Trial Outcomes & Findings for Neural Substrates in Nicotine Withdrawal (NCT NCT01001520)

NCT ID: NCT01001520

Last Updated: 2014-07-02

Results Overview

Subjects completed two, 11-day study medication periods (one taking active tolcapone; one taking placebo). On Day 8 of each period, after at least 24 hours of smoking abstinence, subjects had an fMRI scan to measure changes in brain activity that occur during a memory test. The subjects completed a commonly used working memory test referred to as the "N-back". This test presented complex geometric figures on a projection screen for 0.5 seconds; each figure is separated by 2.5 seconds of black screen. There were 4 conditions requiring increasing memory demands: 0-back, 1-back, 2-back, \& 3-back. Subjects had to respond to the target geometric figure that was separated by 0, 1, 2, or 3 figures before it is repeated. Between each condition, there was a brief rest period. To identify brain signal change, we calculated the difference in the amount of brain activity detected by the fMRI scan for each condition compared to the rest periods. This was a within-subject analysis.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 218 participants
• Primary outcome timeframe: At fMRI scan sessions - Days 8 and 29
• Results posted on: 2014-07-02

Participant Flow

Recruitment began in March 2010. Former study subjects with a known catechol-O-methyltransferase (COMT) genotype and who asked to be contacted for future studies were invited to participate, as well as potential subjects who called our center in response to advertising. All sessions were completed in our clinic at the University of Pennsylvania.

2670 subjects completed initial screening over the phone; 669 (25%) were eligible. Of these, 418 (62%) scheduled an in-person screening visit; 218 (50%) attended this visit. 73 (17%) provided blood samples to determine final eligibility, based on genetic & liver function tests. 54 (74%) reached final eligibility; 46 (85%) started study medication.

Participant milestones

Measure	Placebo First, Then Tolcapone Subjects were asked to take study medication each day during two 11-day study medication periods. Between the two study medication periods was a washout period (no medication or visits) that lasted at least 10 days. During this washout period, subjects did not take any study medication and were asked to return to their normal smoking levels. Study medication assignment for each subject was randomized and counterbalanced, meaning approximately 50% of subjects took placebo during the first medication period, followed by tolcapone during the second medication period. During the placebo medication period, subjects followed a medication regimen and took capsules that were identical to those in the active tolcapone medication period (see protocol section for complete description).	Tolcapone First, Then Placebo Subjects were asked to take study medication each day during two 11-day study medication periods. Between the two study medication periods was a washout period (no medication or visits) that lasted at least 10 days. During this washout period, subjects did not take any study medication and were asked to return to their normal smoking levels. Study medication assignment for each subject was randomized and counterbalanced, meaning approximately 50% of subjects took tolcapone during the first medication period, followed by a placebo during the second medication period. During the active tolcapone medication period, subjects followed a tapered dosing schedule (see protocol section for complete description).
Medication Period 1 STARTED	22	24
Medication Period 1 COMPLETED	18	17
Medication Period 1 NOT COMPLETED	4	7
Washout Period STARTED	18	17
Washout Period COMPLETED	16	16
Washout Period NOT COMPLETED	2	1
Medication Period 2 STARTED	16	16
Medication Period 2 COMPLETED	16	13
Medication Period 2 NOT COMPLETED	0	3

