A Prospective Trial of Varenicline and Incentives for Tobacco Cessation in Adults
Phase: PHASE4
Conditions: Tobacco Use Disorder
Sponsor: Medical University of South Carolina

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Study Title: A prospective trial of varenicline and incentives for tobacco cessation in adults 
 
NCT Number: NCT04228965 
 
Grant Title: Determining the impact of cannabis use and severity on tobacco cessation outcomes: A 
prospective tobacco treatment trial 
 
US NIH Grant/Contract Award Number: R37CA237245 
 
Document Date: January 29, 2024 
 
 
 

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PROTOCOL TITLE: A prospective trial of varenicline and incentives for tobacco 
cessation in adults 
PRINCIPAL INVESTIGATOR: Erin A. McClure, Ph.D. 
1.0 
Objectives / Specific Aims 
Though tobacco use rates in the United States (US) have been steadily declining over the past several 
decades, the burden resulting from tobacco continues to be staggering and disparities still exist in tobacco 
use rates and resulting adverse health effects. Further, rates of tobacco use are two to three times higher 
among those with co-occurring substance use disorders and psychiatric conditions compared to the general 
population. In particular, cannabis co-use among tobacco users is exceedingly common and rates of co-use 
appear to be increasing among US adults. Cannabis use rates, in general, appear to be rising in the US, in 
large part due to the reduced perception of harm, its perceived and real medical benefits and increasingly 
relaxed legislation restricting its use. These factors are likely to lead to further increases in cannabis use 
and may result in continued increases in the co-use of cannabis and tobacco.  
The harms resulting from continued tobacco use have been clearly demonstrated and several efficacious 
treatments exist, yet there still remain important barriers to successful tobacco cessation that must be 
addressed to improve abstinence rates for sub-populations of smokers. Specifically, the impact of cannabis 
use on tobacco cessation outcomes is not well understood and may serve as an obstacle to successful tobacco 
cessation among co-users. The literature on the impact of cannabis co-use on tobacco cessation has been 
mixed and fraught with limitations, which precludes the development of treatment recommendations for 
co-users. The studies that have explored this relationship are limited by their methodological variation, lack 
of biochemical verification to confirm cannabis use, and variations in study samples used. To date, no 
prospective studies have evaluated the impact of cannabis use and severity on tobacco cessation outcomes. 
Further, no studies have collected cannabis use changes during tobacco cessation treatment to assess for 
concurrent reductions, abstinence, or of greater concern, compensatory (i.e., increased) cannabis use. 
This proposed study is a prospective 12-week tobacco cessation trial using established methods and 
outcomes typical of tobacco cessation trials, but specifically recruiting co-users of cannabis to; 1) evaluate 
the impact of co-use on tobacco cessation (compared to tobacco only users), and 2) assess changes in 
cannabis use during tobacco treatment. Adult tobacco users (ages 18-40; N=208) who are motivated to quit 
smoking will be recruited. Cannabis co-users will be oversampled (2:1). All participants will receive a first-
line tobacco cessation pharmacotherapy (varenicline) paired with a behavioral intervention to bolster 
abstinence (contingency management and psychosocial counseling) for 12 weeks, while cannabis use will 
not be specifically addressed. Biochemical verification and self-reports (through mobile daily diaries) of 
substance use will be collected throughout treatment. A subset of cannabis-tobacco co-use participants (N 
= 48) will engage in an additional ecological momentary assessment (EMA) portion of the study (EMA 
supplement) for granular observation of patterns of co-use.  
Specific Aims of the proposed research are: 
Aim #1: examine the impact of cannabis co-use on tobacco cessation among co-users compared to tobacco 
only users. 
Hypothesis 1: Co-users will have lower rates of 7-day point prevalence abstinence from tobacco at 
the end of treatment (Week 12) compared to tobacco only users. 

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Aim #2:  Among co-users, assess changes in cannabis use during tobacco cessation treatment. 
Hypothesis 2: Co-users with moderate to high severity of nicotine dependence will demonstrate 
increases in concurrent cannabis use, while lower severity of nicotine dependence will yield no 
changes in cannabis use. 
 
Exploratory Aim: To assess for a dose-dependent impact of cannabis use severity on tobacco cessation 
outcomes among co-users.  
 
2.0 
Background 
 
A1. The Prevalence and Harms of Cannabis and Tobacco Co-Use. Tobacco use rates have been steadily 
declining over the past several decades in the United States (US) (1), though the burden resulting from 
tobacco continues to be staggering (2). Tobacco is the leading cause of preventable disease and mortality 
in the US and tobacco-related illnesses cost approximately $300 billion per year in the US alone (2, 3). Of 
concern, the population of tobacco users has evolved in recent years. Disparities in tobacco use rates exist 
and disproportionately affect those with lower levels of education and income and among racial and ethnic 
minorities (4). Rates of tobacco use are two to three times higher in those with co-occurring substance use 
disorders (5-7) and psychiatric conditions (8, 9) compared to the general population. In particular, cannabis 
co-use among tobacco users is exceedingly common and rates of co-use appear to be rising among adults. 
 
A.1.a. Increasing prevalence of cannabis-tobacco co-use. Cannabis and tobacco are frequently used 
together (10-19) and co-use may occur in several forms; such as, simultaneous use (cigar wrappers filled 
with cannabis ‘blunts’), sequential use (‘chasing’ cannabis with tobacco), for substitution purposes (using 
one when the other is not available), or in an asynchronous manner. While the overall rates of cannabis and 
tobacco co-use in the US appear to have increased modestly (~18%) from 4.4% in 2003 to 5.2% in 2012 
(20), the prevalence of daily cannabis use among daily cigarette smokers has nearly doubled from 4.9% in 
2002 to 9.0% in 2014 (21). One out of every 14 daily cigarette smokers (aged 26+) are daily cannabis users, 
while among those aged 18-25, one out of every five daily cigarette smokers are daily cannabis users. For 
comparison, one out of every 100 never cigarette smokers are daily cannabis users (21). This increase may 
be partially explained by the overall increase in cannabis use in the US. Rates of past month cannabis use 
for adults increased from 10.7% in 2002 to 14% in 2016, with substantial increases occurring among adults 
aged 26 and over (4% in 2002 to 7.2% in 2016), while use rates among 18-25 year olds remain high (20.8%) 
(22). Increases in cannabis use prevalence are in large part due to the reduced perception of harm, its 
perceived and real medical benefits and relaxed cannabis legislation (23-26). These factors are likely to lead 
to further increases in cannabis use and may result in continued increases in the co-use of cannabis and 
tobacco. 
 
A.1.b. Harms associated with co-use. Cannabis and tobacco co-use is associated with public health burden 
in the form of greater prevalence of psychiatric and psychosocial problems (27, 28), additive health risk 
(29), and lower self-reported ratings of health (30). There are also treatment-related concerns specific to co-
use. Though prevalence of co-use is high, there is surprisingly little consensus regarding treatment 
recommendations and cessation strategies tailored for co-users. Few published studies of co-use treatment 
interventions exist and all have been pilot/feasibility trials (31-34). While co-use treatment is needed, the 
degree to which co-use affects treatment success for a single, targeted substance remains in question. 
Specifically, the impact of cannabis use on tobacco cessation outcomes is not well understood in the 
literature and may serve as an obstacle to successful tobacco cessation among co-users. Also unknown is 
the degree to which compensatory substance use (i.e., increased use) occurs as a result of reduction or 
cessation from the other substance. Though the harms resulting from continued tobacco use have been 

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demonstrated and several efficacious treatment strategies exist (35-39), there remain important barriers to 
successful tobacco cessation that must be addressed to improve abstinence outcomes for sub-populations 
of smokers.  
 
A2. The Impact of Co-Use on Cessation Outcomes. Cannabis use has been associated with an increased 
risk of nicotine dependence and greater nicotine dependence among co-users (12, 40-43). However, the 
literature on tobacco cessation success among co-users has been mixed, fraught with methodological 
limitations, and to date, no prospective studies to inform tobacco treatment among co-users have been 
conducted. Some evidence, including recent studies, suggests that co-use has an adverse impact on tobacco 
outcomes. Specifically, cannabis co-use has been associated with lower rates of tobacco cessation when 
compared to non-cannabis users (44-50), lower levels of sustained tobacco abstinence, increased odds of 
relapse (51, 52), and lower odds of tobacco quit attempts (53).  
 
However, other studies have found no evidence of an adverse impact of cannabis on tobacco cessation (54-
59), no differences in tobacco outcomes based on cannabis use frequency (42, 55), no impact on intentions 
to quit using tobacco (53, 60), and no adverse influence on the beneficial effects of low nicotine content 
cigarettes (61). This mixed literature on tobacco cessation outcomes supports the need to study co-use with 
a rigorous, prospective study design to better answer these important public health questions and inform the 
research and clinical care of tobacco use disorder. Currently, no prospective studies have evaluated the 
impact of cannabis use and its severity on tobacco cessation, which is a major objective of this proposed 
study.  
 
