UW Quitting Using Intensive Treatment Study
Phase: PHASE4
Conditions: Tobacco Dependence
Sponsor: University of Wisconsin, Madison

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“Quitting Using Intensive Treatment Study (QUITS)” 
PI: Timothy B. Baker, Ph.D and James H. Stein, MD ; UW-CTRI Grant: 
 
 
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UW HS-IRB # 2017-0404 
 
“Quitting Using Intensive Treatment Study (QUITS)” 
 
Principal Investigators: Timothy B. Baker, Ph.D.  
and James H. Stein, MD, (608) 262-8673 
Coordinating Center: UW-Center for Tobacco Research and Intervention (UW-CTRI) 
Funding Sponsor: DHHS, PHS, National Institutes of Health (NIH) 
 
 
 

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Study Overview 
 
Current smoking cessation pharmacotherapies are effective but most smokers fail to quit 
with even the best medications. This may occur because medication use strategies have not 
been developed in a methodologically principled manner, which had kept clinicians from using 
available medications most effectively. Some evidence suggests that innovative medication use 
strategies such as combining varenicline and nicotine replacement therapy may boost 
medication effectiveness markedly; however, because of a lack of systematic research, we do 
not know which innovative strategies are optimal.  
 
Building on our recent NHLBI-funded publication in JAMA7 that described the modest 
effectiveness of varenicline pharmacotherapy, the proposed research will use a factorial design 
to evaluate two different medication use strategies on their ability to markedly enhance 
varenicline effectiveness in a large cohort of current smokers. Smokers (N=1250) will be 
randomly assigned to one of two levels for each of two factors: 1) an Adjuvant factor (varenicline 
+ placebo patch versus varenicline + nicotine patch), and 2) a Duration factor (12 versus 24 
weeks of active medication). Thus, this factorial design yields a “standard” varenicline treatment 
(12 weeks of active varenicline and 12 weeks of placebo varenicline + 24 weeks of placebo 
patch), and 3 enhanced treatments: 1) 12 weeks of active varenicline and 12 weeks of placebo 
varenicline + 24 weeks of active patch, 2) 24-weeks of active varenicline + 24 weeks of placebo 
patch, and 3) 24 weeks of active varenicline + 24 weeks of active patch. Both treatment 
modifications, longer duration therapy and use of a nicotine replacement therapy (NRT) adjuvant, 
have produced some quite promising effects. However, in both cases these modifications have 
been little researched, their effects are not consistently positive, and they have not been 
implemented in a potentially optimal manner. We will implement each modification in an 
innovative manner designed to enhance its effectiveness. In addition, all participants will be 
given counseling that supports adherent medication use and that is readily translatable to 
healthcare settings. The scientific rigor of this work will be enhanced by the use of placebo 
medication, a large sample, and a factorial design. The latter will allow us to test both the main 
and interaction effects of the experimental factors. We will also be able to compare each 
enhanced treatment with standard 12-week varenicline-only therapy to determine whether any 
of these medication use strategies significantly enhances treatment effectiveness. Outcomes 
will include long-term smoking abstinence (52 weeks), cost-effectiveness, adverse events, and 
withdrawal severity. This design will allow us to evaluate two major pharmacotherapy strategies 
(an NRT adjuvant, extended duration) that yield four distinct varenicline-based treatments. 
Specific aims of this research are: 
 
Specific Aim 1: To determine whether varenicline pharmacotherapy is enhanced by 
either a nicotine replacement adjuvant (i.e., patch NRT) or extended medication duration (i.e., 
24 vs. 12 weeks postquit). The effects of these pharmacotherapy strategies will be reflected in 
main effects for both experimental factors, and in direct comparisons of the enhanced 
varenicline conditions with standard 12-week varenicline-only. The primary outcome will be 52-
week biochemically confirmed smoking abstinence (7-day point-prevalence).   
 
Specific Aim 2: To determine the effects of the varenicline conditions on additional 
critical outcomes such as 23-week point prevalence and prolonged abstinence, smoking 
cessation milestones (abstinence, latency to lapse, and lapse-relapse latency), cost-
effectiveness, withdrawal severity, and adverse events. The variables that mediate and 
moderate (e.g., genotype) the effects of the different pharmacotherapies will also be identified.  

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This research will determine whether two highly promising modifications to varenicline 
treatment, use of a nicotine patch adjuvant and extended 24-week duration, produce superior 
smoking outcomes when they are used either individually or together. Despite their promise, the 
tested modifications have never been experimentally evaluated relative to standard varenicline 
pharmacotherapy. Thus, this innovative research will produce novel evidence regarding how 
best to help smokers quit, and thereby address the leading cause of preventable mortality and 
morbidity related to cardiovascular and pulmonary diseases.    
 
Recruitment & Study Entry 
      
We will recruit participants via multi-media methods (i.e., TV, radio, newspapers and 
newsletters and other print media, flyers, referral cards, minority outreach, emails to UW 
employees, social media such as Facebook, and earned media), which we have previously 
used very successfully30,47,82. Within 1 week, respondents will be called, screened, and 
potentially eligible smokers will be scheduled to attend a group orientation session. At the 
Orientation session, interested individuals will be introduced to the study, have a chance to ask 
questions and provide written informed consent. Participants will complete a final 
inclusion/exclusion assessment and complete the baseline assessments. Randomization to a 
treatment condition will also occur at the Orientation (see Table 2), with stratification on sex, 
site, dependence, and race.  
 
Inclusion/Exclusion 
Participants must: plan to stay in the area for the next 12 months, ability to read and 
write in English, smoke on average ≥5 cigarettes per day over the last 6 months, be ≥18 years 
old, desire to quit smoking but not be engaged currently in cessation treatment, report no use of 
pipe tobacco, cigars, snuff, e-cigarettes or chew in the last 30 days, have reliable phone access, 
willing and able to use both nicotine patch and varenicline, access to transportation to come to 
our clinic and, if female, not be pregnant and be using an acceptable birth control method/ 
method to prevent pregnancy. Smoking will be biochemically confirmed via a carbon monoxide 
breath test at the first visit. Preparticipants must blow a CO of ≥5ppm to continue. Exclusion 
criteria include: current treatment for schizophrenia or a psychotic disorder; suicidal ideation in 
the past 12 months; history of suicidal attempts within the last 10 years; on dialysis or being told 
you have severe kidney disease; hospitalization for a stroke, heart attack, congestive heart 
failure, uncontrolled diabetes mellitus within the past year; history of seizure within the last year, 
currently taking Wellbutrin, Zyban, or Buproprion (Contrave is a weight-loss drug that has 
Wellbutrin in it) for reasons other than to quit smoking or taking to help quit smoking and not 
willing to stop for duration of the study;  currently using any form of nicotine replacement (e.g., 
nicotine patch, nicotine gum, nicotine lozenge) or using Chantix or varenicline and not willing to 
stop for duration of the study;  had a reaction to the nicotine patch that prevented them from 
continuing to use it; or currently participating in another smoking cessation study.     
 
