A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study to Determine the Maximum Tolerated Dose of Arbaclofen Placarbil in Subjects With Alcohol Use Disorder
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Maximum Tolerated Dose (MTD) of Arbaclofen Placarbil
研究概览
简要总结
This study will determine the maximum tolerated dose (MTD) of arbaclofen placarbil (AP) in the treatment of subjects with Alcohol Use Disorder (AUD). For every two subjects receiving AP, one subject will receive placebo.
详细描述
This is a randomized, double-blind, placebo-controlled dose-escalation study to determine the MTD of AP in subjects with AUD. Eighteen (18) subjects will be randomized to receive either AP or placebo in a 2:1 ratio; ie, 12 subjects will be assigned to AP and 6 will be assigned to placebo. Efforts will be made to enroll all subjects in the same period of time at one clinical center. The expected maximum duration of participation for each subject is 11 weeks and will consist of up to a 3-week screening period, up to a 30-day residential (inpatient) treatment period, up to a 4-week non-residential (outpatient) treatment period, and an end of study / early termination clinic visit.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •18 to 65 years of age.
- •Diagnosis of AUD confirmed by the Mini-International Neuropsychiatric Interview.
- •For those requiring medical detoxification from alcohol, subjects will be required to have completed a program for detoxification from alcohol within 4 days prior to screening.
- •Provide written informed consent prior to any study-specific procedures.
- •Self-report of at least 2 heavy drinking days per week in each of the 4 weeks prior to the screening interview.
- •Willing to abstain from drinking for the time he/she is participating in the study.
- •Able to identify at least 1 "locator" person to assist study staff in tracking the subject for the non-residential clinic days.
- •Able to read, speak, and understand English and be willing to cooperate with study procedures.
- •For female subjects, women of childbearing potential must have a negative pregnancy test prior to enrollment and must agree to use a medically acceptable means of contraception from screening through at least 3 months after the last dose of IMP. Male subjects with female partners of childbearing potential must agree to use medically acceptable contraception from informed consent through at least 3 months after the last dose of IMP. Male subjects must also agree not to donate sperm during the study and for 3 months after receiving the last dose of IMP (Investigational Medicinal Product).
排除标准
- •Has present symptoms or history of any of the following disorders:
- •Schizophrenia
- •Schizoaffective Disorder
- •Delusional Disorder
- •Bipolar I Disorder
- •Any mood disorder with psychotic features or any psychotic disorder
- •Anorexia Nervosa
- •Bulimia Nervosa
- •Post-Traumatic Stress Disorder that could interfere with the study
- •Any Personality Disorder that could interfere with the study
- •Current diagnosis of any substance use disorder, except for nicotine, cannabis (mild or moderate), or alcohol.
- •Positive result for any prohibited medication.
- •History of suicidal ideation within 30 days prior to providing written informed consent.
- •History of seizures or delirium tremens.
- •Intention to initiate or continue additional formal alcohol-related treatment, including pharmacotherapy, during the active treatment period.
- •Have had inpatient treatment for a non-alcohol substance use disorder in the 12 weeks prior to informed consent.
- •Total bilirubin >1.5× the upper limit of normal (ULN), alanine aminotransferase (ALT) >3×ULN, aspartate aminotransferase (AST) >3×ULN, serum creatinine >2×ULN, international normalized ratio (INR) >1.5×ULN, lipase >3×ULN, amylase >3×ULN, or any abnormal pancreatic enzyme value above ULN that is associated with clinically significant active pancreatic disorder.
- •Creatinine clearance of <80 mL/min, as calculated according to the Cockcroft-Gault equation.
- •Hemoglobin at screening of <11.5 g/dL (for females) or <12.5 g/dL (for males).
- •Body mass index (BMI) >
- •Diagnosed with unstable medical disorders that could increase the potential risk of study treatment or interfere with study participation, including the following:
- •Abnormal cardiac conditions, including:
- •Uncontrolled hypertension.
- •History of myocardial infarction in the last year or any prior history of myocardial infarction with active complication.
- •Syncopal event within the past year.
- •Congestive heart failure.
