A Translational Randomized Clinical Trial of Varenicline Sampling to Promote Smoking Cessation and Scalable Treatment Dissemination
Phase: PHASE1
Conditions: Smoking, Smoking Cessation, Tobacco Smoking, Cigarette Smoking
Sponsor: Medical University of South Carolina

 
 
 
 
Grant Title: A Translational Randomized Clinical Trial of Varenicline Sampling to Promote Smoking Cessation 
and Scalable Treatment Dissemination 
 
Short Title: STARS (Smoking Treatment And Remote Sampling) Study 
Principal Investigator: Matthew Carpenter, PhD 
Funding Source: NCI (R01 CA246729) 
Registration: NCT 04525755 
Original Approval Date:  3/11/2020 
Last Approval Date (with protocol change): 10/14/2024  
Date of Final Amendment (without protocol change): 5/28/2025 
 
 
 

 
 
 
I. 
Background & Significance 
Despite advances in treatment of tobacco dependence, smoking continues to be the leading cause of 
preventable mortality, resulting in an estimated 480,000 U.S. deaths annually(1) and incurring nearly $170 billion 
in direct medical care for adults.(2) Tobacco control is cancer control, and novel approaches to cessation are 
needed. Such efforts must not only identify new treatments, but also find new ways to apply them at the 
population level. Given the lengthy duration to identify and test new treatments, we focus on the latter: wider 
implementation of existing treatments. Public health efforts must increase the incidence of evidence-based quit 
attempts (i.e., use of FDA-approved cessation pharmacotherapies), a clear goal of Healthy People 2020 
recommendations. Indeed, modeling research suggests that increasing population penetrance of evidence-
based quit methods will do more for population cessation rates than would increasing the efficacy of any given 
treatment.(3) USPHS clinical practice guidelines(4) and other meta-analyses(5-8) have made clear 
recommendations that 1) all tobacco users should be offered brief advice to assist in quitting, and 2) unless 
medically contraindicated, all smokers should be offered pharmacotherapy. However, our studies(9, 10) and 
those of many others(11-18) consistently demonstrate that use of pharmacotherapies is unacceptably low, with 
<25% of quit-attempters using these treatments (See Figure 1; not counting the many smokers not making a quit 
attempt).  
Individual Barriers to Evidence Based Quit Attempts 
Nicotine dependence is the primary cause of persistent smoking at the 
individual level.(19) But there are additional reasons as to why many smokers 
are unable or unwilling to engage in an evidence-based quit attempt. Many 
smokers make ill-supported, i.e., unassisted quit attempts over time,(20) 
creating a “rollercoaster” of motivation, confidence, and willingness to try 
again.(21) Our research group has recently explored the notion of “cessation 
fatigue,” i.e., general feelings of burnout, hopelessness, and pessimism, that 
likely drives and derives from this rollercoaster. Building on our formative 
work to develop a multidimensional scale of cessation fatigue,(22) we 
subsequently demonstrated that cessation fatigue prospectively predicts 
important cessation milestones (both initiation of quit attempt and 
lapse/relapse) and thus is a novel target for cessation intervention(23) 
Elsewhere, we(24, 25) and others(12, 26-28) have also shown that many 
smokers are unfamiliar with cessation medications, or hold misperceptions 
about them that likely undermine their use. These views are particularly entrenched among smokers of lower 
socioeconomic status,(25, 29, 30) which further undermines pharmacotherapy use among these groups, yet 
again undermining treatment engagement at the population level. Collectively, these factors work to undermine 
a smoker’s self-control over the quitting process, giving them fewer tools to succeed. Much like a muscle that 
needs to be exercised,(31, 32) self-control can also be strengthened, which has been empirically demonstrated 
to improve tobacco abstinence.(33) There is thus an important public health need to capitalize on existing 
treatments and deliver them in ways that specifically enhance a smoker’s capacity to initiate and sustain 
evidence-based quit attempts. Such methods should bolster smoker motivation and confidence, increase 
familiarity with and acceptance of treatments, and enhance self-control, all in an effort to increase the incidence 
and success of quit attempts at the population level. Such interventions should be brief, concrete, and offer 
potential for scalability into larger populations of smokers. We believe that medication sampling meets this need 
(Figure 
2: 
Conceptual 
Model). Whether and how 
these mechanisms differ for 
varenicline vs. NRT sampling 
is unclear. Though this is not 
the central focus on this 
application, we will be able to 
test this.  
Medication Sampling 
Medication sampling simply refers to providing starter packs of cessation medications. Unlike traditional models 
that first rely on smoker intent to quit, sampling is readily scalable to smokers regardless of their quit intention, 
offering a concrete, behavioral cue to facilitate quitting. It is not meant to replace more intensive treatment, but 
rather serve as a catalyst to it. We would never suggest that sampling will yield similar cessation outcomes 
compared to full-course treatment (it will not; see Table 1 below). Sampling simply extends reach and gives 
Figure 2: Conceptual Model to Increase Evidence Based Quit Attempts 
Medication 
(Varenicline) 
Sampling
­ Motivation & 
Confidence
­ Autonomy
­ Familiarization
¯ Cessation 
Fatigue
­ Self-Control
­ Evidence-
Based Quit 
Attempts
­ Abstinence
Figure 1: Treatment Utilization Among 
Smokers Making a Quit Attempt in Past 
Year (Source: TUS-CPS) 
0
20
40
60
80
100
National Average
SC
Percent
Used NRT
Used Varenicline
Called Quitline

 
 
 
smokers an immediately actionable evidence-based treatment method, designed primarily to heighten smoker 
acceptance and enhance motivation and self-confidence.  
Table 1 demonstrates the population impact 
of current strategies for smoking cessation, 
assuming that 55% of smokers make a quit 
attempt,(34) 25% of them use cessation 
medication,(9) and 25% these will result in 
quitting success.(4) Medication sampling 
could increase population impact even if it 
resulted in a nominal increase in incidence of quit attempts, if not all quit attempters use the medication (a low 
estimate, given universal, free provision of product) and even if quit success is markedly lowered as compared 
to traditional RCT outcomes (as we would expect). Each of the above inputs for medication sampling are 
supported by our preliminary data, below. These data clearly show the potential of medication sampling at the 
population level.  
Uptake of cessation treatment is higher when medication accessibility is increased.(35) One simple but very 
interesting study assessed stages of change among two separate groups of smokers.(36) One group was asked 
about their intentions to quit, and the other group was asked the same question, but was preceded by a free 
offer of a cessation medication. The medication “carrot” significantly altered the distribution of motivation, with 
more smokers expressing quit interest. Translating this to cessation outcomes is more important, and is 
evidenced by our preliminary data, below. Many quitline studies show that provision of free medication improves 
cessation rates.(37-42) Some(38, 43) but not all(39) research even suggests that 2-week provision of NRT is as 
cost-effective for promotion of quitting as is extended supply.  
Our view of sampling is supported by the quitline literature above but extends beyond it in both conceptualization 
and methods. Quitlines reach a very small portion (~3%) of the smoker population.(9) They also reach a very 
narrow population: smokers who want to quit. And they provide medications in very structured ways, with guided 
instructions for cessation-focused use, and with support calls to follow. In contrast, our view of sampling is more 
naturalistic and self-determined. We target a wider group of smokers, including those not wanting to quit, with 
the belief that sampling is a concrete, behavioral catalyst (cue to action), consistent with major theories of health 
behavior change.(44-46) Instructions are kept minimal to increase translational, scalable potential for eventual 
provision within clinical settings. While not an explicit outgrowth of self-determination theory,(47, 48) medication 
sampling is wholly consistent with it; i.e., with the rationale that smokers will be more invested in the quitting 
process if they decide for themselves the goals and pace for changing tobacco use.  
Varenicline Sampling: Similar Benefits (or Not)? 
Varenicline is a well-established cessation medication(49-53) that reduces withdrawal and blunts the reinforcing 
effects of nicotine.(54) Its efficacy is well-documented, known to be superior to all other monotherapies.(49, 50, 
55-57) One survey of >900 medication users assessed a range of satisfaction measures across a range of 
medications.(58) Varenicline yielded the strongest endorsement of any: 77% called it an “excellent” medication 
(vs. 67%, the highest for any NRT product); 37% said it reduced tobacco consumption prior to a quit attempt (vs. 
19%, the highest for any NRT). Among smokers who used both varenicline and NRT (a within participant 
comparison), most favored the former over the latter, and 77% would suggest varenicline to a friend (vs. 59% 
for patch users, the highest of any NRT). These data show smoker preference for varenicline despite: a) 
prescription status, b) higher side effect profile, and c) anecdotal reports of medication harm. Prior to 2015, we 
could never have proposed a hands-off sampling study of varenicline, due to FDA black box warnings. The 
EAGLES trial(56, 57) changed that, as did a number of other persuasive reviews,(50, 59-62) all of which 
demonstrated a strong safety profile, even among smokers with psychiatric conditions. The black box warnings 
were removed, which now allows for greater population dissemination. Given prior studies that examined flexible 
administration of varenicline, including reduce-to-quit,(63, 64) flexible quit date(65) and lower dosing 
protocols,(66, 67) a sampling approach offers another compelling option to increase use and accessibility of our 
strongest medication option.  
Prior studies of short-term varenicline delivery; Prior studies of novel varenicline delivery  
We could find no studies that conform to our approach per se, but other studies offer indirect support. Two 
quitline studies examined the effects of varenicline distribution. The first was a non-randomized comparison 
between smokers who self-selected to receive varenicline or NRT via their quitline.(68) Abstinence at 3 months 
(RR=1.7) and 6 months (RR=1.5) favored varenicline. Three design elements constrain interpretation. First, 
these groups were non-randomized, and it was clear that varenicline users were very different from NRT users 
Table 1: Potential Population Impact of Medication Sampling 
 