Reasons for withdrawal

Measure	Placebo First, Then Tolcapone Subjects were asked to take study medication each day during two 11-day study medication periods. Between the two study medication periods was a washout period (no medication or visits) that lasted at least 10 days. During this washout period, subjects did not take any study medication and were asked to return to their normal smoking levels. Study medication assignment for each subject was randomized and counterbalanced, meaning approximately 50% of subjects took placebo during the first medication period, followed by tolcapone during the second medication period. During the placebo medication period, subjects followed a medication regimen and took capsules that were identical to those in the active tolcapone medication period (see protocol section for complete description).	Tolcapone First, Then Placebo Subjects were asked to take study medication each day during two 11-day study medication periods. Between the two study medication periods was a washout period (no medication or visits) that lasted at least 10 days. During this washout period, subjects did not take any study medication and were asked to return to their normal smoking levels. Study medication assignment for each subject was randomized and counterbalanced, meaning approximately 50% of subjects took tolcapone during the first medication period, followed by a placebo during the second medication period. During the active tolcapone medication period, subjects followed a tapered dosing schedule (see protocol section for complete description).
Medication Period 1 Withdrawal by Subject	2	2
Medication Period 1 Ineligible: Positive Urine Drug Screen	0	3
Medication Period 1 Ineligible: fMRI contraindicated metal	0	2
Medication Period 1 Ineligible: Claustrophobia in fMRI	2	0
Washout Period Withdrawal by Subject	2	1
Medication Period 2 Withdrawal by Subject	0	3

Baseline Characteristics

Neural Substrates in Nicotine Withdrawal

Baseline characteristics by cohort

Measure	Entire Study Population n=46 Participants Includes all subjects who were randomized to both study treatment groups (i.e., receive both placebo first and tolcapone first) and initiated study medication.
Age, Continuous	38.3 Years STANDARD_DEVIATION 12.2 • n=5 Participants
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	46 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants
Sex: Female, Male Female	17 Participants n=5 Participants
Sex: Female, Male Male	29 Participants n=5 Participants
Race/Ethnicity, Customized African American	15 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian	29 Participants n=5 Participants
Race/Ethnicity, Customized More than one race	2 Participants n=5 Participants
Region of Enrollment United States	46 participants n=5 Participants
Nicotine Dependence	4.8 Scores on a scale STANDARD_DEVIATION 1.5 • n=5 Participants
Cigarettes smoked per day	17.1 Cigarettes smoked per day STANDARD_DEVIATION 4.9 • n=5 Participants
Number of years smoked	21.8 years STANDARD_DEVIATION 13.7 • n=5 Participants

PRIMARY outcome

Timeframe: At fMRI scan sessions - Days 8 and 29

Population: 29 subjects completed both fMRI scan sessions; however, data from 9 subjects were excluded from analysis, due to either poor fMRI data quality, low task accuracy (defined as task scores falling two standard deviations below the mean), or a failure to respond to more than 30% of the task's items. Below, we report on the 20 remaining subjects.

Subjects completed two, 11-day study medication periods (one taking active tolcapone; one taking placebo). On Day 8 of each period, after at least 24 hours of smoking abstinence, subjects had an fMRI scan to measure changes in brain activity that occur during a memory test. The subjects completed a commonly used working memory test referred to as the "N-back". This test presented complex geometric figures on a projection screen for 0.5 seconds; each figure is separated by 2.5 seconds of black screen. There were 4 conditions requiring increasing memory demands: 0-back, 1-back, 2-back, & 3-back. Subjects had to respond to the target geometric figure that was separated by 0, 1, 2, or 3 figures before it is repeated. Between each condition, there was a brief rest period.

To identify brain signal change, we calculated the difference in the amount of brain activity detected by the fMRI scan for each condition compared to the rest periods. This was a within-subject analysis.

Outcome measures

Measure	Placebo n=20 Participants An 11-day placebo-controlled medication period. Both medication periods involved taking identical capsules in the same tapered-dose regimen (Day 1: 100mg three times daily, Days 2-8: 200mg three times daily, Day 9: 200mg twice daily, Day 10: 200mg once daily, Day 11: 100mg once daily). The only difference was that, during the placebo period, the capsules did not contain tolcapone. All medication was encapsulated by the University of Pennsylvania's Investigational Drug Service (IDS).	Tolcapone n=20 Participants 11-day medication period following a tapered dosing scheduled (Day 1: 100mg three times daily, Days 2-8: 200mg three times daily, Day 9: 200mg twice daily, Day 10: 200mg once daily, Day 11: 100mg once daily). The only difference was that, during this period, the capsules contained the active medication, tolcapone. All medication was encapsulated by the University of Pennsylvania's Investigational Drug Service (IDS)
Measure of Brain Activity: Blood Oxygen Level Dependent (BOLD) fMRI Signal Change During the "N-back" Working Memory Task (Brain Region: Right Dorsolateral Prefrontal Cortex; Right DLPFC)	0.27 BOLD signal Standard Error 0.04	0.27 BOLD signal Standard Error 0.03

PRIMARY outcome

Timeframe: At fMRI scan sessions - Days 8 and 29

Population: See previous sections.

