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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
18
Arbaclofen Placarbil
Placebo matched tablets
Research Centers of America
Oakland Park, Florida, United States
Maximum Tolerated Dose (MTD) of Arbaclofen Placarbil
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.
Time frame: Up to 30 day residential (inpatient) treatment period
Maximum Observed Plasma Concentration of Arbaclofen Placarbil (AP) (Cmax)
Blood samples will be obtained and plasma concentrations determined using a validated liquid chromatography with tandem mass spectrometry methods
Time frame: 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
Time to Maximum Observed Plasma Concentration of Arbaclofen Placarbil (AP) (Tmax)
Blood samples will be obtained and plasma concentrations determined using a validated liquid chromatography with tandem mass spectrometry methods
Time frame: 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
Area Under the Concentration -Time Curve from time 0 to the time of the last quantifiable plasma concentration (AUClast)
Blood samples will be obtained and plasma concentrations determined using a validated liquid chromatography with tandem mass spectrometry methods
Time frame: 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
Area Under the Concentration -Time Curve from time 0 extrapolated to infinite time (AUCinf)
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Blood samples will be obtained and plasma concentrations determined using a validated liquid chromatography with tandem mass spectrometry methods
Time frame: 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
Area Under the Concentration -Time Curve from time 0 to 12 hours post dose(AUC0-12)
Blood samples will be obtained and plasma concentrations determined using a validated liquid chromatography with tandem mass spectrometry methods
Time frame: 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 Plasma Half-Life (t 1/2)
Blood samples will be obtained and plasma concentrations determined using a validated liquid chromatography with tandem mass spectrometry methods
Time frame: 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
Apparent Terminal Phase Rate Constant
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.
Time frame: 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
Percentage of AUCinf obtained by extrapolation (%AUCex)
If the extrapolated area is greater than 20% of AUCinf, then AUCinf will be listed but not included in summary presentations or statistical analyses
Time frame: 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 Oral Clearance (CL/F)
Calculated as Dose/AUCinf
Time frame: 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
Apparent Volume of Distribution (Vz/F)
Calculated as Dose/apparent terminal phase rate constant \* AUCinf
Time frame: 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
Area Under the Plasma Concentration-Time Curve From Time Zero To The End of Dosing Interval (AUCtau)
Area Under the Plasma Concentration-Time Curve From Time 0 to the End of the Dosing Interval
Time frame: 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
Minimum Observed Plasma Concentration (Cmin)
Blood samples will be obtained and plasma concentrations determined using a validated liquid chromatography with tandem mass spectrometry methods
Time frame: 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
Pre-Dose Plasma Concentration (Ctrough)
Blood samples will be obtained and plasma concentrations determined using a validated liquid chromatography with tandem mass spectrometry methods
Time frame: Prior to dose of AP on days 6, 12, 18, 19, 20, 21, 22, 23, and 24 hours post dose
The Number of Participants Who Experienced Serious or Non-Serious Adverse Events
A non-serious adverse event is any untoward medical occurrence. A serious adverse event is any adverse event that meets one or more of the following: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is a medically important event, as defined in the protocol
Time frame: Up to 11 weeks
Columbia Suicide Severity Rating Scale (C-SSRS)
All events of suicide-related behavior will be carefully monitored. These include emergence or significant worsening of reported suicidal ideation, plans, suicide attempts, and completed suicides. The C-SSRS will be used by the Investigator in the assessment of suicide risk.
Time frame: Up to 11 weeks
The Obsessive-Compulsive Drinking Scale (OCDS)
All continuous outcome measures including time to event endpoints collected will be summarized using descriptive statistics (n, mean, standard deviation (SD), median, min, and max). Categorial variables will be summarized using frequencies.
Time frame: Up to 11 weeks
Hospital Anxiety and Depression Scale (HADS)
The HADS is a 14-item scale that generates original data. Seven f the items relate to anxiety and 7 relate to depressive symptoms. Zigmond and Snaith created this outcome measure specifically to avoid reliance on aspects of these conditions that are also common somatic symptoms of illness; eg, fatigue, insomnia, or hypersomnia
Time frame: Up to 11 weeks
Alcohol Liver Biomarkers (Carbohydrate Deficient Transferrin and Gamma Glutamyl Transferase
Blood samples will be collected and sent to the central laboratory.
Time frame: Up to 11 weeks
Timeline Follow Back (TLFB) Interview for Cigarette and Alcohol Use
The TLFB interview is a method to assess recent alcohol use and will be administered by an interviewer to estimate retrospectively their alcohol use (frequency and number of drinks consumed)
Time frame: Up to 11 weeks
Short Inventory of Problems-Revised (SIP-R)
The SIP-R is a 17 item self-reported inventory of adverse consequences associated with drug and alcohol use developed by Blanchard (2003). The SIP instructs participants to indicate how often each of the listed consequences has occurred during the past month on a 4-point scale (0-3). Item responses are summed to produce a total score and 5 subscale scores
Time frame: Up to 11 weeks