Agitation Associated With, Alzheimer's Disease, Alzheimer's Type, Mental Disorder, Nervous System Diseases
Conditions
Keywords
OPC-34712, brexpiprazole, Dementia, Alzheimer's Disease, Cognitive Disorders, Agitation
Brief summary
To compare the efficacy of 2 fixed doses of brexpiprazole with placebo in participants with agitation associated with dementia of the Alzheimer's type.
Detailed description
Behavioral symptoms, such as agitation, are core features in participants with Alzheimer's disease and related dementias and develop in the majority of dementia participants. The presence of agitation in participants with Alzheimer's disease places a significant burden not only on participants and their caregivers but also on the healthcare system. This is a trial designed to assess the safety and efficacy of brexpiprazole in the treatment of participants with agitation associated with dementia of the Alzheimer's Type. The trial consists of a continuous 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.
Interventions
Once-daily, tablets
DRUGPlacebo Oral Tablet
Once-daily, tablets
Sponsors
H. Lundbeck A/S
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
55 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
* Male and female participants 55 to 90 years of age, inclusive, at the time of informed consent. * Participants 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. * Participants with a diagnosis of probable Alzheimer's disease according to National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association. * Participants with a Mini-Mental State Exam score of 5 to 22, inclusive, at screening and baseline visits. * Participants with onset of symptoms of agitation at least 2 weeks prior to the screening visit. * Participants with a score of ≥ 4 on the agitation/aggression item of the Neuropsychiatric Inventory-Nursing Home at the screening and baseline visits. * Participants who require pharmacotherapy for treatment of agitation per the investigator's judgment, after an evaluation for reversible factors (for example, pain, infection, polypharmacy) and a trial of nonpharmacological intervention. * Participants must have a previous magnetic resonance imaging or computed tomography 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
* Participants with dementia or other memory impairment not due to Alzheimer's disease * Participants with a history of stroke, well-documented transient ischemic attack, pulmonary or cerebral embolism. * Participants who currently have clinically significant neurological, hepatic, renal, metabolic, hematological, immunological, cardiovascular, pulmonary, gastrointestinal, or psychiatric disorders. * Participants who have been diagnosed with an Axis I disorder (Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision criteria) * Participants with uncontrolled hypertension * Participants with uncontrolled insulin-dependent diabetes mellitus * Participants with epilepsy or a history of seizures * Participants considered in poor general health based on the investigator's judgment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline In The Cohen-Mansfield Agitation Inventory (CMAI) Total Score After 12 Weeks Of Brexpiprazole Treatment | Baseline, Week 12/Early Termination (ET) | To compare the efficacy of 2 fixed doses (1 mg/day and 2 mg/day) of brexpiprazole with placebo in participants with agitation associated with dementia of the Alzheimer's type, by the assessment of CMAI after 12 weeks of treatment. The CMAI assesses the frequency of agitated behaviors in elderly persons, such as hitting, cursing, and restlessness. It consists 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 is 29, and the maximum possible CMAI total score is 203. A decrease in score indicates improvement in symptoms. To control the overall type I error at 0.05 level when making 2 comparisons of brexpiprazole doses versus placebo, statistical testing was carried out using a hierarchical testing procedure in the order of: 1) comparison of 2 mg/day brexpiprazole versus placebo, and 2) comparison of 1 mg/day brexpiprazole versus placebo. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline In The Clinical Global Impression-Severity Of Illness (CGI-S) Score, As Related To Symptoms Of Agitation After 12 Weeks Of Brexpiprazole Treatment | Baseline, Week 12/ET | To compare the efficacy of 2 fixed doses (1 mg/day and 2 mg/day) of brexpiprazole with placebo in participants with agitation associated with Alzheimer's dementia, by the assessment of CGI-S score after 12 weeks of treatment. 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 indicates improvement in symptoms. |
Countries
Croatia, Germany, Russia, Serbia, Spain, Ukraine, United States
Participant flow
Recruitment details
Participants who met all the inclusion and none of the exclusion criteria were enrolled in this study. The study was conducted in 433 participants at 81 sites in 7 countries: Croatia, Germany, Serbia, Spain, Russia, Ukraine, and the United States.