Even though we screen out participants who are pregnant, plan to become pregnant, 
nursing, or are unwilling to take steps to avoid pregnancy, there is a chance that a participant 
eligible at consent could become pregnant later. She would then be considered part of a 
vulnerable group. Given the longitudinal nature of the research, a participant who becomes 
pregnant after enrolling will be given the choice of whether to 1) continue in the study (for 
counseling and other assessments) and agree to immediately stop taking study meds for the 
remaining duration of the study and return any unused medications, OR 2) withdraw. No further 

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medications will be given to this study participant while in the study.  
 
Incarcerated individuals will not be enrolled in this study. However, given the longitudinal nature 
of the research, participants could be incarcerated for periods during their participation. If study 
staff learn that a participant is incarcerated at a time point before or at their Week 8 phone call, 
the participant will be withdrawn from the study. If study staff learn that a participant is 
incarcerated subsequent to Week 8, the participant will not be withdrawn unless that 
incarceration will take them beyond the study period.  In that case, staff will not contact the 
participant while incarcerated and will not provide any treatment (counseling or medication) nor 
conduct any assessments during the period of incarceration.  Services and assessments will be 
re-initiated if the participant is released at a later study time point.   
 
Study Design 
 
      
All participants (N=1250) will receive at least 12 weeks of V plus counseling that 
emphasizes adherent medication use. Participants will also be randomized to one level of each 
of the two factors: 1) an Adjuvant factor: active P vs. placebo P; and 2) a Duration factor: 24 vs. 
12 weeks of active medication.     
 
Assessments 
 
Baseline: These will constitute covariates for analyses (e.g., smoking dependence, 
heaviness, history), characterize the cohort, and capture baseline levels of potential mediators 
of treatment effects. They also will permit assessment of constructs that will be used to develop 
an optimal, patient-centered treatment algorithm. The surveys (gathered at Visit 1: Table 2; 
associated references provide psychometric data) will include: (1) The Smoking History 
Questionnaire30, which provides accurate information about lifetime smoking cessation 
treatment history, family smoking, environmental exposure, and psychiatric history; (2) The Brief 
Wisconsin Smoking Dependence Motives questionnaire (Brief WISDM)83; (3) The Fagerstrom 
Test for Cigarette Dependence (FTCD)84; (4) Alcohol use and problems assessed with a 
quantity-frequency measure for the past week86-88; (5) The Wisconsin Predicting Patients’ 
Relapse questionnaire (WI-PREPARE) which may inform algorithm development90; (6) The 5-
trial Adjusting Delay Task to assess ability to delay reward; (7) interview about changes to make 
to quit successfully; and (8) the Depression, Anxiety and Stress Scales (DASS-21) to assess 
current symptoms of depression, anxiety and stress. In addition, a psychiatric history will be 
gathered that assesses prior diagnoses and treatment for psychiatric disorders including 
substance use (as per78). Blood will be drawn (about 2 tablespoons) for DNA extraction and 
genotyping as in prior UW-CTRI RCTs and for serum cotinine analysis. Breath carbon monoxide 
will be assessed.  
 
DNA assessments. Samples for DNA analysis will only be taken from those providing consent 
for this. As outlined in the Biological Samples protocol supplement, blood will be drawn for 
samples of DNA for genetics, DNA for methylation (Madison site only), and RNA(Madison site 
only). DNA for genetics will be extracted by the UW Biotechnology Center. All three samples will 
be relabeled at the UW Biotechnology Center with DNA IDs/ barcodes, which allows connecting 
additional data secured from participants at later visits but does not contain HIPAA identifiers 
that can be connected back to the study. Samples will be stored at both the UW Biotech Center 
(DNA for genetics @-80oC) and CTRI Madison (DNA for methylation and RNA @-20oC) until 
shipped in batches to Washington University. Banking will occur at Washington University in St. 

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Louis within a genetics research facility.  In this facility samples will remain labeled with only 
DNA IDs.  All study information is stored in secure computer databases at that location.   
In addition, we plan that DNA data and associated phenotype information from study 
participants will be sent to an NIH GWAS center, where stringent controls are in place for 
security of genomic information and any study information related to the samples.  GWAS will 
utilize these samples, combined with others submitted to the repository, for additional research 
questions  
Note: Participants can withdraw their DNA consent by request to the study PI   
IVR Assessments: To enhance scientific rigor, participants will provide nightly data (via 
phone keypad responses to voice prompts or complete an on-line survey) for a total of 31 days 
(3 days prior to starting treatment, 14 days during pre-cessation treatment, 14 days post-target 
quit day; see Table 2). Each report will take about 3-4 minutes to complete. Reports will assess 
mood, anhedonia, withdrawal85, cessation fatigue (post-quit), cue exposure and reactivity, and 
tobacco and medication use with brief items used in our prior successful research19,49,50,82,101. 
Medication effects and reasons for not using medications will also be assessed. All reports will 
end with a reminder of the number participants can call to discuss any concerns they have 
about study medications. Nightly IVR data collection reduces error that might arise from memory 
decay and recall biases97. This time frame should capture key pharmacotherapy effects, the 
peak of withdrawal98,99, and most lapse occurrences100. These assessments will capture 
potential treatment mechanisms/mediators, treatment effects, and variables related to 
safety/side effects. Our procedures entail minimal burden (~3-4 min/day) and yield high (~80%) 
completion rates31. Those who report having difficulty maintaining a stable phone/email service 
will be provided phones to take IVR phone calls. 
 
      
Phone Follow-Up Assessments: These person-to-person phone assessments will occur 
at 4, 8, 11, 17, 23, 39, and 52 weeks post-TQD (Table 2). Data will be gathered on daily 
smoking, new quit attempts, use of other cessation medication, potential mediators (e.g., 
withdrawal, affect, cigarette liking/effects, stressors, cue exposure, motivation), use of any 
nicotine product, medication use, and adverse events. Participants claiming abstinence at the 6-
and 12-month calls will be invited to a visit for biochemical testing and short questionnaire on 
CO exposure to confirm abstinence self-report via exhaled CO. If participants claim abstinence 
from cigarettes but blow a 6 or greater on the CO breath test at the Week 52 Follow-Up Visit, we 
will ask the participant if they will give us a saliva sample to test for cotinine. This will allow us to 
be more certain that these participants have not been smoking cigarettes (as evidenced by 
cotinine-free saliva or saliva with low levels of cotinine). At the 12-month call all participants will 
be asked to estimate the likelihood that their pill and their lozenge contained active medication.  
 

