Clinical trial NCT02740582
Conditions: Alcohol Abuse Impulsive Behavior
Sponsor: Jennifer Mitchell
Start date: 2016-10-01; Completion date: 2019-11-01
Enrollment: 62 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to determine the effects of tolcapone on decision making and alcohol intake using a laboratory bar (on-site alcohol self-administration) in alcohol drinkers.

Detailed description:
The study is a 7-session, double blind, placebo-controlled crossover study of the effects of tolcapone, the COMT inhibitor, on decision making and alcohol intake using a laboratory bar in moderate to heavy social alcohol drinkers. Subjects will be moderate to heavy social users of alcohol, defined as at least 10 standard drinks per week for women and at least 14 standard drinks per week for men. There will be one screening session followed by six additional visits including 2 laboratory bar sessions. On each study drug administration day, subjects will come in to the clinic for a medication dispensation visit and instructions on when and how to take the study drug for the remainder of the study. Study drug bottles will be equipped with MEMS caps to ensure compliance. After 5 days of drug administration, subjects will return to the clinic for a laboratory bar. This session will consist of administration of a standardized laboratory bar paradigm and a series of computerized and written decision-making tasks. Subjects will then be crossed over and complete the same series of study visits on the alternate study drug.

Arms: arm 1: Tolcapone arm first: 5 days of 100 mg tolcapone TID, followed by washout period, then 5 days of placebo TID arm 2: Placebo arm first: 5 days placebo, followed by washout period, followed by 5 days of 100 mg tolcapone TID
Interventions: intervention 1: Tolcapone intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
 1
Title of Study: Effects of Tolcapone on Decision Making and Alcohol Intake in Alcohol Users  
 
Publication:  
 
The Catechol-O-methyltransferase Inhibitor Tolcapone Modulates Alcohol Consumption and 
Impulsive Choice in Alcohol Use Disorder  
 
NCT 02740582  
 
01 September 2019


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Study Protocol and Analysis 
Experimental Design  
Subjects participated in a total of seven visits: Screening, Drug Dispensation x 2, Compliance x 
2, and Laboratory Session x 2 (described below). Upon completion of both the first randomized 
double blind drug cycle and a drug washout, subjects crossed over to complete the second drug 
cycle.  
 
To increase subject retention, and given previous work that even a single dose of tolcapone can 
influence decision making (Kayser et al., 2012), we evaluated a 5-day treatment period. This 5-
day dosing regimen included a weekend, thereby both allowing us to capture self-reported 
weekend drinking (Friday-Sunday) on study drug, and also permitting subjects to return on the 
final day of the treatment window for the Laboratory Session (on either a Monday or a Tuesday 
evening). Based on previous work with this subject population, we felt that subjects might 
display higher drinking over the weekends and therefore that we would be best able to capture a 
drug effect during this time.  
 
The trial was registered at ClinicalTrials.gov, NCT 02740582. 
 
Figure 1  
 
 
Subjects 
Non-treatment seeking individuals with AUD (ages 21 – 40; Table 1) were recruited via a 
Craigslist posting, which requested that subjects be “moderate to heavy alcohol drinkers”, as 
well as referrals from study subjects. The age range was chosen to minimize safety concerns 
regarding possible tolcapone effects on hepatic function (Tan, Eastment, Poudel, & Hubbard, 
2015) and to avoid age-related changes in the dopamine system that can begin as early as age 40 
(Volkow et al., 1996). While there are important differences in treatment seeking and non-
treatment seeking subjects (Rohn et al., 2017), we intentionally chose to evaluate the effects of 
tolcapone in a non-treatment seeking population to minimize both regression to the mean and the 
need to assess subject motivation. Using this population also represents an intrinsically more 
conservative approach, in that subjects who are not motivated to reduce alcohol consumption 
may be less likely to show large declines in alcohol consumption. 
 
Following a brief telephone screening procedure, potentially eligible subjects were invited in for 
a screening visit.  
 
Screening Visit 
Written informed consent was obtained in accordance with the Institutional Review Board at the 
University of California, San Francisco. Study visits took place in the research clinic within the 


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Li Ka Shing building at UC Berkeley. Acute intoxication was assessed via a breath alcohol 
sensor (Alcomate, Palisades Park, NJ); subjects were required to have a 0.00 blood alcohol 
concentration (BAC) to provide consent. To capture multiple dimensions of alcohol use, 
inclusion criteria incorporated both self-reported alcohol consumption (>10 drinks/week for 
females and >14 drinks/week for males) and a requirement to meet DSM-5 criteria for AUD in 
the last 12-months (as assessed via the AUD section of the Mini-International Neuropsychiatric 
Interview (Sheehan et al., 1998)). The mean AUDIT score in the study population was 14.3, and 
98.1% of subjects showed an AUD severity of moderate or severe (Table 2). 
 
