Clinical trial NCT02120365
Conditions: Alcoholism
Keywords: Alcoholism Heavy Drinking Perampanel
Sponsor: Virginia Commonwealth University
Start date: 2019-06-01; Completion date: 2022-02-16
Enrollment: 22 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to determine whether perampanel alters the response to alcohol for heavy drinkers. It is hypothesized that perampanel will reduce the rewarding and reinforcing properties of alcohol in the laboratory setting.

Detailed description:
The main goal of the proposed study is to determine whether the alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor (AMPA-R) antagonist perampanel alters the response to ethanol (i.e., the rewarding and reinforcing effects) using a validated laboratory paradigm of intravenous (IV) ethanol infusion. Fifty non-treatment seeking heavy drinkers (NTSHDs), N=50, and twenty-five social drinkers (N=25) will undergo three test days each: once after receiving a placebo medication, once after receiving moderate dose perampanel, and once after receiving a higher dose of perampanel. This experiment is the first step in a series of expedient studies that will rapidly determine perampanel's potential as a treatment for alcohol dependence. If findings show perampanel reduces the rewarding and reinforcing properties of alcohol in the laboratory setting (in humans), it would provide a strong rationale for clinical treatment trials with this medication. This approach is innovative because it tests a highly novel AMPA-R antagonist for the treatment of alcoholism, and uses a state-of-the-art computer assisted IV alcohol pump infusion system (called CAIS) to reduce variability in blood alcohol concentrations, thus improving the data quality.

Arms: arm 1: Participants will have 3 test days each, 2 weeks apart, in a randomized order, following either pretreatment with daily perampanel 2mg days prior to each test day, and then observed dosing moderate 6mg dose perampanel in the lab 1 hour before a one-time alcohol infusion . Each lab session occurs exactly a week after starting the medication for that round. The wash out period between lab test session phases will be 7-10 days. Subjects will receive 2 days of 2mg perampanel after each lab to taper down (included in the washout period). The next appointment will be brief at the start of the next phase, at which point the next week of low dose perampanel or placebo will be started. With the washout period and the 7 day taper of the next phase, the actual lab sessions will occur 14-17 days apart. All test days will involve administration of alcohol with the same 3 target doses \[target Breath Alcohol Concentration (BrAc) =20mg%, 60mg%, and 100mg%\] in a step-wise fashion. arm 2: Participants will have 3 test days each, 2 weeks apart, in a randomized order, following either pretreatment with placebo 7 days prior to each test day, and then observed dosing of placebo in the lab 1 hour before a one-time alcohol infusion . Each lab session occurs exactly a week after starting the medication for that round. The wash out period between lab test session phases will be 7-10 days. Subjects will receive 2 days of 2mg perampanel after each lab to taper down (included in the washout period). The next appointment will be brief at the start of the next phase, at which point the next week of low dose perampanel or placebo will be started. With the washout period and the 7 day taper of the next phase, the actual lab sessions will occur 14-17 days apart. All test days will involve administration of alcohol with the same 3 target doses \[target Breath Alcohol Concentration (BrAc) =20mg%, 60mg%, and 100mg%\] in a step-wise fashion. arm 3: Participants will have 3 test days each, 2 weeks apart, in a randomized order, following either pretreatment with daily perampanel 2mg 7 days prior to each test day, and then observed dosing of high dose perampanel (10mg) in the lab 1 hour before a one-time alcohol infusion . Each lab session occurs exactly a week after starting the medication for that round. The wash out period between lab test session phases will be 7-10 days. Subjects will receive 2 days of 2mg perampanel after each lab to taper down (included in the washout period). The next appointment will be brief at the start of the next phase, at which point the next week of low dose perampanel or placebo will be started. With the washout period and the 7 day taper of the next phase, the actual lab sessions will occur 14-17 days apart. All test days will involve administration of alcohol with the same 3 target doses \[target Breath Alcohol Concentration (BrAc) =20mg%, 60mg%, and 100mg%\] in a step-wise fashion.
Interventions: intervention 1: Perampanel intervention 2: Placebo
Intervention descriptions: intervention 1: 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). To date, there have been no clinical trials of AMPA-R antagonists (e.g., perampanel) for the treatment of alcoholism. intervention 2: Placebo given in place of perampanel during the pre-treatment period and lab session days.

Protocol documents:
Prot_SAP_002.pdf: 
VCU IRB PROTOCOL NUMBER: HM20014446.  V.5 06APR2021 
 
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1.  Principal Investigator: Albert Arias, MD  
2. Title of the project: 
Rapid Determination of The Clinical Utility Of Perampanel For The Treatment Of Alcohol 
Dependence 
 
3. Purpose, hypothesis and key questions 
 
3.A. PURPOSE: There is a great need to develop more effective medications to treat alcohol 
dependence. 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 dependence. A good way to test the potential 
usefulness of a medication in the treatment of alcohol dependence (in humans) is to examine its 
effects on the response to alcohol in the laboratory setting. The main goal of the proposed study 
is to determine whether the AMPA-R antagonist perampanel alters the response to ethanol (i.e., 
the rewarding and reinforcing effects) using a validated laboratory paradigm of intravenous (IV) 
ethanol infusion. Fifty non-treatment seeking heavy drinkers (NTSHDs, N=50), and twenty-five  
social drinkers (N=25) will undergo three test days each: once after receiving a placebo 
medication, once after receiving moderate dose perampanel, and once after receiving a higher 
dose of perampanel. This experiment is the first step in a series of expedient studies that 
will rapidly determine perampanel’s potential as a treatment for alcohol dependence. If 
findings show perampanel reduces the rewarding and reinforcing properties of alcohol in the 
laboratory setting (in humans), it would provide a strong rationale for clinical treatment trials with 
this medication. This approach is innovative because it tests a highly novel AMPA-R antagonist 
for the treatment of alcoholism, and uses a state-of-the-art computer assisted IV alcohol pump 
infusion system (called CAIS) to reduce variability in blood alcohol concentrations, thus 
improving the data quality. 
 
3.B. SPECIFIC AIMS/DESIGN/HYPOTHESES: This is a within subject, randomized, double-
blind, counterbalanced, crossover study, in which subjects receive perampanel (or a placebo) 
titrated over 1 week, and then participate in a three-stage, clamped, IV alcohol administration 
procedure. Each subject will have three IV alcohol administration sessions; two preceded by 
perampanel (moderate and higher dose), the other preceded by pretreatment with placebo, in 
double-blind fashion, separated by a 21 day “wash-out” period.  
 
3.B.1. Primary Aim/Hypothesis: To evaluate perampanel’s effects on the subjective response 
to (i.e., the perceived positive and negative reinforcing, as well as aversive effects of) IV alcohol 
administration such as stimulation, sedation, and euphoria (or “high”), using the Biphasic 
Alcohol Effects Scale (BAES) and the Drug Effects Questionnaire (DEQ) for the co-
primary outcome measures (perampanel will be given orally, alcohol will be given IV), in N=50 
NTSHDs and N=25 Social Drinkers. We hypothesize that NTSHDs will have less self-reported 
stimulation, increased sedating/unpleasant effects, and attenuated euphoric effects during an IV 
alcohol administration session after pretreatment with perampanel, dose-dependently, 
compared to placebo.  
 
3.B.2. Secondary Aim/Hypothesis: To examine the effects of perampanel on ratings of 
craving for alcohol, alcohol-induced changes in mood, anxiety, and impulsivity (inhibition) in 
NTSHDs during IV administration of alcohol.  We hypothesize that subjects will endorse a 


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significant attenuation of cravings and mood changes during an IV alcohol administration after 
pretreatment with perampanel as compared with pretreatment with placebo. Further we 
hypothesize that alcohol-induced impulsivity will be attenuated by perampanel. Secondary aims 
will be measured using the Subjective Effects of Alcohol Scale (SEAS) the Alcohol Urge 
Questionnaire (AUQ), the Go-No-Go task, the balloon-analogue risk task (BART), and the 
Profile of Mood States (POMS, short version). 
 
3.B.3. Exploratory Aims/Hypothesis: We will also obtain DNA for genotyping. The subjects’ 
family history of alcoholism (FHA) will also be explored as a moderating factor in the response 
to alcohol and the investigational medication. We hypothesize that subjects on perampanel, 
compared to placebo, will experience less change in mood, and greater reduction in anxiety 
levels,. We hypothesize that perampanel effects on alcohol response are moderated by 
variation in genes related to glutamatergic neurotransmission, and that the effect of genotype is 
greater than that of FHA status.  
 
4. BACKGROUND:  
4.A. Glutamate and Addiction:  Glutamate, the major excitatory neurotransmitter in the brain, 
participates in neuroprolific, neurotoxic, and neuromodulatory processes (1). Altered 
glutamatergic neurotransmission plays a significant role in the pathophysiology of alcoholism (2, 
3). Glutamatergic neurotransmission within and on dopaminergic pathways is thought to be a 
key and likely necessary component for the development and maintenance of addiction (4). 
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” (4).  
 
4.B. AMPA Receptors and Alcoholism Pathophysiology: Glutamate acts on N-methyl-D-
aspartate (NMDA), alpha-amino-3-hydroxyl-5-methyl-isoxazole-4-proprionic acid (AMPA), and 
kainite receptors. AMPA receptors may have a more significant role than other glutamatergic 
receptors in glutamate-facilitated dopamine release in the NAS and subsequent reward. AMPA 
receptors play a significant 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, but activation of AMPA receptors pre-synaptically in the 
NAS, and also activation of AMPA receptors 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 antagonist does (4, 5). This may be 
related to the physiology of medium spiny neurons of the NAS in which AMPA but not NMDA 
receptors are active due to the relative state of hyperpolarization. AMPA-R antagonists may 
reduce the reward and reinforcement of alcohol and other drugs and may reduce craving and 
relapse. More recent animal studies have confirmed these previous findings and suggest that 
AMPA-Rs are involved in the return to drug seeking behaviors (6-11). 
 
