Trial Outcomes & Findings for A Trial to Evaluate the Safety, Efficacy, and Tolerability of Brexpiprazole in Treating Agitation Associated With Dementia of the Alzheimer's Type (NCT NCT03548584)

Last Updated: 2023-09-18

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

345 participants

Primary outcome timeframe

Baseline and Week 12

Results posted on

2023-09-18

Participant Flow

A total of 345 participants were randomized, and participated in the study from 16 May 2018 to 1 June 2022.

Participant milestones

Participant milestones
Measure	Brexpiprazole 2 mg 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.	Brexpiprazole 3 mg 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.	Placebo Participants received matching placebo, once daily for 12 weeks.
Overall Study STARTED	75	153	117
Overall Study Intent-to-treat Population	73	153	116
Overall Study COMPLETED	68	130	104
Overall Study NOT COMPLETED	7	23	13

Reasons for withdrawal

Reasons for withdrawal
Measure	Brexpiprazole 2 mg 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.	Brexpiprazole 3 mg 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.	Placebo Participants received matching placebo, once daily for 12 weeks.
Overall Study Lost to Follow-up	0	0	1
Overall Study Adverse Event	1	11	5
Overall Study Site Terminated by Sponsor	1	3	2
Overall Study Subject Withdrew Consent to Participate	5	5	3
Overall Study Lack of Efficacy	0	1	0
Overall Study Non-compliance with Study Drug	0	1	0
Overall Study Reason not Specified (Not Related to Coronavirus Disease 2019 [COVID-19])	0	2	2

Baseline Characteristics

A Trial to Evaluate the Safety, Efficacy, and Tolerability of Brexpiprazole in Treating Agitation Associated With Dementia of the Alzheimer's Type

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Brexpiprazole 2 mg n=75 Participants Participants followed a titration schedule, to gradually increase their dose from 0.5 mg/day in the starting to 2 mg/day from Day 15. Participants continued to receive brexpiprazole 2 mg, once daily until Week 12.	Brexpiprazole 3 mg n=153 Participants 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.	Placebo n=117 Participants Participants received matching placebo, once daily for 12 weeks.	Total n=345 Participants Total of all reporting groups
Age, Continuous	74.3 years STANDARD_DEVIATION 7.3 • n=5 Participants	74.6 years STANDARD_DEVIATION 8.0 • n=7 Participants	73.0 years STANDARD_DEVIATION 7.0 • n=5 Participants	74.0 years STANDARD_DEVIATION 7.5 • n=4 Participants
Sex: Female, Male Female	43 Participants n=5 Participants	92 Participants n=7 Participants	60 Participants n=5 Participants	195 Participants n=4 Participants
Sex: Female, Male Male	32 Participants n=5 Participants	61 Participants n=7 Participants	57 Participants n=5 Participants	150 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	25 Participants n=5 Participants	46 Participants n=7 Participants	37 Participants n=5 Participants	108 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	50 Participants n=5 Participants	107 Participants n=7 Participants	80 Participants n=5 Participants	237 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	3 Participants n=7 Participants	1 Participants n=5 Participants	4 Participants n=4 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	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	5 Participants n=5 Participants	6 Participants n=7 Participants	1 Participants n=5 Participants	12 Participants n=4 Participants
Race (NIH/OMB) White	70 Participants n=5 Participants	144 Participants n=7 Participants	115 Participants n=5 Participants	329 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Cohen-Mansfield Agitation Inventory (CMAI) Total Score	78.6 score on a scale STANDARD_DEVIATION 15.5 • n=5 Participants	81.2 score on a scale STANDARD_DEVIATION 17.2 • n=7 Participants	79.4 score on a scale STANDARD_DEVIATION 17.6 • n=5 Participants	80 score on a scale STANDARD_DEVIATION 17 • n=4 Participants

PRIMARY outcome

Timeframe: Baseline and Week 12

Population: The ITT Population consisted of all participants in the randomized sample, who took at least 1 dose of IMP and had a baseline and at least one post-baseline evaluation for the CMAI total score. Overall number analyzed is the number of participants with data available for analyses.