A.2.b. Compensatory substance use among co-users. A treatment concern for co-users is the issue of 
compensatory (i.e., increased) use of the other, non-treated substance, during cessation. Among co-users, 
there are data exploring compensatory tobacco use during cannabis reduction/cessation (opposite 
relationship of the proposed study), though findings have been mixed. Some studies have shown 
compensatory use (increases in tobacco use during cannabis abstinence/reduction) (62-65), while our 
research group and others have found no evidence of compensatory tobacco use during cannabis cessation 
(66-68). We have also found individual differences associated with changes in tobacco use among; 1) 
those who concurrently reduced their cannabis use (69), and 2) those with lower levels of nicotine 
dependence (70). A recent study among co-users with schizophrenia found that compensatory use of 
tobacco was most pronounced in the first seven days of cannabis abstinence, but returned to baseline 
levels by Day 28 of abstinence (71). This study suggests that the relationship between these two 
substances may be complicated and transient and therefore must be studied with a design that captures 
changes in use of the non-treated substance. Patterns of compensatory use are important to determine as 
tobacco cessation could lead to greater cannabis use and associated adverse effects (72-76). There is a 
dearth of data available to address the issue of transient or sustained compensatory cannabis use and how 
reliably compensatory use occurs during tobacco treatment.  
 
A3. Addressing Critical Gaps in the Literature. All of the above studies exploring the impact of cannabis 
use on tobacco outcomes have been secondary analyses or epidemiological studies using community 
samples. Available data to better understand this relationship are limited, resulting in critical gaps in the 
literature, which will be addressed by the proposed study. To further illustrate the significance, 
innovation, and novelty of the proposed work, Table 1 summarizes and compares design features of 
recent studies (past 8 years) versus what we are proposing here. Listed studies were all conducted among 
tobacco users and published on the impact of cannabis use on tobacco cessation. As Table 1 suggests, our 
study design features, in combination, will provide the most comprehensive, well-controlled, rigorous 
study to date. Additional gaps in the literature are further outlined below.  
 

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A.3.a. Excluding co-users from tobacco studies. It is generally standard practice in tobacco cessation trials 
to exclude for concurrent substance use disorders, which would eliminate most regular cannabis users. 
Secondary analyses of co-users in tobacco trials are limited by small sample sizes and may not be 
representative of the co-using population. If cannabis users are included, they are likely infrequent users or 
are inaccurately reporting use. Broad spectra of co-using populations are not specifically recruited and 
comparisons to tobacco only controls are not always possible. As such, severity of cannabis use may be an 
important variable that predicts treatment response, but tobacco trials are not equipped to answer that 
question. For example, in a study listed above, cannabis co-use was present in 15% of the sample and 
participants did not meet clinical thresholds for cannabis use disorder (CUD; 56). That study found that 
cannabis use did not impact tobacco cessation, which could be due to the level of cannabis use severity.  
 
A.3.b. Insufficient collection of cannabis use data. When co-users are enrolled in tobacco trials, assessment 
of cannabis use is insufficiently collected, if collected at all, and data are not available to detect changes in 
use during treatment. It is possible that the successful treatment of tobacco is resulting in an unintended 
negative effect on cannabis use. However, the collection of cannabis use data during tobacco trials is time-
intensive, costly, notoriously challenging (when self-reported), and not the primary outcome, all of which 
contribute to the limited capacity to collect these data. A strength of the current proposal is the detailed 
cannabis quantification that will occur daily via mobile surveys (77). We will also quantify combustible 
(78) and non-combustible cannabis use preparations (edibles, oils, concentrates) throughout the trial. 
 
A.3.c. Patterns of co-use. The temporal ordering and relationship between cannabis and tobacco co-use is 
also not routinely collected in tobacco trials or national surveys. The degree of relatedness between these 
substances (i.e., their temporal order, exerting synergistic drug effects when used concurrently or close in 
time, etc.) is important to capture prospectively as it may impact tobacco cessation success or the likelihood 
of compensatory use. Our group has recently published on patterns of cannabis-tobacco co-use and the 
related nature of these substances (79), which will be captured in the proposed study and represents another 
notable strength of this proposal and contribution to the literature. 
 
A.3.d. Rapidly changing cannabis environment. The landscape of cannabis use has changed dramatically in 
the US, which may result in a separation of tobacco and cannabis use. Typically, cannabis and tobacco have 
shared a similar route of administration, potentially contributing to their prevalent co-use (11). Due to 
changing legislation and commercial availability, there is now massive variation in cannabis products and 
methods of administration. Edibles, concentrates (e.g., wax, dabs), and vaporizers are increasingly popular 
and allow for cannabis use through administration methods that do not involve combustion, potentially 
 
Design Features (within Tobacco Trials or National Surveys) specific to 
Cannabis Use Assessment/Collection 
Outcome 
 
Prospectivea 
Biomarkers 
Severityb 
Daily 
Use 
Quant 
Related Co-
Usec 
Adverse impact of 
cannabis 
Haskins et al. (2010) (47) 
 
 
X 
 
 
 
Yes 
Metrik et al. (2011) (55) 
 
 
X 
X 
 
 
No 
Hendricks et al. (2012) (58) 
 
 
 
X 
 
 
No 
Leyro et al. (2015) (59) 
 
 
 
 
 
 
No 
Rabin et al. (2016) (56) 
 
[Qual] 
 
 
 
 
No 
Pacek et al. (2016) (61) 
 
[Qual] 
 
X 
 
 
No 
Schauer et al. (2017) (51) 
 
 
X 
 
 
 
Yes 
Weinberger et al. (2018) (52) 
 
 
 
 
 
 
Yes 
El-Khoury et al. (2018) (50) 
 
 
 
 
 
 
Yes 
Vogel et al. (2018) (49) 
 
 
 
 
 
 
Yes 
McClure (proposed) 
X 
X 
X 
X 
X 
X 
? 
Qual=Qualitative drug test 1x; Quant=quantification of cannabis use, including non-combustibles; a=Prospective indicates that the study was designed 
to assess the impact of cannabis use on tobacco outcomes (a priori hypotheses and powered as such); some parent trials were prospective; b=severity of 
cannabis use (at least 2 levels); c=data collected on the temporal ordering of use.  
Table 1. Comparison of Study Design Features 

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distinguishing them from tobacco. Indeed, it has been suggested that the uptake of cannabis vaporizers may 
lead to lower rates of cannabis-tobacco co-use (80). 
 
A4. Summary/Scientific Premise. The scientific premise of the current application is based on mixed 
evidence regarding the impact of cannabis use on tobacco cessation and limitations in the current literature, 
such as methodological variation, lack of biochemical verification to confirm cannabis use status and 
severity (Table 1), and variations in the study samples used. Currently, no prospective studies have 
evaluated the impact of cannabis use and its severity on tobacco cessation. Further, granular data are not 
available to detect compensatory cannabis use during tobacco treatment, which may represent an 
unintended adverse consequence of successful cessation. This proposed prospective tobacco treatment 
study focuses on tobacco cessation among cannabis-tobacco co-users and evaluates how cannabis use may 
serve as a barrier to successful tobacco cessation. The results from this study will be uniquely positioned 
for public health impact in the treatment of tobacco use disorder among those using cannabis. Co-occurring 
cannabis use may be adversely affecting tobacco treatment, in which case, it should be standard practice to 
address cannabis as part of treatment. Alternatively, if cannabis use does not impact tobacco cessation, it 
may be unnecessary to encourage cannabis cessation in unmotivated co-users, which may be discouraging 
their engagement in tobacco treatment. This study will be the first prospective examination of cannabis use 
impact and changes during tobacco cessation and will provide the necessary information to further develop 
and personalize treatment strategies for co-users. As cannabis use rates continue to increase, the presence 
of co-users in tobacco cessation trials and presenting in clinical care will continue to be common. Co-users 
may require tailored and potentially enhanced tobacco treatment and the results from this study will help to 
guide tobacco treatment in cannabis co-users and provide them with the best chances of successful long-
term abstinence. 
 
B. Approach 
B1. Study Overview. This proposed prospective tobacco cessation study will evaluate the impact of 
concurrent cannabis use and severity on tobacco abstinence among co-users and assess changes in cannabis 
use during treatment. Adult tobacco users (ages 18-40) who are motivated to quit smoking will be recruited. 
Cannabis co-users will be oversampled (2:1) and will be compared to tobacco only participants (using 
appropriate propensity score models). All participants will receive first-line tobacco cessation 
pharmacotherapy (varenicline) paired with a behavioral intervention to bolster abstinence rates 
(contingency management and psychosocial counseling) for a standard 12-week treatment period. Cannabis 
use will not be targeted with treatment. This is not a treatment outcome study per se and thus we are not 
evaluating (with a control group) an intervention. Rather, cannabis use status (co-use vs. not) is our 
independent variable. Biochemical verification of tobacco and cannabis use will be collected at screening 
and throughout the 12-week treatment period in addition to daily self-reports of use. Specifically, this study 
will: 1) examine the impact of cannabis co-use on tobacco cessation among co-users compared to tobacco 
only users (Aim #1); 2) with the use of frequent measurement, assess changes in cannabis use (among co-
users) during tobacco treatment and determine if profiles of changes in cannabis use emerge (i.e., 
compensatory use, reduction, no change) (Aim #2); and 3) assess for a dose-dependent impact of cannabis 
use severity on tobacco cessation outcomes among co-users (Exploratory Aim).  
 
It should be noted that while this is not a randomized and blinded study (cannabis co-use status will be 
known to research staff), it is important to not bias the results of the study. The hypothesis is that cannabis 
co-use will adversely impact tobacco cessation, but it’s important to the scientific integrity of this study to 
obscure that hypothesis from study participants and manage biases with research staff.  Staff will be 
educated about introducing bias into the study and methods to manage bias in non-randomized and non-
blinded trials.  For research participants, the aim of the study will intentionally broad and ambiguous to not 

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overtly influence their behavior and tobacco quit attempt.  The title of the study and consent document, 
therefore, are not as specific as they would normally be to maintain the integrity of this research.  
 
