal Code
32763
Country
United States
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30331
Country
United States
City
Smyrna
State/Province
Georgia
ZIP/Postal Code
30080
Country
United States
City
Honolulu
State/Province
Hawaii
ZIP/Postal Code
96817
Country
United States
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46256
Country
United States
City
Quincy
State/Province
Massachusetts
ZIP/Postal Code
02169
Country
United States
City
South Dartmouth
State/Province
Massachusetts
ZIP/Postal Code
02747
Country
United States
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48105
Country
United States
City
Brooklyn
State/Province
New York
ZIP/Postal Code
11214
Country
United States
City
Buffalo
State/Province
New York
ZIP/Postal Code
14215
Country
United States
City
New Hyde Park
State/Province
New York
ZIP/Postal Code
11040
Country
United States
City
Charlotte
State/Province
North Carolina
ZIP/Postal Code
28270
Country
United States
City
Raleigh
State/Province
North Carolina
ZIP/Postal Code
27609
Country
United States
City
Austin
State/Province
Texas
ZIP/Postal Code
78757
Country
United States
City
Dallas
State/Province
Texas
ZIP/Postal Code
75231
Country
United States
City
Dallas
State/Province
Texas
ZIP/Postal Code
75243
Country
United States
City
Woodstock
State/Province
Vermont
ZIP/Postal Code
05091
Country
United States
City
Burgas
ZIP/Postal Code
8000
Country
Bulgaria
City
Kardzhali
ZIP/Postal Code
6600
Country
Bulgaria
City
Pazardzhik
ZIP/Postal Code
4400
Country
Bulgaria
City
Ruse
ZIP/Postal Code
7003
Country
Bulgaria
City
Sofia
ZIP/Postal Code
1113
Country
Bulgaria
City
Sofia
ZIP/Postal Code
1154
Country
Bulgaria
City
Sofia
ZIP/Postal Code
1431
Country
Bulgaria
City
Varna
ZIP/Postal Code
9020
Country
Bulgaria
City
Veliko Tarnovo
ZIP/Postal Code
5000
Country
Bulgaria
City
Penticton
State/Province
British Columbia
ZIP/Postal Code
V2A 4M4
Country
Canada
City
Kentville
ZIP/Postal Code
B4N 4K9
Country
Canada
City
Kuopio
ZIP/Postal Code
70210
Country
Finland
City
Turku
ZIP/Postal Code
20520
Country
Finland
City
Bourg en Bresse
ZIP/Postal Code
01012
Country
France
City
Douai
ZIP/Postal Code
59500
Country
France
City
Elancourt
ZIP/Postal Code
78990
Country
France
City
Limoges
ZIP/Postal Code
87042
Country
France
City
Nice
ZIP/Postal Code
06100
Country
France
City
Toulouse
ZIP/Postal Code
31059
Country
France
City
Tonnel'nyy
State/Province
Stavropol Region
ZIP/Postal Code
357034
Country
Russian Federation
City
Ekaterinburg
ZIP/Postal Code
620030
Country
Russian Federation
City
Saratov
ZIP/Postal Code
410060
Country
Russian Federation
City
St. Petersburg
ZIP/Postal Code
188820
Country
Russian Federation
City
St. Petersburg
ZIP/Postal Code
190005
Country
Russian Federation
City
St. Petersburg
ZIP/Postal Code
195176
Country
Russian Federation
City
St. Petersburg
ZIP/Postal Code
197341
Country
Russian Federation
City
Ljubljana
ZIP/Postal Code
1000
Country
Slovenia
City
Maribor
ZIP/Postal Code
2000
Country
Slovenia
City
Sempeter pri Gorici
ZIP/Postal Code
5290
Country
Slovenia
City
Donetsk
ZIP/Postal Code
83037
Country
Ukraine
City
Kharkiv
ZIP/Postal Code
61068
Country
Ukraine
City
Kharkov
ZIP/Postal Code
61068
Country
Ukraine
City
Kherson
ZIP/Postal Code
73488
Country
Ukraine
City
Kiev
ZIP/Postal Code
04080
Country
Ukraine
City
Kiev
ZIP/Postal Code
04114
Country
Ukraine
City
Lviv
ZIP/Postal Code
79021
Country
Ukraine
City
Poltava
ZIP/Postal Code
36013
Country
Ukraine
City
Simferopol
ZIP/Postal Code
95006
Country
Ukraine
City
Vinnytsia
ZIP/Postal Code
21005
Country
Ukraine
City
Crewe
ZIP/Postal Code
CW1 2ER
Country
United Kingdom
City
Manchester
ZIP/Postal Code
M8 5RB
Country
United Kingdom
City
Margate
ZIP/Postal Code
CT20 1JY
Country
United Kingdom
City
Torpoint
ZIP/Postal Code
PL11 2TB
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Anonymized Individual participant data (IPD) that underlie the results of this study will be shared with researchers to achieve aims pre-specified in a methodologically sound research proposal. Small studies with less than 25 participants are excluded from data sharing.
IPD Sharing Time Frame
Data will be available after marketing approval in global markets, or beginning 1-3 years following article publication. There is no end date to the availability of the data.
IPD Sharing Access Criteria
Otsuka will share data on an Otsuka-owned remotely accessible data sharing platform with Python and R analytical software. Research requests should be directed to clinicaltransparency@Otsuka-us.com
IPD Sharing URL
https://clinical-trials.otsuka.com
Citations:
PubMed Identifier
31708380
Citation
Grossberg GT, Kohegyi E, Mergel V, Josiassen MK, Meulien D, Hobart M, Slomkowski M, Baker RA, McQuade RD, Cummings JL. Efficacy and Safety of Brexpiprazole for the Treatment of Agitation in Alzheimer's Dementia: Two 12-Week, Randomized, Double-Blind, Placebo-Controlled Trials. Am J Geriatr Psychiatry. 2020 Apr;28(4):383-400. doi: 10.1016/j.jagp.2019.09.009. Epub 2019 Oct 1.
Results Reference
derived
Learn more about this trial
Safety and Tolerability Study of Flexible Dosing of Brexpiprazole in the Treatment of Subjects With Agitation Associated With Dementia of the Alzheimer's Type
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