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A multi-center, open-label clinical pharmacology trial to investigate the pharmacokinetics, tolerability, and safety of brexpiprazole once-weekly (QW) formulation administered as single and multiple oral doses in patients with schizophrenia

A clinical pharmacology trial of brexpiprazole once-weekly (QW) formulation administered as single and multiple oral doses

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In Cohort 1, of the 38 enrolled subjects, 22 subjects completed the trial (completed Period 3). In Period 1, 4 (10.5%) of 38 subjects were terminated from the trial by the sponsor. In Period 2, 11 (32.4%) of 34 subjects were discontinued from the trial for the following reasons: AEs (low blood pressure for 1 subject and extrapyramidal symptoms for another subject), withdrawal by 1 subject (concerned about severe acute respiratory syndrome coronavirus [SARS-CoV-2] pandemic, also known as coronavirus disease 2019 [COVID-19]), investigator decision (1 subject might have been infected with SARS-CoV-2), and 7 subjects were terminated from the trial by the sponsor. In Period 3, 1 (4.3%) of 23 subjects was discontinued for vomiting within 12 hours after receiving the 48 mg QW formulation. In Cohort 2, of the 35 enrolled subjects, 32 subjects completed the trial (completed Period 2). In Period 1, 1 (2.9%) of 35 subjects withdrew (difficult to continue hospitalization). In Period 2, 2 (5.9%) of 34 subjects were discontinued from the trial for the following reasons: subject withdrew from the trial due to feeling burdened by the examinations and another was discontinued due to an AE (creatine phosphokinase increase).

A single dose of 48 mg of brexpiprazole QW formulation resulted in 1 serious adverse event ([SAE] schizophrenia). Severe adverse events of extrapyramidal symptoms occurred in a single dose of 24 mg of brexpiprazole QW formulation and schizophrenia (SAE) occurred in a single dose of 48 mg. Adverse events were frequently mild or moderate in severity. Compared to the safety profile of conventional tablets of brexpiprazole, overall, there were no safety concerns associated with the 24 mg and 48 mg brexpiprazole QW formulations administered.

The median tmax of the 2 mg conventional tablet was 4.00 hours, and the median tmax of the 24 mg and 48 mg QW formulations were 25.37 and 25.00 hours, respectively, indicating that the median tmax of the QW formulation was longer than that of the conventional tablet. The mean Cmax of the QW formulation increased dose-dependently between the 24 mg and 48 mg QW formulations. The results for OPC-34712 plasma trough concentration indicated that steady state was reached by the fourth administration of the 48 mg QW formulation in Period 2.

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The median tmax of the QW formulation at each dose was longer than that of the conventional tablet in Cohort 1. OPC-34712 plasma concentration for the 48 mg QW formulation reached steady state by the fourth administration in Cohort 2. Overall, the brexpiprazole QW formulations were considered safe and well tolerated as single and repeated oral dose administrations in subjects with schizophrenia.

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.

Otsuka Pharmaceutical Co., LTD.

CL_OPCJ_RDA_Team@otsuka.jp

Otsuka Pharmaceutical Co., LTD.

+81-3-6361-7314

completed

Oct. 17, 2019

Interventional

A multi-center, open-label clinical pharmacology trial to investigate the PK, tolerability, and safety of brexpiprazole QW formulation administered as single and multiple doses. The trial comprises the single-dose period (Cohort 1) and the multiple-dose period (Cohort 2). The dose used in the multiple-dose period (Cohort 2) will be determined based on plasma drug concentrations obtained in the single-dose period (Cohort 1).

other

1

1)Patients with a diagnosis of schizophrenia based on the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5)
2)Patients capable of staying at the trial site from the day before investigational medicinal product (IMP) administration to the 8th day following IMP administration in both Period 1 and Period 2
3)Patients with a body mass index [BMI = body weight (kg)/height (m)2] of 18.5 or higher and lower than 35.0 at screening
4)Persons who provide written informed consent before commencement of any trial-related procedures and whom the investigator or subinvestigator judges to be capable of following all the conditions of this trial
6)Patients who, in the judgement of the investigator or subinvestigator, have stable psychotic symptoms maintained by administration of an antipsychotic (other than clozapine) within the dosing range indicated separately, before commencement of investigational medicinal product (IMP) administration

1)Patients with a diagnosis of a concurrent mental disorder besides schizophrenia (schizoaffective disorder, major depressive disorder, bipolar I disorder, bipolar II disorder, general anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, dementia or mild neurocognitive disorder, personality disorder, etc) based on the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) (However, this exclusion does not apply to caffeine- or tobacco-related disorders)
2)Patients who fail to meet the specified requisite washout periods for the prohibited concomitant drugs and foods before commencement of IMP administration, or patients who are anticipated to take any of these drugs or foods during the study period
3)Patients who have previously undergone gastrointestinal surgery that could affect pharmacokinetic evaluations
4)Patients who are using clozapine at the time of informed consent
5)Patients who have received electro-convulsive therapy within 60 days before commencement of IMP administration
6)Patients with clinically problematic disorders of the nervous system, liver, kidneys, metabolic system, blood, immune system, cardiovascular system, lungs, or digestive system (However, such patients may be included if the condition is mild or well-controlled and is considered to not affect safety or pharmacokinetic evaluations.)

Both

Schizophrenia

investigational material(s)
Generic name etc : Brexpiprazole
INN of investigational material : -
Therapeutic category code : 117 Psychotropic agents
Dosage and Administration for Investigational material : In each cohort, subjects will receive a brexpiprazole 2 mg conventional tablet on Day 1of Period 1, the QW formulation on Day 1 of Period 2 and 3, as single and multiple dose in a fasted state.

control material(s)
Generic name etc : -
INN of investigational material : -
Therapeutic category code :
Dosage and Administration for Investigational material : -

pharmacokinetics
Plasma concentrations and PK parameters of brexpiprazole after single and multiple doses of QW formulation

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+81-3-3917-6561

July. 17, 2019