Clinical trial NCT02448654
Conditions: Nicotine Dependence
Sponsor: Yale University
Start date: 2015-10-23; Completion date: 2019-06-30
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to use a medication tolcapone and or placebo to test if the symptoms of nicotine withdrawal lessens , and or changes in smoking urges, and mental reasoning in female smokers over a 72 hour period.

Detailed description:
The proposed trail will be use a double-blind, placebo-controlled design to conduct the first randomized controlled trial of the COMT inhibitor, tolcapone, in nicotine dependent women. This study will determine if tolcapone is superior to placebo by attenuation the severity of nicotine withdrawal and smoking urges during short-term abstinence. Withdrawal severity will be assessed by a self-report scale and cognitive assessment, including a sustained-attention task. Smoking urges will be assessed by a self-report scale.

Arms: arm 1: 100mg tolcapone three times a day for 7 days then 100mg once a day on day 8 arm 2: Sugar pill
Interventions: intervention 1: Tolcapone intervention 2: Sugar Pill
Intervention descriptions: intervention 1: Tolcapone will be compared to sugar pill intervention 2: The sugar pill (placebo) will be compared to tolcapone

Protocol documents:
Prot_000.pdf: 
Official Title in ClinicalTrials.gov: Treatment for Nicotine Addiction in Women  
NCT: NCT02448654 
Document Date: 10/8/19 
 


PI: Elise DeVito, Ph.D. 
 
ED002 
                             COMT Inhibition as a Novel Treatment for Nicotine Addiction in Women 
 
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PROJECT DESCRIPTION 
 
In addition to the Application and the Abstract, briefly describe the research project using the numbered 
headings below.  Give sufficient detail for each of the following points to facilitate local review. Use "none" 
or "NA" if appropriate.  NOTE:  This description is for local review committees only and does not need to 
have the same technical detail as the narrative portion of an application for funding submitted for outside 
review.  However, the description of involvement of human subjects must not differ in substance from the 
relevant application.   
 
1.  Principal Investigator:  
Elise E. DeVito, Ph.D.  
Co-Investigators While all research staff are trained to provide informed consent, those 
identified with an asterisk (*) will provide informed consent for this study. All the research staff 
will have access to the PHI 
Co-Principal Investigator: Mehmet Sofuoglu, M.D., Ph.D. 
Authorized Prescriber: Mehmet Sofuoglu, M.D, Ph.D.  
Nursing Staff: *Ellen Mitchell, RN 
Research Staff: *Stacy Minnix, B.S.W., and *Chris Cryan 
 
2.  Purpose:  
The proposed trial will use a double-blind, placebo-controlled design to conduct the first 
randomized controlled trial of the COMT inhibitor, tolcapone, in nicotine dependent women.  
Aim #1. To determine if tolcapone is superior to placebo in attenuating the severity of nicotine 
withdrawal and smoking urges during short-term abstinence. Withdrawal severity will be 
assessed by a self-report scale and cognitive assessment, including a sustained-attention task. 
Smoking urges will be assessed by a self-report scale. 
Hypothesis #1: Tolcapone will be superior to placebo in reducing the severity of withdrawal and 
smoking urges during short-term abstinence.  
Aim #2. To determine if tolcapone is superior to placebo in reducing smoking self-
administration in a human laboratory model (Smoking Choice Paradigm) and reducing 
subjective ratings of smoking reinforcement. 
Hypothesis #2A: In the smoking choice paradigm following short-term abstinence, the group 
receiving tolcapone will choose fewer cigarette puffs than the group receiving placebo.  
Hypothesis #2B: In the smoking choice paradigm following short-term abstinence, the group 
receiving tolcapone will rate smoking as less reinforcing than the group receiving placebo. 
 
3.  Background:  
Existing smoking cessation pharmacotherapies may be less effective in women than men 
(Cepeda-Benito et al, 2004), which may contribute to poorer quit rates in women (Perkins, 
2009). Women may also have higher risks of tobacco-related morbidity and mortality than men 
smokers(USDHHS, 2001, 2004). Thus, there is a great need for treatments tailored for women 
smokers.  
There are several reasons why the inhibition of the catechol-O-methyltransferase (COMT) 
enzyme may be a promising smoking cessation pharmacotherapy in women.  


PI: Elise DeVito, Ph.D. 
 
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                             COMT Inhibition as a Novel Treatment for Nicotine Addiction in Women 
 