B2. Preliminary Studies.  
Rates of co-occurring cannabis use in tobacco trials. Prior and ongoing trials at the Medical University of 
South Carolina (MUSC) provide indirect data to support the feasibility of recruiting co-using participants. 
First, in a recently completed tobacco cessation trial (NIDA U01 DA0317779; PI Gray), varenicline was 
evaluated for safety and efficacy among youth smokers (Mean age=19; SD=1.5; Range=14-21). Among 
this sample, 59% (93/157 randomized) tested positive for urinary cannabinoids at screening and 25% of 
those who reported cannabis co-use were regular users (at least 20 of the past 30 days). Second, in an 
ongoing adult tobacco cessation study (NIDA R34 DA042228; PI McClure; Mean age=41; SD=11.5; 
Range=23-62), 27% (20/74 randomized) have tested positive for urinary cannabinoids at screening. This 
co-use rate is lower than the adolescent trial described above, but is consistent with age-related cannabis 
use trends. Notably, participants are excluded from the adult trial if they are unwilling to reduce or quit 
using cannabis during the tobacco quit attempt, which may result in lower co-use rates. Finally, another 
ongoing study is recruiting treatment-seeking cannabis users (NIDA UG3 DA043231; MPI McRae-Clark 
and Gray), and 38% of the sample thus far have reported being daily co-users of tobacco. None of these 
trials are explicitly focused on outcomes tested herein, but they do provide assurance of recruitment goals.  
 
Tobacco abstinence among co-users. In the recently completed 
adolescent varenicline trial described above (U01 DA 
0317779), we evaluated differences between participants with 
baseline cannabis use (positive urine drug screen or self-
reported use in the past 30 days) compared to participants with 
no baseline cannabis use (negative urine drug screen and no 
self-reported use). Self-reported tobacco use was assessed 
across study weeks and the percentage of 7-day point 
prevalence abstinence is shown in Figure 1 (varenicline group 
only). The overall percentage of tobacco abstinent visits for 
cannabis use participants was 14.8%, while the percentage of 
abstinent visits for non-cannabis participants was 29.7% 
(RR=1.9; 95% CI=0.9-3.7; p=0.06). 
 
Severity of cannabis use was explored to assess for dose-dependent effects of cannabis use on tobacco 
cessation. Since quantitative levels of urinary cannabinoids 
were not collected, severity categorizations were based on 
qualitative cannabinoid tests and self-reported days of use 
(≥20 days of use=severe; positive cannabinoid test and <20 
days 
of 
use=intermittent; 
negative 
cannabinoid 
test=infrequent/no use). The percent of point prevalence 
tobacco abstinence in the varenicline-treated group 
separated by cannabis severity in shown in Figure 2. The 
risk ratio between no cannabis use and severe cannabis use 
groups was 4.2 (95% CI=1.4-12.3) and between no use and 
intermittent use was 1.7 (95% CI=0.9-3.4), suggesting that 
as baseline cannabis co-use severity escalates, rates of 
tobacco abstinence decrease. 
 
Figure 1. 
Figure 2. 

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Finally, we explored cannabis use changes and secondary 
efficacy of varenicline on cannabis use. Days of self-
reported cannabis use in the past week for both varenicline 
and placebo groups during treatment is shown in Figure 3. 
Slightly more days of cannabis use were reported in the 
varenicline group beginning in Week 6 and persisting until 
Week 12. This result suggests that varenicline did not 
exhibit secondary efficacy on cannabis use among co-users 
in this trial, and in fact, cannabis use appeared to increase 
slightly for the varenicline group later in the trial. 
 
Age differences in co-users. In the adult tobacco cessation 
trial described above (R34 DA042228), we compared cannabis co-users with tobacco only participants to 
assess for differences, on which to inform the control group characteristics for the proposed study. Co-users 
were similar to tobacco only users on several demographic and tobacco use characteristics, but did differ in 
age (M=43.4; SD=11.6 for tobacco only users; M=34.7; SD=8.7 for co-users). These data are consistent 
with epidemiological data on cannabis use prevalence (22), which suggest higher rates of cannabis use for 
those under the age of 40. To achieve similarity between tobacco only participants and co-users in the 
proposed study, we will restrict the upper age range for participants to ensure the most appropriate 
comparison group.  
 
Quit interest in co-users. Cross-sectional survey data collected from our group assessed quit interest and 
compensatory drug use in co-users (81). Among an online sample (N=182), interest in quitting tobacco was 
high (7.1±2.9; 10-point scale), while interest in quitting cannabis was low (2.4±2.3; 10-point scale). This 
study also found that among participants who had ever tried to quit tobacco (80%), half self-reported 
increases in their cannabis use during the quit attempt. While these data were retrospective, this result 
further emphasizes the importance of measuring cannabis use changes during tobacco treatment. These data 
also suggest that the proposed design will be acceptable to co-users given that tobacco treatment will be 
provided while not addressing cannabis use, as co-users show low interest in cannabis cessation.   
 
3.0 
Study Endpoints  
Below is a table of the study endpoints and outcomes.   
 
Type 
Name 
Time Frame  
Brief Description 
Primary 
7-day point prevalence 
tobacco abstinence at the 
end of treatment (Week 
12) 
Final 7 days of treatment 
(Week 12)  
 
7-day point prevalence 
abstinence from tobacco 
at the end of treatment 
(Week 12) will be 
assessed via biochemical 
verification and 
participant self-report and 
rates of abstinence will be 
compared between 
cannabis co-users and 
tobacco only controls. 
Secondary 
Changes in cannabis use 
during tobacco cessation 
treatment (among co-
users) 
Final 4 weeks of study 
treatment (Weeks 8-12) 
Among cannabis co-users, 
cannabis use rates and 
amounts during the final 4 
weeks of tobacco 
treatment (Weeks 8-12) 
will be assessed and 
Figure 3. 

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nicotine dependence will 
be the primary model 
predictor. 
 
Other: Exploratory 
Cannabis co-use severity 
on tobacco cessation 
(among co-users) 
Throughout trial 
participation 
Tobacco abstinence and 
indicators of tobacco 
reduction (average 
cigarettes per day, 
quantitative cotinine, etc.) 
throughout the trial will 
be examined as a function 
of baseline cannabis use 
severity (determined by 
days of use in the past 30) 
to assess for dose-
dependent impact on 
tobacco outcomes based 
on cannabis use severity. 
 
 
4.0 
Inclusion and Exclusion Criteria/ Study Population 
 
Adult tobacco users (ages 18-40) who are motivated to quit smoking (N=208) will be recruited for the study.  
 
Inclusion criteria: 
a)  
Between the ages of 18 and 40 years old 
b) 
Must be able to understand the study and provide written informed consent 
c) 
Daily cigarette smoker for ≥ 6 months, smoking ≥ 5 cigarettes per day 
d) 
Must submit a breath carbon monoxide (CO) sample of ≥ 7 parts per million (ppm) and/or a 
positive qualitative cotinine test at the screening visit 
e) 
Be interested in quitting smoking tobacco cigarettes (defined as a 5 or above on a 10-point Likert 
scale assessing interest in quitting [1=not at all interested, 10=extremely interested]) 
f) 
Must be willing to take varenicline for the standard 12-week course of treatment  
g) 
If female, agreement to use birth control (any form) to avoid pregnancy during study procedures 
 
Additional inclusion criteria will be implemented for cannabis co-users, which include: 
h) 
Self-reported use of cannabis on at least 10 out of the past 30 days or submit a positive qualitative 
urinary cannabinoid test at screening (limit of detection is 50 ng/ml)  
 
Exclusion criteria:  
a) 
Any serious or unstable medical/psychiatric disorder (including severe substance use disorders, 
other than cannabis or tobacco use disorders) or other significant concern in the past three months 
that may interfere with study performance, impact participant safety, compliance with study 
procedures, or potentially confound the interpretation of findings  
b) 
Currently pregnant, lactating, or contemplating pregnancy in the next 6 months  
c) 
Current use of medications with smoking cessation efficacy 
d) 
Use of any medications that would interfere with varenicline (i.e., tafenoquine or quinolones) 
e) 
Regular use of other tobacco or nicotine products other than combustible cigarettes (e.g., 
smokeless tobacco, electronic cigarettes, etc.) in the past month prior to the quit attempt 
 
 

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5.0 
Number of Subjects 
A total of 270 participants will be consented with the goal of attaining a total final sample size of 208 
(137 co-users, 71 tobacco only users) participants.  
 
6.0 
Setting 
 
The research will be conducted at three study sites; 1) the offices of the Addiction Sciences Division at the 
Medical University of South Carolina, located in the Roper Medical Office Building, 2) Behavioral Health 
Services (BHS) of Pickens County, located in Pickens, South Carolina, and 3) MUSC Florence. All 
locations have conducted research studies before and are equipped with several private interview rooms to 
conduct informed consent and participant visits, a room for conducting physicals and medical histories, 
bathrooms for collecting urine samples, and storage space for files and study supplies. When possible, 
remote procedures will be utilized as needed. Participants may engage with study staff at any of the 
participating sites to complete study procedures. Charleston and Pickens staff will conduct the majority of 
study procedures with Florence participants.   
 
7.0 
Recruitment Methods 
 
This proposed study will enroll 208 participants over the course of 46 months, at a rate of 4.5 participants 
per month at both participating sites. Several tobacco trials at the Medical University of South Carolina 
(MUSC) have recruited adolescent and adult cigarette smokers at a rate of 3-5 participants per month (NIDA 
grants U01DA031779; P50DA16511; R34 DA042228). BHS has experience with recruiting substance 
using populations into research studies, and similar methods of recruitment will be used in Pickens (and 
surrounding areas) as are being used in the Charleston area. A recruitment goal of 4.5 enrolled participants 
per month at both study sites is a reasonable target for the current study.  
 
