Agitation Associated With Dementia of the Alzheimer's Type
Conditions
Brief summary
To evaluate the superiority of brexpiprazole 1 mg or 2 mg over placebo after a 10-week treatment regimen for agitation associated with dementia of the Alzheimer's type in patients who require medication, and to investigate the safety of brexpiprazole and identify the optimum dose.
Interventions
DRUGBrexpiprazole
Drug: 1 tablet /day Once daily for 10 weeks
DRUGPlacebo
Placebo: 1 tablet /day Once daily for 10 weeks
Sponsors
Otsuka Pharmaceutical Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
55 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
* Patients who satisfy both of the following diagnostic criteria: 1. Diagnosis of Dementia due to Alzheimer's Disease according to DSM-5. 2. Diagnosis of Probable Alzheimer's Disease according to NINCDS-ADRDA. * Hospitalized patients or care facility patients or care at home patients * Patients with an MMSE score of 1 to 22 * Patients who have the agitation defined according to the Consensus provisional definition of agitation in cognitive disorders from the International Psychogeriatric Association (IPA)
Exclusion criteria
* Patients who have dementia other than dementia of the Alzheimer's type * Patients diagnosed with delirium between 30 days before the screening examination and baseline evaluation according to DSM-5. * Patients diagnosed with any of the following disorders according to DSM-5: * Schizophrenia spectrum and other psychotic disorders * Bipolar and related disorders * Major depressive disorder
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Cohen-Manfield Agitation Inventory(CMAI) Score at 10 Weeks After Dosing. | Baseline and 10 weeks first dose, on average 10 weeks | The CMAI assessed the frequency of agitated behaviors in elderly persons, such as hitting, cursing, and restlessness. It consisted of 29 items all rated on a 1 to 7 scale with 1 being the best rating and 7 being the worst rating. The minimum possible CMAI total score was 29, and the maximum possible CMAI total score was 203. A decrease in score indicated improvement in symptoms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Clinical Global Impression of Severity (CGI-S) Score at 10 Weeks After Dosing. | Baseline and 10 weeks first dose, on average 10 weeks | The CGI-S was used to rate the severity of agitation. Scores 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. A decrease in score indicated improvement in symptoms. |
| Clinical Global Impression of Improvement (CGI-I) Score at 10 Weeks After Dosing. | Baseline and 10 weeks first dose, on average 10 weeks | The CGI-I Scale was clinician-rated scale which assessed the total improvement of the patient's condition compared to that at baseline. Scores range from 0 to 7: 0 = Not assessed, 1= Very much improved, 2 = Much improved, 3= Minimally improved, 4= No change, 5= Minimally worse, 6= Much worse, 7= Very much worse. Higher scores indicate worse condition. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Brexpiprazole 1 mg Participants received a brexpiprazole 0.5 mg tablet once daily for 1 week followed by a 1 mg tablet once daily for 9 weeks. | 112 |
| Brexpiprazole 2 mg Participants received a brexpiprazole 0.5 mg tablet once daily for the first week, followed by a 1 mg tablet once daily for the second week, and then, subsequently, a 2 mg tablet once daily for the following 8 weeks. | 149 |
| Placebo Participants received placebo tablet once daily for 10 weeks. | 149 |
| Total | 410 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 14 | 38 | 25 |
| Overall Study | Lack of Efficacy | 2 | 1 | 1 |
| Overall Study | Non-compliance with Study Drug | 1 | 1 | 0 |
| Overall Study | Physician Decision | 7 | 4 | 4 |
| Overall Study | Protocol Violation | 1 | 2 | 1 |
| Overall Study | Withdrawal by Care Giver | 2 | 0 | 1 |
| Overall Study | Withdrawal by Legal Representative | 2 | 1 | 1 |
Baseline characteristics
| Characteristic | Brexpiprazole 1 mg | Placebo | Brexpiprazole 2 mg | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 105 Participants | 145 Participants | 145 Participants | 395 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 4 Participants | 4 Participants | 15 Participants |
| Age, Continuous | 79.3 years STANDARD_DEVIATION 7.4 | 80.3 years STANDARD_DEVIATION 6.7 | 80.2 years STANDARD_DEVIATION 6.4 | 80.0 years STANDARD_DEVIATION 6.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 112 Participants | 149 Participants | 149 Participants | 410 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Japan | 112 participants | 149 participants | 149 participants | 410 participants |
| Sex: Female, Male Female | 71 Participants | 87 Participants | 105 Participants | 263 Participants |
| Sex: Female, Male Male | 41 Participants | 62 Participants | 44 Participants | 147 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 112 | 0 / 149 | 0 / 149 |
| other Total, other adverse events | 77 / 112 | 113 / 149 | 93 / 149 |
| serious Total, serious adverse events | 7 / 112 | 9 / 149 | 7 / 149 |
Outcome results
Primary
Change From Baseline in Cohen-Manfield Agitation Inventory(CMAI) Score at 10 Weeks After Dosing.