Current 
Evidence 
Medication 
Sampling 
Probability (P) of Quit Attempt (x) 
.55 
.65 
(P) of Using Evidence-Based Quit Method (y) 
.25 
.8 
(P) Success Per Method (z) 
.25 
.1 
Impact: Population Quit Rate (x*y*z) 
3.4% 
5.2% 

 
 
 
(older, with longer duration of smoking). Second, there was no biological verification of smoking. Third, there 
was no non-sampling comparison. These are all issues we address herein. The other quitline study is a recent 
trial from Dr. Toll (co-investigator) that randomized smokers to receive mailed NRT (n=100) or vouchers for 
varenicline (n=200), to be redeemed for free at a local pharmacy.(69) Only 27% of smokers in the varenicline 
group redeemed the voucher, which limited tests of abstinence. This suggests that free coverage of medications 
alone is not sufficient, and that there needs to be more immediate access: i.e., actually giving it to the smoker. 
Again, the study did not include a non-sampling control group, nor did it biologically verify smoking outcomes.  
Outside the quitline context, and beyond short-term delivery, two studies examined varenicline as recommended 
(12 weeks), but with nuanced delivery that is highly relevant here. One was a study from Ontario that examined 
full course (12 weeks) varenicline vs. bupropion.(70) This was NOT a sampling study, adjunctive support was 
not minimal (extensive motivational emails throughout follow-up), nor was it open to a wide spectrum of smokers 
(eligibility based on wanting to quit in next 30 days). It is presented here because direct physician involvement 
was non-existent. Eligibility, assessment, and provision of prescription were managed entirely through an 
electronic process. Abstinence outcomes significantly favored the groups that received varenicline (RR=1.9) but 
not bupropion (RR=1.5), relative to smokers who did not receive medication. Like the Toll study above, uptake 
of medications through faxed prescription to a local pharmacy resulted in modest initiation and use of the 
medication, which again suggests that physical hand-off of medications might yield better outcomes. The other 
trial with novel delivery of varenicline was the COMPASS trial,(71) which tested various iterations of 
web/phone/proactive counseling. It is presented here because all trial participants received varenicline 
through mail without any formal clinical evaluation, as proposed here. In fact, our eligibility process largely 
mirrors theirs. Secondary analysis from this trial demonstrated high varenicline adherence,(72) particularly early 
on, which lends support to our approach. The COMPASS trial did not manipulate; (i.e., test) varenicline sampling 
per se, but offers guidance and rationale for remote delivery of varenicline as proposed here.  
Summary, Significance, & Scientific Premise 
None of the studies above, nor our preliminary studies below, would suggest that medication sampling is a 
panacea for smoking cessation. This is about reach, not efficacy. Sampling is ideally suited for a clinical setting, 
offering a brief, pragmatic, and behavioral strategy to complement advice to quit. It is meant for all smokers, 
regardless of their motivation to quit. It requires minimal instruction, either from the person giving it, or to the 
smoker receiving it. While cessation is of course the ultimate outcome of interest, sampling is primarily about 
treatment engagement, inducing further use of the medication and inducing quit attempts. Medication sampling 
is simply about getting more smokers to use better treatments, sooner. Strong evidence supports NRT 
sampling, but whether this translates to varenicline sampling is less clear. It could be the case that medication 
sampling is only effective for NRT (agonist, OTC availability, minimal side effects & easy dosing), or, as we 
believe, more generalized and inclusive of wholly different types of cessation medication (agonist/antagonist, Rx 
status, moderately more side effects, and somewhat more complicated dosing). This is a question worth testing, 
and testing well. The manufacturer may or may not get OTC status for varenicline, which, either way raises the 
significance of our study even further. Thus, in sum, varenicline sampling offers at least tri-fold significance: 1) 
clinical aid to cessation (broad dissemination of proven cessation agent); 2) policy implications (packaging, 
marketing to broad smokers, including those not ready to quit); and 3) regulatory consequences (mimic of 
potential OTC environment, with minimal clinician involvement). 
If this and future trials suggest efficacy of our sampling approach, this would suggest that physicians can and 
should give out samples of medications to all smokers, regardless of intent to quit. Our NRT sampling work 
(below) already supports this view, but whether this applies to varenicline is an entirely different story. It would 
be a leap to suggest that varenicline sampling would compare to NRT sampling, and this is the very reason this 
proposal offers innovation. Indeed, if varenicline sampling is found not effective to promote quitting, then this 
would suggest: a) sampling should be restricted to OTC products, b) sampling should be restricted to products 
that do not have rigid instructions for administration, and/or c) physician guidance is needed for varenicline use. 
Whether this trial is positive or negative, outcomes will have important influence on clinical practice.  
We are now in prime position for a randomized clinical trial within which our goals are to assess the effects of 
varenicline sampling across a range of cessation related behaviors: a) use and conversion to sustained 
medication use beyond sampling, b) quit attempts and cessation (7 day point prevalence abstinence), and to c) 
evaluate the mechanisms of change: i) confidence,/motivation, ii) autonomy, iii) attitudes towards medication, iv) 
expectancies. With added comparison group of NRT, we can now make head-to-head comparisons of these two 
medications on each of these outcomes, even if this comparison is secondary. Sensitivity analyses will examine 
these outcomes/mechanisms separately for smokers with and without interest in quitting.  

