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

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01922258
• Collaborator: H. Lundbeck A/S (Industry)
• Enrollment: 270
• Locations: 71
• Arms: 2
• Actual Duration (Months): 42
• Patients Per Site: 3.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Agitation Associated With; Alzheimer's Disease; Alzheimer's Type; Mental Disorder; Nervous System Diseases	Drug: Brexpiprazole, OPC-34712	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 270 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, 12-week, Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy, Safety, and Tolerability of Flexible Dosing of Brexpiprazole (OPC-34712) in the Treatment of Subjects With Agitation Associated With Dementia of the Alzheimer's Type
• Actual Study Start Date: Sep 1, 2013
• Actual Primary Completion Date: Mar 1, 2017
• Actual Study Completion Date: Mar 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Matching Placebo Once-Daily	Drug: Brexpiprazole, OPC-34712; Flexible dose of 0.5 to 2 mg/day or placebo tablets for up to 12 weeks
Experimental: Brexpiprazole (flexible dose range 0.5 to 2 mg) 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.	Drug: Brexpiprazole, OPC-34712; Flexible dose of 0.5 to 2 mg/day or placebo tablets for up to 12 weeks

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 55 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Imperial	California	United States	92251
2		Lakewood	California	United States	08755
3		Long Beach	California	United States	90806
4		Long Beach	California	United States	90822
5		Panorama City	California	United States	91402
6		Universal City	California	United States	91950
7		Denver	Colorado	United States	80209
8		Bradenton	Florida	United States	34205
9		Miami	Florida	United States	33142
10		Miami	Florida	United States	33165
11		Miami	Florida	United States	33176
12		Orange City	Florida	United States	32763
13		Atlanta	Georgia	United States	30331
14		Smyrna	Georgia	United States	30080
15		Honolulu	Hawaii	United States	96817
16		Indianapolis	Indiana	United States	46256
17		Quincy	Massachusetts	United States	02169
18		South Dartmouth	Massachusetts	United States	02747
19		Ann Arbor	Michigan	United States	48105
20		Brooklyn	New York	United States	11214
21		Buffalo	New York	United States	14215
22		New Hyde Park	New York	United States	11040
23		Charlotte	North Carolina	United States	28270
24		Raleigh	North Carolina	United States	27609
25		Austin	Texas	United States	78757
26		Dallas	Texas	United States	75231
27		Dallas	Texas	United States	75243
28		Woodstock	Vermont	United States	05091
29		Burgas		Bulgaria	8000
30		Kardzhali		Bulgaria	6600
31		Pazardzhik		Bulgaria	4400
32		Ruse		Bulgaria	7003
33		Sofia		Bulgaria	1113
34		Sofia		Bulgaria	1154
35		Sofia		Bulgaria	1431
36		Varna		Bulgaria	9020
37		Veliko Tarnovo		Bulgaria	5000
38		Penticton	British Columbia	Canada	V2A 4M4
39		Kentville		Canada	B4N 4K9
40		Kuopio		Finland	70210
41		Turku		Finland	20520
42		Bourg en Bresse		France	01012
43		Douai		France	59500
44		Elancourt		France	78990
45		Limoges		France	87042
46		Nice		France	06100
47		Toulouse		France	31059
48		Tonnel'nyy	Stavropol Region	Russian Federation	357034
49		Ekaterinburg		Russian Federation	620030
50		Saratov		Russian Federation	410060
51		St. Petersburg		Russian Federation	188820
52		St. Petersburg		Russian Federation	190005
53		St. Petersburg		Russian Federation	195176
54		St. Petersburg		Russian Federation	197341
55		Ljubljana		Slovenia	1000
56		Maribor		Slovenia	2000
57		Sempeter pri Gorici		Slovenia	5290
58		Donetsk		Ukraine	83037
59		Kharkiv		Ukraine	61068
60		Kharkov		Ukraine	61068
61		Kherson		Ukraine	73488
62		Kiev		Ukraine	04080
63		Kiev		Ukraine	04114
64		Lviv		Ukraine	79021
65		Poltava		Ukraine	36013
66		Simferopol		Ukraine	95006
67		Vinnytsia		Ukraine	21005
68		Crewe		United Kingdom	CW1 2ER
69		Manchester		United Kingdom	M8 5RB
70		Margate		United Kingdom	CT20 1JY
71		Torpoint		United Kingdom	PL11 2TB

Sponsors and Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.
• H. Lundbeck A/S

Investigators

• Study Director: Eva Koheygi, MD, Otsuka Pharmaceutical Development and Commercialization, Inc.

Study Documents (Full-Text)

• Study Protocol - Sep 10, 2015
• Statistical Analysis Plan - Mar 22, 2017

More Information

Publications

None provided.

• Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
• ClinicalTrials.gov Identifier: NCT01922258
• Other Study ID Numbers: 331-12-284
• First Posted: Aug 14, 2013
• Last Update Posted: Nov 20, 2020
• Last Verified: Nov 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.: OPC-34712; brexpiprazole; Dementia; Alzheimer's Disease; Cognitive Disorders; Agitation
• Additional relevant MeSH terms: Alzheimer Disease; Dementia; Psychomotor Agitation; Nervous System Diseases; Mental Disorders; Brexpiprazole

Study Results

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 Detail	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.