AMPA-R antagonists injected into the Nucleus Accumbens Core (NAC) attenuate cue-induced 
relapse to cocaine (12). Sanchis-Segura et al., (13) showed the AMPA antagonist GYKI 52466 
reduced cue-elicited reinstatement of alcohol seeking behavior and the alcohol deprivation 
effect in two animal models. An AMPAR antagonist injected into the NA reduced conditioned 
place aversion from naloxone in rats (14). 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 crave alcohol 
after being exposed to cues (15). In that study, an AMPA-R agonist increased ethanol 


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consumption and 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, and also gives us good 
genetic targets to examine when devising a pharmacogenetically-guided intervention. 
 
The next step in translating this research would be to use a three-stage, fixed-dose alcohol 
administration paradigm (such as the one described in this application) to study perampanel’s 
effects on the reinforcing and rewarding properties of alcohol in humans. Fixed-dose alcohol 
administration paradigms’ have been used successfully in the development of other medications 
for alcohol use disorders such as naltrexone and topiramate, as both have been shown to 
reduce the positively reinforcing effects of alcohol (16, 17). Use of the IV paradigm is innovative, 
delivers alcohol without the variability of oral alcohol administration, and is the most efficient and 
accurate way to test new medications for their clinical utility ahead of clinical treatment trials. 
Alternative approaches include a cue-elicited craving paradigm or self-administration paradigm. 
Craving is a complicated concept and not reliable for medication development. For example 
topiramate which is clearly efficacious for alcoholism, does not consistently reduce cue-elicited 
craving in the laboratory (16). Further, some medications such as memantine decrease craving 
but do not reduce drinking (18-20). Floor effects limit self-administration paradigms because the 
artificial setting of a laboratory can deter subjects from drinking. 
 
 
4.C. Perampanel: 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) (21). 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 (22-24). In vitro studies of rat 
hippocampal slices have demonstrated the selective action of perampanel on the AMPA 
receptor (25). Perampanel does not appear to block the ion channel, but binds the AMPA-R at 
an allosteric site referred to as the GYKI receptor (25, 26).  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 (23, 24). Medication related adverse events/side effects with chronic 
dosing in epilepsy trials have included; dizziness, somnolence, irritability, headache, fall, and 
ataxia (23, 24). For the proposed study, subjects will receive perampanel for a week, followed 
by a brief taper/washout period. Because of that, we will use a 2mg daily dosing for 1 week, and 


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then subjects will take a one-time larger dose (moderate 6 mg or high 10mg) the morning of the 
lab test session. This brief titration with a one-time higher dose for the test session should be 
safe and well tolerated, and will allow us to estimate the effects of a larger dose of the drug 
without taking several additional weeks to titrate the drug. Pharmacokinetically, perampanel has 
an elimination half-life T1/2 of over 52 hours (estimated at 70 hours, but with a wide range from 
52-129 hours) and reaches peak plasma concentration (Tmax) approximately 1 hours post-
ingestion (21). 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. 
 
5. Significance: This study will gather critical information about perampanel’s potential as a 
treatment for alcohol dependence. It will provide information on perampanel’s effects on craving 
and impulsivity with alcohol, and help describe the mechanism of action of the medication 
relative to alcohol dependence treatment. New treatments are needed, and perampanel has 
pharmacodynamic and safety profiles that suggest it could be a beneficial addition to the 
treatment options for alcohol dependence.  
 
6. RESEARCH PLAN/EXPERIMENTAL METHODS:  
6.A. Subjects/Recruitment: Standard NIAAA alcohol administration study recruitment and 
safety guidelines will be followed to determine patients’ eligibility for participation (27). 
Participants will consist of fifty NTSHD (N=50) and twenty-five (N=25) Social Drinkers,. To meet 
criteria for NTSHD, subjects will have to  drink more than 4 standard drinks (SD) per day on at 
least one day per week on average for men, and >3 SD/day at least once weekly for women, 
and must have become intoxicated to the point of being “drunk” on at least one occasion 
(meaning at least 5 SD) within the last year without untoward effects. Criteria for Social Drinkers 
is defined as drinking at least twice per month (two occasions), and have tolerated 5 standard 
drinks (in one drinking occasion) over the past year without untoward effects.  The NTSHD 
population has been used in prior alcohol administration studies (28, 29).  Baseline drinking, 
and drinking in between the lab administration sessions will be evaluated using the Timeline 
Follow Back Method (TLFB). The study plan will be to enter 75 subjects in the sessions, 50 
NTSHD approximately 35 male and 15 female and 25 social drinkers approximately 15 males 
and 10 females, with the sample inclusive of minorities and representative of the greater 
Richmond Metro Area.  Participants will be recruited through advertisement in the community 
and we may access our CARI registry (HM20014185) of previously screened participants who 
have indicated that they may be contacted for future studies.  We will recruit and screen up to 
150 subjects, with the goal to enter 75 subjects and to complete 50 subjects. Subjects will earn 
$315 for the first session, $315 for the second, and $315 for the third laboratory session. 
Subjects can earn up to an additional $90 from the study based on their scoring on one of the 
tasks in the study, the Balloon Analogue Risk Task. Subjects will also receive $50 for 
completing the screening process and $15 for the initial outpatient visit and $25 at the outpatient 
visits prior to Phase II and Phase III (3 separate visits to pick up the take home supply of study 
medication). If there is a need to repeat a laboratory test to confirm any values obtained at 
screening, we will offer them an additional $10 . We will ask the first 5-10 participants to return 
to the clinic for an additional visit between days 7-10 post-lab sessions in order to evaluate a PK 
level. We may choose to extend this to all participants if it becomes clear that it is necessary for 
monitoring, and they will receive $20 for this visit. Thus, participants can potentially earn up to 
$1200 for their participation.  
 
The inclusion criteria will be: 1) males and females; 2) between the ages of 21 and 70 years 
(inclusive); 3) NTSHDs as defined above, and must have had at least 5 SD in one day on at 


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least one occasion in the past and been able to tolerate it without an adverse reaction, or Social 
Drinkers who drink at least twice per month and on at least one occasion in the past been able 
to tolerate 5 drinks without an adverse reaction, 4) generally medically and neurologically 
healthy on the basis of history, physical examination, EKG, screening laboratory results (CBC 
w/ differential, TSH, Free-T4, AST, ALT, GGT, BUN, creatinine, electrolytes, urinalysis, beta-
HCG, infectious hepatitis serology).  Individuals with LFTs that are no more than 2-3 times 
above the normal levels will be included; we will use the AST, ALT, and Total Bilirubin to 
determine this (AST or ALT must be no more than 2-3 times above normal, with a Child-Pugh 
score of no greater than 5, and total bilirubin no more than 2 times above normal based on the 
normal cutoff levels for assays at the laboratory); 5) women of child-bearing potential (i.e. no 
hysterectomy, bilateral oophorectomy, or tubal ligation or <2 years postmenopausal), must be 
non-lactating, practicing two reliable methods of birth control and one must be a non-hormonal 
based method (like condoms or a diaphragm and spermicide), and have a negative serum 
pregnancy test prior to initiation of treatment 6) negative breath alcohol at screening and on 
each test day; 7) In past 30 days: are not taking opioids, are not taking any CNS depressants 
(e.g. benzodiazepines, barbiturates, sedating anthistamines), are not taking any anti-epileptic 
drugs; and 8) are non-treatment seeking.  
 
Exclusion criteria: 1) Need for detoxification determined by a CIWA (Clinical Institute 
Withdrawal Assessment for Alcohol Scale) (30) score >8 or history of alcohol detoxification in 
the past; 2) have been in treatment for an alcohol problem within the last 6 months, or if the 
severity of their alcohol problem based on the research physician’s assessment warrants 
definitive treatment; 3) may not have a history of bipolar or primary psychotic disorder (e.g., 
Schizophrenia)  (assessed by Structured Clinical Interview for DSM-V Disorders: SCID 5)(31); 
other psychiatric diagnoses that are not currently active (e.g. major depression) and are under 
control (e.g. with medication or other treatment), or in remission, are not exclusions; 4) May not 
have a currently active psychiatric or substance use disorder diagnosis (i.e., one that is not 
under control or in remission), other than alcohol abuse/dependence, cannabis 
abuse/dependence, and nicotine dependence; those diagnoses will be allowed; participants can 
be either smokers up to 1 pack per day or non-smokers, based on history and psychiatric 
evaluation that includes a structured diagnostic interview 5) unwillingness to remain alcohol-free 
12 hours prior to test days; 6) have a significant ongoing serious medical condition such as 
Diabetes Mellitus, liver disease (see above LFT guideline), renal disease (as evidenced by 
serum creatinine above our laboratory’s reference limit of 1.7 mg/dL, or have a history of 
adverse reaction to IV placement/blood draw; 7) 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).  
 