Subjects completed two, 11-day study medication periods (one taking active tolcapone; one taking placebo). On Day 8 of each period, after at least 24 hours of smoking abstinence, subjects had an fMRI scan to measure changes in brain activity that occur during a memory test. The subjects completed a commonly used working memory test referred to as the "N-back". This test presented complex geometric figures on a projection screen for 0.5 seconds; each figure is separated by 2.5 seconds of black screen. There were 4 conditions requiring increasing memory demands: 0-back, 1-back, 2-back, & 3-back. Subjects had to respond to the target geometric figure that was separated by 0, 1, 2, or 3 figures before it is repeated. Between each condition, there was a brief rest period.

To identify brain signal change, we calculated the difference in the amount of brain activity detected by the fMRI scan for each condition compared to the rest periods. This was a within-subject analysis.

Outcome measures

Measure	Placebo n=20 Participants An 11-day placebo-controlled medication period. Both medication periods involved taking identical capsules in the same tapered-dose regimen (Day 1: 100mg three times daily, Days 2-8: 200mg three times daily, Day 9: 200mg twice daily, Day 10: 200mg once daily, Day 11: 100mg once daily). The only difference was that, during the placebo period, the capsules did not contain tolcapone. All medication was encapsulated by the University of Pennsylvania's Investigational Drug Service (IDS).	Tolcapone n=20 Participants 11-day medication period following a tapered dosing scheduled (Day 1: 100mg three times daily, Days 2-8: 200mg three times daily, Day 9: 200mg twice daily, Day 10: 200mg once daily, Day 11: 100mg once daily). The only difference was that, during this period, the capsules contained the active medication, tolcapone. All medication was encapsulated by the University of Pennsylvania's Investigational Drug Service (IDS)
Measure of Brain Activity: Blood Oxygen Level Dependent (BOLD) fMRI Signal Change During the "N-back" Working Memory Task (Brain Region: Left Dorsolateral Prefrontal Cortex; Left DLPFC)	0.32 BOLD signal Standard Error 0.03	0.28 BOLD signal Standard Error 0.03

PRIMARY outcome

Timeframe: At fMRI scan sessions - Days 8 and 29

Population: See previous sections.

Subjects completed two, 11-day study medication periods (one taking active tolcapone; one taking placebo). On Day 8 of each period, after at least 24 hours of smoking abstinence, subjects had an fMRI scan to measure changes in brain activity that occur during a memory test. The subjects completed a commonly used working memory test referred to as the "N-back". This test presented complex geometric figures on a projection screen for 0.5 seconds; each figure is separated by 2.5 seconds of black screen. There were 4 conditions requiring increasing memory demands: 0-back, 1-back, 2-back, & 3-back. Subjects had to respond to the target geometric figure that was separated by 0, 1, 2, or 3 figures before it is repeated. Between each condition, there was a brief rest period.

To identify brain signal change, we calculated the difference in the amount of brain activity detected by the fMRI scan for each condition compared to the rest periods. This was a within-subject analysis.

