Clinical trial NCT02378714
Conditions: Nicotine Dependence Major Depressive Disorder
Keywords: Smoking Cessation Major Depressive Disorder Nicotine Dependence Varenicline Behavioral Activation Therapy Cigarette Smoking
Sponsor: Northwestern University
Start date: 2015-07-24; Completion date: 2020-03-13
Enrollment: 300 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Persons who struggle with depression smoke at high rates and experience low quit rates in treatment. The best way to improve cessation treatment for this underserved population remains unknown. The proposed trial tests whether the combination of varenicline and behavioral mood management treatment enhances long-term abstinence for depressed smokers and, if so, whether this treatment achieves its effects through addressing the unique psychological factors that appear to maintain tobacco dependence for these smokers.

Detailed description:
Upwards of 43% of persons with major depressive disorder (MDD) are daily smokers who are more likely to smoke heavily, show greater tobacco dependence, suffer more severe withdrawal, and experience lower quit rates than smokers without MDD. Little is known about treatment strategies that might optimize smoking cessation for smokers with MDD because almost all randomized clinical trials have excluded these smokers. This project answers many prominent but largely unanswered calls over the last decade to address tobacco dependence in persons with mental health disorders, especially major depressive disorder (MDD). Using a double-blind, placebo-controlled, randomized design, the investigators will evaluate the efficacy of behavioral activation for smoking cessation (BASC) plus varenicline for treating tobacco dependence in smokers with current or lifetime MDD. Three hundred and thirty daily (≥1 cigarettes/day) smokers will be randomized to receive 12 weeks of one of four treatments: 1) Standard behavioral cessation treatment (ST) + placebo; 2) Behavioral activation integrated with ST (BASC) + placebo; 3) ST + varenicline; or 4) BASC + varenicline. Both BASC and ST will be administered in eight 45 minute sessions, occurring weekly for the first four weeks and biweekly for the final eight weeks. Randomization will be stratified on clinical site (Northwestern, University of Pennsylvania), gender, and severity of depressive symptoms (minimal/mild vs. moderate/severe). The primary outcomes will be carbon monoxide (CO) verified 7-day point prevalence abstinence at 24-weeks post-quit. Additional aims include assessing adverse event rates between varenicline and placebo arms, and testing for mediation of treatment effects by anhedonia, cognitive function (attention and memory), cigarette reward value, and craving and withdrawal. This randomized controlled trial will be the first adequately powered trial of BASC in this population; the first trial to evaluate varenicline among a community sample of smokers with MDD; and the first trial to assess the main and combined effects of these two treatments.

Arms: arm 1: Standard behavioral smoking cessation treatment plus placebo varenicline arm 2: Behavioral activation for smoking cessation plus placebo varenicline arm 3: Standard behavioral smoking cessation treatment plus active varenicline arm 4: Behavioral activation for smoking cessation plus active varenicline
Interventions: intervention 1: Varenicline intervention 2: BASC intervention 3: Standard treatment
Intervention descriptions: intervention 1: Participants will be randomly assigned to 12 weeks of either placebo or varenicline medication (1mg twice daily). Participants and research personnel will be blind to treatment assignment. intervention 2: The goal of behavioral activation therapy is to increase engagement in rewarding activities, a problem for smokers with depression who find smoking especially rewarding and prefer it over many other traditionally rewarding activities, by reducing patterns of behavioral avoidance, withdrawal, and inactivity. In this study, behavioral activation will be integrated with standard behavioral smoking cessation treatment.

Treatment will be delivered in eight 45-minute sessions over 12 weeks occurring weekly for the first four sessions and biweekly for the final four sessions. intervention 3: Standard behavioral smoking cessation treatment is an effective treatment for nicotine dependence. Treatment focuses on self-monitoring of smoking behavior, identifying smoking triggers and alternative trigger management strategies, relaxation, social support for non-smoking, and relapse prevention. Treatment will be delivered in eight 45-minute sessions over 12 weeks occurring weekly for the first four sessions and biweekly for the final four sessions.

Protocol documents:
Prot_SAP_000.pdf: 
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Behavioral activation and varenicline for smoking cessation in depressed smokers
Principal Investigators:
Brian Hitsman, Ph.D. (Lead PI)
Northwestern University
b-hitsman@northwestern.edu
Robert A. Schnoll, Ph.D. (Site PI)
University of Pennsylvania
schnoll@nmmedicine.upenn.edu
Biostatistician:
George D. Papandonatos, Ph.D.
Brown University
gdp@stat.brown.edu
Version Date:
January 17, 2019 
STUDY OBJECTIVES
The overall aim of this randomized controlled trial is to enroll and randomize 576 daily smokers with current or 
lifetime major depressive disorder (MDD) to receive 12 weeks of either: 1) Standard behavioral cessation 
treatment (ST) + varenicline; 2) Behavioral activation integrated with standard cessation treatment (BASC) + 
varenicline; 3) ST + placebo; or 4) BASC + placebo. Randomization will be stratified by gender, severity of 
depressive symptoms (minimal/mild vs. moderate/severe), and clinical site (Northwestern, PENN). 
We will secondarily address mediators of treatment effects, as well as the effects of incentives on research 
participation. 
The following aims and hypotheses will be tested:
Primary Aim 1: Compare behavioral activation for smoking cessation with standard cessation therapy 
for enhancing abstinence among smokers with current or lifetime major depressive disorder. 
Hypothesis: BASC will increase bioverified 7-day point prevalence abstinence at 24-weeks post-quit versus ST 
among participants randomized to placebo.
Primary Aim 2: Compare varenicline with placebo for enhancing abstinence among smokers with 
current or lifetime MDD. Hypothesis: Varenicline will increase bioverified 7-day point prevalence abstinence 
at 24-weeks post-quit versus placebo among participants randomized to ST.
Primary Aim 2a: Compare varenicline with placebo on rate of adverse events (AE), including 
psychiatric and cardiovascular events, in smokers with current or lifetime MDD. Hypothesis: There will 
be no significant difference between conditions in AE rates.
Primary Aim 3: Compare BASC plus varenicline with ST plus varenicline, BASC plus placebo, and ST 
plus placebo for enhancing abstinence among smokers with current or lifetime MDD.  Hypothesis: 
BASC plus varenicline will increase bioverified 7-day point prevalence abstinence at 24-weeks post-quit versus 
the other three conditions.
Secondary Aim 1: Evaluate anhedonia, cognition (attention/memory), cigarette reward value, and 
craving/withdrawal as mediators of the effects of BASC, varenicline, and their combination on 
abstinence among smokers with current or lifetime MDD. Hypothesis: Increases in hedonic capacity and 
cognition and decreases in craving and withdrawal will mediate the effects of treatment on bioverified 7-day 
point prevalence abstinence at 24-weeks post-quit.
IRB #: STU00100303 Approved by NU IRB for use on or after 9/9/2019 through 9/8/2020.


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Secondary Aim 2: Determine if the ethical concerns with incentives for research participation actually 
manifest. Hypothesis: Research incentives will augment participants’ perception of research risks while not 
disproportionately encouraging economically disadvantaged participants to enroll.  
Secondary Aim 2a: Assess the possible scientific and ethical benefits of financial incentives for RCT 
participation. Hypothesis: Research incentives will increase the enrollment fraction in the smoking cessation 
trial, thereby enhancing the scientific value and validity of the research by augmenting the precision of the 
study. 
Secondary Aim 2b: Evaluate the cost-effectiveness of using financial incentives to increase RCT 
enrollment rates. Hypothesis: Incentives are sufficiently cost-effective to justify their use as a means to 
expedite recruitment in RCTs.
BACKGROUND
Problem of Tobacco Dependence in Major Depressive Disorder (MDD)
The prevalence of smoking among adults with current mental health disorders is 2-3 times higher than the rate 
among the U.S. population (40-60% vs. 19%) (Centers for Disease Control and Prevention, 2013), an alarming 
disparity that is widening (B. L. Cook et al., 2014; Lawrence, Mitrou, & Zubrick, 2009). MDD is one of the most 
common mental health disorders in the U.S. (Centers for Disease Control and Prevention, 2010). The 12-
month prevalence of MDD is 6.7% while the lifetime prevalence is 16.5% (Kessler, Chiu, Demler, Merikangas, 
& Walters, 2005). The high comorbidity between tobacco dependence and MDD has been well documented 
(Grant, Hasin, Chou, Stinson, & Dawson, 2004; Lasser et al., 2000; Lawrence et al., 2009; Pratt & Brody, 
2010). Smokers have a higher prevalence of MDD vs. never-smokers (Breslau, Kilbey, & Andreski, 1991; 
Glassman et al., 1990). Up to 43% of persons with MDD are smokers (Pratt & Brody, 2010). Tobacco 
dependence increases risk of first incidence and severity and recurrence of MDD (Breslau, Kilbey, & Andreski, 
1993; Breslau, Novak, & Kessler, 2004; Breslau, Peterson, Schultz, Chilcoat, & Andreski, 1998; Leventhal, 
Kahler, Ray, & Zimmerman, 2009) and heavier smokers are at higher risk (Colman et al., 2011). Smokers with 
MDD are more likely to smoke heavily, perceive smoking as more pleasurable than many other traditionally 
rewarding activities, show greater tobacco dependence, and suffer more severe withdrawal (including craving) 
than smokers without MDD (Breslau, Kilbey, & Andreski, 1992; Pratt & Brody, 2010; Spring, Pingitore, & 
McChargue, 2003; Weinberger, Desai, & McKee, 2010). Psychological processes that are impaired in persons 
with MDD, namely hedonic capacity and cognition (attention and memory), are associated with smoking 
relapse (J. Cook, Spring, McChargue, & Doran, 2010; Leventhal, Waters, Kahler, Ray, & Sussman, 2009; 
Patterson et al., 2009). 
Smokers with MDD and Interest in Quitting Smoking
An important barrier to the development and evaluation of smoking cessation treatment for smokers with MDD 
has been the perception among clinicians and researchers that they are not motivated to quit. About 25% of 
smokers with MDD are motivated to quit and do accept formal treatment (Acton, Prochaska, Kaplan, Small, & 
Hall, 2001; Haug et al., 2005; Prochaska et al., 2004). Severity of depression is unrelated to readiness to quit 
smoking (Prochaska et al., 2004). In a study of treatment acceptance among smokers with MDD (Haug et al., 
2005), acceptors were more likely than refusers to report a desire to quit, to report expectancy for success, and 
to be taking antidepressant medication. Treatment acceptance was unrelated to severity of depression, degree 
of dependence, gender, age, or education. In contrast to the popular belief that quitting smoking causes or 
worsens depression, depression has been found to improve with abstinence (Prochaska et al., 2008; Shahab, 
Andrew, & West, 2013). Another barrier to addressing tobacco dependence among smokers with MDD has 
been the expectation that they will not be able to quit or achieve long-term abstinence (Hitsman, Moss, 
Montoya, & George, 2009).
MDD and Response to Smoking Cessation Treatment 
The 2008 Public Health Service Clinical Practice Guideline (Fiore, 2008) recommends that the treatments 
found to be effective for the general population be applied to smokers with current mental health disorders. 
This recommendation is based on the premise that studies upon which the Guideline is based included them. 
However, little is known about treatment strategies that optimize cessation outcomes for smokers with current 
or lifetime MDD (Fiore, 2008; Gierisch, Bastian, Calhoun, McDuffie, & Williams Jr, 2012; Hitsman et al., 2009; 
Weinberger, Mazure, Morlett, & McKee, 2013), largely because almost all randomized controlled trials (RCTs) 
IRB #: STU00100303 Approved by NU IRB for use on or after 9/9/2019 through 9/8/2020.


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excluded these smokers (Hitsman, Papandonatos, et al., 2013). Nevertheless, past major depression (MD) has 
been well-documented. We published a systematic review and meta-analysis of smoking cessation among 
smokers with and without past MD in 42 RCTs conducted 1988-2009 (Hitsman, Papandonatos, et al., 2013). 
Note: MD is distinguished from MDD to reflect that many of the studies in our database did not rule out lifetime 
manic or hypomanic episode or psychotic disorder, which is needed for a diagnosis of lifetime MDD. To 
minimize any influence of treatments (e.g., CBT mood management; MM) that might have selectively 
benefitted smokers with past MD (MD+), we analyzed data from only the lowest intensity control arms of the 
included studies. MD+ smokers had 17% lower odds of short-term abstinence (OR=0.83, 95% CI=0.72–0.95) 
and 19% lower odds of long-term abstinence (OR=0.81, 95% CI=0.67–0.97) than MD- smokers. 
In contrast to what we have learned about cessation outcomes for smokers with past MD, little is known about 
how to optimize outcomes for smokers with current or lifetime MDD (Fiore, 2008; Gierisch et al., 2012; Hitsman 
et al., 2009; Weinberger et al., 2013). To date, there have only been five RCTs of smokers with mood disorder 
including MDD. Three of these have been limited by sample sizes of less than 90 participants (Blalock, 
Robinson, Wetter, Schreindorfer, & Cinciripini, 2008; Chengappa et al., 2001; Evins et al., 2008). Hall et al. 
(2006) compared a stepped-care intervention that involved a computerized expert system and option of six 30-
minute therapy sessions that included CBT MM, nicotine patch and bupropion. Participants were 322 smokers 
with MDD. Abstinence rates at 12-months were higher for the stepped-care group (20%) than for the brief 
contact control group (13%). In one recent RCT involving 525 smokers with current or recent (past two years) 
MDD, varenicline nearly doubled abstinence at 52 weeks vs. placebo (28.5% vs. 17.5%) (Anthenelli et al., 
2013). These studies provide evidence that smokers with MDD can achieve abstinence. However, because 
more than two-thirds of smokers with MDD do not quit even with the best treatment (i.e., varenicline), novel 
interventions are needed to optimize smoking cessation for smokers with MDD.
In preparation for this project, we conducted a new meta-analysis of the 42 RCTs to re-evaluate which 
treatments are most effective for MD smokers. Our methods, including study characteristics, are described in 
Hitsman et al. (2013). Cognitive behavioral treatment (CBT) mood management (MM) doubled short-term (≤3 
months) abstinence rates (OR=2.04, 95% CI=1.17, 3.57), while varenicline nearly tripled short-term rates 
(OR=2.92, 95% CI=1.73, 4.92) and more than doubled long-term (≥6 months) abstinence (OR=2.49, 95% 
CI=1.58, 3.95). While varenicline is promising for this subgroup of smokers, data are limited on its efficacy and 
safety for smokers with current or lifetime MDD. Further, among smokers with past MDD, CBT MM was not 
effective for long-term abstinence. The limitations of CBT MM for depression, including the complexity of 
treatment and efficacy that may depend in part on the skill of the individual therapist (S. Rhodes et al., 2014), 
could contribute to its lack of an effect on long-term abstinence by interfering with skill attainment and 
maintenance. A treatment that overcomes these limitations is behavioral activation (BA) (Cuijpers, van Straten, 
& Warmerdam, 2007; Dimidjian, Barrera, Martell, Munoz, & Lewinsohn, 2011; Jacobson et al., 1996; Lejuez, 
Hopko, & Hopko, 2001; MacPherson et al., 2010). The goal of BA, one component of CBT MM, is to increase 
engagement in rewarding activities, a problem for smokers with MDD who find smoking especially rewarding, 
by reducing patterns of avoidance, withdrawal, and inactivity. BA has greater dissemination potential because 
it is simpler to administer for clinicians with limited experience in psychotherapy (Cuijpers et al., 2007; Ekers, 
Richards, & Gilbody, 2008).
Another limitation of this literature is that the studies targeting smokers with current MDD have been limited to 
the clinic setting requiring face-to-face treatment. To achieve the critical goal of increasing access and 
scalability, treatment will need to extend beyond the clinic. CBT for MDD has been successfully administered 
by telephone (Mohr et al., 2005; Mohr et al., 2012; Mohr et al., 2010) and the effectiveness of phone-based 
cessation treatment has been well-demonstrated (Fiore, 2008). CBT MM for cessation has also been 
administered by phone. In a study targeting smokers with recent or past MDD, van der Meer et al. (2010) 
observed that 12 weeks (ten 30-minute sessions) of CBT MM (n=243) improved 24-week abstinence rates 
compared with standard treatment (n=242; 30.5% vs. 22.3%).  
Psychological Barriers to Cessation for Smokers with MDD: A New Theory 
Limited understanding of psychological barriers imposed by MDD stems from the few RCTs that have included 
smokers with MD. These smokers are more likely to suffer severe craving and withdrawal during cessation 
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than smokers without lifetime MD (Weinberger et al., 2010; Weinberger, McKee, & George, 2012). Severe 
craving and withdrawal have also been found for smokers with current MDD (Lyons et al., 2008; Malpass & 
Higgs, 2007). Anhedonia, a core symptom of depression, predicts relapse in smokers with and without past 
MD (J. Cook et al., 2010; Leventhal et al., 2013; Leventhal, Waters, et al., 2009), as does cognitive impairment 
(attention and memory) (J. Cook et al., 2010; Leventhal, Waters, et al., 2009; Patterson et al., 2009). Smokers 
with MDD perceive smoking as more pleasurable than other traditionally rewarding activities (Spring et al., 
2003). This response may reflect a dysfunctional brain reward system that increases responsiveness to 
substances (e.g., nicotine) that activate these systems (Cardenas et al., 2002; Markou, 2007).
A major barrier to the development of smoking cessation treatments for smokers with MDD has been that there 
is no guiding theoretical framework for the psychological processes that serve to maintain tobacco dependence 
among persons with MDD (Hall, 2004; Ziedonis et al., 2008). To address this important gap, we developed the 
model presented in Figure 1, which integrates the findings reviewed above, those from our collective work 
(Audrain-McGovern et al., 2012; Audrain-McGovern, Rodriguez, Rodgers, & Cuevas, 2011; Hitsman et al., 
2009; Schnoll, Leone, & Hitsman, 
2013; Spring et al., 2008; Spring 
et al., 2003; Ziedonis et al., 
2008), as well as our contribution 
to the 2010 Surgeon General’s 
Report on the role of learning 
and conditioning processes in 
tobacco dependence (United 
States Public Health Service, 
2010). We propose and plan to 
test here that tobacco 
dependence is maintained 
through highly conditioned effects involving anhedonia, depressed mood, and cognitive function. Smoking 
acquires high reward value through positive reinforcement (a) effects fostering cognitive enhancement and 
reward functioning in the context of a constricted range of positive reinforcers. The positive reinforcing action of 
nicotine is attributable in large part to its influence on core brain reward centers (Doyle et al., 2014). A meta-
analysis by Heishman et al. (2010) found that nicotine improves cognitive performance (e.g., attention and 
memory) during satiated states. Negative reinforcement (b) processes are involved in that smoking dispels 
withdrawal symptoms, namely anhedonia, depressed mood, and cognitive impairment, which accompany brief 
periods of abstinence between cigarettes among heavy smokers like those with MDD. Because these 
withdrawal symptoms mimic depression, smokers with MDD acquire the generalized expectation that their 
depression (anhedonia, depressed mood, cognitive impairment) is relieved by smoking (Perkins, Karelitz, 
Conklin, Sayette, & Giedgowd, 2010)
Targeted Treatment for Smokers with MDD
CBT MM and varenicline individually have shown promise for treating tobacco dependence in smokers with 
MDD. CBT MM, however, has a positive effect only on short-term quitting according to our meta-analysis 
findings. CBT MM for depression has been noted for several limitations, including the complexity of treatment 
(for the patient and the therapist) and efficacy that may depend in part on the skill level of the therapist 
(Cuijpers et al., 2007; S. Rhodes et al., 2014), which could contribute to its lack of benefit on long-term 
abstinence. A treatment that addresses these barriers is behavioral activation (BA) (Cuijpers et al., 2007; S. 
Rhodes et al., 2014) one of three components of CBT MM (Dimidjian et al., 2011; Jacobson et al., 1996; 
Lejuez et al., 2001). BA alone is as effective as CBT MM in treating depression (Cuijpers et al., 2007; Dobson 
et al., 2008; Jacobson, Martell, & Dimidjian, 2001). Given that BA is simpler to administer, especially for 
clinicians with limited experience in psychotherapy (Cuijpers et al., 2007; Ekers et al., 2008), it may have 
greater potential for broad dissemination. BA treatment targets increasing engagement in rewarding activities 
by reducing patterns of avoidance, withdrawal, and inactivity. We believe that it is well suited for smokers with 
MDD who prefer smoking over other traditionally rewarding activities and who use smoking as a primary 
avoidance coping strategy (Kahler, Brown, Strong, Lloyd-Richardson, & Niaura, 2003; Spring et al., 2003). A 
IRB #: STU00100303 Approved by NU IRB for use on or after 9/9/2019 through 9/8/2020.


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small pilot study showed that BA for smoking cessation (n=35) vs. ST (n=33) increased long-term abstinence 
among smokers with elevated depressive symptoms but no MDD (MacPherson et al., 2010).
Treatment combining BASC and varenicline uniquely addresses the psychological barriers to long-term 
cessation for smokers with current or lifetime MDD. Barriers include anhedonia, cognitive impairment (attention 
and working memory), cigarette reward value, cigarette craving, and tobacco withdrawal. Figure 2 presents 
either known or predicted effects of BASC, varenicline, and their combination. Varenicline attenuates smoking  
reward, craving, and withdrawal severity (Cinciripini et al., 2013; Dolan et al., 2004; Hitsman, Hogarth, et al., 
2013; E. A. McClure, Vandrey, Johnson, & Stitzer, 2013; Patterson et al., 2009; Perkins, Mercincavage, Fonte, 
& Lerman, 2010; Sofuoglu, Herman, Mooney, & Waters, 2009; West, Baker, Cappelleri, & Bushmakin, 2008) 
and has cognitive enhancing effects in treatment motivated smokers (J. D. Rhodes, Hawk, Ashare, Schlienz, & 
Mahoney, 2012) and non-smokers. It also reduces the cognitive impairment that accompanies withdrawal 
(Patterson et al., 2009). BASC decreases avoidance coping and increases pleasure through increasing 
engagement in rewarding activities (Cuijpers et al., 2007; Dimidjian et al., 2011; Hopko, Lejuez, Ruggiero, & 
Eifert, 2003). BASC may be an ideal complement to varenicline because varenicline attenuates smoking 
reward, but does not help smokers approach and access positive alternative rewards in their lives. 
Varenicline’s attenuation of smoking reward also could enhance the effect of BASC on increasing engagement 
in alternative rewarding experiences and hedonic capacity, and further reducing smoking reward. Treatment 
combining BASC and varenicline has not been evaluated but represents a novel strategy that may optimize 
long-term cessation, especially for smokers with current or lifetime MDD.
We expect that treatment combining BASC and varenicline will achieve its effects by: 1) reducing anhedonia 
and cognitive impairment that maintain smoking behavior through positive reinforcement processes; 2) 
reducing tobacco craving and withdrawal that maintain smoking behavior through negative reinforcement 
processes – especially the affective and cognitive components that mimic depression; and 3) reducing 
cigarette reward value.
Incentives for Research Participation
As with other underrepresented groups, it can be challenging to engage and retain individuals with MDD in 
clinical trials. Through a partnership with the University of Pennsylvania-led Randomized Evaluation of Trial 
Acceptability by INcentive (RETAIN) study, we will conduct a sub-study to test a financial incentive strategy 
designed to maximize recruitment and retention. The sub-study’s innovative design will enable a definitive test 
IRB #: STU00100303 Approved by NU IRB for use on or after 9/9/2019 through 9/8/2020.


