Clinical trial NCT04502589
Conditions: Alcohol Disorders
Sponsor: Virginia Commonwealth University
Start date: 2020-10-15; Completion date: 2021-08-11
Enrollment: 4 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this research study is to test the safety, tolerability, and effectiveness of the drug Perampanel when used in persons who drink and wish to stop drinking. Perampanel has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of seizures but has not yet been approved to treat alcohol use disorders. For this reason, it is considered an investigational drug. Some people in this study will receive Perampanel alone and some people will receive Perampanel and Disulfiram, this will be determined by the pharmacy.

Detailed description:
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.

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Perampanel Tablet intervention 2: Disulfiram
Intervention descriptions: intervention 1: Subjects will be titrated over 3 weeks to a target dose of 8mg perampanel daily in both groups intervention 2: Disulfiram will be kept at 250mg daily

Protocol documents:
ICF_000.pdf: 
 
 
Title: Open Label Pilot Study of Perampanel for the Treatment of Alcohol Use 
Disorder 
 
NCT #: NCT04502589 
 
Document date: August 10, 2021 (approval date) 
 
Document Type: Informed Consent Form 
 
 
 


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RESEARCH PARTICIPANT INFORMATION AND CONSENT FORM
STUDY TITLE: Open Label Pilot Study of Perampanel for the Treatment of Alcohol Use 
Disorder
VCU INVESTIGATOR: Albert  J. Arias, MD (203) 800-1928
SPONSOR: National Institute on Alcohol Abuse and Alcoholism/ NIH/ DHHS
ABOUT THIS CONSENT FORM
You are being invited to participate in a research study. It is important that you 
carefully think about whether being in this study is right for you and your 
situation.
This consent form is meant to assist you in thinking about whether or not you want to be 
in this study. Please ask the study doctor or the study staff to explain any 
information in this consent document that is not clear to you. You may take home 
an unsigned copy of this consent form to think about or discuss with family or friends 
before making your decision.
Your participation is voluntary. You may decide not to participate in this study. If you do 
participate, you may withdraw from the study at any time. Your decision not to take part 
or to withdraw will involve no penalty or loss of benefits to which you are otherwise 
entitled. 
AN OVERVIEW OF THE STUDY AND KEY INFORMATION
Why is this study being done?
The purpose of this research study is to test the safety, tolerability, and effectiveness of 
the drug Perampanel when used in persons who drink and wish to stop drinking. 
Perampanel has been approved by the U.S. Food and Drug Administration (FDA) for 
the treatment of seizures but has not yet been approved to treat alcohol use disorders.  
For this reason, it is considered an investigational drug. Some people in this study will 
receive Perampanel alone and some people will receive Perampanel and Disulfiram, 
this will be determined by the pharmacy. 
What will happen if I participate?
In this study, you 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, you will be asked questions about your medical history, drinking behavior and life 
events, have bloodwork checked routinely, have regular medication counseling, and 
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perform some computer tasks.  Throughout the study, there will be regular phone calls 
from staff. You will also be asked to use a device called “Soberlink” which is like an at-
home breathalyzer test to help track your progress throughout the study.
You will be randomly assigned (like the flip of a coin) to receive either Perampanel 
alone or Peramanel and Disulfiram. You have an equal chance of being assigned to any 
one of the groups.
Your participation in this study will last up to 10 weeks. Approximately 20 individuals will 
participate in this study. 
This study will use your samples to sequence all or part of your DNA. This is a 
necessary part of the study and if you do not want to have your blood taken for a DNA 
sample, then you will not be able to participate in this study.
Deoxyribonucleic acid (DNA) is the “blueprint” or “recipe” that gives the body’s cells 
instructions on how to do their jobs. Scientists can use a test called whole genome 
sequencing to determine the order of all or part of the molecules that make up your 
DNA, like reading all the letters in a book. Sequencing is usually done to look for 
changes in the molecules of DNA that may cause health problems.  
Before starting the study, you may be referred to an alcohol detoxification program 
(medical treatment of an alcoholic), if clinically indicated. You should NOT be taking any 
other alcohol treatment medications such as Disulfiram, Acamprosate or Naltrexone at 
the time of study enrollment.
What alternative treatments or procedures are available?
This is not a treatment study, it is a clinical trial of a medication that is not currently 
approved to treat people who want to stop drinking.  
If you decide not to enter this study and want to seek treatment to help you stop drinking 
alcohol, staff will give you resources on local programs or offices where you can get 
help.  If you are interested in being treated with just Disulfiram or other medications 
approved to help people stop drinking, we can help you find resources for treatment.  
You can receive the usual care that you would receive even if you were not in the study. 
This includes being treated by a physician with other approved medications to help 
people stop drinking. The study doctor will discuss these options with you. You do not 
have to participate in this study to be treated for alcohol use.
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What are the risks and benefits of participating?
There are both risks and benefits of participating in research studies. We want you to 
know about a few key risks right now. We will give you more information in the “WHAT 
RISKS AND DISCOMFORTS CAN I EXPECT FROM BEING IN THE STUDY?” section.
Risks and Discomforts
Benefits to You and Others
 
. There is a risk that study drug may not 
be as good as the usual approach for 
treating alcohol dependence or alcohol 
use disorder. 
. There is also a risk that you could have 
side effects from taking a study drug. 
Below are some of the most common 
side effects:
Dizziness, Headache
Mood changes (irritability, aggression)
Nausea or abdominal pain 
Fatigue or change in memory
Change in ability to balance which may 
result in decreased coordination, or falls
Rash or bruising
Drowsiness that could impair ability to 
drive or operate heavy machinery
There may be some risks that the study 
doctors do not know about yet, so we 
will let you know of any new findings. 
Blood draws may cause pain, bleeding, 
and/or bruising. You may faint and 
could develop an infection at the site 
where blood is drawn. 
The study questionnaires ask questions 
that are personal and sensitive in 
nature and may make you feel 
uncomfortable. 
Participation in research might involve 
some loss of privacy. There is a small 
risk that someone outside the research 
study could see and misuse information 
about you.
There is some evidence 
anticonvulsants may be effective in 
alcohol use disorder because of how 
they affect the brain. Perampanel is an 
anticonvulsant. However, it is unlikely 
that it will work with everyone, and we 
cannot promise that it will help you. 
This study may help the study doctors 
learn things that may help other 
people in the future. 
 
This is not a treatment study, and you 
are not expected to receive any direct 
medical benefits from your 
participation in the study. The 
information from this research study 
may lead to a better treatment in the 
future for people with alcohol 
dependence. 
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Now that you have a general overview of the study, we want to provide the details about 
what your participation involves. 
Please read, or have someone read to you, the rest of this document. If there is 
anything you don’t understand, be sure to ask the study staff.
WHY IS THIS STUDY BEING DONE?
The purpose of this study is to test the effectiveness of the medication Perampanel in 
people who want to stop drinking alcohol. Perampanel is an anticonvulsant, which 
means it is used to treat seizures and is not currently approved by the FDA for the 
treatment of alcohol cessation. For this reason, it is considered an investigational drug 
because it is being tested to see if it can help people stop drinking. If you participate in 
this study, you will either be placed on Perampanel or Perampanel + Disulfiram. 
Disulfiram is FDA approved to help people stop drinking, and has been marketed under 
the name “Antabuse”.  You will be randomly assigned (like flipping a coin) by the 
pharmacy to be in one of those two groups. 
 
