Optimized Chronic Care for Smokers: Developing and Implementing Integrated Clinical and Systems Interventions in Primary Care - Cessation Trial
Phase: PHASE4
Conditions: Nicotine Dependence
Sponsor: University of Wisconsin, Madison

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“P01 Cessation Screening Study” 
PI: Megan E. Piper, Ph.D.; UW-CTRI Grant: 
 
 
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UW HS-IRB # 2019-0054 
 
NCT 04188873 
 
“P01 Cessation Screening Study” 
 
Principal Investigator: Megan E. Piper, Ph.D. (608) 265-5472  
Coordinating Center: UW-Center for Tobacco Research and Intervention (UW-CTRI) 
Funding Sponsor: DHHS, PHS, National Institutes of Health (NIH) 
 
 
 

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“P01 Cessation Screening Study” 
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Study Overview 
Smoking causes almost 30% of cancer-related deaths1 and continues to be the leading 
preventable cause of death and disease in the US2. While effective smoking treatments exist3-6, 
their effectiveness in clinical contexts is likely limited because: 1) most treatments have been 
evaluated under tightly controlled research conditions (i.e., efficacy trials) using highly screened 
samples recruited via advertisement; and 2) virtually no treatments have been developed via 
careful evaluation of the individual and joint effects of the intervention components7,8 (e.g., 
intervention components may not work well together thereby reducing overall effectiveness, 
some components may be ineffective but increase cost and patient burden9-14). Thus, we have 
not yet identified optimized strategies for using the two most effective smoking cessation 
medications (combination nicotine replacement therapy [C-NRT] and varenicline) in primary 
care so that each is especially effective and cost-effective.  
This study will use the Multiphase Optimization Strategy (MOST)8,15,16 to guide the development 
of optimized treatment strategies for the two most effective smoking cessation medications (C-
NRT and varenicline). We will recruit daily smokers from primary care to participate in a fully 
crossed, 2x2x2x2 factorial experiment (N=608) that evaluates 4 different factors: 1) Medication 
Type (Varenicline vs. C-NRT), 2) Preparation Medication (4 Weeks vs. Standard), 3) Medication 
Duration (Extended [24 weeks] vs. Standard [12 weeks]); and 4) Counseling (Intensive vs. 
Minimal). We will examine main and interactive effects of these four factors (including 
Medication Type) to identify especially effective components and determine which components 
significantly enhance or reduce the effectiveness of other components due to synergistic or 
subtractive interactions. These results will be used to identify optimized treatments for both 
varenicline and C-NRT, providing new options for a precision medicine approach to smoking 
treatment (e.g., smokers may have contraindications for one medication, one medication may 
perform better for a group of smokers). In this factorial experiment, we will also examine 
potential moderators of intervention component effectiveness including sex, tobacco 
dependence, and psychiatric history, and potential mediators (e.g., withdrawal suppression, 
enhanced self-efficacy). In sum, this study is designed to produce data on four different smoking 
treatment factors, allowing us to achieve the following aims: 
Primary Aim 1: To determine which smoking cessation intervention components, and 
combinations of components, significantly improve smoking abstinence and cost-
effectiveness based on main and interactive effects on 12-month biochemically 
confirmed abstinence. This aim addresses the vital question of which individual intervention 
components are significantly beneficial and which significantly enhance or degrade the effects 
of other components.  
Primary Aim 2: To identify two optimized smoking cessation treatments: one for 
varenicline and one for C-NRT. Data on both the 12-month abstinence effect sizes and costs 
of the different intervention components and combinations of components will be examined and 
multiple criteria decision analysis will be used to determine how to use each medication so that 
it is highly effective and but low in cost.  
Secondary Aims: To determine: 1) whether person factors (e.g., sex, dependence, psychiatric 
history) moderate response to different treatment strategies; and 2) the main and interactive 
effects of the cessation interventions on cost-effectiveness.  
This proposed research builds on our expertise and prior research findings, using an efficient 
and innovative methodology (e.g., MOST) to identify cessation treatment components that 