Pre-assignment details
Participants attended a screening period ranging from 2 to 42 days. The purpose of the screening period was to determine the participant's eligibility and to washout prohibited concomitant pharmacotherapy prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| Brexpiprazole 0.5 mg/Day All randomized participants received orally brexpiprazole 0.25 milligrams (mg)/day as a starting dose, which was up titrated to 0.5 mg/day. The investigational medicinal product (IMP) was administered once daily in the form of a tablet. | 20 |
| Brexpiprazole 1 mg/Day All randomized participants received orally brexpiprazole 0.25 mg/day as a starting dose, which was up titrated to 1 mg/day. The IMP was administered once daily in the form of a tablet. | 137 |
| Brexpiprazole 2 mg/Day All randomized participants received orally brexpiprazole 0.25 mg/day as a starting dose, which was up titrated to 2 mg/day. The IMP was administered once daily in the form of a tablet. | 140 |
| Placebo All randomized participants received orally brexpiprazole-matching Placebo. The Placebo was administered once daily in the form of a tablet. | 136 |
| Total | 433 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 10 | 6 | 8 |
| Overall Study | Participant Met Withdrawal Criteria | 1 | 1 | 2 | 1 |
| Overall Study | Participant Withdrawn by Investigator | 0 | 1 | 1 | 1 |
| Overall Study | Protocol Deviation | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 4 | 8 | 5 |
Baseline characteristics
| Characteristic | Brexpiprazole 0.5 mg/Day | Total | Placebo | Brexpiprazole 2 mg/Day | Brexpiprazole 1 mg/Day |
|---|---|---|---|---|---|
| Age, Continuous | 73.9 years STANDARD_DEVIATION 9.1 | 73.9 years STANDARD_DEVIATION 8.3 | 74.1 years STANDARD_DEVIATION 8 | 73.7 years STANDARD_DEVIATION 8.1 | 73.8 years STANDARD_DEVIATION 8.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 4 Participants | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 12 Participants | 5 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 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 | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 20 Participants | 417 Participants | 130 Participants | 133 Participants | 134 Participants |
| Sex: Female, Male Female | 12 Participants | 239 Participants | 70 Participants | 79 Participants | 78 Participants |
| Sex: Female, Male Male | 8 Participants | 194 Participants | 66 Participants | 61 Participants | 59 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 20 | 2 / 137 | 1 / 140 | 0 / 135 |
| other Total, other adverse events | 11 / 20 | 27 / 137 | 43 / 140 | 29 / 135 |
| serious Total, serious adverse events | 5 / 20 | 11 / 137 | 13 / 140 | 7 / 135 |
Outcome results
Primary
Change From Baseline In The Cohen-Mansfield Agitation Inventory (CMAI) Total Score After 12 Weeks Of Brexpiprazole Treatment
To compare the efficacy of 2 fixed doses (1 mg/day and 2 mg/day) of brexpiprazole with placebo in participants with agitation associated with dementia of the Alzheimer's type, by the assessment of CMAI after 12 weeks of treatment. The CMAI assesses the frequency of agitated behaviors in elderly persons, such as hitting, cursing, and restlessness. It consists 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 is 29, and the maximum possible CMAI total score is 203. A decrease in score indicates improvement in symptoms. To control the overall type I error at 0.05 level when making 2 comparisons of brexpiprazole doses versus placebo, statistical testing was carried out using a hierarchical testing procedure in the order of: 1) comparison of 2 mg/day brexpiprazole versus placebo, and 2) comparison of 1 mg/day brexpiprazole versus placebo.
Time frame: Baseline, Week 12/Early Termination (ET)
Population: The modified intention-to-treat population consisted of all participants in the randomized sample who took at least 1 dose of IMP (excluding 20 subjects randomized to Brexpiprazole 0.5 mg/day, as doses lower than 1 mg/day were unlikely to be efficacious) and had a baseline and at least 1 post baseline evaluation for the CMAI total score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Brexpiprazole 2 mg/Day | Change From Baseline In The Cohen-Mansfield Agitation Inventory (CMAI) Total Score After 12 Weeks Of Brexpiprazole Treatment | -21.6 units on a scale | Standard Error 1.32 |
| Brexpiprazole 1 mg/Day | Change From Baseline In The Cohen-Mansfield Agitation Inventory (CMAI) Total Score After 12 Weeks Of Brexpiprazole Treatment | -17.6 units on a scale | Standard Error 1.33 |
| Placebo | Change From Baseline In The Cohen-Mansfield Agitation Inventory (CMAI) Total Score After 12 Weeks Of Brexpiprazole Treatment | -17.8 units on a scale | Standard Error 1.34 |
p-value: =0.040495% CI: [-7.38, -0.17]Mixed-effect model repeated measure
p-value: =0.901595% CI: [-3.4, 3.86]Mixed-effect model repeated measure
Secondary
Change From Baseline In The Clinical Global Impression-Severity Of Illness (CGI-S) Score, As Related To Symptoms Of Agitation After 12 Weeks Of Brexpiprazole Treatment
To compare the efficacy of 2 fixed doses (1 mg/day and 2 mg/day) of brexpiprazole with placebo in participants with agitation associated with Alzheimer's dementia, by the assessment of CGI-S score after 12 weeks of treatment. 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 indicates improvement in symptoms.
Time frame: Baseline, Week 12/ET
Population: The modified intention-to-treat population consisted of all participants in the randomized sample who took at least 1 dose of IMP (excluding 20 participants randomized to Brexpiprazole 0.5 mg/day) and had a baseline and at least 1 post baseline evaluation for the CMAI total score.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Brexpiprazole 2 mg/Day | Change From Baseline In The Clinical Global Impression-Severity Of Illness (CGI-S) Score, As Related To Symptoms Of Agitation After 12 Weeks Of Brexpiprazole Treatment | -1.29 units on a scale | Standard Deviation 1.05 |
| Brexpiprazole 1 mg/Day | Change From Baseline In The Clinical Global Impression-Severity Of Illness (CGI-S) Score, As Related To Symptoms Of Agitation After 12 Weeks Of Brexpiprazole Treatment | -1.04 units on a scale | Standard Deviation 1.12 |
| Placebo | Change From Baseline In The Clinical Global Impression-Severity Of Illness (CGI-S) Score, As Related To Symptoms Of Agitation After 12 Weeks Of Brexpiprazole Treatment | -1.08 units on a scale | Standard Deviation 0.89 |
p-value: =0.156695% CI: [-0.39, 0.06]Mixed-effect model repeated measure
p-value: =0.44495% CI: [-0.14, 0.32]Mixed-effect model repeated measure