- •Angina pectoris.
- •QTcF (QT Fridericia-corrected) ≥450 msec for males and ≥470 msec for females at screening or randomization.
- •Clinically significant abnormal finding on the physical exam or 12-lead ECG.
- •Diabetes mellitus (type 1 or 2) fulfilling any of the following criteria:
- •Glycosylated hemoglobin (HbA1c) >7.5% at screening.
- •Uncontrolled diabetes mellitus.
- •Have any other clinically significant abnormal laboratory result
- •Must not have donated blood or have had any therapeutic phlebotomy (in an amount >300 mL) or received blood transfusion within 90 days preceding enrollment.
- •Must not have a history of surgical procedures involving the brain or meninges, encephalitis, meningitis, degenerative central nervous system disorder (eg, Alzheimer's or Parkinson's Disease), epilepsy, mental retardation, or any other disease/procedure/accident/intervention associated with significant injury to or malfunction of the central nervous system (CNS), or a history of significant head trauma within the past 2 years, or currently receiving anticonvulsant therapy for any reason.
- •Must not have acquired immunodeficiency syndrome (AIDS).
- •Have any other active medical condition or organ disease that may either compromise subject safety or interfere with the safety and/or outcome evaluation of the IMP.
- •History or presence of allergic or adverse response (including rash or anaphylaxis) to baclofen or any ingredient of the IMP.
- •Have used baclofen within 30 days prior to informed consent.
- •Taking medications which may be expected to significantly interfere with the metabolism or excretion of AP, may be associated with a significant drug interaction with AP, or may pose a significant risk to the subject's participation in the study.
- •Participation in an interventional clinical study within 30 days prior to informed consent.
- •Use of exclusionary drugs (e.g. antipsychotics, anticonvulsants, benzodiazepines, naltrexone, acamprosate).
- •Site staff or subjects affiliated with, or a family member of, site staff directly involved in the study.
- •Be unable to comply fully with the study requirements.
研究组 & 干预措施
Arbaclofen Placarbil (AP)
Orally administered Arbaclofen Placarbil (AP) sustained release (SR) tablets
干预措施: Arbaclofen Placarbil (Drug)
Placebo
Subjects remain on placebo for entire study
干预措施: Placebo (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD) of Arbaclofen Placarbil
时间窗: Up to 30 day residential (inpatient) treatment period
A data monitoring committee (DMC) will review and make a recommendation to stop dosing escalation based on the review of the unblinded AE and safety assessments or when at least one subject on active investigational product experiences an SAE related to the investigational product. The MTD and the dosage that will not be exceeded in the further development of this compound will be based upon a comprehensive review of the safety data.
Maximum Observed Plasma Concentration of Arbaclofen Placarbil (AP) (Cmax)
时间窗: Prior to the initial dose of AP on day 1 and 0.5, 1, 2, 3, 4, 5, 6, 7, 8,10, 12, 16, 20, and 24 hours post-dose (predose day 2); and prior to dose of AP on days 6, 12, 18, and 24 and 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 hours post dose
Blood samples will be obtained and plasma concentrations determined using a validated liquid chromatography with tandem mass spectrometry methods
Time to Maximum Observed Plasma Concentration of Arbaclofen Placarbil (AP) (Tmax)
时间窗: Prior to the initial dose of AP on day 1 and 0.5, 1, 2, 3, 4, 5, 6, 7, 8,10, 12, 16, 20, and 24 hours post-dose (predose day 2); and prior to dose of AP on days 6, 12, 18, and 24 and 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 hours post dose
Blood samples will be obtained and plasma concentrations determined using a validated liquid chromatography with tandem mass spectrometry methods
Area Under the Concentration -Time Curve from time 0 to the time of the last quantifiable plasma concentration (AUClast)
时间窗: Prior to the initial dose of AP on day 1 and 0.5, 1, 2, 3, 4, 5, 6, 7, 8,10, 12, 16, 20 hours post dose
Blood samples will be obtained and plasma concentrations determined using a validated liquid chromatography with tandem mass spectrometry methods
Area Under the Concentration -Time Curve from time 0 extrapolated to infinite time (AUCinf)
时间窗: Prior to the initial dose of AP on day 1 and 0.5, 1, 2, 3, 4, 5, 6, 7, 8,10, 12, 16, 20 hours post dose
Blood samples will be obtained and plasma concentrations determined using a validated liquid chromatography with tandem mass spectrometry methods
Area Under the Concentration -Time Curve from time 0 to 12 hours post dose(AUC0-12)
时间窗: Prior to the initial dose of AP on day 1 and 0.5, 1, 2, 3, 4, 5, 6, 7, 8,10, 12, 16, 20 hours post dose
Blood samples will be obtained and plasma concentrations determined using a validated liquid chromatography with tandem mass spectrometry methods
Apparent Terminal Phase Rate Constant
时间窗: Prior to the initial dose of AP on day 1 and 0.5, 1, 2, 3, 4, 5, 6, 7, 8,10, 12, 16, 20 hours post dose
Apparent terminal rate constant (1/h), determined by linear regression of the terminal points of the log-linear concentration-time curve. Visual assessment will be used to identify the terminal linear phase of the concentration-time profile. A minimum of 3 data points will be used for determination.