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i) High COMT enzyme activity is implicated in risk for nicotine dependence and poor smoking 
cessation outcomes. Individuals with the high COMT enzyme activity allele (Val), are more 
likely to smoke(Enoch et al, 2006; Shiels et al, 2008),  have higher risk for nicotine dependence 
(Tammimaki and Mannisto, 2010),  experience more withdrawal symptoms (Loughead et al, 
2009) and smoking urges (Wang et al, 2008)) during nicotine-abstinence, have poorer smoking 
cessation outcomes(Colilla et al, 2005), and have diminished therapeutic effects of nicotine 
replacement therapy for smoking cessation(Johnstone et al, 2007), relative to relative to those 
with the allele that inhibits COMT enzyme activity (Met).   
ii) There are several biologically plausible mechanisms by which COMT enzyme inhibition could 
counter nicotine dependence. COMT enzyme is abundant in the brain and affects prefrontal 
cortical (PFC) and striatal dopaminergic systems implicated in nicotine dependence.  
The COMT enzyme metabolizes dopamine (DA) (Tammimaki et al, 2010). A functional variant 
of the gene which codes for the COMT enzyme, reduces enzymatic activity (i.e., Met relative 
Val allele carriers) (Chen et al, 2004) results in higher basal DA levels, primarily in the 
prefrontal cortex, but also in the striatum(Gogos et al, 1998; Tammimaki et al, 2010; Yavich et 
al, 2007) and lower nicotine-induced DA release in ventral striatal regions(Brody et al, 2006).  
Nicotine-induced striatal DA release increases nicotine’s reinforcing and hedonic properties 
(Barrett et al, 2004) and alleviates abstinence-related smoking urges (Brody et al, 2004) and 
mood disturbances (Brody et al, 2009). So, the fact that COMT enzyme inhibition reduces 
nicotine-induced striatal DA release suggests it may also reduce nicotine’s reinforcing properties, 
which should reduce smoking maintenance.  Smoking abstinence normally results in reduced 
basal DA levels in the ventral striatum, which is associated with withdrawal symptoms (Zhang et 
al, 2012). Since inhibition of the COMT enzyme increases basal striatal DA levels, it should 
diminish abstinence-related withdrawal symptoms. This is important because withdrawal 
symptoms (e.g., irritability, negative affect) and smoking urges increase relapse-risk during 
smoking cessation attempts (Allen et al, 2009a; Allen et al, 2009b; Allen et al, 2008b). PFC DA 
levels influence cognitive function. Abstinence-related cognitive decrements are a core feature of 
withdrawal(Hughes, 2007) and increase smoking relapse risk (Patterson et al, 2010) (de Wit, 
2009). As such, cognition has been proposed as a treatment target for smoking 
cessation(Sofuoglu et al, 2013). High COMT enzyme activity is associated with poor 
performance on cognitive functions implicated in relapse risk (e.g. working memory, sustained 
attention (Barnett et al, 2007; Egan et al, 2001) (Diaz-Asper et al, 2008; Dumontheil et al, 2011; 
Loughead et al, 2009)) and with greater nicotine-abstinence related cognitive 
decrements(Herman and Sofuoglu, 2010; Loughead et al, 2009). Therefore, since COMT 
enzyme inhibition increases PFC DA levels, it is expected to diminish abstinence-related 
cognitive decrements, which could reduce relapse-risk since abstinence-related cognitive 
decrements increase smoking relapse.  
iii) Many of the effects of COMT enzyme inhibition may be sex-sensitive.  Inhibition of COMT 
enzyme activity has sex-sensitive effects on psychiatric risk factors(Tunbridge and Harrison, 
2010). Such sex-sensitive effects may arise from neurobiological sex differences in DA systems 
which are regulated by the COMT enzyme (drug-stimulated striatal DA release(Munro et al, 
2006) and basal striatal DA levels(Laakso et al, 2002)); gonadal hormones’ modulation of DA 
(e.g. estradiol’s DA agonist-like effects(Becker, 1990a, b, 2000; Becker and Hu, 2008; 
Pasqualini et al, 1995; Thompson and Moss, 1994; Xiao and Becker, 1994)); or gonadal 
hormone’s modulation by COMT (COMT enzyme’s catabolism of estrogens(Tunbridge et al, 
2010)).  


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                             COMT Inhibition as a Novel Treatment for Nicotine Addiction in Women 
 
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For example, COMT enzyme activity’s affects on nicotine-abstinence related cognitive 
decrements are sex-sensitive and moderated by menstrual cycle phase(Jacobs and D'Esposito, 
2011). Nicotine withdrawal symptoms and smoking urges may be stronger in women (al'Absi et 
al, 2002; Leventhal et al, 2007), symptoms of anxiety and depression are more strongly linked 
with nicotine withdrawal and smoking relapse in women (Weinberger et al, 2009) and high 
COMT enzyme activity has been more strongly linked with depression, anxiety and related 
phenotypes in women than men (Baune et al, 2008; Domschke et al, 2012; Domschke and 
Dannlowski, 2010; Domschke et al, 2007; Domschke et al, 2004; Eley et al, 2003; Enoch et al, 
2003; Funke et al, 2005; Hamilton et al, 2002; Hettema et al, 2008; Kempton et al, 2009; Kim et 
al, 2006a; Lonsdorf et al, 2010; Massat et al, 2005; Olsson et al, 2005; Opmeer et al, 2010; 
Rothe et al, 2006; Stein et al, 2005; Weiss et al, 2007; Williams et al, 2010).   
iv) Our preliminary data support our hypotheses in women smokers. We recently demonstrated 
that overnight-abstinent women smokers with high COMT enzyme activity reported greater 
severity of certain withdrawal symptoms (e.g., difficulty concentrating) than Met carrier women 
or men with high or low COMT enzyme activity (Herman et al, 2013). Our preliminary data 
extend these findings in a larger sample to show that in women, but not in men, high COMT 
enzyme activity is associated with more severe withdrawal, smoking urges and worse cognitive 
function following overnight abstinence. Additionally, high COMT enzyme activity women 
rated their anxiety higher during placebo yet reported greater alleviation of anxiety symptoms 
with nicotine administration. As such, inhibition of COMT enzyme activity would be expected to 
ameliorate withdrawal symptoms (including negative mood) and smoking urges, particularly in 
women, providing another mechanism by which this intervention would be expected to improve 
smoking cessation outcomes in women.  
v) Approved medications that inhibit COMT enzyme activity are available for clinical use. 
COMT enzyme activity can be pharmacologically inhibited with tolcapone, which crosses the 
blood-brain barrier and inhibits COMT enzyme activity in the brain (Ceravolo et al, 2002) to a 
similar degree as the genetic variant described above (i.e., Met allele; 25% reduction (Apud et al, 
2007)). While it is approved as an adjunct to DA treatments in Parkinson’s disease(Haasio, 
2010), tolcapone has been shown to improve aspects of cognitive function in healthy 
individuals(Apud et al, 2007) and patients with Parkinson’s disease(Gasparini et al, 1997) or 
Pathological Gambling(Grant et al, 2013) and in pre-clinical studies(Liljequist et al, 1997; 
Tunbridge et al, 2004). Tolcapone reduced gambling urges and behaviors(Grant et al, 2013) and 
another COMT inhibitor (entacapone) diminished cannabis-craving in dependent 
individuals(Shafa et al, 2009). Taken together, these findings support tolcapone’s safety and 
efficacy in improving symptoms implicated in addiction risk, including cognitive performance 
and craving in other addicted populations.  
 