 
 
 
 
Preliminary Studies 
NRT Sampling Study 1: Our first trial of NRT sampling (R01 DA021619) recruited smokers who were exclusively 
unmotivated to quit (N=849) from across the country and randomized them to receive mailed samples of nicotine 
lozenge or not, and was prominently published in Archives of Internal Medicine.(73, 74) Participants in both 
groups were asked to engage in a practice quit attempt; i.e., merely a brief period of trial abstinence which we 
believed would remove pressures to quit for good. NRT samples were intended to augment that experience, 
allowing smokers to see how medications worked and how they could be used. Even among these unmotivated 
smokers, 73% used the nicotine lozenges given to them. NRT sampling yielded higher rates of quit attempts 
(43% vs. 34%; RR = 1.3; 95% CI: 1.1-1.5) and marginally higher rates of “floating abstinence” (any 7 day period 
of non-smoking, ever in study; 19% vs. 15%; RR=1.3; 95% CI: 1.0-1.7). Interestingly, the effect of NRT sampling 
(vs. not) was greater among African Americans than among Whites, both for inducing quit attempts (OR=2.4 for 
AA vs. OR=1.5 for White), and for achieving point prevalence abstinence at six month follow-up (OR=3.2 for AA 
vs. OR=1.2 for White). The race x treatment interaction was not significant, as this study was not adequately 
powered to detect it. Nonetheless, these widely discrepant effect sizes suggest that NRT sampling could be 
more effective for underserved populations. Follow-up analyses from this same trial revealed that sampling 
promoted quitting though many of the pathways shown above. Providing a mere 2 week sample of NRT 
increased motivation and confidence to quit, increased positive attitudes towards and overall knowledge of NRT, 
and decreased negative attitudes toward NRT.(75) In fact the effect sizes for these mechanisms were fairly 
robust (Table 2). Cessation outcomes 
were modest, and we would never 
claim that sampling is superior to 
more intensive treatments. But if a 
$60 intervention that takes <1 minute 
to deliver can have any improvement 
towards this goal, it could have higher 
impact with wider reach.  
 
NRT Sampling Study 2: With intramural pilot funding, we followed the above trial with a smaller study (N=157) 
of smokers across South Carolina.(76) Whereas the above trial tested NRT sampling exclusively among 
unmotivated smokers, Study 2 explicitly examined the effects of sampling and the role of motivation among three 
groups of smokers: A) smokers motivated to quit, mailed 2-week samples of both nicotine patch and lozenge, 
vs. B) unmotivated smokers, given same treatment, vs. C) unmotivated smokers, no treatment. We were 
particularly interested in Group B, who had shared commonality with both Group A (both received sampling) and 
Group C (both unmotivated to quit). Over 85% of participants in the two sampling groups used medication. 
Results after 3 months of follow-up demonstrated that, while initial motivation to quit enhances the likelihood of 
making an attempt (A >B>C; p<.05), it is not a necessary precursor to quitting success: A~B>C, with ~3-fold 
increase in abstinence among the two sampling groups, relative to control.  
NRT Sampling Study 3: Our latest study of NRT sampling is our most real-world test yet: a cluster randomized 
clinical trial within primary care settings, across South Carolina (22 clinics; N=1245 participants; 2R01 
DA021619).(77) Our focus was on the translational potential of medication sampling as a brief, pragmatic 
intervention that can be offered to a broad spectrum of smokers within clinical context. Outcomes were 
impressive, and a manuscript is now in review at a top tier journal. More smokers in the NRT group (vs. control) 
used cessation medication immediately following the clinic visit (55% vs. 10%; AOR = 12.2; 95% CI: 8.3–18.0). 
That itself is not that impressive, but the fact that medication usage was persistently higher at six months is (25% 
vs. 14%; AOR = 2.0; 95% CI: 1.5–2.8). NRT sampling increased the rate of quit attempts in the initial month 
(24% vs. 18%; AOR = 1.7; 95% CI: 1.1–2.6). Most impressively, self-reported point prevalence abstinence rates 
were significantly higher within the NRT group at 1- (5% vs2%; AOR = 4.4; 95% CI: 1.8-11.1), 3- (10% vs 5%; 
AOR = 2.6; 95% CI: 1.6-4.2), and 6-month follow-up (12% vs 8%; AOR = 1.7; 95% CI: 1.1–2.6). Sensitivity 
analyses revealed comparable results among smokers who were motivated to quit vs. not, demonstrating that 
NRT sampling was similarly effective for a broad spectrum of smokers. Despite low absolute rates of all quit 
outcomes (in line with expectation: see Table 1), there was a robust beneficial treatment effect.  
One separate but thematically relevant trial, led by Dr. Cropsey (consultant within; co-author Carpenter), 
examined more hands on, experiential learning through in vivo sampling.(78) We demonstrated that NRT 
sampling increases adherence for subsequent use, and again demonstrated improvements in attitudinal barriers 
Table 2: Changes in Hypothesized Mediators following Medication Sampling 
 
Pre – Post Change 
Effect Size 
d 
 
NRT 
Sampling 
Control 
Group 
Motivation to Quit (range 0-10) 
2.0 
0.4 
.46 (small to intermediate) 
Knowledge about NRT (0-10) 
2.0 
1.0 
.42 (small to intermediate) 
+ Attitudes Towards NRT (1-4) 
0.2 
0.0 
.5 (intermediate) 
- Attitudes Towards NRT (1-4) 
- 0.8 
0.0 
-1.1 (large) 

 
 
 
that undermine use. Collectively, these NRT sampling studies demonstrate: a) the importance and benefits of 
randomized yet naturalistic medication sampling studies as a pragmatic means to promote quitting, b) the well-
established methods to conduct sampling studies, and c) our collective expertise in doing so.  
Proof of Concept Varenicline Sampling: Through intramural pilot funds, we have an ongoing pilot study (eventual 
N=80) to establish feasibility and to get an early sense of effect size. Thus far, 60 smokers have been recruited 
from across SC (another remote trial) and have been randomized to receive a short supply (identical to proposed 
here) of varenicline vs. not. Of the 45 smokers (22 control; 23 VRN) to have reached 1-month follow-up, 83% of 
those in the sampling group are still using varenicline, with self-reported decreases in smoking (7-day CPD avg) 
far greater than controls (45% vs 14%). About a third (6/19) of those in the sampling group have titrated to 2mg 
by Week 4, though use has been inconsistent. At 4 weeks, 89% of sampling participants (vs. 56% of control) 
endorsed the belief that “varenicline can help people quit smoking.” While sample size numbers are still small, 
this experience supports the clinical potential of varenicline sampling, and the importance of rigorous evaluation. 
We have adequate precautions in place for both pregnancy testing and adverse event monitoring, including 
potential though unlikely increases in depression and suicidal ideation. Even more importantly, this experience 
paves the path forward with regard to regulatory oversight, i.e., all procedures proposed herein have already 
been IRB-approved, allowing us to quicken the startup pace for this proposed trial.  
Elsewhere, we have published studies on the attitudinal barriers of medication usage, using both quantitative 
and qualitative methods,(24, 25) demonstrating eagerness to sample cessation medications, even when 
smokers hold attitudinal barriers against them. Through our qualitative work, we often heard themes ~’I’d use 
this medication if a doctor suggested that I should.’ Lastly, we have conducted a number of conventional, full-
course clinical trials of varenicline. These include trials of varenicline for adolescent smoking cessation (ongoing 
U01 DA031779), comparisons of varenicline vs. bupropion for adolescent smoking cessation,(79) pilot trials of 
varencline vs. nicotine patch for adult women,(80) and combination varenicline and N-acetylcysteine for adult 
smokers.(81) As noted above, Dr. Toll led a trial of varenicline distribution through quitline, and the results guide 
Finally, Dr. Cropsey is primary mentor of an almost completed F31 award (DA047015) that examines the 
separate pharmacologic vs. expectancy-related effects of varenicline, which has clear relevance to the proposed 
trial. In total, we have broad, thorough expertise on the clinical and regulatory issues relevant to varenicline.  
II. 
Specific Aims 
 
We propose a randomized clinical trial with primary aims to evaluate the: 1) use, 2) consequences (on 
cessation), and 3) mechanisms of varenicline sampling. We will recruit between 648-660 smokers and randomize 
them to receive a 4-week sample of varenicline, NRT, or no sample, and will follow all for 6 months. Our remote 
focus derives from our hands-off (i.e., translatable) intent, yet our methods include both daily diary assessment 
and remote biological verification of smoking to enhance rigor. We are mindful of requirements for physician 
oversight and embed full precautions for safety. Our study sample will include smokers both wanting to quit and 
not (recruitment of each, with stratified randomization), which will allow for exploratory sensitivity analyses to 
assess the role of smoker motivation on outcomes.  
In accordance with these Aims, we hypothesize that: 1) use of varenicline will be strong: >80% of study sample 
using medications on at least 50% of the sampling period; 2) relative to non-medication controls, sampling will 
result in higher incidence of quit attempts and biochemically verified cessation; 3) with greater changes in 
hypothesized mediators (motivation/confidence, decreases in treatment fatigue). Comparisons of varenicline vs 
NRT sampling a) uptake, b) mechanisms and c) outcomes are secondary but nonetheless compelling and offer 
additional significance, innovation, and rigor to our trial. 
 