The CMAI assessed the frequency of agitated behaviors in elderly persons, such as hitting, cursing, and restlessness. It consisted of 29 items all rated on a 1 to 7 scale with 1 being the best rating and 7 being the worst rating. The minimum possible CMAI total score was 29, and the maximum possible CMAI total score was 203. A decrease in score indicated improvement in symptoms.
Time frame: Baseline and 10 weeks first dose, on average 10 weeks
Population: The full analysis set (FAS) comprised subjects who, after randomization, have received at least 1 dose of the IMP, and from whom CMAI total scores have been obtained at baseline and at least 1 time point after initiation of the treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Brexpiprazole 1 mg | Change From Baseline in Cohen-Manfield Agitation Inventory(CMAI) Score at 10 Weeks After Dosing. | -11.7 units on a scale | Standard Error 1.2 |
| Brexpiprazole 2 mg | Change From Baseline in Cohen-Manfield Agitation Inventory(CMAI) Score at 10 Weeks After Dosing. | -15.2 units on a scale | Standard Error 1.05 |
| Placebo | Change From Baseline in Cohen-Manfield Agitation Inventory(CMAI) Score at 10 Weeks After Dosing. | -8.0 units on a scale | Standard Error 1.03 |
Comparison: Statistical analysis to compare brexpiprazole 2 mg/day and placebo was performed at Week 10.p-value: <0.000195% CI: [-10, -4.3]Mixed Models Analysis
Comparison: Statistical analysis to compare brexpiprazole 1 mg/day and placebo was performed at Week 10.p-value: 0.017595% CI: [-6.8, -0.7]Mixed Models Analysis
Secondary
Change From Baseline in Clinical Global Impression of Severity (CGI-S) Score at 10 Weeks After Dosing.
The CGI-S was used to rate the severity of agitation. Scores 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. A decrease in score indicated improvement in symptoms.
Time frame: Baseline and 10 weeks first dose, on average 10 weeks
Population: Efficacy sample（FAS）consisted of all participants who have received at least 1 dose of the IMP and have Baseline and at least one Post-Baseline efficacy evaluation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Brexpiprazole 1 mg | Change From Baseline in Clinical Global Impression of Severity (CGI-S) Score at 10 Weeks After Dosing. | -1.0 units on a scale | Standard Error 0.1 |
| Brexpiprazole 2 mg | Change From Baseline in Clinical Global Impression of Severity (CGI-S) Score at 10 Weeks After Dosing. | -1.4 units on a scale | Standard Error 0.09 |
| Placebo | Change From Baseline in Clinical Global Impression of Severity (CGI-S) Score at 10 Weeks After Dosing. | -0.6 units on a scale | Standard Error 0.09 |
Comparison: Statistical analysis to compare brexpiprazole 2 mg/day and placebo was performed at Week 10.p-value: <0.000195% CI: [-1, -0.5]Mixed Models Analysis
Comparison: Statistical analysis to compare brexpiprazole 1 mg/day and placebo was performed at Week 10.p-value: 0.008395% CI: [-0.6, -0.1]Mixed Models Analysis
Secondary
Clinical Global Impression of Improvement (CGI-I) Score at 10 Weeks After Dosing.
The CGI-I Scale was clinician-rated scale which assessed the total improvement of the patient's condition compared to that at baseline. Scores range from 0 to 7: 0 = Not assessed, 1= Very much improved, 2 = Much improved, 3= Minimally improved, 4= No change, 5= Minimally worse, 6= Much worse, 7= Very much worse. Higher scores indicate worse condition.
Time frame: Baseline and 10 weeks first dose, on average 10 weeks
Population: Efficacy sample（FAS) consisted of all participants who have received at least 1 dose of the IMP and have Baseline and at least one Post-Baseline efficacy evaluation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Brexpiprazole 1 mg | Clinical Global Impression of Improvement (CGI-I) Score at 10 Weeks After Dosing. | 3.1 units on a scale | Standard Deviation 1.3 |
| Brexpiprazole 2 mg | Clinical Global Impression of Improvement (CGI-I) Score at 10 Weeks After Dosing. | 2.6 units on a scale | Standard Deviation 1.2 |
| Placebo | Clinical Global Impression of Improvement (CGI-I) Score at 10 Weeks After Dosing. | 3.5 units on a scale | Standard Deviation 1.4 |
Comparison: Statistical analysis to compare brexpiprazole 2 mg/day and placebo was performed at Week 10.p-value: <0.000195% CI: [-1.2, -0.6]Cochran-Mantel-Haenszel
Comparison: Statistical analysis to compare brexpiprazole 1 mg/day and placebo was performed at Week 10.p-value: 0.005295% CI: [-0.8, -0.1]Cochran-Mantel-Haenszel