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Smoking Outcome Measures: As per Society for Research on Nicotine and Tobacco 
recommendations102, we will analyze abstinence at 52 weeks (primary) and 23 weeks using two 
abstinence measures to enhance scientific rigor: (1) 7-day point-prevalence (CO-confirmed self-
report of abstinence from smoking for 7 days before and including the follow-up day: CO cutoff ≤ 
5ppm)103 and (2) prolonged (a continuous abstinence measure that ignores smoking in the first 
week post-quit). Per our intention-to-treat data analysis plan, any randomized smoker who does 
not provide biochemically confirmed evidence of abstinence will be counted as a smoker; 
multiple imputation also will be performed in secondary analyses to further enhance scientific 
rigor. A daily smoking calendar will permit determination of lapse/relapse latencies for survival 
and milestones analyses104,105. In order to enhance scientific transparency, we will post all 
assessment instruments and, ultimately, de-identified data, online (e.g., the UW-CTRI website; 
average of 7,000 hits/month over last year from 17,387 visitors), so that other researchers can 
use our de-identified data and instruments (see detail in Data Sharing Plan). 
 
 
 
Table 2. Schedule of Study Activities 
 
Pre-
Cessation 
Treatment   
Phase 
Phone  
Follow-up  
 
Orientation 
V1 C1 
V2 
V3 C2 C3 C4 C5 C61 C7 C81 
Week 
Orientation Wk -
2 
-1 TQD 
2 
4 
8 
11 17 23 39 52 
Screening & Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
Pre-cessation counseling 
 
X 
X 
 
 
 
 
 
 
 
 
 
Cessation counseling 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
Exhaled CO  
X 
X 
 
X 
X 
 
 
 
 
X1 
 
X1 
Short questionnaire on 
CO exposure 
X 
X 
 
X 
X 
 
 
 
 
X1 
 
X1 
Smoking status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood sample for 
DNA/RNA and cotinine 
 
X 
 
 
 
 
 
 
 
 
 
 
Non-cigarette nicotine 
use 
X 
X 
 
X 
 
X 
X 
 
 
X 
 
X 
Baseline questionnaires 
X 
X 
 
 
 
 
 
 
 
 
 
 
IVR assessments 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Treatment mechanisms 
assessment2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication provision 
 
X 
 
X 
 
 
X 
 
 
 
 
 
Medication use 
assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X3 
 
 
Adverse events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
1If participants claim abstinence during this assessment call, they will be invited to an in-person visit to 
provide biochemical verification of abstinence (CO assessment).  
2Treatment mechanisms include withdrawal, affect, fatigue, cigarette liking/effects, stressors, cue 
exposure, motivation, and self-efficacy.  
3Timeline follow back only 

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Interventions 
 
Pharmacotherapy: Pharmacotherapies will be V-only (with placebo Patch) and V+P. As 
in the successful Koegelenberg trial14, we will start NRT therapy (for both placebo and active P) 
2 weeks prior to the target quit date (TQD). The V lead-in will start 1 week prior to the TQD. 
Table 3 displays the dosing information for the relevant experimental conditions. To enhance 
scientific rigor, placebo medication will be used to double-blind medication assignment. Thus, V-
only condition participants will be given placebo patch. Also, 12 week duration condition 
participants will receive placebo medication week 13 through 23 (pill) /24 (patch) to match the 
24 week duration condition participants’ active medication regimen. Therefore, each participant 
will be given both medications for 6 months so that the number of medications provided and 
medication duration will not signal assignment; use instructions will be the same for placebo 
products as for the respective active medication (see Table 3 note). 
 
      
 
Participants will receive medications and use instructions at Visit 1 and 2 and following 
the Week 8 call (via the mail: Table 2). Participants will be given an information sheet with 
medication instructions and a number to call with questions or to report concerning side effects 
or toxicity. Adverse events will be assessed at each person-to-person study contact during the 
treatment phase. Medication use will be assessed during each study contact during the 
treatment phase. 
      
Counseling: Participants will receive counseling based on our recent factorial 
research42,56 and on Guideline recommendations2. Pre-cessation counseling will occur at Visit 1 
and Call 1 (3- and 1-week pre-TQD: Table 2). Counseling in these sessions will include 
instructions for using the medications with a special focus on smoking reduction, clear smoking 
reduction goals, and behavioral training to facilitate smoking reduction56. Recent research 
suggests the value of combining precessation medication and reduction counseling78. Cessation 
counseling will occur during Visits 3 & 4 and Calls 2 & 3 (Table 2) and will provide support, 
inculcate coping skills, promote motivation for quitting, and provide clear instructions regarding 
proper medication use2,56. The medication adherence training will include elements that yielded 
promising effects in our prior research (e.g., data-based feedback on medication use, problem 
solving regarding adherence challenges, and motivational intervention to support medication 
Table 3. Medication Dosing Regimens for the Factorial Experiment 
 
Pre-Cessation Meds 
Cessation Meds:  
12 Weeks Duration 
Cessation Meds:  
24 Weeks Duration 
Varenicline 
Pills 
Days -7 to -5: 0.5 mg pill 
QD  
Days -4 to -1: 0.5 mg pill 
BID  
Days 1 to Week 11:  
 1 mg pill BID  
Weeks 12-23: placebo pill 
BID 
Weeks 1 to 23: 1 mg pill 
BID 
 
Active 
Patch 
Days -14 to TQD: 14 mg 
patch 14 mg patch 
Weeks 1 to 12: 14 mg 
patch 
Week 13-24: placebo 
patch 
 
Weeks 1 to 24: 14 mg 
patch 
 
Note: The timing and dose adjustments for active nicotine patch shown above will be matched with the 
placebo patch given to the V-only condition. Also, medications may be discontinued or doses may be reduced 
in the case of adverse events.    

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use42). All counseling sessions will last about 15 min. Most counseling will occur close to the 
target quit day since some research suggests that such early counseling may be especially 
effective106, and because most relapse occurs early in a quit attempt100. We have a long history 
of successfully conducting such interventions and have existing counseling manuals that will 
require only modest adaptations for this work42,56. Counselors will be bachelor-level health 
educators supervised by licensed psychologists. To support the scientific rigor of the work, 
quality/fidelity assurance strategies developed in our prior work30,33 will include intensive training 
in counseling techniques and ethical conduct (20 hours over 2 weeks), practice sessions, 
regular supervision using audio recordings of session, and quarterly team meetings to discuss 
safety, confidentiality, and counseling fidelity. Participants will be paired with a single counselor 
for all treatment contacts. The timeline for the conduct of the experiment is depicted in Figure 1.  
 
Promoting Continued Experimental Participation 
 
We will utilize participant retention strategies that were effective in our prior research, 
including strategies such as scheduling flexibility, calling participants’ cell phones if they request 
that, continued interaction with the same health counselor, and providing medication contingent 
upon visit attendance/call completion. If participants appear to have dropped out of the study 
(they miss appointments and do not reschedule, or they do not answer our phone calls, but they 
have not formally withdrawn from the study), we may write them (via standard mail or email) to 
encourage their renewed participation.  Finally, consented participants who we are not able to 
reach using contact information obtained at the baseline and subsequent visits, we will call 
and/or send a letter to the alternate contacts provided by the participant, designated as a 
contact for this specific situation. 
 