WHAT WILL HAPPEN IF I PARTICIPATE IN THE STUDY?
If you agree to participate in this study, you will complete an initial screening that 
includes a medical history, physical examination, blood and urine samples will be taken 
for routine lab evaluations and electrocardiogram (EKG) to ensure that you are 
medically healthy. A urine sample will be used for drug screening.  At each visit, you will 
be asked to spit into a cup and will need to have a saliva alcohol level of less than .08, 
and may be asked to wait until your level is suitable or possibly reschedule if you come 
in either with a higher level than .08 or if you appear to be intoxicated.  You will also 
complete a psychiatric evaluation. You will be asked to complete questionnaires at 
every visit.
Female subjects will have a blood pregnancy test performed at screening and a urine 
pregnancy test performed on each test day. To your knowledge, you are not pregnant at 
this time. You also agree to avoid becoming pregnant. If you change your mind about 
becoming pregnant we ask that you tell us immediately because these medications are 
not safe for use in pregnancy and could harm a fetus. 
Based on the results of these evaluations, we will determine whether you may be 
eligible to participate in the clinical study. Usually the screening can be completed in 1 
visit, although sometimes you might have to come back for a second appointment to 
finish everything.   
You will be asked to provide a blood sample for DNA analysis.  This is not optional, but 
we will only collect the sample when we have determined that you are eligible to 
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participate in this study.  In most cases, we will draw the blood sample when you come 
in to pick up your first set of take-home medication.  The sample will be used to see if 
common (and some less common) variations in genes affect the response to the 
medication and alcohol.  It may also be used to see if those genetic variations affect 
drinking and other behaviors measured in this study.
Screening will last about 3-4 hours and may be split into two separate visits.
Once all of your screening information is reviewed and if it is determined that you are 
eligible, you will be asked to come in for a short baseline visit (30-60 minutes) where 
you will complete several surveys.  You will first receive counseling and you will be 
given a week (7 day) supply of a low dose of the study medication (Perampanel or  
Perampanel + Disulfiram) to take prior for the following week. If you are assigned to 
receive Perampanel alone, you will be given the medication in tablet form. If you are 
assigned to receive Perampanel + Disulfiram, you will be given the medication in liquid 
form.  All liquid study medication must be kept refrigerated during the length of the 
study.  
You will begin with a low dose of Perampanel (2mg) and will slowly increase your dose 
over a period of 4 weeks until you are at 8mg per day. If you are in the group that is 
taking the Perampanel + Disulfiram, the dose of Disulfiram will increase from 62.5mg 
per day until you are at 250mg per day. From weeks 4-8, you will take the 8mg dosing 
of Perampanel, or Perampanel at 8mg and 250 mg dosing of Disulfiram.  At visit 10 you 
will be instructed to slowly decrease your dose every 4 days. There will be a follow-up 
visit once a week for 2 weeks after your complete the medication regimen. 
Here is an example of the medication schedule:
During the 8-week treatment period. You will come to the clinic for a visit within 1 week 
after starting the study medication (week 1) and then weekly for visits until the end of 
the study.  At each visit, you will have a saliva alcohol level test, weight and vital signs 
will be measured.  Female subjects will have a urine pregnancy test.  Blood and urine 
samples will be collected.  You will complete questionnaires and be interviewed by the 
Week
Perampanel 
dose
+/-Disulfiram 
dose
1
2 mg daily
62.5 mg daily
2
4 mg daily
125mg daily
3
6 mg daily
187.5 mg 
daily
4-8
8 mg daily
250 mg daily
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study team about any medications you are taking, and asked about any side effects that 
you may be experiencing.  
At every treatment visit, you will receive Medical Management (MM) intervention 
counseling, advise on how to reduce or stop drinking and instructed on the importance 
of daily medication compliance.  You will be given medication at each visit with 
instructions that tell you how you should take your study medication.  We will review 
with you how you should take your study medication at each visit.  You should keep all 
medication out of the reach of children.
A study nurse or Research Assistant will contact you by phone once between each visit 
to check in and see how you are doing and answer any questions you may have.  You 
may be asked to come to the research center for evaluation if there are any concerns 
about your safety.
You will be asked to download a video application to your phone or tablet.  If you do not 
own a phone or tablet, one will be provided for your use during the study.  You will use 
the app to video yourself taking study medications daily (full face recording).  Only the 
Investigator and Clinical Study Nurse Practitioner will have access to view your videos 
to confirm medication is taken daily.  Videos are identified using your study identification 
number and are stored on a secure server for up to 6 months following study 
completion, after which time, they will be deleted.  
You may also be asked to download a video application called “Zoom”.  This application 
can be downloaded to your smartphone or tablet.  Rather than video yourself taking the 
study medication daily, you will click on a provided link each day and have a live “zoom” 
meeting with Dr. Arias, or another member of the study staff.  The staff member will ask 
you to take your medication, and will confirm medication is taken daily.  
Two weeks after you complete the study medication you will be asked to visit the clinic 
weekly, for two weeks (visits 11 and 12).  These visits will last approximately 1 hour and 
you will be asked to complete surveys and discuss how you are doing with decreasing 
the medication.  
Throughout the study, we will repeat bloodwork at least 5 times to make sure there are 
no unwanted effects on your health and if we have any concerning results, we will share 
them with you as soon as we can. 
You will also be asked to use a device called “Soberlink”, which is a handheld 
breathalyzer. This will help researchers track your progress and help give us a better 
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idea of whether or not the medication may help people to stop drinking. This device 
must be returned to us at the end of the study. 
You will also be asked to refrain from taking any illicit drugs while you are in this study.
The investigators will also collect information from your medical records about your 
health history. Medical record information will be collected during your participation in 
the study.
WHAT RISKS AND DISCOMFORTS COULD I EXPERIENCE FROM BEING IN THE 
STUDY?
Risks due to the study medication (perampanel):
This medication is approved by the U.S. Food and Drug Administration (FDA) for the 
treatment of Epilepsy. The FDA and Sponsor of Perampanel suggest avoiding the use 
of Perampanel with strong CYP3A inducers (enzymes which remove toxins from the 
body) like rifampin or St. John’s wort, as it could weaken or strengthen Perampanel.
The most common side effects seen with perampanel have been: dizziness, excessive 
sleepiness (drowsiness), irritability, headache, fall, and problems with coordination. 
Dizziness and excessive sleepiness were common in epilepsy trials. 
Due to possible drowsiness and excessive sleepiness, the ability to drive, operate 
heavy machinery, or perform other tasks requiring alertness and coordination may be 
impaired. For this reason, you should avoid driving or operating heavy machinery until 
you are familiar with the effects of this medication. 
Side effects occurring in 1-10% of subjects in epilepsy clinical trials were appetite 
changes, aggression, anger, anxiety, confusion, irritability, difficulty with coordination, 
double vision, blurred vision, nausea, back pain, room-spinning dizziness, headache, 
difficulty walking and falls. 
You will be monitored closely for rare potential side effects such as violent or homicidal 
thoughts, as these symptoms have been reported (though rarely) in epilepsy trials with 
the medication. You will be monitored regularly for suicidal thoughts, as this can be a 
risk with all anticonvulsants. 
Serious or life threatening psychiatric and behavioral adverse reactions, including 
aggression, hostility, irritability, anger, and homicidal thoughts and threats have been 
reported in patients taking perampanel.  If suicidal intent or other major clinical findings 
are detected during clinical or research assessments, the study physician will be notified 
immediately.  You would not be allowed to leave the clinic until you are considered safe 
to do so.
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The combination of alcohol and perampanel was studied by the company that markets 
the drug, and they noted that perampanel impaired performance on a simulated driving 
task, and it basically impaired control of the body more so than just with alcohol alone. 
You will be informed of any new risks that become known with regard to combining the 
two. There is the possibility that alcohol and perampanel, when combined, could make 
you feel tired, or you may have difficulty driving a car or operating machinery.
Because perampanel is newly FDA approved, all the side effects may not yet be known. 
However, we will work to anticipate possibilities for additional side effects known to 
occur with similar medications, such as problems producing blood cells in the right 
amount.  The US Drug Enforcement Agency (DEA) has determined that there is some 
potential for people to abuse perampanel.
Risks due to the study medication (Disulfiram): Disulfiram can cause damage to the 
liver, and throughout the study we will check bloodwork to monitor your liver function. If 
you drink alcohol (this includes cough syrups or other medications which may contain a 
form of alcohol) within 12 hours of taking disulfiram, you may become ill and experience 
various symptoms, including vomiting, nausea, stomach pain, flushing, chest pain, 
difficulty breathing, loss of consciousness dizziness or in severe cases heart attack, 
seizure, death. The effects of disulfiram can last up to two weeks. 
Disulfiram should not be taken if you have been diagnosed with severe myocardial 
disease (which could cause a heart attack), coronary occlusion (blocked arteries) or 
psychoses (symptoms of impaired reality).
You should not be exposed to ethylene dibromide (poison used in pesticides, 
insecticide, additive in leaded gasoline) or its vapors as the combination has been 
linked to higher rates of tumors and death in rats. 
You should not take phenytoin, also called Dilantin and Phenytek. Pheytoin is an anti-