4.  Significance:   
Nicotine dependence has been a persistent public health problem and identifying effective 
medications for the treatment remains a high priority. Women smokers, compared to men, have 
lower smoking quit rates (Perkins, 2009), may find smoking cessation medications to be less 
effective(Cepeda-Benito et al, 2004), and may have higher risks of tobacco-related morbidity 
and mortality (USDHHS, 2001, 2004). Thus, there is a great need for treatments tailored for 
women smokers. The results will provide important evidence that COMT inhibition is a viable 
therapeutic target for smoking cessation in women, and contribute to a better understanding of its 
potential mechanisms of action. 
 


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5. Research Plan:   
A. Overview 
The proposed study will assess the effects of the COMT inhibitor, tolcapone, versus placebo on 
reducing withdrawal symptoms (including cognitive decrements), smoking urges and smoking 
behavior, in women smokers. This will be a double-blind, placebo-controlled study, with 60 
women smokers. After completing an ad libitum smoking baseline, participants will be 
randomized to 8-days of the COMT inhibitor tolcapone (100mg three times a day (TID) for 7 
days then 100mg once on day 8) or placebo (Apud et al, 2007; Grant et al, 2013). For the first 
two days of the medication period, participants will continue to smoke ad libitum and attend 
brief check-in sessions once daily to take one dose and be given the remaining two doses to take 
at home. On medication days 3-5, they will be given take-home doses and will be asked to check 
in daily by phone or in person and continue to smoke ad libitum. On the evening of medication 
day 5, the 60-hr (2 ½ day) abstinence period will begin. During the 2 ½ day abstinence period, 
participants will attend brief check-ins daily, to receive their dose (plus take-home doses) and to 
be screened for abstinence adherence (breath CO levels; urine cotinine). Measures of withdrawal 
and smoking urges will be collected at all sessions. On Medication Day 8, a test session will be 
conducted where assessment of cognitive function and smoking behavior will be collected. At 
the conclusion of the session on Medication Day 8, subjects will be stop the medication. A brief 
follow-up session will be completed approximately 1-week after the final medication day then 
subjects will be discharged from the study. A between-subject design will be used since the study 
involves numerous visits and several days of abstinence and we predict that a within-subject 
design would be overly burdensome to participants and result in high attrition rates. A between-
subject design also avoids possible medication carryover effects.  
 
 
Subjects: Women smokers, aged 18-45, who are able to read and write English and are in good 
health (as verified by medical history, screening examination, and screening laboratory tests) will 
be included. Smoking status will be determined by self-reported history of smoking daily for the 
past 12 months, ≥5 cigarettes daily, , a urine cotinine of at least 3 (out of 6) as measured by the 
NicAlert dipstick method to measure smoking status. Subjects will be excluded if they are using 
other psychotropic medications, have countraindications to tolcapone use based on medical 
history (including allergy to tolcapone, lifetime history of diagnoses associated with liver disease 
(e.g., alcohol dependence, hepatitis), renal impairment, history of nontraumatic rhabdomyolysis 
or hyperpyrexia and confusion possibly related to a medication or lifetime history of syncope), 
screening examination (e.g., symptomatic orthostatic changes during screening), or screening 
laboratory tests (e.g., LFT>2 times greater than the upper limit of the normal range))  have other 
substance use disorders, are pregnant or breast-feeding or not using acceptable birth control 
methods, have current psychotic disorder, bipolar disorder, homicidal or suicidal ideation, have 
current (past month) substance use disorder, other than nicotine dependence, or are unable to 
fulfill the scheduled visits and procedures.  
 
 
 
 
B. Outcome Measures  


PI: Elise DeVito, Ph.D. 
 
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Table 1. Schedule of 
Assessments and 
Interventions 
Time 
(min) 
Screen 
 
Ad Libitum 
Baseline 
Brief Medication  
Visits 
1visit/day, 4 days 
2 ½ day 
Abstinence 
End of Trial 
 
1-week  
Follow-up 
Screen & Baseline Measures & Smoking Behavior Measures 
 
 
Psychiatric and Medical 
Screen  
35 
X 
 
 
 
 
Demographics, 
Menstrual Cycle 
(MCAQ)  
7 
 
X 
 
 
 
Smoking History, 
Nicotine 
Dependence(FTND), 
urine cotinine dipstick 
5 
X 
 
 
 
 
Timeline Followback 
5 
 
X 
 
 
X 
Pill Administration, Abstinence Adherence and Physiological Measures 
 
 
Tolcapone or Placebo 
2 
 
 
X 
X 
 
CO levels, Breathalyzer, 
urine cotinine 
2 
X 
X 
X 
X 
X 
Urine toxicology 
3 
X 
X 
X (day 1) 
X 
 
Urine pregnancy screen 
3 
X 
 
X (day 1) 
X 
X 
Vitals (HR, BP) 
2 
X 
X 
X 
X 
X 
Blood Draws 
 
 
 
 
 
 
Genetics (rs4680) 
3 
X 
 
 
 
 
Labs for liver function 
3 
X 
 
 
X 
X 
Nicotine, Cotinine, 
Hormones 
3 
 
X 
 
X 
 
Self-report Measures of Withdrawal, Craving, Drug Effects, Mood and 
Impulsivity 
 
 
Withdrawal (MNWS); 
Smoking Urges(BQSU) 
6 
 
X 
X 
X 
X 
Subjective Nicotine Effect
(DEQ) 
2 
 
X 
 
X 
 
Adverse Drug Effects 
(AEF) 
3 
 
 
X 
X 
X 
Depression (CES-D);  
Anxiety (STAI) 
8 
 
X 
 
X 
X 
Affect (PANAS) 
3 
 
X 
X 
X 
X 
Impulsivity (BIS-II, 
BIS/BAS) 
7 
 
X 
 
 
 
Cognitive Tasks 
 
 
IQ 
10 
X 
 
 
 
 
Memory; Learning (digit 
span, HVLT) 
25 
 
X 
 
X 
 
Sustained Attention 
(RVP, CPT) 
10 
 
X 
 
X 
 
Cognitive Flexibility 
 (CGT, SOC, Stroop)) 
10 
 
X 
 
X 
 
Laboratory Smoking 
Behavior 
 
 
 