Outcome measures

Outcome measures
Measure	Brexpiprazole 2 and 3 mg n=225 Participants Participants followed a titration schedule, to gradually increase their dose from 0.5 mg/day in the starting to 2 mg/day from Day 15 or from 0.5 mg/day in the starting to 3 mg/day from Day 29. Participants continued to receive brexpiprazole 2 or 3 mg, once daily until Week 12.	Placebo n=116 Participants Participants received matching placebo, once daily for 12 weeks.
Change From Baseline to Week 12 in the CMAI Total Score	-22.6 score on a scale Standard Error 1.08	-17.3 score on a scale Standard Error 1.44

SECONDARY outcome

Timeframe: Baseline and Week 12

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.

Outcome measures

Outcome measures
Measure	Brexpiprazole 2 and 3 mg n=225 Participants Participants followed a titration schedule, to gradually increase their dose from 0.5 mg/day in the starting to 2 mg/day from Day 15 or from 0.5 mg/day in the starting to 3 mg/day from Day 29. Participants continued to receive brexpiprazole 2 or 3 mg, once daily until Week 12.	Placebo n=116 Participants Participants received matching placebo, once daily for 12 weeks.
Change From Baseline to Week 12 in the Clinical Global Impression Severity of Illness (CGI-S) Score, as Related to Agitation	-1.20 score on a scale Standard Error 0.06	-0.93 score on a scale Standard Error 0.08

SECONDARY outcome

Timeframe: Baseline and Week 12

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.

Outcome measures

Outcome measures
Measure	Brexpiprazole 2 and 3 mg n=225 Participants Participants followed a titration schedule, to gradually increase their dose from 0.5 mg/day in the starting to 2 mg/day from Day 15 or from 0.5 mg/day in the starting to 3 mg/day from Day 29. Participants continued to receive brexpiprazole 2 or 3 mg, once daily until Week 12.	Placebo n=116 Participants Participants received matching placebo, once daily for 12 weeks.
Change From Baseline to Week 12 in CMAI Subscale Scores Aggressive Behavior	-9.09 score on a scale Standard Error 0.42	-7.13 score on a scale Standard Error 0.56
Change From Baseline to Week 12 in CMAI Subscale Scores Physically Nonaggressive Behavior	-6.45 score on a scale Standard Error 0.40	-5.04 score on a scale Standard Error 0.53
Change From Baseline to Week 12 in CMAI Subscale Scores Verbally Agitated Behavior	-4.39 score on a scale Standard Error 0.31	-3.14 score on a scale Standard Error 0.40
Change From Baseline to Week 12 in CMAI Subscale Scores Hiding and Hoarding	-1.50 score on a scale Standard Error 0.17	-1.14 score on a scale Standard Error 0.23

SECONDARY outcome

Timeframe: Baseline, Weeks 2, 4, 6, 8, 10, and 12

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.

Outcome measures

Outcome measures
Measure	Brexpiprazole 2 and 3 mg n=225 Participants Participants followed a titration schedule, to gradually increase their dose from 0.5 mg/day in the starting to 2 mg/day from Day 15 or from 0.5 mg/day in the starting to 3 mg/day from Day 29. Participants continued to receive brexpiprazole 2 or 3 mg, once daily until Week 12.	Placebo n=116 Participants Participants received matching placebo, once daily for 12 weeks.
Change From Baseline in CMAI Total Score for Each Trial Visit During the Double-blind Treatment Period Change From Baseline at Week 2	-5.76 score on a scale Standard Error 0.71	-6.61 score on a scale Standard Error 0.90
Change From Baseline in CMAI Total Score for Each Trial Visit During the Double-blind Treatment Period Change From Baseline at Week 4	-12.1 score on a scale Standard Error 0.82	-11.0 score on a scale Standard Error 1.06
Change From Baseline in CMAI Total Score for Each Trial Visit During the Double-blind Treatment Period Change From Baseline at Week 6	-16.2 score on a scale Standard Error 0.91	-13.9 score on a scale Standard Error 1.19
Change From Baseline in CMAI Total Score for Each Trial Visit During the Double-blind Treatment Period Change From Baseline at Week 8	-19.4 score on a scale Standard Error 0.96	-14.4 score on a scale Standard Error 1.28
Change From Baseline in CMAI Total Score for Each Trial Visit During the Double-blind Treatment Period Change From Baseline at Week 10	-22.2 score on a scale Standard Error 0.97	-15.7 score on a scale Standard Error 1.29
Change From Baseline in CMAI Total Score for Each Trial Visit During the Double-blind Treatment Period Change From Baseline at Week 12	-22.6 score on a scale Standard Error 1.08	-17.3 score on a scale Standard Error 1.44