convulsant and taking it with disulfiram may cause the medication levels to become 
unstable and potentially too high for your safety. 
You should not take anticoagulants such as warfarin, also called Coumadin. Coumadin 
is a commonly used blood thinner and taking it with disulfiram may cause the 
medication levels to become unstable and potentially too high for your safety. 
You should not take metronidazole, also called Flagyl. Metronidazole is a common 
antibiotic and taking it with disulfiram can damage your liver and cause the medication 
levels to become higher than they should be. If you have a skin sensitivity to rubber and 
things containing rubber then you might not be a good candidate to take disulfiram.
FOR WOMEN: Because alcohol has adverse effects on the fetus, and some 
medications like perampanel can be harmful to a fetus, you will not be able to 
participate in this study if you are pregnant or breastfeeding. If you are pregnant or 
become pregnant, this research may have a bad or unforeseen effect on a fetus and 
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should not be done during pregnancy.  To your knowledge, you are not pregnant at the 
present time and you agree to avoid becoming pregnant (use contraceptives, take 
precautions against becoming pregnant, etc.) during this study.  If you are a woman, 
you will be screened for pregnancy before and during your participation in the study.  
You will not be allowed to participate if you are pregnant or breastfeeding. 
Perampanel may lower your oral contraceptive’s ability to prevent pregnancy if your oral 
contraceptive contains levonorgestrel.  Because of this, women will be asked to use at 
least two forms of contraception, such as condom with spermicide, and at least one 
form must be non-hormone based such as a barrier method like a condom.  If you 
change your mind about becoming pregnant we ask that you tell us immediately.  You 
will receive a blood pregnancy test at the initial screening appointment and a urine 
pregnancy test on each test day.  You will be excluded (dropped) from the study if you 
become pregnant.
Reproductive Risks
As the study procedures might injure an unborn child, pregnant women may not 
participate. Women who might become pregnant should use a medically accepted form 
of birth control such as total abstinence, birth control pills, an IUD, diaphragm, 
progesterone injections or implants, or condoms plus a spermicide. Methods of birth 
control other than total abstinence are not 100% effective, and should a woman become 
pregnant there is a risk of injury to an unborn child. For similar reasons, women who are 
nursing an infant may not participate.
For men, the study procedures might increase the risks for birth defects of any child 
conceived during treatment and several months after treatment is stopped. Men in this 
study who have the potential of fathering children should be aware of this possibility and 
consider using a medically accepted form of birth control. For men this would include 
total abstinence and condoms plus a spermicide, or for the female partner, birth control 
pills, an IUD, diaphragm, progesterone injections or implants. Methods of birth control 
other than total abstinence are not 100% effective, and should a woman become 
pregnant there is a risk of injury to an unborn child.
Only the study participant can take the study drug. It must be kept out of the reach of 
children and persons who may not be able to read or understand the label.
During this study you will be asked to have multiple blood draws (we estimate no more 
than 10TBSP of blood) to monitor for any negative effects on your body. Because this is 
for your safety, if you do not want your blood drawn then you may be asked to leave the 
study. Blood draws can be uncomfortable, may cause bruising, dizziness  and some 
people experience passing out during blood draws. If this is a problem for you, please 
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tell staff immediately. Although the amount is less than a typical blood donation (16 
ounces), you should refrain from blood donations eight weeks before and after testing.  
Non-Physical Risks
Participation in research might involve some loss of privacy. There is a small risk that 
someone outside the research study could see and misuse information about you.
Questionnaires may contain questions that are sensitive or personal in nature. You may 
refuse to answer any question that makes you feel uncomfortable.
This study will ask you questions about personal topics that might be embarrassing to 
talk about and that could affect your family relationships if this information were to 
become known outside of the study. You will also be asked about illegal activities, which 
could have legal and financial consequences if this information were to become known 
outside of the study.
Genetic Risks:
If known to employers or insurance companies, the results of genetic tests might affect 
a person's ability to obtain a job or health or life insurance. If this information were 
released, it could be misused. Such misuse could be distressing, and it could cause you 
or your family members to have difficulty obtaining insurance coverage and/or a job. 
A federal law called the Genetic Information Nondiscrimination Act (GINA) makes it 
illegal for health insurance companies, group health plans, and most employers to 
discriminate against you based on your genetic information. However, this legal 
protection still may not keep someone from trying to discriminate against you in this 
way.
While all efforts are aimed at protecting and guarding your blood and/or DNA samples, 
there remains the possibility that VCU could be compelled by a court or a law 
enforcement agency to produce such samples.  In more than six years of collecting 
DNA samples at VA Connecticut, where similar studies were previously run, in which 
many hundreds of samples have been collected, no outside agency has ever tried to 
gain access to any research participant's blood or DNA samples.  Dr. Arias believes that 
the risk of this happening to your sample is extremely small.
Unknown or Unforeseeable Risks
Perampanel involves risks that are currently unknown or unforeseeable. The 
researchers will let you know about any significant new findings (such as additional 
risks, side effects or discomforts) that might make you change your mind about 
participating in the study.
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WHAT ARE THE COSTS?
Study drug will be provided by the sponsor at no cost to you. You will not be charged for 
any study visits, tests, or procedures. 
You will need reliable transportation throughout the study because you will have weekly 
visits.  If you do not have reliable transportation, please tell staff and we will discuss any 
available options with you.
WILL I BE PAID TO PARTICIPATE IN THE STUDY?
You will be paid in cash, by check or clincard and if you complete all scheduled study 
visits, you will have received a total of $800. If you withdraw before the end of the study, 
you will only be paid for completed visits. 
After completion of the screening visit you will receive $50, and $75 for each weekly 
treatment visit (8) that is scheduled. At the endpoint visit, you will be paid $100, and 
then $25 at each post-treatment visit. 
Total payments within one calendar year that exceed $600 will require the University to 
report these payments annually to the IRS and you. This may require you to claim the 
compensation you receive for participation in this study as taxable income. VCU is 
required by federal law to collect your social security number. Your social security 
number will be kept confidential and will only be used to process payment.
Please be aware that the investigative team and the University may receive money for 
the conduct of this study.
WHAT HAPPENS IF I AM INJURED OR BECOME SICK BECAUSE I TOOK PART IN 
THE STUDY?
If you are injured by, or become ill, from participating in this study, please contact your 
study doctor immediately. You will be given an emergency wallet card with the study 
doctor’s contact information on it. Medical treatment is available at the Virginia 
Commonwealth University Health System (VCU Health System). Your study doctor will 
arrange for short-term emergency care at the VCU Health System or for a referral if it is 
needed. 
Fees for such treatment may be billed to you or to appropriate third party insurance. 
Your health insurance company may or may not pay for treatment of injuries or illness 
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as a result of your participation in this study. To help avoid research-related injury or 
illness, it is very important to follow all study directions.
CAN I STOP BEING IN THE STUDY?
You can stop being in this research study at any time. Leaving the study will not affect 
your medical care, employment status, or academic standing at VCU or VCU Health. 
Tell the study staff if you are thinking about stopping or decide to stop.
If you leave the study before the final regularly scheduled visit, we may ask you to have 
a few clinic visits so that we can safely reduce your medication dosing if necessary. 
Perampanel is normally tapered because in people who take it for seizures,  it can 
cause someone to be more likely to have seizures if it is not tapered.
If you are taking Disulfiram, you should not drink any alcohol or take any medications 
that contain alcohol (such as cough syrups) for at least 12 hours after your last dose. 
Disulfiram can stay in your body at a low level for up to 2 weeks, and there is the risk of 
having a reaction if you drink alcohol while Disulfiram is still in your system.
Your participation in this study may be stopped at any time by the study doctor without 
your consent. The reasons might include:
●
the study doctor thinks it necessary for your health or safety
●
you are found to not be eligible for the study 
●
the sponsor has stopped the study 
●
you have not followed study instructions
●
administrative reasons require your withdrawal
If you withdraw from the study, data that has already been collected about you will 
remain part of the study database and may not be removed.
HOW WILL INFORMATION ABOUT ME BE PROTECTED?
VCU and the VCU Health System have established secure research databases and 
computer systems to store information and to help with monitoring and oversight of 
research. Your information may be kept in these databases but are only accessible to 
individuals working on this study or authorized individuals who have access for specific 
research related tasks. 
Identifiable information in these databases are not released outside VCU unless stated 
in this consent or required by law. Although results of this research may be presented at 
meetings or in publications, identifiable personal information about participants will not 
be disclosed. 
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Personal information about you might be shared with or copied by authorized 
representatives from the following organizations for the purposes of managing, 
monitoring and overseeing this study:

The study Sponsor, representatives of the sponsor and other collaborating 
organizations

Representatives of VCU and the VCU Health System

Officials of the Department of Health and Human Services or the Federal Food 
and Drug Administration
It will be noted in your protected electronic health record at VCU Health that you are in 
this study. Information about the study, such as the medications you receive, may be 
included in the record. This information is protected just as any of your other health 
records are protected. 
In general, we will not give you any individual results from the study. If we find 
something of medical importance to you, we will inform you, although we expect that 
this will be a very rare occurrence. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Website will include a summary of the results. You can search this Web site at 
any time.
If you tell us that you may hurt yourself or someone else, the law says that we must let 
people in authority know.
There are no plans to share any money or profits with you if the use of your sample(s) 
results in inventions or discoveries that have commercial value. 
In the future, identifiers might be removed from the information and samples you 
provide in this study, and after that removal, the information/samples could be used for 
other research studies by this study team or another researcher without asking you for 
additional consent.
Certificate of Confidentiality
To help us protect your privacy, we have obtained a Certificate of Confidentiality from 
the National Institutes of Health. If this certificate is obtained, it will offer the protections 
described here. A Certificate of Confidentiality helps the researchers keep your 
information private. For example, researchers can refuse to give out your information in 
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a court case.  Researchers may have to give your information if the study is audited, or 
if the information is required by the Food and Drug Administration (FDA).
The researchers may share information about you or your participation in the research 
project without your consent if you disclose that there is the risk of abuse to others or 
harm to yourself or others.
The researchers cannot prevent you or others, for example a member of your family, 
from sharing information about you or your involvement in this research. If you give an 
insurer, employer, or other person permission to receive research information, then the 
researchers may not use the Certificate to withhold that information.
HOW WILL MY HEALTH INFORMATION BE USED AND SHARED DURING THIS 
STUDY?
As part of this research study, we will ask you to share identifiable health information 
with us and/or permit us to access existing information from your healthcare records. 
New health information may also be created from study-related tests, procedures, visits, 
and/or questionnaires. This type of information is considered “Protected Health 
Information” that is protected by federal law. 
What type of health information will be used or shared with others during this 
research?
The following types of information may be used for the conduct of this research:
 Complete health record
 Diagnosis & treatment 
codes
 Discharge summary
 History and physical exam
 Consultation reports
 Progress notes
 Laboratory test results
 X-ray reports
 X-ray films / images
 Photographs, videotapes
 Complete billing record
 Itemized bill
 Information about drug or alcohol abuse
 Information about Hepatitis B or C tests
 Information about mental health 
 Information about sexually transmitted 
diseases
 Other physical or mental health information (specify):      
Who will use or share protected health information about me?
VCU and VCU Health are required by law to protect your identifiable health information. 
By consenting to this study, you authorize VCU/VCU Health to use and/or share your 
health information for this research. The health information listed above may be used by 
and/or shared with the following people and groups to conduct, monitor, and oversee 
the research:
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●
Principal Investigator and 
Research Staff 
●
Study Sponsor 
●
Health Care Providers at VCU 
Health 
●
Data Coordinators 
●
Institutional Review Boards 
●
Research Collaborators
●
Government/Health Agencies 
●
Data Safety Monitoring Boards
●
Others as Required by Law
Once your health information has been disclosed to anyone outside of this study, the 
information may no longer be protected under this authorization.
When will this authorization (permission) to use my protected health information 
expire? 
This research study involves the use of a Data Registry or Sample Repository and will 
never expire.
Statement of Privacy Rights
You may change your mind and revoke (take back) the right to use your protected 
health information at any time. However, even if you revoke this authorization, the 
researchers may still use or disclose health information they have already collected 
about you for this study. If you revoke this Authorization, you may no longer be allowed 
to participate in the research study. To revoke this Authorization, you must write to the 
Principal Investigator 
Dr. Albert Arias 
Institute for Drug and Alcohol Studies
203 E Cary St, Suite 202 
Richmond, VA 23219
Email: albert.arias@vcuhealth.org
OPTIONAL STORAGE FOR FUTURE RESEARCH STUDIES 
To advance science, it is helpful for researchers to share information. They do this by 
putting data or samples into one or more scientific databases (called registries or 
repositories), where it is stored along with information from other studies. Researchers 
can then study the information in other ways and combine information from many 
studies to learn even more about health and disease.
As part of this study, we would like to keep the information and/or samples that you 
provide in a registry/repository to be available for other research studies in the future. 
Your information and samples would be stored at VCU by Dr. Albert Arias and could be 
used for other research studies about any topic. Your data/samples will be protected, 
but there is always a possibility that information could be accessed by individuals 
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without authorization. There is no limit on the length of time we will store your 
information/samples.
Your samples, genomic data and/or health information will be stored indefinitely by VCU 
in one or more scientific databases, and shared with other researchers. The samples 
and information will be available for any research question, such as research to 
understand what causes certain diseases (for example heart disease, cancer, or 
psychiatric disorders), development of new scientific methods, or the study of where 
different groups of people may have come from. This information will not be labeled with 
your name or other information that could be used to easily identify you. However, it is 
possible that the information, when combined with information from other public sources 
could be used to identify you, though we believe it is unlikely that this will happen.
Your individual genomic data and health information will be put in a controlled-access 
database at the National Institutes of Health. This means that only researchers who 
apply for and get permission to use the information for a specific research project will be 
able to access the information. Your genomic data and health information will not be 
labeled with your name or other information that could be used to identify you. However, 
it is possible that the information from your genome, when combined with information 
from other public sources could be used to identify you, though we believe it is unlikely 
that this will happen. Researchers approved to access information in the database will 
agree not to attempt to identify you.
In the future, if you decide that you don’t want to be part of this registry, you can request 
that your information/samples be removed and destroyed by contacting Dr. Albert Arias. 
However, information that has already been shared with other researchers will continue 
to be used.
In addition, identifiers will only be kept for 5 years following study conclusion. After that 
time, withdrawal will no longer be an option because the individual specimens will no 
longer in any way be linked to the person from which they were originally drawn.
Permission to Store Data and/or Samples for Future Research Studies
I agree that my blood, DNA, tissue and other data may be stored and used for 
future research as described in this document. I understand that by choosing 
“NO”, I will be unable to participate in this study and am opting out.
Please circle your answer and initial:
YES
NO                              Initials ________________
WHOM SHOULD I CONTACT IF I HAVE QUESTIONS ABOUT THE STUDY?
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The investigator and study staff named below is the best person(s) to contact if you 
have any questions, complaints, or concerns about your participation in this research:
Dr. Albert Arias 
Institute for Drug and Alcohol Studies
203 E Cary St, Richmond, VA 23298
860-558-2273 or (804) 828-5793
Email: albert.arias@vcuhealth.org
If you have general questions about your rights as a participant in this or any other 
research, or if you wish to discuss problems, concerns or questions, to obtain 
information, or to offer input about research, you may contact:
Virginia Commonwealth University Office of Research
800 East Leigh Street, Suite 3000, Box 980568, Richmond, VA 23298
(804) 827-2157; https://research.vcu.edu/human_research/volunteers.htm 
Do not sign this consent form unless you have had a chance to ask questions and have 
received satisfactory answers to all of your questions. 
STATEMENT OF CONSENT 
I have been provided with an opportunity to read this consent form carefully. All of the 
questions that I wish to raise concerning this study have been answered. By signing this 
consent form, I have not waived any of the legal rights or benefits to which I otherwise 
would be entitled. My signature indicates that I freely consent to participate in this 
research study. I will receive a copy of the consent form for my records.
Signature Block for Enrolling Adult Participants
________________________________________________
Adult Participant Name (Printed)
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Date
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Name of Person Conducting Consent Discussion (Printed)
________________________________________________
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Signature of Person Conducting Consent Discussion
Date
________________________________________________
________________
Principal Investigator Signature (if different from above) 
Date 
Approved by the VCU IRB on 8/10/2021

Prot_SAP_002.pdf: 
 
 
Title: Open Label Pilot Study of Perampanel for the Treatment of Alcohol Use 
Disorder 
 
NCT #: NCT04502589 
 
Document date: June 30, 2021 
 
Document Type: Protocol and SAP 
 
 
 


Open Label Pilot Perampanel V.7 June 30 2021  HM20015846 
 
 
1
Open Label Pilot Study of Perampanel for the Treatment of Alcohol Use Disorder 
Principal Investigator: Albert Arias, M.D., M.S.  
 
 
SPECIFIC AIMS: Better medications to treat Alcohol Use Disorder (AUD) are greatly needed. 
Existing treatments are very limited in their effects, and are often not well adhered to or 
tolerated by patients. Pre-clinical studies show that activation of glutamatergic AMPA receptors 
(AMPA-Rs) promotes the return to drug and alcohol seeking behavior in mammals. Thus 
AMPA-R antagonist medications like perampanel, a recently FDA approved anticonvulsant, 
have clear potential in treating AUD, a fact which is supported by additional preclinical studies in 
animals. Though several glutamatergic medications have shown efficacy in treating AUD, 
selective AMPA- R antagonists remain unexplored in the treatment literature.  
 
Perampanel administration was perceived as pleasing by subjects in one study, 
suggesting that it may be more acceptable to patients, and thus better adhered to, than current 
treatments are. Furthermore, perampanel could be a potential treatment for co-occurring anxiety 
disorders (e.g., posttraumatic stress disorder) and other addictive disorders (e.g., cocaine 
dependence). While we suspect perampanel has strong anti-alcohol addiction properties by 
itself, we plan to also explore combining perampanel with disulfiram, an FDA approved 
treatment for AUD which is poorly adhered to, thus making a multi-faceted (multi-mechanism of 
action) approach to reducing drinking. We predict that perampanel will reduce drinking by 
reducing the rewarding and reinforcing properties of alcohol. Disulfiram has an aversive effect 
making people physically ill when they drink alcohol. We suspect that by combining the two 
medications we will have a highly effective treatment for AUD, and one which is analogous to 
buprenorphine in the treatment of opioid use disorder in that it reduces anxiety, craving, and the 
motivation to drink, and once ingested it essentially blocks the ability to drink (due to the 
disulfiram-ethanol reaction). 
 
 
Specific Aim 1: To test the efficacy of perampanel treatment of AUD in a small, open-label, 
eight-week, quasi-experimental clinical trial in which 20 subjects with AUD will be randomized 
1:1 to one of two groups; perampanel by itself, and perampanel combined with disulfiram. 
Subjects will be titrated over 3 weeks to a target dose of 8mg perampanel daily in both groups, 
and disulfiram will be kept at 250mg daily. Subjects will be compared on the primary outcome of 
percent abstinent days, in quasi-experimental fashion to 20 placebo treated subjects from our 
existing clinical trial databases. We hypothesize that perampanel will reduce drinking and 
craving significantly more than placebo, and that the combined perampanel/disulfiram group will 
reduce drinking the most, with no difference in adherence compared to perampanel without 
disulfiram. Drinking data measurement and safety efforts will be augmented with twice-daily 
breathalyzer measurements collected with a smartphone-based monitoring platform and relayed 
to investigators daily.  
 
