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A phase 2/3 multicenter, placebo-controlled, randomized, double-blind, parallel-group comparison trial to evaluate the efficacy and safety of Brexpiprazole (OPC-34712) in the treatment of patients with agitation associated with dementia of the Alzheimer's type

Brexpiprazole for the treatment of patients with agitation associated with dementia of the Alzheimer's type

410

The demographic and other baseline characteristics of subjects did not differ significantly between the brexpiprazole 1mg, brexpiprazole 2mg, and placebo groups. The mean age overall was 80.1 years (age range: 59 to 90 years), with subjects aged 75 years or older accounting for the highest percentage at 81.9%, subjects aged 65 years or older and less than 75 years accounting for 14.4%, and subjects aged less than 65 years accounting for 3.7%. In regard to sex, the percentage of women (63.8%) was greater than that of men (36.2%).

A total of 410 subjects who were judged to be eligible at the screening examination were randomized, comprising 112 subjects in the brexpiprazole 1mg group, 149 subjects in the brexpiprazole 2mg group, and 149 subjects in the placebo group. All randomized subjects received the IMP, and the percentage of subjects who completed IMP treatment was 74.1% (83 of 112 subjects) in the brexpiprazole 1mg group, 68.5% (102 of 149 subjects) in the brexpiprazole 2mg group, and 77.9% (116 of 149 subjects) in the placebo group.

The incidence of TEAEs was 76.8% (86 of 112 subjects) in the brexpiprazole 1mg group, 84.6% (126 of 149 subjects) in the brexpiprazole 2mg group, and 73.8% (110 of 149 subjects) in the placebo group. Treatment-emergent adverse events that occurred in 5% or more in either brexpiprazole group were somnolence, bradykinesia, insomnia, salivary hypersecretion, muscle rigidity, gait disturbance, fall, pyrexia, sedation complication, contusion, decreased appetite,skin abrasion, back pain, and dystonia. Among them, TEAEs with an incidence in either brexpiprazole group that was at least double that in the placebo group were somnolence (8.0% [9 of 112 subjects] in the brexpiprazole 1mg group, 16.1% [24 of 149 subjects] in the brexpiprazole 2mg group, and 2.0% [3 of 149 subjects] in the placebo group; data are presented in the same order hereinafter), bradykinesia (7.1% [8 of 112 subjects], 13.4% [20 of 149 subjects], 0.0% [0 of 149 subjects]), salivary hypersecretion (0.9% [1 of 112 subjects], 12.1% [18 of 149 subjects], and 0.7% [1 of 149 subjects]), muscle rigidity (8.0% [9 of 112 subjects], 10.7% [16 of 149 subjects], and 0.7% [1 of 149 subjects]), gait disturbance (4.5% [5 of 112 subjects], 10.1% [15 of 149 subjects], and 0.7% [1 of 149 subjects]), sedation complication (2.7% [3 of 112 subjects], 7.4% [11 of 149 subjects], and 1.3% [2 of 149 subjects]), decreased appetite (6.3% [7 of 112 subjects], 5.4% [8 of 149 subjects], and 0.7% [1 of 149 subjects]), back pain (5.4% [6 of 112 subjects], 4.0% [6 of 149 subjects], and 2.0% [3 of 149 subjects]), and dystonia (6.3% [7 of 112 subjects], 2.7% [4 of 149 subjects], and 0.7% [1 of 149 subjects]). Most TEAEs were mild or moderate in severity. Subjects in the brexpiprazole 1mg group died due to TEAEs that occurred during the trial period. The TEAEs resulting in death were cardiac death and pneumonia aspiration, which were both assessed as not related to the IMP. The incidence of serious TEAEs was 6.3% (7 of 112 subjects) in the brexpiprazole 1mg group, 6.0% (9 of 149 subjects) in the brexpiprazole 2mg group, and 4.7% (7 of 149 subjects) in the placebo group. Serious TEAEs that occurred in 2 or more subjects in either brexpiprazole group were pneumonia aspiration, which occurred in 2 of 112 subjects (1.8%) in the brexpiprazole 1mg group and 2 of 149 subjects (1.3%) in the brexpiprazole 2mg group.