 
 
6.B. Laboratory Session Overview: Participants will complete 3 test days each, at least 21 
days apart, in a randomized counter-balanced order, under double-blind conditions, following 
either pretreatment with daily perampanel 2mg or placebo 7 days prior to each test day, and 
then observed dosing (of placebo, moderate 6mg dose perampanel, or high dose 10mg) in the 
lab 1.5 hours before alcohol infusion (a one time dose). Adherence will be assessed by addition 
of riboflavin 25mg to medication, and detection of riboflavin in urine on test days. Each lab 
session occurs exactly a week after starting the medication for that phase, which means 
participants will have taken it for 7 days prior to the lab session, and the lab session will be the 
eighth day in a row on the study medication. The wash out period between lab test session 
phases will be 21 days. Subjects will receive 2 days of 2mg perampanel after each lab to taper 


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down (included in the washout period). Subjects will receive the observed 6mg and 10mg 
perampanel doses on lab session days only after the week of pretreatment with perampanel 
2mg daily. Those sessions will be followed by the tapering dose of actual perampanel. The 
observed placebo dose on placebo lab session days will occur following a week of placebo pre-
treatment, and will be followed by a tapering period using placebo pills.  
 
The next appointment after a lab session will be a brief one at the start of the next phase (see 
day 1 of the phases in figure 1 below), at which point the next week of low dose perampanel or 
placebo will be started. We will allow the dose dispensation to occur up to 2 days prior to the 
first day of dosing. With the washout period (21 days) and the 7 day medication administration 
of the next phase, the actual lab sessions will occur approximately 28 days apart. All test days 
will involve administration of alcohol with the same 3 target doses (target BrAc=20mg%, 
BrAc=60mg%, and BrAc=100mg%) in a step-wise fashion. We will maintain phone contact with 
subjects during the week that they are on medication and will talk to them once by phone in 
days 2-4 on the medication, and once between days 5-7, inquiring about side effects, especially 
neuropsychiatric side effects. If there is a concern we will ask them to come to the research 
center for evaluation by study staff and/or a study physician as needed. They will be able to 
contact the Principal Investigator or study staff personnel at any time. After the screening visits, 
which will take place most likely on 2 separate days (1-2 visits), subjects will begin the 
medication and laboratory administration phases (see below schematic). We will ask the first 5-
10 participants to return to the clinic for an additional visit between days 7-10 post-lab sessions 
in order to evaluate a PK level. We may choose to extend this to all participants if it becomes 
clear that it is necessary for monitoring. 
 
FIGURE 1: OVERVIEW SCHEMATIC 
 
                        Phase I 
                         Phase II 
                        Phase III 
Day 1 
Outpatient 
Visit: 
Start PRM 
2mg daily 
or PLC (up 
to - 2 days 
prior to 
starting 
medication) 
Day 8 
Lab 
Session: 
PRM 6mg 
or 10mg, 
or PLC 
Washout for 
14 days: 
Includes 2 
days of 2mg 
PRM or PLC 
taper 
Day 1 
Outpatient 
Visit: 
Start PRM 
2mg daily 
or PLC 
Repeat 
labs (up to 
- 2 days 
prior to 
starting 
medication) 
Day 8 
Lab 
Session: 
PRM 6mg 
or 10mg, or 
PLC 
Washout for 
14 days: 
Includes 2 
days of 2mg 
PRM or PLC 
taper 
Day 1 
Outpatient 
Visit: 
Start PRM 
2mg daily 
or PLC 
Repeat 
labs (up to 
- 2 days 
prior to 
starting 
medication) 
Day 8 
Lab 
Session: 
PRM 6mg 
or 10mg, or 
PLC 
Finish 
Includes 2 
days of 2mg 
PRM or PLC 
taper 
PRM= Perampanel, PLC= Placebo 
6.C. Screening and Initial Assessments:  After providing written informed consent, subjects 
will be interviewed using the SCID. We may opt to use an online version of the SCID for ease 
and clarity. The timeline follow-back (TLFB) (33) will be used to document heavy drinking status 
and the degree of daily alcohol consumption prior to entry.  The CIWA will be used to assess for 
current symptoms of alcohol withdrawal.  EKG, urine toxicology, and other screening labs (CBC 
w/ differential, TSH, Free-T4, AST, ALT, GGT, BUN, creatinine, electrolytes, urinalysis, beta-
HCG, infectious hepatitis serology) will be collected at this appointment. Subjects will have a 
psychiatric/medical examination by a study psychiatrist or Nurse Practitioner. Family history of 
alcohol problems will be evaluated using the family history assessment module (FHAM) (34). 
Trait impulsivity will be measured with the Barrett Impulsivity Scale (BIS) (35). The screening 
and initial assessments will likely be completed in 1-2 visits. During the initial lab session 
bloodwork, a DNA sample will also be collected to be evaluated for potential genetic variants 
which may contribute to alcoholism. 
 


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6.D. Experimental procedure: After initial screening, eligible participants will be randomized to 
receive double-blind perampanel (moderate and high dose) or placebo in a counterbalanced 
order (i.e., each subject will receive all three conditions; perampanel moderate dose, high dose, 
and placebo, but in a random and counterbalanced order). Perampanel and placebo will be 
packaged in identical looking capsules. The research pharmacist will perform randomization. 
Study staff will be blinded during the study to medication/order assignment. All subjects will be 
informed of receiving alcohol and how much (peak BrAC) on both occasions but will be kept 
blind to the real-time BrAC levels during the lab sessions. Participants will be asked to refrain 
from using caffeine and alcohol for 12 hours before their scheduled test session (example: 
refrain from 8:00 PM if test day starts at 0800) and to fast starting at midnight the night before 
the scheduled test session.  Participants will be asked to come to the laboratory at 
approximately 8:00 A.M on test days.  Upon arriving for each test session, subjects will have a 
urine drug screen, urine pregnancy test (females), and Breathalyzer to measure breath alcohol 
levels.  Symptoms of alcohol withdrawal will be assessed using the CIWA.  If the CIWA score is 
> 8, or if the urine drug screen, pregnancy test, or Breathalyzer is positive, then a decision will 
be made by study staff and the PI about whether to end the subject’s participation or to allow 
them to reschedule for some point over the next 7 days. The 2mg daily perampanel would be 
extended for up to 7 days in the case of rescheduling. Otherwise, before eating a standardized 
breakfast, an IV line will be inserted and we will take a blood sample for a CBC, the DNA 
sample, and perampanel trough levels. Participants will then take their 6mg,10mg perampanel, 
or placebo dose in the lab.  In order to maximize perampanel absorption breakfast will be given 
60 minutes after the medication is taken. One and a half hours (1.5) after ingesting perampanel, 
the infusion of alcohol will begin.  
 
The infusion will begin with a placebo alcohol infusion (i.e. y-tubing using normal saline at 50mL, 
infused over 10-15 minutes to gauge participant baseline and placebo effect) prior to the alcohol 
infusion. Alcohol will be administered by IV for 7 minutes to achieve the first target BrAc level of 
20mg%. Once the first BrAc is achieved, it will be maintained using a clamp procedure for 35 
minutes for measurements (outcomes) to be obtained.  This will be followed by additional 
administration of alcohol to achieve BrAc level of 60mg% for 14 minutes.  This alcohol level will 
be maintained for 35 minutes. The last phase of the alcohol administration will consist of alcohol 
infusion to reach BrAc level of 100mg%, over 14 minutes, and this level will be maintained for 
35 minutes. The subjects will remain on the Clinical Research Services Unit for several hours 
until the effects of alcohol have worn off.  A healthcare provider will clear subjects at the end of 
each test day. For safety monitoring, during the initial few (potentially between 3-5) participants’ 
laboratory sessions, we plan to observe them overnight in our hospital-based Clinical Research 
Services Unit which is where the infusions and labs will occur. If we determine that there is 
additional benefit that outweighs participant burden, we may adjust to have additional 
participants stay overnight.  Subjects must have a BrAC of ≤ 20mg% before leaving the unit. 
The 3 step increasing IV ethanol dose paradigm is a reliable and valid method (17, 36, 37). See 
Table 1 below.  Prior to testing, subjects will be asked to make arrangements for transportation 
home from the test session, or the study staff will arrange for a car service to drive the subject 
home, in order to avoid difficulties driving with any residual sedation. 
 
 
IV Alcohol Solution: The IV alcohol solution is a 6% alcohol solution in 0.9% saline, with 
approximately 2 oz. of ethanol in each bag. We will use two IV solution bags with a dual pump 
controlled by a computerized assisted infusion system that adjusts for optimal alcohol 
administration based on personalized parameters. 
 


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6.E. Behavioral Assessments: On experimental session days (after the pretreatment with 
perampanel or placebo), participants will complete self-report measures of recent 
substance/alcohol use. Smokers will complete the Fagerstrom Test for Nicotine Dependence 
[FTND] (38) at baseline, and will complete the Minnesota Nicotine Withdrawal Scale (39) along 
other measures during lab sessions, in order to measure and control for nicotine withdrawal 
effects. Subjects will be asked to have their last cigarette prior to starting pre-lab medication 
administration and activities, at each session.  
 
6.E.a. During the ethanol infusion sessions: measures of subjective responses to alcohol 
activation, stimulation, and craving (“the alcohol effects battery”), will be administered at 
baseline and at each of the BrAC levels 0.00, 0.02, 0.06, and 0.10 g/dL (see Table 1). 
Participants will also be assessed by research staff using the H Impairment Index (HII), and the 
SEAS (Subjective Effects of Alcohol Scale) and direct observations by the PI will be made 
before proceeding further. 
 
Co-Primary Outcomes:  
 
Biphasic Alcohol Affects Scale (BAES): A 14-item scale with 7 items designed to assess 
stimulant effects from alcohol intoxication and 7 items developed to measure the sedative 
effects of alcohol. This scale was selected as a primary outcome measure because it is 
sensitive to the effect of alcohol (40).  
 
Drug Effects Questionnaire (DEQ) (41): consists of four items that measure current alcohol 
effects: 'feel alcohol', 'feel high', 'like alcohol', and 'want more alcohol'. 
 