Our research team has used a number of successful recruitment methods to reach and enroll cigarette 
smokers and cannabis users. We will implement similar recruitment strategies. Since this study is focused 
on tobacco treatment, we will employ advertisements that focus on tobacco treatment-seekers, but also will 
advertise to those using both tobacco and cannabis, especially later in the study when only tobacco-cannabis 
co-users are needed for enrollment. Several tobacco studies conducted by our research team (in Charleston) 
fall under the umbrella of “Project Quit,” which has general advertisements targeting smokers of all ages 
and motivation levels. Through marketing of the “Project Quit” brand and continued activity, such as social 
media educational posts or presence at community events, we maintain a constant presence in the 
Charleston and surrounding areas, rather than having specific recruitment for one study at a time. This has 
been a successful recruitment campaign for several research studies. Each study is unique, with its own 
exclusion criteria, and competition between studies for participants has been minimal. All cigarette smokers 
interested in research opportunities call or text the same phone number and trained research staff are able 
to triage interested participants based on their characteristics and interest in quitting. Successful methods of 
recruitment that have been used previously will be used for this study and include (but are not limited to): 
print and internet-based recruiting methods (i.e. newspaper advertisements, flyers, billboards, buses, 
advertisements on Facebook, or other social media platforms, posting on Craigslist, etc.), tv or radio 
commercials (including streaming services, etc.), primary care, urgent care, and/or hospital or physician 
referrals (MUSC affiliated clinics or independent medical facilities), postings at local colleges with proper 
approval(s) (i.e. College of Charleston, The Citadel, Trident Technical Institute, Clemson University, etc.), 
etc. Potential participants will be directed to a REDCap survey where they can provide us with their contact 
information. The link to the contact card will be included in our materials such as our website and social 
media pages. We will also utilize TrialFacts and/or BuildClinical to aid in recruitment for this study (in 
addition to other potential clinical research organizations that may provide services during the course of 

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enrollment). TrialFacts, BuildClinical, and other clinical research advertising businesses utilize targeted 
digital media advertising to recruit participants.   
 
We will also employ additional recruitment methods to research potential study participants. First, we will 
use ResearchMatch.org to contact potential study volunteers (using IRB approved language) to see if they 
may be interested and a good fit for this study. We will attempt to search for potential participants near 
study sites. Second, given the success of cold-contact recruitment used in a current study (Pro105269) and 
at MUSC generally to reach a wide range of patients that might not otherwise take part in research studies, 
we propose to use cold contact methods to reach smokers in study location areas. Patient reports will be 
requested from the MUSC Biomedical Informatics Center [BMIC]). We will ask for searches of the medical 
record that identify smokers, ages 18-40, within 30-40 miles of Charleston, Pickens, or Florence from 
MUSC and all regional hospitals. BMIC will gather contact and demographic information (name, phone 
number, street address, zip code, etc.) for potential study participants, as well as smoking status. All 
potentially eligible patients will be selected for recruitment unless they have specifically opted out of 
research communication.  Patients’ opt-out preferences will be documented in their REDCap Research 
Contact Form.  The study team will not cold contact any patients who already have opt-out preferences 
noted in their electronic health records. 
 
Additionally, Respondent-Driven Sampling (RDS) will be used to enhance recruitment. The RDS sampling 
methodology is based on recruiting the eligible friends and acquaintances of each participant so that the 
sample “snowballs.” Each eligible participant who is enrolled into the study, and agrees to take part in this 
recruitment assistance, is eligible to receive compensation for successful referrals. A referral will be 
instructed to call the study team to be screened for eligibility. If that person successfully enrolls into the 
study (i.e., completes the Day 0 visit and begins taking study medication), the participant who referred them 
can receive $30 in compensation for each eligible participant that is referred and enrolled in the study. The 
research team has used these methods successfully in the past.  
 
Interested participants will have a brief phone screen conducted to ensure that participants are the 
appropriate age and are regular tobacco users. Eligible participants will be scheduled for a screening visit. 
Participants will complete an in-lab screening visit with trained study staff.  
 
 
8.0 
Consent Process 
 
Prior to the initiation of any study procedures, written informed consent and HIPAA authorization will be 
obtained by the designated research staff.  The informed consent process will include a thorough discussion 
of potential risks associated with participation, including potential adverse effects of study medication.  
 
Potential participants will be given a copy of the IRB-approved consent form and asked to read the 
document with ample opportunity to take their time in its review.  The participant will have the consent 
documents reviewed with delegated study personnel and have all questions and concerns addressed to their 
satisfaction. Anyone who cannot demonstrate appropriate understanding of the study or who expresses an 
unwillingness to participate in the protocol will be ineligible to participate and will be assisted in finding 
treatment resources.  Those who demonstrate understanding of the study and voluntarily agree to participate 
will be asked to sign the informed consent form and proceed with the screening assessments.  As part of the 
informed consent procedures, participants will be asked to provide or decline consent to be contacted for 
future studies. Copies of the signed consent documents will be given to the participants for their reference 
and resource.  
 

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We may also use several different methods to complete electronic informed consent, if applicable, that 
include the following: 1) via MUSC’s doxy.me system (teleconsent), or 2) via REDCap electronic consent 
(e-consent) combined with a video discussion (doxy.me). As a last resort, we will also email the consent 
document to the participant and conduct the informed consent via video chat (doxy.me). Participants can 
then email or mail the signed consent back to the research team. Video chat functionality will only be used 
if all parties have the availability.   
 
All doxy.me signed consent forms will be saved as PDF files within our study records. E-consent via 
REDCap will be saved with a separate informed consent database. This database will not include any data 
collected as part of the trial. Using these systems, signatures on the consent form may be obtained 
electronically via REDCap/doxy.me. In the case that participants mail back hard copies of the consent (in 
rare instances), those will be stored in locked file cabinets in the offices of research staff. Participants will 
also be asked to complete a W-9 during the informed consent/e-consent process. 
 
To manage participant bias, the title of the study details in the informed consent document are not as specific 
as they would normally be to maintain the integrity of this research.  
 
A waiver of consent will be obtained for quality improvement saliva samples. These results will be not used 
for research purposes. 
 
 
9.0 
Study Design / Methods 
 
Screening Visit: Interested individuals will receive a telephone screening to determine if they may be 
eligible. They will then be scheduled for a screening visit, consisting of informed consent, followed by a 
medical history and physical exam by a study clinician, self-report questionnaires, and semi-structured 
interviews to determine eligibility. If an individual is a patient at MUSC, our medical clinician will have 
access to his or her medical record and will check for current health issues or medications that may affect 
safety. At this visit, participants will also see an example mobile diary (on their own mobile device or a 
loaner smartphone) 
and complete it in 
office. 
Participants 
will then begin to 
receive daily diaries, 
which 
they 
will 
complete 
every 
morning to report on 
their 
cigarettes 
smoked, 
other 
tobacco use, other 
drug use, and alcohol 
used during the previous day. Participants will complete these morning reports daily through 
their week 12 visit.  For those who are eligible, we will employ a training visit separating 
screening and the start of medication (Day 0) to ensure adequate compliance before the 12-week treatment 
begins. At this training visit, participants will see an example medication video (on their own mobile device 
or a loaner smartphone) and complete it in office. After the training visit, participants will begin receiving 
daily example medication videos, which they will be instructed to complete twice a day to prepare for Day 
0. This period constitutes a pre-quit monitoring lead-in prior to the dispensation of medication. The study 
design is shown in Figure 4.  
 
Figure 4. 

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Training Visit:  At this training visit, participants will see an example medication video (on their own 
mobile device or a loaner smartphone) and complete it in office. After the training visit, participants will 
begin receiving daily medication videos, which they will be instructed to complete twice a day so as to 
prepare for Day 0. Participants will complete these medication videos twice a day through their week 12. 
This period constitutes a pre-quit monitoring lead-in prior to the dispensation of medication. Participants 
will receive a brief counseling session in preparation for their target quit date (Day 8).  
 
Day 0: On Day 0, participants will be given their first week of varenicline. The standard dose titration 
schedule will be used, which includes 0.5 mg once per day (q.d.) on Days 1-3, 0.5 mg twice per day (b.i.d.) 
on Days 4-7, and 1.0 mg b.i.d. starting on Day 8. Dosing of 2.0 mg per day will be maintained for the next 
11 weeks. They will be given contact information if they are experiencing adverse events, including an 
emergency number for after-hour issues with medication. Participants will be encouraged to contact study 
personnel at any time to address concerns. The medical clinician/Co-I will provide medical supervision for 
this study and designated medical clinicians will provide oversight for any adverse events. MUSC medical 
clinician(s) will have the ability to support non-Charleston based site staff with adverse events and other 
medical concerns remote via telephone, doxy.me, or other HIPAA-compliant, MUSC-IS approved 
platforms for telehealth. If a participant experiences intolerable medication-related adverse events, a dose 
reduction to 0.5 mg twice per day may be undertaken (temporary or permanent dose reduction depending 
on alleviation of symptoms). If the participant is unable to tolerate the reduced dose, the medication will be 
discontinued, and the participant will continue to be tracked. At this visit, participants will be reminded or 
retrained on how to upload videos of themselves taking their medication (twice daily) via REDCap. 
Medication to be used by non-Charleston study sites will be ordered through MUSC and shipped directly 
to research staff or directly to the participant’s home via registered courier. Staff will store medication in a 
controlled access environment and only accessed by designated staff.  
 
