A Dose-Escalation Study to Determine the Maximum Tolerated Dose of Arbaclofen Placarbil in Subjects With Alcohol Use Disorder

NCT02511886 | Completed Phase 2 DMC FDA Drug

• 1 other identifier: RB-US-14-0001
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

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.

Conditions

Alcohol Use Disorder

Keywords

Alcoholism; Alcohol Abuse; Alcohol Addiction; Alcohol Dependence; Alcohol Induced Disorders; Alcoholic Intoxication

Outcome Measures

Primary Outcomes (14)

• 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.

  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

  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

  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

  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)

  Blood samples will be obtained and plasma concentrations determined using a validated liquid chromatography with tandem mass spectrometry methods

  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

  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

  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.

  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

  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

  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

  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

  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

  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

  Prior to dose of AP on days 6, 12, 18, 19, 20, 21, 22, 23, and 24 hours post dose

Secondary Outcomes (7)

• 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

• The Obsessive-Compulsive Drinking Scale (OCDS)

  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

Study Arms (2)

Arbaclofen Placarbil (AP)

EXPERIMENTAL

Orally administered Arbaclofen Placarbil (AP) sustained release (SR) tablets

Drug: Arbaclofen Placarbil

Placebo

PLACEBO COMPARATOR

Subjects remain on placebo for entire study

Drug: Placebo

Interventions

Arbaclofen Placarbil DRUG

Arbaclofen Placarbil

Arbaclofen Placarbil (AP)

Placebo DRUG

Placebo matched tablets

Also known as: Sugar Pill

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Indivior Inc.: lead

Study Sites (1)

Research Centers of America

Oakland Park, Florida, 33334, United States

Location

MeSH Terms

Conditions

Alcoholism; Alcohol-Induced Disorders; Alcoholic Intoxication

Interventions

arbaclofen placarbil; Sugars

Condition Hierarchy (Ancestors)

Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Carbohydrates

Study Officials

• Global Clinical Development Manager

  Indivior Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 24, 2015
• First Posted: July 30, 2015
• Study Start: September 1, 2015
• Primary Completion: January 1, 2016
• Study Completion: January 1, 2016
• Last Updated: January 23, 2017

Record last verified: 2017-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)