Secondary Outcomes:  
 
Visual Analog Scales of Mood States (VAS): A 5-item scale designed to assess subjective 
alcohol effects: high, anxious, drowsy, irritable, and nauseous. It has been used in previous 
studies by our group and has good sensitivity to drug effect.  
 
Alcohol Urge Questionnaire (AUQ): A valid eight-item Likert-type scale designed to assess 
acute alcohol craving (42).   
 
Subjective Effects of Alcohol Scale (SEAS): a psychometric self-rating scale of 22 variables 
which measures self-reported alcohol effects immediately after the “final drink” and again at 90 
minutes after the “final drink”. 
 
 
Side Effect Questionnaire (SEQ): This consists of a list of side effects associated with 
perampanel (e.g., fatigue, dizziness), rated from 0=”none” to 4=”severe”.  
 
POMS 2 Short Versions: The POMS 2 short version contains a subset of 35 items from the full-
length versions. This subset comprises those five items on full version POMS scale that 
exhibited good item-total correlations and best predicted their respective scale scores (44, 45).  
 
Stop Signal Test (SST, also know as Go/No-Go): SST is a commonly used test of response 
inhibition. This test consists of two parts. In the first part, the subject is introduced to the press 
pad, and told to press the left hand button when they see a left-pointing arrow or press the right 
hand button when they see a right-pointing arrow. There is one block of 16 trials for the subject 
to practice this. In the second part, the subject is told to continue pressing the buttons on the 


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press pad when they see the arrows, as before, but, if they hear an auditory signal (a beep), 
they should withhold their response and not press the button.  
 
The Balloon Analogue Risk Task (BART): This is a valid and commonly used test of risk-taking, 
an aspect of impulsivity. This task is computerized, and subjects press a button to analogously 
pump air into a balloon on the screen. Subjects are told they can earn 1 cent for each pump of 
the balloon banked to a reward account before they cash out and stop pumping. The balloons 
break at various random intervals and if the balloon breaks, the subjects lose money out of the 
reward account. We will use a 10-balloon paradigm, a briefer but valid version of this task. They 
can earn a maximum of 7.5 dollars per administration, with 4 administrations per lab, for a total 
of up to $90 additional pay over the course of the study, though actual payouts will likely be 
substantially less.  
 
Number of Drinks Scale (NDS): used to assess how many drinks the subject feels he/she has 
consumed at a specific timepoint. 
 
Safety Questionnaires: 
 
H-Impairment Index (HII): A 5-question scale scale which uses a group of common bedside 
tests to determine the severity of alcohol impairment. 
 
Clinical Institute Withdrawal Assessment Scale (CIWA):   A clinician administered assessment 
used to rate the severity of alcohol withdrawal symptoms.  The CIWA will be administered at 
each appointment. 
 
Columbia-Suicide Severity Rating Scale (C-SSRS) (46): The C-SSRS has both lifetime/recent 
and since last visit versions.  The “Lifetime/Recent” version gathers information on lifetime 
history of suicidality and recent suicidal ideation/self-injurious behavior.  The “Since Last Visit” 
version of the C-SSRS asks about any suicidal thoughts or behaviors the subject has exhibited 
since the last time administered the C-SSRS. 
 
 
SAFTEE: (47) A technique that is used for the systematic assessment of side effects in clinical 
trials.  The SAFTEE will be reviewed by the study nurse and specific symptoms, as well as 
severity, will be recorded. The SAFTEE will be administered during each outpatient visit and test 
session.    
 
 
Table 1.  Experimental Session Day 
Time (minutes) 
Assessments 
T-100 
Urine drug screen, urine pregnancy test (females), breathalyzer, CIWA, TLFB, SAFTEE, Vital Signs, IV 
line inserted, perampanel blood level drawn, blood sample for CBC collected, DNA 
T-90 
Take oral study medication (either perampanel or placebo), Vital Signs,  
T-45 
Alcohol-effects assessment battery (NDS, BAES, DEQ, VAS, AUQ, MNWS, SEQ , POMS, SST, BART, 
HII, SEAS) 
T-30 
Standardized breakfast 
0 
Infusion begins, Vital Signs 
During PLC infusion: Alcohol-effects battery (NDS, BAES, DEQ, VAS, AUQ, MNWS, SEQ, POMS, SST, 
HII, SEAS) and BrAC 0.00 g/dL 
T+07 
Infusion clamped (approximately 35min) alcohol BrAC 0.02 g/dL, Vital Signs 
T+12 
Alcohol-effects assessment battery (NDS, BAES, DEQ, VAS, AUQ, MNWS, SEQ , POMS, SST, BART, 
HII, SEAS) 
T+42 
Infusion increased to target next alcohol level, Vital Signs 


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T+56 
Infusion clamped (approximately 35 min) alcohol BrAC 0.06 g/dL, Vital Signs 
T+61 
Alcohol-effects assessment battery (NDS, BAES, DEQ, VAS, AUQ, MNWS, SEQ, POMS, SST, BART, 
HII, SEAS) 
T+91 
Infusion increased to target next alcohol level, Vital Signs 
T+105 
Infusion clamped (approximately 35 min) alcohol BrAC 0.10 g/dL, Vital Signs 
T+110 
Alcohol-effects assessment battery (NDS, BAES, DEQ, VAS, AUQ, MNWS, SEQ, POMS, SST, BART, 
HII, SEAS),   
T+140 
Infusion ends 
T+ 170 
Lunch 
T+ 200 
Alcohol-effects assessment battery (NDS, BAES, DEQ, VAS, AUQ, MNWS, SEQ, POMS, SST, HII, 
SEAS), Vital Signs 
T+260 
Test day debriefing, C-SSRS, Vital Signs, and discharge when BrAC ≤ 0.02 g/dL 
 
 
6.F. Data Analysis: We have well developed statistical methods to analyze alcohol challenge 
studies. All statistical testing will be at a two-tailed alpha level of 0.05 and will be performed in 
SAS. For the primary, and secondary hypotheses we will use mixed-effects models to assess 
change in stimulation, sedation, and craving for alcohol during intravenous infusion of alcohol. 
Pretreatment medication (perampanel moderate versus high dose versus placebo) and gender 
will be used as between-subject factors, and alcohol concentration doses (target BrACs of 0.00, 
0.02, 0.06, and 0.10 g/dL) as a four-level within-subject factor.  The primary goal of these 
analyses will be to test for differences in measures of stimulation, enjoyment, craving, and 
sensitivity to alcohol as a function of perampanel pretreatment. The primary outcome dependent 
variable will be stimulation as measured by BAES. We will explore the measure of trait 
impulsivity (BIS) as a covariate, but will also explore the effect of genotype in a mixed model 
analysis as in independent variable in a pharmacogenetic model. We will explore the effects of 
perampanel, alcohol, and genotype on measures of state impulsivity and risk taking.  
 
Power Analysis: No human studies have examined perampanel in psychiatric/substance-using 
populations. We calculated an effect size for naltrexone based on Ray et al. (17), for the effect 
of naltrexone on stimulation (BAES) and will extrapolate this effect to perampanel.  Based on 
this calculated effect size (d) of 0.45 (e.g. a moderate effect size), we should be able to show a 
significant difference between perampanel and placebo groups using a two-sided, paired 
sample t-test, with alpha = 0.05 and power (1-Beta) of at least 0.80 with n = 25 subjects in each 
experimental group (total N = 50).  We will recruit and enter N = 150 subjects, in order to 
complete at least 50.   
 
 
7. Limitations and/or potential pitfalls: Perampanel is a new medication, and we may need to 
adjust the dosing slightly in the beginning of the study, but this should not be a major pitfall.  
We will assess the tolerability and safety during of the proposed dosing regimen in the first 3-5 
subjects and make a determination of whether or not changes need to be made. We would 
only decrease the dosing, not increase it in response to the experience and review of 
data from the first few subjects. Essentially, if there are too great a degree of adverse 
effects from the 6mg and 10mg dosages, we will decrease the dosages to ensure safety 
and adequate tolerability.  
 
 
8. HUMAN SUBJECTS PROTECTION: 
 
8.A. Data and Safety Monitoring Plan (DSMP): Albert Arias, M.D., a board certified psychiatrist 
and the principal investigator of the study, will be charged with the duty of determining the 


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severity rating of adverse events. The study staff (P.I., co-investigators, clinical research 
coordinator) is responsible for collecting and recording all clinical data.  As these results are 
collected, all toxicities and adverse events will be identified, graded for severity and assigned 
causality, reported to the required entities, and compiled for periodic review.  After assigning 
causality, the P.I. will decide the course of action for the study participant. The P.I. will evaluate 
every adverse event and determine whether it affects the risk/benefit ratio of the study and 
whether modifications to the protocol or informed consent form are required. Serious adverse 
events will be reported to the VCU IRB, as well as the NIAAA, within 48 hours. An annual report 
summarizing all adverse events will be prepared and reported to both IRB and the NIAAA. In 
addition, other co-investigators will be notified. Reports of adverse events, protocol deviations, 
and any other relevant safety information (drop outs, etc.) will be reviewed by the research team 
on an ongoing weekly basis at regular meetings, and the research team will discuss whether the 
study should continue as planned, or if changes are needed, or if the study should be stopped.  
 
As noted above, precautions for pregnant or reproductive age women are in accordance with 
NIAAA requirements and this will be monitored on an ongoing basis by the PI and co-
investigators. All adverse events in the taper/follow-up time-period will be reported to the VCU 
IRB, as well as the NIAAA, with serious adverse events being reported within 48 hours.  
 