Behavioral strategies will also be used to promote tobacco abstinence. First, psychosocial counseling will 
be administered at the training visit and Day 0 in preparation for the target quit date (Day 8). During the 
treatment phase, brief counseling (<5-10 minute) will be provided at all weekly visits by trained research 
staff and will include motivational enhancement for medication adherence and tobacco cessation. The 
content of counseling will be skills-based and focused on enlisting social support, recognizing smoking 
triggers, managing craving/withdrawal/stress, etc. Cannabis use will not be addressed as part of counseling. 
If the participant expresses a desire to reduce/quit using cannabis, standard information and resources will 
be provided, but this will be kept minimal to avoid researcher-imposed impact on cannabis use. Participants 
will be encouraged to pursue desired cessation, but will be reminded that the current study is focused on 
tobacco cessation. 
 
Mobile sessions: Each morning during the 12-week study (and one week leading up to Day 0), participants 
will receive a text message and email link to complete their daily diary. Daily diaries will be administered 
and data will be managed through the Research Electronic Data Capture system (REDCap) (82). Our 
research team has previously used daily diaries through REDCap (77). Standard questions will be 
administered regarding substance use that occurred during the prior day (midnight to midnight of the past 
calendar day). 
 
Weekly Visits (Weeks 1 - 12): Participants will be asked to complete weekly visits for the next 11 weeks. 
During visits, research staff will review compliance with daily diaries and discuss medication adherence 
over the past week (assessed through REDCap medication videos, smart bottle caps, daily diaries, and pill 
counts). Medication tolerability will be systematically assessed, and medical clinicians will be contacted if 
any potentially related adverse events are reported. Self-report assessments will be administered (e.g., 
craving, withdrawal, etc.). Brief cessation counseling will be conducted and bonus compensation (i.e., 

Version 30 (Version Date: 29JANUARY2024) 
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contingency management) will be provided based on tobacco abstinence. Vitals will be obtained at weeks 
4, 8, 12, or as needed throughout the study (any visit). Urine samples will be collected and separated for: 1) 
immediate tests conducted by research staff (cotinine, cannabinoids, pregnancy [weeks 4, 8, 12, or as 
needed], other drugs); and 2) delivery to the MUSC Charleston laboratory for quantitative urinary cotinine 
and cannabinoid (creatinine-normalized) assay runs. Staff will label and store urine samples (if not in 
Charleston) to be shipped to MUSC per laboratory protocols. A sub-sample of 10 participants who are 
cannabis co-users will also be asked to participate in a study addendum that includes the collection of a 
saliva sample to test for various cannabinoids. Participants will complete their end-of-treatment study visit 
(Week 12), and a follow-up visit at Week 26. Early termination (ET) visits (in-person or remote) may occur 
if a participant wishes to withdraw from the study.  Week 12 assessments and procedures will be conducted 
for ET visits, should they occur.  
 
Follow-up Phone Visit (Week 16): During this follow-up visit, participants will be contacted for a brief 
phone call to assess overall health, as well as current tobacco and cannabis use.  
 
Follow-Up Visit (Week 26): During this final follow-up visit participants will complete self-report 
questionnaires (e.g., craving, withdrawal, etc.). Daily use of cigarettes, other substances, alcohol, and other 
tobacco will be gathered during the follow-up period. 
 
Unscheduled Visit (PRN): Participants may be asked to return to the study office for unexpected incidental 
needs such as addressing a technological concern with the loaned study equipment (phone) or any other 
issue that cannot be resolved remotely. It is not anticipated that any supplemental data would be collected 
at these visits and they should take less than 15 minutes to complete. 
 
If a participant has an unexpected conflict with attending a visit or the visit must be completely by staff 
remotely (e.g., transportation issue or travel), arrangements (i.e., phone visit) may be made to remotely 
complete visit procedures, in order to maintain data collection and study engagement. There is the potential, 
with proper planning, that participants may be able to complete urine needs at home. Participants will be 
given proper materials and properly instructed on how to collect/store urine while at home.  
 
Remote Visits: All procedures that can be conducted remotely or through minimized participant contact 
are possible and will be used as needed (i.e., phone visits, online REDCap surveys, remote consent, detailed 
medical histories through telehealth platforms). When in-person contact is needed, steps will be taken to 
minimize contact or the need for a participant to enter a shared research suite (i.e., returning medication 
bottles in the parking lot, breath CO in their car, at home urine collection procedures, etc.) to comply with 
any MUSC restrictions in place at that time. At home urine procedures may be conducted (instant-read 
cotinine, urine drug screen and pregnancy tests), in addition to freezing and returning samples at a later time 
for laboratory assays (based on supply availability, participant or staff comfort with at home procedures, 
etc.). If occurring at Day 0, a pregnancy test will be completed prior to medication administration. 
Participants will be given proper instructions on how to complete the test, and all testing procedures will be 
performed in real time with participants via video conference (i.e., Zoom, Doxy.me, etc.). Study staff will 
confirm instant-read cotinine results over video.  
 
Most study procedures can be done remotely, and this will be utilized at the Florence site. Staffing at that 
site will be minimal and most procedures will be conducted by Charleston or Pickens staff approved and 
trained on study procedures. Florence staff will engage in human subjects research, data and specimen 
collection, etc. and will be trained and approved on this study. 
 
Research staff may arrange for taxis to transport participants to research offices when personal 
transportation is not possible. In rare circumstances, when taxis are not possible, research staff may meet 

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participants in the community at a public location in order to exchange study supplies (e.g., at home urine 
samples, medication bottles, or provide study supplies to participants). Safety procedures will be followed 
if this option is deemed necessary.   
 
EMA 
Supplement 
Procedures: In addition to 
procedures 
described 
above, 
tobacco-cannabis 
co-using 
participants 
(N=48) will be asked to 
complete 1-week bursts of 
EMA data collection at four 
timepoints during the study: 
1) baseline/pre-medication 
(to occur between screening and the Day 0 visit where medication is dispensed), 2) Week 1 (starting at the 
target quit date and going until Week 2), 3) Week 11 (starting at Week 11 and ending at the Week 12 end-
of-treatment visit, and 4) Week 25 (starting at Week 25 and ending at the Week 26 final follow-up visit; 
see Figure below). The timeframes listed are ideal. The bursts can shift if there are issues such as technology 
issues or the participant is difficult to contact. The EMA protocol is part of an NIH-funded EMA supplement 
to the parent study and will be implemented via the ilumivu mEMA platform, which is compatible with 
Android and iOS devices.  During each 1-week EMA burst during the parent study, participants will be 
asked to complete four semi-random surveys over a 16-hour period (separated into 4-hour time blocks, 1 
session randomly prompted in each block).  
Instruments and measures:  A complete listing of specific instruments/measures is shown below in Table 
2 (Assessment Timeline). Cannabis-related instruments will only be administered among co-users.   
Screening/Diagnostic Assessments: Detailed demographic information will be collected at screening, 
which is necessary to inform the propensity score analysis methods. Locator information will be collected 
and updated throughout the study. Medical and psychiatric assessments will be conducted by designated 
medical clinicians and trained research staff to ensure eligibility criteria are met.  
Biochemical Verification of Tobacco, Cannabis, and Other Substances: At each study visit, a urine 
sample will be collected and an instant-read urine drug screen will be conducted, which includes a 
qualitative urinary cannabinoid test (cut-off of 50 ng/ml) to determine cannabis use status, as well as assays 
for other commonly used substances (amphetamines, opioids, etc.). Urinary cotinine (a metabolite of 
nicotine) will be the primary indicator of tobacco abstinence (83). Qualitative urinary cotinine will be tested 
via instant-read, immunoassay test strips for purposes of contingency management. Urine samples will be 
aliquoted and delivered to the laboratory for determination of quantitative cotinine levels. Abstinence 
criteria for quantitative cotinine will be set at 80 ng/ml. Urinary quantitative cannabinoid values (11-nor-9-
carboxy-Δ9-tetrahydrocannnabinol; THCCOOH) will be tested at MUSC. Urine creatinine will also be 
obtained, to allow for creatinine-normalized urine cannabinoid levels. Saliva samples will be collected for 
10 study participants at one time point. A saliva sample may be collected in addition to other biochemical 
measures for quality improvement purposes and will not be used for research purposes. 
Substance Use Assessments: Several substance use assessments will be conducted throughout the study, 
including; detailed use history (for all substances), dependence level, motivation to quit (tobacco and 
cannabis), craving, withdrawal, satisfaction and subjective effects (cannabis and tobacco), and motives for 
use (full listing in Table 2). TLFB procedures (84) will be used  at screening (30-day calendar) to assess the 
frequency and quantity of tobacco use (cigarettes per day and other tobacco use), cannabis, alcohol and 
other drug use. In order to determine an individual-specific cannabis unit, cannabis quantification 
procedures will be conducted at screening and as needed when new methods of cannabis use are endorsed. 
For plant material-based methods, grams of cannabis will be estimated using a surrogate substance (78). 