 
III. 
Methods 
Our three-fold objective is to determine 1) use, 2) consequences, and 3) mechanisms of varenicline sampling. 
We propose a three-group, randomized clinical trial in which adult smokers, recruited remotely across SC, 
inclusive of smokers wanting to quit and not, receive a 2-4 week sample of varenicline, combo NRT, or neither, 
to use as they wish. Remote, serial assessment of carbon monoxide will be used to verify smoking behavior. 
Uptake and use will be operationally defined as: a) use of medication (incidence, quantity, duration of use), b) 
conversion to independent use (i.e., obtaining a prescription for further use), and c) adverse events. We 
anticipate a side effect profile consistent with other trials of varenicline (some insomnia, nausea) but otherwise 
benign. Cessation-related outcomes include: a) use of additional quit resources (e.g., calls to quitline), b) quit 
attempts, and c) cessation (7-day point prevalence abstinence, CO verified). Mechanisms include measures of 

 
 
 
motivation, confidence, knowledge of and attitudes toward medication, autonomy to quit, expectancies, and 
cessation fatigue. This is an expanded list from our earlier studies, which allows comparability to NRT sampling 
but also an opportunity to move forward. Whether and how these non-pharmacologic mechanisms differ for 
varenicline vs. NRT is an interesting question we can now address, though comparison of mediational models 
is not our primary focus. An overview of study design is shown in Figure 3. 
 
IIIa 
Important Design Issues 
First, sending prescription medication through mail is not only acceptable, but common in clinical practice. We 
restrict our recruitment to South Carolina alone given medical oversight from our study physician. Since 
statewide tobacco policy is a constant (vs. nationwide heterogeneity), this is another advantage of keeping this 
within South Carolina. Second, we do not capture carbon monoxide levels at baseline (which would also allow 
us to verify baseline smoking status), and instead rely on self-report of smoking. We recognize this as a limitation, 
particularly if we wanted to examine levels of CO over time. To address this, we would have to separately send 
the CO monitor (before baseline assessment) and varenicline (after), which adds unnecessary complexity. CO 
is used to verify smoking status at follow-up, not to assess changes over time. Third, all participants receive a 
referral to the SC quitline, with rationale and benefits of use. We believe this is a minimum standard to provide 
for all smokers. Fourth, our design further extends our progression into technology-based remote assessment. 
This includes teleconsent, remote CO, and daily diaries during the sampling period. Consistent with translational 
intent for remote delivery, Week 0 contact will be via phone, but all subsequent follow-up will be online, with 
adequate precautions in place for safety monitoring. Fifth, our screening procedures now include methods to 
enhance sample diversity, to increase generalizability. For example, we can ensure that at least 30% of our 
sample is non-white, and at least 40% are of each gender. Other demographic minimums can be considered 
(e.g., income, education) if our initial sample is insufficiently representative.  
 
 
 
 
 
IIIb 
Participants 
As before, we will recruit smokers statewide through various media outlets. Advertising will solicit smokers both 
motivated to quit and not; this will not be pitched as a treatment study. Smokers will be screened online for study 
eligibility, which includes innovative and automated methods to protect against duplicate entries, including those 
who might try to game (falsify) the criteria to gain study access. In our prior statewide sampling study, we 
recruited 157 participants in five months, in our ongoing trial of e-cigarettes, we’ve recruited 375+ in 15 months. 
Recruitment pace herein might be a bit slower given extra eligibility criteria. We are also excited by our newly 
developed procedures to ensure sample diversity. Online screening for our remote trials now includes methods 
to ensure at minimum 40% of each gender, and minimum 30% non-white participants. This is particularly 
important because a number of eligibility criteria are focused on technological reach (e.g., smartphone 
ownership), and these new methods provide greater assurance of sample generalizability.  
a) Eligibility will be contingent upon: 1) age 18+; 2) daily smoker (25+ days per previous month); 3) smoking 
5+ cigarettes/day; 4) smoking > 1yr; 5) has access to a medical provider who could write a prescription 
if needed; 6) not currently pregnant, breastfeeding, or planning to become pregnant (remote pregnancy 
testing is included within our ongoing proof-of-concept study of varenicline, and is working well); 7) no 
suicidal ideation in past month, nor any lifetime suicide attempt; 8) no current (past month) psychotic 
Figure 3: Study Design 
* All follow-up assessments include remote CO. Follow-up weeks are offset by 3 days, to allow for lag in mailing 
(ex. Week 1 to occur at 10 days) 
Online 
Screening 
Consent & 
Randomization 
Varenicline 
Sampling + 
Quitline Referral 
Control (n=180) 
Quitline Referral 
Mail Varenicline, NRT 
Mail CO monitor 
[All groups]  
Assessments*, Week #  
0  
1 
2 
3 4 8 12 24 
[--------------daily diaries------------]  
NRT Sampling + 
Quitline Referral 

 
 
 
symptoms (auditory/visual hallucinations) or self-reported lifetime diagnosis of or treatment for bipolar 
disorder, schizophrenia, or other psychotic disorders; 9) no medical contraindications for varenicline (e.g., 
cardiac or renal disease, seizure disorders), 10) own a smartphone (either iOS or Android), and 11) have 
regular email access. Clinical symptomatology (criteria 7-8) will be based on both the NIMH toolkit for 
suicidal ideation (5 yes/no items), as well the MINI(82): a] In the past month, have you heard things other 
people couldn’t hear, such as voices? And b] In the past month, have you had visions when you were 
awake, or have you seen things other people couldn’t see? And c] do you have or are you currently in 
treatment for: schizophrenia, bipolar disorder, or mania. These criteria follow a prior trial that provided 
varenicline via mail and without direct physician contact.(71) Anyone who screens out on these criteria 
will receive an individual, separate phone call by Drs. Carpenter, Dahne, Toll, or Gray, be referred 
elsewhere as needed, and not be included in the study. Our rationale for having access to a medical 
prescriber (#5 above) is to allow for and promote conversion; so that smokers can readily obtain 
varenicline after sampling it, if desired. This was unnecessary within our NRT sampling studies, as we 
just advised participants to seek it out as an OTC product and assessed this as a study outcome. We 
again assess such conversion in this study but believe it wise to restrict eligibility to those smokers with 
a means to convert i.e., those with an established healthcare provider. We do not view this as a threat to 
generalizability, since 70% of smokers visit a physician yearly.(4) Next, although EAGLES trial outcomes 
documented clear safety (and efficacy) of varenicline even among smokers with comorbid psychiatric 
disorders, we exclude those with suicidal history and psychosis herein, in an abundance of caution. We 
require smartphone/email access to allow for daily diary assessment during the sampling period 
(methods below). If there is a digital divide, it is shrinking. According to latest Pew survey, 81% of 
Americans own a smartphone, with every demographic >66% (except ages 65+: 53%).(83) Requirement 
to own smartphone might reduce external validity, but it should not affect internal validity.(84)  
 
