Back to resultsA Trial to Evaluate the Safety, Efficacy, and Tolerability of Brexpiprazole in Treating Agitation Associated With Dementia of the Alzheimer's Type
Primary Purpose
Agitation Associated With Alzheimer's Dementia, Alzheimer Dementia
Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Brexpiprazole
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Agitation Associated With Alzheimer's Dementia focused on measuring Agitation
Eligibility Criteria
Inclusion Criteria:
- Subjects with a diagnosis of probable Alzheimer's disease.
- Subjects with a diagnosis of agitation
- Subjects with a MMSE score of 5 to 22, inclusive, at screening and baseline visits.
- Subjects with a previous MRI or CT scan of the brain, that was performed after the onset of symptoms of dementia, with findings consistent with a diagnosis of Alzheimer's disease.
- Subjects who are residing at their current location for at least 28 days before screening and are expected to remain at the same location for the duration of the trial.
- Institutionalized subjects with an identified caregiver who has sufficient contact (minimum of 2 hours per day for 4 days per week) to describe the subject's symptoms and has direct observation of the subject's behavior. Non-institutionalized subjects may not be living alone and must have an identified caregiver who has sufficient contact (minimum of 2 hours per day for 4 days per week) to describe the subject's symptoms and has direct observation of the subject's behavior.
- Subjects with onset of symptoms of agitation at least 2 weeks prior to screening visit.
- Subjects will and able to discontinue all prohibited concomitant medications to meet protocol required washouts prior to and during the trial period.
Exclusion Criteria:
- Subjects with dementia or other memory impairment not due to Alzheimer's disease.
- Subjects with a history of stroke, well-documented transient ischemic attack, or pulmonary or cerebral embolism.
- Subjects who had an insufficient response, based on the investigator's judgment, to 2 or more previous antipsychotic medications.
- Subjects who have been diagnosed with an Axis I disorder.
- Subjects who currently have clinically significant neurological, hepatic, renal, metabolic, hematological, immunological, cardiovascular, pulmonary, gastrointestinal, or psychiatric disorders.
- Subjects with uncontrolled hypertension or symptomatic hypotension, or orthostatic hypotension.
- Subjects with diabetes mellitus (insulin-dependent and non-insulin-dependent) may be eligible for the trial if their condition is stable and well-controlled.
Sites / Locations
- For additional information regarding sites, contact 844-687-8522
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Placebo Comparator
Arm Label
Brexpiprazole 2 mg
Brexpiprazole 3 mg
Placebo
Arm Description
Participants followed a titration schedule, to gradually increase their dose from 0.5 milligrams per day (mg/day) in the starting to 2 mg/day from Day 15. Participants continued to receive brexpiprazole 2 milligrams (mg), once daily until Week 12.
Participants followed a titration schedule, to gradually increase their dose from 0.5 mg/day in the starting to 3 mg/day from Day 29. Participants continued to receive brexpiprazole 3 mg, once daily until Week 12.
Participants received matching placebo, once daily for 12 weeks.
Outcomes
Primary Outcome Measures
Change From Baseline to Week 12 in the CMAI Total Score
The CMAI score is used to assess the frequency of manifestations of agitated behaviors in participants. The CMAI consists of 29 agitated behaviors that are rated on a 7-point scale of frequency across four subscales of aggressive behavior, physically nonaggressive behavior, verbally agitated behavior and hiding and hoarding as: 1=never; 2=less than once a week; 3=once or twice a week; 4=several times a week; 5=once or twice a day; 6=several times a day; 7=several times an hour. The CMAI total score ranges from 29 to 203. Higher scores indicate worsening of the condition. A negative change from baseline indicates improvement. Mixed model repeated measures (MMRM) was used for the analysis. As prespecified in the statistical analysis plan (SAP), data for this outcome measure was analyzed and reported in a combined way for brexpiprazole 2 and 3 mg.