 
 
 
Smoking Choice 
Paradigm 
90 
 
 
 
X 
 
TOTAL ESTIMATED 
TIME (hours):  
 
1  
1 ¾  
1 ½  
(20min/visit) 
3 
½  


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                             COMT Inhibition as a Novel Treatment for Nicotine Addiction in Women 
 
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Subjective/Questionnaires 
Mini International Neuropsychiatric Interview (M.I.N.I.): At screening, Axis I psychiatric 
disorders will be assessed with the Mini International Neuropsychiatric Interview 
(M.I.N.I.)(Sheehan et al, 1998) plus questions for classification by new DSM-V as well as DSM-
IV criteria. This assessment will be administered once only at initial screening and will be used 
to help determine eligibility of the subject to participate in the trial.  
Fagerstrom Test of Nicotine Dependence (FTND): This self-report measure FTND (Heatherton 
et al, 1991) will assess degree of nicotine dependence. It will be administered at screening. 
Barrett Impulsivity Scale (BIS-11): This self-report measure assesses facets of impulsivity and is 
designed to measure impulsivity as a ‘trait’(Patton et al, 1995). The questionnaire is composed of 
30 items scored from 1 (rarely/never) to 4 (almost always/always). Impulsivity has been 
proposed to relate to the development and maintenance of addictive behaviors (de Wit, 2009; 
Krishnan-Sarin et al, 2007; Moeller et al, 2001). It will be administered at ad libitum baseline.  
Behavioral Inhibition/Activation Scale (BIS/BAS): This self-report measure consists of 20 items, 
scored from 1 (strongly disagree) to 4 (strongly agree) and assesses ‘behavioral inhibition’ (i.e., 
anticipation of punishment) and ‘behavioral activation’ subscales (i.e., reward responsiveness, 
drive, fun-seeking)(Carver and White, 1994). These traits have been linked with impulsive 
behaviors and with the development and maintenance of addictive behaviors (de Wit, 2009; 
Krishnan-Sarin et al, 2007; Moeller et al, 2001). It will be administered at ad libitum baseline. 
Menstrual Cycle Assessment (MCAQ): This questionnaire will be administered at ad libitum 
baseline and asks about use of contraception, including hormonal contraception, date of last 
period, frequency and regularity of cycles and symptoms of menopause or peri-menopause.  
Demographics, smoking history: At screening, subjects will also be asked about self-described 
race and ethnicity as well as years of smoking, age of onset, and past cessation attempts and use 
of other nicotine products (e.g., e-cigarettes).  
Minnesota Nicotine Withdrawal Symptom Checklist (MNWS): At all sessions except screening, 
smokers will be asked to rate nicotine withdrawal symptoms (cigarette craving, irritability/anger, 
anxiety/tension, difficulty concentrating, restlessness, increased appetite, depressed mood, and 
insomnia) on a 100 mm scale, "not at all" to "extremely" (Hughes and Hatsukami, 1986).  
Brief Questionnaire on Smoking Urges (BQSU): This 10-item scale reliably measures cigarette 
craving (Tiffany and Drobes, 1991) and will be administered at all sessions except screening.  
Positive and Negative Affect Schedule (PANAS ): The PANAS is a 20-item scale that assesses 
both negative and positive affective states (Watson et al, 1988). This scale is sensitive to the 
affective symptoms of tobacco withdrawal and predicts relapse to smoking (Kenford et al, 2002) 
and will be administered at all sessions except screening.  
Premenstrual Assessment Form (PAF): Given their potential overlap with withdrawal 
symptoms(Allen et al, 1996; Allen et al, 1999; Carpenter et al, 2006), premenstrual symptoms 
will be assessed with the 10-item PAF (Halbreich et al, 1982) at all sessions except screening so 
they can be used as covariate in analyses focusing on withdrawal symptoms. 
Drug Effects Questionnaire (DEQ): Smokers will rate 10 items that are related to nicotine effect 
on a 100 mm scale, "not at all" to "extremely." The items are feeling “stimulated”, “high”, 
“anxious”, “sedated”, “down”, “good drug effects”, “bad effects”, “drug strength” as well as 


PI: Elise DeVito, Ph.D. 
 
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                             COMT Inhibition as a Novel Treatment for Nicotine Addiction in Women 
 
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“wanting more of the drug” and “liking the drug”. This instrument allows rapid detection of 
nicotine effects, is adapted from a VAS (Soria et al. 1996), and has been used in our prior human 
laboratory studies with smokers (e.g., (DeVito et al, 2013)). This questionnaire will be 
administered at the ad libitum baseline based on the last cigarette they smoked that day (or one 
they smoke during allowable breaks) and post--abstinence final session based on the cigarette 
puffs smoked during the Smoking Choice Paradigm. 
Center for Epidemiologic Studies Depression (CES-D) scale: The CES-D is a 20-item self-report 
measure of depressive symptoms (Radloff, 1977)) and will be administered at ad libitum baseline 
and final sessions. 
State-Trait Anxiety Inventory (STAI): The STAI is a self-report questionnaire that includes two 
components: a 20-item component that measures ‘trait’ anxiety, which is expected to be stable 
over time, and a 20-item component that measures ‘state’ anxiety, which is expected to fluctuate 
across time (Kendall et al, 1976). Questions are rated on a 4 point scale from “almost never” to 
“almost always”. The ‘state’ component will be assessed at ad libitum baseline only while the 
‘trait’ component will be included at ad libitum baseline and the post--abstinence final session.  
Adverse Events Form: The SAFTEE  form tracks adverse -effects of the medication and will be 
tracked at each visit and phone check-in once the medication (or placebo) has begun (Sofuoglu et 
al, 2001; Sofuoglu et al, 2005). 
Timeline Follow-Back: Retrospective day-by-day self-report of past week smoking and 
substance use volumes(Robinson et al, 2014) will be carried out at the ad libitum baseline 
session and the one week follow-up.  
  