IIIc 
Teleconsent, Baseline Assessment, & Randomization 
In our prior studies, recruitment from national sources was based on mail-based return of the consent form. That 
is, after determination of eligibility, we mailed a consent form (2 copies) and asked the participant to sign one 
copy and return to us in a pre-addressed, pre-stamped envelope. Receipt on our end is the start of official 
consent, and official enrollment begins with first phone call (Week 0). While this process generally worked, it was 
inefficient. For one, mailing delays often meant a lag between the person expressing interest and when s/he was 
officially enrolled. Second, there are occasional instances where the person does not fully complete the consent 
form (e.g., missing date), or does not return all necessary pages, and the process repeats itself (back and forth 
mailing) until we get all forms in full. Third, a large number (~55%) of the consent forms go un-returned, for any 
number of reasons. Thus, if we want a minimum of 648 participants, we would need to identify ~1180 who would 
be eligible and interested. Loss of interest in the study is a possibility (which we abide by), but we also believe 
that consents get lost, thrown away, regarded as junk mail (particularly if seen by someone else), etc. For the 
current study, we will continue with this procedure of mail-based consenting and add a new teleconsent process 
that addresses this inefficiency. After the initial determination of study eligibility, assessed online in our secure 
survey, participants will be asked about their capacity for teleconsent procedures, including access to a device 
and internet on which they can complete remote consent. For those who have the required hardware and 
software for teleconsent, we will then describe the basic mechanics of online consent process and ask for their 
preference for mode of consent: to be consented online or to receive a mailed consent. Participants can choose 
their preferred method of consent, and none of this is an eligibility requirement. Participants who do not meet 
teleconsent requirements will be mailed a consent form following standard procedures. Thus, we are simply 
offering another, more immediate option for study consent that may be preferable for some participants.  
For those who elect teleconsent, we will follow IRB-approved procedures as per precedent. Participants who 
elect to complete the consent process online using doxy.me or REDCap will be consented by IRB-approved 
study personnel: the PI, study coordinator, or research assistants. All doxy.me signed consent forms will be 
saved as .pdf files within our study records and all REDCap documents are immediately saved in REDCap. Most 
of our ongoing studies employ this method, and a growing number of participants prefer this route of consent 
(currently ~55%). For those opting to receive consent packet through the mail, we will follow our prior procedures 
described above. Once they have received the consent form in the mail, we will have a scheduled phone call to 
discuss the consent and study with them. They will have the opportunity to ask any questions at this time, and 
participants cannot be enrolled without completing the phone discussion step of the consenting process. This 
phone call was added to our prior mailed consent procedures to ensure that participants have a full 
understanding of the consent form before enrolling in the study, as they would in person or with online consent. 

 
 
 
We have a toll-free phone line to support anyone who calls with questions. Upon return to our office, data are 
entered into our database, and these individuals comprise the consented sample. However, the sample is 
reduced further to those with whom we are able to establish first phone contact (Day 0); i.e., the enrolled sample. 
This enrolled sample is the intent-to-treat sample.  
Pre-Randomization Verification of Non-Pregnancy: For females age <55, we impose one additional step to verify 
pregnancy status. We will mail these participants a commercially available pregnancy test to verify non-
pregnancy status. We will then require these participants to confirm in writing via REDCap that they have 
completed the pregnancy test and have received a negative result. Participants are also informed that they 
should let us know if they become pregnant during the trial. Medications will not be sent until this verification is 
in place. These methods are IRB approved (and required) for our proof-of-concept pilot study. 
Pre-Randomization Physician Approval for Medications: Finally, prior to study randomization, our study physician 
will review a summary of eligibility criteria, collected during Primary (e.g., smoking history, age, medical history 
and comorbidities) and Secondary screening (psychiatric history, suicidal history, pregnancy status) steps before 
the participant can be randomized and be enrolled into our trial. We will deliver this summary with a report that 
we create within our REDCap screening database, to be delivered electronically to the study physician.  He will 
review each individual’s information, and will make a determination to: 1) accept the individual into the study, 2) 
reject the individual into the study (i.e., not eligible for varenicline), or 3) ascertain more information from the 
individual before either of the decision to accept/reject the participant.  In the latter, the study physician may 
contact the individual to engage in further clinical interview.  The disposition of each participant will be tracked 
within this screening database, allowing us to complete all CONSORT steps to study flow. The individual will not 
proceed to randomization and Week 0 baseline call until we have signed, explicit documentation from the study 
physician to do so.  This step for pre-randomization physician approval will sequentially follow the pregnancy 
test evaluation, since the former depends on the latter.  Any individuals removed through either pregnancy test 
(test positive or non-responsive) or through physician discretion will not be counted in the final enrolled study 
sample.  A summary of the overall study flow is depicted in the figure below (following page). 
Thus, this procedure ensures that we retain physician oversight and approval of varenicline disbursement at 
study outset. Our study physician retains his role in evaluation of adverse events as noted elsewhere within this 
application.   
While the source of varenicline within our trial is not yet clear, we will work with a TBD pharmacy to package and 
label varenicline.  Both packaging and labelling will be done within TBD pharmacy, following all applicable 
laws.  Under no circumstances will non-credentialed study staff package or label the medication. The TBD 
pharmacy will package and label the varenicline under our prescriber’s order. 
 
 
 
 

 
 
 
Figure of Study Flow for STARS 
 
 
 
Advertisement: redcap screener link 
Online screener (redcap: no human engagement) 
If eligible, schedule for: a) consent and b) secondary 
screening (same ‘visit’) 
Secondary Screening: 1) consent, 2) Clinical Assessment 
(suicidal ideation) 
1) Send pregnancy test (women of age) 
2) Provide Clinical summary for medication approval (which includes pregnancy confirmation) 
REMOVAL: Physician discretion based 
on clinical summary (eligibility for VRN) 
1.
Negative Pregnancy AND 2. Explicit (signed) 
physician approval for VRN 
Week 0 Phone call 
Notify group status; 
Delivery scripts, Send meds (NRT or VRN) 
Start diaries, send iCO 
All future follow-up assessments are automated 
(no human engagement) 
Randomization 
REMOVAL: pregnant or non-response to 
pregnancy test 

 
 
 
Randomization, Stratification We recruit smokers wanting to quit (>7 on 0-10 scale) and not, and we use this as 
a stratification variable. We considered a number of other stratification variables (e.g. cigs/day, insurance status) 
but believe that randomization will adequately handle these. We will randomize participants to group in a 2:1:1 
ratio, with intent to increase precision of our parameter estimates within the varenicline group (n=324), consistent 
with our intent to understand use patterns and uptake of varenicline.  
 