Secondary Outcome Measures
Change From Baseline to Week 12 in the Clinical Global Impression Severity of Illness (CGI-S) Score, as Related to Agitation
CGI-S was used to rate the severity of agitation. The score ranges from 0 to 7 with response choices as, 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 higher the value, the more severe the agitation. A negative change from baseline indicates improvement. MMRM was used for the analysis. As prespecified in the SAP, data for this outcome measure was analyzed and reported in a combined way for brexpiprazole 2 and 3 mg.
Change From Baseline to Week 12 in CMAI Subscale Scores
The CMAI score is used to assess the frequency of manifestations of agitated behaviors in participants. It consists of 29 agitated behaviors that are rated on a 7-point scale of frequency across four subscales of aggressive behavior, physically nonaggressive behavior, verbally agitated behavior and hiding and hoarding, as: 1=never; 2=less than once a week; 3=once or twice a week; 4=several times a week; 5=once or twice a day; 6=several times a day; 7=several times an hour. The four subscales include 12, 6, 4, and 2 items, respectively. The score of the subscale is the sum of the individual items included in the subscale, so the score range for each of the 4 subscales is 0 to 84, 0 to 42, 0 to 28, and 0 to 14, respectively. Higher scores indicate worsening of the condition. A negative change from baseline=improvement. MMRM was used for the analysis. As prespecified in the SAP, data for this outcome measure was analyzed and reported in a combined way for brexpiprazole 2 and 3 mg.
Change From Baseline in CMAI Total Score for Each Trial Visit During the Double-blind Treatment Period
The CMAI score is used to assess the frequency of manifestations of agitated behaviors in participants. The CMAI consists of 29 agitated behaviors that are rated on a 7-point scale of frequency across four subscales of aggressive behavior, physically nonaggressive behavior, verbally agitated behavior and hiding and hoarding as: 1=never; 2=less than once a week; 3=once or twice a week; 4=several times a week; 5=once or twice a day; 6=several times a day; 7=several times an hour. The CMAI total score ranges from 29 to 203. Higher scores indicate worsening of the condition. A negative change from baseline indicates improvement. MMRM was used for the analysis. As prespecified in the SAP, data for this outcome measure was analyzed and reported in a combined way for brexpiprazole 2 and 3 mg.
Change From Baseline in CGI-S for Each Trial Visit During the Double-Blind Treatment Period
CGI-S was used to rate the severity of agitation. The score ranges from 0 to 7 with response choices as, 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 higher the value, the more severe the agitation. A negative change from baseline indicates improvement. MMRM was used for the analysis. As prespecified in the SAP, data for this outcome measure was analyzed and reported in a combined way for brexpiprazole 2 and 3 mg.
Clinical Global Impressions-Improvement (CGI-I) Score at Each Trial Visit During the Double-Blind Treatment Period
CGI-I is a 7-point scale that requires the clinician to assess whether a participant's condition has improved or worsened relative to a baseline state at the beginning of the intervention. This was rated as: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; or 7=very much worse. Higher scores indicate worse condition. As prespecified in the SAP, data for this outcome measure was analyzed and reported in a combined way for brexpiprazole 2 and 3 mg.
CMAI Response Rate Assessed as Percentage of Participants With CMAI Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period
The CMAI assesses frequency of agitated behaviors in elderly persons. The scale consists of 29 agitated behaviors that are further categorized into distinct agitation syndromes, also known as CMAI factors of agitation. Each of the agitated behaviors are scored 1 (never) to 7 (several times an hours), with the total scale score ranging from 29 to 203. Higher score indicates greater frequency of agitated behavior. As prespecified in the SAP, data for this outcome measure was analyzed and reported in a combined way for brexpiprazole 2 and 3 mg.
CMAI Response Rate Assessed as Percentage of Participants With CMAI Response Based on Improvement From Baseline in Agitation Status at Every Scheduled Trial Visit in the Double-Blind Treatment Period
The CMAI assesses frequency of agitated behaviors in elderly persons. The scale consists of 29 agitated behaviors that are further categorized into distinct agitation syndromes, also known as CMAI factors of agitation. Each of the agitated behaviors are scored 1 (never) to 7 (several times an hours), with the total scale score ranging from 29 to 203. Higher score indicates greater frequency of agitated behavior. As prespecified in the SAP, data for this outcome measure was analyzed and reported in a combined way for brexpiprazole 2 and 3 mg.