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Participants are asked to show research staff the average amount of cannabis that they use (with the 
surrogate) for each combustible modality endorsed (e.g., joints, blunts) and report the estimated dollar 
amount associated with that quantity. The surrogate substance is then weighed on a scale to determine 
average grams per method. That amount then serves as the individual’s standard unit (e.g., “standard blunt”) 
for future reporting. This quantification procedure has been successfully implemented previously (85, 86), 
is being used in an ongoing study at MUSC (R01 DA038700), and has been shown by our team to improve 
the predictive validity of clinical outcomes (87). The gram estimation procedure will not work for non-plant 
based cannabis use methods, which are challenging to quantify. We will quantify these non-combustible 
methods with techniques used in an ongoing study (R01 DA038700). We will assess times used or hits 
taken (waxes, dabs, concentrates, lotions), milligrams ingested (edibles, drinks), and milliliters used (oils, 
tinctures, liquids). We expect that non-combustible methods will continue to evolve and we will modify 
our procedures accordingly.  
Safety Assessments and Medication Adherence: Adverse events will be systematically collected at all 
visits and will be coded in Medical Dictionary for Regulatory Activities (MedDRA) terms. Medication 
adherence will be monitored through several methods; pill counts, smart bottle caps, daily self-report of 
doses taken through the daily diaries, and review of medication videos submitted through REDCap.      
EMA measures: EMA items will include 10-30 items assessing cannabis use, tobacco use, and cannabis-
tobacco co-use and relevant variables related to co-use relationships. At each EMA session signal, 
participants will be asked to report whether they have used cannabis, tobacco, or both substances since the 
previous assessment. Branching logic will be used to administer follow-up items on quantity and frequency 
of use since the previous assessment, subjective effects, cannabis intoxication, tobacco craving, etc. Each 
assessment is expected take 1-3 minutes to complete. 
 
 
                                                                                                           
 
 

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Table 2. Assessment Schedule 
 
SC 
T 
Treatment Phase 
F/U 
Study Week  
SC 
T 
M 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
16 
26 
Informed Consent/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Locator Form and Updates 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical/Psychiatric Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History and Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MINI International Neuropsychiatric Interview 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Columbia Suicide Severity Rating Scale (C-SSRS) 
– Clinician Administered 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospital Anxiety and Depression Scale (HADS) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Test (females only)a 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Biochemical Measures of Substance Use 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Carbon Monoxide 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Urine Drug Screen (instant-read) g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Urine Cotinine (lab assay and instant-read) g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Urine Cannabinoids (lab assay)* g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Substance Use Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Substance Use History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Timeline Follow-Back 
X 
X 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
X 
X 
Tobacco 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fagerström Test for Nicotine Dependence (FTND) 
X 
 
 
 
 
 
Xf 
 
 
 
Xf 
 
 
 
X 
 
X 
Stages of Change - Short Form (Tobacco) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Readiness/Confidence/Interest to Quit Smoking 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minnesota Nicotine Withdrawal Scale 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Modified Cigarette Evaluation Questionnaire 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Questionnaire on Smoking Urges – Brief 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Smoking Abstinence Self-Efficacy 
X 
 
 
 
 
 
Xf 
 
 
 
Xf 
 
 
 
X 
 
X 
Wisconsin Predicting Patient’s Relapse 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quit Smoking Methods 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Cannabis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cannabis Quantification 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cannabis Use Disorder Identification Test-Revised 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Cannabis Quit Interest 
Xd 
 
X 
 
 
 
Xf 
 
 
 
Xf 
 
 
 
X 
 
X 
Marijuana Craving Questionnaire 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Modified Lyons Battery for Subjective Effects 
X 
 
X 
 
 
 
Xf 
 
 
 
Xf 
 
 
 
X 
 
X 
Marijuana Problems Scale  
X 
 
X 
 
 
 
Xf 
 
 
 
Xf 
 
 
 
X 
 
X 
Cannabis Withdrawal Scale 
X 
 
X 
 
 
 
Xf 
 
 
 
Xf 
 
 
 
X 
 
X 
Marijuana Motives Measure 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patterns of Co-Use Assessment 
X 
 
X 
 
 
 
Xf 
 
 
 
Xf 
 
 
 
X 
 
X 
Acceptability Surveys 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication Acceptability Survey 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Participant Satisfaction Survey 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Co-Use Treatment Preferences Survey 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Medication Safety/Adherence 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsa 
Blood Pressure, Pulse 
Height [screening] 
Weight [screening, Weeks 12 and 26] 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication Adherence 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pill counts 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Pillsy cap 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
REDCap videos 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Mobile Surveys 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Daily Diaries 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
 
 
REDCap Medication Videos 
 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
 
 
EMA Mobile Sessions (ilumivu) 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
SC=Screening/Assessment; T=Training Visit; M=Medication Dispensation (Day 0); F/U=Post-Medication Follow-Up 
a=can be completed as needed throughout the study (at any study visit) 
b=completed at weekly visits when daily dairies are missed 
c=conducted at screening and then throughout the study when new methods of cannabis use are endorsed; should be completed for any ppt who endorses 
cannabis use (even if NOT categorized as a co-user) 
d=administered at screening as part of a cannabis history questionnaire, and then administered alone at subsequent visits 
administered daily (diaries) or twice daily (med videos) 
e=administered daily (diaries) or twice daily (med videos) 
f=Study assessments completed at Weeks 4 or 8 may be completed at Weeks 5 and 9 
g=Saliva sample may be collected in addition to other biochemical measures for quality improvement purposes, will not be used for research purposes 

Version 30 (Version Date: 29JANUARY2024) 
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*=Saliva sample will also be collected for 10 study participants to assess for cannabinoids 
 
Participant Compensation: Participants will be compensated $40 for the Screening visit and $30 per visit 
for Training, Day 0, other weekly visits (13 visits) and/or early termination (ET) that occurs at any point 
other than during the Week 12 window ($50 for Week 12 window visits). They will be compensated $50 
for the end-of-treatment visit (Week 12), and $50 for the 6-month follow-up visit (Week 26). Compensation 
is based on completion of all study procedures. Partial 
compensation may be given for partially completed study 
visits. For example, payment amounts for remote visits 
will be contingent on return of the urine sample to study 
staff at the next in-person study visit. Compensation will 
be delivered contingent on tobacco abstinence at weekly 
visits starting at Week 2 ($20 per visit; $220 possible). 
Participants will be compensated for completing daily 
dairies and medication videos during the 12-week 
treatment phase. Compensation amount for remote surveys and videos will be based on the percentage of 
videos and morning reports completed over the past week and will be paid at weekly visits. The 
compensation scheduled based on the percentage of completed sessions is shown to the right ($300 
maximum for ≥90% compliance over 12 weeks). Participants may earn a total of $1,050 for study 
participation and completion of all study procedures. 
 
Payment for study visits will be made using a pre-paid debit card, called a ClinCard. It works like a bank 
debit card and participants may use the card to purchase goods or services everywhere Debit MasterCard is 
accepted. Participants will be given or mailed a ClinCard at the beginning of the study.  Each time they 
receive payment for participation in this study, the money will be added to the card, as outlined in the 
payment schedule above.  Details of the debit card system are explained on an additional sheet.  
 
If an Unscheduled Visit is required during study participation, the participant will be compensated $10/visit 
in return for the time and travel demands asked of them. 
 
Additionally, Respondent-Driven Sampling (RDS) will be used to enhance recruitment. The RDS sampling 
methodology is based on recruiting the eligible friends and acquaintances of each participant so that the 
sample “snowballs.” Each eligible participant who is enrolled into the study, and agrees to take part in this 
recruitment assistance, is eligible to receive compensation for successful referrals. A referral will be 
instructed to call the study team to be screened for eligibility. If that person successfully enrolls into the 
study (i.e., completes the Day 0 visit and begins taking study medication), the participant who referred them 
can receive $30 in compensation for each eligible participant that is referred and enrolled in the study. The 
research team has used these methods successfully in the past.  
 
In addition to compensation described above, participants enrolled in the EMA supplement portion of the 
study will be compensated contingent on completion of EMA surveys. For each 1-week burst of EMA data 
collection, participants may earn a maximum of $70 for completion of sessions on a sliding scale. A 
maximum of $280 can be earned over the four, 1-week bursts of EMA data collection. 
 
10.0 
Statistical Analysis and Data Management  
 
Analytic Strategy.  
 
Medication Videos and Logs 
(% completed each week) 
Payment 
90-100% compliance 
$25 
80-89.9% compliance 
$20 
70-79.9% compliance 
$15 
50-69.9% compliance 
$10 
30-49.9% compliance 
$5 
<30% compliance 
$0 