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of how patients make research decisions in the face of money, and will provide the best possible evidence 
regarding the scientific and ethical pros and cons of incentives for research participation.
PARTICIPANT ELIGIBILITY 
Target Population
Five hundred seventy-six males and females who smoke at least 1 cigarette per day, have a current or lifetime 
DSM-5 diagnosis of MDD without psychotic features (first episode of MDD can be prior to past two years) will 
be randomized to treatment. Two hundred and eighty-eight participants will be enrolled at Northwestern (lead 
clinical site) and 288 will be enrolled at the University of Pennsylvania (PENN). Randomization will be stratified 
by gender, severity of depressive symptoms (minimal/mild vs. moderate/severe), and clinical site 
(Northwestern, PENN). 
Key Inclusion Criteria
Eligible participants will be males and females who:
1.
Are 18 years of age or older and who report daily smoking of at least 1 cigarette per day.
2.
Have been diagnosed with current or lifetime MDD without psychotic features according to the 
Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-5); Note: first episode MDD 
diagnosis date may be prior to the past two years.
3.
Have or are willing to acquire a personal email address and access to the Internet, fax machine, PDF 
scanner, or camera phone for submission of therapy practice assignments;
4.
Are able to speak, read, and write fluently in English.
5.
Are able to provide written informed consent, which includes compliance with requirements and 
restrictions listed in the combined consent/HIPAA form.
6.
Intend to reside in the geographic area for >8 months.
7.
If women of childbearing potential, based on medical history and regardless of sexual orientation, 
consent to use a medically acceptable method of birth control (e.g., condoms, oral contraceptive, 
contraceptive injection, contraceptive patch, tubal ligation) or abstain from sexual intercourse during the 
time they are taking study medication and for at least one month after the medication period ends.
Key Exclusion Criteria
Participants who present or self-report any of the following will not be eligible to participate in the study:
Smoking Behavior
1.
Current enrollment or plan to enroll in another smoking cessation program in the next 8 months.
2.
Regular (daily) use of e-cigarettes, chewing tobacco, snuff, snus, or other tobacco product.
3.
Plan to use nicotine replacement therapy (NRT; e.g., gum, patch, lozenge, e-cigarette) or other 
smoking cessation pharmacotherapy in the next 8 months.
Note: Once determined to be eligible for the study, participants will be instructed to refrain from using 
non-study smoking cessation pharmacotherapy for the duration of the study. However, if a participant 
reports cessation medication use during the study, s/he may be permitted to continue pending study 
physician and PI approval.
Medication
Current use or recent discontinuation (within last 14 days) of the following medications: 
1.   Smoking cessation medications (e.g. varenicline, bupropion - if prescribed specifically for smoking 
cessation - nortriptyline, NRT). 
Note: Once determined to be eligible for the study, participants will be instructed to only use the 
medication provided to them by the study staff. If a participant reports use of a non-study smoking 
cessation medication, the study physician and PI will evaluate the situation and determine if it is safe for 
the participant to continue.
IRB #: STU00100303 Approved by NU IRB for use on or after 9/9/2019 through 9/8/2020.


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2.  Medications indicated for bipolar or psychotic disorder if specifically taken for bipolar or psychotic 
disorder.
Medical
1.
Women who are pregnant, planning a pregnancy within the next 8 months, or breast feeding;
2.
History of seizures or current seizure disorder without medication (if stable and medicated, requires 
physician approval).
3.
History of severe (defined as stage IV or V) chronic kidney disease including current or prior end stage 
renal disease on either hemodialysis or peritoneal dialysis or prior renal transplant.
4.
Any prior solid organ transplant or prior hematopoietic stem cell transplant.
5.
Heavy drinking as defined by more than 28 drinks per week.
6.
Cirrhosis or end-stage liver disease.
7.
Systolic blood pressure >185 mmHg or diastolic blood pressure >110 mmHg after two averaged 
readings or symptomatic uncontrolled stage II hypertension (systolic blood pressure >160 mmHg or 
diastolic blood pressure > 100 mmHg after two averaged readings with current reported symptoms of 
chest pain, dyspnea, headache, or blurred vision).
8.
Unstable cardiovascular disease within 3 months prior to baseline assessment, including unstable 
angina, myocardial infarction, percutaneous coronary intervention, transient ischemic attack, stroke, or 
other cardiovascular disease requiring hospitalization.
9.
Prior hospitalization for heart failure.
10. Previous allergic reaction to varenicline.
Psychiatric
1.
Active suicidal ideation within the last 30 days with at least some intent to act, with or without a specific 
plan. This would be reflected in a score of 4 or 5 on the Suicidal Ideation section of the Columbia 
Suicide Severity Rating Scale (C-SSRS).
2.
As measured using the C-SSRS, a suicide attempt over the past 12 months, not including preparatory 
acts or behavior, defined by a potentially self-injurious act committed with at least some wish to die as a 
result of the act. 
3.
Lifetime bipolar or psychotic disorder as determined by either self-report or Mini International 
Neuropsychiatric Interview (MINI).
General
1.    Any medical condition or concomitant medication that could compromise participant safety or treatment, 
as determined by the PI or study physician.
2.    Inability to provide informed consent or complete any of the study tasks (e.g., medical condition with a 
life expectancy < 1year) as determined by the PI or study physician.
Vulnerable Populations
Children under 18 years of age, pregnant women, fetuses, neonates, or prisoners will not be included in this 
study. Socioeconomically disadvantaged persons will be included in this study, but not targeted for recruitment. 
It is possible that Northwestern and PENN employees or students may choose to participate. However, status 
of participation in the study will be independent of the participant’s work or school activities. 
Recruitment and Accrual Procedures 
Treatment Sites
The research teams at Northwestern (lead site) and PENN have extensive experience with smoking cessation 
and other behavioral trials (depression, obesity, multiple behavior change). At Northwestern, the trial will be 
conducted in the Department of Preventive Medicine, which has been the site for large smoking cessation 
(Goelz et al., 2014) and depression (Mohr et al., 2012) studies. At PENN, the trial will be coordinated by the 
Center for Interdisciplinary Research on Nicotine Addiction, which has been the site for several large smoking 
cessation trials (Schnoll et al., 2010). Our two sites collaborated on a recently completed trial (R01DA025078) 
for which we enrolled, with no targeted recruitment, 18.7% (98/525) of participants with current or past MDD. 
IRB #: STU00100303 Approved by NU IRB for use on or after 9/9/2019 through 9/8/2020.


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Participant Recruitment
We will recruit via multiple channels in the Chicago and Philadelphia metropolitan areas, including targeted 
print and electronic advertisements in the community and on relevant social media (i.e., targeted Facebook 
and Twitter advertising). Recognizing: 1) the need for a large sample; and 2) the goal of including a community 
sample, we developed infrastructure and partnerships with the Departments of Public Health in Chicago and 
Philadelphia, community-based mental health centers in Chicago and Philadelphia, and the primary care 
networks at Northwestern and PENN to recruit the participants. As done in our previous clinical trials, we will 
use targeted print and electronic media ads (public transportation, newspaper, radio, television, internet, and 
social media groups/sites) as the primary form of recruitment. Our 30-second television advertisement will run 
on targeted broadcast channels designed to reach a diverse group of cigarette smokers who may be interested 
in participating in the study. Where applicable, we will provide a secure link within electronic ads to an online 
pre-screener (managed through REDCap and NU NITRO Recruit) or landing page (UPENN’s iConnect) within 
which readers may provide their contact information if they express interest in learning more about the study. 
We will use media sources with a varied range of viewership or listenership as doing so in our past clinical 
trials has allowed us to ascertain large (i.e., >500) and diverse (i.e., >30% racial/ethnic minorities) samples. 
In addition, we will recruit within clinical departments and services at Northwestern-and PENN-affiliated 
hospitals. Through our collaboration with researchers in the Department of Psychiatry and Behavioral Sciences 
at NU, we will use the NU-CRP Recruitment Pipeline (IRB #59328) to identify potentially eligible patients who 
have previously agreed to be contacted regarding future research projects.  We will use Research Match 
through NUCATS; Research Match (www.researchmatch.org) is an online registry that connects research 
studies with a database of candidate participants. It was created through collaborations between the Clinical & 
Translational Science Awards (CTSA) Consortium and funded by the National Center for Research Resources, 
a component of NIH. We will also recruit via outreach to our community partners through the extensive Cook 
County Health and Hospital System (at Northwestern, facilitated by Andrew Segovia Kulik, M.D., Interim 
Chairman of Psychiatry, CCHHS) and community medical- and mental health centers. 
Potential participants and data may also be identified through reports generated by the Northwestern Medicine 
Enterprise Data Warehouse (NMEDW), a joint initiative across the Northwestern University Feinberg School of 
Medicine and Northwestern memorial HealthCare (NMHC), a corporate parent of Northwestern Memorial 
Hospital, Northwestern Memorial Group, and Northwestern Medicine Lake Forest Hospital. NMEDW data 
sources include Cerner PowerChart, PRIMES, Epic, IDX, eNOTIS, and 50+ other systems from the campus. 
Once approved by the treating provider, potential participants reported by NMEDW to the Project Director may 
then be contacted with an opt-out letter followed by telephone calls, and provided with study information and 
asked if they are interested in completing the telephone pre-screen. Additionally, the PENN site will use the 
volunteer registry in iConnect to identify potential participants.
The PENN site will also collaborate with mental health clinics in the Philadelphia metropolitan area for direct 
recruitment. Clinics that agree to refer patients to the trial will provide study staff with contact information for 
patients identified as potentially eligible based on an internal medical record review. A Research Assistant will 
contact these patients to assess interest in the study and screen for initial eligibility.
Potential participants and data may also be identified through reports generated by the University of 
Pennsylvania Data Analytics Center through the Penn Data Store. Data sources include Aria, TheraDoc, 
EMTRAC, DocuSys, MedView, Sunrise, EPIC, Cerner and HDM & ClinTrac. Potential participants identified by 
the reports may then be contacted with an opt-out letter followed by telephone calls, and provided with study 
information and asked if they are interested in completing the telephone pre-screen.
After obtaining the necessary training and clearances to access PennChart for participating UPHS 
departments, PENN Research Assistants will review patient electronic medical records to identify potential 
subjects on a weekly basis (patient smoking status indicated on the record). Individual medical records will be 
evaluated for eligibility based on the inclusion and exclusion criteria for this study. RAs will contact potentially 
eligible patients after EMR review by telephone based on their provider’s specified research contact 
preference. Providers may choose one of the following contact options: 1) all patients identified as initially 
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eligible may be contacted 2) all patient records identified as initially eligible will be sent to the provider via 
PennChart for review and approval prior to contact 3) all patient records identified as initially eligible may be 
sent to the provider, who assumes full responsibility and discretion regarding the research contact (no contact 
may be made by the research staff). Those patients deemed eligible for contact will be contacted by telephone. 
RAs will introduce the research study and the collaboration between the researchers and the patient’s provider. 
After assessing the patient’s interest, he or she will then be provided with additional study information and an 
opportunity to assess his/her intake eligibility based on a screening questionnaire.
Research Recruitment Best Practice Advisories (BPAs) will also be integrated into electronic medical record 
recruitment at PENN. BPAs are designed to fire passive alerts within PennChart at the point of care, notifying 
providers that a patient may be eligible for a specific study. This specific BPA will evaluate if a patient meets 
specific criteria associated with the trial and will present the provider with the option to indicate if a patient is 
interested in participating in the study or not. This BPA will only present if the patient meets the initial screening 
criteria based on smoking status and problem list diagnoses and will only present in specified departments 
(Internal Medicine and Family Medicine). This indication of interest only serves to trigger a notification to study 
staff that a patient has met initial screen criteria and further follow-up is requested to determine eligibility of the 
patient. This alert is a passive alert and will not interrupt the provider’s workflow, but will be listed in the same 
section as other clinically warranted BPAs.
To ensure high retention and adherence in this trial, we will: 1) educate participants about the benefits of 
adherence (Ebbert, Wyatt, Hays, Klee, & Hurt, 2010); 2) schedule sessions at convenient times; 3) incorporate 
a medication adherence component into the BASC and ST protocols (Gariti et al., 2009; Schnoll et al., 2008); 
and 4) as is standard practice in smoking cessation trials (Niaura et al., 2005; Schnoll et al., 2010), provide 
modest financial compensation for session completion and transportation costs. We expect that <20% of 
participants will withdraw from the study and >70% of participants will complete follow-up evaluations, which 
would exceed rates in varenicline trials (Jorenby et al., 2006).
STUDY DESIGN 
This is a Phase IV, randomized, double-blind, placebo-controlled, two-site clinical trial (Figure 3). 
Rationale for Treatment and Design
We chose combination BA and varenicline for smokers with current or lifetime MDD given the results of our 
meta-analysis of treatment response among smokers with past MD. Varenicline had the strongest association 
with long-term abstinence but CBT MM was effective for only short-term abstinence. Compared with CBT MM, 
BA is simpler to administer, time-efficient, and less complicated for patients (Dimidjian et al., 2011; Jacobson et 
al., 2001; Lejuez et al., 2001) and thus may enhance skill acquisition/maintenance and long-term abstinence. 
BA alone is as effective as CBT MM for depression (Cuijpers & Schoevers, 2004) and preliminary efficacy of 
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BA for long-term cessation has been found in 
smokers with elevated depressive symptoms 
but screened out for current MDD 
(MacPherson et al., 2010). Combination BA 
and varenicline has the potential to optimize 
long-term cessation considering: 1) the 
psychological impairments in MDD; 2) the 
psychological factors associated with 
smoking behavior and cessation, especially 
in smokers with MDD; 3) the documented 
behavioral effects of BA in MDD; and 4) the 
psychological effects of varenicline during 
smoking cessation. We chose the 2x2 design 
because it provides comparison arms to 
evaluate efficacy and mediators of 
combination BA and varenicline vs. either BA 
alone or varenicline plus ST. This design 
also provides the placebo control to fully 
evaluate AEs in smokers with MDD for whom 
varenicline has been discouraged given 
safety concerns (Williams, 2012). 
Length of Study Participation
Participants will be involved in study-related 
activities for approximately 7 months (28 
weeks) from initial eligibility assessment 
through follow-up. A participant’s length of 
involvement may be affected by site or 
participant scheduling conflicts.
Study Timeline (Table 1)
We expect to complete accrual in about 48 months, enrolling about 12 participants per month.  
DRUG/DEVICE INFORMATION
Study Medication (Varenicline Tartrate)
Medication Course and Dosing
Participants will begin medication during week 2 (Pre-Quit 2) and continue for 12 weeks according to the 
following regimen in accordance with FDA-approved labeling for varenicline: Day 1-Day 3 (0.5mg once daily); 
Day 4-Day 7 (0.5 mg twice daily); Day 8-Day 84 (1.0 mg twice daily) (Gonzales et al., 2006; Jorenby et al., 
2006). The TQD will occur on Day 8 of varenicline or placebo, the first day of full-strength dose. The first two 
weeks of medication (week 2-3) will be dispensed at week 1 (Pre-Quit 1). Medication blister packs for weeks 4-
7 will be dispensed at TQD; blister packs for weeks 8-13 will be dispensed at the Week 7 in-person 
assessment. Fifty-five percent (n = 320) of the participants in the BASC and ST arms will be randomized to 
receive active varenicline while the remaining 45% (n = 256) of participants across both arms will receive 
placebo pills that look and taste like active varenicline medication. Participants will take this medication until 
Day 84. If a participant is not able to attend a medication pick-up visit (Weeks 3 or 7) within the specified 
window (see details below), the session will be completed by telephone and, if able to safely continue with the 
medication after potential side effect review, one week of medication will be mailed to the participant by the 
research pharmacy or a brief in-clinic pick-up will be arranged. Participants will need to attend a clinic visit to 
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complete a blood pressure assessment before additional medication is dispensed. Participants may also be 
asked to visit the clinic for a brief medication pick up if a complete course of medication is not available on a 
scheduled medication pick-up visit or if the participant loses medication and requires replacement kits. 
Because no data is being collected during these brief encounters, no additional compensation will be provided. 
Participants who discontinue study medication for 14 or more consecutive days will require approval from the 
PI and study physician before restarting the study medication. 
Side Effects and Adverse Events (AEs)
Following a large-scale trial supporting the safety of varenicline for smoking cessation among those with and 
without a current psychiatric disorder (Anthenelli et al., 2016), the FDA removed the boxed warning on 
varenicline in December, 2016. Several additional varenicline trials of smokers with lifetime mental health 
disorders have provided evidence of safety (Gibbons & Mann, 2013; Hays, Croghan, Schroeder, Ebbert, & 
Hurt, 2011; J. B. McClure et al., 2009; Meyer et al., 2013; Pachas et al., 2012; Philip, Carpenter, Tyrka, 
Whiteley, & Price, 2009; Spirling, Stapleton, & Sutherland, 2008; Stapleton et al., 2008; Wu et al., 2012). In the 
only RCT of varenicline to target depressed smokers (Anthenelli et al., 2013), there were no suicidal ideation or 
behavior events in the varenicline condition. In the placebo condition (N=269), there were three cases of 
suicidal ideation and a case of self-injurious behavior. Approximately 75% of the sample was antidepressant 
medication stable (i.e., ≥2 months without a dosage change), while the remaining 25% of the sample was not 
currently on medication for mood (R. Anthenelli, personal communication, December 7, 2015). Analyses 
indicated no differences in side effects or adverse events between the medicated and unmedicated groups, 
and the medication was shown to be safe overall. Although we will assess for potential antidepressant-
varenicline interactions in the current trial, varenicline has no known pharmacokinetic interactions (Faessel et 
al., 2010; Rollema, Wilson, Lee, Folgering, & Flik, 2011) or clinically meaningful interactions with other 
medications that are renally cleared, such as antidepressants ("Clinical Pharmacology [database online]," 
2014). Please also see “Potential Study Risks” section.
Supply, Preparation, Storage, Packaging and Dispensing of Study Medication
Varenicline and matching placebo is provided at no-cost by Pfizer and packaged and stored at Northwestern 
Memorial Hospital’s (NMH) Investigational Research Pharmacy. The NMH Research Pharmacy will oversee 
the randomization and labeling of study medication, and will assign each kit, which contains 12 weeks of 
medication for one participant, a unique Pharmacy Randomization Number (PRN) or kit number. Once a new 
participant is enrolled and eligible, the research staff will assign the participant the PRN kit number based on 
the blinded randomization scheme. Blister packs will then be labeled with the participant’s full name per Illinois 
Pharmacy Practice Act regulations. The PRN and participant’s name must match for each blister pack. 
A centralized system helps to preserve internal validity and maintain study blinding of clinical site personnel. 
The Northwestern project director will work with the NMH pharmacy to ensure that an adequate supply of 
medication is available at both sites. Medication will be stored in locked, climate controlled cabinets. 
Medication supply, in increments, will be given to participants at Week 1 (Pre-Quit 1), Week 3 (TQD), and 
Week 7 sessions.
Regular study drug reconciliation will be performed to document drug assigned, drug consumed, and drug 
remaining. This reconciliation will be logged on the drug reconciliation form, and signed by the research 
personnel who perform the reconciliation. At the completion of the study, there will be a final reconciliation of 
drug shipped, drug consumed, and drug remaining. This reconciliation will be logged on the drug reconciliation 
form, signed and dated by the research staff. Any discrepancies noted will be investigated, resolved, and 
documented prior to return or destruction of unused study drug. Once a participant has completed the course 
of the study drug (i.e., 12 weeks) and medication adherence data has been recorded, any remaining pills will 
be destroyed on site or sent to a recognized third party disposal agency and this will be documented in the 
study files.
STUDY PROCEDURES
Screening and Baseline Procedures
Initial Eligibility Screening 
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Study candidates will complete an initial eligibility assessment in the clinical site from which they were recruited 
(Northwestern or PENN) or by telephone. This assessment reduces the likelihood that participants will attend 
an intake session only to learn that they are ineligible, and allows us to ascertain physician’s clearance should 
the participants have a medical condition that requires approval. Participants who are initially eligible will be 
screened against our registration database to confirm that they are not currently participating in another 
research study at our Center and have not previously reported a condition or circumstance that would make 
them ineligible for the current study. Those participants who are deemed initially eligible during a telephone 
screening who remain initially eligible will then be invited to attend an Intake Visit at our Center (completed 
within 60 days of the initial eligibility screening) during which they will be presented with the IRB-approved 
Informed Consent Form and have their final eligibility confirmed. during which the purpose and procedures of 
this study will be described to them and final eligibility will be confirmed. Participants may be mailed a letter 
detailing the study visit, directions to the study site, and contact information. Callers who do not pass the pre-
screening may be directed to other research studies they may be interested in (e.g., clinicaltrials.gov, The 
Center for Behavioral Intervention Technologies [CBITs] at Northwestern or Mood and Anxiety Disorders 
Program at PENN) or provided with other smoking cessation resources (e.g., the Illinois/Pennsylvania State 
Quitline), as appropriate. 
Once a participant is determined to be preliminarily eligible for MDD, the research staff will ask the RETAIN 
eligibility prompt to assess for prior knowledge of the specific incentives or randomization used for RETAIN. 
Participants who do not have prior knowledge of the RETAIN incentives or randomization will be silently 
randomized by the research staff to one of three incentive conditions via the MDD trial’s DMS ($0, $200, or 
$500; described under Data Analysis below), and immediately present participants with information regarding 
their assigned condition. Participants who are randomized to the RETAIN sub-study will complete baseline 
questionnaires over the phone to assess 1) demographics and personal financial well-being, 2) attitudes 
towards biomedical research, 3) previous experience in research, and 4) perceptions of research risk.
Prospective participants who have prior knowledge of the incentives or randomization used for RETAIN will not 
be randomized, enrolled, or receive RETAIN-related messaging on the phone call. They will receive the 
standard study information regarding session and travel compensation for the MDD trial without RETAIN 
messaging. These participants will not be debriefed or paid the RETAIN incentives. 
Baseline Intake Session (Week 0): Eligibility, Consent, Randomization, Baseline Measures
Participants who pass the pre-screening will be invited to attend a 2-3½ hour Intake session where the 
following activities will occur:
1.
Informed consent/HIPAA forms will be reviewed with participants, during which they will hear a 
description of all study procedures, risks, benefits, and information about the study medication. 
Participants’ questions will be answered. Following this discussion, the combined informed consent and 
HIPAA form will be completed. 
2.
A urine pregnancy test will be administered to all female participants. 
3.
A carbon monoxide (CO) breath assessment to measure recent tobacco exposure. The handheld device 
uses a disposable mouthpiece, reports CO in parts per million (PPM), and takes about three minutes to 
administer.
4.
A 5mL saliva sample (about 1 teaspoon) will be taken to assess nicotine metabolic rate.
5.
A 12.5 mL blood sample will be drawn to measure cholesterol and glucose levels for participants who 
consent to this procedure. 
6.
A structured psychiatric interview (Mini-International Neuropsychiatric Interview, Columbia Suicide 
Severity Rating Scale) with a trained research staff member.
7.
Medical history and evaluation of vital signs and anthropometry to be completed by research staff.
8.
A concomitant medication review, including antidepressant medication. 
9.
Once the above steps have been completed and if eligible at this point, the participant will complete 
baseline paper and pencil measures to assess: 1) variables that may serve as covariates and that allow 
for the assessment of antidepressant-varenicline interactions (antidepressant medication use and type) 
and external validity (e.g., demographics); 2) mediator variables (e.g., hedonic capacity); 3) psychiatric 
symptoms; and 4) smoking behavior.
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10. If eligible, the participant will be randomized to treatment condition using a randomization scheme 
provided by Dr. Papandonatos and implemented through the data management system. Randomization 
will be stratified by clinical site, gender, and severity of depressive symptoms (minimal/mild vs. 
moderate/severe, as defined using the BDI-II (Beck, Steer, & Brown, 1996)) and will be by permuted 
blocks of fixed size (18 participants per block) with unequal 4:4:5:5 allocation ratio across the four study 
arms, such that a minimum of N=128 participants be assigned to each psychological treatment group 
(BASC, ST) receiving placebo, while a minimum of N=160 participants be assigned to each 
psychological treatment group (BASC, ST) receiving varenicline. 
11. Once randomized, participants are scheduled for the first treatment session (Pre-Quit, Week 1). There 
must be no more than two weeks between the intake session and the first treatment session.
At the baseline intake session, participants who are randomized for the RETAIN sub-study will complete the 
following additional procedures:
1.
Informed consent/ HIPAA forms with additional information regarding the RETAIN sub-study 
randomization condition, viewed via REDCap survey. We will assess the amount of time participants 
spend reading each part of the main trial consent form by presenting each section (e.g., Study 
Introduction, Procedures by Visit, Possible Risks and Discomforts, etc.) as a survey in REDCap. A 
timestamp function will allow us to assess the time at which participants move from one section of the 
consent to the next. Research staff will then administer a trial quiz assessing understanding of key trial 
elements, and review responses with participants. Participants will have the opportunity to ask any 
questions they have regarding information in the Informed Consent and HIPAA forms prior to providing 
their signature.    
2.
Before signing, participants will complete brief questionnaire measures of a) perceptions of research 
risk, b) perceptions of the difference between research and individualized patient care, and c) 
understanding of the smoking cessation study via a trial elements quiz. The responses to the quiz will 
be reviewed with participants, during which participants’ questions will be answered. 
3.
After signing, participants will complete brief questionnaire measures of a) perceived coercion, and b) 
prior persuasion (described in Measures section below). 
4.
Lastly, participants will receive a full debriefing regarding the purpose of the RETAIN sub-study. 
Research staff will explain that all RETAIN sub-study participants receive up to $500 ($300 RETAIN 
incentive payment and up to $200 for time and travel), regardless of what was stated in the Informed 
Consent Form.
Procedures During Treatment
Psychological Treatment Plan (Weeks 1-12)
All participants will receive manual-based treatment from a therapist trained and supervised by Drs. Jackie 
Gollan (Northwestern), Anita Hole (PENN), and Brian Hitsman (PI). After final eligibility has been confirmed by 
either the project director, study physician or PI (lead and PENN clinical site), participants will be randomized 
to receive either the BASC or ST interventions. BASC treatment will integrate behavioral activation therapy 
(Dimidjian et al., 2011; Jacobson et al., 1996; Lejuez et al., 2001) and ST. ST will be based on the 2008 PHS 
Clinical Practice Guideline (Fiore, 2008) and on ST in our recently completed and ongoing two-site trials 
(R01DA025078 and R01CA165001, respectively). BASC and ST will be delivered in eight 45-minute sessions 
over 12 weeks, weekly for the first four sessions and every other week for the final four sessions. Session 
frequency and duration are based upon past CBT MM trials (Haas, Munoz, Humfleet, Reus, & Hall, 2004; 
Patten, Martin, Myers, Calfas, & Williams, 1998). BASC and ST will follow the same schedule, equated on 
number of sessions and total participant-therapist contact time. The schedule for both psychological treatment 
arms is described next.
Pre-quit sessions 1 and 2 (Weeks 1 and 2): BASC and ST begin with two “Pre-Quit” therapy sessions 
(Pre-Quit 1 in-person, Pre-Quit 2 by phone) designed to help participants prepare for the target quit day 
(TQD/Week 3). These sessions focus on reviewing participant’s history and experience with quitting and, per 
random assignment, will also introduce either the BASC or ST treatment models and participants will initiate a 
quitting plan that aligns with techniques from the assigned therapeutic approach. Two weeks of medication are 
dispensed at Pre-Quit 1 and participants will be instructed to wait until the day of Pre-Quit 2 (Week 2) to start 
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taking the study medication. During the Pre-Quit 2 (Week 2) phone session, participants will be instructed to 
take their medication starting that day. The therapist will contact participants two days later to ensure that 
instructions regarding medication use are being followed.
Target quit day session (Week 3): At Week 3, participants will complete their in-person “Quit Day” 
session to review the initial quit attempt, identify potential reasons for relapse, and review their quit plans. 
Medication for weeks 3-7 will be dispensed at this visit.
Booster therapy sessions (Weeks 4, 6, 8, 10, and 12): Participants will then receive five additional 1-
hour therapy sessions by phone at Weeks 4, 6, 8, 10, and 12 which either reinforce success and review the 
quit plan or reestablish a quit date and restart the cessation process. The sessions are designed to use BASC- 
or ST-specific strategies to assist the person in developing skills to quit and avoid relapse, instruct the smoker 
on varenicline use, and address medication compliance or study participation adherence (as applicable). 
Session windows: The first Pre-Quit session (Week 1) must occur within 2 weeks of the baseline intake 
visit. Any exception to this procedure will require PI approval and re-administration of the BDI-II by phone, to 
ensure current assessment of depressive symptoms for stratification purposes. Pre-Quit 2 (Week 2) may occur 
5-10 days after completion of Pre-Quit 1. The TQD session (Week 3) may occur +3 days from the target date 
(Day 8 of study medication). Week 4 may occur +/- 4 days from the target date (Day 15 of medication). Weeks 
6, 8, 10, and 12 sessions may occur +/-1 week from their target date. The Week 7 assessment session must 
occur after the Week 6 therapy session +/- 3 days from the target Week 7 date. The Week 14 session must 
occur on or up to +1 week after the participant has completed drug treatment. The Week 27 follow-up session 
may occur -1 or up to +2 weeks from the target date. Participants who report abstinence at the Week 27 phone 
session may complete the Week 27 in-person clinic visit anytime immediately after completing their Week 27 
phone session and up to 2 weeks after their Week 27 phone session. Throughout the study period, a session 
will be considered missed if it is not completed within the session window. Following any missed session(s), 
the participant will be contacted for the next scheduled session according to the study calendar.
Behavioral Activation for Smoking Cessation Intervention
BASC aims to increase engagement in rewarding activities by reducing patterns of avoidance, withdrawal, and 
inactivity. Our BA treatment model is based on Jacobson et al.’s BA model (Jacobson et al., 1996) given its 
emphasis on reward management and session sequence that can be integrated with 12+ weeks of ST 
consistent with the current conceptualization of tobacco dependence as chronic and requiring longer-term 
treatment (Fiore, 2008). Key components of BASC include activity monitoring and rewarding activity 
scheduling, assessment of personal goals and values, assessment and altering of avoidance behavior and 
other maladaptive coping strategies, and contingency management. BASC focuses on reducing stress pile-up 
and loss of pleasure that accompanies the cessation process and on identifying and establishing 
environmental/social changes that will promote abstinence. BASC addresses smoking as a behavior that 
prevents and restricts opportunities for contact with healthy rewarding behaviors. These changes are achieved 
through altering daily routines that had been previously been associated with smoking in ways that increase 
pleasure and mastery across life domains, reducing rumination, and increasing behavioral skills to prevent 
return to smoking as a means of avoiding stressors. 
Two pre-quit sessions (Pre-Quit 1 and 2) will introduce participants to: 1) self-monitoring of mood and behavior 
using the Daily Activity Monitoring Record; 2) assessment of personal values to refine the treatment plan; and 
3) scheduling of substitute rewarding activities that align with their abstinence goal. Participants will submit 
their completed homework (or follow-through) assignments to their study therapist by either email/fax, 
completed electronically using web-based forms, or camera phone.    
At the TQD session (Week 3), participant experiences with abstinence will be reviewed and functional analysis 
of behavior will be introduced, especially as it relates to smoking and avoidance patterns. Information obtained 
will be used to help generate behavioral activation plans that increase rewarding activities and relationships, 
reduce avoidant responses to distressing experiences, and facilitate successful implementation of smoking 
trigger management strategies. 
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Booster sessions 4-8 will incorporate strategies to address avoidance patterns, especially those involving 
smoking, and to replace them with adaptive coping strategies. Strategies include managing stress pile-up 
using step-by-step task deconstruction (i.e., breaking large tasks into small manageable steps), recognizing 
rumination (Stiles-Shields, Kwasny, Cai, & Mohr, 2014) as avoidance coping, becoming more proactive and 
less mood-dependent, short-term goal setting, especially as it pertains to relapse prevention, and long-term 
goal planning to promote increased pleasure and mastery that aligns with personal life goals.
Standard Treatment Intervention
The ST protocol is based on U.S. PHS guidelines for smoking cessation treatment (Fiore, 2008) and used in 
our recently completed and ongoing trials at Northwestern and PENN (R01 DA025078 and R01CA165001, 
respectively). ST arm will focus on self-monitoring of smoking behavior, identifying smoking triggers and 
alternative trigger management strategies, relaxation, social support for non-smoking, and relapse prevention. 
Two pre-quit sessions help prepare participants for their TQD by reviewing their experience with quitting, 
beliefs about smoking/quitting, perceived barriers to cessation, and creating a quit plan to identify smoking 
triggers and implement alternative strategies to manage those triggers without smoking. TQD and booster 
sessions will help participants use “avoid, alter, or substitute” strategies for trigger management to prevent 
relapse.
Treatment Fidelity
The same study therapists will conduct both the BASC and ST interventions. Therapists will use condition-
specific session checklists to guide session content. Sessions will be audio-recorded and a random sample of 
25% of BASC and ST sessions, respectively, will be assessed for protocol adherence per study site. Drs. 
Gollan (Northwestern) and Hole (PENN) will perform independent ratings. The fidelity assessment will provide 
scores for therapist competence, adherence, and contamination. To assure ongoing fidelity, therapists will 
attend bi-weekly supervision by teleconference with Drs. Gollan and Hole for review of audio-recorded 
sessions. Retraining will be triggered if adherence is less than 90% or if there is any evidence of cross-
condition contamination. Because the therapist will handle both the BASC and ST interventions, s/he will not 
conduct any assessments, if possible. Therapists will be blind to study drug randomization.
Pharmacological Treatment Plan (Weeks 2-14)
A 12-week course of varenicline or matched placebo will be used in accordance with FDA approved labeling: 
Day 1-Day 3 (0.5mg once daily); Day 4-Day 7 (0.5 twice daily); Day 8-Day 84 (1.0 mg twice daily). The first 
week of medication (Week 2) will be dispensed during Pre-Quit 1 (Week 1). Medication blister packs for weeks 
3-7 will be dispensed on the TQD (Week 3); blister packs for weeks 8-13 will be dispensed at the Week 7 in-
person assessment. At each session following Pre-Quit 2, medication adherence will be evaluated by self-
report.  Therapists will monitor and address medication adherence issues as a regular part of therapy 
sessions. For the TQD session and the Week 7 and 14 sessions, adherence will also be evaluated by pill 
count. Specific strategies to address non-adherence will be used, if necessary. Our approach to evaluating 
medication adherence assesses participant reasons for medication non-adherence using scenarios and 
counters with specific strategies to enhance compliance.
Mid-treatment Assessments 
Assessments will be conducted at Weeks 0, 1 (Pre-Quit 1), 3 (TQD), 4, 6, 7, 8, 10, 12, and 14 (EOT) by a 
research assistant and supervised by the study physician and study psychologist. Assessments during phone 
sessions will require ~20 minutes to complete and will be conducted before therapy sessions. Assessments at 
Weeks 1, 7, and 14 in-person visits will take ~90 minutes to complete. Assessments include measures of 
mediating variables, psychiatric status, side-effects, treatment adherence (pill count, collection of blister 
packs), and smoking behavior. Only the research assistants, blind to condition, will conduct assessments, if 
possible.
Side Effect Monitoring
Repeated assessments will permit close monitoring of participant safety as done in our completed and ongoing 
two-site trials involving pharmacotherapy (R01DA025078 and R01CA165001/STU00064871, respectively). 
IRB #: STU00100303 Approved by NU IRB for use on or after 9/9/2019 through 9/8/2020.


