Trial Outcomes & Findings for Safety and Tolerability Study of Flexible Dosing of Brexpiprazole in the Treatment of Subjects With Agitation Associated With Dementia of the Alzheimer's Type (NCT NCT01922258)

NCT ID: NCT01922258

Last Updated: 2020-11-20

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

270 participants

Primary outcome timeframe

From screening to week 12/early termination

Results posted on

2020-11-20

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	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.	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.
Overall Study STARTED	133	137
Overall Study COMPLETED	117	121
Overall Study NOT COMPLETED	16	16

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.
Overall Study Lost to Follow-up	1	1
Overall Study Adverse Event	9	2
Overall Study Met Withdrawal Criteria	0	4
Overall Study Withdrawn by the Investigator	1	4
Overall Study Withdrawal by participant	5	5

Baseline Characteristics

Safety and Tolerability Study of Flexible Dosing of Brexpiprazole in the Treatment of Subjects With Agitation Associated With Dementia of the Alzheimer's Type

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Brexpiprazole (Flexible Dose Range 0.5 to 2 mg/Day) n=133 Participants 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.	Placebo (Flexible Dose Range 0.5 to 2 mg/Day) n=137 Participants 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.	Total n=270 Participants Total of all reporting groups
Age, Customized <65 years	24 Participants n=5 Participants	19 Participants n=7 Participants	43 Participants n=5 Participants
Age, Customized >=65 <75 years	46 Participants n=5 Participants	49 Participants n=7 Participants	95 Participants n=5 Participants
Age, Customized >=75 years	63 Participants n=5 Participants	69 Participants n=7 Participants	132 Participants n=5 Participants
Sex: Female, Male Female	82 Participants n=5 Participants	88 Participants n=7 Participants	170 Participants n=5 Participants
Sex: Female, Male Male	51 Participants n=5 Participants	49 Participants n=7 Participants	100 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	4 Participants n=5 Participants	5 Participants n=7 Participants	9 Participants n=5 Participants
Race (NIH/OMB) White	128 Participants n=5 Participants	129 Participants n=7 Participants	257 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Brexpiprazole (Flexible Dose Range 0.5 to 2 mg/Day) n=131 Participants 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.	Placebo (Flexible Dose Range 0.5 to 2 mg/Day) n=135 Participants 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.
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	-16.5 units on a scale Standard Error 1.13

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Brexpiprazole (Flexible Dose Range 0.5 to 2 mg/Day) n=131 Participants 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.	Placebo (Flexible Dose Range 0.5 to 2 mg/Day) n=135 Participants 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.
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	4.51 units on a scale Standard Deviation 0.74

Adverse Events

Brexpiprazole (Flexible Dose Range 0.5 to 2 mg/Day)

Serious events: 7 serious events

Other events: 24 other events

Deaths: 0 deaths

Placebo (Flexible Dose Range 0.5 to 2 mg/Day)

Serious events: 6 serious events

Other events: 29 other events

Deaths: 1 deaths

Serious adverse events

Serious adverse events
Measure	Brexpiprazole (Flexible Dose Range 0.5 to 2 mg/Day) n=132 participants at risk 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.	Placebo (Flexible Dose Range 0.5 to 2 mg/Day) n=137 participants at risk 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.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/132 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).	0.73% 1/137 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).
General disorders Non-Cardiac Chest Pain	0.76% 1/132 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).	0.00% 0/137 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).
Infections and infestations Pneumonia	0.76% 1/132 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).	0.73% 1/137 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).
Injury, poisoning and procedural complications Femur Fracture	0.00% 0/132 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).	0.73% 1/137 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).
Injury, poisoning and procedural complications Hip Fracture	0.00% 0/132 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).	0.73% 1/137 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).
Injury, poisoning and procedural complications Subdural haematoma	0.76% 1/132 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).	0.00% 0/137 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).
Metabolism and nutrition disorders Dehydration	0.00% 0/132 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).	0.73% 1/137 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).
Metabolism and nutrition disorders Failure to thrive	0.00% 0/132 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).	0.73% 1/137 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).
Nervous system disorders Loss of consciousness	0.76% 1/132 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).	0.00% 0/137 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).
Nervous system disorders Presyncope	0.76% 1/132 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).	0.00% 0/137 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).
Nervous system disorders Seizure	1.5% 2/132 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).	0.00% 0/137 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).
Nervous system disorders Syncope	0.00% 0/132 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).	0.73% 1/137 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).
Respiratory, thoracic and mediastinal disorders Dyspnoea Exertional	0.76% 1/132 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).	0.00% 0/137 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).
Vascular disorders Hypertensive crisis	0.76% 1/132 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).	0.00% 0/137 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).

Other adverse events

Other adverse events
Measure	Brexpiprazole (Flexible Dose Range 0.5 to 2 mg/Day) n=132 participants at risk 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.	Placebo (Flexible Dose Range 0.5 to 2 mg/Day) n=137 participants at risk 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.
Nervous system disorders Somnolence	6.1% 8/132 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).	3.6% 5/137 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).
Nervous system disorders Dizziness	4.5% 6/132 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).	5.1% 7/137 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).
Nervous system disorders Headache	7.6% 10/132 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).	12.4% 17/137 • Through the trial: From screening to Week 12 and 30 (+2) days follow-up period. Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).

Additional Information

Global Clinical Development

Otsuka Pharmaceutical Development & Commercialization, Inc.

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Sponsor reserves the right to review results publications prior to public release and can delay such publications for a period greater than 60 days but no more than 120 days from the date that the publication is submitted to the Sponsor for review. Sponsor can require changes to the publication to protect Sponsor's intellectual property rights and/or confidential information and reserves the right to limit publication timing and scope of data published based on the number of study locations.
Publication restrictions are in place

Restriction type: OTHER