SECONDARY outcome

Timeframe: Baseline, Weeks 2, 4, 6, 8, 10, and 12

Outcome measures

Outcome measures
Measure	Brexpiprazole 2 and 3 mg n=225 Participants Participants followed a titration schedule, to gradually increase their dose from 0.5 mg/day in the starting to 2 mg/day from Day 15 or from 0.5 mg/day in the starting to 3 mg/day from Day 29. Participants continued to receive brexpiprazole 2 or 3 mg, once daily until Week 12.	Placebo n=116 Participants Participants received matching placebo, once daily for 12 weeks.
Change From Baseline in CGI-S for Each Trial Visit During the Double-Blind Treatment Period Change From Baseline at Week 2	-0.21 score on a scale Standard Error 0.03	-0.27 score on a scale Standard Error 0.04
Change From Baseline in CGI-S for Each Trial Visit During the Double-Blind Treatment Period Change From Baseline at Week 4	-0.53 score on a scale Standard Error 0.05	-0.50 score on a scale Standard Error 0.06
Change From Baseline in CGI-S for Each Trial Visit During the Double-Blind Treatment Period Change From Baseline at Week 6	-0.74 score on a scale Standard Error 0.05	-0.68 score on a scale Standard Error 0.07
Change From Baseline in CGI-S for Each Trial Visit During the Double-Blind Treatment Period Change From Baseline at Week 8	-0.97 score on a scale Standard Error 0.06	-0.70 score on a scale Standard Error 0.08
Change From Baseline in CGI-S for Each Trial Visit During the Double-Blind Treatment Period Change From Baseline at Week 10	-1.14 score on a scale Standard Error 0.06	-0.86 score on a scale Standard Error 0.08
Change From Baseline in CGI-S for Each Trial Visit During the Double-Blind Treatment Period Change From Baseline at Week 12	-1.20 score on a scale Standard Error 0.06	-0.93 score on a scale Standard Error 0.08

SECONDARY outcome

Timeframe: Baseline, Weeks 2, 4, 6, 8, 10, and 12

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.

Outcome measures

Outcome measures
Measure	Brexpiprazole 2 and 3 mg n=225 Participants Participants followed a titration schedule, to gradually increase their dose from 0.5 mg/day in the starting to 2 mg/day from Day 15 or from 0.5 mg/day in the starting to 3 mg/day from Day 29. Participants continued to receive brexpiprazole 2 or 3 mg, once daily until Week 12.	Placebo n=116 Participants Participants received matching placebo, once daily for 12 weeks.
Clinical Global Impressions-Improvement (CGI-I) Score at Each Trial Visit During the Double-Blind Treatment Period Week 2	3.70 score on a scale Standard Deviation 0.75	3.57 score on a scale Standard Deviation 0.69
Clinical Global Impressions-Improvement (CGI-I) Score at Each Trial Visit During the Double-Blind Treatment Period Week 4	3.19 score on a scale Standard Deviation 0.85	3.39 score on a scale Standard Deviation 0.87
Clinical Global Impressions-Improvement (CGI-I) Score at Each Trial Visit During the Double-Blind Treatment Period Week 6	2.92 score on a scale Standard Deviation 0.94	3.19 score on a scale Standard Deviation 0.95
Clinical Global Impressions-Improvement (CGI-I) Score at Each Trial Visit During the Double-Blind Treatment Period Week 8	2.80 score on a scale Standard Deviation 1.00	3.16 score on a scale Standard Deviation 1.01
Clinical Global Impressions-Improvement (CGI-I) Score at Each Trial Visit During the Double-Blind Treatment Period Week 10	2.62 score on a scale Standard Deviation 0.99	2.97 score on a scale Standard Deviation 1.00
Clinical Global Impressions-Improvement (CGI-I) Score at Each Trial Visit During the Double-Blind Treatment Period Week 12	2.66 score on a scale Standard Deviation 1.09	2.97 score on a scale Standard Deviation 1.12

SECONDARY outcome

Timeframe: Weeks 2, 4, 6, 8, 10, and 12

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.