Version 30 (Version Date: 29JANUARY2024) 
Page 19 of 31 
Power and sample size. The proposed study is powered to detect a meaningful difference in end of treatment 
tobacco abstinence between cannabis co-users and tobacco only users. Secondarily, the study will assess 
the relationship between cannabis use patterns during treatment and nicotine dependence severity in co-
users. Specific Aim #1: Examine the impact of cannabis co-use on tobacco cessation outcomes among co-
users compared to tobacco only users. Hypothesis 1: Co-users will have lower rates of 7-day point 
prevalence abstinence from tobacco at the end of treatment (Week 12) compared to tobacco only users. In 
a cross-sectional survey of national household data (51), tobacco cessation was reported among 65.5% of 
respondents who endorsed no cannabis use as compared to 21.8% of tobacco cessation in those reporting 
current cannabis use (Δ=43%). Studies examining the efficacy of varenicline for tobacco cessation (108, 
109) noted near 50%-point prevalence abstinence at treatment conclusion (Week 12) in the varenicline-
treated group. Finally, in our recently completed adolescent varenicline trial (U01 DA0317779), youth 
cannabis co-users reported point prevalence tobacco abstinence in 20% of participants at Week 12 and 43% 
in those who use tobacco only (analysis with all available data). The proposed R01 study intends to apply 
a successful tobacco treatment (varenicline) paired with contingency management in treatment-seeking 
smokers.  Assuming a similar abstinence rate in tobacco only users (45%) and a successful abstinence rate 
in participants who are cannabis co-users as compared to the adolescent study (20%; Δ=25%), to achieve 
80% power with a 5% type 1 error rate, a sample of 82 participants in the cannabis co-using cohort and 41 
in the tobacco only cohort.  However, to account for the inclusion of 2 study sites in the design, an additional 
fixed factor of site will be included in the analytic models.  Although we hope that equal proportions of co-
users and non co-users present at each site, we understand that the fundamental differences between the 
Charleston metro area, Pickens County SC, and Florence exist and may cause some correlation between co-
use group and study site.  Assuming that the proportion of variance in co-use groups due to study site and 
other covariates may be moderate (R2=0.25) and that attrition will not exceed 25%, we have adjusted our 
study sample size to account for this scenario.  This increases our randomized sample to a total of 208 (139 
cannabis co-users and 69 tobacco only users) accounting for both site correlations with co-use group and 
anticipated attrition.  If site correlations with study outcomes or attrition are lower than pre-specified, our 
statistical power will exceed 80%. Specific Aim #2: Among co-users, assess changes in cannabis use during 
tobacco cessation treatment. Hypothesis 2: Co-users with moderate to high severity of nicotine dependence 
will demonstrate increases in concurrent cannabis use, while lower severity of nicotine dependence will 
yield no changes in cannabis use. To attain adequate power to assess Aim #2, a within co-use cohort 
comparison, the study will oversample the cannabis co-use cohort as compared to the tobacco only cohort 
(2:1). At screening, nicotine dependence will be assessed via the Fagerström Test for Nicotine Dependence 
(FTND) (92) and categorized accordingly: low nicotine dependence (0-4), medium or high nicotine 
dependence (5-6; 7-10). Cannabis use during the final 4 weeks of study treatment as compared to baseline 
use will be assessed among co-users. Based on our preliminary data from an ongoing adult tobacco cessation 
trial (R34 DA042228), we have nearly equivalent numbers of participants falling into low and 
moderate/high nicotine dependence categorizations (Mean=4.5; Median=5). Therefore, we anticipate ~40% 
will have medium/high nicotine dependence. With 208 participants, 139 in the cannabis co-use cohort (104 
completers), we will achieve 80% power with a type 1 error rate of 5% to detect a between group cannabis 
use difference of Cohen’s d≈0.6 (Med/High nicotine dependence vs. low nicotine dependence). 
 
Statistical analyses.  Demographic, clinical and substance use characteristics will be collected at baseline 
and tabulated for the overall study cohort and between study groups. Categorical variables will be assessed 
between groups by chi-square tests of independence, while continuous variables will be assessed using 
Student’s t-test. In addition to baseline group differences, preliminary analysis of baseline characteristics 
with tobacco use outcomes of interest will examine significant correlates of abstinence in the study 
population. 
 
Propensity Score Methods: Both cannabis co-using cigarette smokers and tobacco only smokers will be 
recruited in a 2:1 allocation and all participants will receive varenicline, contingency management, and 

Version 30 (Version Date: 29JANUARY2024) 
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psychosocial counseling. Non-randomized trials often suffer from inherent selection bias due to systematic 
baseline differences in study populations (110). The use of propensity scores has been shown to reduce 
selection bias and increase parameter estimate precision in non-random designs better than traditional 
covariate adjustment (111). In the proposed study population, we anticipate a mild, yet systematic difference 
in baseline factors between cannabis co-users and tobacco only users. Specifically, we expect that age and 
race (112) may be substantially imbalanced as well as baseline severity of tobacco use and nicotine 
dependence. To account for such differences, augmented inverse probability of treatment weighting using 
the propensity score (AIPW) methods will be used to account for observed covariate values (113). This 
methodology will provide unbiased parameter estimates and standard errors of the average treatment effect 
even when either the propensity model or outcome model is mis-specified (doubly robust) (114). All 
observed variables that may potentially influence the self-selection into the co-use group will be included 
into the calculation of the propensity score (gender, education, motivation to quit, nicotine dependence, 
social influences, etc.). Prior to model analysis, weighted means of the measured baseline characteristics 
will be assessed between groups to assess balance. Additionally, weights will be checked for values close 
to either zero or one and adjustments to the probability model will be made when necessary. Augmented 
propensity score weighting strategies (AIPW) were chosen as the primary analytic approach as opposed to 
matching or stratification such that all study participants will be retained in the final analysis and statistical 
power would be preserved with the proposed sample size. 
 
Primary Study Aims: Aim 1: To assess the difference in the log-odds of abstinence from tobacco at the end 
of treatment (Week 12) between baseline cannabis co-users compared to tobacco only participants, 
augmented inverse probability weighted logistic regression models will be developed. The inverse of the 
conditional probability of being in the cannabis co-use cohort will be included in the model to account for 
inherent imbalances between study groups and to reduce bias by resembling a randomized controlled trial. 
In addition to the inverse propensity weights, AIPW methods incorporate a covariate and study site adjusted 
model for the study group outcome (114). Aim 2: To assess the association of baseline nicotine dependence 
severity (Med/High nicotine dependence vs. low nicotine dependence) with cannabis use rates during study 
treatment, generalized linear mixed effects models will be assessed with cannabis use rates and amounts 
during the final 4 weeks of treatment as the primary indicator of cannabis use severity and nicotine 
dependence group as the primary model predictor. In addition to grouping by nicotine dependence severity, 
continuous levels of dependence severity (FTND score) will be modeled to assess possible linear and 
quadratic relationships between dependence severity and cannabis use. Following examination of the 
differences in end of treatment cannabis use rates based on baseline nicotine dependence, rates of cannabis 
use will be assessed by group (nicotine dependence severity) over all weekly study visits to determine if 
those with increased dependence severity exhibit a different trajectory (slope and pattern) of cannabis use 
during the entire study treatment. Model-based means and associated standard errors will be used to test 
group level differences. Exploratory Aim: To assess the relationship between baseline cannabis use severity 
and tobacco outcomes, generalized linear mixed effects models will be developed with weekly 7-day point 
prevalence abstinence from tobacco as the primary model outcome. In addition to tobacco abstinence, 
weekly average cigarettes per day will be examined as an indicator of use reduction differences over time. 
Longitudinal patterns in tobacco abstinence and use amounts will be modeled through the inclusion of 
baseline cannabis use severity indicators, study visit, and baseline tobacco use rates as model covariates. 
Additionally, differential effects over time will be examined with the inclusion of the interaction of cannabis 
use severity and study visit. Model-based means and associated standard errors will be used to test group 
level differences across the study treatment. 
 
Secondary Data Analysis:  In addition to end of treatment point prevalence tobacco abstinence rates, similar 
analytic models will be used to assess abstinence rates at the 6-month follow-up visit. Additionally,  
longitudinal analysis of weekly tobacco abstinence will be assessed using repeated measures logistic 
regression models using a general estimating equations framework (GEE) (115) and working correlation 

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structures will be independently compared using the quasi-likelihood under the independence model 
criterion statistic (116). Similarly, the number of smoking days per week and cigarettes per day will be 
collected via daily diaries and compared between co-use cohorts using generalized linear mixed effects 
regression models.  Finally, weekly cannabis and tobacco use will be collected to develop group-based 
trajectory models and time naïve covariates will be used to determine group membership. Additionally, 
changes in cannabis craving, withdrawal, use, and subjective effects during treatment with varenicline will 
be examined in the cannabis co-use group. Specifically, changes in cannabis craving, withdrawal 
(synchronous effects of varenicline) and cannabis use severity (substitution) will be assessed for 
correlations with changes in tobacco use.  Generalized linear mixed effects models will be developed with 
cannabis use outcomes and the time varying effects of tobacco use as the primary independent variable. 
Further, noting possible differences in the relationship between tobacco outcomes and combustible/non-
combustible cannabis use, model effect modification will be assessed using cannabis use type groupings 
(primarily combustible vs. primarily non-combustible). All analyses will be conducted using SAS version 
9.4 (SAS Institute, Cary, NC, USA). 
 
Missing data and attrition. The study team has procedures in place to minimize missing data and attrition 
(e.g., reminders, compensation, updated and detailed locator information, etc.); however, these methods do 
not ensure that all data will be collected. Appropriate analysis methods will be employed to accommodate 
missing data. Methods of maximum likelihood yield valid inferences assuming ignorable attrition (i.e., 
attrition is accounted for by covariates or the dependent variable measured prior to dropout). In addition, in 
keeping with the Intent to Treat Principle, we will make every effort to continue assessments for the entire 
course of treatment, even among those who stop participating in study procedures. 
 
Data Management. Data will be collected by trained and approved research staff and will only be identified 
with the study’s ID of the participant. The codes linking the name of the participant to the study ID will be 
kept confidential in a secured cabinet or password-protected data file. Collected study forms will be kept 
within the office suite of the PI and research staff (Charleston) and within research office suites at 
participating sites and will not be taken outside of any office buildings. Research staff will enter data into 
a database management system maintained by MUSC, Research Electronic Data Capture (REDCap). 
REDCap is a secure, web-based application designed exclusively to support data capture for research 
studies. These procedures are effective in minimizing data entry errors (e.g., missing or errant data). Direct 
entry of data by study participants (self-reports) will also be conducted in this study. This is done through 
a front-end survey interface that allows the participant to enter data on select questionnaires/assessments, 
but not access any other study records or data in REDCap. A REDCap survey link will be used to collect 
mobile daily diaries and videos of medication dosing, which are immediately transmitted into REDCap with 
de-identified subject IDs. Videos are uploaded and stored within REDCap, and not the user’s device. Server 
maintenance will be conducted by Information Technology Specialists at MUSC. The PILLSY platform 
will house PHI (email and phone number) that is necessary to setup a participant with a smart cap. PILLSY 
has been vetted by MUSC IS and is approved to house data. The platform is password protected and only 
accessible by study team members.  
 