A. BACKGROUND AND SIGNIFICANCE: Pre-clinical studies show that activation of 
glutamatergic AMPA receptors (AMPA-Rs) promotes the return to drug and alcohol-seeking 
behavior in mammals. AMPA receptor (AMPA-R) antagonist (i.e., blocking) medications such as 
perampanel, a recently FDA approved anticonvulsant, may be useful in treating alcohol use 
disorder (AUD). The main goal of the proposed study is to determine if perampanel reduces 
drinking in a small, open-label, pilot study, it would provide a strong rationale for further clinical 
trials with this medication.  
A.1. Critical need for new AUD treatments:  There is a great need to develop more 
effective medications to treat AUD. AUD is among the most prevalent and disabling disorders in 
the world, with an estimated impact of $185 billion in the U.S. annually, and is the third leading 
preventable cause of death (1-3). The currently available medications to treat AUD have modest 


Open Label Pilot Perampanel V.7 June 30 2021  HM20015846 
 
 
2
effects, and many patients don’t respond well, thus there is a need for more efficacious 
pharmacologic treatments (4, 5).  
Despite a recommendation from the NIAAA to offer medication as a first line treatment for 
AUDs, their use has not been widely adopted by physicians. Many people with an AUD that 
might benefit from a pharmacologic treatment never receive it (6, 7). A study of barriers to the 
use of medications found that side effects were thought to present a significant barrier to use, 
based not only on patients’ reports, but the reports of physicians (7). Perampanel may be better 
tolerated than some other available treatments for reducing drinking such as topiramate. The 
study by Mark et al. (7) showed that a perceived lack of research into medication efficacy was a 
barrier to medication use in practice. Thus, there is a great need for research evaluating the 
efficacy of new medications. The research proposed here will help to address that need by 
testing perampanel’s effects on the rewarding and reinforcing properties of alcohol. We will also 
generate critical pilot clinical trial data. 
A.2. Treating AUDs with Anticonvulsants:  Anticonvulsants have shown evidence of 
efficacy in treating alcoholism (8). Perampanel is an anticonvulsant and a promising potential 
treatment for AUD.  The potential utility of anticonvulsants to reduce the risk or severity of 
relapse was demonstrated initially in studies by Mueller et al. (9) and by Brady et al. (10) 
showing some benefits compared to placebo treatment. Johnson et al. (11) demonstrated the 
efficacy of topiramate for AD in a double blind, randomized, placebo-controlled trial. In a follow-
up, larger (N=371), multi-center, randomized placebo-controlled trial, topiramate was again 
found superior to placebo with a moderate effect size (12). A more conservative analysis of the 
topiramate data, which assumed a return to baseline drinking levels for dropouts, reduced the 
effect on heavy drinking by about half. The frequency and severity of side effects from 
topiramate limit its effectiveness (12-14).  
A.3. Glutamate and Addiction: Altered glutamatergic neurotransmission plays a 
prominent role in the pathophysiology of AUD (15, 16). Glutamatergic neurotransmission within 
and on brain dopaminergic pathways is thought to be a key and necessary component for the 
development and maintenance of addiction to alcohol (17). Glutamatergic efferents from the 
prefrontal cortex (PFC), amygdala, and hippocampus, innervate the cell bodies of neurons in 
the ventral tegmental area (VTA) and the nucleus accumbens shell (NAS), facilitating 
dopaminergic transmission in these key areas of the “reward pathway” (17).  
A.4. AMPA Receptors and AUD Pathophysiology: Glutamate acts on N-methyl-D-
aspartate (NMDA), alpha-amino-3-hydroxyl-5-methyl-isoxazole-4-proprionic acid (AMPA), 
kainite, and metabotropic receptors. AMPA-Rs may have a more significant role than other 
glutamatergic receptors in glutamate-facilitated dopamine release in the NAS and subsequent 
reward.  AMPA-Rs play a prominent role in addiction related neuroplasticity and learned 
behaviors. Glutamatergic activation of VTA dopaminergic neurons and subsequent dopamine 
release in the NAS is important in addiction to any substance, but activation of AMPA-Rs pre-
synaptically in the NAS, and also activation of AMPA-Rs in the PFC further potentiates 
dopaminergic neurotransmission (and thus reward and reinforcement) in the NAS. Infusion of an 
NMDA antagonist into the NAS of rats does not block cocaine-induced relapse to cocaine self-
administration, but infusion into the NAS of an AMPA-R antagonist does (17, 18). AMPA-R 
antagonists may reduce the reward and reinforcement of alcohol and other drugs and may 
reduce craving and relapse risk. More recent animal studies have confirmed these previous 
findings and suggest that AMPA-Rs are involved in the return to drug seeking behavior (19-24). 
AMPA-R antagonists injected into the Nucleus Accumbens Core (NAC) attenuate cue-
induced relapse to cocaine (25). Sanchis-Segura et al., (26) showed the AMPA-R antagonist 
GYKI 52466 reduced cue-elicited reinstatement of alcohol seeking behavior and the alcohol 
deprivation effect in two animal models. An AMPA-R antagonist injected into the NA reduced 
conditioned place aversion from naloxone in rats (27). A very recent study in rats confirmed the 
theory that enhanced AMPA-R mediated glutamatergic transmission due to neuroadaptation 
from chronic alcohol exposure is a main component of the drive to drink excessively and to 


Open Label Pilot Perampanel V.7 June 30 2021  HM20015846 
 
 
3
crave alcohol after being exposed to cues (28). In that study, an AMPA-R agonist increased 
ethanol consumption in a self-administration paradigm, as well as cue-elicited relapse in alcohol 
preferring rats; an effect that was blocked by an AMPA-R antagonist (like perampanel). These 
studies strongly support perampanel as a good candidate for alcoholism treatment.  
Additional support for the critical role of the AMPA receptor in AUD pathophysiology comes 
from genetic studies of AUD, which emphasize the network of genes related to trafficking of the 
AMPA-R as a component of addiction-related neuroplasticity. Karpyak et al., (29) examined 
variants in the genes encoding proteins in this so-called “NMDA dependent AMPA receptor 
trafficking cascade” in association to alcoholism in humans.  They studied a set of ~1000 single 
nucleotide polymorphisms (SNPs) in 13 genes related to the pathway, finding via gene set 
analysis that the set was significantly associated with AUD. Further, some of the most 
significantly associated SNPs were located in genes responsible for encoding subunits of AMPA 
receptors, specifically GRIA2A, GRIA3, and GRIA4. Meyers et al., (30) studied genetic variants 
in the mGluR–eEF2–AMPAR pathway in association to alcohol drinking behaviors in humans. 
They found that 206 genetic variants across the same pathway (including ones in the GRIA1 
and GRIA4 genes) were found to predict number of drinking days per month (corrected P-value 
<0.01) when considered as a set. They were able to replicate the finding to some degree in 
another sample, where variants in two of the genes seemed to be predictive of amount of 
alcohol consumed. This genetic work strengthens the evidence base linking AMPA-R related 
glutamatergic neurotransmission to AUD pathophysiology. 
A.5. Perampanel Pharmacology: Perampanel is a noncompetitive (allosteric) antagonist of 
the AMPA-R that is well-absorbed (100% bioavailability), has good blood-brain-barrier 
penetration, and rapidly reaches peak plasma concentrations (1 hour) (31). Perampanel is now 
FDA approved for the adjunctive treatment of refractory partial-onset seizures. Phase III trials in 
epilepsy have demonstrated that perampanel is very well tolerated, and safe (32-34). In vitro 
studies of rat hippocampal slices have demonstrated the selective action of perampanel on the 
AMPA receptor (35). Perampanel does not appear to block the ion channel, but binds the 
AMPA-R at an allosteric site referred to as the “GYKI receptor” (35, 36).  In human subjects, 
perampanel is well tolerated at doses of 8mg or 12mg daily, although some titration is needed to 
reach those doses for ongoing therapy (33, 34, 37). Medication related adverse events/side 
effects with chronic dosing in epilepsy trials have included; dizziness, somnolence, irritability, 
headache, fall, and ataxia (33, 34, 37). Pharmacokinetically, perampanel has an elimination 
half-life T1/2 of over 52 hours (estimated at average ~70 hours, but with a wide inter-individual 
range from 52-129 hours) and reaches peak plasma concentration (Tmax) approximately 1 hours 
post-ingestion (31). Perampanel is primarily metabolized by CYP3A4 and exhibits linear 
pharmacokinetics. To date, there have been no clinical trials of AMPA-R antagonists (e.g., 
perampanel) for the treatment of alcoholism. 
Perampanel is a DEA schedule III drug, owing to a study that showed that very high doses 
of perampanel (i.e., 2-3 times the maximum recommended dose) caused some euphoria and 
drug liking similar to alprazolam and ketamine (38). However at normal doses (and the ones we 
will use here in this study) that effect did not occur. We anticipate that at normal doses, 
perampanel will produce a pleasant mood, reduction in anxiety, and decrease in the drive to 
drink alcohol. This is important, because the currently FDA approved medications for AUD do 
not really have any effect on mood or anxiety. We think that alcoholics will want to take 
perampanel because they will feel “normal” again, and like they don’t need to drink. Perampanel 
will have the stabilizing good effects that they sought out of alcohol, but without the negative 
effects, and it will decrease the desire for alcohol as well as its other reinforcing effects 
Disulfiram ingestion makes it impossible to drink alcohol without getting physically ill (i.e., the 
disulfiram reaction), however disulfiram lacks efficacy in treating AUD under normal treatment 
conditions because patients stop taking it. Combining perampanel with disulfiram would give 
AUD patients the feeling that they don’t need to drink, along with a deterrent from drinking. Thus 
the role of the combination drug in AUD treatment would be somewhat analogous to that of 
buprenorphine treatment in opioid use disorder treatment; it would make patients feel like they 


Open Label Pilot Perampanel V.7 June 30 2021  HM20015846 
 
 
4
don’t need to drink, and would make it impossible to get drunk while on it. We envision that it 
would be used for a limited amount of time, perhaps 3-6 months, under close medical 
supervision, to help patients gain some sobriety and work on their recovery. In our study, 
diversion and inappropriate use will be thwarted by issuing only a one-week supply of 
medication at any one time. We envision that eventually perampanel will be used for the 
treatment of AUD as a combination of disulfiram and perampanel mixed together (compounded) 
in one pill, hence stability testing for this combination is in development for future protocols.  
Note that modafinil and buprenorphine are both controlled substances, but both are efficacious 
medications in treating opioid and cocaine addiction. We don’t have an AUD treatment that is as 
effective as buprenorphine for opioid use disorder, but one is needed. 
A.6. A Precision-Medicine approach for treating AUD: Pharmacogenetic studies of 
alcoholism to date suggest that we may be able to guide treatment selection based on variation 
in a patient’s genes (39, 40). Glutamatergic neurotransmission genes have been implicated in 
numerous studies. Karpyak et al. (41) found that variation in glutamateric genes were 
associated to difference in length of time that AUD subjects were able to maintain abstinence 
from alcohol during treatment with acamprosate. Also, recently, a study of variation in 
metabolism of many key biological compounds showed that subjects with AUD that had 
increased serum glutamate levels responded better to the medication acamprosate in treatment 
(42).  
 