IIId 
Interventions and procedures 
All smokers in all groups will receive a mailing consisting of standard cessation support materials and specific 
contact information and benefits of using South Carolina quitline. Quitline benefits will convey the option, for 
some smokers, to receive free medication. Varenicline participants will receive one-time supply of medication in 
childproof pill bottle. In our prior sampling studies, we have been largely non-directive of medication use, simply 
suggesting to participants that they might use it in any number of ways, including not at all. This messaging was 
consistent with our naturalistic intent, i.e. to allow smokers to self-determine if and how to try the product. For a 
study of varenicline sampling, we aim to retain naturalistic context but may need to be more directive, including 
guidance on titration (see dosage comments below). Thus, our messaging will state ~ “We are offering you a up 
to a four-week supply of varenicline, which we hope you find helpful. Evidence shows that varenicline is among 
the best medications to help smokers quit. It is also helpful for smokers who are not yet ready to quit. It is 
completely up to you if and how you take this. If you decide to try varenicline, start with taking one pill each day 
for 3 days, followed by a pill in the morning and a pill in the evening thereafter. If you want a stronger dose of 
medicine to help you quit, you may also go up to two pills in the morning and two pills in the evening after a 
week. If you ever take a day off and want to re-start, just start this process over again.” This messaging was 
drafted and refined by four clinicians and is working well in our pilot study above. This messaging will be 
conveyed directly during intervention call and also within mailing (with accompanying calendar graphics to 
facilitate understanding). Both the phone-based and mailing messaging of varenicline sampling will suggest 
options for continued use beyond the sampling period and will be tailored to individual insurance status. As noted 
above, study eligibility is restricted to smokers who have access to a medical prescriber who can “convert” 
interested smokers into more sustained varenicline use. Our mailing will also include a generic letter that smokers 
can give to their provider stating that they have been pre-screened for and have received varenicline and should 
be considered for further use upon provider approval. It will be up to the participant to decide if and when to offer 
this letter to their individual provider. We cannot ensure that this conversion will be seamless, i.e., to occur 
immediately at the end of sampling period. The extent and timing of conversion is one study outcome.  
We extensively debated varenicline dosing and sampling duration. Typical practice is to titrate as follows: .5mg 
QD for days 1-3, .5mg BID for days 4-7, and 1mg BID from day 8 and beyond. On one hand, we want to provide 
the strongest, most evidence-based dosage possible. If varenicline sampling results in null effect, we do not want 
this to be due to dosing. On the other hand, providing multiple dosages within a self-paced sampling experience 
could add unwanted confusion and risk. We are also aware of two large trials that showed similar outcomes of 
1mg vs. 2mg dosing, with fewer adverse events in the former.(66, 67) To balance these perspectives, we: a) 
provide .5mg tablets only, 60 total, b) with instructions to titrate as noted within italicized instructions above, c) 
give instructions to take no more than two in the morning and two in the evening, d) give the participant the 
ultimate choice to self-pace usage. This choice and pattern of titration becomes an interesting study outcome 
that aligns with our focus on participant uptake and is wholly consistent with our naturalistic intent. Thus, we view 
the sampling experience as lasting 2-4 weeks depending on participant choice. For anyone who might ignore 
the titration schedule and start/restart with 2mg, nausea is the most likely consequence, nothing worse. 
Smokers in the NRT group will follow our prior protocol: 4-week supply of both nicotine patch (14mg) and lozenge 
(4mg), with comparable instructions for self-determined use as above. As in our prior trials, we provide both 
patch and lozenge given different mechanisms of action (slow, cumulative dosing of patch vs. acute delivery for 
momentary craving with lozenges), and also because of strong evidence to show that superiority of combo NRT 
over placebo and single NRT products (85-87). We neither explicitly advise nor discourage combined use. Thus, 
this is an opportunity for smokers to learn about two NRT products, to be used individually or together (participant 
choice, including none at all). We will caution all participants on signs of receiving too much nicotine (nausea, 
dizziness) and will monitor adverse events, expected to be rare/mild.  
IIIe 
Follow-Up Procedures 
Follow-up assessments will be auto-sent to participants at +17 days (2 weeks beyond initial mailing, accounting 
for ~ 3 day delay in mailing), +33 days (same delay), +2, +3 and +6 months. Participants are reimbursed for 
completion of each of five interviews at an escalating rate and with bonus for completion of all. We have excellent 

 
 
 
history of participant retention across our prior studies. Spanning at least 5 trials, encompassing >10,000 
participant phone contacts, we consistently complete 80-90%. In our prior study of NRT sampling in South 
Carolina, we completed 96% of all scheduled contacts, our best yet. Payments are sent after each completed 
assessment (gift card or code for online purchase), and again the procedures are well established. Participants 
will also be able to earn referral bonuses for referring friends and family who enroll in the study. 
IIIf 
Assessments 
All interview data are entered in real time within a REDCap database, ensuring high data quality. We have 
established assessment protocols for all outcomes. Our follow-up interview has been extensively used in our 
prior studies and is timed at ~20 minutes. Self-report data include the following: 
Baseline questionnaire will ascertain basic demographics and smoking history, including measures of 
dependence,(88) prior use of medications, and all hypothesized mediators (*listed below). 
Smoking (Reduction) Using Timeline Follow Back (TLFB) methods, we assess cigarettes per day over the 
previous seven days, and from this can calculate abstinence (defined below), as well as smoking reduction, and 
percent who achieve 50% reduction. We also track use of other tobacco products, including e-cigarettes. 
Abstinence is defined as both “floating” (any 7 day period of non-smoking) and point prevalence, as 
recommended for “cessation-induction” studies.(89) We will track longest duration of abstinence and relapse 
following stated quit attempts.  
Quit Attempts We will track the incidence of any self-defined and “serious” quit attempts over the 3-month follow-
up period. The latter is the typical measure of quit attempts, used in CDC reports, and is defined as an attempt 
lasting >24hrs. We will also report on the maximum duration, and latency of each QA since baseline.  
Use of varenicline, NRT other meds We will determine the incidence and frequency of medications used, both 
during the sampling period and beyond. For varenicline, we will assess actual dosage used as well as titration 
patterns, days of use, and whether or not the person “converted” to sustained use (when, how, through whom). 
*Self-Efficacy, Motivation, & Confidence to Quit We will use single item (0-10 visual analog scale) measures for 
each. Our ladders have adequate test-retest stability and predictive validity.(90)  
*Attitudes Towards varenicline, NRT Based largely on prior work in this area(58, 91), we have published(25, 75) 
on 1) positive, and 2) negative attitudes towards medications, as well as 3) general knowledge of them.  
*Treatment Self-Regulation Questionnaire The TSRQ(47) is a well-established measure of autonomous 
motivation; i.e., the degree to which decisions on quitting are self-determined and/or controlled by others.  
*Cessation Fatigue We will use a brief measure of hopelessness from our recently developed Cessation Fatigue 
Scale,(22) which we have subsequently shown to be predictive smoking/relapse.(23)  
*Expectancies – We adapt a 6-item measure of medication expectancies from Dr. Toll’s work in bupropion.(92) 
This adapted version is also used within Dr. Cropsey’s mentee’s F31 (see above).  
*Self-Control – We will use a 13-item measure of general self-control, with strong internal consistency and retest 
reliability.(93)  
Depression: We are mindful to assess potential emergence of depressive symptoms, which will be assessed via 
PHQ9(94). Anyone who reports emergent suicidal ideation within PHQ will be managed by licensed mental 
health providers (Drs. Carpenter, Dahne, Toll or Gray). Our existing procedures within our proof-of-concept trial 
include automated data monitoring to identify in real-time any participant who endorses suicidal ideation. 
Adverse Events Adverse events will be tracked and rated as mild, moderate or severe by the patient and rated 
for relatedness to medication by the research assistant using guidelines, with oversight from our study physician. 
We will determine if any adverse events result in dropouts or are serious according to FDA guidelines. 
 
IIIg 
Electronic Diaries during Sampling 
All participants will be asked to complete a brief diary to assess smoking behavior and use of meds. These 
diaries, which will include brief mood assessments, provide additional, real-time risk monitoring, not to replace 
traditional adverse event assessment (above), but to complement. Our intent is to better capture day-to-day 
fluctuations in medication use and smoking. Each of our recent trials have used this diary approach, with 
excellent compliance (88% for one study, 83% for another). Diaries will assess cigarettes smoked per day, 
medications/products used, purposes of that use (to reduce/quit), and mood/affect. Diaries (<2 min each) will be 
electronically collected daily throughout the sampling period (28 days). We have established procedures to auto-
send an email/text on a set schedule. Thus, per eligibility criteria above, we require participants to have 
smartphone capacity, and they will be compensated for compliance based on % diaries completed (e.g., $100 
for 90-100% compliance, $70 for 75-90% compliance, etc.). There is some debate as to whether EMA/diary 
procedures alter behavior, but recent evidence suggests not,(95, 96) but even if so this is equal between groups.  