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The research team has clinical psychologists and physicians at each clinical site to review ongoing eligibility 
status and to monitor and address potential AEs associated with the study drug during the trial. 
As is done in another IRB-approved protocol involving varenicline (STU00064871), we will regularly assess 
participant reactions to treatment with a previously-used varenicline adverse event checklist and validated 
depression and suicidality scales. These assessments are conducted 10 times during the study before, during 
and after the treatment phase by research staff supervised by the clinical site study physician and 
psychologist. Given conflicting reports indicating there may be potential risk of adverse cardiovascular effects 
from varenicline (Prochaska & Hilton, 2012; Singh, Loke, Spangler, & Furberg, 2011) participants will undergo 
evaluation of recent medical history, blood pressure, and heart rate at Weeks 0, 1, 3, 7, 14,  and 27 to monitor 
cardiovascular reactions to study medication. 
We will use an established coding and reporting system for adverse events used in our ongoing two-site trial of 
varenicline for smokers (R01CA165001/STU00064871). Study personnel are trained by physicians and 
psychologists to administer adverse event instruments, including validated depression and suicidality scales. If 
an adverse event or serious adverse event report or a score on a scale indicates a safety concern, site PIs and 
physicians or psychologists are immediately notified and determine a course of action (e.g., stop medication). 
Participants are instructed to contact their counselors if an AE occurs, as well as given contact information so 
that they can contact the study physician at each site 24 hours/day if an SAE occurs. Adverse events are also 
coded and managed by PIs and site physicians or psychologists. All SAEs are subject to reporting to the IRB, 
NCI, FDA, and Pfizer as outlined in the Data Safety Monitoring Plan and may be referred to an outpatient or 
emergency department. Lastly, a study-specific Data Safety and Monitoring Board (DSMB) will be convened 
for this trial to monitor side effects.
Follow-Up Procedures
Outcome Assessments 
The primary outcomes will be 7-day point prevalence abstinence at Week 27 (24-weeks post-TQD) confirmed 
with CO (Hughes et al., 2003), and AE rates. CO-verified 7-day point prevalence abstinence at weeks 7 and 14 
(4- and 10-weeks post-TQD, respectively) will be secondary outcomes. Other outcomes at 24-weeks post-TQD 
will include: prolonged abstinence (relapse defined as 7 consecutive days of self-reported smoking after a 2-
week grace period), continuous abstinence (no smoking between TQD and follow-up), and time to 7-day 
relapse (no grace period). All participants will be asked to attend in-person sessions at Weeks 7 and 14 to 
provide CO breath samples. At Week 27, all participants will complete the assessments by phone and only 
those who self-report abstinence will be asked to attend an in-person session for CO verification. Safety 
Assessments Side effect monitoring, suicidality assessments, medication adherence assessments will be 
administered as done during the treatment phase of the trial. A follow-up session will occur in-person at the 
end of treatment (EOT, Week 14) and at 6-months post-TQD for participants who report abstinence (Week 27). 
Measures (see Table 2)
Screening/Covariates
Medical and psychiatric history: All medical conditions and medications related to risk for potential 
adverse reactions to varenicline will be assessed. A urine pregnancy test will be conducted for women. Blood 
pressure and heart rate will be assessed at each clinic visit. Diagnostic and Statistical Manual of Mental 
Disorders (American Psychiatric Association, 2013) mood, psychotic, and substance use disorders 
(current/past) will be evaluated using: 1) the Mini-International Neuropsychiatric Interview (MINI) (Sheehan et 
al., 1998) adapted to the DSM-5; and 2) the Columbia Suicidality Severity Rating Scale (C-SSRS; 
www.cssrs.columbia.edu). The MINI is a 30-45 minute structured interview developed by the World Health 
Organization to assess psychiatric diagnoses. Administered at the intake session, the MINI permits both 
current (past 30 days) and lifetime assessments of psychiatric disorder. The MINI modules to be administered 
include: major depressive episode, (hypo)manic episode, panic disorder, agoraphobia, social anxiety disorder, 
obsessive-compulsive disorder, posttraumatic stress disorder, psychotic disorders, alcohol use disorder, 
substance use disorder, and generalized anxiety disorder. Suicidality will be assessed in more detail at each 
session using the Columbia Suicide Severity Rating Scale (C-SSRS). The C-SSRS is a semi-structured 
interview that assesses suicidal ideation (passive, active, and intensity of ideation) and four types of suicidal 
IRB #: STU00100303 Approved by NU IRB for use on or after 9/9/2019 through 9/8/2020.


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behaviors (actual, interrupted, and aborted attempts, and preparatory acts or behavior). It was developed and 
designed to track suicidal events across depression treatment and provides standardized, explicit definitions of 
suicidal ideation and behaviors to improve safety monitoring data collection.
Blood pressure: At the baseline intake visit study candidates will have two blood pressure readings 
taken, each after a five-minute period in which the person will be instructed to sit comfortably in a quiet setting. 
If, after taking the average of the two readings, a candidate has a blood pressure reading above either: (a) 185 
mmHg systolic and/or 110 mmHg diastolic, or (b) above 160 mmHg systolic and/or 110 mmHg diastolic with 
co-occurring symptoms of chest pain, dyspnea, headache, or blurred vision, s/he will be ineligible for the study.
Blood pressure will be measured at every clinic visit. If a participant presents with elevated blood pressure 
(≥185/110 or ≥160/100 and symptomatic, averaged from two readings) at any clinic visit following the intake 
session, the study physician will be notified to determine how to proceed. For example, the participant may be 
discontinued from study medication and invited to continue in the trial to complete psychological treatment and 
assessments only. Additional study drug will not be given to the participant until cleared by the study physician.
Psychiatric treatment and depression/anxiety symptoms:  We will collect information about treatment 
history, including psychotropic medication, psychotherapy, and hospitalization. Use and type of antidepressant 
medication will be measured across treatment using a timeline follow-back (TLFB) interview (Brown et al., 
1998) and recorded on a depression medication adherence questionnaire. This TLFB interview is the same as 
what we have used in our completed and ongoing two-site trials involving pharmacotherapy (R01DA025078 
and R01CA165001/STU00064871, respectively). The depression medication adherence questionnaire also 
asks about reasons why participants have missed taking their antidepressants. Depression symptoms will be 
measured using the Beck Depression Inventory (BDI-II) (Beck et al., 1996). The BDI-II yields a total score 
ranging from 0-63, with scores of 0-13 indicating minimal depression, 14-19 indicating mild depression, 20-28 
indicating moderate, and 29-63 indicating severe depression. Anxiety symptoms will be measured using the 
Beck Anxiety Inventory (BAI) (Beck & Steer, 1990). The BAI also yields a total score ranging from 0-63 points, 
with scores of 0-7 indicating minimal anxiety, 8-15 indicating mild anxiety, 16-25 indicating moderate anxiety, 
and 26-63 indicating severe anxiety.
Demographic and smoking history: We will collect demographic and smoking history data (e.g., age at 
smoking initiation). The Fagerstrom Test for Nicotine Dependence (FTND), a 6-item measure of nicotine 
dependence validated in smokers with mental health disorders, will be administered (Buckley et al., 2005; 
Fagerstrom, Heatherton, & Kozlowski, 1992; Heatherton, Kozlowski, Frecker, & Fagerstrom, 1991). The brief 
Wisconsin Inventory for Smoking Dependence Motives (WISDM; (Smith et al., 2010)) will be administered to 
assess smoking motives. 
Caffeine consumption: A brief questionnaire is being used to measure caffeine consumption and 
positive and negative effects of caffeine. Participants are instructed to report on their caffeine consumption 
and caffeine-related effects over the past month. Participants are asked at the intake session (Week 0) to 
indicate whether their current consumption of caffeine containing beverages, foods, medication or dietary 
supplements reflects a change from their usual consumption. This questionnaire will be used to assess the 
degree to which baseline caffeine consumption changes across treatment or is associated smoking cessation. 
It will be given to participants at intake, week 7, and week 14, and takes about 5 minutes to complete.
Mediators 
Cigarette reward value: Preferences for engaging in smoking vs. other traditionally rewarding activities 
will be measured using a questionnaire developed by Spring and colleagues (Spring et al., 2003). The test 
requires participants to make 15 forced choices between smoking and a variety of rewards likely to be 
accessible and enjoyed. The choice of smoking is scored as 1; the choice of the alternative reward is scored 
as 0. Scores range from 0 to 15, and the test has exhibited acceptable internal consistency (alpha=0.74) 
(Spring et al., 2003).  
Reinforcing value of cigarettes versus money: The reinforcing value of cigarettes versus money will be 
measured using the Cigarette Purchase Task (CPT) (MacKillop et al., 2008). The CPT assesses estimated 
IRB #: STU00100303 Approved by NU IRB for use on or after 9/9/2019 through 9/8/2020.