Cognitive  
The Shipley Institute of Living Scale (SILS): This is a brief, well validated means of estimating 
intelligence quotient (IQ) (Zachary, 1991). The form consists of 60 items comprising 2 sub-
scales, a vocabulary subscale (40 items) which asks subjects to indicate which of four words is 
most similar in meaning to the target word, and an abstract thinking subscale (20 items) wherein 
subjects are asked to fill in a letter or number to complete a pattern. The SILS will be 
administered at the screening session to check for baseline group differences, since cognitive 
measures are included as outcomes and are expected to differentially change with withdrawal 
across medication groups. 
Computerized Testing: Cognitive testing, administered at ad libitum smoking baseline and the 
post-2 ½ day-abstinence final assessment, will include computerized tasks of sustained attention 
(ANAM Continuous Performance Task (CPT)); CANTAB Rapid Visual Information Processing 
(RVP) ), executive function in including cognitive flexibility, cognitive control planning and 
decision-making (CANTAB Stockings of Cambridge (SOC), CANTAB Cambridge Gamble 
Task (CGT), ANAM Stroop); and memory/learning (Hopkins Verbal Learning Task (HVLT); 
Digit Span) (Owen et al, 1991) (Owen et al, 1990) (Wechsler, 2008) (Brandt, 1991) (Reeves et 
al, 2002).    Parallel task versions will be used where available. These tasks were chosen for the 
cognitive domains’ sensitivity to DA(Ersche et al, 2011; Harmer et al, 2001; Lange et al, 1992; 
Levin et al, 2011; Mehta et al, 1999; Owen et al, 1992), or nicotine(Sahakian et al, 1989); 
engagement of PFC-striatal neurocircuitry (Chase et al, 2008; Clark et al, 2007; Cools et al, 
2004; Ersche et al, 2011; Kim et al, 2006b; London et al, 2005; Mehta et al, 2000; Owen et al, 


PI: Elise DeVito, Ph.D. 
 
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                             COMT Inhibition as a Novel Treatment for Nicotine Addiction in Women 
 
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1991); impairment in smokers(Durazzo et al, 2012; Hughes, 2007); relevance to smoking 
outcomes(de Wit, 2009; Patterson et al, 2010); and proposed relevance as treatment targets for 
smokers(Sofuoglu et al, 2013). 
 
Biochemical 
Genetics: Blood samples for DNA extraction will be collected at screening to examine whether 
the Val158Met single nucleotide polymorphism (SNP) of the COMT gene modifies the effects of 
nicotine. To protect confidentiality, each subject’s blood sample will be encoded with a numeric 
designation and the name of the individual will be stored in a separate database. The samples 
will be transferred to the Genetic Laboratory at the VA medical Center for processing and 
storage.   
Laboratory Bloods: Standard laboratory blood screening will include liver and thyroid function 
tests, CBC, serum electrolytes, BUN, creatinine, PT and PTT. This will be done at screening, 
again at the post-2 ½ day abstinence testing session and at the 1-week follow-up.  
Urine screens: Urine pregnancy screens will be administered at screening, ad libitum baseline, 
prior to medication initiation, and prior to Smoking Choice Paradigm at the post-abstinence final 
session and at the 1-week follow-up. Urine drug screens will be administered at screening, ad 
libitum baseline, prior to medication initiation, and at the post-abstinence final session. Urine 
cotinine levels will be measured at baseline and check-in sessions and at post-abstinence testing 
session. 
Serum estradiol and progesterone analysis: Serum estradiol and progesterone levels will be 
measured before the ad libitum smoking baseline and post-abstinence final session for use as 
covariates in our analysis, since female sex hormones may contribute to variation in women’s 
response to nicotine or withdrawal (Allen et al, 2009b; DeVito et al, 2013) or women’s smoking 
cessation ability (Allen et al, 2008a). 
Plasma cotinine, 3-hyroxycotinine (3-HC), and nicotine levels: Plasma samples will be taken at 
the ad libitum smoking baseline session and at the post-abstinence final session. 3-HC is the 
main metabolite of cotinine and the ratio of 3-HC/cotinine, also known as the nicotine metabolite 
ratio, reflecting the rate of nicotine clearance. Smokers with high 3-HC/cotinine ratio (faster 
metabolizers) reported greater craving for cigarettes following overnight abstinence and greater 
nicotine-induced subjective drug effects, suggesting the 3-HC/cotinine ratio may influence the 
reinforcing effects from nicotine or experience of abstinence. Plasma nicotine levels will also be 
measured at baseline to confirm smoking status and at the post- abstinence session to confirm 
abstinence. Assays for nicotine, cotinine, and 3-HC levels will be performed in Dr. Peter 
Jatlow’s laboratory. Briefly, nicotine, cotinine and 3-HC are measured using HPLC coupled to 
tandem mass spectrometry (LC/MS/MS) employing stable isotope labeled internal standards as 
previously described. 
Alveolar carbon monoxide: A measure of expired CO levels will be taken at the beginning of 
each visit and during the Smoking Choice Paradigm. At the medication stabilization ad libitum 
check-in sessions, CO readings will be collected as a secondary measure of smoking levels. 
During the check-in sessions and final session during the abstinence period, CO readings ≤ 8ppm 
will be used to verify compliance with smoking abstinence on the first morning check-in 
following overnight abstinence. This level was recommended by the SRNT Subcommittee on 