      
 
Compensation: Participants will be paid for: attending the Orientation Visit) and Visit 1 
($20/visit), completing the follow-up calls for Weeks 4, 8, 11, 17, and 39 ($10/call) and Weeks 
23 & 52 ($20 at Wk23, $60 at Wk52), and for attending the two in-person follow-up visits for 
biochemical confirmation of abstinence, if needed ($40 at Wk23; $200 at Wk 52). If participants 
are unable to be reached for their follow-up calls at Weeks 23 and 52, they will be mailed a 
questionnaire that assesses their current smoking status and asked to complete and return it. 
Those who return the Week 23 mailed questionnaire will receive $20 and those who return the 
Week 52 mailed questionnaire will receive $40. All participants will receive $50 if they complete 
at least 80% (26) of the nightly IVR assessments (this means answering at least 1 question) or 
$25 if they answer between 60 and 79% of assessments (20-25 assessments). This would 
result in a total potential compensation of $460. Checks will be issued after Visit 1 (up to $40), 
after Week 4 (up to $60), after Week 23 (up to $50), after Week 52 (up to $70) and at the Week 
23 and Week 52 visits, if they are invited ($40 at Wk23; $200 at Wk52). 
 
Update: Due to COVID-19 pandemic, participants will not be brought in for Week 52 in-person 
visits for biochemical confirmation of abstinence. Regardless, participants eligible for that visit 
will receive the full $200 payment, as described above.  
 
Analytic Approach       
 
Cessation: The primary outcome (biochemically confirmed, self-reported point-
prevalence abstinence at 52 weeks post-TQD) will be analyzed via two strategies. First, we will 
conduct factorial design analyses using logistic regression with dummy coding that examines 

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the main and interactive effects of the two factors. Importantly, main effects obtained with 
dummy coding in 2-factor designs are directly interpretable even in the presence of a significant 
interaction as long as the interaction effect is included in the model. Thus, main effects will 
reflect the effects of V+P vs. V-alone, and the effects of 24- vs. 12-week treatment duration. 
Interaction effects would reveal whether the magnitude of differences in effects of the levels of V 
treatment varies in a multiplicative manner depending on duration. While we hypothesize that 
we will see only main effects in this research, interactions would be interpreted via visual 
inspection (the highest and lowest scores for the interacting treatment combinations should be 
readily apparent) and via simple effects tests107-109. Second, we will conduct analyses typical of 
an RCT, which use logistic regression models with dummy coding to contrast each of the three 
enhanced varenicline treatments (12-week V+P, 24-week V-only and 24-week V+P) with the 
standard V-based treatment (12-week V-only). The V-only condition will serve as the reference 
condition because the intent is to determine if any of the enhanced V-based treatments is 
superior to that condition. Covariates will include sex, race, treatment site, and level of tobacco 
dependence (FTND item 1). Results will be reported with and without covariate adjustment and 
the specific effects of sex and race on each outcome will be explored. The same analytic 
approach will be used for secondary abstinence analyses (e.g., point-prevalence at 6-months 
and prolonged abstinence47). The intent-to-treat principle with the assumption of 
missing=smoking will be used for abstinence analyses but will be supplemented with sensitivity 
analyses and multiple imputation for missing data to support scientific rigor 47,110. The latter 
models will assume that 80% of dropouts return to smoking and that abstinence likelihood is 
related to baseline smoker covariates42,47,56. Analyses of secondary abstinence outcomes will 
support scientific rigor by controlling for experiment-wise error in families of related tests111,112. 
Milestones analyses will be conducted as in our prior research104,105. For instance, latency 
between initial abstinence and lapsing, and latency between lapsing and relapse, will be 
computed with Cox proportional hazards regression/survival models.       
  
Mediation and Moderation: Candidate mediators of cessation treatment effects, gathered 
from IVR and follow-up phone assessments will be: medication use and side effects, withdrawal 
symptoms (e.g., craving, negative affect, anhedonia19), anticipatory pleasure from smoking, 
adverse events, nicotine reward, nicotine anticipation, and reports of cue-elicited urges. 
Treatment will be modeled both as main effects and as contrasts of particular Adjuvant X 
Duration combinations that differ significantly in abstinence rate from the standard V treatment 
condition at follow-up. Mediation will be tested using multiple indices including the joint 
significance test49,50. Care will be taken to preserve mediator/outcome temporal priority and the 
occurrence of smoking during the quit attempt will be statistically controlled49,50. Mediation 
models including multiple mediators49 will use methods developed for use with dynamic 
mediator assessments (maximum likelihood estimation using hierarchical linear modeling: HLM 
5.04101). Both 23- and 52-week abstinence will be used as outcomes, which will be modeled 
via a weighted least squares approach in Mplus. The 23-week outcome may be more sensitive 
to treatment mediation than the 52-week outcome75. We will attempt to characterize orthogonal 
routes to outcome change via use of multiple covariates and models of multiple mediation. In 
these models, the individual mediators revealed as strongest in univariable analyses will be 
included in multi-mediator models as per our prior research49.  
 
Analysis of moderators of abstinence outcomes will use both logistic regression with 
model-fitting techniques113 and regression tree analyses that reflect differential treatment 
responses71,114 in 23- and 52-week abstinence. The logistic regression and regression tree 
approaches are complementary since the former fits interactions in the entire sample whereas 

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the latter identifies the most robust interactions amongst subpopulations of a sample (groups of 
participants nested within levels of another predictor, which could include either a covariate or 
treatment condition71,114. Candidate moderators of treatment effects on abstinence will include 
tobacco dependence, contextual factors such as household smoking, and biological variables 
such as sex and genotype. In the logistic regression analyses moderators will be evaluated with 
regards to their interactions with treatment main effects and interactions.       
 
 
Cost-Effectiveness: Cost-effectiveness of key comparison treatments will be evaluated 
using methods recommended by the United States Panel on Cost-Effectiveness in Health and 
Medicine and consistent with our prior research in this area72-74. We will: (1) measure all costs 
from the societal perspective; (2) convert cost estimates to a common year; (3) use a rate of 3% 
to discount future outcomes and costs to present value; (4) use QALYs as the outcome metric; 
and (5) conduct Monte Carlo sensitivity analyses115. The proposed research will cost out all 
intervention component combinations that reflect significant main and synergistic interaction 
effects. We will determine net monetary benefit (NMB), cost per quit, and incremental cost-
effectiveness ratios (ICERs)116. The components of NMB will be the added costs of the 
treatments and the monetized value of the QALYs added by the treatments. Using methods 
described by Stapleton, we will convert the increased effectiveness of the treatments from quits 
to added QALYs117.  
 