In addition to monitoring by Dr. Arias, this protocol will be reviewed weekly in study meetings.  
We will use a Data and Safety Monitoring Plan (DSMP) which will be referred to in order to 
determine safety and feasibility of continuing the study. 
 
All data will be stored without direct identifiable information, but will be identifiable via a linking 
code. Any hard copy records associated with the study will be kept in locked offices in our 
research facility. The secured research records are labeled with code numbers only (names and 
other identifying information are kept separate from research records). Access to hard copy data 
is only given to staff members working on the study. Only staff members designated to handle 
or analyze study samples will have access to the samples and their storage. We may use 
REDCap for data tracking and storage. As per routine in the IDAS, all electronic files (e.g., 
database, spreadsheet) will be password protected.  Any computer hosting such files will have a 
password-protected drive to prevent access by un-authorized users.  
 
Data used for safety monitoring will include serious adverse events, dropout rates and reasons 
for dropout, enrollment numbers, subject interviews, medication compliance, review of 
symptoms or performance status, review of clinical/diagnostic test results, review of physical 
examination, review of vital signs, review of evaluation performed, protocol deviations, and 
blinded data. If it has been determined, for any reason, that there will be a suspension of this 
study, the PI will suspend enrollment of new subjects but continue intervention/monitoring of 
previously enrolled subjects if it is in the best interest of those subjects. We have determined 
that this study involves only a greater than minimal risk to subjects, and that potential benefits 
outweigh potential risks of participation. 
  
The administration of alcohol to human subjects proposed in this study is in compliance 
with NIAAA guidelines for alcohol administration. (27)  
 
8.B.  RISK/BENEFIT RATIO.  Risk/Benefit Ratio.  The risk associated with ethanol is minimal. 
Although the pharmacological intervention carries some risks, perampanel is generally well 
tolerated. The potential risks of these agents are minor, and research has shown that non-
treatment seeking subjects who participate in self-administration studies significantly reduced 
their drinking after participation (48). Thus, the risk/benefit ratio appears most favorable toward 
the proposed treatments. Subjects will receive the benefit of free medical, laboratory, and 


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psychiatric examinations. The benefit to society that would result from improved effectiveness in 
treating alcoholism is also significant, given the high societal cost of alcoholism.  
This study is expected to contribute to knowledge regarding whether perampanel influences the 
response to alcohol and how that may affect treatment response for alcoholism. Subjects 
participating in the alcohol challenge sessions will receive a free medical evaluation, including 
physical examination and laboratory testing and will be paid $50 for the screening appointment. 
If there is a need to repeat a laboratory test to confirm any values obtained at screening, we will 
offer them an additional $10, They will also be compensated $15 for the initial outpatient visit 
they attend and $25 for the outpatient visits prior to Phase II and Phase III (3 visits for a 
maximum amount of $65). Subjects will be paid $315 for each lab session (3 sessions total so 
they can earn a maximum of $945 for lab sessions). Subjects can also earn additional money in 
each lab session with the Balloon Analogue Risk Task (BART). They can earn a maximum of 
$7.50 dollars per administration of the BART, with 4 administrations per lab ($30 maximum each 
lab session), subjects can earn a total of up to $90 additional pay over the course of the study, 
though actual payouts will likely be substantially less from this task (likely under $50 per 
subject). We will ask the first 5-10 participants to return to the clinic for an additional visit 
between days 7-10 post-lab sessions in order to evaluate a PK level. We may choose to extend 
this to all participants if it becomes clear that it is necessary for monitoring. Altogether, subjects 
will be able to earn up to $1200 for their participation in the study. 
 
Subjects will also receive feedback and education about their “risky” drinking, and the option of 
referral for treatment if they so decide. There is no other direct benefit for subjects.  The benefit 
to society concerns the effects of perampanel on behavioral effects of alcohol, which may be 
important to understanding the neuropsychopharmacologic basis of alcohol’s effects and the 
etiology of alcohol dependence and for the improvement upon existing treatments, as well as 
development of novel pharmacological treatments for alcoholism.  Although the risk is greater 
than minimal risk, we believe that risk-benefit ratio for this study is favorable. Furthermore: 
 
§ 
The administration of ethanol to human subjects described in this protocol is in 
compliance with NIAAA guidelines for ethanol administration. 
§ 
We will carefully screen NTSHD subjects to exclude alcohol naïve subjects. 
(please see below for special consideration for heavy drinkers). All subjects 
must meet the minimum recent drinking requirements; To meet criteria, subjects will 
have to drink more than 4 standard drinks (SD) per day on at least one day per week 
on average for men, and >3 SD/day at least once weekly for women, and must have 
become intoxicated to the point of being “drunk” on at least one occasion (meaning 
at least 5 SD) within the last year without untoward effects. 
§ 
 Subjects with a history of alcohol use disorder that are abstinent currently will be 
excluded. They will be informed exactly what level of BrAC they will reach in the 
study, and the approximate drink equivalent. 
§ 
The investigators in this protocol have extensive experience with the administration 
of ethanol to healthy individuals and to alcohol abusing or dependent individuals 
using a number of different laboratory paradigms. 
o a) Since 1992, we have administered ethanol at doses comparable to those 
described in this protocol to well over 300 subjects, both healthy subjects and 
heavy drinkers. Of these subjects over 150 have participated in an IV ethanol 
“clamp” procedure and over 150 have participated in an alcohol drinking 
paradigm.  
o b) We have had no reportable medical adverse events associated with the IV 
clamp procedure. 
§ 
The clamping procedure has several safety measures in place: 
o a) The concentration of ethanol in the infusate is 6% by volume. 


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o b) The limit on the amount of ethanol that can be infused is determined by 
hanging two one liter bag of the infusate (6% by vol ethanol ~ 2 oz ethanol at 
most) at a time. 
o c) Frequent BrAC measurements, using a rotation of 5 instruments, assure 
that the BrAC will not exceed 105 mg%   
o d) The research nurse will be monitoring breath alcohol levels at proscribed 
times (never less frequent than every 10 minutes) with a breathalyzer.  
§ 
Experienced medical personnel will be present during the entire laboratory session.  
In case of a significant adverse event, a physician will be called immediately.  
Subjects will not be released from the Laboratory until the BrAC is less than or equal 
to 20mg% (20mg% = 0.02%), confirmed with at least two tests, which is below the 
threshold of BrAC associated with any impairment in motor coordination or judgment 
in humans.  
§ 
If the subject reports disturbing experiences, these will be reviewed in detail and 
support will be offered.  If adverse experiences occurred, a decision will be made at 
that time whether to discontinue further testing.  If the subject reported significant 
distress or if clinicians observed significant distress associated with testing, but no 
residual effects are reported at the end of the test day, the PI will still review the 
incident and the potential advisability of overnight hospitalization for observation. 
§ 
The PI will be available on-call while subjects are on the Clinical Research Services 
Unit, and subjects can contact research staff and physicians after hours with any 
problems they might have. 
 
 
8.C. Special Considerations for Individuals who are Heavy Drinkers: Ethanol is a drug of 
abuse.  The entire protocol is in accordance with the NIAAA Guidelines on Ethyl Alcohol 
Administration.  These guidelines have stated that heavy drinkers need not be excluded from 
this type of research, but should receive special consideration in assessing risk/benefit ratio.  In 
this study, we have instituted several safeguards to ensure the safety of participants.  Subjects 
are warned about the potential abuse liability of ethanol, and treatment-seeking subjects will be 
excluded. Further, we will carefully screen subjects to ensure that they are not physiologically 
dependent on alcohol and will standardize the approach by excluding individuals with a CIWA 
rating >8. Finally, we will conduct a brief safety and wellbeing check in follow-up contact with 
research subjects and propose to contact each research subject by telephone 1 week following 
their last test day to monitor the impact of participating in this research study. 
 
All subjects will be advised of their “risky” drinking status and will be informed if they meet 
criteria for alcohol abuse or dependence. They will also be advised about health risks of their 
continued heavy drinking and will be offered referral to treatment. Subjects choosing treatment 
will be assisted by study staff and physicians in obtaining treatment, and we will help them 
investigate treatment options, including setting appointments for subjects, not just giving them a 
list of options. They may also qualify for a clinical treatment trial. At the end of the third 
laboratory session, participants will be presented with normative drinking information, as well as 
guidelines for non-hazardous alcohol consumption, and they will also receive a brief motivational 
interviewing session about their drinking along with the offer for a referral for further treatment. 
Subjects may decline the brief intervention at the end of the study if they continue to have no 
interest in any level of treatment engagement. The motivational brief session will be tailored to 
each individual’s level of drinking and related consequences and other assessments.  
 
 
8.D. MEDICATION RISKS AND SIDE EFFECTS: 
 (PERAMPANEL): 
The most common side effects seen with perampanel have been, 
dizziness, somnolence, irritability, headache, fall, and ataxia(23, 24, 44). Dizziness and 


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somnolence were common in epilepsy trials (>10% of subjects). 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, difficulty walking and falls. Subjects will be monitored closely for 
rare potential neuropsychiatric side effects such as violent or homicidal ideation, as these 
symptoms have been reported in epilepsy trials with the medication. All subjects will be 
monitored regularly for suicidal ideation as this can be a risk with all anticonvulsants. 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 anticonvulsants, 
such as agranulocytosis.   The US Drug Enforcement Agency (DEA) has determined that there 
is some potential for people to abuse perampanel.  Because some anticonvulsants can be 
harmful to a fetus, women will be screened for pregnancy before and during participation in the 
study. Pregnant and breastfeeding women will be excluded. Perampanel is a category C 
medication. Women will be required to be using two forms of birth control for the study duration, 
and one must be non-hormonal based.  Perampanel may lower the effectiveness of oral 
contraception containing levonorgestrel. The doses of perampanel used in this study were NOT 
found (in epilepsy trials) to decrease blood levels of oral contraceptive hormones, but a 12mg 
daily dose was. We choose to err on the side of caution with regard to birth control in this study. 
We will obtain a CBC at each lab session to monitor for blood dyscrasia, a side effect of many 
anticonvulsants. We will maintain frequent phone contact with subjects while taking medication, 
and will also contact them the day after lab sessions by phone to assess any changes in mood 
or neuropsychiatric side effects. 
 