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produce especially high levels of abstinence in primary care patients who want to quit smoking. 
Optimization methods will yield two smoking cessation treatments that are especially effective 
and affordable when used in healthcare settings. The development of two different, highly 
effective smoking cessation treatments has the potential to increase treatment reach and 
substantially reduce smoking prevalence in healthcare populations. 
It should be noted that in June, 2021 Pfizer found that some lots of varenicline contained 
elevated levels of a novel nitrosamine that exceeded the level thought to be safe by the FDA for 
traditional nitrosamines. When this occurred, we paused all study enrollment. To ensure 
participant safety, but continue to obtain data, we will resume study recruitment but not 
randomize anyone to any of the 8 varenicline conditions until we can get varenicline that Pfizer 
can verify does not have elevated levels of nitrosamine. When we can get safe medication, we 
will petition the IRB to resume recruitment into all 16 treatment conditions. 
On 8/11/2021, the FDA approved a generic version of varenicline. The generic varenicline was 
found to be bioequivalent and therapeutically equivalent to the Pfizer version of varenicline, with 
levels of novel nitrosamine well below the acceptable daily intake (ADI) set forth by the FDA. 
The study will resume providing the generic version of varenicline to participants according to 
study protocol. The study will not resume providing Pfizer varenicline (Chantix) to study 
participants until new laboratory information has been released proving it’s safety.  
Recruitment & Study Entry 
Participants will be patients from 12 large primary care clinics in two Wisconsin healthcare 
systems that treat diverse populations of patients with a large percentage of smokers. UW 
Health is the integrated health system of the University of Wisconsin-Madison serving more than 
600,000 patients each year in the Upper Midwest and beyond at six hospitals and more than 80 
outpatient sites. Aurora Health Care (Aurora) is the largest healthcare delivery system in 
Wisconsin and serves ~1 million Wisconsin residents including Medicaid-eligible, commercially 
insured, and indigent patients in urban (e.g., Milwaukee) and suburban areas in eastern 
Wisconsin.  
All EHR-identified smokers in a clinic will receive an invitation in the mail and, if they are active 
on MyChart, via a MyChart message, to find out more about smoking treatment by calling a 
Care Manager (CM) within the health system. In addition, Medical Assistants (MAs), using an 
EHR-guided prompt, will refer patients seen at in-person or tele-health visits who report smoking 
to a CM using an opt-out strategy. The CM will call and tell patients about the smoking 
cessation options available for them including the availability of this smoking cessation study. 
As part of a sister study (IRB # 2022-0973), all patients automatically enrolled in 2022-0973 will 
receive information on the Cessation study. In addition, all patients automatically enrolled in 
sister study 2022-0973 who are on the smoking registry at our active recruitment clinics and are 
not currently enrolled in the Cessation Study will receive a second outreach mailing letting them 
know about the Cessation Study, along with their standard care options (care from the 
Wisconsin Tobacco Quitline or from their primary care team). Patients in all clinics will be 
directed to call their Tobacco Care Manager for more information about this P01 Cessation 
Screening Project. Patients at a sub-set of clinics will receive additional, quarterly 
communications regarding these and additional smoking cessation options available as part of 
this sister study (IRB # 2022-0973). This quarterly outreach will occur via mailed letter and 
applicable patient-preferred modalities including e-mail (if participant consents to e-mail 
communication with the TCM) and text messages (if participant consents to text message 
communication with the TCM). Patients in the clinics receiving quarterly outreach will have the 

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option to contact their Tobacco Care Manager by phone, or by filling out a brief webform to 
request the Tobacco Care Manager call them to talk about this study. Thus, there will be 
additional outreach to patients about this treatment study (in addition to alternative treatment 
options) as part of this sister study (IRB # 2022-0973). 
If patients are interested in participating in this study, the CM will obtain oral assent for 
screening and sharing contact information, primary care team, and screening data with the UW 
research team before screening patients for eligibility in a UW REDCap database. Eligible 
patients will learn more about the study and have a chance to ask questions and provide verbal 
informed consent. Finally, participants will complete a brief series of questions and then the CM 
will schedule a call with the study staff (i.e., a Health Counselor) in the REDCap database to 
initiate treatment and complete study assessments. Participants interested in quitting but not 
eligible for this study will be electronically referred to the Wisconsin Tobacco Quit Line and/or 
told to make an appointment with their primary care provider (PCP) by the CM. 
After providing consent at Call 1, the Health Counselor (HC) will ask if the participant gives the 
study permission to stay in touch with them and send them reminders about upcoming study 
contacts and to remind them that it is time for a refill on their study medication during the study 
via email and/or text message. The HC will remind them that email and text messaging are 
generally not a secure way to communicate about their health as there are many ways for 
unauthorized users to access email and text messages. The HC will also inform them that they 
do not have to provide their email address or text message number to participate in this study.  
 
Inclusion/Exclusion 
 
To ensure the generalizability of these findings, we kept our inclusion criteria as broad as 
possible, focusing on ensuring that participants were medically appropriate to use the study 
medications. Therefore, inclusion criteria will be: age >17 years; smoking >4 cigarettes/day for 
the previous 6 months; able to read, write, and speak English; not currently taking bupropion or 
varenicline; if currently using NRT, agreeing to use only study medication for the duration of the 
study; medically eligible to use study medications (e.g., no severe renal disease, no allergic 
reactions to tested agents); and, for women of childbearing potential, using an approved method 
of birth control during treatment. Patients will be excluded if they report suicidal ideation within 
the last 12 months or any suicide attempts in the past 10 years.  
Those who agree to and pass the screening for the inclusion/exclusion criteria for study 
participation will be asked to complete an oral consent and HIPAA authorization process next. 
During this process, participants will be read a consent script that conveys the key points 
regarding study procedures; risks; and participant rights, protections, and benefits in accessible, 
lay language. Prospective participants will be given an opportunity to ask questions and raise 
concerns during this process, which will be addressed prior to assessing participant consent to 
participate in the study. Informed consent for study participation will be formally documented 
electronically in a REDCap database. Following consent, study staff will send the participant the 
Study Information Sheet that will remind the participant of study procedures and will include 
detailed information including all required elements of informed consent and HIPAA 
authorization. Those who decline the screening invitation, do not meet eligibility criteria, or do 
not provide oral consent for study participation will be advised to quit smoking and offered 
standard smoking cessation treatment (told to make an appointment with their primary care 
provider and/or referral to the Wisconsin Tobacco Quit Line or other tobacco quit line, as 
appropriate given state of residence). 
 