Outcome measures

Outcome measures
Measure	Brexpiprazole 2 and 3 mg n=225 Participants Participants followed a titration schedule, to gradually increase their dose from 0.5 mg/day in the starting to 2 mg/day from Day 15 or from 0.5 mg/day in the starting to 3 mg/day from Day 29. Participants continued to receive brexpiprazole 2 or 3 mg, once daily until Week 12.	Placebo n=116 Participants Participants received matching placebo, once daily for 12 weeks.
CMAI Response Rate Assessed as Percentage of Participants With CMAI Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period >/= 20%: Week 2	11.3 percentage of participants	13.2 percentage of participants
CMAI Response Rate Assessed as Percentage of Participants With CMAI Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period >/= 20%: Week 4	29.3 percentage of participants	27.6 percentage of participants
CMAI Response Rate Assessed as Percentage of Participants With CMAI Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period >/= 20%: Week 6	43.1 percentage of participants	37.9 percentage of participants
CMAI Response Rate Assessed as Percentage of Participants With CMAI Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period >/= 20%: Week 8	59.6 percentage of participants	38.8 percentage of participants
CMAI Response Rate Assessed as Percentage of Participants With CMAI Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period >/= 20%: Week 10	65.8 percentage of participants	45.7 percentage of participants
CMAI Response Rate Assessed as Percentage of Participants With CMAI Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period >/= 20%: Week 12	68.4 percentage of participants	47.4 percentage of participants
CMAI Response Rate Assessed as Percentage of Participants With CMAI Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period >/= 30%: Week 2	3.62 percentage of participants	3.51 percentage of participants
CMAI Response Rate Assessed as Percentage of Participants With CMAI Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period >/= 30%: Week 4	10.7 percentage of participants	10.3 percentage of participants
CMAI Response Rate Assessed as Percentage of Participants With CMAI Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period >/= 30%: Week 6	22.7 percentage of participants	20.7 percentage of participants
CMAI Response Rate Assessed as Percentage of Participants With CMAI Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period >/= 30%: Week 8	32.9 percentage of participants	19.0 percentage of participants
CMAI Response Rate Assessed as Percentage of Participants With CMAI Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period >/= 30%: Week 10	38.2 percentage of participants	24.1 percentage of participants
CMAI Response Rate Assessed as Percentage of Participants With CMAI Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period >/= 30%: Week 12	42.7 percentage of participants	25.9 percentage of participants
CMAI Response Rate Assessed as Percentage of Participants With CMAI Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period >/= 40%: Week 2	1.81 percentage of participants	1.75 percentage of participants
CMAI Response Rate Assessed as Percentage of Participants With CMAI Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period >/= 40%: Week 4	4.89 percentage of participants	5.17 percentage of participants
CMAI Response Rate Assessed as Percentage of Participants With CMAI Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period >/= 40%: Week 6	10.7 percentage of participants	8.62 percentage of participants
CMAI Response Rate Assessed as Percentage of Participants With CMAI Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period >/= 40%: Week 8	16.9 percentage of participants	8.62 percentage of participants
CMAI Response Rate Assessed as Percentage of Participants With CMAI Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period >/= 40%: Week 10	20.9 percentage of participants	11.2 percentage of participants
CMAI Response Rate Assessed as Percentage of Participants With CMAI Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period >/= 40%: Week 12	23.1 percentage of participants	14.7 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Weeks 2, 4, 6, 8, 10, and 12

Outcome measures

Outcome measures
Measure	Brexpiprazole 2 and 3 mg n=225 Participants Participants followed a titration schedule, to gradually increase their dose from 0.5 mg/day in the starting to 2 mg/day from Day 15 or from 0.5 mg/day in the starting to 3 mg/day from Day 29. Participants continued to receive brexpiprazole 2 or 3 mg, once daily until Week 12.	Placebo n=116 Participants Participants received matching placebo, once daily for 12 weeks.
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 Week 2	8.14 percentage of participants	14.0 percentage of participants
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 Week 4	20.4 percentage of participants	19.0 percentage of participants
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 Week 6	33.8 percentage of participants	26.7 percentage of participants
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 Week 8	44.0 percentage of participants	31.0 percentage of participants
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 Week 10	50.2 percentage of participants	34.5 percentage of participants
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 Week 12	52.4 percentage of participants	37.1 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Weeks 2, 4, 6, 8, 10, and 12