Both the brexpiprazole 1mg and 2mg groups showed a statistically significant improvement in the primary endpoint, change in CMAI total score from baseline to Week 10, compared with the placebo group (LS mean difference between the brexpiprazole 1mg and placebo groups = -3.7 [95% confidence interval: -6.8, -0.7], p = 0.0175; LS mean difference between the brexpiprazole 2mg and placebo groups = -7.2 [95% confidence interval: -10.0, -4.3], p < 0.0001).

The results of the secondary endpoints (CGI-S score, CGI-I score) showed a similar trend to that of the primary endpoint and supported the result of the primary endpoint.

This trial in which patients with agitation associated with dementia of the Alzheimer's type received brexpiprazole at doses of 1 and 2 mg once daily for 10 weeks demonstrated the efficacy of brexpiprazole 1 and 2 mg for agitation associated with dementia of the Alzheimer's type. Brexpiprazole administered at 1 and 2 mg once daily for 10 weeks raised no major safety concerns and both doses were well tolerated.

Yes

Anonymized Individual participant data (IPD) that underlie the results of this study will be shared with researchers to achieve aims pre-specified in a methodologically sound research proposal. Supporting Materials: Study Protocol and Statistical Analysis Plan (SAP) Data will be available after marketing approval in global markets, or beginning 1-3 years following article Publication. There is no end date to the availability of the data. Otsuka will share data on an Otsuka-owned remotely accessible data sharing platform with Python and R analytical software. Research requests should be directed to clinicaltransparency@Otsuka-us.com.

Matsumaru Takehisa

Otsuka Pharmaceutical Co., LTD.

3-2-27, Otedori, Chuo-ku, Osaka, Japan

CL_OPCJ_RDA_Team@otsuka.jp

Otsuka Pharmaceutical Co., LTD.

2-16-4, Konan, Minato-ku, Tokyo, Japan

+81-3-6361-7314

opc_ctr@otsuka.jp

completed

Aug. 20, 2018

Interventional

Multicenter, Randomized, Double-blind, Placebo-controlled Trial

treatment purpose

2-3

1. Patients who satisfy both of the following diagnostic criteria:
- Diagnosis of "Dementia due to Alzheimer's Disease" according to DSM-5.
- Diagnosis of "Probable Alzheimer's Disease" according to NINCDS-ADRDA.
2. Hospitalized patients or care facility patients or care at home patients
3. Patients with an MMSE score of 1 to 22
4. Patients who have the agitation defind according to the "Consensus provisional definition of agitation in cognitive disorders" from the International Psychogeriatric Association (IPA)

1. Patients who have dementia other than dementia of the Alzheimer's type
2. Patients diagnosed with delirium between 30 days before the screening examination and baseline evaluation according to DSM-5.
3. Patients diagnosed with any of the following disorders according to DSM-5:
- Schizophrenia spectrum and other psychotic disorders
- Bipolar and related disorders
- Major depressive disorder

Both

Agitation Associated With Dementia of the Alzheimer's Type

investigational material(s)
Generic name etc : Brexpiprazole (1mg,2mg)
INN of investigational material : Brexpiprazole
Therapeutic category code : 117 Psychotropic agents
Dosage and Administration for Investigational material : Once daily for 10 weeks

control material(s)
Generic name etc : Placebo
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : Once daily for 10 weeks

efficacy
Cohen-Mansfield Agitation Inventory(CMAI)
Change from baseline at 10 weeks

efficacy
Clinical Global Impression-Severity of Illness(CGI-S), Clinical Global Impression-Global Improvement(CGI-I)
Change from baseline(CGI-S) at 10 weeks,score at10 weeks(CGI-I)

+81-3-6804-2227

July. 02, 2018