A Pharmacogenetic Human Laboratory Investigation of Brexpiprazole in Alcohol Use Disorder
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 250
- 试验地点
- 2
- 主要终点
- Number of drinks consumed in natural environment
研究概览
简要总结
Few medications are currently Food & Drug Administration (FDA)-approved for the treatment of Alcohol Use Disorder (AUD), and those that are have, on average, modest effects on drinking. "Precision medicine" research has explored whether patient-level variables, such as genetic variation, may identify subgroups of individuals with larger medication effects, but few findings have been replicated. A promising novel medication for AUD is brexpiprazole (BREX), a serotonin/dopamine activity modulator (SDAM). The investigators conducted a prior study in which the effects of another SDAM, aripiprazole, were influenced by genetic variation in the gene encoding the dopamine transporter (DAT1). This study will evaluate the effects of two doses of BREX, relative to placebo, among non-treatment-seeking individuals with AUD, and will test whether DAT1 genotype influences these effects. Primary outcomes are drinking under natural conditions and in a laboratory paradigm. Functional magnetic resonance imaging (fMRI) will be used to explore whether BREX effects on brain activation associated with cognitive control or elicited by alcohol cues accounts for its effects on drinking. The investigators hypothesize that BREX, relative to placebo, will reduce drinking under natural conditions and in the lab, and will do so to a greater extent among individuals who carry the DAT1 9-repeat allele, relative to those homozygous for the 10-repeat allele. If these hypotheses are supported, BREX may represent a novel pharmacogenetic treatment for AUD.
详细描述
The overarching hypothesis of this study is that brexpiprazole (BREX) (2 or 4 mg/day), relative to placebo, will reduce alcohol consumption and modulate the neural substrates of moderate-severe Alcohol Use Disorder (AUD), and that genotype at a variable number tandem repeat polymorphism (VNTR) in the DAT1/SLC6A3 gene will predict BREX effects. Participants will be non-treatment-seeking AUD individuals, and will be prospectively randomized to medication on the basis of their DAT1 VNTR genotype. Since BREX affects both cortical and striatal neurophysiology, the investigators will use functional magnetic resonance imaging (fMRI) to test its effects on cortical (right inferior frontal gyrus; rIFG) activation associated with response inhibition and on striatal activation elicited by alcohol cues, and will explore whether either of these measures mediates BREX effects on drinking in the natural environment vs. a bar-lab setting, which may reflect different aspects of lost control over drinking.
Aim 1: Test BREX effects on inhibition-related cortical activation and alcohol cue-elicited striatal activation, and evaluate whether DAT1 VNTR genotype predicts these effects.
Hypothesis 1: There will be a linear effect of BREX dose, relative to placebo, in increasing inhibition-related rIFG activation and reducing cue-elicited ventral striatum (VS) activation, and these effects will be greater among DAT1 9R carriers than 10R homozygotes.
Aim 2: Test BREX effects on drinking in the natural environment and alcohol self-administration in the bar lab, and evaluate whether DAT1 VNTR genotype predicts these effects.
Hypothesis 2: There will be a linear effect of BREX dose, relative to placebo, in reducing natural drinking and alcohol self-administration, and these effects will be greater among DAT1 9R carriers.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Participants will be blind to medication assignment, as will all care providers and investigators.
入排标准
- 年龄范围
- 21 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Meet DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th edition) diagnostic criteria for AUD, as assessed by the Structured Clinical Interview for DSM-5 (SCID-5).
- •Currently not engaged in, and does not want treatment for, AUD.
- •Currently not taking any medication for AUD.
- •Able to read and understand questionnaires and informed consent.
- •Lives within 50 miles of the study site.
- •Physically healthy with no history of significant medical illness.
- •Negative urine drug screen (UDS) for all substances of abuse prior to taking the first dose of medication.
- •Please contact clinical site for additional inclusion criteria.
排除标准
- •Refusal of valid written consent.
- •Insufficient English skills for consenting or interviews.
- •Severe claustrophobia or morbid obesity that preclude placement in the MRI scanner.
- •Contraindications to MRI scanning, ferrous metal in the body including intracranial, intraorbital, or intraspinal metal, pacemakers, cochlear implants or other non-MRI-compatible devices.
- •History of head injury with loss of consciousness for more than 2 minutes, neurological illness, or history of neurosurgical procedures.
- •Current DSM-5 diagnosis of any other substance use disorder except Nicotine Use Disorder.
- •Current DSM-5 psychotic, mood, anxiety, obsessive-compulsive, trauma-related, or eating disorder, as assessed by SCID-
- •Current suicidal ideation or homicidal ideation.
- •Current use of any psychoactive medication, as evidenced by self-report and UDS.
- •History of severe alcohol withdrawal (e.g., seizure, delirium tremens), as evidenced by self-report and assessment with Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar).
- •Clinically significant medical problems such as cardiovascular, renal, gastrointestinal, or endocrine problems, as evidenced by medical history and physical exam.
- •Past alcohol-related medical illness, such as gastrointestinal bleeding, pancreatitis, or peptic ulcer.
- •Current or past hepatocellular disease, as indicated by verbal report or elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 3 times the upper limit of the normal range at screening.
- •Females of childbearing potential who are pregnant (by plasma or urine HCG), nursing, or who are not using a reliable form of contraception.
- •Current charges pending for a violent crime (not including DUI-related offenses).
- •Currently incarcerated.
- •Lack of a stable living situation.
- •History of head injury with loss of consciousness for more than 2 minutes, neurological illness, or history of neurosurgical procedures.
- •Decisionally challenged.
研究组 & 干预措施
Placebo
Participants in this Arm will take a medically inert placebo. To ensure pill equivalence between groups, tablets will be packaged in the same capsule; thus, each participant will take one capsule per day. Participants will be instructed to ingest the capsule orally each morning.
干预措施: Placebo (Drug)
BREX 4mg
The BREX 4mg group will start at the same dose as the BREX 2mg group and titrate up at the same rate, so the BREX 4mg Arm will take .5 mg of brexpiprazole on day 1-2, 1 mg on day 3-4, 2mg on day 5-6, and 4mg on day 7 to reach its final 4mg dose for days 7-14. To ensure pill equivalence between groups, tablets will be packaged in the same capsule; thus, each participant will take one capsule per day. Participants will be instructed to ingest the medication orally each morning.
干预措施: Brexpiprazole (Drug)
BREX 2mg
The BREX 2mg group will start at the same dose at the BREX 4mg group and titrate up at the same rate, so the BREX 2mg Arm will take .5 mg of brexpiprazole on day 1-2, 1 mg on day 3-4, and 2mg on day 5, to reach its final 2mg dose for day 5-14. To ensure pill equivalence between groups, tablets will be packaged in the same capsule; thus, each participant will take one capsule per day. Participants will be instructed to ingest the medication orally each morning.
干预措施: Brexpiprazole (Drug)
结局指标
主要结局
Number of drinks consumed in natural environment
时间窗: First 13 days of medication period
The number of standard alcoholic drinks participants consume during the first 13 days of the medication period, as reported on the Timeline Follow-Back Interview.
Number of drinks consumed in bar lab
时间窗: Day 14 of medication period
The number of drinks (out of 8 possible) that participants choose to consume in the bar lab.
Change in alcohol cue-elicited brain activation (fMRI)
时间窗: 14 days - change between baseline and day 14 scan.
Magnitude of change between baseline and day 14 fMRI scan in the blood oxygenation level dependent (BOLD) signal to alcohol cues, relative to neutral beverage cues on the Alcohol Cue Reactivity Task.
次要结局
未报告次要终点