 
B. METHODS: 
 
OVERVIEW: Testing the efficacy of perampanel treatment of AUD in a small, open-label, 
trial. Twenty (N=20) treatment seeking subjects with DSM-5 AUD that are currently heavy 
drinking regularly will be randomized (1:1) to two non-blinded conditions; perampanel by itself, 
or perampanel in combination with disulfiram.  All subjects will take the Perampanel for eight 
weeks, with a three-week titration, increasing 2mg weekly, to a target dose of 8mg daily that 
they will take for 5 weeks (table 2). Subjects who are randomized to also receive Disulfiram with 
Perampenel for eight weeks, will receive a combination liquid, to also include a disulfiram three-
week titration, increasing weekly to a target dose of 250mg daily (table 2). .  Subjects will be 
seen weekly and data on drinking will be collected with the timeline follow-back method (TLFB) 
(43). Craving will be measured with the AUQ weekly. To monitor for diversion, and reduce the 
risk of taking more than prescribed amount of medication, subjects will only be dispensed a 1-
week supply of medication at any visit. Subjects will also be called mid-week in between visits to 
assess for any severe psychiatric side effects, and so they will be queried twice weekly for any 
suicidal or homicidal ideation. Subjects will be tapered off the medication over two weeks at the 
end of the study and followed closely during that time to assess side effects. Subjects will also 
be monitored daily with the “Soberlink” breath alcohol monitoring system, which is a 
smartphone-based system that transmits twice daily breathalyzer measurements to 
researchers. It automatically notifies researchers if there is a positive measurement. All subjects 
will receive a minimal behavioral platform for medical management (MM), that maximizes 
medication adherence in AUD treatment (44).  We have well developed methods for subject 
recruitment, screening, and data management. This study will be conducted at our VCU Institute 
for Drug and Alcohol Studies site in Richmond or in the VCU Health Motivate clinic. Subjects will 
be pre-screened by telephone and if suitable, will be screened further in person. Study 
physicians will evaluate all subjects with medical/psychiatric history and physical exam. 
Subjects will participate in twelve total study visits and will be paid a total of $800 in cash, by 
check or clincard. 
Inclusion Criteria: a) Men and women ages 21-70 with DSM-5 AUD; b) regular heavy 
drinkers as defined by averaging ≥ 2 heavy drinking days per week over the 60 days baseline 


Open Label Pilot Perampanel V.7 June 30 2021  HM20015846 
 
 
5
pre-treatment TLFB, and recognize a need to completely stop drinking; c) willingness to provide 
written, informed consent to participate in the study; d) 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 e) 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: a) 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. Other 
exclusionary disorders include; b) history of renal compromise or current renal disease (as 
evidenced by serum creatinine above our laboratory’s reference limit of 1.7 mg/dL; c) history of 
seizure disorder; d) 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; e) schizophrenia, bipolar disorder, current major 
depressive episode, or substantial suicide or violence risk on the basis of history or psychiatric 
examination; f) currently dependent on, stimulants, opioids or sedatives; g) subjects with any 
substantial alcohol withdrawal will be required to be detoxified by regular clinical services prior 
to study entry; g) 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) h) are taking phenytoin or warfarin 
Study Procedures:  
6.D.Temporal Sequence of Study Procedures: Following telephone screening to determine 
initial eligibility, patients will be invited to the clinical site for an in-person visit.  At the first in-
person visit, informed consent will be obtained and patients will undergo a screening interview 
to assess inclusion and exclusion criteria.  Patients excluded at any point in the recruitment 
process will be referred for appropriate treatment based upon consultation with the study 
physician. If subjects are unable to complete the entire screening procedures in 1 visit due to 
their schedule, they may be allowed to return for additional visits if needed prior to baseline.  
 
6.E.  Schedule of Visits: 
6.E.1.  Visit 1 (Screening Visit):  At the screening visit (visit 1), patients will be asked to 
provide informed consent. The PI and/or the study Nurse Practitioner (NP) will obtain a medical 
and psychiatric history, and perform a physical exam.  Drinking data for the 60 days prior to the 
screening visit will be collected via the Timeline Follow-Back (TLFB) Method. Blood (or saliva)  
and urine samples will be taken for routine clinical laboratory evaluations (including GGTP, 
ETG/ETS), drug screening, pregnancy testing (in females of reproductive potential), and DNA 
extraction. All projected amounts will be discussed in the consent form, we estimate the total 
amount of blood drawn to be approximately 10 TBSP for the entire study, but additional labs 
may need to be repeated at the discretion of the PI to ensure participant health and safety. 
Additional blood will only be drawn if determined medically necessary. Screening will last about 
3-4 hours total.  This visit may be split into two clinic visits. 
 
6.E.2.  Visit 2 (Baseline Visit): After the screening visit, eligible patients will undergo the 
baseline visit prior to randomization.  They will complete a packet of questionnaires. The subject 
begins a 3-week titration phase, during which the perampanel dosage will be titrated up as 
indicated below in Table 1, to a maximum of 8mg/day and disulfiram will be dosed as indicated 
in Table 1.  Subjects will receive compensation for all visits, including follow-up visits (see Table 


Open Label Pilot Perampanel V.7 June 30 2021  HM20015846 
 
 
6
3). Compensation will not be prorated. We will provide taxi rides to assist with return 
transportation from the clinic, as long as it is within bus line limits or a 20mile radius. Staff will 
work with participants to determine individual needs.  
 
TABLE 1: Medication Titration Schedule  
           
 
 
 
 
 
 
 
 
 
6.E.4.  Visits 2b-10 (Treatment and End-of-Treatment Visits):  Patients will first receive 
counseling and study medication during a treatment session (visit 2b) scheduled on the same 
day as the baseline assessment.  Patients will be given study medications consisting of 
Perampanel or perampanel/disulfiram and titrated up to a maximum of 8 mg/day of perampanel 
(see Table 1). Participants will be instructed to refrigerate study medication.  We will use 
blocked stratified randomization with use of antidepressants/psychotropic (yes/no) and sex as 
the stratification variables.  Block sizes of 4 in each stratum to achieve treatment balance 
throughout the randomization process. During the 8-week treatment period, patients will come in 
for a visit within 1 week after starting the study medication (week 1).  They will then come in 
weekly for visits until the end of the study. (Note: a research staff member will call the patient in 
the middle of each week to check on their wellbeing and safety. The purpose of this call will be 
to check in with the patient and make sure they do not have any questions and that they are 
tolerating the medication. Furthermore, the call will be used to assess for any suicidal, 
homicidal, or violent ideation, or any other untoward effects.  Subject medication adherence will 
be monitored using a video application, downloaded to the participant’s phone or tablet.  A 
phone or tablet will be provided to participants who do not have a personal a phone or tablet.  
Participants will be instructed to open the app and video themselves taking two study 
medications, then sending the video to a secure cloud based server.  The PI or Clinical 
Research NP will have access to view the video and confirm that medication was taken.   
At each visit, the patient's breath alcohol level (BAL), weight, and vital signs will be measured.  
A BAL of less than .08 is required for each visit, and At screening, a BAL of less than or equal to 
.02 is needed for the consent process. all female subjects will have a blood pregnancy hCG 
quantitative titer drawn to detect pregnancy. Urine samples will be collected at each visit for 
drug screening and once monthly for female subject’s pregnancy testing. Samples for ETG 
(urine) will be collected as indicated in Table 2.   Patients will then complete questionnaires and 
be interviewed by the study nurse about their concomitant medications, adverse events, and 
protocol compliance.  At every treatment visit (i.e., for a total of 8 sessions), the nurse will 
deliver the MM intervention. At the end of treatment, the research assessment will be repeated, 
including a query of the patient’s belief as to their treatment condition (using the Medication 
Questionnaire; MED-Q).  Blood samples for measurement of serum GGTP will be obtained to 
assess the validity of self-reported drinking.  All patients will be asked to complete an end-of-
treatment evaluation and to complete all scheduled assessments to facilitate intent-to-treat (ITT) 
analyses. At that last visit (visit 10) the subjects will be instructed to taper the medication at a 
rate of 2 mg every 4 days.  
Week 
Perampanel dose 
+/-Disulfiram 
dose 
1 
2 mg daily 
62.5 mg daily 
2 
4 mg daily 
125 mg daily 
3 
6 mg daily 
187.5 mg daily 
4-8 
8 mg daily 
250 mg daily 


Open Label Pilot Perampanel V.7 June 30 2021  HM20015846 
 
 
7
 
6.E.6. Visits 11 and 12 (Follow-up): A follow-up visit will occur weekly for two weeks after the 
patient completes the 8 weeks of the study medication.  These visits will last approximately 1 
hour and the patient will be asked to complete the same surveys they had completed during the 
weekly visits and will be assessed as to how they are doing with the taper of the medication.  
 