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consumption of cigarettes at escalating levels of price, ranging from no cost and very low prices to intermediate 
and very high prices. The resulting data is then modeled using demand curve analysis to generate multiple 
indices of the value of tobacco to the individual. The CPT takes approximately 2-3 minutes to complete.
Hedonic capacity: Hedonic capacity will be assessed with the 14-item Snaith-Hamilton Pleasure Scale 
(SHAPS) (Snaith et al., 1995). The SHAPS has excellent psychometric properties in nonclinical and clinical 
samples (Franken, Rassin, & Muris, 2007; Leventhal, Chasson, Tapia, Miller, & Pettit, 2006; Snaith et al., 
1995). High scores characterize someone who perceives a broad array of life experiences as rewarding and 
who experiences a high degree of pleasure in response to rewards; low scores characterize someone who 
does not respond fully to typical rewarding experiences. 
Reward learning: A modified version of the Probabilistic Reward Task (PRT) will be used to measure 
hedonic capacity as indexed by reward learning (Liverant et al., 2014; Pizzagalli, Jahn, & O'Shea, 2005). The 
task comprises two 8-minute blocks of 100 trials administered using E-Prime 2.0 (Psychological Software 
Tools; http://www.pstnet.com/). Simple cartoon faces with two different mouth lengths, 11.5 mm (short) vs. 13.0 
mm (long) are presented for 100 ms in the center of the computer screen. Participants are instructed to identify 
which mouth was shown (short or long) with a button press, and are told that the goal of the task is to win as 
much money as possible by choosing the correct mouth length. Correct responses for the "rich stimulus" are 
rewarded with money at three times the rate of correct responses for the "lean stimulus." A response bias is 
induced for the "rich stimulus" vs. "lean stimulus" via positive feedback for the correct answer ("Correct!! You 
win 5 cents."). Participants can earn up to $4.20 for completing the task. The designation of short vs. long 
mouth as the "rich stimulus" is counterbalanced across participants, with this assignment maintained across 
the three administrations. Outcome variables include response bias, discriminability, and response time.
Alternative reinforcers: A 45-item version of the Pleasant Events Schedule (PES)(MacPhillamy & 
Lewinsohn, 1982) will be used to measure traditionally rewarding activities that occur in a person’s natural 
environment (Audrain-McGovern et al., 2011). The cross-product score of frequency (0=none to 2=often) and 
level of enjoyableness (0=none to 2=very) for each item provides a measure of activity reward. Participants are 
also asked whether they associate the activity with smoking or the urge to smoke. If the activity is associated 
with smoking, it is considered a complementary reinforcer. If the activity is not associated with smoking, it is 
considered a substitute reinforcer. The cross products of substitute reinforcers are summed to provide a score 
for substitute alternative reinforcers and those for complementary reinforcers are summed to provide a score 
for complementary alternative reinforcers. Scores have been associated with depression (Audrain-McGovern 
et al., 2011), discriminate between ex-smokers and current smokers, and predict smoking abstinence in 
cessation treatment (Audrain-McGovern et al., 2009; Goelz et al., 2014).
 
Cognitive function: Cognitive function will be assessed using the NIH Toolbox for the Assessment of 
Neurological and Behavioral Function (NIH-TB) (Weintraub et al., 2013) The NIH-TB was designed to provide 
a brief, convenient set of computerized measures for clinical trials involving a wide range of populations. The 
NIH-TB Flanker Inhibitory Control and Attention Test will be used to assess participants’ ability to focus, 
sustain and shift their attention. Working memory, which refers to the ability to temporarily store and 
manipulate information for complex cognitive tasks, will be measured using the List Sorting task. Average total 
administration time for these two tasks is 11 minutes. 
Mood induced tobacco choice task: The concurrent choice task developed by Hogarth and colleagues 
will be used to measure preferential choice of tobacco over natural rewards (i.e., chocolate) (Hogarth, 2012; 
Hogarth & Chase, 2012). This measure is sensitive to individual differences in nicotine dependence (Hogarth & 
Chase, 2012), nicotine replacement pharmacotherapy (Hogarth, 2012), and negative mood induction (Hogarth 
et al., Under review). The 10-minute test is administered using E-Prime 2.0 (Psychological Software Tools; 
http://www.pstnet.com/). The task provides a behavioral measure of background craving indexed by 
preferential tobacco choice, and the modulation of tobacco choice following induced negative and positive 
mood states. The task will test of whether varenicline and behavioral activation training reduce tobacco-choice 
overall, reduce negative mood induced increases in tobacco-choice, or increase positive mood induced 
decreases in tobacco choice. The outcome of this measure will provide insight into the affective mechanisms 
IRB #: STU00100303 Approved by NU IRB for use on or after 9/9/2019 through 9/8/2020.


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Week
0C
1C
2
3C
4
6
7C
8
10
12
14C
27
27C1
TREATMENT
BASC or ST
X
X
X
X
X
X
X
X
Varenicline or Placebo
X
X
X
X
X
X
X
X
SCREENING/COVARIATES
Urine Pregnancy Screen
X
Medical Hx Form,  MINI Psychiatric 
Interview
X
Suicidality (C-SSRS)
X
X
X2
X
X
X
X
X
X
X
X
X
X
Depression Inventory (BDI-II)
X
X
X2
X
X
X
X
X
X
X
X
X
Anxiety Symptoms (BAI)
X
X
X
X
X
X
X
X
X
X
Demographics
X
Smoking History, Nicotine Dependence 
(WISDM), Readiness Rulers
X
Psychiatric History
X
Outside Treatment
X
X
X
X
X
X
X
Antidepressant Med Use
X
X
X
X
X
X
X
X
X
X
Nicotine Metabolism
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
Caffeine Consumption
X
X
X
MEDIATORS
Cigarette Reward Value (CRV)
X
X
X
X
X
Reinforcing Value of Cigarettes Versus 
Money (CPT)
X
X
X
X
Hedonic Capacity (SHAPS)
X
X
X
X
X
Reward Learning (PRT)
X
X
X
Alternative Reinforcers (PES)
X
X
X
X
X
Cognitive Function (Flanker & List Sort)
X
X
X
Mood Induced Tobacco Choice Task
X
X
X
Craving (QSU) and Withdrawal (MNWS)
X
X
X
X
X
HEALTH DATA
Cholesterol, Glucose
X
X
Sleep, Diet, Alcohol, Physical Activity 
(Health Behavior Assessment)
X
X3
X
X
Height/Weight 
X
X
X
X
X
X
TREATMENT DATA
Adherence: Medication Accountability
X
X
X
Adherence: Self Report Pill Count
X
X
X
X
X
X
X
X
Side Effects Checklist & Adverse Events
X
X
X
X
X
X
X
X
X
X
Recent Medical Hx
X
X
X
X
X
X
Blood Pressure/Heart Rate
X
X
X
X
X
X
Integrity of the Blind and Satisfaction
X
Brief Mood Assessment
X
X
OUTCOME
Smoking Status, Cigarettes/Day
X
X
X
X
X
X
X
X
X
X
X
X
Carbon Monoxide (CO)
X
X
X
X
X
X
3 Parts IV and V only (page 5).
2 BDI-II and C-SSSRS are only administered if the participant endorses a mood change 
Table 2. Measures/Events
Target Quit Date = Week 3 (Day 8 of study medication); End of treatment = Week 14
C = clinic visit (in-person session)
1 Week 27 is conducted by telephone with self reported abstainers to complete a clinic visit for expired CO verification
by which the treatment manipulations influence smoking motivation.
IRB #: STU00100303 Approved by NU IRB for use on or after 9/9/2019 through 9/8/2020.


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Subjective cigarette craving: Craving will be measured using the Questionnaire of Smoking Urges-Brief 
version (QSU-Brief) (Cox, Tiffany, & Christen, 2001). The QSU-Brief is a widely used scale that yields an 
overall measure of cigarette craving (or urge to smoke) and two subscale scores: positive reinforcement and 
negative reinforcement. The full-scale score is computed by summing the 10 items. Higher scores indicate 
greater urges to smoke. 
Nicotine withdrawal symptoms: Withdrawal will be measured with the Minnesota Nicotine Withdrawal 
Scale (MNWS) (Hughes & Hatsukami, 1986), which comprises nine questions: urge to smoke, depressed 
mood, irritability, anxiety, difficulty concentrating, restlessness, increased appetite, and two sleep questions, 
each rated from 0 to 4 (0 not at all, 1 slight, 2 moderate, 3 quite a bit, 4 extreme). A composite withdrawal 
score is computed by summing the nine items.
Health Data
Objective measures: Non-fasting blood plasma at weeks 0 and 14 will be tested for cholesterol and 
glucose levels as indices of cardiovascular health. Blood pressure and height/weight to determine body mass 
index will be measured at all in-person study visits (weeks 0, 1, 3, 7, 14, and 27)
Self-report measures of behavioral risk factors for cardiovascular disease: At weeks 0, 14, and 27, 
participants will complete questionnaires that assess sleep, diet, physical activity, and alcohol use. Past week 
sleep will be assessed using the PROMIS short-form sleep disturbance (4 items) and sleep-related impairment 
(8 items) scales (Buysse et al., 2010). Past week physical activity will be measured using 3 items the Godin 
Leisure Time Exercise Questionnaire (Godin & Shephard, 1985). Past week sedentary behavior will be 
measured will be measured using one item from the International Physical Activity Questionnaire (Craig et al., 
2003). The Health Information National Trends Survey (HINTS)(Thompson et al., 2011) and Coronary Artery 
Risk Development in Young Adults (CARDIA) study (Lloyd-Jones, 2010; Lloyd-Jones et al., 2010) items were 
used as a basis to assess average consumption of fruits, vegetables, whole grains, sugar-sweetened 
beverages, and sodium (7 items). Alcohol consumption will be assessed using the 3-item AUDIT Alcohol 
Consumption (AUDIT-C) scale (Bush, Kivlahan, McDonell, Fihn, & Bradley, 1998). Marijuana use over the past 
30 days will be assessed using one item regarding frequency adapted from the AUDIT-C scale and one item 
regarding timing of most recent use. These health behavior questions will take about 7-8 minutes to complete.
Treatment Measures
Medication adherence: Medication adherence will be assessed at each session by self-report using the 
same timeline follow-back (TLFB) interview and by pill count via collection of used blister packs (clinic visits 
only) as done in past varenicline trials (Ebbert et al., 2009; Gonzales et al., 2006; Jorenby et al., 2006; Niaura 
et al., 2008) and in our current varenicline trial (STU00064871). Self-reported pill count has adequate 
sensitivity and specificity compared to plasma varenicline concentration (Buchanan et al., 2012). Adherence to 
BASC and ST will also be tracked.
Adverse events (AEs) and suicidality:  As done in our ongoing varenicline trial (R01CA165001/ 
STU00064871), we will use a structured checklist followed by open-ended questions to assess for incidence and 
severity of varenicline-related adverse events, including neuropsychiatric AEs. These assessments will be used 
to monitor safety and enable dose reductions or suspension as needed during the trial. Dose reductions or 
suspension of drug may be considered if the study physician has determined that the endorsed symptom(s) are 
“likely” or “definitely” related to taking the study drug, the symptom(s) cause the participant moderate or severe 
distress, and the participant expresses concern about continuing on the study drug at the FDA-recommended 
dose. If this is the case, a reduction to 1mg daily or 0.5mg twice daily will be the initial reduced dose 
recommended, with close monitoring of the participant’s side effect profile. If the endorsed side effect(s) continue 
to cause the participant moderate to severe distress at the reduced dose, stopping of the study drug may be 
considered and the participant will be invited to proceed in the trial completing therapy treatment and 
assessments only. We will administer the Columbia Suicidality Severity Rating Scale (C-SSRS) at each session 
to assess for suicidality. Recent history of cardiovascular symptoms (e.g., angina) or hospitalization/emergency 
department visit will be assessed at each session to monitor any cardiovascular events associated with 
varenicline. Blood pressure and heart rate will be measured at every clinic visit.  
IRB #: STU00100303 Approved by NU IRB for use on or after 9/9/2019 through 9/8/2020.


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Integrity of the blind: Participants’ perception of drug treatment assignment may influence their 
treatment adherence. This question is the one used by Schnoll and colleagues (Schnoll et al., 2008). 
Satisfaction with the program (3 questions): Given the negative perception that many individuals have 
of varenicline, understanding patient’s satisfaction with the program may be useful information to evaluate in 
the outcome analyses and can provide a basis for clinical relevance. These questions were modeled after 
patient satisfaction questionnaires used in a variety of smoking cessation programs. The four questions will be 
administered at the Week 14 (end of treatment) visit and take about 2 minutes for the participant to complete.
Outcomes Measures
Abstinence (primary outcome): Smoking will be assessed using a TLFB interview (Brown et al., 1998), 
and by breath carbon monoxide (CO) to verify self-report. Participants will be considered abstinent if they 
report abstinence (not even a puff of a cigarette) for >7 days prior to week 27 (24-weeks post-TQD) and have a 
CO ≤8 ppm at the time-point (Hughes et al., 2003). As per convention, participants are assumed to be smoking 
if they report smoking at the time-point, cannot be reached to provide data at the time-point, fail to provide a 
breath sample at the time-point, or provide a breath sample at the time-point that is >8 ppm (Hughes et al., 
2003). Daily smoking will be assessed at each session using the TLFB. The TLFB interview provides data that 
can be used to assess the timing and rates of lapses (smoking episodes not lasting 7 days), recovery events 
(return to abstinence), and relapse events, as well as to monitor changes in cigarettes smoked per day. These 
data will also be used to compute and assess secondary measures of smoking cessation (below). CO will be 
measured at each in-person visit to confirm smoking status. To obtain participants’ CO value, the participant 
takes 3 deep breaths. On the third deep breath, participants are instructed to inhale and hold their breath for 10 
seconds, then place their mouth securely around the disposable mouthpiece on the handheld CO monitor and 
to blow through the tube until they have completely expelled all of the air in their lungs. 
Smoking behaviors (secondary outcome): CO-verified 7-day point prevalence abstinence at weeks 7 
and 14 (4- and 10-weeks post-TQD, respectively) will be secondary measures. As per guidelines (Hughes et 
al., 2003), secondary outcomes at 24-weeks post-TQD will include: prolonged abstinence (relapse defined as 7 
consecutive days of self-reported smoking after a 2-week grace period), continuous abstinence (no smoking 
between TQD and follow-up), and time to 7-day relapse (no grace period).
RETAIN Sub-Study Measures
Mediators/ moderators: 1) Income and personal financial wellbeing. Annual household income will be 
assessed using a 6-level variable. Participants’ economic wellbeing (e.g., whether participants have recently 
borrowed money to “make ends meet”) will also be assessed. 2) Participant characteristics. Other factors that 
may influence response to financial assessments will be assessed; including prior research participation, age, 
race, gender, ethnicity, education, and marital status; with items taken from main trial demographic forms 
where possible. 
Main outcome: Proportion of participants assigned to each incentive amount who consent to participate 
in the main trial.
Secondary outcomes: 1) Attention to Informed Consent Document (i.e., time spent reading each 
section, as described in Procedures above). 2) Research Attitudes Questionnaire (Kim, Kim, McCallum, & 
Tariot, 2005). 3) Perceived research risk (Cryder, London, Volpp, & Loewenstein, 2010). 4) Therapeutic 
misconceptions (S. L. Kim SH, Wilson RM, Frank SA, Holloway RG, Keiburtz K, De Vries RG, 2009; W. R. Kim 
SH, De Vries R, Kim H, Holloway R, Kieburtz K, 2015; Pentz et al., 2012). 5) Trial Elements Quiz (S D Halpern, 
2002; S D Halpern, Karlawish, Casarett, Berlin, & Asch, 2004). 6) Perceived Coercion Scale (Gardner W et al., 
1993). 7) Study retention (i.e., proportion of participants assigned to each incentive amount who complete 
study procedures through week 27). 
RISK/BENEFIT ASSESSMENT
Potential Study Risks
A detailed description of the study will be given to all participants, which will include the risks of participation, 
assurance of full confidentiality, and the knowledge that their freedom to refuse participation or withdraw from 
the project will not affect the availability of treatment at Northwestern or PENN. Informed consent procedures 
will comply with current standards of the IRBs at Northwestern and PENN. Participants can choose, as an 
IRB #: STU00100303 Approved by NU IRB for use on or after 9/9/2019 through 9/8/2020.


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alternative, to not enroll in this study. Adverse reactions will be assessed and reported as required by Federal 
law and the regulations of Northwestern and PENN. Potential study-related risks are listed below. 
Mild Emotional Distress in Response to Assessments or Therapy
Participants may experience emotional distress during assessments from receiving information about mental 
health diagnostic status based on the clinical interview (i.e., new diagnosis of Major Depressive Disorder), 
discussing feelings and attitudes about smoking, or from learning about the risks from smoking. Study 
personnel will be alerted to expect some level of emotional distress from a small number of participants and 
will be trained to respond appropriately, maintain rapport with participants, and effectively utilize supervision 
from study physicians and psychologists. In addition, measures of depression, anxiety, and suicidality will be 
administered throughout the trial to detect acute changes in psychiatric status and provide appropriate referrals 
if requested. Northwestern and PENN have developed a protocol to monitor, assess, and refer for treatment 
any serious psychiatric concern that emerges within our trials (please see Safety Monitoring and Reporting 
Protocol). 
Nicotine Withdrawal
Most individuals who stop smoking exhibit nicotine withdrawal symptomatology. These symptoms can include: 
sadness and anxiety, irritability, difficulty concentrating, anger, appetite change and weight gain, insomnia, and 
decreased heart rate. Eliminating the risk for these would not be possible, although in most cases these events 
are short-lived and have low intensity, lasting for 2-3 weeks. Use of varenicline should minimize the severity of 
withdrawal symptoms and the psychological treatments will offer strategies for reducing withdrawal. The study 
personnel will be trained to recognize these symptoms and to educate participants about them (e.g., their 
duration, their time-limited nature, methods for reducing them). 
Varenicline
Some individuals who take varenicline may experience nausea, sleep disturbance, constipation, flatulence, 
and vomiting. These are the most common side effects and are experienced by 5- 25% of patients. However, 
these symptoms are usually mild and temporary, and do not lead to treatment discontinuation in most cases. 
There have been rare reports of allergic and skin reactions, including swelling of the face, mouth (tongue, lips, 
and gums), extremities, and neck (throat and larynx). The risk for these reactions is low (0.01%). Participants 
will be instructed to discontinue medication and seek medical help immediately if they experience any difficulty 
breathing or any of the noted allergic reactions, and then follow-up with research study staff once their 
symptoms have stabilized. Participants will be told that varenicline may impair their ability to perform tasks that 
require judgment or motor skills and that they should proceed with caution in this regard until they are certain 
that varenicline is not affecting their performance. Participants will also be told that varenicline may lower their 
tolerance to alcohol and that there have been rare reports of aggressive behavior and/or impaired memory 
following the consumption of alcohol while taking varenicline. In these cases, which number less than 30 
across the United States, the amount of alcohol consumed was not sufficient to explain the symptoms. 
Therapists will instruct participants to restrict their alcohol intake while taking the study drug or until they know 
how varenicline affects their alcohol tolerance. Participants will be advised to inform the study staff if they are 
taking or plan to take any prescription or over-the-counter drugs. 
Varenicline may be associated with new or worsening seizures during the first month of treatment. Some 
patients had no history of seizures, whereas others had a history of seizure disorder that was remote or well-
controlled. We will screen for and exclude people who have an unstable, untreated history of seizures.
There have been reports, though rare, of suicidal thoughts, aggression, and changes in emotional functioning 
and behavior while taking varenicline. To minimize the likelihood of participants experiencing these adverse 
events we will:
1.  Employ a stringent list of exclusionary criteria to limit the chance of adverse events occurring;
2.  Administer the standard and recommended dose run-up to the 1mg BID dose;
3.  Monitor self-reported adverse events at each session; and
4.  Conduct open-ended evaluation of any potential adverse events at each session.
IRB #: STU00100303 Approved by NU IRB for use on or after 9/9/2019 through 9/8/2020.


