A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study to Determine the Maximum Tolerated Dose of Arbaclofen Placarbil in Subjects With Alcohol Use Disorder
Overview
- Phase
- Phase 2
- Intervention
- Arbaclofen Placarbil
- Conditions
- Alcohol Use Disorder
- Sponsor
- Indivior Inc.
- Enrollment
- 18
- Locations
- 1
- Primary Endpoint
- Maximum Tolerated Dose (MTD) of Arbaclofen Placarbil
- Status
- Completed
- Last Updated
- 9 years ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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).
Exclusion Criteria
- •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
Arms & Interventions
Arbaclofen Placarbil (AP)
Orally administered Arbaclofen Placarbil (AP) sustained release (SR) tablets
Intervention: Arbaclofen Placarbil
Placebo
Subjects remain on placebo for entire study
Intervention: Placebo
Outcomes
Primary Outcomes
Maximum Tolerated Dose (MTD) of Arbaclofen Placarbil
Time Frame: 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)
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
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)
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
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)
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
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)
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
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)
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
Blood samples will be obtained and plasma concentrations determined using a validated liquid chromatography with tandem mass spectrometry methods
Apparent Terminal Phase Rate Constant
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 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)
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
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)
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
Blood samples will be obtained and plasma concentrations determined using a validated liquid chromatography with tandem mass spectrometry methods
Apparent Oral Clearance (CL/F)
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
Calculated as Dose/AUCinf
Apparent Volume of Distribution (Vz/F)
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
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)
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
Area Under the Plasma Concentration-Time Curve From Time 0 to the End of the Dosing Interval
Minimum Observed Plasma Concentration (Cmin)
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
Blood samples will be obtained and plasma concentrations determined using a validated liquid chromatography with tandem mass spectrometry methods
Pre-Dose Plasma Concentration (Ctrough)
Time Frame: 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
Secondary Outcomes
- 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)