Female subjects were administered a pregnancy test, and were required to be non-pregnant, non-
lactating, and using a reliable contraceptive method. Exclusion criteria included a positive urine 
drug screen (with the exception of THC), or use of any illicit substance within 72 hours of the 
start of the study; current attempts to either reduce or eliminate alcohol consumption (e.g. via 
current enrollment in an alcohol or drug treatment program); history of alcohol related 
complications (e.g., liver failure/cirrhosis, pancreatitis, esophageal varices); abnormal results on 
tests of liver injury (alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values 
greater than the upper limit of normal); regular use of any drugs with catecholaminergic actions 
such as SSRIs or amphetamines; and severely low or uncontrolled high blood pressure. 
Information about subjects’ past substance use, psychiatric history, medical history, current 
medications, and family history of problem drinking was collected. The study clinician 
performed a physical examination, a 12-lead electrocardiogram, and a blood draw to evaluate 
markers of liver injury. To establish a baseline prior to laboratory bar sessions, subjects were 
also asked to perform components of a standard field sobriety test that assessed horizontal gaze 
nystagmus, walk-and-turn, and a timed one-leg stand. Together with evaluation of BAC, these 
direct measures of neurological function were used to ensure that subjects were free of alcohol-
induced motor impairments prior to dismissal from the laboratory bar sessions. The screening 
visit concluded with the administration of behavioral inventories including the Alcohol Use 
Disorders Identification Test (AUDIT; (Saunders, Aasland, Babor, de la Fuente, & Grant, 1993)) 
and the Barratt Impulsiveness Scale (BIS; (Patton, Stanford, & Barratt, 1995)). Eligible subjects 
were scheduled into groups of 4-8 subjects for study drug administration.  
 
Study Drug 
Study drug was provided by Valeant Pharmaceuticals. Wellspring Compounding Pharmacy 
(Berkeley, CA) held the study blind and re-compounded study drugs to add 10 mg riboflavin to 
both tolcapone and placebo in order to facilitate medication compliance checks: ultraviolet light 
was used to detect the presence of riboflavin in the urine at the Check Visit and the Laboratory 
Session. Enrolled subjects self-administered tolcapone (100 mg) or placebo three times a day 
(TID) for 5 days, for a total of 300 mg tolcapone per day. This dosing regimen is in keeping with 
the FDA approved dosing regimen for Parkinson’s disease, the approved indication for tolcapone 
treatment.  
 
Drug Administration Visit 
Subjects returned to the clinic on a Thursday or Friday morning to begin the study drug 
administration cycle. Given that the half-life of tolcapone is 2.5 hours, we expect the drug 
reached steady-state at approximately 12.5 hours (5 half-lives). The initiation of drug 
administration on a Thursday or Friday was designed to capture weekend drinking (see below) 


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during the 5-day administration window. Subjects completed a side effects scale, a pulse and 
blood pressure check, and a pregnancy test (females). Subjects ingested their first dose of study 
drug under clinical supervision and were instructed to continue medication administration three 
times daily, ending on the 5th day (Monday or Tuesday) when they ingested their final dose at the 
start of the Laboratory Session (Figure 1). Subjects and investigators were blind to the 
medication condition. Medication bottles were equipped with Medication Event Monitoring 
System (MEMS) caps (AARDEX, Zurich, Switzerland) that generated a time stamp each time 
the bottle was opened. MEMS caps data were downloaded at each study visit.  
 
Weekend Drinking 
Subjects were instructed on “standard alcoholic drink” volumes and provided an information 
card for reporting weekend drinking. Subjects were contacted via a HIPAA compliant text 
message system each day during medication administration to capture the number of alcoholic 
drinks the subject had consumed the previous night. To confirm standard drink values, the type, 
amount, and volume of alcohol were reviewed in person with the study staff at the Compliance 
Check. “Weekend drinking” was calculated as the total number of alcoholic drinks from Friday 
to Sunday. 
 