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The U.S. FDA recommends that patients taking varenicline should contact their healthcare provider if they 
experience mood or behavior changes. Participants will be asked to notify the research staff as soon as 
possible if these changes do occur (if not already determined by formal study assessments), and will be 
reminded that they have a medical contact card with information about how to contact the study physician 24 
hours per day. Varenicline trials of smokers with and without mental health disorders have provided evidence 
of safety (Gibbons & Mann, 2013; Hays et al., 2011; J. B. McClure et al., 2009; Meyer et al., 2013; Pachas et 
al., 2012; Philip et al., 2009; Spirling et al., 2008; Stapleton et al., 2008; Wu et al., 2012). In the only RCT of 
varenicline to target smokers with current or recent (past two years) MDD (Anthenelli et al., 2013), there were 
no suicidal ideation or self-injurious behavior events in the varenicline treated group (2mg/day for 12 weeks; 
N=256). In the placebo condition (N=269), there were three cases of suicidal ideation and one case of self-
injurious behavior. Further, a recent trial including smokers both with and without psychiatric disorders did not 
find any varenicline treatment-associated changes on either suicidality or other neuropsychiatric adverse 
events (Anthenelli et al., 2016). Varenicline has no known pharmacokinetic interactions (Faessel et al., 2010; 
Rollema et al., 2011) or clinically meaningful interactions with other medications that are renally cleared, such 
as antidepressants ("Clinical Pharmacology [database online]," 2014). 
Varenicline may be associated with an increased risk of certain cardiac and vascular AEs, including chest pain, 
heart attack, and stroke. These risks are rare and are still being studied to determine their validity. However, 
our study staff follows strict procedures to monitor for the presence of these adverse events, including 
monitoring blood pressure and heart rate at each in person visit and asking specific side effect questions 
related to cardiovascular events (e.g. chest pain, weakness on one side, etc.) during each session. Cases of 
somnambulism have been reported in patients taking varenicline. Participants will be asked to notify research 
staff as soon as possible if they experience somnambulism  
Study physicians and psychologists will be alerted to any reported AEs that are coded as requiring further 
review (see Safety Monitoring and Reporting Protocol for coding definitions and corresponding severity ratings 
by symptom). They will review the information provided by research staff and, if applicable, contact the 
participant to gather more information and determine the appropriate course of action. Ultimately, the study 
physician, with the help of the study psychologists as necessary, will decide if the AE is related to study 
medication and whether or not the participant should discontinue taking study medication. Dose reductions, 
which will be tracked, may also be employed to minimize any side effects.
Blood Draw
The blood draws may result in bruising and/or slight bleeding at the needle site and, occasionally, may result in 
a feeling of faintness. These side effects are rare, so the chances of these discomforts are minimal. Sample 
collection will be conducted by study personnel trained in phlebotomy to minimize risk of discomfort.
Reproductive Risks
The safety of varenicline for an unborn baby is unknown, therefore participants will be told that they should not 
become pregnant or breast-feed a baby while in this study. Women will be asked to take a pregnancy test 
before starting the study. If the woman is of childbearing potential, she must agree to use an adequate form of 
contraception for at least one month prior to initiation of the study drug, while study medication is taken, and for 
at least one month after the end of the trial. Women who are pregnant, breast-feeding or planning to become 
pregnant will be excluded from the trial, and if an enrolled participant becomes pregnant during the study, she 
will be discontinued from the study medication but allowed to continue with psychological therapy and 
assessments.
Threats to Privacy/Confidentiality
Because self-report and medical data will be collected and stored as part of this study, it is possible that 
participant privacy or confidentiality could be threatened. To address this concern, the Data Management 
System (DMS) has established safeguards to prevent unauthorized access to study data. An automatically 
generated index number is assigned to a participant’s study identification number. A linked participant 
identification table is created for the storing of participant name, address and telephone contact information. 
This table uses the automatically generated index number rather than the study identification number. The 
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master participant map and participant identification information tables are maintained in a separate database. 
Using this method, no identifying information is directly linked to medical information or other study data. 
Northwestern and PENN have long-established protocols to guard against improper use of hard copies of data 
(e.g., locked files, numeric coding procedures). Neither of our two research teams has experienced the 
unauthorized use of study data. All electronic data (including any audio files) are kept on secure servers, 
behind a firewall within the Northwestern Department of Preventive Medicine, and will require a Northwestern 
network ID (NetID) and password for access and data entry. Any electronic communication with participants for 
the purposes of assessment and treatment are conducted using best practice data encryption and 
transmission standards. All electronic data collected as a part of psychological treatment (i.e., between-session 
practice or “homework” forms) will be transmitted using Transport Layer Security (TLS) encryption to prevent 
eavesdropping on and tampering while it is in the transmission pipeline.
Potential Risks of RETAIN Sub-Study
Coercion
There is a risk that the incentives used in the RETAIN-related procedures for this study may unfairly coerce 
participants to participate in a trial that they would not otherwise participate in. This is a primary question of the 
RETAIN sub-study. The RETAIN PENN PI has convened a study-specific data and safety monitoring board 
(DSMB) in conjunction with NIH to monitor any indication that this is occurring. Our hypothesis is that no 
population will be unfairly manipulated into participating in a trial that they would not otherwise participate in, 
and that financial incentives may lead to participants examining the potential risks of a study more closely than 
they would have otherwise. 
Supporting Research
A study led by RETAIN PENN PI Halpern and RETAIN Co-I Karlawish assessed 126 hypertensive patients’ 
willingness to participate in RCTs of experimental antihypertensive drugs(S D Halpern et al., 2004).  We used 
a 3 x 3 within-subjects factorial design in which hypertensive patients were administered, in random sequence, 
9 hypothetical RCTs which differed in their risk level (10%, 20%, or 30% chance of drug-related adverse 
events) and payment ($100, $1,000, or $2,000 for a 10-week trial). We found that increasing payments 
motivated greater RCT participation, and that increasing risk levels reduced participation levels (p < 0.001 for 
each). Importantly, patients’ participation rates declined equivalently with increasing risk levels across all 
payment levels studied, and the statistical interaction between risk and payment was not statistically significant 
(p=0.30).   This shows that patients were equally sensitive to risk despite very different payment amounts, 
suggesting that research incentives are not undue inducements.  
Furthermore, this study of payments for RCT enrollment(S D Halpern et al., 2004), as well as another study by 
PI Halpern of payments for living kidney donation(S. D. Halpern et al., 2010), counter the notion that payments 
are unjust inducements. Specifically, in both studies, increasing payment levels were similarly motivating 
among patients with higher and lower incomes. Indeed, in the RCT participation study(S D Halpern et al., 
2004), there was an indication that larger payments may preferentially motivate wealthier people to participate 
(payment-by-income interaction p=0.09). The validity of these results is enhanced by the income diversity 
among the study samples and the substantial statistical power to identify such income-by-payment interactions 
if they existed. 
RETAIN Co-I Volpp and colleagues asked participants to rate the riskiness of a new technology (transcranial 
magnetic stimulation) being tested in RCTs after being told they would receive $25 or $1,000 for trial 
participation (Cryder et al., 2010). Participants assigned to review the trials offering $1,000 spent more time 
reading about study risks and other research aspects (mean = 3.7 minutes) than did patients assigned to trials 
offering $25 (mean = 1.0 minutes) (p < 0.01). Larger incentives also decreased the odds that participants 
would skip the page of the informed consent form that described study contraindications (p < 0.05). These 
findings suggest that payments alert people to the possibility of risk, and encourage them to learn more about 
the study (Cryder et al., 2010), rather than contravening the goals of informed consent, incentives may actually 
promote informed decision-making.
Deception
The RETAIN sub-study involves an element of deception (i.e., participants are told that they are randomized to 
one of three financial incentive conditions, when in fact all participants receive the same amount of financial 
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compensation). We believe deception is an essential element of this sub-study, as it would not be feasible to 
address study aims without incomplete disclosure related to the random assignment of financial incentives. 
Adverse events from the incomplete disclosure will be minimized through the debriefing process. Participants 
will be debriefed at the end of the first in-person intake session. This debriefing will therefore happen within a 
few days of the deception, and will provide participants with full disclosure of the research and an opportunity 
to withdraw their participation or their data. We believe the value of the study is sufficient to warrant waiving 
some aspects of the requirement for full disclosure in the informed consent process. 
Additional Ethical Considerations for RETAIN Sub-Study
Although some participants will enroll in the main trial without enrolling in the RETAIN sub-study, there are 
several reasons why these different paths to enrollment, and different associated incentives, do not unduly 
disadvantage participants who do not wish to participate in the RETAIN sub-study:

The main trial was conceived independently from and prior to the RETAIN sub-study, and has commenced 
accrual without additional financial incentives. Participants who choose not to participate in the RETAIN 
sub-study are no worse off than if the RETAIN sub-study had never been proposed, or if the participants 
had been recruited prior to the RETAIN sub-study launching. 

Per available federal regulations, incentives for research participation ought not be construed as a benefit 
to research participation. While the Common Rule requires “risks to subjects [to be] minimized” (45 C.F.R. 
§46.111(a)) and requires that risks be “reasonable in relation to anticipated benefits, if any, to subjects and 
the importance to the knowledge that may reasonably result” (45 C.F.R. § 46.111(b)), it cautions that “[i]n 
evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from 
the [specific] research.” Thus, federal regulations do not consider risks or benefits of opportunities 
(research or otherwise) external to the main trial as relevant in adjudicating the fairness of the trial.

There is no regulatory requirement of equal treatment. Rather, the regulations incorporate the principle of 
justice by requiring the equitable selection of participants, which responds to historical abuses of vulnerable 
populations in research and seeks to achieve equitable distribution of benefits and burdens of research. 
This distinction between equal selection from among potential participants and equal treatment of enrolled 
participants is fundamental to RCTs.

Finally, any difference in payment to individuals who do or do not participate in the RETAIN sub-study 
stems from participants’ choices. The most fundamental ethical principal in research, embodied in the 
federal regulations and international ethics guidelines, is that research participation must be voluntary. By 
extension, people have the right to refuse participation in any study. The federal regulations require 
researchers to provide specific information about study participation (45 C.F.R. § 46.116), but, after 
providing information and answering individuals’ questions, investigators must respect individual choice.
Potential Study Benefits
Participants in this study will have the opportunity to participate in a smoking cessation program at no cost. 
They will receive 12 weeks of psychological treatment and the opportunity to receive 12 weeks of varenicline, a 
medication with proven efficacy for treating tobacco dependence in the general population of smokers. Thus, 
participants will have the opportunity to stop smoking completely or reduce their amount of use. Participants 
may also benefit from the knowledge that they are contributing in an important way to potentially further 
scientific knowledge concerning ways to improve cessation treatment for smokers.
Alternatives to Study Participation
As an alternative to enrolling in this study, participants may choose to continue to smoke or to seek assistance 
with quitting smoking through other treatment programs located in their area, including contacting the national 
quitline. At any point in this trial, participants may decide not to continue in the study. Choosing not to 
participate or revoking informed consent once enrolled in the study will not negatively affect their right to any 
present or future treatment at Northwestern or PENN affiliated clinics, nor will it affect their class standing 
(Northwestern or PENN students) or current or future employment (Northwestern or PENN employees).
IRB #: STU00100303 Approved by NU IRB for use on or after 9/9/2019 through 9/8/2020.


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Risk/Benefit Assessment Summary
There is minimal risk for serious AEs. The treatments and procedures used in this study have been 
demonstrated to be safe. Varenicline has also been studied in several clinical trials and shown to be safe and 
effective, including in smokers with major depressive disorder (MDD). Nevertheless, there are some potential 
risks associated with participating in this trial, which are described above.
The potential benefits of this study far outweigh the potential risks. Nicotine dependence is a chronic condition 
that disproportionately affects people with mental health disorders like MDD. Smokers with MDD demonstrate 
greater nicotine dependence, suffer more severe nicotine withdrawal, and do not respond as well to evidence-
based smoking cessation treatment versus smokers without MDD (Hitsman, Papandonatos, et al., 2013). Little 
is known about how to improve smoking cessation treatment in this population because smokers with MDD 
have been underrepresented in smoking cessation treatment research and underserved in clinical practice, 
despite substantial tobacco-related disease burden. Individuals will be screened prior to admission into the 
study and those at increased risk for adverse reactions will be excluded. Enrolled participants will be monitored 
closely for side effects and AEs. Another anticipated benefit of participation in the current research is that it will 
advance our understanding of the efficacy of targeted treatment for smokers with MDD. It will be the first trial to 
combine varenicline with behavioral activation integrated with standard behavioral cessation treatment. Study 
findings will have implications for national clinical practice guidelines. 
While the RETAIN sub-study introduces some degree of additional risk to participants, we believe that the risk/ 
benefit ratio remains clearly in the favor of research participants. Further, importance of the information to be 
gained confers significant benefit. The RETAIN sub-study will be the first to explore how financial incentives 
impact actual decisions made by patients contemplating participation in a real trial, which will provide important 
information about the impact of financial incentives on decision-making, with implications for future conduct of 
clinical trials. 
DATA AND SAFETY MONITORING
We will use established procedures and infrastructure for data and safety monitoring (e.g., STU0064871) and a 
protocol-specific DSMB. Safety and data quality monitoring will be performed on an ongoing basis by the 
investigators and study personnel. Study personnel will be responsible for collecting and recording all clinical 
data using a Manual of Operations (MOP) that will be developed for this study. This includes ensuring that 
source documents exist for all the data collected on the case report forms (CRFs), ensuring all fields are 
completed appropriately, and ensuring that all corrections are done according to Good Clinical Practice (GCP). 
Inconsistencies or deviations will be documented. The study physicians and psychologists at the two sites will 
review data for each participant on an ongoing basis and will document reviews by initialing and dating reports. 
Study personnel conduct 100% quality assurance (QA) on data, comparing all hard copy data to computer 
files. 
Staff training will consist of a detailed explanation of the protocol and review of the CRFs. In addition, the 
duties of each research staffer will be outlined and all applicable regulations will be reviewed. Mock sessions 
with constructive critical feedback will be conducted. The MOP will be used for staff training and to guide 
procedures during the trial. Senior personnel will supervise junior staff and provide re-training as needed.
Monitoring will be conducted in accordance with GCP and the U.S. Department of Health and Human Services 
Code of Federal Regulations Title 45, Part 46.a (http://www.hhs.gov/ohrp/policy/ohrpregulations.pdf). 
Recruitment and enrollment will stop when 576 participants are consented, randomized and complete the 
study. On average, about 12 participants will be enrolled per month across the two study sites. 
Monitoring for AEs will be conducted in real-time by the study personnel and the site PI and study physician 
and psychologists. Research staff will complete thorough side effect assessments and send this information to 
the study physician and psychologists, who will determine the severity of the adverse events. The relationship 
of the event to the study drug and the course of action for the participant will be decided by the site physician 
and psychologists after reviewing the report. Participants will be monitored for the development of AEs by 
assessing side effects at each session between weeks 0 and 27 as well as through open-ended questions 
during assessments (at least 10 times during the trial). Monitoring may increase if required. Additionally, 
participants will be given a 24-hour emergency number they can call if necessary. 
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The PIs, study physicians, and psychologists will follow all participants who discontinue due to a serious AE 
until it resolves and becomes completely stable, unless a referral to another physician (i.e., specialist) is 
indicated or requested by the participant. All AEs and serious AEs will be documented in an Adverse Events 
CRF. This information will, in turn, be reported immediately to all necessary regulatory committees, including 
the FDA (see Data and Safety Monitoring Plan and Safety Monitoring and Reporting Protocol). 
All serious AEs, as defined in the adverse event procedures in the Safety Monitoring and Reporting Protocol, 
will be reported within 24 hours to the PIs (lead and PENN PI). These events will be maintained in a unique 
database and reviewed monthly by senior study personnel. The site physician and psychologists will review all 
AE forms in “real-time” to ensure appropriateness of the data and timeliness of reporting. The Northwestern 
database manager and research assistants will be responsible for monitoring data integrity as data are 
collected. This includes ensuring that source documents exist for the data on the CRFs, ensuring all fields are 
completed appropriately, all corrections are done according to GCP and any inconsistencies and deviations 
are documented.  
The study will be monitored by the PIs (lead and PENN site), co-investigators, and regulatory committees at 
Northwestern and PENN as well as by a study-specific DSMB. The following monitoring activities will be 
conducted according to standard operating procedures. 
Initial Assessment Monitoring
The Northwestern database manager and site project directors will conduct a manual review of source 
documents and CRFs for a random 25% subset of participants enrolled in the study. This inspection is the 
visual comparison of source documents to CRFs in a quantitative assessment of accuracy based on the 
number of data fields. A brief, internal report will be generated to describe findings. If the data are less than 
acceptable (i.e., >1% discrepancy between data values from source documents compared to CRFs), additional 
cases are requested, with appropriate counseling/training for staff.
Protocol Monitoring
Protocol monitoring includes a survey of those activities that are associated with protocol adherence such as 
study visit deviation and violation of inclusion/exclusion criteria. All accrued cases will be subjected to protocol 
monitoring throughout the duration of the trial.
Database Auditing
The Northwestern database manager and research assistants will review data entered into the database 
versus that recorded on the CRFs. All accrued cases will be subjected to database auditing throughout the 
duration of the trial. Re-training will be provided should problems, such as increased errors, be detected.
Data Auditing
The site physician and psychologists will review safety data recorded on the CRF versus that contained on the 
actual source document (patient chart, lab report, etc.). All accrued cases could potentially be subjected to 
auditing throughout the duration of the trial.  
Data Security
Using network firewall technologies, the database will prevent the three major sources of data security 
problems: unauthorized internal access to data, external access to data, and malicious intent to destroy data 
and systems. Controlled user access will ensure that only appropriate and authorized personnel are able to 
view, access, and modify trial data. All modifications to data will document user access and data associated 
with the modification, as well as values prior to modification.
IRB Monitoring
As the official IRB of record indicated in the approved IRB authorization agreement (IAA, Federalwide 
Assurance #00004028), the protocol will be reviewed by the Northwestern IRB and will only be implemented 
after successful approval. Annual reporting and auditing will be conducted by the Northwestern IRB. All 
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procedures will be approved by the Northwestern IRB and monitored locally by both the Northwestern and 
PENN IRBs. A protocol-specific DSMB will be used for this trial (see below). The Northwestern and PENN 
IRBs will ensure participant safety and data integrity in collaboration with the DSMB.
Evidence of Training in Human Subject Research 
All personnel working on the study will be required to review the protocol, complete training in the protection of 
human subjects (developed and implemented by the Northwestern and PENN IRBs), and undergo training. 
The Data and Safety Monitoring Board (DSMB)
A DSMB will convene regularly for this study. The DSMB will consist of a physician (Michael Fleming, M.D., 
Department of Psychiatry and Behavioral Sciences), a behavioral scientist (Matthew Smith, Ph.D., Department 
of Psychiatry and Behavioral Sciences), and a biostatistician (Juned Siddique, DrPH., Department of 
Preventive Medicine). The primary concern of the DSMB will be the monitoring of side effects in placebo vs. 
varenicline groups. The DSMB will meet every 6 months to review accrual, retention, and side effect and AE 
reports. The study biostatistician (George Papandonatos, Ph.D.) will present unblinded data to the DSMB to 
determine if unacceptable side effects are occurring. The DSMB can request additional data or recommend 
trial suspension. We are using a DSMB and the current DSM plan in our ongoing varenicline trial 
(R01CA165001). 
Details of the DSMB meetings are as follows:

Data and safety monitoring will be performed on an ongoing basis by the DSMB led by a Northwestern 
biostatistician unaffiliated with the project and by study personnel and the site IRBs. The chair of the 
DSMB and the DSMB committee will review the trial data as described below. The DSMB will consist of 
three members: a biostatistician (Dr. Jovanovic), who will serve as DSMB chair, a physician (Dr. 
Fleming), and a behavioral scientist (Dr. Smith). The DSMB will meet twice per year to review data 
concerning recruitment, randomization, retention, compliance, form completion, gender and minority 
inclusion, intervention effects, and safety. In addition, the DSMB will: 1) identify specific safety concerns 
for participants and communicate these to the study PI; 2) consider the need for additional data 
concerning participant safety; 3) consider the rationale for the continuation of the study; 4) provide a 
written report concerning the protocol to the IRB and to the study PI; and 5) review manuscripts 
reporting study results prior to submission.  

The following will be reviewed at the DSMB meeting and included in the report which will be compiled 
following DSMB meetings and then updated at the trial’s conclusion: 1) brief description of the trial; 2) 
baseline sociodemographic characteristics; 3) accrual, retention and disposition of study participants 
(recruitment versus goal, withdrawal rate); 4) quality control issues (assessment of randomization 
procedures, including stratification); 5) regulatory issues (review of protocol changes); 6) side effects by 
treatment arm (overall and by site); 7) serious adverse events by treatment arm (overall and by site); 
and 8) efficacy.
Structure of DSMB meeting. Each meeting will consist of three parts. First, an open session will occur in which 
the Dr. Hitsman and the DSMB will review the conduct of the trial (e.g., accrual, protocol compliance, general 
toxicity). Second, to maintain the study blind, a closed session involving only the DSMB and Dr. 
Papandonatos, the study biostatistician, will be held during which he will present side effect results to the 
DSMB as requested. A report of unblinded side effects results will be prepared; however, it will only be 
presented if specifically requested by the DSMB. This will focus on the presentation of the rate of increase in 
any side effect from baseline to a follow-up across treatment arms. Finally, an executive session involving only 
DSMB members will be held to allow the DSMB the opportunity to discuss the conduct of the trial and 
outcomes, including toxicities and adverse events, develop recommendations, and take votes as needed. The 
DSMB written recommendations will be provided to Dr. Hitsman and to the IRBs. The DSMB will summarize 
AE reports for Dr. Hitsman and the IRB chair, and Dr. Hitsman must implement any DSMB recommendations 
expeditiously. All DSMB recommendations will also be forwarded to the NIH and the FDA (where necessary).
RETAIN Sub-Study DSMB.
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Ongoing oversight of the RETAIN sub-study is provided by a DSMB committee, whose members are: Jennifer 
S. Blumenthal-Barby, PhD (Chair, Associate Professor of Medicine and Medical Ethics, Baylor College of 
Medicine), Salma Jabbour, MD (Associate Professor, Department of Radiation Oncology, Robert Wood 
Johnson Medical School, Rutgers Cancer Institute of New Jersey), Brenda F. Kurland, PhD (Research 
Associate Professor, Biostatistics, University of Pittsburgh, Graduate School Public Health), Jeffrey M. 
Peppercorn, MD, MPH (Associate Professor, Medicine, Harvard Medical School), and Kim Vernick (Patient 
Advocate). 
The RETAIN PI (Scott Halpern), assisted by the PENN project manager (Jackie McMahon), will be responsible 
for maintaining communication between the DSMB and the individual project staff for all RETAIN-related 
activities.  The DSMB will be responsible for monitoring the trial and making decisions about the termination of 
individual study arms or the study itself. The DSMB will review and approve the research protocol. They will 
also assess the progress of the trial, including the assessment of data quality, participant recruitment, accrual 
and retention, participant risk versus benefit, and study outcomes.  
Data Management System (DMS)
The Northwestern database manager will oversee the DMS for this trial and direct the Northwestern DMS to 
link with PENN. MS ACCESS permits real-time data entry, storage, and QA by NU secured network remote 
access and scannable forms, which increase standardization across personnel. This system is being used in 
our ongoing varenicline trial of smokers with cancer (R01CA165001/STU00064871). The DMS generates 
database tables in a NIH-compliant format, constructs semantic constraints on fields, and is used for data 
entry, storage, retrieval, and security. The DMS uses session dates to describe procedures and measures to be 
ascertained. The DMS mimics the appearance of CRFs completed at sessions. During data entry, validation 
occurs via the following procedures: 1) Variable type checks - variables defined as specific type, e.g., integer, 
and entry is restricted to type; 2) Range checks - entry of data outside a range is rejected; 3) List of possible 
values checks - value of data is checked against acceptable values; 4) Internal logical consistency checks - 
dependent fields are logical (e.g., study entry date occurs after birth date); 5) Data completeness checks - data 
inspected for completeness; and 6) Duplicate record checks - data are inspected to prevent duplication. Daily 
backups occur to protect against accidental corruption or deletion. We compare 100% of hard copy to computer 
data. Protection of participant privacy is accomplished by minimizing use of identifying information, use of ID 
numbers rather than participant names, keeping all data in locked files, and limiting access to the dataset that 
links participant names with ID numbers strictly to the study biostatistician.
RETAIN Sub-Study Data Management
All RETAIN survey data will be managed in REDCap (Research Electronic Data Capture), a secure data 
management system available at both PENN and NU. Questionnaire measures will either be entered into 
REDCap directly by participants (i.e., at the in-person intake session), or completed via pen and paper 
questionnaires and entered into REDCap by study staff. The RETAIN Project Data Managers will maintain the 
database with oversight from key study personnel.
All datasets and computer files and study ID numbers will be further secured as follows. We will implement 
multiple, redundant protective measures to guarantee the security of participant data. All data for this project 
will be stored on the secure/firewalled servers of the Center for Clinical Epidemiology and Biostatistics (CCEB). 
These data servers are maintained in a guarded facility behind several locked doors, with very limited physical 
access rights. They are also cyber-protected by extensive firewalls and multiple layers of communication 
encryption. Electronic access rights are carefully controlled by Penn system managers. We will use highly 
secure methods of data encryption for all transactions involving participants’ financial information, such as W-9 
forms, using a level of security comparable to what is used in commercial financial transactions. This multi-
layer system of data security, identical to the system protecting the University of Pennsylvania Health System’s 
medical records, greatly minimizes privacy risks. 
Only authorized personnel will have access to the data. All of these personnel will have completed research 
and confidentiality training (specifically, CITI training). Through REDCap, each study subject will be given a 
IRB #: STU00100303 Approved by NU IRB for use on or after 9/9/2019 through 9/8/2020.