Outcome measures

Measure	Placebo n=20 Participants An 11-day placebo-controlled medication period. Both medication periods involved taking identical capsules in the same tapered-dose regimen (Day 1: 100mg three times daily, Days 2-8: 200mg three times daily, Day 9: 200mg twice daily, Day 10: 200mg once daily, Day 11: 100mg once daily). The only difference was that, during the placebo period, the capsules did not contain tolcapone. All medication was encapsulated by the University of Pennsylvania's Investigational Drug Service (IDS).	Tolcapone n=20 Participants 11-day medication period following a tapered dosing scheduled (Day 1: 100mg three times daily, Days 2-8: 200mg three times daily, Day 9: 200mg twice daily, Day 10: 200mg once daily, Day 11: 100mg once daily). The only difference was that, during this period, the capsules contained the active medication, tolcapone. All medication was encapsulated by the University of Pennsylvania's Investigational Drug Service (IDS)
Measure of Brain Activity: Blood Oxygen Level Dependent (BOLD) fMRI Signal Change During the "N-back" Working Memory Task (Brain Region: Dorsal Cingulate/Medial Prefrontal Cortex; MF/CG)	0.39 BOLD signal Standard Error 0.03	0.37 BOLD signal Standard Error 0.03

PRIMARY outcome

Timeframe: At fMRI scan sessions - Days 8 and 29

Population: See previous sections.

Subjects completed two, 11-day study medication periods (one taking active tolcapone; one taking placebo). On Day 8 of each period, after at least 24 hours of smoking abstinence, subjects had an fMRI scan to measure changes in brain activity that occur during a memory test. The subjects completed a commonly used working memory test referred to as the "N-back". This test presented complex geometric figures on a projection screen for 0.5 seconds; each figure is separated by 2.5 seconds of black screen. There were 4 conditions requiring increasing memory demands: 0-back, 1-back, 2-back, & 3-back. Subjects had to respond to the target geometric figure that was separated by 0, 1, 2, or 3 figures before it is repeated. Between each condition, there was a brief rest period.

To identify brain signal change, we calculated the difference in the amount of brain activity detected by the fMRI scan for each condition compared to the rest periods. This was a within-subject analysis.

Outcome measures

Measure	Placebo n=20 Participants An 11-day placebo-controlled medication period. Both medication periods involved taking identical capsules in the same tapered-dose regimen (Day 1: 100mg three times daily, Days 2-8: 200mg three times daily, Day 9: 200mg twice daily, Day 10: 200mg once daily, Day 11: 100mg once daily). The only difference was that, during the placebo period, the capsules did not contain tolcapone. All medication was encapsulated by the University of Pennsylvania's Investigational Drug Service (IDS).	Tolcapone n=20 Participants 11-day medication period following a tapered dosing scheduled (Day 1: 100mg three times daily, Days 2-8: 200mg three times daily, Day 9: 200mg twice daily, Day 10: 200mg once daily, Day 11: 100mg once daily). The only difference was that, during this period, the capsules contained the active medication, tolcapone. All medication was encapsulated by the University of Pennsylvania's Investigational Drug Service (IDS)
Measure of Brain Activity: Blood Oxygen Level Dependent (BOLD) fMRI Signal Change During the "N-back" Working Memory Task (Brain Region: Posterior Cingulate Cortex; PCC)	-0.34 BOLD signal Standard Error 0.05	-0.33 BOLD signal Standard Error 0.04

PRIMARY outcome

Timeframe: At fMRI scan sessions - Days 8 and 29

Population: See previous sections.

Subjects completed two, 11-day study medication periods (one taking active tolcapone; one taking placebo). On Day 8 of each period, after at least 24 hours of smoking abstinence, subjects had an fMRI scan to measure changes in brain activity that occur during a memory test. The subjects completed a commonly used working memory test referred to as the "N-back". This test presented complex geometric figures on a projection screen for 0.5 seconds; each figure is separated by 2.5 seconds of black screen. There were 4 conditions requiring increasing memory demands: 0-back, 1-back, 2-back, & 3-back. Subjects had to respond to the target geometric figure that was separated by 0, 1, 2, or 3 figures before it is repeated. Between each condition, there was a brief rest period.

To identify brain signal change, we calculated the difference in the amount of brain activity detected by the fMRI scan for each condition compared to the rest periods. This was a within-subject analysis.