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Biochemical Verification to confirm overnight abstinence (Benowitz et al. 2002). At subsequent 
abstinence check-ins (across the 60 hr abstinence) the subject will be considered to have met the 
criteria for abstinence-related bonus payment if their CO is ≤ 8ppm and has not increased since 
their prior abstinence visit.  
Physiological 
Vitals: Heart rate and blood pressure will be collected once at each visit and again at the end of 
the Smoking Choice Paradigm.  
Behavioral 
Smoking Choice Laboratory Paradigm: Nicotine self-administration behavior will be measured 
with the number of “puffs” from a cigarette chosen during the Smoking Choice Paradigm. This 
paradigm will be administered once at the post-abstinence visit.  
Apparatus: Measures of smoking behavior will be obtained using a smoking topography device. 
Subjects will smoke through a plastic cigarette holder that is fitted to the filter end of a cigarette 
and connected to a smoking topography device (CreSS from Plowshare Technologies). The 
cigarette brand will be the choice of each subject and will be provided by the investigator. 
Sample Smoking: The sample smoking will be administered using a Directed Smoking 
Procedure. In this procedure, the puff duration (3 sec), the interval between 2 puffs (20 sec), and 
the puff volume (40 cc) are predetermined to minimize the variation in the amount of cigarette 
smoke inhaled across smoking choices (Zacny et al, 1987). The selected puff volumes reflect the 
average puff volumes in female smokers (Battig et al, 1982; Eissenberg et al, 1999; Hofer et al, 
1992). To take puffs of a cigarette, subjects will light a cigarette, without inhaling, and insert it 
into the cigarette holder. A tone will guide subjects as to when to start and end inhaling each 
puff. When puff volume reaches the target volume, a tone will sound indicating that the subject 
should stop inhaling. 
Paradigm Procedure: Participants will complete this paradigm in a designated, negative pressure 
room in our laboratory. The Smoking Choice Laboratory Paradigm will offer participants 2 
sample ‘puffs’ followed by 10 additional smoking opportunities (2 ‘puffs’ per smoking 
opportunity) spanned across 90 minutes, for a total of 12 “puff” opportunities, wherein tokens 
can be exchanged for money ($0.75/token) or 2 cigarette puffs. If participants choose cigarette 
puffs instead of money at every opportunity, they will smoke the equivalent of slightly more than 
one cigarette within the 90-minute laboratory paradigm. 
This paradigm represents a slight adaptation from the Smoking Choice Laboratory Paradigm that 
our group has previously used by our group (e.g., (Sofuoglu et al, 2009)). In prior studies, the 10 
puff (in exchange for token) opportunities were spaced by 15 minutes each, therefore spaced 
over a duration of 2hr15 minutes. In this version the puff opportunities will be spaced by 9 
minutes to condense the 10 puff opportunities into 90 minutes, to reduce subject burden. Since 
the total number of puffs will remain the same as prior protocols and will amount to only slightly 
more than one cigarette, this dosing remains moderate. If participants self-administer every puff 
offered, the cigarette will still be spread over much more time than most smokers would use to 
smoke a single cigarette (which normally lasts 5-10 minutes, rather than 90 minutes).  
 
D. Drugs 
Tolcapone: Generic tolcapone will be purchased by the Research Pharmacy from McKesson 


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Corp. Following oral administration, tolcapone reaches peak plasma levels within 1.5-2.0 hours 
and maximum inhibition of COMT activity in red blood cells is observed in 1-4 hours (Jorga, 
1998; Jorga et al, 1998; Mannisto and Kaakkola, 1999).  
Tolcapone’s primary clinical use is in Parkinson’s disease, as an adjunct to dopaminergic 
medications (e.g., levodopa) to optimize the balance and transitions between “on” and “off” 
states. In our study, smokers will take tolcapone at 100 mg dose three times a day (TID) for 7 
days, and will receive a 100 mg dose on Day 8. Dose administration will be spaced by 
approximately 6 hours. Medication administration and oversight during the approximately one-
week trial will be carefully monitored by our study nurse and physician. 
 
Justification for the tolcapone doses: This dosing schedule is consistent with the manufacturer’s 
recommended use of tolcapone. Previous recent studies with significant effects of the 
manipulation without problematic adverse drug effects began at 100mg TID for the first day then 
increased to 200mg TID (Apud et al, 2007; Grant et al, 2013), so our dosing is more 
conservative relative to these recent studies. Our dosing schedule is chosen to provide enough 
time to reach steady-state tolcapone levels (approximately 5 half-lives of tolcapone) prior to 
initiation of the abstinence period, then provide continued administration during the abstinence 
period.  
Placebo: To maintain the double-blind, placebo pills will be designed to be visually identical to 
the tolcapone pills, and contain 25mg riboflavin to match the urine discoloration produced by 
tolcapone. 
 
E. Study Procedures 
Subjects will be asked to refrain from consuming alcoholic beverages and drugs during study 
participation, which will be verified by a urine drug quick test and breathalyzer. If results 
indicate non-compliance with these study procedures, subjects will be discharged from the study. 
Subjects will be instructed to drink their typical amount of caffeinated beverages in the morning 
to minimize caffeine withdrawal, which could confound the study measures. For outline of 
protocol per session and estimated timings, see Table 1. Briefly, sessions will include: 
In person Screening Session: This session will involve: a) obtaining informed consent; b) 
smoking history and assessment of nicotine dependence severity based on FTND; c) CO levels 
will be measured ; d) urine cotinine of 3 (out of 6) or higher on the semi-quantitative cotinine 
dipstick will be measured to ensure smoking status and a urine sample will be collected for 
quantitative cotinine assay; e) screening for co-morbid psychiatry conditions using the MINI; f) 
physical examination including ECG and vitals; g) urine analysis for drug screening and urine 
pregnancy test; h) ) blood draws for: 1.) laboratory examination including CBC, ALT, AST, 
alkaline phosphatase, glucose, BUN, creatinine and 2.) DNA; i) SILS to measure estimated IQ. 
Ad libitum Smoking Session: Those found eligible will complete the ad libitum smoking baseline 
assessment, consisting of self-report measures of mood, withdrawal and smoking urges, 
cognitive tasks and vitals. Biochemical measures will include CO levels, breathalyzer, urine 
toxicology for drug screening, urine cotinine, blood draws for: 1.) nicotine and nicotine 
metabolite levels and 2.) gonadal hormone levels (progesterone, estradiol). 
Medication Initiation (Medication Days 1-2) and Abstinence Phase (Medication Days 6-7) 
Sessions: Those subjects who were found eligible will be randomized to medication 