      
Statistical Power for Primary Outcome: Power was determined for effects that we 
prognosticated based upon prior data2,3,14,23,24. Table 4 depicts predicted 52-week abstinence 
outcomes. We propose an abstinence rate for 12-week V treatment of 25%. This is comparable 
to that found in Koegelenberg for 12-week V-only treatment (28.8% at 24 weeks follow-up; 
abstinence rates tend to fall about 5 percentage points from 24 to 52 weeks post-TQD118,119). 
This abstinence rate is higher than that produced by V-only in our recent clinical trial (19% 
abstinent at 52 weeks), but somewhat lower than the rates reported in the initial studies on V 
(52-week rates of about 30%118,119; thus, we set the expected abstinence rate for 12 weeks of V 
at a mid-point (25%). Table 4 shows that we predict an increase in 52-week abstinence from 12 
weeks of V alone (25%) to 34% for 12 weeks of V+P. We believe this increase of 9 percentage 
points is reasonable and somewhat conservative. It is midway between increases seen by 
Koegelenberg14 (15%) and Ramon et al.,22 (5%, in 24-week continuous abstinence). Also, a 9 
percentage point increase is somewhat less than the boost in abstinence seen with combination 
NRT vs. NRT monotherapy (36.5% vs. 23.4% at 5+ months as per the PHS Clinical Practice 
Guideline meta-analyses2). In sum, we believe the estimated effect of the P adjuvant at 12-
weeks duration seems reasonable and somewhat conservative.  
 
 
Table 4. Predicted Biochemically Confirmed Abstinence Rates at 52-Weeks After the Target 
Quit Date 
  
V-only 
V+ML 
Marginals 
12 Weeks of Medication 
25.0% (78/312) 
34.0% (106/312) 
29.5% (184/624) 
24 Weeks of Medication 
32.0% (100/312) 
44.9% (140/312) 
38.5% (240/624) 
Marginals 
28.5% (178/624) 
39.4% (246/624) 
  
Note: Koegelenberg et al.,14 found abstinence rates of 65.1% (with multiple imputation) and 44% (with intent-to-
treat) at 6-month follow-up with 12-weeks of V+P treatment. Thus, our predicted rates for V+ML may be 
conservative.  Also, note that the new enrollment goal of 1250 does not divide evenly by 4=312.5, so we rounded 
down to 312 for the purposes of this chart. 

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In terms of the effects of increased duration of medication use, Schnoll et al.,44 found 
that 24 versus 8 weeks of nicotine patch increased abstinence rates by only about 5 percentage 
points at 52-week follow-up. However, extended V treatment (24 weeks total) increased 
abstinence rates at 52 weeks post-TQD by about 10 percentage points in one study just among 
patients who were abstinent early in treatment38, and by about 40 percentage points in another, 
smaller study39. We believe that extended medication will increase abstinence rates by 7-11 
percentage points (with regard to the V-only and V+P conditions, respectively) because 
research shows that extended pharmacotherapy both reduces relapse in those who are 
abstinent39,119 and increases the likelihood of cessation amongst those who have lapsed35,40,45. 
Moreover, both NRT and V produce such effects, thus, these actions could be additive in those 
using both active agents. Because of the possibility of an additive effect, we posit slightly higher 
increases in Duration-related abstinence rates for the V+P condition than for the V-only 
condition. However, the uncertainty about the effect of Duration highlights the innovativeness of 
this work; we know very little about the effects of extended V treatment and nothing about the 
effects of extended V+NRT treatment. While the abstinence rates forecast may seem high, we 
believe they are reasonable given that they reflect the effects of 3 pharmacotherapy elements or 
dimensions (vareniciline therapy, 24 week duration, and an NRT adjuvant) all supported by 
evidence of efficacy. The predicted outcomes result from the reasonable assumption that these 
3 components will produce at least additive effects.  
The predicted data would strongly implicate the additive effects of both 24-week duration 
and the P adjuvant as being necessary to achieve a marked increase in abstinence over 
standard V-based therapy. Of course, we might discover instead that a single treatment 
modification or enhancement confers as much benefit as the combination of the two 
components (e.g., 24-week V-only produces as much benefit as 24-week V+P). This finding 
would be welcome to the extent that it means that exceptionally strong results are obtained with 
the use of only one treatment enhancement, which would save money and perhaps reduce 
adverse events and burden.  
      
Statistical Power: We computed power (via SAS PROC POWER) for the abstinence 
outcomes in Table 4, assuming p <.05 and two-tailed tests. Power is .88 for the main effect for 
Duration (n’s=625), and .97 for the main effect of Varenicline (V+P vs. V: n’s=625). Moreover, 
power is > .99 for the key hypothesis that the 24-week V+P combination will be superior to 12-
weeks of V-only (n’s=312). The N used clearly provides some room for error if the predicted 
outcomes are too sanguine. For instance, we noted above that some data suggest that the 
increase in abstinence seen with extended medication might be as small as 7%. The proposed 
N (1250) would permit detection of a 7 point difference with power = .80. Thus, the N proposed 
would provide good power to detect the proposed effects, and even effects that are modestly 
weaker, but still of public health significance.  
 
 
Protection of Human Subjects   
 
Risks to the Participants   
 
Human Subjects Involvement and Characteristics: Up to 1100 adult smokers will be 
consented from the community in order to enroll (randomize) at least 1250 participants (up to 
1300). Participants must: plan to stay in the area for the next 12 months, ability to read and write 
in English, smoke ≥10 cigarettes per day, be ≥18 years old, desire to quit smoking but not be 

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engaged currently in cessation treatment, report no use of pipe tobacco, cigars, snuff, e-
cigarettes or chew in the last 30 days, have reliable phone access, and, if female, not be 
pregnant and be using an acceptable birth control method. Exclusion criteria include: current 
treatment for schizophrenia or a psychotic disorder; suicidal ideation in the past 12 months; 
history of suicidal behavior within the last 10 years; on dialysis or being told you have severe 
kidney disease; hospitalization for a stroke, heart attack, congestive heart failure or uncontrolled 
diabetes mellitus within the past year; or currently participating in a smoking cessation study.   
 
Sources of Materials:  Participants will provide data for the express purpose of research. 
Data will consist of answers to questionnaires and interviews assessing smoking history, 
demographics, nicotine dependence, personality, affect and psychiatric history, disease status 
and health history. In addition, certain physiologic and medical tests will be done that assess 
disease status or biomarkers thought to index disease risk. These will include provision of blood 
samples that will later be used for nicotine/cotinine tests and genetic assays. Breath tests and a  
brief questionnaire will be used to assess exhaled carbon monoxide.    
 