Percentage of AUCinf obtained by extrapolation (%AUCex)
时间窗: Prior to the initial dose of AP on day 1 and 0.5, 1, 2, 3, 4, 5, 6, 7, 8,10, 12, 16, 20 hours post dose
If the extrapolated area is greater than 20% of AUCinf, then AUCinf will be listed but not included in summary presentations or statistical analyses
Apparent Terminal Plasma Half-Life (t 1/2)
时间窗: Prior to the initial dose of AP on day 1 and 0.5, 1, 2, 3, 4, 5, 6, 7, 8,10, 12, 16, 20 hours post
Blood samples will be obtained and plasma concentrations determined using a validated liquid chromatography with tandem mass spectrometry methods
Apparent Oral Clearance (CL/F)
时间窗: Prior to the initial dose of AP on day 1, 6, 12, 18, 24 and 0.5, 1, 2, 3, 4, 5, 6, 7, 8,10, 12, 16, 20 hours post dose
Calculated as Dose/AUCinf
Apparent Volume of Distribution (Vz/F)
时间窗: Prior to the initial dose of AP on day 1 and 0.5, 1, 2, 3, 4, 5, 6, 7, 8,10, 12, 16, 20 hours post dose
Calculated as Dose/apparent terminal phase rate constant \* AUCinf
Area Under the Plasma Concentration-Time Curve From Time Zero To The End of Dosing Interval (AUCtau)
时间窗: Prior to dose of AP on days 6, 12, 18, and 24 and 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 hours post dose
Area Under the Plasma Concentration-Time Curve From Time 0 to the End of the Dosing Interval
Minimum Observed Plasma Concentration (Cmin)
时间窗: Prior to dose of AP on days 6, 12, 18, and 24 and 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 hours post dose
Blood samples will be obtained and plasma concentrations determined using a validated liquid chromatography with tandem mass spectrometry methods
Pre-Dose Plasma Concentration (Ctrough)
时间窗: Prior to dose of AP on days 6, 12, 18, 19, 20, 21, 22, 23, and 24 hours post dose
Blood samples will be obtained and plasma concentrations determined using a validated liquid chromatography with tandem mass spectrometry methods
次要结局
- The Obsessive-Compulsive Drinking Scale (OCDS)(Up to 11 weeks)
- Timeline Follow Back (TLFB) Interview for Cigarette and Alcohol Use(Up to 11 weeks)
- Short Inventory of Problems-Revised (SIP-R)(Up to 11 weeks)
- The Number of Participants Who Experienced Serious or Non-Serious Adverse Events(Up to 11 weeks)
- Columbia Suicide Severity Rating Scale (C-SSRS)(Up to 11 weeks)
- Hospital Anxiety and Depression Scale (HADS)(Up to 11 weeks)
- Alcohol Liver Biomarkers (Carbohydrate Deficient Transferrin and Gamma Glutamyl Transferase(Up to 11 weeks)