The black box warning states that serious or life threatening psychiatric and behavioral adverse 
reactions, including aggression, hostility, irritability, anger, and homicidal ideation and threats 
have been reported in patients taking perampanel. Monitor patients for these reactions as well 
as for changes in mood, behavior, or personality that are not typical for the patient, particularly 
during the titration period and at higher doses. Perampanel should be reduced if these 
symptoms occur and should be discontinued immediately if symptoms are severe or are 
worsening 
 
 
Alcohol Effects: Possible effects of consuming alcohol are blurred vision, nausea, vomiting, 
flushing, headache, and lightheadedness.  These effects should reach their peak during the 
infusion and decline thereafter.  There is a potential for people to abuse alcohol.  It is unclear 
whether exposure to alcohol in the laboratory can result in problems with alcohol abuse or 
alcoholism..  It should be noted drinking more than 2 drinks per day in healthy men and 1 drink 
per day in healthy women can be hazardous to a person’s health.  Also, if at any point after 
completing this study a subject becomes concerned about abusing alcohol, they are 
encouraged to contact us.  We will refer subjects to the VCUHS Motivate clinic or an appropriate 
treatment facility if necessary.  To minimize possible injury as a result of alcohol consumption, 
participants will be kept on the Clinical Research Services Unit until their blood alcohol level is 
at a very low level (Breathalyzer ≤ 0.02).  If a participant does not feel comfortable and does not 
want to continue or the research staff feels that they are at risk, the test day will be 
discontinued. 
 
 
Risks of combining alcohol and perampanel: 
This was studied a little bit by the drug company marketing the drug, and they found that 
combining the two can impair psychomotor activity greater than with just alcohol alone, and 
impaired complex psychomotor tasks such as driving a car (tested in a simulator). If new risks 


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become known we will notify the IRB and subjects. Subjects will be advised to notify us of any 
side effects during pre-treatment in a timely manner. We will advise them that there is the 
possibility that alcohol and perampanel, when combined, could make them oversedated, or 
have difficulty with their balance or coordination, including with driving a car. We will advise 
them to avoid driving if drinking alcohol while on the perampanel. Additionally, we will advise 
them to see how they react to the initial perampanel 2mg dose on day 1 before driving or 
operating heavy machinery.  
 
 
Additional safety measures:  
Subjects will be asked to arrange for a ride home after each laboratory session. Transportation 
will be arranged for those who cannot arrange it on their own. We will provide a taxi (20mile 
radius). Subjects will be asked to follow general seizure precautions for 48 hours after each lab 
session such as showering instead of taking baths, no swimming, and no driving. Given the long 
half-life of the medication and two-day 2mg taper dose after each lab session, “rebound” or 
withdrawal seizures are unlikely after the lab sessions but we will err on the side of caution.  
 
9. REFERENCES 
 
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3.  Davis KM, Wu JY. Role of glutamatergic and GABAergic systems in alcoholism. J Biomed 
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4.  Tzschentke TM, Schmidt WJ. Glutamatergic mechanisms in addiction. Mol Psychiatry. 
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5.  Cornish JL, Kalivas PW. Glutamate transmission in the nucleus accumbens mediates relapse 
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6.  Conrad KL, Tseng KY, Uejima JL, Reimers JM, Heng LJ, Shaham Y, Marinelli M, Wolf ME. 
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12.  Backstrom P, Hyytia P. Involvement of AMPA/kainate, NMDA, and mGlu5 receptors in the 
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21.  Templeton D. Pharmacokinetics of perampanel, a highly selective 
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26.  Rogawski MA, Hanada T. Preclinical pharmacology of perampanel, a selective non-
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28.  Holdstock L, King AC, de Wit H. Subjective and objective responses to ethanol in 
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Environment, Wiley Online Library 2008 
 
 
 
  