CGI-I Response Rate Assessed as Percentage of Participants With CGI-I Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period
CGI-I is a 7-point scale that requires the clinician to assess whether a participant's condition has improved or worsened relative to a baseline state at the beginning of the intervention. This was rated as: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; or 7=very much worse. Higher scores indicate worse condition. As prespecified in the SAP, data for this outcome measure was analyzed and reported in a combined way for brexpiprazole 2 and 3 mg.
Full Information
NCT ID
NCT03548584
First Posted
May 7, 2018
Last Updated
September 14, 2023
Sponsor
Otsuka Pharmaceutical Development & Commercialization, Inc.
Collaborators
H. Lundbeck A/S
1. Study Identification
Unique Protocol Identification Number
NCT03548584
Brief Title
A Trial to Evaluate the Safety, Efficacy, and Tolerability of Brexpiprazole in Treating Agitation Associated With Dementia of the Alzheimer's Type
Official Title
A Phase 3, 12-Week, Multicenter, Randomized, Double-blind, Placebo-controlled, 2-Arm, Fixed-dose Trial to Evaluate the Efficacy, Safety, and Tolerability 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
September 2023
Overall Recruitment Status
Completed
Study Start Date
May 16, 2018 (Actual)
Primary Completion Date
May 23, 2022 (Actual)
Study Completion Date
June 1, 2022 (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
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
5. Study Description
Brief Summary
This study compares the efficacy of 2 doses of brexpiprazole with placebo in participants with agitation associated with dementia of the Alzheimer's type.
Detailed Description
This is a phase 3, 12-week, multicenter, randomized, double-blind, placebo-controlled, fixed-dose trial designed to assess the efficacy, safety, and tolerability of brexpiprazole compared with placebo. 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 participants 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 participant is not living alone. This trial will analyze data gathered from approximately 330 participants at multiple countries. Participants may also be eligible to enter an active treatment extension trial.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Agitation Associated With Alzheimer's Dementia, Alzheimer Dementia
Keywords
Agitation
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
345 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Brexpiprazole 2 mg
Arm Type
Experimental
Arm Description
Participants followed a titration schedule, to gradually increase their dose from 0.5 milligrams per day (mg/day) in the starting to 2 mg/day from Day 15. Participants continued to receive brexpiprazole 2 milligrams (mg), once daily until Week 12.
Arm Title
Brexpiprazole 3 mg
Arm Type
Experimental
Arm Description
Participants followed a titration schedule, to gradually increase their dose from 0.5 mg/day in the starting to 3 mg/day from Day 29. Participants continued to receive brexpiprazole 3 mg, once daily until Week 12.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Participants received matching placebo, once daily for 12 weeks.
Intervention Type
Drug
Intervention Name(s)
Brexpiprazole
Other Intervention Name(s)
OPC-34712
Intervention Description
Oral tablets
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Oral tablets
Primary Outcome Measure Information:
Title
Change From Baseline to Week 12 in the CMAI Total Score
Description
The CMAI score is used to assess the frequency of manifestations of agitated behaviors in participants. The CMAI consists of 29 agitated behaviors that are rated on a 7-point scale of frequency across four subscales of aggressive behavior, physically nonaggressive behavior, verbally agitated behavior and hiding and hoarding as: 1=never; 2=less than once a week; 3=once or twice a week; 4=several times a week; 5=once or twice a day; 6=several times a day; 7=several times an hour. The CMAI total score ranges from 29 to 203. Higher scores indicate worsening of the condition. A negative change from baseline indicates improvement. Mixed model repeated measures (MMRM) was used for the analysis. As prespecified in the statistical analysis plan (SAP), data for this outcome measure was analyzed and reported in a combined way for brexpiprazole 2 and 3 mg.
