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

Exclusion Criteria

• •1. 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
• •2. Current diagnosis of any substance use disorder, except for nicotine, cannabis (mild or moderate), or alcohol.
• •3. Positive result for any prohibited medication.
• •4. History of suicidal ideation within 30 days prior to providing written informed consent.
• •5. History of seizures or delirium tremens.
• •6. Intention to initiate or continue additional formal alcohol-related treatment, including pharmacotherapy, during the active treatment period.
• •7. Have had inpatient treatment for a non-alcohol substance use disorder in the 12 weeks prior to informed consent.
• •8. 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.
• •9. Creatinine clearance of \<80 mL/min, as calculated according to the Cockcroft-Gault equation.
• •10. Hemoglobin at screening of \<11.5 g/dL (for females) or \<12.5 g/dL (for males).
• •11. Body mass index (BMI) \>30.
• •12. Diagnosed with unstable medical disorders that could increase the potential risk of study treatment or interfere with study participation, including the following:
• •1. 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.
• •2. Diabetes mellitus (type 1 or 2) fulfilling any of the following criteria:
• •* Glycosylated hemoglobin (HbA1c) \>7.5% at screening.
• •* Uncontrolled diabetes mellitus.
• •13. Have any other clinically significant abnormal laboratory result
• •14. 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.
• •15. 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.
• •16. Must not have acquired immunodeficiency syndrome (AIDS).
• •17. 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.
• •18. History or presence of allergic or adverse response (including rash or anaphylaxis) to baclofen or any ingredient of the IMP.
• •19. Have used baclofen within 30 days prior to informed consent.
• •20. 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.
• •21. Participation in an interventional clinical study within 30 days prior to informed consent.
• •22. Use of exclusionary drugs (e.g. antipsychotics, anticonvulsants, benzodiazepines, naltrexone, acamprosate).
• •23. Site staff or subjects affiliated with, or a family member of, site staff directly involved in the study.
• •24. Be unable to comply fully with the study requirements.