Compliance Check 
Subjects returned to the clinic for a compliance check the day prior to their laboratory session. 
This visit assessed medication compliance (including evaluation of MEMS cap data), collected 
side effects information, and obtained a urine sample to confirm riboflavin florescence. All 
subjects had positive riboflavin screens at their study visits. MEMs caps data indicated that on at 
least 4 of the 5 treatment days, 95.5% of the subjects opened their MEMs cap 1x/day or more, 
90.0% opened the MEMs cap 2x/day or more, and 59.1% opened the MEMs cap 3x/day or more, 
demonstrating reasonable medication compliance. 
 
Laboratory Session  
Subjects arrived at the clinic for the laboratory session (in groups of 4-8 subjects) on a Monday 
evening (for subjects started on a Thursday) or Tuesday evening (Friday start). Subjects were 
asked to fast for 1 hour prior to the start of the session and were drug screened and assessed for 
acute intoxication upon arrival. Those subjects with a positive screen or BAC were not permitted 
to consume alcohol. Subjects ingested the final dose of study medication immediately prior to 
completing the tasks below.  
 
Delay Discounting Task  
Detailed methods have been previously described and validated in a similar subject population 
(Boettiger et al., 2007; Mitchell et al., 2005). At the start of each trial, subjects were cued to one 
of four trial types: “Want”, “Don’t Want”, “Sooner”, and “Larger”. For each of these trial types, 
subjects were presented with two hypothetical alternatives on the left and right sides of the 
screen: a smaller amount of money available sooner and a larger amount available at a future 
point in time. Subjects made a button press to select the option associated with the left and right 
sides of the screen in accordance with trial type. Subjects selected the option they wanted in the 
“Want” trials and the option they did not want in the “Don’t Want” trials. “Sooner” and “Larger” 
trials, in which subjects simply identified the sooner and larger options respectively, were 
included as control conditions to ensure that subjects followed task instructions. The choice was 


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presented as one of six variations: a “sooner” option of “today” versus a “later” option of five 
future time points (1 week, 2 weeks, 1 month, 3 months, or 6 months), or a “sooner” option of “3 
months” versus a “later” option of “6 months”. The “larger” value consisted of six amounts ($1, 
$2, $5, $10, $20, or $100), while the “sooner” value represented one of four percentages (70%, 
85%, 90%, and 95%) of the larger delayed amount. Subjects completed 6 blocks of 47 trials each 
(for a total of 282 trials) presented in pseudorandom order and were permitted to take breaks 
between each block. The “Want” condition comprised 50% of all trials, the “Don’t Want” 
condition comprised 34%, and the two control conditions combined comprised 16% of the trials. 
The primary behavioral outcome was the impulsive choice ratio (ICR), which represents the ratio 
of the number of sooner choices to the number of total choices in the “Want” condition. More 
impulsive subjects are thus characterized by higher ICR values. Previous work has demonstrated 
that this intuitive score correlates strongly with other model-based measures of delay discounting 
(Kayser et al., 2012; Kayser, Mitchell, Weinstein, & Frank, 2015; Mitchell et al., 2005). Study 
participants completed this task together in the same testing room prior to the laboratory bar. 
 
Assessment of Side Effects  
Subjects completed a side effects scale reporting the extent to which they were experiencing 17 
side effects (scored on a 0 – 3 scale, indicating “none”, “slight”, “moderate”, and “severe” 
effects) at each study visit. Because tolcapone may be hepatotoxic, the side effects were selected, 
in consultation with the FDA, to monitor effects associated with compromised liver function. All 
subjects who reported a side effect as “moderate” or “severe” were immediately evaluated by the 
study clinician. Over the course of the study, 11 subjects reported a moderate or severe side 
effect; 4 of those subjects were taking tolcapone at the time (see Results). 
 
Laboratory alcohol consumption 
The laboratory session included a proof-of-principle, group laboratory bar protocol. All 
behavioral testing occurred prior to any alcohol consumption. This protocol was designed to 
create a more naturalistic setting for social drinkers. Laboratory sessions took place in a room 
outfitted with couches, coffee tables, and music to achieve a social bar-like atmosphere. Minimal 
guidance on social interaction was prescribed: subjects were seated together, instructed not to use 
phones during the experiment, and encouraged to interact during the laboratory session. To best 
account for variability in administration times across subjects, the final dose of study medication 
was ingested in the laboratory, and the laboratory session was timed to be in the peak effective 
window of this dose. Eighty-minutes following the final medication administration, subjects 
were given a priming drink. Alcohol content in the priming drink was calculated based on the 
subject’s weight and sex and designed to bring the blood alcohol concentration (BAC) to 
approximately .04. The formula for calculating grams of pure alcohol was based on the Widmark 
formula (Posey & Mozayani, 2007): g = kg * r * BAC * 10, where r = .68 for males and .55 for 
females, and where BAC = .04. Subjects were required to consume the priming drink within 15 
minutes. Both alcohol and soda were refrigerated and drinks were served without ice to maintain 
a 1:3 ratio. 
 