Outcome measures

Measure	Placebo n=20 Participants An 11-day placebo-controlled medication period. Both medication periods involved taking identical capsules in the same tapered-dose regimen (Day 1: 100mg three times daily, Days 2-8: 200mg three times daily, Day 9: 200mg twice daily, Day 10: 200mg once daily, Day 11: 100mg once daily). The only difference was that, during the placebo period, the capsules did not contain tolcapone. All medication was encapsulated by the University of Pennsylvania's Investigational Drug Service (IDS).	Tolcapone n=20 Participants 11-day medication period following a tapered dosing scheduled (Day 1: 100mg three times daily, Days 2-8: 200mg three times daily, Day 9: 200mg twice daily, Day 10: 200mg once daily, Day 11: 100mg once daily). The only difference was that, during this period, the capsules contained the active medication, tolcapone. All medication was encapsulated by the University of Pennsylvania's Investigational Drug Service (IDS)
Measure of Brain Activity: Blood Oxygen Level Dependent (BOLD) fMRI Signal Change During the "N-back" Working Memory Task (Brain Region: Ventromedial Prefrontal Cortex; vmPFC)	-0.29 BOLD signal Standard Error 0.06	-0.45 BOLD signal Standard Error 0.07

SECONDARY outcome

Timeframe: At fMRI scan sessions - Days 8 and 29

Population: 29 subjects completed both fMRI scan sessions; however, data from 9 subjects were excluded from analysis, due to either poor fMRI data quality, low task accuracy (defined as task scores falling two standard deviations below the mean), or a failure to respond to more than 30% of the task's items. Below, we report on the 20 remaining subjects.

Subjects underwent two, 11-day study medication periods (one taking active tolcapone; one taking placebo). On Day 8 of each study medication period, after at least 24 hours of smoking abstinence, subjects completed an fMRI brain scan. During these fMRI scan sessions, participants completed computer tasks that were designed to test working memory and attention. These tasks were similar to computer games, in that participants would push a button in response to the pictures they see.

Specifically, we tested whether subjects, while taking tolcapone, would display increased accuracy during the N-back working memory task compared to their performance while they took the placebo. We measured accuracy by counting the absolute number of true positives scored (the number each subject got correct during the task). This was a within-subject analysis.

Outcome measures

Measure	Placebo n=20 Participants An 11-day placebo-controlled medication period. Both medication periods involved taking identical capsules in the same tapered-dose regimen (Day 1: 100mg three times daily, Days 2-8: 200mg three times daily, Day 9: 200mg twice daily, Day 10: 200mg once daily, Day 11: 100mg once daily). The only difference was that, during the placebo period, the capsules did not contain tolcapone. All medication was encapsulated by the University of Pennsylvania's Investigational Drug Service (IDS).	Tolcapone n=20 Participants 11-day medication period following a tapered dosing scheduled (Day 1: 100mg three times daily, Days 2-8: 200mg three times daily, Day 9: 200mg twice daily, Day 10: 200mg once daily, Day 11: 100mg once daily). The only difference was that, during this period, the capsules contained the active medication, tolcapone. All medication was encapsulated by the University of Pennsylvania's Investigational Drug Service (IDS)
Cognitive Performance: Accuracy	49.9 Number of true positives Standard Error 1.3	51.8 Number of true positives Standard Error 0.87

SECONDARY outcome

Timeframe: At fMRI scan sessions - Days 8 and 29

Population: 29 subjects completed both fMRI scan sessions; however, data from 9 subjects were excluded from analysis, due to either poor fMRI data quality, low task accuracy (defined as task scores falling two standard deviations below the mean), or a failure to respond to more than 30% of the task's items. Below, we report on the 20 remaining subjects.

Subjects underwent two, 11-day study medication periods (one taking active tolcapone; one taking placebo). On Day 8 of each study medication period, after at least 24 hours of smoking abstinence, subjects completed an fMRI brain scan. During these fMRI scan sessions, participants completed computer tasks that were designed to test working memory and attention. These tasks were similar to computer games, in that participants would push a button in response to the pictures they see.