Outcome measures

Outcome measures
Measure	Brexpiprazole 2 and 3 mg n=225 Participants Participants followed a titration schedule, to gradually increase their dose from 0.5 mg/day in the starting to 2 mg/day from Day 15 or from 0.5 mg/day in the starting to 3 mg/day from Day 29. Participants continued to receive brexpiprazole 2 or 3 mg, once daily until Week 12.	Placebo n=116 Participants Participants received matching placebo, once daily for 12 weeks.
CGI-I Response Rate Assessed as Percentage of Participants With CGI-I Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period Week 2	4.98 percentage of participants	5.26 percentage of participants
CGI-I Response Rate Assessed as Percentage of Participants With CGI-I Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period Week 4	21.8 percentage of participants	12.1 percentage of participants
CGI-I Response Rate Assessed as Percentage of Participants With CGI-I Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period Week 6	35.1 percentage of participants	23.3 percentage of participants
CGI-I Response Rate Assessed as Percentage of Participants With CGI-I Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period Week 8	44.4 percentage of participants	24.1 percentage of participants
CGI-I Response Rate Assessed as Percentage of Participants With CGI-I Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period Week 10	52.4 percentage of participants	33.6 percentage of participants
CGI-I Response Rate Assessed as Percentage of Participants With CGI-I Response at Every Scheduled Trial Visit in the Double-Blind Treatment Period Week 12	52.4 percentage of participants	40.5 percentage of participants

Adverse Events

Brexpiprazole 2 mg

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Brexpiprazole 3 mg

Serious events: 6 serious events

Other events: 10 other events

Deaths: 1 deaths

Placebo

Serious events: 3 serious events

Other events: 8 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Brexpiprazole 2 mg n=73 participants at risk Participants followed a titration schedule, to gradually increase their dose from 0.5 mg/day in the starting to 2 mg/day from Day 15. Participants continued to receive brexpiprazole 2 mg, once daily until Week 12.	Brexpiprazole 3 mg n=153 participants at risk 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.	Placebo n=116 participants at risk Participants received matching placebo, once daily for 12 weeks.
Cardiac disorders Cardiac failure	0.00% 0/73 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	0.65% 1/153 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	0.00% 0/116 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.
Infections and infestations Covid-19	0.00% 0/73 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	0.65% 1/153 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	0.00% 0/116 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.
Infections and infestations Pneumonia	0.00% 0/73 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	0.65% 1/153 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	0.00% 0/116 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.
Infections and infestations Urinary tract infection	0.00% 0/73 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	1.3% 2/153 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	0.00% 0/116 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.
Injury, poisoning and procedural complications Fall	0.00% 0/73 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	0.65% 1/153 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	0.00% 0/116 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.
Injury, poisoning and procedural complications Hip fracture	0.00% 0/73 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	0.65% 1/153 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	0.86% 1/116 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.
Investigations Sars-Cov-2 test positive	0.00% 0/73 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	0.00% 0/153 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	0.86% 1/116 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.
Metabolism and nutrition disorders Cachexia	0.00% 0/73 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	0.65% 1/153 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	0.00% 0/116 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.
Metabolism and nutrition disorders Dehydration	0.00% 0/73 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	0.65% 1/153 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	0.00% 0/116 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.
Metabolism and nutrition disorders Metabolic acidosis	0.00% 0/73 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	0.65% 1/153 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	0.00% 0/116 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.
Psychiatric disorders Mental status change	0.00% 0/73 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	0.65% 1/153 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	0.00% 0/116 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.
Psychiatric disorders Psychotic disorder	0.00% 0/73 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	0.00% 0/153 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	0.86% 1/116 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.
Renal and urinary disorders Acute kidney injury	0.00% 0/73 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	0.65% 1/153 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	0.00% 0/116 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.
Vascular disorders Hypertension	0.00% 0/73 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	0.65% 1/153 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	0.00% 0/116 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.

Other adverse events

Other adverse events
Measure	Brexpiprazole 2 mg n=73 participants at risk Participants followed a titration schedule, to gradually increase their dose from 0.5 mg/day in the starting to 2 mg/day from Day 15. Participants continued to receive brexpiprazole 2 mg, once daily until Week 12.	Brexpiprazole 3 mg n=153 participants at risk 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.	Placebo n=116 participants at risk Participants received matching placebo, once daily for 12 weeks.
Nervous system disorders Headache	6.8% 5/73 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	6.5% 10/153 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.	6.9% 8/116 • From signing of informed consent up to end of study (Week 16) Randomized Sample was used to assess all-cause mortality. It consisted of all participants who were randomized into this trial. Safety Sample was used to assess serious adverse events (SAEs) and other adverse events (AEs) and consisted of all participants who were administered at least one dose of IMP.

Additional Information

Director of Clinical Trials

Otsuka Pharmaceutical Co., LTD.

Phone: +81-3-6361-7366

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