PET Trial to Assess the Receptor Occupancy of Brexpiprazole in Adult Subjects With Schizophrenia

NCT01854944 | Completed Phase 1 Results

• 1 other identifier: 331-09-219
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to determine how low and high does of brexpiprazole binds to certain receptors in the brain. This will be determined by PET scans taken pre-dose and post-dose.

Conditions

Schizophrenia

Outcome Measures

Primary Outcomes (4)

• Change in Percentage Dopamine D2/D3 Receptor Occupancy

  Dopamine receptor occupancy measured using the radiotracer \[11C\]-(+)-PHNO in low and high dose. The binding of brexpiprazole to the D2/D3 receptors were assessed by comparing the binding potential from the Baseline scan (prior to treatment) to that of Day 10 (after treatment). The D2/D3 receptors following administration of a 1- and 4-mg doses of brexpiprazole were assessed and the occupancy estimates were averaged across brain regions 4 hours post-last dose on Day 10.

  Baseline to 4 hours post-last dose on Day 10

• Change in Percentage 5-HT1A Receptor Occupancy

  Mean (±SD) Serotonin 5-HT1A Receptor Occupancy Using the Radiotracer \[11C\]CUMI101 in high dose only. In cohorts 1, 2 and 3, the binding of brexpiprazole to the 5-HT1A receptors was assessed by comparing the binding potential from the Baseline scan (prior to treatment) to that of Day 10 (after treatment). The 5-HT1A receptors following administration of a 4-mg dose of brexpiprazole was assessed and the occupancy estimates were averaged across brain regions 4 hours post-last dose on Day 10.

  Baseline to 4 hours post-last dose on Day 10

• Change in Percentage 5-HT2A Receptor Occupancy

  Mean (±SD) Serotonin 5-HT2A Receptor Occupancy Using the Radiotracer \[11C\]MDL100907 (in low and high dose). The 5-HT2A receptors following administration of 1- and 4-mg doses of brexpiprazole were assessed and the occupancy estimates were averaged across brain regions 4 hours post-last dose on Day 10.

  Baseline and 4 hours post-last dose on Day 10

• Change in Occupancy at Serotonin Transporter (SERT)

  Mean (±SD) SERT Occupancy Using the Radiotracer \[11C\]DASB in high dose only. Occupancy estimates were averaged across brain regions 4 hours post-last dose.

  Baseline to 4 hours post-last dose on Day 10

Secondary Outcomes (13)

• Area Under the Concentration-time Curve (AUCτ) During a Dosing Interval at Steady-state for Brexpiprazole and Its Metabolite DM-3411

  Baseline to Day 10

• Peak (Maximal) Concentration of Drug in Plasma (Cmax) for Brexpiprazole and Its Metabolite DM-3411

  Baseline to Day 10

• Apparent Clearance of Drug From Plasma After Extravascular Administration (CL/F; Only Brexpiprazole)

  Baseline to Day 10

• Time to Maximum (Peak) Plasma Concentration (Tmax) for Brexpiprazole and Its Metabolite DM-3411

  Baseline to Day 10

• Mean Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Score

  Baseline to Day 6, 11 and Last Visit

Study Arms (1)

Brexpiprazole 1mg to 4mg

EXPERIMENTAL

Three cohorts of subjects will be evaluated: \- Cohorts 1 and 3 will receive high doses of brexpiprazole, and Cohort 2 will receive low doses of brexpiprazole.

Drug: Brexpiprazole 1mg to 4mg

Interventions

Brexpiprazole 1mg to 4mg DRUG

Also known as: Brexpiprazole

Brexpiprazole 1mg to 4mg

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• A diagnosis of Schizophrenia.
• Ability to provide written informed consent.
• Ability to understand the protocol and meet the protocol requirements.
• Must be in good physical health determined by ECG and laboratory values, medical history and physical examinations.
• Has stable disease, defined as meeting all of the following criteria: A CGI-S score \<= 4 (moderately ill); A PANSS total score \<= 60; A score of \<= 4 (moderate) on any of the following PANSS items: (P7 (hostility); G8 (uncooperativeness)).
• Body mass index of 19 to 35 kg/m2

You may not qualify if:

• Sexually active males and females of childbearing potential who are not practicing double-barrier birth control, or who will not remain abstinent, during the trial and for 30 days following the last dose of trial medication. If employing birth control, 2 of the following precautions must be used: vasectomy, partner who uses hormonal contraception, tubal ligation, vaginal diaphragm, nonhormonal intrauterine device, condom, or sponge with spermicide.
• Females who are pregnant or lactating. A negative serum pregnancy test must be confirmed prior to the first dose of trial medication for all female subjects.
• Subjects presenting with a first episode of schizophrenia based on the clinical judgment of the investigator.
• Subjects who have received continuous medication therapy to treat schizophrenia for less than 6 months prior to the drug-free interval.
• Subjects with schizophrenia who are considered resistant/refractory to antipsychotic treatment by history, who have a history of failure to clozapine, or who are responsive only to clozapine treatment.
• Subjects with a current DSM-IV-TR Axis I diagnosis other than schizophrenia including MDD, bipolar disorder, delirium, dementia, amnestic, or other cognitive disorders or subjects with borderline, paranoid, histrionic, schizotypal, schizoid, or antisocial personality disorder.
• Subjects who, in the opinion of the investigator, cannot be rated reliably on the battery of movement rating scales required by the protocol.
• Subjects with a significant risk of violent behavior, a significant risk of committing suicide based on history or investigator's judgment, or who have attempted suicide within 2 years of cohort assignment.
• Subjects with clinically significant tardive dyskinesia at enrollment.
• Subjects who experience clinical deterioration during the drug-free interval, such that they require prohibited rescue therapy, will not meet the trial criteria and will be replaced.
• Subjects who experienced an acute exacerbation requiring hospitalization within 3 months prior to the Screening Visit or between the Screening and Baseline Visits.
• Subjects who experienced an acute exacerbation requiring change in antipsychotic medication (with reference to drug or dose) within the last 4 weeks prior to baseline.
• Subjects who have a history of myocardial infarction, hypertension, or diabetes or who have evidence of other medical conditions that would expose them to an undue risk of a significant AE or interfere with assessments of safety or efficacy during the course of the trial, including, but not limited to, hepatic, renal, respiratory, cardiovascular, endocrine, neurologic, hematologic, or immunologic disease. The medical monitor must be contacted to discuss any such condition prior to cohort assignment.
• Subjects who have any of the following neurologic diagnoses, whether under treatment or not, whether stable or not: migraine, epilepsy, Parkinson's disease, Alzheimer's disease, multiple sclerosis, residual of stroke, transient cerebral ischemic attacks, cerebral palsy, or any condition that requires intermittent or maintenance treatment or which is manifested by any abnormality on neurologic examination. A subject with tardive dyskinesia or other nonclinically significant symptoms of EPS due solely to the current or prior use of antipsychotic medications is not excluded by this criterion. Single-nerve peripheral palsies are also not excluded by this criterion: eg, Bell's palsy or radial-nerve palsy or fixed residuals from traumatic injury.
• History of or current hepatitis or acquired immunodeficiency syndrome or carriers of HBsAg and/or anti-HCV or HIV antibodies.

Sponsors & Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.: lead

Study Sites (1)

Columbia University

New York, New York, 10032, United States

Location

Related Publications (1)

• Girgis RR, Forbes A, Abi-Dargham A, Slifstein M. A positron emission tomography occupancy study of brexpiprazole at dopamine D2 and D3 and serotonin 5-HT1A and 5-HT2A receptors, and serotonin reuptake transporters in subjects with schizophrenia. Neuropsychopharmacology. 2020 Apr;45(5):786-792. doi: 10.1038/s41386-019-0590-6. Epub 2019 Dec 17.

  PMID: 31847007 DERIVED

MeSH Terms

Conditions

Schizophrenia

Interventions

brexpiprazole

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders

Results Point of Contact

• Title: Global Medical Affairs
• Organization: Otsuka Pharmaceutical Development and Commercialization, Inc.

800 562-3974

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 7, 2013
• First Posted: May 16, 2013
• Study Start: September 1, 2013
• Primary Completion: July 1, 2014
• Study Completion: August 1, 2014
• Last Updated: February 4, 2016
• Results First Posted: February 4, 2016

Record last verified: 2016-01

Locations

US (1)