Following the priming drink, BAC was assessed via a breath alcohol sensor (Alcomate, Palisades 
Park, NJ). Subjects received 4 (empty) cups to represent the maximum of 4 drinks they could 
order during the 1-hour session. Each drink was ½ the size of each subjects’ initial priming drink 
and valued at $4. Subjects were told that they had a pre-paid tab valued at $16 and the value of 


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any drinks they did not consume would be added to their study payment. Salty snacks and water 
were available throughout the session.  
 
After the 1 hour drinking session, subjects were provided with dinner. Subjects were required to 
have BAC ≤ 0.04 and to pass a Field Sobriety Test (see above) before they were eligible for 
dismissal. All participants were driven home via car service (either Lyft or Uber). 
 
Crossover 
After the laboratory session and following a washout window, subjects were crossed over to the 
alternate study drug. Given the 2.5-hour half-life of tolcapone (Jorga, 1998), a minimum of 3 
days of washout ensured that, if tolcapone were administered during the first cycle, at least 24 
half-lives had passed before the second cycle began. To control for day-of-the-week effects on 
behavior, the crossover cycle was scheduled to begin on the same day as the first cycle, resulting 
in either a 3-day or 10-day washout window based on scheduling availability. To control for 
social dynamics, lab bar group composition was maintained across medication cycle crossover 
whenever possible; however not all subjects completed the laboratory sessions (see Statistical 
Analysis below).  
 
Genetic Analysis 
Although our sample size was not powered to examine genotype, an exploratory analysis was 
conducted to ascertain whether the previously published relationship between COMT and 
decision-making might also be apparent in this study sample. DNA was extracted from saliva 
samples by the UCSF Genomics Core using Gentra Puregene reagents and protocols and 
quantified using the Pico Green method (Molecular Probes/Invitrogen). COMT genotyping was 
carried out by direct DNA sequencing of genomic DNA using fluorescent Sanger chemistry and 
analyzed using Mutation Surveyor from SoftGenetics LLC. Sequencing genotype accuracy was 
cross-validated with TaqMan (Applied Biosystems, Foster City, CA).  
 
Statistical Analysis 
Our sample size was calculated based on previous changes in alcohol consumption observed in a 
laboratory bar setting (Mitchell, Bergren, Chen, Rowbotham, & Fields, 2009). We calculated 
that, for a mean difference of .5 drinks per session and a standard deviation of 1.2 drinks, we 
would need a sample size of at least 48 subjects to achieve an alpha of .05 with a power of .80 
for the pilot group laboratory bar protocol. Due to low enrollment and high drop-out rates in this 
subject population, we projected that we would need to enroll 80 subjects to achieve a final 
sample size of 48 subjects.  
 
We enrolled a total of 62 enrolled subjects, and 55 subjects successfully completed the weekend 
drinking paradigm. Of the 7 subjects who did not complete the paradigm, 1 was excluded for 
non-adherence to the study protocol, 1 asked to withdraw, 1 experienced a drug dispensing error, 
1 did not show for the scheduled visit, and 3 subjects had positive urine drug screens at the first 
lab bar visit and ended their participation. 50 of 55 subjects completed both lab bar sessions. The 
5 who did not complete both lab bar sessions had positive urine drug screens and were excluded 
from drinking at these sessions. Three additional subjects were excluded from the DDT decision 
making task analysis for performing at less than 60% accuracy on control trials designed to 
assess task compliance (Mitchell et al., 2005), leaving 47 subjects for the DDT analysis. 


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The primary outcome measure of “weekend drinking” was defined as total number of alcoholic 
drinks consumed (Friday to Sunday) to capture drinking on study drug across dosing schedules. 
Secondary outcome measures included the change in impulsive choice ratio (ICR) on the DDT 
task following tolcapone, the number of alcoholic drinks consumed in the lab bar, and the impact 
of genotype on tolcapone effects. Data is reported as mean ± SEM unless otherwise noted. 
 
Change in weekend drinking and ICR on tolcapone versus placebo were assessed using a within 
subjects paired t-test. Differences in DDT responses across genotypes were assessed using a one-
way ANOVA. The relationship between tolcapone effects on weekend drinking and ICR was 
assessed with correlation analysis. All statistical tests were conducted using VassarStats and 
Microsoft Excel V15.23.2.