Specifically, we tested whether subjects, while taking tolcapone, would display increased average reaction time (in milliseconds) during the N-back working memory task compared to their performance while they took the placebo. This was a within-subject analysis.

Outcome measures

Measure	Placebo n=20 Participants An 11-day placebo-controlled medication period. Both medication periods involved taking identical capsules in the same tapered-dose regimen (Day 1: 100mg three times daily, Days 2-8: 200mg three times daily, Day 9: 200mg twice daily, Day 10: 200mg once daily, Day 11: 100mg once daily). The only difference was that, during the placebo period, the capsules did not contain tolcapone. All medication was encapsulated by the University of Pennsylvania's Investigational Drug Service (IDS).	Tolcapone n=20 Participants 11-day medication period following a tapered dosing scheduled (Day 1: 100mg three times daily, Days 2-8: 200mg three times daily, Day 9: 200mg twice daily, Day 10: 200mg once daily, Day 11: 100mg once daily). The only difference was that, during this period, the capsules contained the active medication, tolcapone. All medication was encapsulated by the University of Pennsylvania's Investigational Drug Service (IDS)
Cognitive Performance: Reaction Time	518 Milliseconds Standard Error 16	520 Milliseconds Standard Error 16

SECONDARY outcome

Timeframe: Days 1 through 7 of each study period

Population: 29 subjects completed both fMRI scan sessions; however, data from 9 subjects were excluded from analysis, due to either poor fMRI data quality, low task accuracy (defined as task scores falling two standard deviations below the mean), or a failure to respond to more than 30% of the task's items. Below, we report on the 20 remaining subjects.

In order to determine if tolcapone (vs. placebo) would affect subject smoking behavior, we collected the daily number of cigarettes each subject smoked from Days 1 through 7 during each study medication period. This allowed us to calculate the average number of daily cigarettes smoked, across all subjects, during each study medication period (i.e., the average number of cigarettes/day smoked while all subjects took tolcapone and the average number of cigarettes/day smoked while all subjects took placebo). Then, we statistically assessed if there was a significant difference between these averages.

Outcome measures

Measure	Placebo n=20 Participants An 11-day placebo-controlled medication period. Both medication periods involved taking identical capsules in the same tapered-dose regimen (Day 1: 100mg three times daily, Days 2-8: 200mg three times daily, Day 9: 200mg twice daily, Day 10: 200mg once daily, Day 11: 100mg once daily). The only difference was that, during the placebo period, the capsules did not contain tolcapone. All medication was encapsulated by the University of Pennsylvania's Investigational Drug Service (IDS).	Tolcapone n=20 Participants 11-day medication period following a tapered dosing scheduled (Day 1: 100mg three times daily, Days 2-8: 200mg three times daily, Day 9: 200mg twice daily, Day 10: 200mg once daily, Day 11: 100mg once daily). The only difference was that, during this period, the capsules contained the active medication, tolcapone. All medication was encapsulated by the University of Pennsylvania's Investigational Drug Service (IDS)
Subjective Symptoms: Smoking Behavior	14.2 Average number of cigarettes smoked/day Standard Deviation 3.9	14.3 Average number of cigarettes smoked/day Standard Deviation 4.0

SECONDARY outcome

Timeframe: Day 8 (fMRI scanning session) of each study period

Population: 29 subjects completed both fMRI scan sessions; however, data from 9 subjects were excluded from analysis, due to either poor fMRI data quality, low task accuracy (defined as task scores falling two standard deviations below the mean), or a failure to respond to more than 30% of the task's items. Below, we report on the 20 remaining subjects

Subjective symptoms were assessed during each in-person session throughout each study medication period. During each visit, we asked subjects to complete the Questionnaire for Smoking Urges-Brief (QSU-B). Specifically, subjects completed the QSU-B at day 5, day 8 (fMRI scanning session 1), day 26 (day 5 of study medication period 2), and day 29 (day 8 of study medication period 2; fMRI scanning session 2).