Potential Risks:  Risks associated with this research are judged to be minimal. None of 
the medical, physiologic, self-report, or behavioral assessments constitute a significant risk. The 
use of cessation medications poses a risk of side-effects. Varenicline is approved by the FDA 
for smoking cessation and is medically safe for most smokers to take except for individuals with 
severe (end-stage) kidney failure or hypersensitivity to varenicline. Current labeling for 
varenicline (FDA, 20091) recommends monitoring for serious neuropsychiatric symptoms 
including changes in behavior, agitation, depressed mood, suicidal ideation, and suicidal 
behavior although no causal relationship has been established. Varenicline labeling also notes 
that some individuals with pre-existing psychiatric conditions may experience worsening of their 
conditions. Labeling of Varenicline also indicates increased risk of certain heart problems in 
people with heart and blood vessel disease. Finally, labeling of Varenicline also indicates risk of 
new or worsening seizures. These seizure findings are from infrequent post-marketing observations 
that are similar to the frequency of epilepsy found in the general population and are not formal 
contraindications.  We ask that participants notify study staff immediately and stop taking the 
study medication and notify study staff immediately if you experience any significant emotional 
or heart-related symptoms, or a seizure. In such cases, it is expected that the study medication 
will be stopped and the participant will remain on study but off study medication. NRT risks are 
well-documented, given their wide-scale use and over-the-counter availability; the nicotine 
patches are available over the counter. According to the package insert, the most likely side 
effects associated with the nicotine lozenge are heartburn, hiccup, nausea, upper respiratory 
tract infections, coughing and sore throat. It is important to note that all studies evaluating the 
combination of varenicline and nicotine patch have found it safe2-5; therefore, there are no data 
suggesting any additional risk of combining varenicline and NRT.  Blood draws can be painful 
and very rarely can lead to infection. There is always a remote, but existing, possibility that 
sensitive or personal information about a participant could be divulged as a function of his/her 
research participation. Finally, smoking withdrawal is associated with a number of unpleasant 
symptoms, such as sleep disturbance, hunger, craving, and negative mood. Most smokers have 
tried to quit before and are familiar with these phenomena. Though unpleasant, smoking 
withdrawal symptoms pose minimal health risk. Participants will be informed about the likely 
effects of smoking withdrawal. Individuals who elect not to participate in this research, or are 
eliminated due to screening failure, will be given a list of alternative smoking cessation 
programs at any point during the pre-consent process.   
 

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Adequacy of Protection Against Risks   
 
Recruitment and Informed Consent: As in our previous research, participants will be 
recruited via TV, print, flyers, referral cards, social media such as Facebook, and earned media 
(e.g., press releases and conferences).   
 
Participants will be recruited in the Milwaukee and Madison metro areas. Advertisements 
and publicity will contain a phone number for interested individuals to call to contact study 
personnel. Study staff will call potential participants and conduct an initial phone screening to 
rule out those with clear contraindications. The study will be briefly described, questions 
answered, and potentially qualifying individuals will be invited to attend an Orientation Session. 
At the Orientation Session the general requirements for participation will be reviewed (e.g., 
session attendance, need for follow-up, participation in assessments). In addition, participants 
will be informed of the nature of the interventions involved. They will be told about the 
pharmacotherapy and counseling interventions that will be studied. Everyone will be told that 
that they will receive counseling designed to aid them in their cessation attempt. The risks of 
taking varenicline will be described including the possibility of changes in behavior, agitation, 
depressed mood, suicidal ideation, and suicidal behavior. Participants will also be told that 
varenicline may worsen pre-existing psychiatric illness. All participants will be informed as to the 
various parts of the study and what will be entailed in each part. Individuals will then be 
screened for any remaining exclusion factors. After answering any participant questions about 
research participation and intervention, screened and eligible participants will be given a 
combined HIPAA/consent form to review and take home. At their first treatment visit (V1) 
potential participants will be allowed to ask questions about the consent form. Interested 
participants will then sign the consent form at the beginning of that visit before they participate in 
any further assessments or research activities. Should eligible smokers decide not to participate 
in the research at V1, the personally identifying information collected at the Orientation session 
and the screening phone call will be destroyed at the point that data for a study consort diagram 
have been cleaned and analyzed. Participants will be encouraged to ask any further questions 
about the study protocol throughout the study.  
 
Protection Against Risk:  As noted above, participants will be screened to ensure that 
they are medically and psychiatrically fit to use varenicline or nicotine patches. Study 
participants will be closely monitored in accordance with current FDA recommendations (last 
update March 20151) as well as the consensus recommendations of the 2008 Guideline Panel6, 
which provides additional, detailed instructions for clinicians regarding all FDA-approved 
cessation medications. In addition, we will make appropriate changes in study procedures if the 
FDA issues updates on varenicline or nicotine patches. We will recommend dosage/use 
alterations including stopping medication treatment as per good clinical practice if the participant 
experiences troublesome side effects once they begin medication treatment. Thus, we will take 
extraordinary care to ensure the safety of study participants.   
 
Study participants will be carefully monitored for side effects including changes in mood, 
agitation, or distress  and suicidal ideation, . Monitoring for these and other symptoms or 
conditions will be accomplished though assessment of adverse events (AEs) and serious 
adverse events (SAEs) at each study visit and follow-up contact during which the participants 
are receiving study medication. For all AEs and SAEs, study staff will take appropriate action to 
ensure the safety of the participant as follows: 1) Nonurgent AEs will be reported in a timely 

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manner to study clinical staff (MDs); and 2) SAEs or AEs that raise concerns (e.g., allergic 
reaction; severe, unresolved  changes in mood or any suicidal ideation) will be immediately 
reported to the study physician who will determine an appropriate course of action. In addition, 
participants will be given a telephone number to contact study staff in the event that participants 
have questions or concerns about study medication or medical/psychiatric reactions that may be 
related to study medication or participation, as well as instructions on when to seek emergency 
medical assistance. Individuals who report any significant mood change or suicidal ideation will 
be contacted immediately by a licensed staff psychologist or physician who will assess the level 
of risk and provide referrals as needed.  
 
Confidentiality of participant data and information will be accomplished by using 
participant numbers as unique identifiers, allowing us to keep participant data separate from 
identifying information. Data generated through study participant and data obtained on medical 
history from participants will be stored in secure databases under protections and procedures 
consistent with the guidelines and regulations of the UW School of Medicine and Public Health 
(UW-SMPH).  Outside access is available only via an encrypted connection to the Department 
of Medicine Citrix server located at the UW Clinical Science Center in Madison. The servers at 
the University of Wisconsin Center for Tobacco Research and Intervention (UW-CTRI) Madison 
office are physically secured in a locked room. Data backups are created nightly and stored in a 
locked safe. Significant safeguards have been implemented to protect data including virus and 
adware protection, firewall, access controls and encryption when appropriate such as wireless 
and remote access. All UW-CTRI staff members have completed HIPAA/human subjects 
training and are aware of the sensitivity of study-related data. The UW SMPH has developed 
school-wide data security policies and procedures. UW-CTRI data security policies and 
procedures conform to those of the SMPH. UW-CTRI will use an enterprise-level database that 
supports audit trails such as access, change logging, and more sophisticated access control for 
managing and tracking user access privileges. In addition, this project will request a Certificate 
 of Confidentiality, related to the collection of genetic material, information on substance abuse, 
and information on sexual orientation.  No publications or presentations resulting from this 
research program will contain any identifying information about individual participants.   
 
Potential Benefits of the Proposed Research to the Participants and Others  
 
The potential benefits for smokers participating in this study include the chance to 
receive free smoking cessation counseling and FDA-approved pharmacotherapy, both of which 
double a smoker’s odds of quitting. The risks of this research are chiefly associated with the 
provision of varenicline as one of the pharmacotherapies. These risks are reasonable because 
this medication has been shown to be safe in numerous large clinical trials, and we are 
exercising additional caution by using varenicline in accordance with FDA recommendations as 
well as the consensus recommendations of the 2008 Guideline Panel6. Because the health risks 
associated with continued smoking dramatically outweigh those associated with varenicline use 
(and NRT as well), and because it is likely that many participants will successfully quit smoking 
as a result of their participation in this research, the potential risks to participants are acceptable 
compared to the potential benefits. The availability of consultation with the research program, 
including physician consultation, also decreases the likelihood of adverse consequences from 
varenicline or patch use. In addition, this research has the potential to provide improved 
treatment strategies for clinicians trying to help patients quit smoking. This could result in more 
efficient provision of maximally efficacious intervention for smokers.     
 

