Open Label Pilot Study of Perampanel for the Treatment of Alcohol Use Disorder

Participants will be asked to take a medication (Perampanel or Perampanel + Disulfiram) every day for approximately 8 weeks and have weekly study visits. At these visits, participants will be asked questions about their medical history, drinking behavior and life events, have bloodwork checked routinely, have regular medication counseling, and perform some computer tasks. Throughout the study, there will be regular phone calls from staff. Participants will also be asked to use a device called "Soberlink" which is like an at-home breathalyzer test to help track progress throughout the study.

Participants will be randomly assigned (like the flip of a coin) to receive either Perampanel alone or Peramanel and Disulfiram.

Participation in this study will last up to 10 weeks. Approximately 20 individuals will participate in this study.

This study will sequence all or part of participant's DNA. This is a necessary part of the study.

Before starting the study, participants may be referred to an alcohol detoxification program (medical treatment of an alcoholic), if clinically indicated.

• Perampanel Tablet (Drug): Subjects will be titrated over 3 weeks to a target dose of 8mg perampanel daily in both groups
• Disulfiram (Drug): Disulfiram will be kept at 250mg daily

Primary outcomes

• Percent Abstinent Days [End of treatment, up to 12 weeks]: Participant will report the number of alcoholic drinks they consumed during the previous weeks period. Participants will be accessed for the full 12 week titration plus treatment period. However, for the purposes of the study, the percent of days the participant was abstinent will be calculated and reported only for the 8 week active treatment period.

Secondary outcomes

• Change in Alcohol Craving [Baseline to end of treatment, up to 12 weeks]: Alcohol craving will be assessed using the Alcohol Urge Questionnaire (AUG). The AUG is an 8-item survey asking participants to rate their craving for alcohol on a 1 to 7 scale. The answers are summed yielding a score ranging from 7 to 56 with higher scores indicated higher alcohol craving.
• Percent Heavy Drinking Days [End of treatment, Up to 8 weeks]: Participant will report the number of alcoholic drinks they consumed during the previous weeks period. Based on participant report, the percent of days the participant drank heavily will be calculated over the 8 week active treatment period.

Sex: All, ages: 21 Years to 70 Years

Inclusion Criteria:

1. Men and women ages 21-70 with DSM-5 AUD;
2. regular heavy drinkers as defined by averaging ≥ 2 heavy drinking days per week over the 60 days baseline pre-treatment TLFB, and recognize a need to completely stop drinking;
3. willingness to provide written, informed consent to participate in the study;
4. Individuals with LFTs that are no more than 2-3 times above the normal levels and with a Child-Pugh score of no greater than 5 will be included and
5. women of child-bearing potential (i.e., no hysterectomy, bilateral oophorectomy, or tubal ligation or <2 years postmenopausal), must be non-lactating, practicing a reliable method of birth control, and have a negative serum pregnancy test prior to initiation of treatment.

Exclusion Criteria:

1. a current, clinically significant physical disease \[i.e., neurologic, renal, pulmonary, cardiovascular, hepatic\] on the basis of medical history, physical examination, or routine laboratory evaluation that, in the context of the study would represent a risk to the subject, or significant laboratory abnormalities related to hepatic function such as marked elevations of hepatic aminotransferase levels (i.e., AST and ALT) or direct bilirubin;
2. history of renal compromise or current renal disease (as evidenced by serum creatinine above our laboratory's reference limit of 1.7 mg/dL;
3. history of seizure disorder;
4. use of any of a number of medications that might prominently influence drinking patterns or cause risk of harm or injury (e.g., other anticonvulsants, medications to treat AUD, opioid pain medication), currently taking CNS depressants (e.g. benzodiazepines, barbiturates, sedating antihistamines;
5. schizophrenia, bipolar disorder, current major depressive episode, or substantial suicide or violence risk on the basis of history or psychiatric examination;
6. currently dependent on stimulants, opioids or sedatives;
7. subjects with any substantial alcohol withdrawal will be required to be detoxified by regular clinical services prior to study entry;
8. are currently taking any medication that is a moderate to strong CYP3A4 inhibitor or inducer if participants are required to initiate these medications by an outside provider during the course of this study, they will be tapered off the study regimen and we will have them terminate early)
9. are taking phenytoin or warfarin

Participant flow

Outcome results

• Percent Abstinent Days (Primary), Mean, Percentage of days: Perampanel by Itself 3.13 (0 to 6.25); Perapanel With Disulfiram 100 (100 to 100)
• Change in Alcohol Craving (Secondary), Mean, score on a scale: Perampanel by Itself 4 (2 to 6); Perapanel With Disulfiram -1 (-2 to 0)
• Percent Heavy Drinking Days (Secondary), Mean, percentage of days: Perampanel by Itself 73.60 (65.6 to 81.6); Perapanel With Disulfiram 0 (0 to 0)

Adverse events

Time frame: At baseline and weekly for eight weeks

Serious adverse events by term

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2021-06-30)
• Informed Consent Form (PDF, 2021-08-10)

• Albert Arias, MD, PhD, Principal investigator, Virginia Commonwealth University

NIH grants: R21AA026681