Time Frame
Baseline and Week 12
Secondary Outcome Measure Information:
Title
Change From Baseline to Week 12 in the Clinical Global Impression Severity of Illness (CGI-S) Score, as Related to Agitation
Description
CGI-S was used to rate the severity of agitation. The score ranges from 0 to 7 with response choices as, 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 higher the value, the more severe the agitation. A negative change from baseline indicates improvement. MMRM was used for the analysis. As prespecified in the SAP, data for this outcome measure was analyzed and reported in a combined way for brexpiprazole 2 and 3 mg.
Time Frame
Baseline and Week 12
Title
Change From Baseline to Week 12 in CMAI Subscale Scores
Description
The CMAI score is used to assess the frequency of manifestations of agitated behaviors in participants. It consists of 29 agitated behaviors that are rated on a 7-point scale of frequency across four subscales of aggressive behavior, physically nonaggressive behavior, verbally agitated behavior and hiding and hoarding, as: 1=never; 2=less than once a week; 3=once or twice a week; 4=several times a week; 5=once or twice a day; 6=several times a day; 7=several times an hour. The four subscales include 12, 6, 4, and 2 items, respectively. The score of the subscale is the sum of the individual items included in the subscale, so the score range for each of the 4 subscales is 0 to 84, 0 to 42, 0 to 28, and 0 to 14, respectively. Higher scores indicate worsening of the condition. A negative change from baseline=improvement. MMRM was used for the analysis. As prespecified in the SAP, data for this outcome measure was analyzed and reported in a combined way for brexpiprazole 2 and 3 mg.
Time Frame
Baseline and Week 12
Title
Change From Baseline in CMAI Total Score for Each Trial Visit During the Double-blind Treatment Period
Description
The CMAI score is used to assess the frequency of manifestations of agitated behaviors in participants. The CMAI consists of 29 agitated behaviors that are rated on a 7-point scale of frequency across four subscales of aggressive behavior, physically nonaggressive behavior, verbally agitated behavior and hiding and hoarding as: 1=never; 2=less than once a week; 3=once or twice a week; 4=several times a week; 5=once or twice a day; 6=several times a day; 7=several times an hour. The CMAI total score ranges from 29 to 203. Higher scores indicate worsening of the condition. A negative change from baseline indicates improvement. MMRM was used for the analysis. As prespecified in the SAP, data for this outcome measure was analyzed and reported in a combined way for brexpiprazole 2 and 3 mg.
Time Frame
Baseline, Weeks 2, 4, 6, 8, 10, and 12
Title
Change From Baseline in CGI-S for Each Trial Visit During the Double-Blind Treatment Period
Description
CGI-S was used to rate the severity of agitation. The score ranges from 0 to 7 with response choices as, 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 higher the value, the more severe the agitation. A negative change from baseline indicates improvement. MMRM was used for the analysis. As prespecified in the SAP, data for this outcome measure was analyzed and reported in a combined way for brexpiprazole 2 and 3 mg.
Time Frame
Baseline, Weeks 2, 4, 6, 8, 10, and 12
Title
Clinical Global Impressions-Improvement (CGI-I) Score at Each Trial Visit During the Double-Blind Treatment Period
Description
CGI-I is a 7-point scale that requires the clinician to assess whether a participant's condition has improved or worsened relative to a baseline state at the beginning of the intervention. This was rated as: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; or 7=very much worse. Higher scores indicate worse condition. As prespecified in the SAP, data for this outcome measure was analyzed and reported in a combined way for brexpiprazole 2 and 3 mg.
Time Frame
Baseline, Weeks 2, 4, 6, 8, 10, and 12
Title
CMAI Response Rate Assessed as Percentage of Participants With CMAI Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period
Description
The CMAI assesses frequency of agitated behaviors in elderly persons. The scale consists of 29 agitated behaviors that are further categorized into distinct agitation syndromes, also known as CMAI factors of agitation. Each of the agitated behaviors are scored 1 (never) to 7 (several times an hours), with the total scale score ranging from 29 to 203. Higher score indicates greater frequency of agitated behavior. As prespecified in the SAP, data for this outcome measure was analyzed and reported in a combined way for brexpiprazole 2 and 3 mg.