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Importance of the Knowledge to be Gained   
 
The results from this study will allow researchers to determine which medication regimen 
is more effective for smoking cessation and which works better for which type of smoker. Also, 
this research will produce valuable new information on the mechanisms via which these 
medication regimen’s aid smokers in quitting. This information will be gathered in a 
contemporary population of smokers so the results will be highly relevant to today’s smokers 
and clinicians, and can be used to motivate clinicians to intervene and to motivate smokers to 
use evidence-based treatments to stop smoking.    
 
Summary   
 
Given the limited risks of varenicline and nicotine patch, the rigorous pre-treatment 
screening, and the availability of both physicians and psychologists to address any adverse 
effects, we believe that the potential risks involved in participating in the study are outweighed 
by the benefits to both the individual study participant and society.    
 
Data Safety Monitoring Plan  
 
The Data Safety and Monitoring Plan (DSMP) for this research comprises not only the 
research conducted directly by the University of Wisconsin Center for Tobacco Research and 
Intervention (UW-CTRI) researchers, but also research conducted by other investigators 
collaborating with UW-CTRI-funded projects. All investigators must agree to comply with the 
procedures outlined in this DSMP. This DSMP does not reduce any investigator’s obligation to 
comply with the requirements of the Institutional Review Board (IRB) at his/her home institution 
or the IRB of any collaborating organizations.  
 
 
Monitoring the progress of trials and the safety of participants. The Principal 
Investigators are responsible for routine monitoring of the trial’s progress. This includes 
scheduled (biweekly during the first few months of the study and monthly thereafter) meetings 
with study staff and review of written documentation. Data reviewed at these meetings include 
the number and type of participants enrolled, the number and reasons for exclusions from 
enrollment, the number treated and the stage of intervention, summary of adverse events (AEs), 
individual review of serious adverse events (SAEs) and study participation, and outcome data. 
In addition, as noted above, SAEs or AEs that raise concerns (e.g., allergic reaction, significant 
change in mood or suicidality) will be immediately reported to the study physician who will 
determine an appropriate course of action. As data become available, Research Administrator 
and Principal Investigators will review the data on a regularly scheduled basis (initially biweekly 
and later monthly) to determine progress.  
 
To facilitate participant safety, study participants must meet study inclusion and 
exclusion criteria. Once enrolled, study protocols will assess the presence of AEs and SAEs at 
all study visits and follow-up contacts. Should either excessive risk to study participants and/or 
convincing evidence of lack of measurable benefit to study participants be determined, the study 
will be stopped and all participants notified in a manner appropriate to the nature of the risk 
and/or lack of benefit. When taking that step the investigators will consult with the IRB and 
NHLBI.  

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Plans for assuring compliance with requirements regarding the reporting of adverse 
events.  This DSMP requires that investigators notify NIH and the University of Wisconsin IRB in 
a timely manner (consistent with IRB and NIH policies) of the occurrence of any SAE or any AE 
which is severe, unexpected, and possibly related to study medication or protocol. All staff will 
assume that patients are taking active medications unless medical treatment requires unblinding 
 
Because this study involves pharmaceutical agents, if an unexpected SAE might be 
related to study drug use, both the Food and Drug Administration (FDA) and the manufacturer 
will also be notified within five days of investigators becoming aware of the event. To be 
compliant with rules for all studies receiving products from Pfizer, Inc, all SAES that occur during 
participant medication use or within 28 days after medication use will be reported to Pfizer within 
24 hours, along with reports of pregnancy. The PI principal investigator will assist Pfizer in 
investigating any AE and will provide any follow-up information reasonably requested by Pfizer. 
Examples of unexpected SAE would be untoward medical or intervention occurrences that 
result in death, are life-threatening, require hospitalization or prolonging of existing 
hospitalization, create persistent or significant disability/incapacity, or involve congenital 
abnormality/birth defects.  
 
Unanticipated AEs, including less serious problems that merit reporting to the DSMC 
because they are severe, unexpected, and possibly related to study participation. Any SAE will 
be queried and reported even if it appears that the serious adverse event is unrelated to study 
participation. The Principal Investigators will also be responsible for the accurate 
documentation, investigation and follow-up of all study-related adverse events. Adverse event 
assessment, recording, reporting, and investigation will be accomplished through staff training, 
structured/standardized assessments of untoward occurrences/events, and regular monitoring 
by study physicians and other study investigators. The Principal Investigators have ultimate 
responsibility for ensuring that SAEs are detected and reported in a timely manner. Additionally, 
the IRB will receive an annual report of all SAEs and AEs meeting the criteria listed above.  
Plans for assuring that any action resulting in a temporary or permanent suspension of 
an NIH-funded clinical trial is reported to the NIH grant program director responsible for the 
grant. The NIH grant program director will be notified within five days if the Principal 
Investigators deem it necessary to suspend the clinical trial. In the case of a temporary 
suspension, the Principal Investigators will develop a plan for continuation of the study and 
discuss this plan with the NIH grant program director in a reasonable time frame.    
 
Plans for assuring data accuracy and confidentiality and protocol compliance. The UW-
CTRI Research Director and Principal Investigators will develop plans for assuring data 
accuracy and protocol compliance. Such plans will include data verification and protocol 
compliance checks. The Data Manager and Principal Investigators shall also be responsible for 
ensuring that the data for the project are securely stored, that storage is in compliance with 
University and federal regulations and that no unauthorized persons have access (electronic or 
physical) to any participant-identifiable data. All HIPAA regulations and guidelines will be 
followed, and all study staff must complete approved human subjects and HIPAA training 
programs.   
 
Data and Safety Monitoring Committee.   
 
In addition to the protections outlined in the DSMP (above), all research activities 

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conforming to the NIH definition of a clinical trial will also have an independent Data Safety and 
Monitoring Committee (DSMC). This application includes a Phase IV clinical trial using FDA-
approved medications. The DSMP specifies overall monitoring that will be conducted by 
Principal Investigators, including timely reporting of AEs and SAEs. Every six months, the 
DSMC will convene to review the overall safety data, as well as data on safety summarized by 
treatment condition. As per NIH guidelines, the objective of these reviews will be to determine 
whether continued conduct of the trial poses any undue risk for participants.  
 