Arm/Group Title	Brexpiprazole (Flexible Dose Range 0.5 to 2 mg/Day)	Placebo (Flexible Dose Range 0.5 to 2 mg/Day)
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	133	137
COMPLETED	117	121
NOT COMPLETED	16	16

Baseline Characteristics

Arm/Group Title	Brexpiprazole (Flexible Dose Range 0.5 to 2 mg/Day)	Placebo (Flexible Dose Range 0.5 to 2 mg/Day)	Total
Arm/Group Description	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.	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 of all reporting groups
Overall Participants	133	137	270
Age, Customized (Count of Participants)
<65 years	24 18%	19 13.9%	43 15.9%
>=65 <75 years	46 34.6%	49 35.8%	95 35.2%
>=75 years	63 47.4%	69 50.4%	132 48.9%
Sex: Female, Male (Count of Participants)
Female	82 61.7%	88 64.2%	170 63%
Male	51 38.3%	49 35.8%	100 37%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	3 2.2%	3 1.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	4 3%	5 3.6%	9 3.3%
White	128 96.2%	129 94.2%	257 95.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 0.8%	0 0%	1 0.4%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Week 12/Early Termination in the Cohen-Mansfield Agitation Inventory (CMAI) Total Score
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Brexpiprazole (Flexible Dose Range 0.5 to 2 mg/Day)	Placebo (Flexible Dose Range 0.5 to 2 mg/Day)
Arm/Group Description	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.	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.
Measure Participants	131	135
Least Squares Mean (Standard Error) [units on a scale]	-18.9 (1.17)	-16.5 (1.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Brexpiprazole (Flexible Dose Range 0.5 to 2 mg/Day), Placebo (Flexible Dose Range 0.5 to 2 mg/Day)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.1454
	Comments
	Method	Mixed-effect model repeated measure
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-2.34
	Confidence Interval	(2-Sided) 95%; -5.49 to 0.82
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in the Clinical Global Impression Severity of Illness (CGI-S) Score, as Related to Symptoms of Agitation
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Brexpiprazole (Flexible Dose Range 0.5 to 2 mg/Day)	Placebo (Flexible Dose Range 0.5 to 2 mg/Day)
Arm/Group Description	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.	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.
Measure Participants	131	135
Mean (Standard Deviation) [units on a scale]	4.54 (0.77)	4.51 (0.74)

Adverse Events

Time Frame	Through the trial: From screening to Week 12 and 30 (+2) days follow-up period.
Adverse Event Reporting Description	Only participants who received at least 1 dose of investigational medical product were analyzed for safety (Brexpiprazole N=132).
Arm/Group Title	Brexpiprazole (Flexible Dose Range 0.5 to 2 mg/Day)		Placebo (Flexible Dose Range 0.5 to 2 mg/Day)
Arm/Group Description	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.		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.
All Cause Mortality
	Brexpiprazole (Flexible Dose Range 0.5 to 2 mg/Day)		Placebo (Flexible Dose Range 0.5 to 2 mg/Day)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/132 (0%)		1/137 (0.7%)
Serious Adverse Events
	Brexpiprazole (Flexible Dose Range 0.5 to 2 mg/Day)		Placebo (Flexible Dose Range 0.5 to 2 mg/Day)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/132 (5.3%)		6/137 (4.4%)
Gastrointestinal disorders
Gastrointestinal haemorrhage	0/132 (0%)		1/137 (0.7%)
General disorders
Non-Cardiac Chest Pain	1/132 (0.8%)		0/137 (0%)
Infections and infestations
Pneumonia	1/132 (0.8%)		1/137 (0.7%)
Injury, poisoning and procedural complications
Femur Fracture	0/132 (0%)		1/137 (0.7%)
Hip Fracture	0/132 (0%)		1/137 (0.7%)
Subdural haematoma	1/132 (0.8%)		0/137 (0%)
Metabolism and nutrition disorders
Dehydration	0/132 (0%)		1/137 (0.7%)
Failure to thrive	0/132 (0%)		1/137 (0.7%)
Nervous system disorders
Loss of consciousness	1/132 (0.8%)		0/137 (0%)
Presyncope	1/132 (0.8%)		0/137 (0%)
Seizure	2/132 (1.5%)		0/137 (0%)
Syncope	0/132 (0%)		1/137 (0.7%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea Exertional	1/132 (0.8%)		0/137 (0%)
Vascular disorders
Hypertensive crisis	1/132 (0.8%)		0/137 (0%)
Other (Not Including Serious) Adverse Events
	Brexpiprazole (Flexible Dose Range 0.5 to 2 mg/Day)		Placebo (Flexible Dose Range 0.5 to 2 mg/Day)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/132 (18.2%)		29/137 (21.2%)
Nervous system disorders
Somnolence	8/132 (6.1%)		5/137 (3.6%)
Dizziness	6/132 (4.5%)		7/137 (5.1%)
Headache	10/132 (7.6%)		17/137 (12.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.