 
 
 
IIIh 
Remote CO Collection  
Our prior remote trials did not include biological verification of smoking. With minimal intensity ‘interventions’ we 
view the bias of demand characteristics as low. However, we recognize that biological verification is certainly a 
strength. MUSC investigators are on the forefront of real-time remote CO collection (K23 DA045766, R34 
DA042228, forthcoming NCI R21), in which all participants are provided an iCO Smokerlyzer at the time of 
enrollment. The device connects to a smartphone (both Android and iOS); thus, we require this as an eligibility 
criterion. The iCO can detect CO concentrations of 0-100 ppm, and has strong test-retest reliability, as well as 
concordance with traditional device.(97) Each follow-up will include instructions to complete the iCO 
breathalyzer, plugging it into their phone to capture video confirmation and all CO readings (time/date stamped). 
Thus, the procedure provides objective recordings. As of this writing, our group is working on methods to 
eliminate the need for an app altogether, instead interfacing with REDCap directly (secure, online, real-time data 
capture); Dr. Dahne has ACS and forthcoming R21 funding explicitly for this purpose. The $70 iCO device can 
be used repeatedly within a person, but it is not returned at end of study as it is not transferable to another user. 
A portion of participant compensation is contingent upon iCO compliance (not abstinence). We do not envision 
iCO testing within each daily diary, but we will add it for any reports of non-smoking, offering an additional method 
to corroborate quit attempts in real-time, heretofore not possible. These procedures have worked well in pilot 
testing, but we recognize that they are far from well-established. Alternative options are less feasible. First, we 
could mail a more established device (piCO), have the person return it after use, and transfer it to another 
participant. We have investigators at MUSC who are doing so with success. Ostensibly, however, this is no 
different than above, and allows fewer participants in the trial at one time (infeasible to purchase one device per 
participant). So, this is not our preferred method. Second, we could send at-home saliva collection kits, and have 
them returned to our lab for cotinine testing. These methods are more established, yet still unsatisfactory, in 
terms of compliance, biased responding, timeliness (asynchronized with survey responding), confounds of 
nicotine (NRT), and cost of assay. In the end, the iCO procedures are imperfect but still the best option available. 
We define abstinence as 7-day point prevalence (no smoking in prior week), with CO <4ppm.(98, 99) 
 
IIIi 
Power Estimations and Data Analyses  
Power: Our three-fold focus on outcomes includes 1) uptake (usage, conversion), 2) consequences (quit 
attempts, abstinence), and 3) mechanisms of varenicline and NRT sampling. We power on the most stringent of 
these to determine sample size: point-prevalence abstinence at six months (Aim 2), and we do so based on 
primary comparison of varenicline vs. inactive (non-sampling) control; see rationale above. Based on our early 
work, and under our belief that varenicline sampling will result in marginally better outcomes than NRT (12-15% 
in our prior studies) we anticipate a quit rate of 18% in varenicline vs. 8% in control, the latter also in line with 
our prior studies. With 2:1 randomization for this comparison (VRN:control), and with power of 80%, this will 
require a total sample size of 413 participants across these two groups. We conservatively inflate this by 15% to 
account for potential attrition, though in past studies this was closer to 12%, thus resulting in 324 varenicline vs. 
162 control participants. We secondarily add another, active comparator group of smokers receiving NRT 
sampling (n=162; 2:1:1 overall randomization), for a total of 648 participants. If we were to power on varenicline 
vs. NRT outcomes, this would require a total sample of 1300 VRN + 650 NRT (+ 160 possible control), and such 
a study would be infeasible within this mechanism, and likely infeasible within any R01, particularly given the 
costs of medication. With anticipated 324 varenicline vs. 162 NRT participants, we have 39% power to detect a 
difference of 18% vs. 12% in abstinence. We have been doing studies this large for some time and have great 
confidence in recruitment. Over a 48-month recruitment span (see Timeline below), we aim to recruit ~11/month. 
For our ongoing nationwide trial of e-cigarettes (eventual N=660), we’ve averaged ~25/month. Considering the 
recruitment process and minor time delays between consent and formal enrollment, it is difficult to stop at an 
exact number. Thus, we will enroll between 648-660 participants to abide by those at earlier steps of the process.    
Outcomes pertaining to uptake, usage and conversion (independent use of varenicline, NRT; Aim 1) are focused 
within each active treatment group individually, though we can compare each of these outcomes between 
medication groups as well, per binary/continuous analyses below. With 360 total participants in varenicline group, 
a two-sided 95% confidence interval will have a maximum half-width of 0.052 (e.g., 95% CI on an observed rate 
of 50% would range from 0.448 to 0.552). With 162 participants in NRT group, the maximum half-width for uptake 
parameters is .077. As the observed proportion deviates from 50% (either higher or lower), the 95% confidence 
interval will decrease in width, providing more precision on the estimate (e.g., 95% CI on 90% would range from 
0.896 to 0.931 with n=324). A confidence interval as wide as +/- 5% is a relatively small width and one we are 
willing to accept for our estimates on uptake, and conversion. Formal mediation analyses (Aim 3: mechanisms 
of change, within and between groups) are not planned, but we can test whether the sampling intervention results 

 
 
 
in greater change in mechanism variables (*above) similarly vs. differently for varenicline vs. NRT.  All analyses 
are based on an intent-to-treat approach and are nearly identical to analyses from our current and prior studies. 
Exploratory analysis will be performed on all variables to determine if transformations are needed. Any significant 
baseline differences between groups will be included in analyses. All analyses will be run separately for full 
intent-to-treat sample and those retained per protocol. We are specifically interested in whether sampling effects 
generalize to those who are and are not motivated to quit, and we will examine this via sensitivity (subgroup) 
analyses. We are under-powered for tests of treatment interactions. 
Missing Data & Dropout: 
The most conservative approach for handling missing data(100) is to substitute 
them with baseline values, assuming outcomes have all returned to baseline, with no quit attempts made or 
abstinence achieved. If this assumption is incorrect, it biases the results towards the null by reducing between 
group differences.(100) We expect few missing data and thus plan for this approach. If missing data >10%, we 
will calculate results using this conservative method but also using methods in which missing data are imputed 
as described in the SRNT guidelines, and will assess whether dropout differs by study group (not the case in our 
prior trials). Abstinence will be reported both with and without (missing samples) CO verification.  
Feasibility and Measures of Uptake: Our ongoing proof-of-concept study provides an early sense of study 
feasibility and thus this is not a main outcome of the trial. Nonetheless, we will deem our approach feasible if: a) 
at least 80% of varenicline group tries the medication, b) with reasonable duration of use (e.g., median days of 
use >14 days), c) at least 50% of varenicline group self-titrates to 2mg, d) at least 30% convert to independent 
use, and e) <5% of adverse events from varenicline are serious. 
Binary Outcomes (incidence rate of quit attempts & cessation; % treatment uptake/conversion) will first be 
examined over the entire study period from baseline to end of follow-up by calculating frequencies/percentages 
as well as 95% confidence intervals for each medication group. Chi-square tests (or Fisher’s exact tests as 
needed) will compare groups on binary outcomes to determine if effects from sampling group exceed those from 
control group. Both the control group (primary/powered comparison) and NRT group (secondary) will serve as 
referent for varenicline group outcomes. Covariates will be included where necessary based on baseline 
differences. All tests will be considered significant at the α=0.05 level of significance.  
Continuous Outcomes (duration of abstinence, smoking reduction) measured over the entire study period from 
baseline to the end of follow-up will be evaluated using general linear modeling with a main effect of group to 
determine group differences. Covariates will be added as necessary to account for baseline group differences. 
Mechanisms of Change: We hypothesize that varenicline sampling will enhance quit motivation & confidence, 
as well knowledge of and attitudes toward medication, autonomy to quit, and will decrease cessation fatigue. We 
will examine all through analyses of continuous outcomes above. It will be interesting to explore whether and 
how these non-pharmacologic mechanisms differ for varenicline vs. NRT. Medication expectancies, knowledge, 
and familiarization might differentially vary through varenicline/NRT sampling, as might motivation and 
confidence. Note that our focus is on non-pharmacologic mechanisms, since the pharmacologic mechanisms of 
both varenicline and NRT are well-established and also since our design does not include a placebo comparator. 
Also note that formal tests of mediation can be explored but we may not be powered for these.  
Diary Analyses: Mixed effects regression models(101) will be used to model diary data outcomes (e.g., days of 
med use) to allow for repeated observations per participant as well as for time-invariant (group, gender, etc.) and 
time-varying covariates (e.g., motivation to quit). These types of models allow for the inclusion of incomplete 
data across time, so we can include all reported data, even if <28 days per ppt. Any results obtained from these 
mixed effects models will be considered exploratory and primarily used to gather information on effect sizes. 
Conclusions 
In an era when most intensive treatments do not lend themselves to real-world implementation, medication 
sampling represents a brief, concrete, easy to explain strategy that has strong empirical and theoretical support. 
Sampling extends the reach of treatment, and thus offers both clinical and policy significance. The proposed 
varenicline sampling study is not merely a rote extension of our NRT sampling work. Yet like our prior work, we 
believe that varenicline sampling offers another and potentially stronger catalyst for further engagement in the 
quitting process. This R01 wholly conforms to recommendations for pragmatic trials,(102, 103) in that our 
intervention is: rigorous, rapid, transparent, user-friendly, feasible, important to practitioners, and eventually 
broadly applicable.(104, 105) This application is also wholly responsive to PAR 18-869, and, as a modular R01, 
offers a tight, streamlined clinical trial that directly tobacco control, which is cancer control. Varenicline sampling, 
applied to a broad spectrum of smokers, could be yet another strategy to get more smokers to make evidence-
based quit attempts, sooner.  