The existing UW-CTRI DSMC is chaired by Dr. James Cleary, leader of the Cancer 
Control Program of the UW Comprehensive Cancer Center. Dr. Cleary is an experienced 
physician and clinical trial researcher with no involvement in any of this project’s research 
activities. Dr. Cleary is joined on the DSMC by Dr. Burke Richmond. Dr. Sosman is Associate 
Professor of Medicine and Medical Director of the HIV/AIDS Comprehensive Care Program at 
UW Hospital and Clinics who has previously collaborated on a clinical trial of smoking cessation 
with UW-CTRI. Dr. Richmond is an otolaryngologist who has served on independent DSMBCs 
for Phase II and III trials involving a nicotine vaccine. Neither has direct involvement with any of 
the proposed research. The Principal Investigators will report to the DSMC; the three DSMC 
members will not be unblinded as to treatment conditions and will make the final determinations 
as to study continuation. 
 
Data Sharing with MiCASA 
Limited data will be shared with the MiCASA study team (IRB 2017-1013) for those subjects that enroll in 
both studies (Madison only). Subjects will consent to this sharing under 2017-1013. The full list of data to 
be shared is maintained by the 2017-1013 IRB protocol. 
 
 
 
 
 
References for Main Protocol 
 
1. 
U.S. Department  of Health and Human Services. The health consequences of smoking 
- 50 years of progress: A report of the Surgeon General. Atlanta, GA. 2014. 
2. 
Fiore MC, Jaen CR, Baker TB, et al. Treating tobacco use and dependence: 2008 
update. Rockville, MD: U.S. Department of Health and Human Services, U.S. Public 
Health Service; 2008. 
3. 
Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking 
cessation: an overview and network meta-analysis. Cochrane Database Syst Rev. 
2013;5:CD009329. 
4. 
Glasgow RE, Klesges LM, Dzewaltowski DA, Bull SS, Estabrooks P. The future of health 
behavior change research: what is needed to improve translation of research into health 
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Shiffman S, Hughes JR, Pillitteri JL, Burton SL. Persistent use of nicotine replacement 
therapy: an analysis of actual purchase patterns in a population based sample. Tob 
Control. 2003;12(3):310-316. 
6. 
Shiffman S. Underutilization of evidence based medications and misperceptions of NRT 
safety. Paper presented at: Society for Research on Nicotine and Tobacco (SRNT) Feb 
21, 2007; Austin, TX. 

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7. 
Stevens VJ, Glasgow RE, Hollis JF, Mount K. Implementation and effectiveness of a 
brief smoking-cessation intervention for hospital patients. Med Care. 2000;38(5):451-
459. 
8. 
Stevens VJ, Glasgow RE, Hollis JF, Lichtenstein E, Vogt TM. A smoking-cessation 
intervention for hospital patients. Med Care. 1993;31(1):65-72. 
9. 
Hyland A, Borland R, Li Q, et al. Individual-level predictors of cessation behaviours 
among participants in the International Tobacco Control (ITC) Four Country Survey. Tob 
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10. 
Hyland A. Perceptions of NRT safety and efficacy: results from the International Tobacco 
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Nicotine and Tobacco (SRNT)  Preconference Symposium. 2007; Austin, TX. 
11. 
International Tobacco Control Policy Evaluation Project. FCTC Article 14: Tobacco 
dependence and cessation. 2010. 
http://www.itcproject.org/files/Article/itccessationreport.pdf. 
12. 
Collins LM, Dziak JJ, Kugler KC, Trail JB. Factorial experiments: efficient tools for 
evaluation of intervention components. Am J Prev Med. 2014;47(4):498-504. 
13. 
Collins LM, Trail JB, Kugler KC, Baker TB, Piper ME, Mermelstein RJ. Evaluating 
individual intervention components: making decisions based on the results of a factorial 
screening experiment. Transl Behav Med. 2014;4(3):238-251. PMCID: PMC4167900 
14. 
Koegelenberg CF, Noor F, Bateman ED, et al. Efficacy of varenicline combined with 
nicotine replacement therapy vs varenicline alone for smoking cessation: a randomized 
clinical trial. JAMA. 2014;312(2):155-161. 
15. 
Coe JW, Brooks PR, Vetelino MG, et al. Varenicline: an alpha4beta2 nicotinic receptor 
partial agonist for smoking cessation. J Med Chem. 2005;48(10):3474-3477. 
16. 
Cunningham CS, Javors MA, McMahon LR. Pharmacologic characterization of a 
nicotine-discriminative stimulus in rhesus monkeys. J Pharmacol Exp Ther. 
2012;341(3):840-849. 
17. 
Fedota JR, Sutherland MT, Salmeron BJ, Ross TJ, Hong LE, Stein EA. Reward 
anticipation is differentially modulated by varenicline and nicotine in smokers. 
Neuropsychopharmacology. 2015;40(8):2038-2046. 
18. 
Sofuoglu M, Herman AI, Mooney M, Waters AJ. Varenicline attenuates some of the 
subjective and physiological effects of intravenous nicotine in humans. 
Psychopharmacology (Berl). 2009;207(1):153-162. 
19. 
Cook JW, Piper ME, Leventhal AM, Schlam TR, Fiore MC, Baker TB. Anhedonia as a 
component of the tobacco withdrawal syndrome. J Abnorm Psychol. 2015;124(1):215-
225. PMCID: PMC4348025 
20. 
Austin AJ, Duka T, Rusted J, Jackson A. Effect of varenicline on aspects of inhibitory 
control in smokers. Psychopharmacology (Berl). 2014;231(18):3771-3785. 
21. 
Hajek P, Smith KM, Dhanji AR, McRobbie H. Is a combination of varenicline and nicotine 
patch more effective in helping smokers quit than varenicline alone? A randomised 
controlled trial. BMC Med. 2013;11:140. 
22. 
Ramon JM, Morchon S, Baena A, Masuet-Aumatell C. Combining varenicline and 
nicotine patches: a randomized controlled trial study in smoking cessation. BMC Med. 
2014;12:172. 
23. 
Chang PH, Chiang CH, Ho WC, Wu PZ, Tsai JS, Guo FR. Combination therapy of 
varenicline with nicotine replacement therapy is better than varenicline alone: a 
systematic review and meta-analysis of randomized controlled trials. BMC Public Health. 
2015;15:689. 

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24. 
Ebbert JO, Burke MV, Hays JT, Hurt RD. Combination treatment with varenicline and 
nicotine replacement therapy. Nicotine Tob Res. 2009;11(5):572-576. 
25. 
Ebbert JO, Hatsukami DK, Croghan IT, et al. Combination varenicline and bupropion SR 
for tobacco-dependence treatment in cigarette smokers: a randomized trial. JAMA. 
2014;311(2):155-163. 
26. 
Ebbert JO, Hughes JR, West RJ, et al. Effect of varenicline on smoking cessation 
through smoking reduction: a randomized clinical trial. JAMA. 2015;313(7):687-694. 
27. 
Hughes JR, Solomon LJ, Naud S, Fingar JR, Helzer JE, Callas PW. Natural history of 
attempts to stop smoking. Nicotine Tob Res. 2014;16(9):1190-1198. 
28. 
U.S. Department of Health and Human Services. Women and smoking: A Report of the 
Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers 
for Disease Control and Prevention, National Center for Chronic Disease Prevention and 
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