Time Frame
Weeks 2, 4, 6, 8, 10, and 12
Title
CMAI Response Rate Assessed as Percentage of Participants With CMAI Response Based on Improvement From Baseline in Agitation Status at Every Scheduled Trial Visit in the Double-Blind Treatment Period
Description
The CMAI assesses frequency of agitated behaviors in elderly persons. The scale consists of 29 agitated behaviors that are further categorized into distinct agitation syndromes, also known as CMAI factors of agitation. Each of the agitated behaviors are scored 1 (never) to 7 (several times an hours), with the total scale score ranging from 29 to 203. Higher score indicates greater frequency of agitated behavior. As prespecified in the SAP, data for this outcome measure was analyzed and reported in a combined way for brexpiprazole 2 and 3 mg.
Time Frame
Baseline, Weeks 2, 4, 6, 8, 10, and 12
Title
CGI-I Response Rate Assessed as Percentage of Participants With CGI-I Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period
Description
CGI-I is a 7-point scale that requires the clinician to assess whether a participant's condition has improved or worsened relative to a baseline state at the beginning of the intervention. This was rated as: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; or 7=very much worse. Higher scores indicate worse condition. As prespecified in the SAP, data for this outcome measure was analyzed and reported in a combined way for brexpiprazole 2 and 3 mg.
Time Frame
Baseline, Weeks 2, 4, 6, 8, 10, and 12
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:
Participants with a diagnosis of probable Alzheimer's disease.
Participants with a diagnosis of agitation
Participants with a MMSE score of 5 to 22, inclusive, at screening and baseline visits.
Participants with a previous MRI or CT scan of the brain, that was performed after the onset of symptoms of dementia, with findings consistent with a diagnosis of Alzheimer's disease.
Participants who are residing at their current location for at least 28 days before screening and are expected to remain at the same location for the duration of the trial.
Institutionalized participants with an identified caregiver who has sufficient contact (minimum of 2 hours per day for 4 days per week) to describe the participant's symptoms and has direct observation of the participant's behavior. Non-institutionalized participants may not be living alone and must have an identified caregiver who has sufficient contact (minimum of 2 hours per day for 4 days per week) to describe the participant's symptoms and has direct observation of the participant's behavior.
Participants with onset of symptoms of agitation at least 2 weeks prior to screening visit.
Participants will and able to discontinue all prohibited concomitant medications to meet protocol required washouts prior to and during the trial period.
Exclusion Criteria:
Participants with dementia or other memory impairment not due to Alzheimer's disease.
Participants with a history of stroke, well-documented transient ischemic attack, or pulmonary or cerebral embolism.
Participants who had an insufficient response, based on the investigator's judgment, to 2 or more previous antipsychotic medications.
Participants who have been diagnosed with an Axis I disorder.
Participants who currently have clinically significant neurological, hepatic, renal, metabolic, hematological, immunological, cardiovascular, pulmonary, gastrointestinal, or psychiatric disorders.
Participants with uncontrolled hypertension or symptomatic hypotension, or orthostatic hypotension.
Participants with diabetes mellitus (insulin-dependent and non-insulin-dependent) may be eligible for the trial if their condition is stable and well-controlled.
Facility Information:
Facility Name
For additional information regarding sites, contact 844-687-8522
City
Los Angeles
State/Province
California
ZIP/Postal Code
90036
Country
United States
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 the Vivli data sharing platform which can be found here: https://vivli.org/ourmember/Otsuka/
IPD Sharing URL
https://clinical-trials.otsuka.com
Learn more about this trial
A Trial to Evaluate the Safety, Efficacy, and Tolerability of Brexpiprazole in Treating Agitation Associated With Dementia of the Alzheimer's Type
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