6.F.  Study Treatments:  Throughout the study, we will maintain open-label conditions 
regarding medication condition to optimize safety.   MM will be delivered by a study nurse who 
is experienced in its use in alcohol pharmacotherapy trials.  The PI will meet with the patient at 
the beginning of treatment and discuss clinical management with the nurse weekly.  The PI will 
evaluate the patient for severe or persistent adverse effects.  At each visit, the nurse will 
dispense study medications prescribed by the physician.   
6.F.1.  Medication Condition: The maximal dosage of perampanel to be used in the present 
study is 8 mg/day. We will use a three-week titration period. The dosage of medication will be 
increased only as tolerated and patients experiencing intolerable adverse effects will have their 
dosage decreased gradually to the highest tolerated dosage or stopped completely if necessary. 
The study nurse (in consultation with the PI) and the PI will provide guidance for patients as 
they increase their medication dosage, per the titration schedule.  Perampanel and Disulfiram 
will be purchased commercially and dispensed by the VCU research pharmacy.   
6.F.2.  Counseling: At each treatment visit, all patients will receive MM, a medically oriented 
intervention that supports the use of pharmacotherapy and maximizes medication adherence in 
AUD treatment (44).  Clinicians with minimal specialty training but who are knowledgeable about 
AUD can deliver this brief and effective intervention, which has been widely used.  In MM, the 
clinician highlights the patient’s AUD symptoms and need for treatment.  The patient is advised 
to reduce or stop drinking, is educated about AUD, is provided a rationale to take medication for 
its treatment, and is instructed on the importance of daily medication adherence.  The clinician 
and patient jointly develop an individualized medication adherence plan; and the patient is given 
information on the medications.  MM enhances adherence, providing treatment comparable to 
what is feasible in most medical settings. It is unlikely to obscure a medication effect on drinking 
outcomes. 
The first MM session will last 30 minutes and subsequent sessions 20 minutes.  During all 
sessions, the study nurse will check the patient’s BAL, vital signs and weight, adverse effects, 
medication adherence, and concurrent medications; perform a brief assessment of the patient’s 
drinking and general functioning; and make recommendations for the patient to follow until the 
next visit.  Patients with severe psychological symptoms (e.g., suicidal or violent thoughts) will 
be withdrawn from treatment and referred for appropriate clinical care.   
6.G.  Assessments:  We include measures from different sources (see Table 2) to cover the 
various domains in which alcohol treatment may exert an effect and to corroborate self-reported 
treatment effects.  
Study data will be collected and managed using REDCap electronic data capture tools hosted at 
VCU. REDCap (Research Electronic Data Capture) is a secure, web-based application 
designed to support data capture for research studies, providing 1) an intuitive interface for 
validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) 
automated export procedures for seamless data downloads to common statistical packages; 
and 4) procedures for importing data from external sources (45). 
6.G.1.  Laboratory/Medical Assessments:  These assessments serve to:  1) screen patients 
for medical exclusion criteria, 2) assess potential adverse effects of perampanel, and 3) 
corroborate self-reported drinking.  Prior to entrance into the study, each patient will receive a 


Open Label Pilot Perampanel V.7 June 30 2021  HM20015846 
 
 
8
physical exam, urinalysis and urine toxicology, CBC, a chemistry panel [which includes 
electrolytes, liver enzymes (ASAT, ALAT, GGTP), bilirubin, uric acid, BUN, and creatinine], and 
pregnancy testing. Pregnancy testing and a CBC, CMP with LFTS, bilirubin will also be 
repeated at the midpoint which is planned to be week 4 but may be adjusted per patient visit 
needs. Subjects with elevated LFTs (from baseline) will be immediately withdrawn from 
medication and closely monitored until a return to normal levels. If a patient reports being 
pregnant or tests positive, she will immediately be excluded or withdrawn from treatment with 
medication, referred for obstetric evaluation, and advised to discontinue all drinking.  At the 
midpoint (week 4) and endpoint (week 8), GGTP will be repeated to corroborate self-reported 
alcohol consumption. Endpoint labs will also include CBC, CMP with LFTs, bilirubin.The patient 
will be in the downward titration phase of the medication at this point (See Table 1: Medication 
Titration Schedule). We will also obtain Ethyl Glucuronide (EtG), and Ethyl Sulfate (EtS) as 
biomarkers to verify subjective claims of drinking during the study.  
6.G.2. Psychological/Behavioral Assessments: The assessments listed below measure 
multiple outcome criteria, because a reduction in drinking may not result in improvement in other 
domains.  
Table 2:  Schedule of Assessments 
 
 
 
Study Week 
 
SC 
BL 
1 
2 
3 
4 
5 
6 
7 
8 
+1 
+2 
Surveys/Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
Overview and Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
Locator Information 
x 
 
 
 
 
 
 
 
 
 
 
 
SCID-V 
x 
 
 
 
 
 
 
 
 
 
 
 
Medical History/ Physical/Psych 
Exam 
x 
 
 
 
 
 
 
 
 
 
 
 
FHAM 
x 
 
 
 
 
 
 
 
 
 
 
 
Table 2 Continued 
 
 
Study Week 
 
SC 
BL 
1 
2 
3 
4 
5 
6 
7 
8 
+1 
+2 
AUQ 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CIWA 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
C-SSRS 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PHQ-9 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SAFTEE 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
STAI 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
TLFB/measures of treatment 
received 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
MM 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
AADUD 
x 
 
 
 
 
 
 
 
 
x 
 
 
AEQ 
 
x 
 
 
 
x 
 
 
 
x 
 
 
BIS 
 
x 
 
 
 
 
 
 
 
 
 
 
BART 
 
x 
 
 
 
 
 
 
 
 
 
 
CGI-I 
 
 
 
 
 
x 
 
 
 
x 
 
 
CGI-S 
 
x 
 
 
 
 
 
 
 
 
 
 


Open Label Pilot Perampanel V.7 June 30 2021  HM20015846 
 
 
9
Table 2 Notes:  
(1) Week 4 is the study midpoint; (2) TLFB data will be collected at each visit to cover the period 
since the last visit (baseline will be 60 days prior to randomization); (4) Abbreviations: SC: 
screening; BL: baseline; all other abbreviations can be found under the assessments sections of 
the project description] (5) Monitoring Labs will include a CBC and CMP 12+8AC 
6.G.3. Areas assessed only at intake: 
a.  Sociodemographic/general patient information: During screening, an assessment of 
medical history, personal and family history of alcoholism, marital status, educational and 
occupational information and substance abuse treatment history will be obtained, along with the 
individual’s self-identified ancestry.   
b.  Locator information:  At the time of enrollment in the study, the research coordinator 
will select patient locators on the basis of relationship to the patient, duration and current status 
of relationship, frequency of contact with the patient, and willingness to participate.  Locators are 
contacted when efforts to reach a patient are unsuccessful, which enhances retention of 
patients in treatment and data collection.   
c.  Psychiatric diagnosis:  The Structured Clinical Interview for DSM-5 (SCID) will be used 
to classify patients according to the presence or absence of standard psychiatric disorders 
according to DSM-5 criteria.  The clinical trials version is now available (46). We may opt to use 
an online version for ease clarity.    
d.  Family history of alcohol dependence: The Family History Assessment Module (47) 
systematically queries the patient about the presence of an alcohol use disorder (AUD) in 
relatives.  The patient will provide information concerning parents’ and siblings’ history of 
alcohol use without their being identified.   
 
e. History of stressful events and trauma: The Life Stressor Checklist (Revised), a 30-
item lifetime inventory of very stressful or traumatic events.  
 
