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 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.
Interventions
Flexible dose of 0.5 to 2 mg/day or placebo tablets for up to 12 weeks
Sponsors
H. Lundbeck A/S
Otsuka Pharmaceutical Development & Commercialization, Inc.
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
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12/Early Termination in the Cohen-Mansfield Agitation Inventory (CMAI) Total Score | From screening to week 12/early termination | 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
| Measure | Time frame | Description |
|---|---|---|
| Change in the Clinical Global Impression Severity of Illness (CGI-S) Score, as Related to Symptoms of Agitation | From screening to week 12/early termination | 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. |
Countries
Bulgaria, Canada, Finland, France, Russia, Slovenia, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
The trial was conducted at 62 sites in 9 countries: Bulgaria, Canada, Finland, France, Russia, Slovenia, Ukraine, the United Kingdom (UK), and the United States (US) and 270 participants were randomized. The date of the first ICF signed by a participant in this trial was 28 October 2013 and the date of the last trial observation was 30 March 2017.
Pre-assignment details
The screening period ranged from 2 to 42 days (with an option to extend with approval of the medical monitor). 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 (Flexible Dose Range 0.5 to 2 mg/Day) 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. | 133 |
| Placebo (Flexible Dose Range 0.5 to 2 mg/Day) Titrate up from 0.25 mg/day placebo to 1 mg/day placebo. 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. | 137 |
| Total | 270 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 9 | 2 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Met Withdrawal Criteria | 0 | 4 |
| Overall Study | Withdrawal by participant | 5 | 5 |
| Overall Study | Withdrawn by the Investigator | 1 | 4 |
Baseline characteristics
| Characteristic | Brexpiprazole (Flexible Dose Range 0.5 to 2 mg/Day) | Placebo (Flexible Dose Range 0.5 to 2 mg/Day) | Total |
|---|---|---|---|
| Age, Customized >=65 <75 years | 46 Participants | 49 Participants | 95 Participants |
| Age, Customized <65 years | 24 Participants | 19 Participants | 43 Participants |
| Age, Customized >=75 years | 63 Participants | 69 Participants | 132 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 5 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 128 Participants | 129 Participants | 257 Participants |
| Sex: Female, Male Female | 82 Participants | 88 Participants | 170 Participants |
| Sex: Female, Male Male | 51 Participants | 49 Participants | 100 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 132 | 1 / 137 |
| other Total, other adverse events | 24 / 132 | 29 / 137 |
| serious Total, serious adverse events | 7 / 132 | 6 / 137 |
Outcome results
Primary
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.
Time frame: From screening to week 12/early termination
Population: The intent-to-treat (ITT) population consisted of all participants in the randomized sample, who took at least 1 dose of the investigational medicinal product (IMP) and had a baseline and at least one postbaseline evaluation for the CMAI total score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Brexpiprazole (Flexible Dose Range 0.5 to 2 mg/Day) | Change From Baseline to Week 12/Early Termination in the Cohen-Mansfield Agitation Inventory (CMAI) Total Score | -18.9 units on a scale | Standard Error 1.17 |
| Placebo (Flexible Dose Range 0.5 to 2 mg/Day) | Change From Baseline to Week 12/Early Termination in the Cohen-Mansfield Agitation Inventory (CMAI) Total Score | -16.5 units on a scale | Standard Error 1.13 |
p-value: =0.145495% CI: [-5.49, 0.82]Mixed-effect model repeated measure
Secondary
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.
Time frame: From screening to week 12/early termination
Population: The intent-to-treat (ITT) population consisted of all participants in the randomized sample, who took at least 1 dose of the IMP and had a baseline and at least one postbaseline evaluation for the CMAI total score.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Brexpiprazole (Flexible Dose Range 0.5 to 2 mg/Day) | Change in the Clinical Global Impression Severity of Illness (CGI-S) Score, as Related to Symptoms of Agitation | 4.54 units on a scale | Standard Deviation 0.77 |
| Placebo (Flexible Dose Range 0.5 to 2 mg/Day) | Change in the Clinical Global Impression Severity of Illness (CGI-S) Score, as Related to Symptoms of Agitation | 4.51 units on a scale | Standard Deviation 0.74 |