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(tolcapone) or placebo, in a double-blind fashion. Urn randomization will endeavor to balance 
medication and placebo groups for race, baseline smoking rate, and menstrual cycle phase. 
Although genotype will not be known for all subjects prior to randomization, in cases when it 
is known (e.g., genetics sample collected at baseline is processed prior to randomization) will 
be counterbalanced for genotype as much as possible.  
Brief once-daily visits during the medication initiation (Medication Days 1-2) and abstinence 
periods (Medication Days 6-7) will serve four purposes: 1) administer pill in person and give 
take-home doses with instructions (100mg three times a day (TID); subjects will be asked to 
self-administer the take-home doses at approximately 6-hour intervals); 2) screen for adverse 
medication effects (Adverse Events Form; heart rate and blood pressure); 3) check for nicotine 
abstinence compliance (expired CO; urine cotinine; self-reported cigarettes per day); 4) collect 
self-report measures of withdrawal, smoking urges and mood, which are hypothesized to 
fluctuate with abstinence and/or medication.  
Medication Initiation and Stabilization Phase (Medication Days 1-5): For the first five days of 
medication, subjects will be told they may smoke their cigarettes as much as they choose (ad 
libitum). They will be asked to attend one brief session per day on Medication Days 1-2. These 
first days will allow the participants to achieve medication optimal dosing and steady state 
levels prior to initiating the abstinence period. For Medication Days 3-5, the subjects will 
maintain the same dose and take the doses at home. During these days, they will have either in 
person/or phone check-in with a member of the research team to check for reported adverse 
effects. Brief questions about smoking (e.g., cigarettes per day) and whether they noticed 
changes in mood or smoking urges will also be asked. These phone check-in days are designed 
to maintain contact to continue monitoring for safety purposes, while reducing the burden on 
the participants. Subjects will have an emergency contact so they can access care if needed 
during this time.  
Abstinence Medication Maintenance Sessions (Medication Days 6-7): Beginning on the 
evening of Medication Day 5, subjects will be asked to refrain from smoking their cigarettes. 
They will be asked to attend one brief check-in session per day on Medication Days 6-7. 
Medication doses continue at 100mg TID during this phase. Smoking abstinence will be 
tracked with CO-levels, urine cotinine screens and self-report.  
 
Post-2 ½ day Abstinence End of Trial Session (Medication Day 8):  At the testing session, 
participants will have been abstinent from smoking for 2 ½ days or more (e.g., 8PM Medication 
Day 5 through 8AM Medication Day 8), and maintained on tolcapone (or placebo) for the 
previous week. Participants will take their final dose (100mg) on the morning of Medication Day 
8 then complete the same self-report measures and cognitive tasks from the baseline Ad libitum 
Smoking session.  Blood will be collected for assessment of nicotine and cotinine (as additional 
confirmation of abstinence), gonadal hormones and liver function tests (to screen for adverse 
effects of tolcapone). 
 
Subjects will then complete the Smoking Choice Laboratory Procedure. As we have done in 
previous studies, participants will complete this paradigm in a designated, negative pressure 
room. After sample smoking (2 sec cigarette puffs separated by a 20 sec interval) to measure 
subjective responses to smoking following abstinence, participants exchange tokens for cigarette 
puffs (2 puffs) or money ($0.75) every 9 minutes until 1.5 hours had elapsed (i.e., 9 min x 10 


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tokens). This token value is sensitive to increases and decreases in smoking behavior (Sofuoglu 
et al, 2009). If participants choose cigarette puffs instead of money at every opportunity, they 
will smoke the equivalent of slightly more than one cigarette within the 90-minute laboratory 
paradigm. Participants will be allowed to decline the sample smoking opportunity if they wish to 
remain abstinent. Even if they decline the sample smoking opportunity, they will still be asked to 
remain at the lab for the remainder of the 90-minute paradigm. If they decline this smoking 
sample opportunity they will also still be allowed to exchange all un-traded tokens for take-home 
pay (totaling $7.50 if they choose not to trade any tokens for “puffs” of the cigarette) at the end 
of the 90-minute paradigm. 
At the end of this session, participants will stop medication at this time.  
 
 
1-Week Follow-up Check-in Session: After medication is ended but prior to the in person check-
in session, subjects will have the ability to check-in by as needed and will have an emergency 
contact so they can access care if needed. Approximately one week after the final medication 
day, participants will be asked to attend a brief in person follow-up check-in session. During this 
session, they will be asked about reported adverse effects, past week smoking and substance use 
and whether they noticed changes in mood or smoking urges. They will be asked to complete 
some questionnaires on these topics. Blood pressure and heart rate will be collected.  A urine 
pregnancy and cotinine screen will be completed. CO levels will be collected. A blood sample 
will be collected for laboratory tests, including liver functions. Subjects will be discharged at the 
end of the follow-up session.  
 
 
Protection of Subjects 
In order to participate in a study, each subject must give informed consent. All potential risks 
will be described in detail to the subjects in the consent form. Confidentiality in this study is of 
the utmost importance to us. All information obtained will be stored in coded form. The names 
of the subjects will be used in hospital records.   
Confidentiality will be protected by having records identified by code number only with the 
master list including names kept in a sealed envelope in a locked file in the Principal 
Investigator's office and by the pharmacy. Subjects will be given telephone numbers to call in 
case of emergency, 24 hours a day.  The potential risk of loss of confidentiality due to data 
sharing will be minimized by creating de-identified data sets that exclude direct and indirect 
identifiers. In addition, researchers requesting data will be required to enter into a data sharing 
agreement. In addition, a Certificate of Confidentiality is being applied for to add some further 
protections against the research team being compelled to disclose information about participants. 
 