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unique study identification number (ID). By default, all direct identifiers will be omitted from data extracts, and 
the study ID will be used exclusively in all analytical files.
STATISTICAL CONSIDERATIONS
Power
To address hypotheses related to Aims 1-3, we base our estimates upon the Anthenelli et al. trial (2013) and 
the study by MacPherson et al (2010) that randomized 68 smokers with elevated depressive symptoms (BDI-II 
scores ≥10) but no current MDD to 8 weeks of treatment with either behavioral activation (BA) or standard 
behavioral treatment (BT). At 26-weeks post-TQD, bioverified 7-day point-prevalence abstinence rates were 
14.3% for BA (n=35) and 0% for BT (n=33). In the Anthenelli et al. trial (2013), smokers with current or past (≤2 
years) MDD received 12 weeks of varenicline or placebo. Bioverified 7-day point-prevalence abstinence rates 
at 24 weeks were 31.3% for varenicline (n=256) and 18.2% for placebo (n=269). Based upon our conceptual 
model of the therapeutic targets of BASC and varenicline individually, we predict that there will be a synergistic 
effect of combination treatment with BASC and varenicline on abstinence (see Figure 2). Assumed 7-day point 
prevalence abstinence rates at 24-weeks post-TQD in our 2x2 design are presented in Table 3, under an ITT 
approach that considers participants lost to follow-up as treatment failures. A minimum of N=128 participants 
be assigned to each psychological treatment group (BASC, ST) receiving placebo, while a minimum of N=160 
participants be assigned to each psychological treatment group (BASC, ST) receiving varenicline. 
Such a sample configuration (N=576 total) guarantees at least 85% power for testing each of the three 
pairwise comparisons of interest in Primary Aim 3: BASC + varenicline vs. ST + varenicline (42% vs. 24% 
abstinence, power = 85%), BASC + varenicline vs. BASC + placebo (42% vs. 18% abstinence, power = 98%), 
and BASC + varenicline vs. ST + placebo (42% vs. 5% abstinence, power > 99%) at a multiplicity-adjusted 
significance level alpha=.053 =.0167. 
This equates to enrolling about 12 
participants per month (6/month/site) 
over the 48 month recruitment period. 
Further, it guarantees 91% power for 
testing the efficacy of BASC vs. ST 
(18% vs. 5% abstinence) among the 
N=256 participants receiving placebo (Primary Aim 1), and power in excess of 99% for testing the efficacy of 
varenicline vs. placebo (24% vs. 5% abstinence) among the N=288 participants receiving ST (Primary Aim 2) 
when the significance level for these tests is fixed at alpha=0.05. Aim 2a will be tested based on a non-
inferiority approach that seeks to establish the maximum increase in the moderate-to-severe AE rates 
(individual, total) in the varenicline arm relative to that in the placebo arm consistent with rejecting at alpha=.05 
the one-sided null hypothesis that the true varenicline vs. placebo AE Rate Ratio (RR) exceeds 1.25 
(Hauschke, Kieser, Diletti, & Burke, 1999). Assuming a 67% AE rate in the placebo arm, we have 84% power 
to establish non-inferiority, provided that the AE rate in the varenicline arm does not exceed 72%. That is, we 
need a true RR <1.075 (72% vs. 67%) to have an 84% chance of observing a sample RR small enough to lead 
to a rejection at alpha=.05 of the null hypothesis that the true RR>1.25. 
Regarding Secondary Aim 1 (Mediation), Fritz and MacKinnon (2007) present sample size requirements for a 
variety of mediation scenaria, assuming a continuous mediator (e.g., change in hedonic capacity) and a 
continuous dependent variable (e.g., change in cigarette reward value). With the exception of a rather unlikely 
complete mediation scenario, under which the entire effect of treatment assignment occurs through differences 
in hedonic capacity, the sample size required for 80% power at the 5% significance level was N=562 provided 
that 1) the main effect of treatment assignment on hedonic capacity, and 2) the effect of hedonic capacity on 
cigarette reward value each explain only 2% of the variance in the respective normal regression models, 
corresponding to “small” effects in Cohen’s nomenclature (Frandsen, Walters, & Ferguson, 2014). This is 
below N=576, suggesting adequate power for detecting mediation of proximal continuous outcomes. For the 
more distal outcome of abstinence (yes/no), the Fritz & MacKinnon (2007) method can still be used, provided 
our effective sample size is adjusted downwards to reflect loss of information due to dichotomization (Gibbons 
& Mann, 2013). Results suggests that detecting mediation of treatment effects on abstinence rates will be more 
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challenging, and will require effects of changes in cigarette reward value on smoking abstinence to be in the 
“medium-to-large” range instead.
Data Analysis
Preliminary analyses will assess sample characteristics by treatment with chi-square or logistic regression 
(tobacco dependence, use of antidepressant medication, number of past depressive episodes, and number of 
other Axis I disorders). These variables will also be examined for their relationship to completion of outcome 
assessments. Variables related to treatment arm and completion of follow-ups will be included as covariates in 
analyses of study aims. Treatment compliance measures (psychological treatment sessions, medication) will 
be evaluated across treatment arms, and controlled for in primary analyses.
Primary Aims 1-3: Outcome Analyses
The primary outcomes will be 7-day point prevalence abstinence at week 27 (24-weeks post-TQD; self-
reported abstinence for 7 days prior to the assessment and breath CO <8 ppm) and AE rates. CO-verified 7-
day point prevalence abstinence at weeks 7 and 14 (4- and 10-weeks post-TQD, respectively) will be 
secondary measures. As per guidelines (Hughes et al., 2003), secondary outcomes at 24-weeks post-TQD will 
include: prolonged abstinence (relapse defined as 7 consecutive days of self-reported smoking after a 2-week 
grace period), continuous abstinence (no smoking between TQD and follow-up), and time to 7-day relapse. 
Other than time to relapse, all outcomes of interest are binary (abstinence and AE rates) and will be analyzed 
using logistic regression. The effect of varenicline on AE rates (Primary Aim 2a) will be based upon the union-
intersection test arm for establishing non-inferiority in the proportion of participants experiencing moderate to 
severe AEs in the varenicline vs. the placebo arm (Hauschke et al., 1999). To ensure that tests on the overall 
sample do not mask differential effects by antidepressant medication use and type, these analyses will be 
preceded by a Breslow-Day for homogeneity across strata of interest. If no evidence of heterogeneity is found, 
stratum-specific estimates will be combined using a Cochran-Mantel-Haenszel weighing scheme (Wiens & 
Heyse, 2003). 
Missing Data Approaches 
Analyses of abstinence rates will be conducted first using an ITT principle, analyzing data from all participants 
randomized to treatment, counting those lost to follow-up as non-responders (missing=treatment failures). We 
will also conduct an adherence sample analysis that includes only participants reached at 24-weeks post-TQD 
(≥70% based on our experience). This approach addresses the question of efficacy more directly, but it is 
subject to more bias if attrition is large or differential by treatment arm. Consequently, we will complement it by 
analysis of non-response patterns using sociodemographic (gender, race, education), smoking (tobacco 
dependence), and psychiatric characteristics (number of lifetime MDEs, current use of psychotropic 
medication, presence of other Axis I diagnoses). These analyses will be used to create propensity scores that 
will allow for inverse-probability-weighing (IPW) of observed outcomes (Cole & Hernan, 2008; Robins, 
Rotnitzky, & Zhao, 1995) to achieve balance across potential confounders of the treatment-to-outcome 
relationship. The distribution of propensity scores should show large overlap across study arms. If not, that will 
be taken as evidence that study completers are not comparable on measured confounders, and that one 
should refrain from further treatment comparisons. Similar findings across all 
three approaches would increase confidence in the results overall. Both raw 
and adjusted rates will be presented for each outcome by study arm. Time 
to 7-day relapse will be evaluated using discrete-time survival models 
(Singer & Willett, 1993), as implemented in PROC LIFEREG of SAS/STAT 
9.2 (SAS Institute, 2009). 
Secondary Aim 1: Mediator Analyses
Secondary Aim 1 hypothesizes that increases in hedonic capacity and 
cognition will mediate the effects of BA plus varenicline on bioverified 7-day 
point prevalence abstinence at 24-weeks post-TQD for participants assigned to the varenicline arm alone. This 
outcome is expected to be achieved via the individual and combined effects of BA and varenicline on lowering 
cigarette reward value, with additional effects on abstinence via reductions in cigarette craving and tobacco 
withdrawal, particularly the anhedonia, depressed mood, and cognitive impairment components. For simplicity 
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of exposition, we present only part of the full mediation model in Figure 4. Here X is the exogenous variable 
(treatment), Z is a putative mediator (e.g., hedonic capacity), and Y one of the two intermediate outcomes 
(e.g., cigarette reward value). To aid interpretation of the regression coefficients as partial correlations, both Z 
and Y (or any normalized transformations thereof) will be standardized to zero mean and unit variance.
We will establish mediation of treatment effects on this intermediate outcome (e.g., cigarette reward value) 
using MacKinnon’s (2008) approach which is more powerful than Baron and Kenny’s causal-steps method 
(Baron & Kenny, 1986). As explained in Cerin and MacKinnon (2009) and successfully implemented by 
Papandonatos et al. (2012) researchers ought to determine whether: 1) the intervention successfully acted 
upon the putative mediator (i.e., “Action Theory test”); 2) changes in the mediator were predictive of changes in 
the target construct/behavior suggested by the conceptual framework underpinning the intervention (i.e., 
“Conceptual Theory test”) over and above any direct treatment effects; and 3) these conditions held 
simultaneously for the putative mediator of interest (i.e., “Mediation test”). Let the regression path coefficients 
between treatment and mediator (action path), mediator and outcome (theory path), and treatment and 
outcome controlling for the effect of the mediator (outcome path) be denoted by a, b, c’ respectively. 
Successful mediation through changes in hedonic capacity requires that the 95% confidence interval for the 
a*b product of path coefficients (which equals c-c’ for continuous outcomes) includes zero. To accommodate 
skewness and kurtosis, interval estimation will be based upon bias-corrected and accelerated (BCA) bootstrap 
confidence intervals (Preacher & Hayes, 2008).
Figure 4 is based upon a simplified 2-group comparison (e.g., with X as an indicator of treatment assignment to 
BA over ST). In reality, treatment assignment will be coded using three contrasts corresponding to the main 
effects of the psychological and pharmacological treatment components and their interaction, so as to 
accommodate the hypothesized moderation of the path between hedonic capacity and cigarette reward value 
by varenicline (Preacher, Rucker, & Hayes, 2007). Simultaneous estimation of the effect of multiple mediators 
(e.g., hedonic capacity and cognition) will be conducted as in Napolitano et al (2008). Once mediation of the 
intermediate outcome (cigarette reward value) has been modeled as described above, we will estimate the 
remaining paths linking intermediate outcomes (cigarette reward value, craving/withdrawal) to the distal 
outcome (abstinence) via logistic regression. Although we see value in building the model in a piecewise 
fashion (e.g., in terms of evaluating the need to adjust for potential confounders of the treatment to outcome 
relationship), we will also estimate the full model in Figure 2 in a single step using the structural equation 
modeling (SEM) package Mplus 6.0 (Muthén & Muthén, 1998-2010), which allows the user to assess the 
statistical significance of any complete mediation path via bootstrapping. One important consideration is the 
choice of measurement points at which to assess the mediators to maximize intervention effects while also 
preserving the temporal precedence between mediator and outcome. Because all putative mediators follow an 
intensive measurement schedule, we will be able to estimate their longitudinal trajectories precisely, and will 
identify appropriate turning points at which the treatment effect is maximized. 
RETAIN Sub-Study Analyses
Randomization
Participants will be randomized to the 3 experimental arms ($0, $200, $500) in equal, 33.3% probabilities. A 
Penn analyst will use the REDCap randomization module to implement block randomization stratified by
phone screeners across the two sites. The trial’s primary statistician on the Penn research staff will create a 
block randomization scheme for each screener and will upload a CSV file of each block assignment to the 
REDCap randomization module.  The screener will select his or her name via the REDCap software through 
an initialization step and will immediately receive the randomization assignment for that participant. This will 
allow the screener to immediately present the participant with the correct incentive amount, and subsequently 
present the correct paper informed consent form at the intake visit. 
Analytic Strategy
In Secondary Aims 2 and 2a of the trial, we will assess bivariate relationships of incentives with the outcomes 
described above using t-tests or Wilcoxon rank-sum tests for normally and non-normally distributed continuous 
variables, and chi-square tests for comparisons of proportions. To examine the hypothesized statistical 
interactions, we will use logistic, linear, or quantile regression, as appropriate based on outcome 
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parameterizations and distributions. For all outcomes other than tests for undue or unjust inducement, we will 
adjust significance levels for multiple comparisons using the Sidak-Holm method.
In all analyses, we will model the center from which patients are recruited as a fixed effect, thereby mitigating 
confounding by center and adjusting variance estimates for clustering of participants within centers.  To adjust 
for chance covariate imbalance among arms, we will include covariates in multivariable models if they are 
significantly associated with the intervention arm and predictive of enrollment in the smoking cessation study in 
bivariate analyses. We will explore temporal trends in incentives’ effects over the study period using stratified 
analyses. If temporal trends are noted, as may occur if prospective patients learn of the incentives study, we 
will adjust for their influence by entering time as a covariate, modeled as a spline.
Our analyses to rule out undue and unjust inducements entail three primary covariates. All models will have 
the primary outcome of enrollment in the parent RCT as the outcome. First, to determine whether incentives 
represent undue inducements for research participation, we will test the statistical interaction between 
incentive size and the primary covariate of risk perception on the outcome of enrollment in the parent RCT.  
Second, to determine whether incentives represent unjust inducements for research participation, we will test 
two interactions, each in a separate model to avoid collinearity: that between incentive size and the primary 
covariate of annual household income, and that between incentive size and the primary covariate of economic 
well-being. 
Analyses of these interaction terms will be structured as tests of non-inferiority, such that the null hypotheses 
are that incentives do meet criteria for undue or unjust inducement, and we reject the null, and conclude the 
absence of undue or unjust inducement, if the interaction terms are “small” according to pre-specified criteria 
(in technical terms, the inferiority margin). Said a different way, our analyses our designed to determine 
whether we can exclude the possibility that incentives represent undue or unjust inducements if the resulting 
interaction terms are sufficiently small. Specifically, we will use one-sided alpha levels of 0.05 to exclude, with 
95% confidence, the possibility that any of these interaction odds ratios are >2.0.  
Secondary Aim 2b explores the incremental cost-effectiveness of using research incentives to recruit a fixed 
sample size from the perspective of the research sponsor and investigators. We define the incremental cost-
effectiveness ratio (ICER) as the incremental costs of conducting the trial with vs. without a given incentive (or 
with one incentive vs. another), divided by the time saved in the presence of the incentive or larger incentive. 
We will evaluate 3 specific ICERs: (i) $500 vs. $0, (ii) $200 vs. $0, and $200 vs. $500. Relevant costs to be 
analyzed include the total costs of the incentives themselves (the incentive amount multiplied by the number of 
patients receiving it) and the costs of conducting the RCT for sufficiently long to recruit that number of patients. 
These latter costs include, for example, the costs of direct recruitment activities such as mailings, 
advertisements, and phone charges, and the duration of salary and benefits support needed for relevant study 
personnel. 
CONFIDENTIALITY
All participant information will be kept in a secure filing cabinet that is accessible only to authorized study 
personnel. All databases containing participant information will be password protected, and again, accessible 
only to authorized study personnel on NU’s password-protected and encrypted network. Prior to access to any 
study-related information, personnel will be required to sign statements agreeing to protect the security and 
confidentiality of identifiable information. Each participant will have a unique study ID number for all data 
collected. In all datasets, we will use ID numbers only. A separate data set linking names with ID numbers will 
be accessible only by the study biostatistician. All communications about participants will use the ID number 
only and never include names or other personal information. All data will be stored until all analyses are 
completed. No data will be shared with any unauthorized party (i.e., aside from study personnel and regulatory 
officials). Any publication of data will not identify subjects by name or with an identifier that could be used to 
reveal identity. Data will be accessible to the study PIs (lead and PENN site PI), co-investigators, the study 
physician, other study staff, and the Northwestern and PENN IRBs and their Offices of Human Research.
Protected Health Information (PHI)
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The following PHI will be collected as part of this study:

Name, address, telephone number

Email address

Date of birth

Social Security Number (PENN site only)

Some personal information that may be considered sensitive, such as medical history, psychological history, 
alcohol and other substance use history, etc. 

Results from physical examinations, tests or procedures

Medical record number
Precautions, as described above, will be taken to ensure that the privacy of subjects’ personal health 
information will be maintained. 
PARTICIPANT COMPENSATION
Main Trial
Participants will be compensated for their time up to a maximum of $140 (see Table 5). Participants will also be 
reimbursed for transportation expenses related to their participation in the study with $10 for each clinic visit 
(up to $60). The Northwestern site will provide compensation in cash for all sessions (except the Week 27 
phone session). The PENN site will provide compensation in cash at the intake visit, but all other visits will be 
compensated using a Greenphire ClinCard, which is a reloadable, pre-paid card. Compensation will be loaded 
onto the ClinCard at the end of successfully completed visits. Participants will be issued the ClinCard at Pre-
Quit 1. Participants at the Northwestern site will receive compensation for achieved phone sessions at the next 
clinic visit , and participants at the PENN site will receive compensation within 24 hours of an achieved phone 
session on the ClinCard. Participants who complete the week 27 phone session but report that they are 
currently smoking will not be eligible to come in for the week 27 clinic visit. To reimburse these participants for 
completing the week 27 phone session at the Northwestern site, an electronic gift card to the retailer of their 
choice (e.g., Target, Walmart, Amazon.com) will be sent to the participant’s email and activated through the e-
voucher link provided in the email. To reimburse these participants at the PENN site, $10 will be loaded onto 
the ClinCard.
Table 4. Participant Compensation
Study Session
Session 
Travel/Parking 
Intake Session (Week 0)
$15
$10
Week 1 (Pre-Quit 1; Clinic)
$15
$10
Week 2 (Pre-Quit 2; Phone)
- (No assessment)
-
Week 3 (Target Quit Day)
$10
$10
Week 4 (Phone)
$10
-
Week 6 (Phone)
$10
-
Week 7 (Clinic)
$15
$10
Week 8 (Phone)
$10
-
Week 10 (Phone)
$10
-
Week 12 (Phone)
$10
-
Week 14 (Clinic)
$15
$10
Week 27 (Phone)
$10
Week 27 (Clinic)
$10
$10
                                 
$140
$60
                       Total: $ 200 
RETAIN Sub-Study
Participants who are eligible for the RETAIN sub-study at phone screen but are not enrolled in the main trial 
will not receive any RETAIN sub-study compensation. Participants who complete all RETAIN sub-study 
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procedures will receive two installments of $150 each following the Intake and Week 27 study sessions, for a 
total payment of $300. This payment will be made in the form of a stored value payment card, with oversight 
from the Penn RETAIN study team. During the debriefing session, research staff will explain that all RETAIN 
sub-study participants receive a $300 payment, regardless of what was stated in the Informed Consent Form. 
 