For EMA data collection in ilumivu, participants will be assigned a deidentified subject ID, which study 
staff will keep confidential in a secured cabinet or password-protected data file. After each participant 
installs the ilumivu app on their personal mobile phone, they will enter a unique code and the app downloads 
surveys and survey schedules for the participant. Once information is downloaded to the participant’s 
phone, the app is operated offline with no connections to the ilumivu server. Periodically, participants are 
asked to click a synchronization button to upload the collected data to a secure server. All data are encrypted 
before being transmitted to the cloud-based storage database. The data are stored in a MariaDB database 
where the only identifying information associating it with the participant is the unique randomly generated 
code. Access to the database is gated; entry is only permitted to users entering through the approved route 

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(cannot be accessed by guessing the URL). Ilumivu, Inc. is an approved vendor with MUSC and is being 
used with other study protocols. MUSC and ilumivu have signed a terms and conditions document to assure 
data protection and privacy. 
 
11.0 
Provisions to Monitor the Data to Ensure the Safety of Subjects  
 
The PI will create a DSMB, comprised of multidisciplinary faculty with expertise in addiction-focused 
pharmacotherapy and behavioral treatment trials. The DSMB will meet annually (more frequently as needed 
for emergency situations) to review any AEs related to the study, as well as review of any data management 
related errors. The board may be called at any point if needed for SAEs, etc. Modification will be made in 
the procedures and/or the protocol if necessary, based on the findings of the board. 
 
Reports provided to the DSMB on an annual basis will address the following areas: 1) the progress of the 
research study, including assessments of data quality and participant recruitment, accrual, and retention; 2) 
review of outcome and adverse event data to determine whether there is any change to anticipated benefit-
to-risk ratio of study participation, and whether the study should continue as originally designed, should be 
changed, or should be terminated; 3) assessment of external factors or relevant information; and 4) review 
of study procedures designed to protect the privacy of the research participants and the confidentiality of 
their data. Following review of the annual update on the study, the DSMB will provide a written report that 
will be submitted annually with the IRB renewal. 
 
Data will be collected by the appropriate individual (PI and/or designated research staff) and will only be 
identified with the study’s ID of the participant. The codes linking the name of the participant to the study 
ID will be kept confidential in a secured cabinet by the PI or password-protected data file.  Only the PI and 
designated research staff will have access to these files. Collected forms will be securely transported to the 
offices of the PI and designated research staff for data entry. Research staff will enter data in REDCap; a 
secure, web-based application designed exclusively to support data capture for research studies. REDCap 
provides: 1) an intuitive interface for data entry (with data validation); 2) audit trails for tracking data 
manipulation and export procedures; 3) automated export procedures for seamless data downloads to 
common statistical packages (SPSS, SAS); 4) procedures for importing data from external sources; and 5) 
advanced features, such as branching logic and calculated fields. These procedures are effective in 
minimizing data entry errors (e.g., missing or errant data). The smartphone application is equipped to 
transmit data immediately into REDCap. Data are transmitted from study devices and identified through 
subject IDs. Once data have been transmitted to the secure study server and web portal from the loaner 
iPhone or participant’s personal smartphone, no personal information will be stored on the device. Any 
information that is stored on the phones will be de-identified. If the loaner iPhone is lost or stolen, devices 
will be reset immediately.  
 
12.0 
Withdrawal of Subjects  
 
Participants will be informed that they may discontinue the study at any time without penalty and that they 
will be pro-rated for all completed research activities. Participants may also be withdrawn from the study 
by the PI if it is determined that it is in the participant’s best interest (safety concern, requiring intervention) 
or due to the participant’s noncompliance with the protocol. 
 
13.0 
Risks to Subjects 
 
 The risks associated with participation in this study include adverse events related to study medication 
(varenicline), nicotine withdrawal, and the potential loss of confidentiality. Potential risk details are 

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described below and the PI will ensure that all risks are clearly defined for study participants and are 
thoroughly understood during the informed consent process and throughout the study period.  
 
Adverse Events Related to Study Medication. The informed consent process will be used to thoroughly 
educate participants about potential medication-related risks. Varencline is the medication being used in 
this study to support tobacco cessation. Several companies now offer varenicline in the US: 1) Chantix® 
(from Pfizer in the US: http://www.pfizer.com/files/products/uspi_chantix.pdf]; 2) Apo-varenicline in 
Canada 
(authorized 
for 
use 
in 
the 
US 
by 
the 
FDA; 
https://www1.apotex.com/products/us/downloads/mon/apo_var_fct_mon.pdf, 
https://www.fda.gov/media/150799/download), 3) generic varenicline from Par Pharmaceuticals: 
https://www.parpharm.com/pdfs/catalog/generic/Varenicline_Tablets_PI_07-2021.pdf), and 4) generic 
varenicline from Glenmark Pharmacueticals: https://glenmarkpharma-us.com/varenicline-tablets/. The 
risks associated with study medication (varenicline) are detailed in the informed consent document and will 
be discussed prior to enrollment. Specifically, it reports that “the most common adverse reactions (>5% and 
twice the rate seen in placebo-treated patients) were nausea, abnormal (e.g., vivid, unusual, or strange) 
dreams, constipation, flatulence, and vomiting.” While no serious or severe adverse events or interactions 
are expected to occur with varenicline, appropriate procedures are in place should participants experience 
adverse events related to varenicline administration. Rigorous screening procedures and exclusion criteria 
are designed to exclude potential participants at elevated risk for adverse events related to study medication. 
This includes comprehensive psychiatric assessment and evaluation to exclude individuals with currently 
unstable psychiatric and/or medical disorders. Designated medical and research personnel will conduct 
serial psychiatric and medical evaluations at screening and will be consulted as needed throughout the study 
to address any concerns that may arise. Comprehensive and detailed adverse event monitoring will be the 
responsibility of the entire research team. Adverse events related to this medication (e.g., nausea, vomiting, 
vivid dreams, constipation, neuropsychiatric events) are possible and will be assessed carefully throughout 
the study. The PI will be immediately contacted in the event of any emergencies and will guide the plan for 
addressing and managing the situation with the help of the designated medical clinicians on the study team. 
Participants experiencing intolerable adverse events will have the opportunity to reduce the dose of study 
medication or discontinue medication altogether, while remaining in the study for ongoing monitoring. 
Loss of Confidentiality. There is the risk of breach of confidentiality. The research team has procedures in 
place to minimize the risk of any confidentiality breach. Participant records are stored in locked files within 
locked offices, or in password-protected databases. Much of the data collected is de-identified and uses a 
participant ID. No specific or general participant information will be left in public access areas, and no oral 
communication regarding participants with identifiers will be made in any public areas. Research staff 
members have been given extensive training in maintaining confidentiality as well as HIPAA regulations. 
Participants will be informed of these potential risks during the informed consent process and will have the 
option to leave the study at any point. In specific instances, participant PHI (name, etc.) may be available 
to other entities, such as for ClinCard registration/payment purposes.  
Nicotine Withdrawal. Participants enrolled in the study will receive comprehensive tobacco cessation 
treatment and may reduce or abstain from tobacco use during the study period. Participants will be daily 
smokers, and as such, they may experience nicotine withdrawal symptoms and/or discomfort during their 
quit attempt. Nicotine withdrawal symptoms may include: anxiety, depressed mood, irritability, 
restlessness, sleep difficulty, strange dreams, increased appetite, headaches, tension, difficulty 
concentrating and general physical discomfort. There are no reports in the current literature of severe 
physiological or psychiatric consequences resulting from nicotine withdrawal. Participants will be informed 
of the potential discomfort they may experience during this brief period of abstinence and will be advised 
to contact research staff if they feel that their withdrawal symptoms worsen during the study.   
 

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Pregnancy. Participants who become pregnant during the trial will be instructed to discontinue study 
medication and withdrawn from the study. Participants will be encouraged to seek medical attention. The 
study team will be conducting pregnancy tests on all female participants at every visit to ensure safety. If 
participants are considering becoming pregnant within the next three months prior to study participation, 
then they will not be included into the study. We will also ask female participants to agree to use some form 
of birth control during the study as an additional precaution.  
 
 
14.0 
Potential Benefits to Subjects or Others 
 
This study will have no direct benefit to the research participant.  
 
 
15.0  Drugs  
 
This study will use varenicline as the study medication (Chantix®, Apo-varenicline, or generic varenicline 
from Par Pharmaceuticals or Glenmark Pharmaceuticals). Apo-varenicline is a generic version of 
varenicline that is approved for use in Canada and has been authorized for use in the US by the FDA 
(https://www1.apotex.com/products/us/downloads/mon/apo_var_fct_mon.pdf, 
https://www.fda.gov/media/150799/download). Varenicline from Par Pharmaceuticals and Glenmark 
Pharmaceuticals is approved by the FDA. Study drug will be housed within research office space. The 
medication will be stored in a controlled environment and locked in a cabinet only assessable by study 
personnel. Medical personnel will assess each participant to determine if they are suitable for this study 
and for medication administration.   
 

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