ICF_003.pdf: 
VCU IRB PROTOCOL NUMBER: HM20014446.  V.5 
STUDY TITLE: Rapid Determination of the Clinical Utility of Perampanel for the Treatment of Alcohol 
Dependence
VCU INVESTIGATOR: Albert  J. Arias, MD (203) 800-1928
SPONSOR: National Institute on Alcohol Abuse and Alcoholism/ NIH/ DHHS
NOTE: In this consent form, “you” always refers to the research participant.
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 alcohol - specifically to understand how a person responds to the medication 
while they are receiving alcohol intravenously (through an IV). This medication is currently used to treat 
seizure disorders, and is currently not U.S. Food and Drug Administration (FDA) approved to treat alcohol use 
disorders. For this reason, it is considered an investigational drug. In this study, the medication is compared to a 
placebo (a look-alike inactive substance, a “sugar pill”). You will be randomly assigned (like the flip of a coin) 
to receive either the medication or a placebo. You have an equal chance of being assigned to any one of the 
groups. There is evidence that anticonvulsants (medications used to treat seizures) can be effective in the 
treatment of alcohol use disorders. Perampanel is an anticonvulsant.
DESCRIPTION OF THE STUDY INCLUDING PROCEDURES TO BE USED.
This study has two parts. Part 1 includes the preliminary screening, and Part 2 includes three test days. During 
each test day you will be given an intravenous (IV) alcohol infusion along with the study medication or a 
placebo. The medication or placebo is given as a pill to take by mouth. We will also give you a small dose of 
the medication or placebo to take each day for a week prior to each test day. 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. All subjects must complete the preliminary screening, which is completed prior to the test 
days and takes approximately 4 hours. Approximately 75 people will be recruited for the study.
Your participation in this study will include a screening visit (lasting approximately 4 hours), 3 outpatient visits 
to pick up your study medication (lasting approximately 30-60 minutes) and 3 test days (which will be at least 21 
days apart and last approximately 7 hours each day). The total time to complete the study is 28 hours, spread out 
over a period of approximately 52 days.
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VCU IRB PROTOCOL NUMBER: HM20014446.  V.5 
What will happen if I participate? 
Part 1. Preliminary Screening:
If you agree to participate in this study, you will complete an initial screening that includes a medical history, 
physical examination, blood test, urine screening (toxicology), and electrocardiogram (EKG) to ensure that you 
are medically healthy. 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. You will also complete a psychiatric evaluation. You will receive a payment of $50 for this initial 
screening. Based on the results of these evaluations, we will determine whether you may be eligible to 
participate in Part 2 of the 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.   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 
visit (30-60 minutes) where you will complete several surveys and you will also be given a week (7 day) supply 
of a low dose of the study medication (perampanel) or placebo to take prior to your scheduled test day. A study 
nurse or Research Assistant will contact you by phone once between days 2-4 and once between days 5-7 to ask 
you about any side effects you might be noticing. 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 provide a blood sample for DNA analysis. This is not optional, but we will only collect 
this sample when we are sure that you are eligible to participate in the 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 the study.
This study will use your samples to sequence all or part of your DNA.
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.
Part 2. Test Days:
We will ask you to refrain from using illicit drugs while you are enrolled in the study. We will also ask you to 
refrain from using caffeine, alcohol, and cannabis for 12 hours before each test day. You will also be instructed 
to not eat after midnight before the session. The morning of test days, you should report to the Clinical 
Research Services Unit (CRSU) at VCU Health (North 8). On your test days, when you first arrive before 
testing can proceed, we will check your blood pressure and pulse, perform a urine toxicology (drug screen), 
urine pregnancy test (females only), breathalyzer and we will look for signs of alcohol withdrawal. If your 
breathalyzer reading is over 0 (meaning that you have recently used alcohol), you appear to be in significant 
alcohol withdrawal, or your urine drug screen shows that you have used illicit drugs, you will likely be 
rescheduled for a later time or we may discontinue you from the study at our discretion and you may not 
receive payment for this day. If you are rescheduled, you may be asked to continue the study medication, or we 
may ask you to stop and then restart the medication again later. If your results are satisfactory to the study 
criteria, the research nurse will then insert an IV line. We will take a blood sample to check your blood count 
levels as well as the levels of study medication in your blood. You will then be asked to complete several brief 
questionnaires asking about your mood, smoking habits, and alcohol use. You will receive either a high, low, or 
placebo dose of the test
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VCU IRB PROTOCOL NUMBER: HM20014446.  V.5 
medication (perampanel) to take orally (by mouth). About 45 minutes later, we will ask you to fill out some 
forms about alcohol, drugs, and your mood.  Approximately 15 minutes later you will be provided with 
breakfast. About 30 minutes after that, you will receive the infusion. We will ask you to fill out some forms 
about alcohol, drugs, and your mood.
Your breath alcohol concentration (BrAC) will be kept at a certain level using a small pump to regulate the 
flow of alcohol into a vein in your arm. The infusion pump rate will be adjusted every few minutes, based 
on the results of the breathalyzer tests. On each test day you will be following the same procedures, and the 
target levels of intoxication will be the same on each test day. During the highest level of alcohol 
administration, your BrAC level may be as high as approximately 0.10. Your heart rate and blood pressure 
will be monitored throughout the infusion.
An hour and a half after taking the dose of study medication, you will start the IV alcohol infusion. You will 
begin with a low dose of alcohol (about what is associated with one to two (1-2) 12 oz cans of beer in an hour 
for a man or one 12oz can of beer for a woman).Then, 30 minutes later, we will administer more alcohol to 
bring your blood level up to a moderate dose of alcohol (about what is associated with four (4) 12 oz cans of 
beer in an hour for a man or three (3) 12oz. cans of beer for a woman).Then, 30 minutes after that we will add 
more alcohol to bring your blood alcohol level to a higher level of alcohol(about what is associated with five to 
six (5-6) 12 oz cans of beer for a man or five (5) 12 oz cans of beer for a woman; you will feel “drunk” at this 
point). You will be asked about your experience with the alcohol (e.g., how much you enjoy it, etc.) at each of 
these three levels of alcohol administration.
You will complete the same questionnaires and tests six times on each test day. This will take about three hours 
and will be completed before your provided lunch. We will ask you to measure how rewarding you think the 
alcohol is and to complete a computer challenge called the “Balloon Analogue Risk Task.” The balloon task 
gives you a chance to win some additional money (up to an additional $30 per lab session). The alcohol 
infusion will end and you will rest in the lab while you sober up from the alcohol.
At the end of the test day you will be debriefed by our study staff. A healthcare provider will examine you 
before you are allowed to go home. Prior to each test day you will need to make plans to be driven home. You 
will not be allowed to drive yourself home. If you can’t find a ride, we will arrange a taxi (within a 20 mile 
radius) for you. This is to avoid any difficulties with driving due to any residual sedation. You will not be 
allowed to leave until your breathalyzer is at or below (≤) 0.02 and a healthcare provider has evaluated you to 
detect any signs of intoxication that would impair you. If you feel uncomfortable for any reason, you will be 
allowed to stay overnight at the CRSU at VCU Health. If you are deemed unsafe to leave due to intoxication, 
you may be not allowed to leave until deemed safe. This procedure will be repeated for your second and third 
test days.
In-between lab visits:
After each test day, we will give you two days of low dose study medication (perampanel) to taper off the 
medication. You are asked to avoid driving, swimming, or baths (showers are ok) for 48 hours after the lab 
visit. These are important safety measures in case you have a seizure (convulsions). You will then begin a 14-21 
day washout period (to allow blood levels of study medication to decrease) prior to your next visit.  You may 
require a brief visit during this time to check the medication level by a blood sample. At the next visit, you will 
briefly come in to receive one week of medication (low dose perampanel or placebo) to lead up to the next test 
session day. You will also be asked to complete several surveys. During the 7 days you are taking the 
medication at home a study nurse will contact you by phone once between days 2-4 and once between days 5-7 
to ask you about any side effects you might be experiencing.  You may be asked to come to the research center
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VCU IRB PROTOCOL NUMBER: HM20014446.  V.5 
for evaluation if there are any concerns about your safety. This will be repeated until you have completed all 
three lab sessions.
Follow-up: After you have completed the 3 test days, you will be contacted for 1 follow up phone interview: 
approximately 1 month, after your last test day. In the interview you will be asked about how you have been 
doing since the last test day.  The phone questionnaire will last approximately 5 minutes.
What alternative treatments or procedures are available?
This is not a treatment study. Your alternative is not to participate. If you are interested in alcohol abuse 
treatment, we will help you to find a treatment program(s).
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 you could have side 
effects from taking study drug. Below are 
some of the most common side effects: 
Dizziness
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
. 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.
Mild to moderate physical activity may cause 
sore or pulled muscles, heart problems, 
physical discomfort, and/or accidental injuries 
such as falling. You may also experience 
some physical discomfort such as increased 
heart rate, chest pain, shortness of breath, 
headache, nausea, and/or fatigue.
The study questionnaires ask questions that 
are personal and sensitive in nature and may 
make you feel uncomfortable.
There is some evidence anticonvulsants may 
be effective in alcohol use disorder because of 
how they affect the brain. Perampanel is an 
anticonvulsant. 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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VCU IRB PROTOCOL NUMBER: HM20014446.  V.5 
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.
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 effects of a medication called perampanel on how you feel while 
receiving alcohol intravenously. You have been invited because you are a frequent drinker of alcohol. 
Perampanel is currently approved to treat seizures. For the purposes of this study, it is an investigational drug, 
which means it has not been approved by the U. S. Food and Drug Administration (FDA) for the way it is being 
used in this study.
WHAT ARE THE BENEFITS OF BEING IN THE STUDY?
You may not personally be helped by taking part in this study, but your participation may lead to knowledge 
that may help others who are seeking treatment for alcohol dependence.
WHAT RISKS AND DISCOMFORTS COULD I EXPERIENCE FROM BEING IN THE STUDY?
The Intravenous Lines and Blood Drawing: Blood drawing may cause pain, bruising, and rarely fainting or 
infection. There is a chance of swelling, redness, bruising or a blood clot forming at the site of blood sampling. 
Approximately 1/2 tablespoon of blood will be drawn during your initial screening. In addition, blood will be 
sampled on all 3-test days to provide information about your blood alcohol levels and you may be asked to have 
an additional sample drawn to check the medication level in between lab sessions. We will also routinely check 
bloodwork to monitor you for safety. Therefore, the total amount of blood drawn will be about 3 tablespoons 
per test day, and about ½ tablespoon to check the medication level (if needed), and about 2 tablespoons on 
repeat labwork days, for a total of 12 tablespoons (6 ounces) for the entire study. Although this amount is less 
than a typical blood donation (16 ounces), you should not donate blood eight weeks before and after testing.
Study Procedures: During the experimental session, you may not leave the test room. You will not be able to 
smoke while you are in the test room. If you are a regular smoker, you may experience some withdrawal from 
nicotine. You may feel irritated or anxious because of this. If you are a regular coffee drinker, you may not 
consume caffeine for 12 hours prior to the lab sessions, which could cause you to feel irritated, tired, or a 
headache. If you are a cannabis user, we ask that you abstain from cannabis use 12 hours prior to the lab 
sessions. At the end of the test session, you will remain in the CRSU until we are satisfied that you are in good 
health and your Breathalyzer is at or below (≤) 0.02. You will not be allowed to drive yourself home. If you 
can’t find a ride, we will provide a taxi (within 20 mile radius) for you. During the study, you will be asked 
questions related to your mental health and drug use history which may make you feel uncomfortable or sad. If, 
in the opinion of the study doctor(s), you are no longer a good fit for the study, your participation may be 
discontinued, without regard to your wishes. This would apply if you do not comply with the requirements for 
participation. For example, if you fail to abstain from illicit drugs prior to lab sessions, you may be dropped 
from the study. Your participation may also be discontinued if it becomes medically unsafe for you to continue, 
if the study is stopped by a sponsor, or if the VCU IRB withdraws approval.
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VCU IRB PROTOCOL NUMBER: HM20014446.  V.5 
EXPECTED RISKS OF STUDY:
Alcohol Effects: Possible effects of consuming alcohol are blurred vision, nausea, vomiting, flushing, 
headache, and lightheadedness. These effects should reach their peak during the infusion and decline thereafter. 
The administration of alcohol intravenously may result in more intense alcohol effects than you would 
experience with regular consumption; however, you will be under the constant supervision of medical 
professionals to intervene if any of these effects become serious.  There is a potential for people to abuse 
alcohol. It is unclear whether exposure to alcohol in the laboratory can result in problems with alcohol abuse or 
alcoholism. If you are worried about this possibility you should not participate in this study. Drinking more than 
2 drinks per day in healthy men and 1 drink per day in healthy women can be hazardous to your health. If at any 
point after completing this study you become concerned about abusing alcohol, you may contact us. We will 
refer you to an appropriate treatment facility if necessary. For your safety, you will need to make arrangements 
to be driven home after each test day. If you do not feel comfortable and do not want to continue participating 
in the lab session, or the research staff feels that you are at risk, the test day will be discontinued.
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 most common side effects seen with perampanel have been, dizziness, somnolence (drowsiness), 
irritability, headache, fall, and problems with coordination. Dizziness and somnolence were common in 
epilepsy trials (more than10% of subjects). 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, difficulty walking and falls. You will be 
monitored closely for rare potential side effects such as violent or homicidal ideation, as these symptoms have 
been reported (though rarely) in epilepsy trials with the medication. You will be monitored regularly for 
suicidal ideation (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 ideation and 
threats have been reported in patients taking perampanel. 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. 
Post marketing data and case reports have shown less than 1% of: Acute psychosis, delirium, DRESS 
syndrome, hallucination, increased serum triglycerides, suicidal ideation. You should not take ketoconazole (a 
common antifungal) while taking perampanel, and perampanel can decrease the efficacy of birth control.
Risks due to the combination of alcohol and perampanel:
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. You will be asked to avoid driving or drinking alcohol while on 
the study medication. Additionally, you will be asked to see how you react to the initial perampanel 2mg dose 
on day 1 of each phase before driving or operating heavy machinery.
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
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VCU IRB PROTOCOL NUMBER: HM20014446.  V.5 
are pregnant or become pregnant, this research may have a bad or unforeseen effect on a fetus and should not be 
done during pregnancy. To your knowledge, you are not pregnant at the present time and you agree to avoid 
becoming pregnant by using two reliable forms of birth control (one method must be non-hormonal, such as 
using condoms or spermicide, or you may take other 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. The study staff will either call you to 
notify you if you test positive for being pregnant during the study or will tell you, in person, if the result is 
available before you leave the research center when and where the sample was given.
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 personal or sensitive 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.
Unknown or Unforeseeable Risks:
The researchers will let you know about any significant new findings (such as additional risks or discomforts) 
that might make you change your mind about participating in the study. Perampanel involves risks that are 
currently unknown or unforeseeable.
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.
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You and your insurance plan will not have to pay for exams, tests, and procedures done for research purposes 
only or that are covered by the study. This includes:

The extra blood draws in this study done at every study visit

The hospital visit for the laboratory sessions
WILL I BE PAID TO PARTICIPATE IN THE STUDY?
You will receive $50 for the completed initial screening, $15 for your first outpatient visit, and $25 for your 
second and third outpatient visit where you will receive your take home study medication (3 visits total), and
$315 for each test day in which you participate (3 sessions). If there is need to do repeat labwork to confirm 
screening lab results, you will receive an additional $10 for a total of (1) extra payment. If you are asked to 
return to the clinic for an additional visit between days 7-10 post-lab sessions to check your medication levels, 
you will earn $20. You may also earn up to an additional $90 over the course of the study depending on how 
you score on one of the tasks during the lab sessions (maximum $30/session). Since there are three separate test 
days, the total amount you could earn during this study is $1200. This payment is for the time and effort related 
to study assessments and procedures.  All payments will be made in cash or check.
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 payment 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.
There are no plans to provide compensation for disability or other losses occurring over the long term or if an 
injury becomes apparent after your participation in the study has ended. However, by agreeing to participate in 
this research study, you are not waiving or giving up any legal rights to seek compensation.
If you are injured by, or become ill, from participating in this study, please contact your study doctor 
immediately. Medical treatment is available at the Virginia Commonwealth University Health System (VCU 
Health). Your study doctor will arrange for short-term emergency care at the VCU Health 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 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.
Please be aware that the investigative team and the University may receive money for the conduct of this study. 
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.
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, you may be asked to taper your medication 
schedule and have an additional follow-up visit if determined necessary by the study PI. Stopping the study 
drug early without tapering may result in withdrawal or side effects including an increased risk for seizure.
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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?
Participation in research may involve a loss of privacy. Your research records will be kept as confidential as 
possible. Only a code number will identify your research records. The code number will not be based on any 
information that could be used to identify you (for example, social security number, initials, birth date, etc.). 
The master list linking names to code numbers will be kept separately from the research data.
All research information will be secured in locked files. Your identity will not be revealed in any reports or 
publications resulting from this study. Only authorized people will have access to the information gathered in 
this study. Authorized persons may include regulatory agencies such as the Food and Drug Administration 
(FDA), NIAAA, as well as members of the VCU IRB (when conducting reviews). Therefore, if you participate 
in this study, a medical record will be created if you do not already have one. Notes from your visits, 
procedures, and laboratory tests will be included in this record. In addition to the research team, and the VCU 
Health Staff who provide clinical services, other researchers may be granted approval to access this information 
in the future. Federal laws and regulation that protect privacy of medical records will apply to your health 
record. Your name, address and social security number will be provided to the VCU Business Office in order to 
process your payment for participating in this study. VCU will also provide you with an IRS 1099 form 
reporting the amount of money paid to you.
It will be noted in your protected electronic health record at VCU Health that you are in this study. Information 
about the study will 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.
Your blood sample will also be tested for hepatitis. Virginia state law requires the study staff to report the 
results of positive tests for hepatitis to a local health agency.
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 web site will include a summary 
of the results.  You can search this web site at any time.
HOW WILL MY RESEARCH RESULTS BE USED?
You and your physician will be informed of any important discoveries made during this study which may affect 
you, your condition, or your willingness to participate in this study. If suicidal intent or other major clinical 
findings are detected during clinical or research assessments, the study physician will be notified immediately.
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You may be not allowed to leave until deemed safe or until you are judged to no longer be considered a threat to 
yourself or to others.
Any identifying information will be kept in locked files. These records will be kept indefinitely. Only research 
staff will have access to your files. If results of this study are reported in medical journals or at meetings, you 
will not be identified by name, by recognizable photograph, or by any other means without your specific 
consent. Your medical records will be maintained according to VCU Health requirements. However, there is a 
possibility that the Food and Drug Administration may inspect the records.
We will use some of the blood we draw to obtain DNA which we will study to try to identify genes that might 
be related to your diagnosis or behavior, or genes important to determining brain structure or function.
Therefore, your sample or cell line may be used for research purposes unrelated to the study for which it was 
collected.
We may also study other genes, and will store the DNA for study in the future. At some point we may create 
permanent cell lines from cells in your blood, to provide a continuous supply of DNA. Also, your sample 
and/or cell line may be shared with investigators not associated with this project. If so, your identity will not be 
shared with these researchers. You will not receive any payment if your cells are used for permanent cell lines, 
even if they are supplied to other researchers commercially.
DNA will be obtained from your blood and used for genetic testing. Your DNA will be kept in the laboratory 
indefinitely (as long as possible) and may be used for many laboratory tests. The blood samples and the DNA 
will be labeled with a number only. Your name will not be attached to the samples in the laboratory. This 
measure is taken to protect your confidentiality, as explained in more detail below.
DNA PROTECTION OF PRIVACY
The use of your blood for genetic testing raises special issues of confidentiality, because it is possible that 
information about your genes could be used against you if this information became known to the wrong people. 
For example, an insurance company could try denying benefits, or an employer could try to deny employment, 
if it became known that you carried certain genes. To reduce this possibility, the following specific measures 
will be taken to protect your confidentiality:
1) The genetic testing of your DNA is for research purposes only. No results of genetic testing from this study 
will appear in your medical record.
2) Genetic test results will not be made available to you, your doctors, your other clinicians or any other 
clinical staff. We do not expect that the genetic testing done in this study to become part of treatment for 
alcohol problems at any time during this study or in the next few years to come.
3) To protect the confidentiality of computer records related to you or your family members, information that 
could be used to identify you individually will be stored only on a protected VCU server.
Thus, even if a "hacker" breaks into the laboratory computer system, there will be no information stored there 
that can identify you as an individual. All paper records containing your identity, will be stored in locked 
cabinets, and will be available only to authorized research staff.
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4) Information about your genes will be stored in the in the Psychiatric Genetics Lab, located at the address 
below, using procedures described above to protect your confidentiality, unless information has become 
completely stripped of information that could identify you.
Virginia Commonwealth University
Virginia Institute for Psychiatric and Behavioral Genetics 
Biotech 1, 800 E Leigh St.
Suite100, Rm 1-110
Richmond, VA 23298-0424 USA
5) There is a federal law called the Genetic Information Nondiscrimination Act (GINA). In general, this law 
makes it illegal for health insurance companies, group health plans, and most employers, except those with less 
than 15 employees, to discriminate against you based on your genetic information. However, it does not protect 
you against discrimination by companies that sell life insurance, disability insurance, or long-term care 
insurance.
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.
Certificate of Confidentiality Statement
To help us protect your privacy, we have obtained a Certificate of Confidentiality from the National Institutes of 
Health. This certificate 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 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 there is voluntary disclosure of harm to self or others, or abuse towards 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.
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, along with your 
de-identified data sets in a registry/repository to be available for other research studies in the future. No 
identifiable personal information is kept in the de-identified data sets. We keep data that has identifying
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information such as name or age secured per institutional policy. Your information and samples would be stored 
at VCU by Dr. Albert Arias and could be used for other research studies about any topic. 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. Your data/samples will be protected, but there is always a 
possibility that information could be accessed by individuals 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 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 the PI, 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  
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
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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:

Principal Investigator and Research 
Staff

Study Sponsor

Health Care Providers at VCU Health

Data Coordinators

Institutional Review Boards

Research Collaborators

Government/Health Agencies

Others as required by law

Data Safety Monitoring Boards

NIH
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 authorization will expire when the research study is closed, or there is no need to review, analyze and 
consider the data generated by the research project, whichever is later.
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 at the address listed below.
RESEARCH SUBJECTS' RIGHTS
I have read or have had read to me all of the above and I voluntarily consent to participate in this study. The 
study has been explained to me and my questions have been answered. I have been told of the risks or 
discomforts and possible benefits of the study.  I have been told of other choices of treatment available to me.
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I understand that I do not have to take part in this study, and my refusal to participate will involve no penalty or 
loss of rights to which I am entitled. I may withdraw from this study at any time without penalty or loss other 
benefits to which I am entitled.  I will receive a signed copy of this consent form.
The results of this study may be published, but my records will not be revealed unless required by law.
In case there are medical problems, a research related injury or complaints, concerns, or pertinent questions 
about the research at any time, I have been told I can contact
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
Telephone:(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.
Conflict of Interest Disclosure: A Conflict of interest occurs when a member of the research team including 
the principal investigator, sub-investigator(s), and/or study coordinator(s), has a significant financial interest or 
other personal involvement that may compromise, or have the appearance of compromising, his or her 
professional judgment or integrity while conducting this study.
All members of the local research team who are conducting this study are required to report any potential 
Conflicts of Interest. Dr. Arias have no reported conflicts relevant to the conduct of this study.
You may speak with Dr. Arias at any time should you have questions regarding these investigator interests. 
Virginia Commonwealth University has no financial interest in the study drug (perampanel) being used in this 
research study. You may also choose to seek the opinion of another doctor not related with Virginia 
Commonwealth University before enrolling in this research study. More importantly, you are not under any 
obligation to participate in this research study and you may withdraw at any time.
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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)
Adult Participant’s Signature
Date
Name of Person Conducting Consent Discussion (Printed)
Signature of Person Conducting Consent Discussion
Date
Principal Investigator Signature (if different from above)
Date
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