The range of possible scores on the QSU-B is 10-70, with higher values indicating an increased craving for cigarettes. This range of scores represent a "total" score; there are no subscales.

While the QSU-B was collected at all in-person sessions, we only analyzed the scores collected from the fMRI scanning sessions of each period (day 8 and day 29). To analyze, we averaged the total scores across all 20 subjects from each fMRI scanning session and statistically analyzed for significant differences between these two averages. This was a within-subject analysis.

Outcome measures

Measure	Placebo n=20 Participants An 11-day placebo-controlled medication period. Both medication periods involved taking identical capsules in the same tapered-dose regimen (Day 1: 100mg three times daily, Days 2-8: 200mg three times daily, Day 9: 200mg twice daily, Day 10: 200mg once daily, Day 11: 100mg once daily). The only difference was that, during the placebo period, the capsules did not contain tolcapone. All medication was encapsulated by the University of Pennsylvania's Investigational Drug Service (IDS).	Tolcapone n=20 Participants 11-day medication period following a tapered dosing scheduled (Day 1: 100mg three times daily, Days 2-8: 200mg three times daily, Day 9: 200mg twice daily, Day 10: 200mg once daily, Day 11: 100mg once daily). The only difference was that, during this period, the capsules contained the active medication, tolcapone. All medication was encapsulated by the University of Pennsylvania's Investigational Drug Service (IDS)
Subjective Symptoms: Cigarette Craving	40.5 units on a scale Standard Deviation 14.7	42.0 units on a scale Standard Deviation 12.6

SECONDARY outcome

Timeframe: Day 8 of each study period

Population: 29 subjects completed both fMRI scan sessions; however, data from 9 subjects were excluded from analysis, due to either poor fMRI data quality, low task accuracy (defined as task scores falling two standard deviations below the mean), or a failure to respond to more than 30% of the task's items. Below, we report on the 20 remaining subjects.

Subjective symptoms were assessed during each in-person session throughout each study medication period. During each visit, we asked subjects to complete the Minnesota Nicotine Withdrawal Scale - Revised version (MNWS). The scale assesses eight DSM-IV items of nicotine withdrawal. The range of possible total scores on the MNWS is 0-60, with higher values indicating an increased nicotine withdrawal. This range of scores represent a "total" score; there are no subscales. The MNWS-N (right now/at the moment) was assessed during each fMRI scanning session visit (Day 8).

To assess if tolcapone (vs. placebo) affect withdrawal symptoms, we statistically analyzed the average of the total MNWS scores across, all 20 subjects, for each study medication period. Specifically, we analyzed for significant differences between reported withdrawal symptoms while taking tolcapone vs. taking placebo.

Outcome measures

Measure	Placebo n=20 Participants An 11-day placebo-controlled medication period. Both medication periods involved taking identical capsules in the same tapered-dose regimen (Day 1: 100mg three times daily, Days 2-8: 200mg three times daily, Day 9: 200mg twice daily, Day 10: 200mg once daily, Day 11: 100mg once daily). The only difference was that, during the placebo period, the capsules did not contain tolcapone. All medication was encapsulated by the University of Pennsylvania's Investigational Drug Service (IDS).	Tolcapone n=20 Participants 11-day medication period following a tapered dosing scheduled (Day 1: 100mg three times daily, Days 2-8: 200mg three times daily, Day 9: 200mg twice daily, Day 10: 200mg once daily, Day 11: 100mg once daily). The only difference was that, during this period, the capsules contained the active medication, tolcapone. All medication was encapsulated by the University of Pennsylvania's Investigational Drug Service (IDS)
Subjective Symptoms: Withdrawal Symptoms	10.9 units on a scale Standard Deviation 7.9	10.0 units on a scale Standard Deviation 7.7

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Tolcapone

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

Caryn Lerman, PhD

University of Pennsylvania

Phone: 215-746-7141

Email: clerman@mail.med.upenn.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place