6.G.4. Areas assessed only at treatment endpoint: 
a.  Overall condition at the end of treatment (for early withdrawal from the study):  The 
Early Termination Form, indicating the patient’s level of functioning at termination, will be 
completed by the study nurse for any patients that leave treatment prematurely.  The form is 
PSS 
 
x 
 
 
 
x 
 
 
 
x 
 
 
Q-LES-Q 
 
x 
 
 
 
 
 
 
 
x 
 
 
SCID Section E 
 
 
 
 
 
 
 
 
 
x 
 
 
SCID-II (antisocial) 
x 
 
 
 
 
 
 
 
 
 
 
 
SIP 
 
x 
 
 
 
 
 
 
 
x 
 
 
SLEI 
 
x 
 
 
 
x 
 
 
 
x 
 
 
SRE 
 
x 
 
 
 
 
 
 
 
x 
 
 
Early Termination Form 
 
 
 
 
 
 
 
 
 
x 
 
 
Med-Q 
 
 
 
 
 
 
 
 
 
x 
 
 
Laboratory/Medical 
 
 
 
 
 
 
 
 
 
 
 
 
Study Week  
SC 
BL 
1 
2 
3 
4 
5 
6 
7 
8 
+1 
+2 
Screening/Monitoring Labs 
x 
 
 
x 
 
x 
 
x 
 
x 
 
 
DNA 
x 
 
 
 
 
 
 
 
 
 
 
 
ETG/EtS (urine) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Urine/blood pregnancy test 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
Breathalyzer/Vitals/Weight 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urine drug screen 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


Open Label Pilot Perampanel V.7 June 30 2021  HM20015846 
 
 
10 
used to identify the reasons for early termination (e.g., symptomatic failure, adverse effects) and 
other relevant circumstances.   
b.  Integrity of the double blind: The Medication Questionnaire (MED-Q) was developed to 
evaluate the masking procedure and will be completed by the patient at the midpoint (week 9) 
and end of treatment.  Patients who are unable to return for the endpoint and are willing to 
complete the assessments will be mailed questionnaires (with a stamped envelope to facilitate 
their timely return) and then be interviewed by telephone to collect all information.  Such 
subjects will be paid the same amount as if they actually attended the endpoint visit to complete 
those endpoint assessments.  
6.G.5. Areas assessed at intake, end of treatment, monthly, or at each visit:  
a.  Alcohol use patterns:  The Timeline Follow-back (TLFB) (43) will be used to estimate 
past 60-day drinking at intake and at every treatment visit going back in time from the last 
assessment.  This interview procedure will provide quantity/frequency of alcohol consumption 
data for each day during the period prior to the interview.  The TLFB is reliable and valid when 
used by trained interviewers.  However, it is less useful than daily measures for detecting 
patterns of alcohol consumption that vary on a day-to-day basis (48, 49). The Clinical Global 
Impression scale (CGI) will be used to assess progress in treatment monthly. The Clinical 
Institute Withdrawal Assessment (CIWA-Ar) will be used to facilitate assessment of withdrawal, 
and decisions regarding appropriateness for study entry and continuation with respect to 
physical dependence will be made based on the judgment of the PI.  
b. Alcohol craving; will be assessed at each treatment visit with the Alcohol Urge 
Questionnaire (AUQ), (50).  
c.  Alcohol-related problems:  The Short Index of Problems (SIP). The SIP, a 15-item 
instrument that is a subset of the 50-item DrInC (51), measures alcohol dependence symptoms 
and medical, psychological, social, occupational, and legal problems.  To reduce respondent 
burden, we chose to use the SIP which, like the DrInC, measures a single factor of alcohol-
related problems (61).  The Quality of life enjoyment and satisfaction survey (Q-LES-Q)(52) 
(REF) will be used to assess quality of life in subjects. 
d.  Drinking motives and expected alcohol effects:  1) Drinking Motives: Drinking motives 
will be measured with the Drinking Motives Questionnaire [DMQ;(53, 54) to explore potential 
changes as a result of treatment in drinking motives. This instrument contains 20 items with 4 
subscales, drink to a) cope motives (e.g., “Because it helps when you are feeling nervous or 
depressed”), b) conformity motives (e.g., “Because it helps me fit in”), c) enhancement motives 
(e.g., “Because it’s fun”), and d) social motives (e.g., “Because it makes a social occasion more 
enjoyable”).  The DMQ will be administered at baseline and for those subjects who continue to 
drink again at midpoint, end of treatment and at the 3-month follow-up visit.  2) Alcohol 
expectancies will be assessed with 24 items from the Alcohol Effects Questionnaire [AEQ;(55) 
probing 4 positive expectancy subscales (social and physical pleasure, aggression and power, 
social expressiveness, and relaxation and tension reduction) and 1 negative subscales 
(cognitive/physical impairment) to explore potential changes as a result of treatment with 
zonisamide.  The AEQ will be administered at baseline and for those subjects who continue to 
drink again at midpoint, end of treatment and 3-month follow-up visit. 3) Self Rating of Effects of 
Alcohol (SRE) (56) is a widely used measure of number of drinks subjects report are needed to 
produce typical alcohol effects (alcohol sensitivity) during the first use of alcohol period in one’s 
life, the past 3 months or period of heaviest use. The SRE will be administered at baseline and 
for those subjects who continue to drink again at end of treatment and 3-month follow-up visit. 
 
e.  Psychological symptoms:  1) The Physician’s Health Questionnaire (PHQ-9), a 
validated 9-item self-report measure of depressive symptoms with a total score of 0-27 (57, 58) 
will be administered at each visit.  2) The State-Trait Anxiety Inventory will be used to measure 
anxiety symptoms at each visit (59). 3) The Columbia Suicide Severity Rating Scale, C-SSRS 
(60) evaluates suicidal risk. A study nurse or research team member will administer the C-SSRS 
at each study visit and, if rated 4 or 5 (i.e., clinically significant suicidal ideation), the PI will be 


Open Label Pilot Perampanel V.7 June 30 2021  HM20015846 
 
 
11 
consulted to decide on the appropriate clinical management.  4) Monthly Stressful Life Event 
Inventory: This is a 34-item questionnaire asking subjects to report and any stressful events in 
the interim period (SLEI). 6) Perceived Stress Scale, a ten item scale measuring perceived 
stress (61).    
 
f. Behavioral assessments: Impulsivity will be assessed through the Balloon Analogue 
Risk Task (BART) and Barrett Impulsivity Scale (BIS). 
g. Medication adverse effects:  Patients will provide subjective reports of side effects at 
each study visit using the Systematic Assessment for Treatment Emergent Effects (SAFTEE) 
interview (62), a widely used measure of adverse events.  A standardized approach was 
developed for use in alcohol treatment trials (63).  
h. Measures of treatment received:  Records of medication taken will be kept and patients 
will be asked to return the unused portion of study medication at each visit.  The nurse will also 
record the number of contact hours patients have been exposed to any alcohol treatment 
outside of the study.  
 
TABLE 3: Subject visit and payment overview: 
Visit title 
VISIT # 
Weeks of 
completed 
medication 
Payment ($) 
Screening 
1 
 
50 
Baseline 
2 
0 
75 
Weekly treatment visit 
3 
1 
75 
Weekly treatment visit 
4 
2 
75 
Weekly treatment visit 
5 
3 
75 
 Weekly treatment visit (midpoint) 
6 
4 
75 
Weekly treatment visit 
7 
5 
75 
Weekly treatment visit 
8 
6 
75 
Weekly treatment visit 
9 
7 
75 
Weekly treatment visit (Endpoint) 
10 
8 
100 
Medication taper visit 1 (post 
treatment) 
11 
n/a 
25 
Medication taper visit 2 (post 
treatment) 
12 
n/a 
25 
Total 
12 
 
800 
FOR ADDITIONAL DETAILS OF SAFETY AND HUMAN SUBJECTS PROTECTION, PLEASE 
REFER TO THE ATTACHED “HUMAN SUBJECTS” APPENDIX FROM THE GRANT. ALSO, 
WE HAVE ATTACHED THE CORRESPONDING GRANT APPLICATION FOR MORE 
INFORMATION.  
 
D.3. Data Analysis/Power/Sample Size:  
The 20 perampanel-treated subjects will be compared to 20 age and sex matched placebo-
treated subjects (with stated goals of abstinence) from the databases of our completed and 
ongoing clinical trials. This quasi-experimental design will allow us to complete an informative 
and reasonably valid pilot study with substantially less cost and time. We will use ANOVA to 
compare the subjects between the two main groups (both perampanel vs placebo) for the 
percent abstinent days (primary outcome) during the eight-week study period. We will also 
compare the three groups directly (perampanel vs disulfiram/perampanel vs placebo). We will 


Open Label Pilot Perampanel V.7 June 30 2021  HM20015846 
 
 
12 
explore several secondary outomes such as perampanel effects on craving, heavy drinking 
days per week, etc. using longitudinal mixed models. Power analysis: No studies have 
examined the clinical response to perampanel in AUD, but we should have power = .80 to 
detect effect sizes = .45 or greater. The secondary outcome analyses with mixed models will 
have greater power.  
 
Personalized Medicine Analysis: In this aim we plan to elucidate metabolic and genetic 
variable important for perampanel efficacy in the treatment of AUD. For the drug Acamposate, 
which is thought to inhibit glutamate in the brain, elevated baseline levels of glutamate in serum 
are associated with positive response to treatment for AUD. Since Perampanel is a glutamate 
receptor antagonist, it is logical that elevated serum glutamate levels may also be a biomarker 
for Perampanel effectiveness against AUD.  
Measurement of glutamate levels in the serum: To determine if serum glutamate levels 
effect the patient’s response to perampanel treatment for AUD serum will be drawn at multiple 
time-points during the clinical trial described in Aim 1: baseline levels (before treatment), after 
each treatment regimen (perampanel).  
In addition to glutamate as a biomarker this aim will also examine the role of genetic 
polymorphisms in response to Perampanel. DNA samples will be genotyped on the Illumina 
PsychChip GWAS array. We will focus on 127 SNPs in 13 genes from the NMDA-dependent 
AMPA receptor trafficking cascade as identified by Karpyak and colleagues as predictive of 
AUD in our analysis of perampanel’s effects on alcohol response. We will use the genotype at 
these SNPs to construct a genetic risk prediction score (GRPS) variable for each subject, which 
allows us to easily include a variable to be compared between-subjects, and eliminates issues 
with multiple testing. The GRPS represents the degree of genetic loading with AUD-risk variants 
across the AMPA-R related gene set.  
 
 


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13 
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