This project will be monitored by the Center’s Data and Safety Monitoring Board (DSMB) 
because the study involves the double-blind treatment of tolcapone and placebo.  This board is 
composed of persons not otherwise affiliated with the clinical study who are experienced in 
various aspects of the conduct of clinical trials for the treatment of addictive disorders. We 
propose three investigators located here in Connecticut who are not directly involved in this 
study – Declan Berry, Ph.D., Sherry McKee, Ph.D., and David Fiellin, M.D. as the members of 


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the DSMB. The members of the DSMB, and all study Investigators, will complete Conflict of 
Interest forms created by VA HSS in accordance with NIH guidelines.  
 
 
Individual Stopping Rules: 
For the purposes of participant safety and data quality control, subjects will be discharged from 
the medication trial if: 1) subject experiences serious side effects which appear related to the study 
medication including liver toxicity (LFT>2 times greater than the upper limit of the normal range); 
2) study physician/medical monitor decides that continued study participation may cause physical 
or psychological harm to the subject; 3) subject misses 3 consecutive medication-administration 
study sessions; 4) subject misses 2 consecutive CO level tests, urine cotinine tests during the 
abstinence phase; 5) subject is found to have used alcohol, illegal drugs or other psychotropic 
drugs during the medication phase of the study. In the case of any of these causes of early discharge 
from the trial, participants who began the medication phase of the study- even if they did not 
complete the medication phase- will still be contacted for phone follow-up and invited to attend 
the in person follow-up check-in for safety purposes.  
 
Study Stopping Rules:  
For the purposes of safety, if more than three subjects are stopped from medication use early due 
to serious side effects which appear related to the study medication, including but not limited to 
increased LFTs, twice as high as the upper limit of the normal range, which is not resolved by one-
week follow-up, the co-PIs will confer with the DSMB to check whether the entire study should 
be halted.   
 
Payment:  
Subjects will be compensated for participation in each study visit up to a cumulative total of 
$592.50, with longer visits compensated at a higher rate than brief visits (see details in Initial 
Review Application). Payments will be made in cash incrementally at each visit as follows: $35 
for the initial in-person screen; $100 for the ad libitum smoking baseline session; $40 for each of 
the four in-person check-in visits; for the weekday visit that is labelled an ‘in-person’ or phone 
check-in, subjects will be paid $40 if they choose to attend the in-person check-in and they will 
be paid $10 if they choose the phone check-in for that weekday visit (i.e., either medication day 
3 or 5 depending on start date); for weekend phone check-in sessions subjects will always be 
paid  $10 for each of the phone check-ins; $100  for the post-2 ½ day--abstinence session and 
$50 for the smoking paradigm procedure and $35 for the final one-week follow-up in-person 
check-in visit. Included in the total possible compensation will be the opportunity to earn an 
additional $15 for study procedure compliance (e.g., $15 for CO levels <8ppm with no increase 
in CO across abstinence visits), and the ability to take home money during the Smoking Choice 
Paradigm wherein smoking opportunities (i.e. ‘puffs’) are traded for tokens with monetary value. 
So if no tokens are traded for puffs, the subject can take home up to $7.50 from the paradigm. 
The compensation schedule is designed to encourage study compliance while avoiding undue 
coercion to remain in the study. If the subjects choose to terminate a session prematurely, or a 
session is terminated early for medical reasons, they will receive full payment for that day. If 


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they become ineligible to continue in the study due to non-compliance with study procedures, 
they will only be paid for the portions of the study in which they have participated.  
 
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SAP_001.pdf: 
Official Title in ClinicalTrials.gov: Treatment for Nicotine Addiction in Women  
NCT: NCT02448654 
Document Date: 7/7/14  
 
 


<from originally planned analysis section- from grant> 
 
Sample Size Considerations and Data Analysis 
Power Analysis: As this is the first randomized clinical trial evaluating the effect of tolcapone 
on withdrawal, smoking urges, and cognition in women smokers during abstinence, we used 
effect sizes from comparisons of Val158Met genotype as general proxies for treatment 
differences. In previous research, we found significant differences in women smokers by Val/Val 
vs. Met/_ genotype in withdrawal (F= 5.7, df=48, p=.02), smoking urges (F= 16.9, df=48, 
p<.001), and sustained attention (F=9.9, df=48, p=.003) during abstinence, and subjective 
ratings of nicotine’s anxiolytic effects (F=3.7, df=47, p=.02) (see Preliminary Data). Using 
G*Power, we found that with a sample of 60, alpha=.05, power=.80, we would be able to detect 
large effects for our planned analyses (f=.37). We expect to enroll 80 subjects to achieve a 
completion N=60. However, with N=52 we would still be able to detect a large effect size (f 
=.40). 
Analysis Plan: The primary statistical models will be analysis of covariance (ANCOVA) to test 
for medication group differences in withdrawal, smoking urges, sustained attention and smoking 
choice post-abstinence. COMT genotype will be used as an independent variable in an 
exploratory two factor ANCOVA. Menstrual cycle phase, race and baseline smoking severity will 
be included as covariates. 
Specific Aim 1: ANCOVAs will examine the effect of tolcapone on reducing a) withdrawal 
severity (MNWS); b) smoking urges (BQSU); and c) cognitive impairment (e.g., CPT) during 
abstinence vs. placebo. With 80% power, we can detect a large medication effect (f=.37).  
Specific Aim 2: ANCOVA will examine the effect of medication vs. placebo on laboratory 
smoking choices post-abstinence. With 81% power, we can detect a large effect (f=.40). 
Exploratory Aim 1: ANCOVAs will examine the effect of Met/_ genotype on reduced a) 
withdrawal severity (MNWS); b) smoking urges (BQSU); and c) cognitive impairment (e.g., CPT) 
during abstinence vs. Val/Val. With 80% power, we can detect a large genotype effect (f=.37).   
Exploratory Aim 2: ANCOVA will assess withdrawal and smoking post abstinence, using both 
medication and genotype as the independent variables and co-varying for baseline scores, to 
test for a medication by genotype interaction. With 81% power, we can detect a large effect 
(f=.40). 
Exploratory Aim 3: Structural equation modeling will examine moderating effects of gonadal 
hormone levels on withdrawal severity and smoking behavior post-abstinence. The mediation 
effect size is unknown.