NCT01854944已完成1 期
PET Trial to Assess the Receptor Occupancy of Brexpiprazole in Adult Subjects With Schizophrenia
Otsuka Pharmaceutical Development & Commercialization, Inc.1 个研究点 分布在 1 个国家目标入组 12 人开始时间: 2013年9月最近更新:
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Change in Percentage 5-HT1A Receptor Occupancy
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
- •Subjects with a history of thyroid pathology (unless the condition has been stabilized with medications for at least the past 3 months) and/or abnormal thyroid laboratory results.
- •Subjects with a history of neuroleptic malignant syndrome.
- •Subjects with a history of seizure disorder.
- •Subjects who meet DSM-IV-TR criteria for substance dependence within 6 months prior to cohort assignment (excluding caffeine and nicotine), including alcohol and benzodiazepines, and/or a positive alcohol (breath or urine) test or a positive urine screen for drugs of abuse. (In the case where a subject had a positive screen for stimulants and/or marijuana and was therefore excluded, the medical monitor should be contacted to determine if rescreening is an option.)
- •Subjects who had any major surgery, any blood transfusion, or donated blood or plasma within 30 days prior to enrollment.
- •The following laboratory test, vital sign, and ECG results are exclusionary:
- •Platelets <= 75,000/mm3
- •Hemoglobin <= 9 g/dL
- •Neutrophils, absolute <= 1000/mm3
- •AST > 2 times upper limit of normal
- •ALT > 2 times upper limit of normal
- •Creatinine >= 2 mg/dL
- •Subjects with electrolytes outside of the normal range will not be enrolled in the trial without prior review and approval from the medical monitor.
- •Subjects who have sitting (performed first) or supine blood pressure, after resting for >= 3 minutes, higher than 140/90 mmHg or lower than 100/50 mmHg. Upon standing from the supine position, subjects who have a fall in systolic blood pressure >= 20 mmHg or a fall in diastolic blood pressure >= 10 mm Hg after 1 to 3 minutes in the standing position. (Any repeated out-of-range values not deemed clinically significant need to be discussed with the medical monitor to determine eligibility.)
- •Subjects who have a supine pulse rate, after resting for >= 3 minutes, outside the range of 40 to 90 bpm.
- •Subjects with any ECG abnormality at Screening, prior to dosing, will be excluded, including but not limited to, a PR interval > 220 msec, QRS interval > 110 msec, QTc > 450 msec, QTcF > 450 msec, QTcB > 450 msec or the increase in QTcB is considered significant by the investigator, abnormal U waves, or other minor ST-T wave changes which are considered clinically significant.
- •Prohibited concomitant medications/therapies used for the following time period prior to Day -1 and for the duration of the trial include:
- •Antipsychotics
- •Use of oral antipsychotics within 21 days prior to Day -1;
- •Use of long-acting injectable antipsychotics within 6 months.
- •Anxiolytics and Sleep Aids
- •Regular use of benzodiazepines for 2 weeks (lorazepam [<= 6 mg daily up to 48 hours prior to PK and PD assessments] can be used as rescue therapy during the 21 days prior to Day -1 and [<= 4 mg daily up to 48 hours prior to PK and PD assessments or up to 24 hours prior to the completion of the EPS rating scales or C-SSRS] during the treatment period).
- •Mood Stabilizers
- •Use of lamotrigine within 14 days.
- •Selective Serotonin Reuptake Inhibitors
- •Use of Prozac within 28 days;
- •Use of Paxil within 14 days;
- •Use of Zoloft, Luvox, or Celexa within 7 days.
- •Serotonin and Norepinephrine Reuptake Inhibitors
- •Use of Effexor within 3 days;
- •Use of duloxetine within 14 days.
- •Use of Symbyax within 28 days;
- •Use of CYP2D6 or CYP3A4 inhibitors or CYP3A4 inducers within 14 days;
- •Use of electroconvulsive therapy within 2 months.
- •Use and discontinuation of any other therapy (prescription medication, over-the counter, herbal medication, or vitamins) not listed above must be approved by the sponsor and the medical monitor.
- 另有 17 项未显示
研究组 & 干预措施
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.
干预措施: Brexpiprazole 1mg to 4mg (Drug)
结局指标
主要结局
Change in Percentage 5-HT1A Receptor Occupancy
时间窗: Baseline to 4 hours post-last dose on Day 10
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.
Change in Percentage Dopamine D2/D3 Receptor Occupancy
时间窗: Baseline to 4 hours post-last dose on Day 10
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.
Change in Percentage 5-HT2A Receptor Occupancy
时间窗: Baseline and 4 hours post-last dose on Day 10
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.
Change in Occupancy at Serotonin Transporter (SERT)
时间窗: Baseline to 4 hours post-last dose on Day 10
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.
次要结局
- 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)
- 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)
- Mean Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Score(Baseline to Day 6, 11 and Last Visit)
- Mean Change From Baseline in Positive and Negative Symptom Scale (PANSS) Total Score(Baseline to Day 6, 11 and Last Visit)
- Mean Change From Baseline in Clinical Global Impression-Improvement (CGI-I) Score(Baseline to Day 6, 11 and Last Visit)
- Mean Change From Baseline in PANSS Negative Subscale Score(Baseline to Day 6, 11 and Last Visit)
- Mean Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score(Baseline to Day 6, 11 and Last Visit)
- Mean Change From Baseline in Simpson-Angus Scale (SAS) Total Score(Baseline to Day 6, 11 and Last Visit)
- Mean Change From Baseline in PANNS Positive Subscale Score(Baseline to Day 6, 11 and Last Visit)
- Mean Change From Baseline in Barnes Akathisia Rating Scale (BARS) Score(Baseline to Day 6, 11 and Last Visit)
- Percentage of Participants Who Reported at Least One Occurrence of Suicidality, Suicidal Behavior and Suicidal Ideation on the Columbia-Suicide Severity Rating Scale (C-SSRS)(Baseline to Last Visit)
研究者
研究点 (1)
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