INFORMED CONSENT
Main Trial
Fully trained research personnel will obtain informed consent using the combined consent and HIPAA form 
approved by the Northwestern and PENN IRBs. The consent process will take place before study data are 
collected and prior to any treatment. Consenting will occur in person at the start of the intake session and will 
involve a one-on-one discussion of the study requirements and procedures and an opportunity for participants 
to ask questions and express concerns. The participants will receive a copy of the combined consent and 
HIPAA form for their records. In addition, the participants will be given the PI and study physician’s contact 
information should they wish to speak to either of them during the course of the study regarding their consent 
or the study procedures. The consent process will take place in English, there will be no waiting period, no 
coercion to participate, and all participants will be considered competent to provide informed consent (i.e., they 
will be asked if they understand to what they are consenting).
RESOURCES AND STUDY MANAGEMENT FOR HUMAN SUBJECTS PROTECTION
Qualifications of PIs
Brian Hitsman, Ph.D. (Lead PI, Northwestern University) 
Dr. Hitsman is a clinical psychologist and assistant professor in the Departments of Preventive Medicine and 
Psychiatry and Behavioral Sciences. His research focuses on the causes and treatment of tobacco 
dependence in underserved populations, especially among persons with mental health disorders. Dr. Hitsman 
has been involved in clinical trial research since 1993 in large efficacy and effectiveness studies of combination 
behavioral therapy and pharmacotherapy (fluoxetine, bupropion, varenicline, nicotine patch). An ongoing NCI-
funded trial being conducted in collaboration with Dr. Schnoll involves extended duration treatment with 
telephone-based behavioral therapy and nicotine patch or varenicline. Dr. Hitsman served on the 2005 NIMH 
Tobacco Use and Cessation in Psychiatric Disorders Workgroup that led to a comprehensive review of 
smoking behavior and tobacco dependence in persons with mental health disorders, including major 
depressive disorder (MDD), and established a comprehensive research agenda that continues to be highly 
relevant today. Finally, Dr. Hitsman was a contributing author of the 2010 Surgeon General’s Report on How 
Smoking Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease (Nicotine 
Addiction: Past and Present) and serves as a Deputy Editor of Nicotine & Tobacco Research. 
Robert Schnoll, Ph.D. (Clinical Site PI, University of Pennsylvania) 
Dr. Schnoll has conducted numerous randomized clinical trials of treatments for nicotine dependence and co-
directed a career development core facility for the NIH-funded Center for Interdisciplinary Research on Nicotine 
Addiction (CIRNA). Over the past decade, Dr. Schnoll has developed behavioral interventions for nicotine 
dependence and completed randomized clinical trials of behavioral and pharmacological interventions for 
nicotine dependence among the general population of smokers and among cancer patients, many times in 
collaboration with Dr. Hitsman. Dr. Schnoll has served as a co-investigator on an American Cancer Society-
funded randomized clinical trial of a behavioral intervention for nicotine dependence among pregnant smokers 
and completed a bupropion clinical trial, stratified by depression, for nicotine dependence among cancer 
patients. Dr. Schnoll has ongoing varenicline trials with cancer patients and smokers with HIV/AIDS. Dr. 
Schnoll has served as Program Chair for the Society of Research on Nicotine and Tobacco annual meeting 
and as Chairperson for the Risk, Prevention, and Intervention for Addiction NIH Study Section. 
Other Members of the Research Team
The following people will be directly involved with study implementation and execution:  
Northwestern
1.
Mark Huffman, M.D., Lead study physician and co-investigator 
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2.
Jacqueline Gollan, Ph.D., Lead psychologist and co-investigator
3.
David Mohr, Ph.D., Co-investigator
4.
Nancy Jao, M.S., Graduate research assistant
5.
Allison Carroll, M.S., Graduate research assistant
6.
Celine Reyes, M.A., Research Study Coordinator
7.
Erica Fox, B.S., Research Assistant
8.
Sue Giovanazzi, Research clinic manager
9.
Ravi Kalhan, M.D., alternate study physician when Dr. Huffman is unavailable
10. Charles Culpepper, M.S., Study Therapist
11. Matthew Olonoff M.A., Graduate Research Assistant
14. Amanda Mathew, Ph.D., Research Assistant Professor
15. Sadiya Khan, M.D., MSc, Study Physician
PENN
1.
Scott Halpern, M.D., Ph.D., Co-investigator and PI, RETAIN Sub-Study
2.
Frank Leone, M.D., Site physician and co-investigator 
3.
Anita (Annie) Hole, Ph.D., Site psychologist and co-investigator
4.
Janet Audrain-McGovern, Ph.D., Co-investigator
5.
Michael Thase, M.D., Site physician
6.
Su Fen Lubitz, B.A., Clinical Research Coordinator
7.
Alex Flitter, M.A., Clinical Research Coordinator
8.
Joseph Bastian, B.A., Research Assistant
9.
Anna-Marika Bauer, B.A., Research Assistant
10. Nathaniel Stevens, Research Assistant
11. Mackenzie Quinn, B.A., Research Assistant
12. Sue Ware, B.S., Database Manager
13. Paul Sanborn, M.S., Samples Manager
14. Tierney Fisher, N.P., Site Nurse Practitioner
15. Elizabeth Cooney-Zingman, M.P.H, RETAIN, Chief of Staff
16. Brian Bayes, M.S., Sc.B., RETAIN Study Data Manager
17. Marzana Chowdhury, Ph.D., RETAIN Statistical Analyst
18. Dominique Spence, Phlebotomist
19. Morgan Thompson, B.A., Phlebotomist
20. Katrina Serrano, B.A., Phlebotomist
21. Molly Ruben, M.P.H, Phlebotomist
22. Erin Louge-Chamberlain, B.A., Phlebotomist
Brown University
George Papandonatos, Ph.D., Biostatistician and co-investigator
Legacy Foundation
Raymond Niaura, Ph.D., Co-investigator 
Training and Quality Assurance
Drs. Hitsman and Schnoll currently collaborate on an ongoing efficacy trial of extended duration varenicline 
with cancer patients (R01CA165001) and a recently completed effectiveness trial of long-term nicotine patch 
therapy (R01DA025078). The PIs have >15 years of experience coordinating multi-site smoking cessation 
trials involving extensive data collection, counseling, and pharmacotherapy. Thus, systems for training and QA 
are established to ensure accurate eligibility screening and recruitment, accurate data collection, entry, and 
management, and optimal protocol delivery. A new Manual of Operations (MOP) will be developed. Training 
sessions will occur at both sites and annually as needed. Monthly conference calls will review progress, assess 
adherence, and determine the need for protocol changes or additional training and QA. The MOP will ensure 
that the trial is conducted uniformly across sites. The MOP will describe responsibilities for all personnel and 
provide a detailed description of procedures for each point of contact with participants (i.e., for each Week in 
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Table 1). For each visit/week, a checklist of events (e.g., each measure, therapy) will be created that will be 
completed by personnel. CRFs will be created for each measure at each week, and every participant will have 
a study chart, with sections for every visit/week. Every visit is “milestoned” (e.g., attended, missed, scheduled) 
in the trial database to ensure subject tracking through the trial. Drs. Hitsman, Schnoll, Gollan and Hole have 
developed the BASC and ST therapy manuals for training. Lastly, a manual for data collection and entry is 
developed. We will use a server-based DMS, already in use at Northwestern, which allows for real-time, 
remote data entry using scannable forms. All training will involve didactic instruction, mock sessions, and 
feedback in the MOP, assessment of eligibility and side effects, therapy, and the DMS by Drs. Hitsman, 
Schnoll, Gollan, Hole, Huffman, Thase, and Leone. QA focuses on protocol adherence and data validity. We 
will conduct 100% QA by comparing all hard copy and computer data. We also will audio-record all therapy 
sessions and assess protocol adherence by selecting a random 15% of sessions for review.
REFERENCES
Acton, G. S., Prochaska, J. J., Kaplan, A. S., Small, T., & Hall, S. M. (2001). Depression and stages of change 
for smoking in psychiatric outpatients. Addict Behav, 26(5), 621-631. 
American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th Ed.). 
Washington, DC: American Psychiatric Association.
Anthenelli, R. M., Benowitz, N. L., West, R., St Aubin, L., McRae, T., Lawrence, D., . . . Evins, A. E. (2016). 
Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and 
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MacPherson, L., Tull, M. T., Matusiewicz, A. K., Rodman, S., Strong, D. R., Kahler, C. W., . . . Lejuez, C. W. 
(2010). Randomized controlled trial of behavioral activation smoking cessation treatment for smokers with 
elevated depressive symptoms. J Consult Clin Psychol, 78(1), 55-61. doi:10.1037/a0017939
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Nicotine & Tobacco Research, 10(12), 1691-1715. doi:10.1080/14622200802443569
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ICF_001.pdf: 
Version Date: V16 – August 21, 2019
Permission to Take Part in a Human Research Study
Do not sign this consent if today’s date is later than the stated expiration date above.
Page 1 of 18
Northwestern University 
Department of Preventive Medicine
Consent Form and HIPAA Authorization for Research
TITLE OF RESEARCH STUDY: Behavioral Activation and Varenicline for Smoking Cessation in 
Depressed Smokers
 
INVESTIGATOR: Brian Hitsman, PhD 
SUPPORTED BY: National Cancer Institute
Key Information: 
The first few pages of this document include a summary of this study to help you decide 
whether or not to participate. Detailed information is provided after the summary.
Why am I being asked to take part in this research study?
We are asking you to take part in this research study because you are a smoker, have expressed an 
interest in quitting, have experienced symptoms of major depressive disorder, and meet the initial 
eligibility requirements of the study.
What should I know about a research study?

Someone will explain this research study to you.

Whether or not you take part is up to you.

You can choose not to take part.

You can agree to take part and later change your mind.

Your decision will not be held against you.

You can ask all the questions you want before you decide.
Why is this research being done?
The main purpose of this research study is to compare traditional behavioral smoking cessation 
therapy with a different type of behavioral treatment, behavioral activation for smoking cessation. The 
study will also compare the use of varenicline, also known as Chantix® (study drug), with both forms 
of behavioral therapy. Half of the participants who enroll in the study will receive active Chantix®  
medication and the other half will receive a placebo, or inactive “sugar” pill. The study will compare 
smoking and quitting behavior between all possible combinations of the two behavioral therapies and 
two medication groups. There are four different treatment group possibilities to which you could be 
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randomized. We will compare the rate of quitting smoking across all four groups at the end of 
treatment (study week 14), and 14 weeks after the end of treatment (study week 27). 
How long will the research last and what will I need to do?
We expect that you will be in this research study for about 28 weeks. 
You will be asked to proceed through today’s intake session. The intake session is necessary to make sure 
it is safe for you to participate. If at the end of today’s visit you are eligible to participate, you will be 
asked to complete up to 12 additional sessions over a 7-month period. While enrolled in this research 
study, you will also be asked not to use any smoking cessation treatment (including medication or 
behavioral therapy) other than that which is provided to you within the context of this clinical study. If 
you have used smoking cessation aids including bupropion (Zyban®) or the nicotine patch, you are 
asked not to use these during the study. You will be asked not to use other treatments for nicotine 
dependence, including nicotine patch, nicotine gum, nicotine spray, nicotine lozenge, and nicotine 
inhaler. We also ask that you not use the e-cigarette while enrolled in this research study.  
More detailed information about the study procedures can be found under the section What happens 
if I say “Yes, I want to be in this research”?
Is there any way being in this study could be bad for me?
The risks from the study procedures include the following: 
Nicotine Withdrawal Syndrome: Most individuals who quit smoking experience symptoms of nicotine 
withdrawal. These symptoms can occur almost immediately and last for about 10-14 days. 
Varenicline (Chantix®): Like any medication, there is the possibility of experiencing drug side effects 
when taking Chantix. The most common side effects of Chantix® include nausea, sleep disturbance, 
constipation, flatulence (gas), or vomiting. Rare but serious mood-related effects have been reported in 
some patients taking Chantix®. These include, but are not limited to, suicidal thoughts or actions, new 
or worsening of mental health problems, and changes in emotional functioning or behavior. These 
events have occurred rarely in patients with and without pre-existing psychiatric disease. Other rare 
but serious potential side effects include allergic and skin reactions, such as swelling of the throat and 
tongue, increased risk of certain cardiovascular problems, particularly in patients with underlying 
cardiovascular disease, and seizures in those with and without a history of seizures. 
Assessments/Questionnaires and Smoking Cessation Therapy: Some people can experience anxiety 
and other types of general distress when they complete questionnaires and take part in smoking 
cessation therapy. This is generally related to your feelings about quitting as well as learning about 
some of the health risks associated with smoking. These reactions are usually very mild and typically 
diminish with time. The staff administering these questionnaires are trained to help you should you 
experience any concerns.
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Blood Drawing: Blood drawing may result in bruising and/or slight bleeding at the needle site. 
Occasionally, blood drawing may result in a feeling of faintness. These side effects are rare, so the 
chances of these discomforts are minimal. Sample collection will be conducted by study personnel 
trained in phlebotomy to reduce the risks of discomforts.
Data and Results: Because we want to protect your confidentiality, we will identify your results with 
an identification number only (not your name). Only authorized study personnel will be able to link 
your identification number with your name. 
Threats to Privacy/Confidentiality: Every attempt will be made by the investigators to maintain the 
strict confidentiality of all information collected in this study. We will store your information in a 
secure room with limited access. We will control access to the computer files that hold this 
information and all computers will be password protected. When the results of the study are published, 
no names or identifying information will be used.  
More detailed information about the risks of this study can be found under “Is there any way being in 
this study could be bad for me? (Detailed Risks)”
Will being in this study help me any way?
We cannot promise any benefits to you or others from taking part in this research. However, potential 
benefits include the opportunity to safely and effectively stop smoking with the support of 
professionals that are sensitive to your difficulties. Additionally, taking part in this study may help 
scientists better understand and handle the treatment of smoking cessation in people who also struggle 
with major depression.
What to do if you have suicidal thoughts or consider harming yourself.
Thoughts of suicide are a common symptom of major depressive disorder and indicate that what you 
are experiencing is more serious than just a “bad mood.” As part of our safety monitoring procedures, 
you will be assessed for suicidal thoughts, urges and intent to harm yourself during your intake session 
as well as at every session using the Columbia Suicide Severity Rating Scale. Study staff will ask you 
a number of detailed questions as part of this assessment.
It is very important that you discuss suicidal thoughts with us, as they are important for us to know 
about. In addition to discussing them with our research staff, it is important that you also contact either 
your mental healthcare provider or primary care physician as soon as possible. Study staff will inform 
you at each step of the way if you require additional assistance or treatment.
What happens if I do not want to be in this research?
Participation in research is completely voluntary. You decide whether or not to participate. If you 
choose to not participate, there will be no penalty to you or loss of benefit to which you are entitled.  
Instead of being in this research study, your choices may include other quit smoking studies at our 
center or other treatment studies located in the Chicagoland area that we can provide you information 
on.
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Detailed Information:
The rest of this document includes detailed information about this study (in addition to the 
information listed above).
Whom can I talk to?
If you have questions, concerns, or complaints, or think the research has hurt you, talk to the research 
team at (877)236-7487. 
Dr. Brian Hitsman is the person in charge of this research study. You can call his office phone (312-
503-2074) Monday through Friday between 9am and 5pm. If you are unable to reach him at his office, 
or if you have a question or encounter problems during evenings or weekends, you can call his cell 
phone (312-504-5834).
You can also call the study’s research coordinator, Celine Reyes (312 503-3098), with questions about 
this research study during normal business hours (Monday through Friday between 9am and 5pm).
This research has been reviewed and approved by an Institutional Review Board (IRB). You may talk 
to them at (312) 503-9338 or irb@northwestern.edu if:

Your questions, concerns, or complaints are not being answered by the research team.

You cannot reach the research team.

You want to talk to someone besides the research team.

You have questions about your rights as a research participant.

You want to get information or provide input about this research.
How many people will be studied?
We expect about 288 people here will be in this research study out of 576 people in the entire study 
nationally. 
What happens if I say “Yes, I want to be in this research”?
Study visits are described in more detail below.
Intake visit. This visit will last between two and two and a half hours and take place at our Preventive 
Medicine research clinic located at 680 N. Lake Shore Dr., Suite 1410, Chicago IL 60611. During this 
session, you will be asked to:

Complete the study informed consent and HIPAA form with a research staff member. You will 
have the opportunity to have your questions answered before signing the study consent and 
HIPAA form. If you chose not to sign this form, no procedures will be performed.

Provide a 30ml (2 tablespoons) urine sample that will be used to assess pregnancy (females 
only). A positive test will result in exclusion from the study. Results of this test is for study 
purposes only and the results will not be shared with anyone but you.

Complete a breath carbon monoxide (CO) assessment to measure your smoke exposure. 
Carbon monoxide is a poisonous gas that comprises less than 1% of the air we breathe and is 
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also produced through smoking a cigarette. Your CO levels provide an indication of how much 
cigarette smoke to which you have been exposed.

Provide one 5 ml (1 teaspoon) saliva sample to assess your rate of nicotine metabolism, or how 
quickly or slowly nicotine leaves your body.

Provide a 12.5 ml blood sample (about 2.5 teaspoons) to measure your cholesterol and glucose 
levels. 

Complete a psychiatric interview, during which we will ask you about any current and past 
depression symptoms as well as other emotional and behavioral symptoms.

Complete a routine medical history. You will have your blood pressure, vital signs, height, and 
weight measured. You will also be asked about your medical history and about any 
medications, including antidepressants, that you are currently taking or have discontinued 
within the last two months. Your smoking rate will also be assessed. 

Paper and pencil assessments of your demographics, alcohol and smoking history, caffeine use, 
smoking and health behaviors, and mood.
If you are eligible at the end of this visit, you will receive one of four treatments. This study is a 
randomized clinical study, which means that you will be assigned at random to receive one of these 
plans. Which treatment you receive will be based on chance, almost like flipping a coin. Neither you 
nor the researcher chooses your assigned treatment group. You will have an equal chance of receiving 
one of the following four treatment plans:
1. Behavioral smoking cessation therapy plus 12 weeks of active medication
2. Behavioral activation for smoking cessation therapy plus 12 weeks of active medication
3. Behavioral smoking cessation therapy plus 12 weeks of placebo medication
4. Behavioral activation for smoking cessation + 12 weeks of placebo medication 
Each of these treatments, even those involving placebo medication, is consistent with U.S. clinical 
treatment guidelines for tobacco use and dependence. Each participant will receive eight therapy 
sessions during the 12 weeks of treatment.
The study drug is approved by the U.S. Food and Drug Administration (FDA) for smoking cessation. 
The placebo pills look and taste just like the active medication but will contain no active ingredients.  
Researchers use a placebo to see if the study drug is safe and effective compared to not taking any 
medication. Neither you nor the research team will know which treatment group to which you have 
been assigned. You will begin your medication treatment plan at your second therapy visit.  
Week 1 Clinic Visit: Pre-Quit 1. This in-person assessment at our clinic (680 N. Lake Shore Dr., Suite 
1410, Chicago IL 60611) will last about 2 hours and 15 minutes. During Pre-Quit 1, you will:

Complete a carbon monoxide, blood pressure, and heart rate reading.

Complete a brief psychiatric interview, recent medical history review and assessments of 
medication use, height and weight, baseline side effects and smoking rate.

Complete paper and pencil assessments of your mood and smoking behavior.

Complete four brief computer-based tasks: 
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1.  A memory task during which you will see pictures of foods, animals, or both on the 
computer screen and then disappear. You will be asked to order them from smallest to 
biggest. This task takes about 6 minutes to complete. 
2. An attention task for which you will press the arrow key pointing the same direction as 
the arrow image in the middle of the screen. This task takes about 5 minutes. 
3. A task that measures your response to reward. You will look at a number of cartoon 
faces and will be asked to judge the length of their noses or mouths. You can win a small 
amount of money for each correct response you provide (up to $4.20 in total given in 
cash immediately after task completion). This task takes about 15 minutes to complete. 
4. A choice task that examines the relationship between cigarette cravings and mood, 
during which you will press a left or right arrow key to view 24 images of either 
chocolate or smoking after reading negative and positive emotional words. This task 
takes about 10 minutes to complete. 

Receive your first two blister packs of study medication (for study weeks 2-3) which will 
include pills and instructions on how the medication should be taken.

Receive a medical card that includes emergency contact numbers and other important 
information about this research study. 

Meet with a smoking cessation therapist to set your Target Quit Date (TQD) and confirm the 
time of your TQD clinic visit. 

Take part in your first 45-minute smoking cessation therapy session to help prepare you for your 
upcoming quit attempt.
All participants will take part in either traditional behavioral smoking cessation therapy or behavioral 
activation therapy for smoking cessation. In total, you will receive eight therapy sessions. All sessions 
will last 45 minutes. Sessions may be audio-recorded to ensure that the therapy is consistent for all 
participants within each of the two therapy groups. Each digital audio file will be password protected 
on a study computer that is also password protected. Only research study personnel will have access to 
the passwords. Audio files will be destroyed at the end of the study. 
Week 2 Phone Session: Pre-Quit 2. Pre-Quit 2 is a therapy-only session completed over the telephone 
that will last 45 minutes. It is designed to build on what you discussed during your first Pre-Quit visit 
about preparing for your target quit date. Your cessation therapist will review the medication and 
instructions on how the medication should be taken. Your therapist will also complete a brief mood 
check-in to make sure that you have not experienced any mood or depression medication changes 
since your last visit. 
You will begin taking the medication in pill form on the day of your scheduled Pre-Quit 2 session. If 
you are unable to complete the session by telephone on your scheduled day, you should still begin 
taking your medication. If you are unable to take your medication as scheduled, please inform the 
study staff as we will have to make adjustments to your study schedule based on your medication start 
date. 
You will continue taking the study drug until Week 13. Half of the participants will receive 12 weeks 
of active study medication. The other half of the participants will receive 12 weeks of placebo.  The 
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dosing schedule used in this research study is consistent with FDA guidelines: Day 1-3 (0.5mg once 
daily); Day 4-7 (0.5mg twice daily); and Day 8-84 (1.0mg twice daily). Extensive information about 
this medication will be provided and you will be contacted by phone two days after you begin taking 
your medication to discuss how it is going for you.
The medication will be packaged in weekly blister packs. Each blister pack will be labeled with clear 
instructions and dosage, and you will be given written instructions regarding when to take your 
medication and what to do if you miss a dose. You will be given supplies of blister packs at Weeks 1, 
3 and 7. You will be asked to return your used blister packs at each subsequent in-person visit.    
Week 3 Clinic Visit: Target Quit Date. On your target quit date (one week following your medication 
start date), you will complete a 2 hour “quit-day” session in our clinic to review your quit attempt. 
This will include a 45 minute session with your therapist to review your quitting plan and discuss 
reasons why people often relapse back into smoking. You will also complete paper and pencil 
assessments of your mood and smoking behavior, a brief psychiatric interview, a recent medical 
history review and assessments of height and weight, medication use, side effects, and smoking rate. 
Additionally, you will complete carbon monoxide, blood pressure, and heart rate readings at this time. 
At this visit you will receive your second supply of study medication for Weeks 4-7.  
Mid-Treatment Assessments  
Following your target quit date session, you will complete five booster therapy sessions by phone at 
Weeks 4, 6, 8, 10, and 12. These sessions will focus on reinforcing your success and reviewing your 
quit plan, or on reestablishing another quit date and restarting the smoking cessation process. Prior to 
each therapy session you will complete a brief psychiatric interview and assessments of your mood, 
medication use, outside treatments, smoking rate and side effects. At Week 12, we will also assess 
aspects of your smoking behavior. These sessions will last about 75 minutes, including a 45-minute 
booster therapy session.
For Week 7, you will be asked to return to our clinic for an in-person visit to do some mid-treatment 
assessments. During this visit you will complete paper and pencil assessments of your mood and 
smoking behavior, a brief psychiatric interview, a recent medical history review and assessments of 
height and weight, medication use, smoking rate and side effects. You will also complete blood 
pressure and heart rate assessments, a carbon monoxide assessment to verify your smoking status, and 
the four computer-based tasks. There is no therapy at this visit. You will be given the last of your 
blister packs of study medication (for weeks 8-13) at this visit. The Week 7 visit will last about two 
hours.
Follow-Up Assessments  
Finally, at Weeks 14 and 27 you will complete the treatment follow-up sessions. Week 14 is an in-
person clinic visit that will take about two hours. You will have your height and weight measured and 
will complete a blood pressure assessment, a carbon monoxide assessment to measure your smoke 
exposure, and the four computer tasks. You will also complete paper and pencil assessments of your 
mood, smoking behavior and satisfaction with the program, a brief psychiatric interview, a recent 
medical history review and assessments of medication use, health behavior, caffeine use, smoking rate 
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and side effects. A 12.5 ml blood sample (about 2.5 teaspoons) will be drawn to obtain a second 
measurement of your cholesterol and glucose levels. 
Week 27 is completed by phone and will last about 30-45 minutes. You will complete a brief 
psychiatric interview as well as assessments of your mood, smoking rate, medication use, outside 
treatments, health behavior and side effects. In addition, if you are quit at Week 27, you will be asked 
to attend a 30-minute clinic visit where your mood, health behavior, side effects, recent medical 
history and medication use will be assessed and you will have your carbon monoxide level blood 
pressure, heart rate and height and weight measured again.  
What are my responsibilities if I take part in this research?
If you agree to participate in this research study, your responsibilities include:

Attending study sessions, both in-person and phone, and completing all aspects of the sessions 
including assessments and questionnaires, computer tasks, specimen collection, and therapy 
homework

Remaining compliant with the study treatment, both medication and therapy

Maintaining open communication with study staff
What happens if I say “Yes”, but I change my mind later?
You can leave the research at any time; it will not be held against you.
If you choose to be in this study, you have the right to be treated with respect, including respect for 
your decision whether or not you wish to continue or stop being in the study. You are free to choose to 
stop being in the study at any time.  
If you decide to leave the research, contact the investigator so that the investigator can collect your 
study medication to be disposed of properly.
Choosing not to be in this study or to stop being in this study will not result in any penalty to you or 
loss of benefit to which you are entitled. Specifically, your choice not to be in this study will not 
negatively affect your right to any present or future medical treatment, your class standing (for 
students enrolled in a class at Northwestern), or your present or future employment (for employees at 
Northwestern or its affiliates).  
If you stop being in the research, already collected data may not be removed from the study database. 
You will be asked whether the investigator can collect data from your routine medical care. 
If you agree, this data will be handled the same as research data. 
Any new findings developed during the course of this research that may affect your willingness to 
continue in this study will be shared with you. 
Detailed Risks: Is there any way being in this study could be bad for me?
Nicotine Withdrawal Syndrome. These feelings include:
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
Sadness and mood changes

Insomnia 

Anxiety

Constipation

Decreased heart rate

Muscle pain

Irritability

Craving for nicotine

Headaches

Anger

Difficulty concentrating

Restlessness and nervousness

Appetite increase and weight gain
Your therapist will work with you to develop strategies to help you deal with any withdrawal 
symptoms that you may experience. If you feel that your withdrawal symptoms are not lessening over 
time or are significantly interfering with your ability to function, you should contact the Principal 
Investigator whose contact information is on page 10 of this consent form under the section “If I have 
questions or concerns about this research study, whom can I call?”
Varenicline (Chantix®). The most common side effects are listed first; the rare potential side effects 
(e.g., allergic reactions, mood-related, etc.) follow:
More Common Side Effects. Potential side effects of taking the study drug are nausea, sleep 
disturbance, constipation, flatulence (gas), or vomiting. These can occur in more than 5% of people 
taking this medication.  
Allergic Reactions. There have been rare reports of allergic and skin reactions to taking the study drug, 
including swelling of the face, mouth (tongue, lips, and gums), extremities, and neck (throat and 
larynx). These types of allergic reactions may be serious and life-threatening. The risk for these 
reactions is low, meaning about 1 out of 1000 people taking this medication. If you experience any 
difficulty breathing, stop using the study drug and seek medical help immediately. At the first 
appearance of any skin rash, you should also stop using the study drug immediately and contact your 
health care provider. If you experience any of these symptoms, contact the study staff as soon as 
possible after seeing your medical provider.
Mood-related Side Effects. Rare serious mood-related effects have been reported in a small number of 
persons taking the study drug. These include, but are not limited to, depression, agitation, hostility, 
suicidal thoughts, suicide attempts, and completed suicide. Some reported cases may have been 
complicated by the symptoms of nicotine withdrawal in patients who stopped smoking. Depressed 
mood may be a symptom of nicotine withdrawal. Depression, rarely including suicidal thoughts, has 
been reported in smokers undergoing a smoking cessation attempt without medication. However, some 
of these symptoms have occurred in patients taking the study drug who continued to smoke. When 
symptoms are reported, most occurred during treatment with Chantix®, while some followed after 
stopping Chantix® therapy. All patients being treated with the study drug will be assessed for such 
symptoms. These events have occurred rarely in patients with and without pre-existing psychiatric 
disease. Although patients with serious psychiatric illness, such as major depression, schizophrenia, or 
bipolar disorder, did not participate in the pre-marketing studies of the study drug, recent clinical trials 
that targeted these populations have demonstrated safety of varenicline use in these populations. 
These studies found no significant differences in mood-related side effect rates or an exacerbation of 
psychiatric symptoms between those taking Chantix® versus placebo. Our research staff and therapists 
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follow strict procedures to help monitor for the presence of these side effects, including asking you 
repeatedly during each study session about your reactions to the study medication. They will work 
closely with the study physicians/psychologists to make sure that you can safely take the study drug.
You should stop taking the study drug and contact a healthcare provider immediately if agitation, 
hostility, depressed mood, or changes in behavior or thinking that are not typical of you are observed, 
or if you develop suicidal thoughts or behavior. In many cases, resolution of symptoms was reported 
after stopping Chantix® therapy, although in some cases the symptoms persisted; therefore, ongoing 
monitoring and supportive care should be provided until symptoms resolve.
Cardiac Side Effects. The study drug may be associated with an increased risk for certain cardiac 
(heart) and vascular (blood vessel) side effects, including chest pain, heart attack, stroke, shortness of 
breath, calf pain when walking or sudden onset of weakness, numbness or difficulty speaking. One 
study showed that these risks are rare (~1% or 1 out of 100 people using the study drug) but a later 
study found no difference between placebo and the study drug in terms of these cardiac risks. Our 
study staff follow strict procedures to help them monitor for the presence of these side effects, 
including asking you repeatedly during the study about your reactions to the study medication and 
assessing your blood pressure.
Somnambulism. Cases of somnambulism (sleep walking) have been reported in patients taking 
varenicline. You should notify research staff as soon as possible if you experience somnambulism.  
Brief Cognitive Side Effects. The study drug may cause noticeable drowsiness, dizziness, headache, 
loss of consciousness or difficulty concentrating that may impair your ability to perform tasks 
requiring judgment or motor and cognitive skills such as driving a car and operating machinery. You 
should proceed with caution in this regard until you are certain that the study drug does not affect your 
performance.  Risk of Seizure. The study drug may be associated with new or worsening seizures 
during the first month of treatment. Some patients had no history of seizures, whereas others had a 
history of seizure disorder that was remote or well-controlled. You should not take the study drug if 
you have an unstable, untreated history of seizures.
Potential Interaction with Alcohol. The study drug may increase the intoxicating effects of alcohol. 
Some individuals have reported lower alcohol tolerance, aggressive behavior, or impaired memory 
following drinking alcohol while taking Chantix®. In these cases, which number less than 30 across 
the United States, the amount of alcohol consumed was not sufficient to explain the symptoms. 
Minimize or reduce your alcohol intake, with no more than 3 drinks per occasion or within a 24-hour 
period, while you are taking the study drug or until you know whether the study drug affects your 
tolerance of alcohol.
A thorough list of medical and psychiatric eligibility requirements will be used to further limit the 
possibility of the above-listed side effects. For your safety, if you are found to be at risk for 
experiencing cardiac events, you will be unable to participate in this study. 
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This study involves the use of your identifiable, personal information and there is a chance that a loss of 
confidentiality could occur. The researchers have procedures in place to lessen the possibility of this happening.  
See the section below titled: “What happens to the information collected for the research?”. 
What do I need to know about reproductive health/sexual activity if I am in this study? 
The research may also hurt a pregnancy or fetus in ways that are unknown. These may be a minor 
inconvenience or may be so severe as to cause death. [The effect of the study drug on human sperm 
and eggs has not been studied. The effects on the developing fetus using the study drug during 
pregnancy and the risk of birth defects are also unknown or may be unforeseeable. Therefore, you 
should not attempt pregnancy and should not be pregnant or breastfeeding while taking part in this 
study. Before entering this study all women will be asked to take a urine pregnancy test to determine if 
you are pregnant. You may not enroll in this study if you are pregnant or breast-feeding. 
If you are sexually active, both men and women should use at least one effective means of birth 
control while participating in this research study. According to the World Health Organization and the 
United States Center for Disease Control and Prevention, the most effective forms of birth control 
include complete abstinence, surgical sterilization (both male and female), intrauterine devices (IUDs), 
and the contraceptive implant.  The next most effective forms of birth control include injectables, oral 
contraceptive pills, the contraceptive ring, or the contraceptive patch.  Acceptable but least effective 
methods of birth control include male condoms (with or without spermicide) and female condoms.
If you or your partner become pregnant while participating in this research study or for ______ months 
after you complete the study, it is important that you tell the study doctor or other research team 
member immediately. You may be required to stop participation in this study; however, other 
treatment options will be discussed with you at that time if necessary.  
If you or your partner [are/is] considered to be postmenopausal, you are not required to use 
contraception while participating in this research study. Postmenopausal women rarely become 
pregnant. If you or your partner become pregnant while participating in this research study, it is 
important that you tell the study doctor or other research team member immediately. You may be 
required to stop participation in this study; however, other treatment options will be discussed with 
you at that time if necessary.
Will it cost me anything to participate in this research study?
Taking part in this research study will not lead to any costs to you.
You and your insurance company will be charged for the health care services that you would ordinarily be 
responsible to pay. In some cases, insurance will not pay for services ordinarily covered because these services 
were performed in a research study. You should check with your insurance to see what services will be covered 
by your insurance and what you will be responsible to pay.
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Will being in this study help me any way?
We cannot promise any benefits to you or others from taking part in this research. However, potential 
benefits include the opportunity to safely and effectively stop smoking with the support of 
professionals that are sensitive to your difficulties. Additionally, taking part in this study may help 
scientists better understand and handle the treatment of smoking cessation in people who also struggle 
with major depression.
What happens to the information collected for this research?
Efforts will be made to limit the use and disclosure of your personal information, including research 
study and medical records, to people who have a need to review this information. We cannot promise 
complete secrecy. Organizations that may inspect and copy your information include the IRB and 
other representatives of this institution.
If we learn about current or ongoing child [or elder] abuse or neglect, we may be required or permitted 
by law or policy to report this information to authorities.
The sponsor, monitors, auditors, the IRB, the Northwestern University Office for Research Integrity, 
the US Office of Research Integrity (ORI), the US Office for the Protection of Human Research 
Protections (OHRP), and the US Food and Drug Administration (FDA) may be granted direct access 
to your medical records to conduct and oversee the research. By signing this document, you are 
authorizing this access. We may publish the results of this research. However, we will keep your name 
and other identifying information confidential.
A description of this clinical trial will be available at http://www.ClinicalTrials.gov, as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time.
Data Sharing
De-identified data from this study may be shared with the research community at large to advance science and 
health. We will remove or code any personal information that could identify you before files are shared with 
other researchers to ensure that, by current scientific standards and known methods, no one will be able to 
identify you from the information we share. Despite these measures, we cannot guarantee anonymity of your 
personal data.
Can I be removed from the research without my OK?
The person in charge of the research study or the sponsor can remove you from the research study 
without your approval. Possible reasons for removal include

The Principal Investigator feels it is necessary for your health or safety. Such an action would 
not require your consent, but you would be informed if such a decision was made and the 
reason for this decision.

You have not followed study instructions (e.g., repeatedly no-showing to all your study visits 
without calling staff to cancel/reschedule)

The Sponsor or Principal Investigator has decided to stop the study.
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We will tell you about any new information that may affect your health, welfare, or choice to stay in 
the research.
What else do I need to know?
The hospital [university, researchers] will not pay for medical care required because of a bad outcome 
resulting from your participation in this research study. This does not keep you from seeking to be 
paid back for care required because of a bad outcome.
If you have an injury or illness from the study device, taking the study drug, or the procedures required 
for this study, the reasonable medical expenses required to treat such injury or illness may be paid for 
by the study sponsor.   
 
The coverage for such injury or illness is only available if the Northwestern University principal 
investigator and study sponsor, if applicable, have decided that the injury/illness is directly related to 
the study drug, device, or procedures and is not the result of a pre-existing condition or the normal 
progression of your disease, or because you have not followed the directions of the study doctor. If 
your insurance is billed, you may be required to pay deductibles and co-payments that apply.  You 
should check with your insurance company about any such payments.
Will I receive payment for participation in this study?    
If you agree to take part in this research study, we will pay you for your time and effort needed for 
completing assessments. You may earn up to $140 for taking part in this research study. You will 
receive $15 for completing the intake session, $15 for each in-person session for which you complete 
the computer tasks (Weeks 1, 7, and 14), and$10 for all other sessions. It will be paid to you in cash at 
the end of each study session. Phone session payments will accrue and be paid to you at the following 
in-person session. If you complete the week 27 phone visit but are not asked to come in for the week 
27 in-person visit, you will be sent an electronic gift card (i.e., e-voucher) of $10 to the retailer of your 
choice (Target, Walmart, or Amazon.com) to reimburse you for the week 27 phone session. A link to 
activate the e-gift card will be sent to your email address. For each in-person session you attend, you 
will also be reimbursed $10 for transportation/parking expenses. If at any point during the intake 
session, you are deemed ineligible for this study, we will compensate you $10 to cover your travel costs. 
If you withdraw from the study, you will be paid for the portions that you completed for which you 
have not already been paid. The payment schedule, including travel and parking reimbursement, is 
detailed in the table below:
You will be given a validated parking voucher and/or reimbursement up to $10 at the end of each in-
person study visit for expenses related to travel (e.g., train fare, bus fare, roadway tolls, etc.) and 
parking. If you do not drive or park in one of the qualifying Northwestern garages, you will still be 
reimbursed $10 for transportation expenses. If you do park in one of the qualifying Northwestern 
garages (Erie-Ontario Garage: 321 E. Erie St., Chicago; or Huron-Superior Parking: 222 E. Huron St., 
Chicago), you will be provided with a parking voucher (value: $5.75) plus $4.25 in cash. If at any point 
during the intake session you are deemed ineligible for this study, we will compensate you $10 to cover 
your travel/parking costs.
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Study Session
Session Compensation
Travel/Parking 
Compensation
Intake Session
$15
$10
Week 1 (pre-quit 1)
$15
$10
Week 3 (target quit day)
$10
$10
Week 4 (phone)
$10
-
Week 6 (phone)
$10
-
Week 7 (in-person assessment)
$15
$10
Week 8 (phone)
$10
-
Week 10 (phone)
$10
-
Week 12 (phone)
$10
-
Week 14 (in-person assessment)
$15
$10
Week 27 (phone)
$10
Week 27 (clinic/if quit)
$10
$10
Subtotal:
$140
$60
Total: $200
HIPAA Authorization We are committed to respecting your privacy and keeping your personal 
information confidential.  When choosing to take part in this study, you are giving us permission to 
use your personal health information that includes health information in your medical records and 
information that can identify you. For example, personal health information may include your name, 
address, phone number or social security number. Your health information we may collect and use for 
this research includes: 

Name, address, and telephone number

Email address

Date of birth

Results of physical examinations

Medical history

Lab tests, or certain health information indicating or relating to a particular condition as well 
as questionnaires

Records about study medication or drugs

Substance abuse information: Smoking, alcohol use and psychoactive substance use history  

Mental health information: psychological and psychiatric history
You have the right to inspect and copy the mental health and developmental disabilities records that will be 
collected as part of this study.
This consent expires on 5/14/2020. After this date, Northwestern University may not gather new 
information about you, use or disclose your personal health information collected in this study for any 
purpose other than the research study described in this consent unless Northwestern University obtains 
permission to do so from you.  Illinois State Law permits use and disclosure of your mental health 
information only to the extent specified in this document. 
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The following clinical providers may give the researchers information about you:  all current and previous 
health care providers, including but not limited to the Shirley Ryan AbilityLab (SRALAB), Northwestern 
Medical Group (NMG), Northwestern Memorial Hospital (NMH), and Northwestern Lake Forest Hospital 
(NLFH).
Once we have the health information listed above, we may share some of this information with the following 
offices or entities outside of Northwestern University and its clinical partners (or affiliates):  the Northwestern 
University Institutional Review Board Office and Office for Research Integrity; the US Office of Research 
Integrity; the US Office for Human Research Protections; the US Food and Drug Administration.  
Any research information shared with outside entities will not contain your name, address, telephone or social 
security number or any other personal identifier unless disclosure of the identifier is necessary for review by 
such parties or is required by law or University policy [except that such information may be viewed by the 
Study sponsor and its partners or contractors at the Principal Investigator’s office].
The following entities may receive your health information: 

Authorized members of the Northwestern University workforce, who may need to see your 
information, such as administrative staff members from the Office for Research, Office for 
Research Integrity and members of the Institutional Review Board.

Clinical affiliates, including but not limited to the Shirley Ryan AbilityLab (SRALAB), 
Northwestern Medical Group (NMG), Northwestern Memorial Hospital (NMH), Northwestern 
Lake Forest Hospital (NLFH), and the Ann & Robert H. Lurie Children’s Hospital of Chicago 
(Lurie Children’s).  Your participation in this clinical trial may be tracked in an electronic 
database and may be seen by investigators running other trials that you are enrolled in and by 
your healthcare providers.

Clinical affiliates, including but not limited to Northwestern Medical Group (NMG), 
Northwestern Memorial Hospital (NMH), and Northwestern Lake Forest Hospital (NLFH), for 
purposes including, but not limited to, the affiliate’s provision of care to you and/or the 
affiliate’s scheduling of appointments and/or billing activities.

Other University research centers and University contractors who are also working on the 
study,

Study monitors and auditors who make sure that the study is being done properly, 

The National Institute of Health, who is sponsoring the study, and that company’s contractors 
and partners.

Government agencies and public health authorities, such as the Food and Drug Administration 
(FDA) and the Department of Health and Human Services (DHHS).
Those persons who get your health information may not be required by Federal privacy laws (such as 
the Privacy Rule) to protect it. Some of those persons may be able to share your information with 
others without your separate permission.
IRB #: STU00100303 Approved by NU IRB for use on or after 9/9/2019 through 9/8/2020.


Version Date: V16 – August 21, 2019
Permission to Take Part in a Human Research Study
Do not sign this consent if today’s date is later than the stated expiration date above.
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However, Illinois law does not allow the re-release of HIV/AIDS, genetic testing, mental health and 
developmental disabilities information by the receivers of the information except in precise situations allowed 
by law. 
The results of this study may also be used for teaching, publications, or presentation at scientific 
meetings. 
Also, Federal Confidentiality Rules, 42 CFR Part 2, prohibit making any further disclosure of substance use 
disorder information unless further disclosure of this information is expressly permitted by written consent of 
the person to whom it pertains or as otherwise permitted by 42 CFR Part 2. 
Unless you revoke your consent, it will expire on 5/14/2020.
If you are assessed as being at high risk of harming yourself or others, it may be necessary to break 
confidentiality to notify emergency services, your healthcare provider or your nominated family 
member or friend (whose details will be collected at your next appointment). This would include 
disclosure of your personal details, medical and mental health information for the purpose of providing 
you with appropriate care. Study personnel will keep you informed of this if it occurs and as it occurs.
Although you may revoke consent to participation in this research at any time and in any 
format, you must revoke authorization for use or disclosure of your health information in 
writing. To revoke your authorization, write to: 
Dr. Brian Hitsman
Department of Preventive Medicine  
Northwestern University Feinberg School of Medicine
680 N. Lake Shore Dr., Suite 1400
Chicago IL 60611 
You do not have to authorize the use or disclosure of your health information; however, you will not be allowed 
to take part in this research study. If you do not authorize the use or disclosure of your health information, it 
will not affect your treatment by health care providers, or the payment or enrollment in any health plans, or 
affect your eligibility for benefits.
Optional Study Elements:
The following research activities are optional, meaning that you do not have to agree to them in order 
to participate in the research study. Please indicate your willingness to participate in these optional 
activities by placing your initials next to each activity.
Audiotaping:
I agree
I disagree
_______
_______
The researcher may audio record me to aid with data analysis. The 
researcher will not share these recordings with anyone outside of 
the immediate study team.
IRB #: STU00100303 Approved by NU IRB for use on or after 9/9/2019 through 9/8/2020.


Version Date: V16 – August 21, 2019
Permission to Take Part in a Human Research Study
Do not sign this consent if today’s date is later than the stated expiration date above.
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Can we notify your healthcare providers?
If you are found eligible and choose to enroll in this research study, we would like your permission to 
inform your current treatment providers that you are a study participant. This would be beneficial for 
your overall healthcare management because good communication between treatment providers can 
help improve the quality of healthcare delivered. Therefore, if you agree, a brief letter will be sent to 
your nominated healthcare or mental healthcare providers as a courtesy, notifying them of your 
enrollment in this study. The letter will contain a brief summary of the research study and description 
of what is required of study participants. You are able to view a template of this letter. We may also 
communicate with your healthcare provider regarding significantly worsening symptoms of depression 
(including high risk of self-harm), changes in your use of study medication, smoking status, and 
enrollment status (if your participation in the study ends).
I agree
I disagree
_______
_______
The study team may contact my primary mental healthcare 
provider as described above.
_____ (Initial) Not applicable. I do not have a primary or mental healthcare provider.
If you consent to allow research staff to notify your primary mental healthcare provider of your 
participation in this study, please nominate the physician that you would like notified:
Name of Provider
Contact Details (Phone & Address)
1
2
If you are not currently in active treatment for Major Depressive Disorder, we recommend that you see 
a mental healthcare or primary care provider who can conduct an assessment of depression symptoms 
and recommend whether treatment is needed. We will provide a list of mental health and primary care 
referrals. If you form a relationship with a mental healthcare provider, we ask that you inform research 
staff and consider offering permission for us to communicate with your provider about your 
participation in the study.
_____ (initial) I do not currently have a mental healthcare provider, and have been provided with the 
referrals noted above. 
_____ (initial) Not applicable. I currently have a healthcare provider who is aware of my symptoms.
Consent Summary: 
IRB #: STU00100303 Approved by NU IRB for use on or after 9/9/2019 through 9/8/2020.


Version Date: V16 – August 21, 2019
Permission to Take Part in a Human Research Study
Do not sign this consent if today’s date is later than the stated expiration date above.
Page 18 of 18
Your signature documents your permission to take part in this research. You will be provided a copy 
of this signed document.
_______________________________________________      __________________
Signature of Participant                                                               Date
_______________________________________________
Printed Name of Participant
____________________________________________            __________________
Signature of Person Obtaining Consent                                     Date
______________________________________________________
Printed Name of Person Obtaining Consent
My signature below documents that the information in the consent document and assent process and 
any other written and verbal information was accurately explained to, and apparently understood by, 
the participant, and that consent was freely given by the participant.
_________________________________________________      
_______
__________
Signature of Witness to Consent/Assent Process      
Date
_________________________________________________   
Printed Name of Person Witnessing Consent/Assent Process
IRB #: STU00100303 Approved by NU IRB for use on or after 9/9/2019 through 9/8/2020.