 
 
 
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Protocol Amendments: 31 amendments in total, all listed below. Details provided for all amendments that are 
NOT any of the following: a) change in study personnel, b) change in study advertising, or c) change in 
study assessments. All amendments received expedited (i.e., not full board) review. 
 
Amend. 
# 
Name 
Date 
31 
Amendment 31 for IRB Study #Pro00098479 – 
• 
Staff change  
5/28/2025 
30 
Amendment 30 for IRB Study #Pro00098479 –  
• 
Fixing protocol version date 
10/14/2024 
29 
Amendment 29 for IRB Study #Pro00098479 –  
• 
Increasing upper limit of study sample from 648 to 660 
09/13/2024 
28 
Amendment 28 for IRB Study #Pro00098479 –  
• 
Staff change 
5/31/2024 
27 
Amendment 27 for IRB Study #Pro00098479 –  
• 
Staff change 
04/22/2024 
26 
iCO window change 
• 
Informed Consent: 
Changing the breathalyzer sample submission window from 24 hours to 72 hours. 
03/12/2024 
25 
Amendment 25 for IRB Study #Pro00098479 
• 
advertising 
03/07/2024 
24 
Amendment 24 for IRB Study #Pro00098479 
• 
Staff change 
1/19/2024 
23 
Increase iCO payment 
• 
Payment to participant language has been updated to reflect increase in 
breathalyzer sample from $5 per sample to $20 per sample. Total amount of 
payment for participants who complete all aspects of the study increased from 
$225 to $300. 
12/20/2023 
22 
new ads ONLY (from Build Clinical) 
• 
New advertising 
11/14/2023 
21 
Personnel Add Only 
• 
Staff change 
09/15/2023 
20 
Personnel Add Only 
• 
Staff change 
   
 
06/12/2023 
19 
Radio Ad 
• 
Adding advertisement through radio ad commercials. 
03/28/2023 
18 
New advertisements & addition of referral recruitment 
• 
New advertising 
02/21/2023 
17 
New Advertisements Only 
• 
Adding additional advertisement photos, flyers, and language. 
09/30/2022 
16 
New ads, remove personnel & removal of 50/50 split based on motivation to quit 
• 
new advertisements 
• 
We are removing the requirement to recruit equal numbers of "motivated" and 
"unmotivated" smokers. We will continue to recruit from both groups and continue 
to stratify on this variable but will no longer exclude participants based on this 
criteria. 
• 
Staffing change 
07/25/2022 
15 
New advertisements only 
• 
Three new study flyers 
06/22/2022 
14 
Add 2nd generic varenicline option; personnel addition 
• 
Add new generic varenicline (PAR) to ICD 
• 
New personnel  
06/03/2022 
13 
Personnel Add Only 
• 
Staff change 
05/23/2022 
12 
Personnel Add Only 
• 
Staff change 
03/04/2022 

 
 
 
11 
Change medical record language on ICD 
• 
Sending study invitations to potential participants through EHR.  
02/25/2022 
10 
Addition of one advertising image & personnel changes 
• 
Updated advertising 
• 
Staffing change  
02/08/2022 
9 
Changes to VRN source and bus ads 
• 
Consent form has been adjusted to reflect the option of giving the FDA authorized 
generic version of varenicline called Apo-varenicline that is approved and available 
for use in Canada. Until Chantix becomes available again in the US, we will offer 
Apo-varenicline in the study. 
 
We had previously adjusted the script for those in the varenicline group and 
created a letter to send out to currently enrolled participants who have received 
varenicline to inform them of a voluntary recall of varenicline at the warehouse level 
due to impurities found during quality control testing. We now have removed these 
changes and have made the changes above to the consent form. We will move 
forward with fda authorized apo-varenicline or chantix once it becomes available 
again without impurities. 
08/11/2021 
8 
Changing Requirements RE: Having a doctor 
• 
Removing the requirement for participants to have a doctor that can prescribe them 
medications. 
• 
Adding a mailed handout to give to ppts with instructions on how to have a 
telehealth visit for a prescription. 
06/30/2021 
7 
Amendment 7 for IRB Study #Pro00098479 -- Epic Recruitment 
• 
Recruitment through EPIC (EHR) 
• 
Staffing change 
06/23/2021 
6 
Amendment 6 for IRB Study #Pro00098479 (New Ad Wording) 
• 
Revisions to advertising 
05/17/2021 
5 
Amendment 5 for IRB Study #Pro00098479 (New Ads) 
• 
New Flyers for Study Recruitment 
• 
Staff change 
05/10/2021 
4 
Amendment 4 for IRB Study #Pro00098479 (Corrections to consent form and changed 
screening questions) 
• 
Fixed typos in consent form, 
adjusted screening/eligibility question from "Have you seen a doctor in the past 
year?" to " Do you have access to a medical provider who could write a prescription 
for you if you needed it?" 
04/07/2021 
3 
Amendment 3 for IRB Study #Pro00098479 (Eligibility corrected and assessment changes) 
• 
Assessments have been reorganized based on the needs of the study at different 
time points. 
iCO collection survey added. 
Correcting eligibility to require email for all participants (instead of email OR 
smartphone) 
02/18/2021 
2 
Amendment 2 for IRB Study #Pro00098479 
• 
Adding questions to the demographics form for physician review.  
• 
Adding DOB to baseline questionnaires. 
• 
Adjusting consent form to clarify payment cut offs. 
• 
Staffing change 
01/22/2021 
 
1 
Amendment 1 for IRB Study #Pro00098479 
• 
Assessments adjusted for clarity 
• 
PHQ cutoff for intervention adjusted - in protocol 
• 
Consent form adjusted to allow us to use screening data in the study 
09/30/2020