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After the patient provides oral consent, the CM will notify the patient’s PCP via EHR that the 
patient has volunteered for a study with C-NRT or varenicline. The PCP will notify the CM via 
the EHR that the patient is medically eligible to receive either agent, as required by the 
collaborating healthcare systems. This will occur within 5 business days. To enhance external 
validity, we will not exclude participants based on their prior use of cessation medication, 
psychiatric diagnoses, or their use of multiple tobacco products including e-cigarettes (these will 
be statistically controlled in analyses). We will encourage participants to discontinue use of all 
tobacco products on their target quit date (TQD). The PCP will be notified via EHR of the 
patient’s treatment assignment and of study-related serious adverse events or adverse events 
that prompt medication discontinuation that may occur. Care coordination with the PCP will 
occur via Tobacco Care Manager entry of data in the patient EHR.  
While this study does not target incarcerated individuals, some participants may be incarcerated 
during the period of study involvement. All study outreach, treatment provision, and assessment 
will be suspended during a participant’s period of incarceration.  
 
Study Design 
The Cessation Screening Project is a 4-factor, fully crossed, factorial screening experiment (i.e., 
2x2x2x2 = 16 experimental conditions) designed to identify the most promising intervention 
components that are especially effective and cost-effective with regard to their main and 
interactive effects on 12-month abstinence (see Table 2). This scientifically rigorous design 
will allow us to: 1) detect main effects and interactions within the factorial experiment and 
identify especially effective medication regimens for varenicline and for C-NRT; 2) compare the 
relative effectiveness of varenicline and C-NRT; and 3) identify the most effective and cost-
effective counseling modality to use with the optimized medication regimens. This will allow us 
to identify two optimized treatment packages for use with primary care smokers interested in 
quitting: packages that include both counseling and pharmacotherapies optimized on the bases 
of effectiveness and cost.  
At the second study call, participants (N=608) will be randomized to one level of each of 4 
factors (see Table 2): 1) Medication Type (Varenicline vs. C-NRT), 2) Preparation Medication (4 
weeks vs. Standard), 3) Medication Duration (Extended vs. Standard), and 4) Counseling 
(Intensive vs. Minimal). Participants will complete phone assessments one week pre-quit, during 
the first week post-target quit date (TQD) and at Weeks 2, 4, 12, 20, 26, and 52 post-TQD.  
Assessments 
Call 1. At Call 1, participants will complete the phone screen, complete the oral consent and 
HIPAA authorization process, and complete a brief demographics assessment. After this call, 
participants will be mailed a Study Information Sheet that contains all of the information related 
to the study. They will also be sent information on how to use WebEx so they can have video 
visits if they so choose. 
Call 2. Participants will answer questions about their smoking and other tobacco use history, 
their self-efficacy and motivation, their physical and emotional health, the impact of Covid-19 on 
their life and their beliefs about Covid-19 and smoking, and their satisfaction with their health 
care and they will complete the Fagerström Test of Cigarette Dependence117 (see Table 1). 
Participants will be randomized to their treatment condition, set a target quit date, and be 
educated about their assigned medication (including how and when to request refills). 
Calls 3-6. Participants will receive a call one week pre-quit, during the first week post-target quit 
date (TQD) and at Weeks 2 and 4 from their Health Counselor. This research staff member will 
assess: a daily smoking calendar using timeline follow-back118, medication use (as appropriate 

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based on study condition), use of alternative nicotine products (e.g., e-cigarettes), withdrawal, 
self-efficacy, and adverse events. We will recommend dosage/use alterations as per good 
clinical practice if participants experience adverse events. Participants will be referred to their 
primary care physician should they require medical consultation. Participants will also receive 
smoking cessation counseling as appropriate, based on their assigned treatment condition. If 
the call does not include treatment it will not be conducted by the participant’s health counselor 
(i.e., Calls 5 and 6 for those in the Minimal Counseling condition). 
Calls 7-10. All participants will get calls at Weeks 12, 20, 26 and 52 from research personnel 
who did not provide treatment to determine: smoking status (7-day point prevalence and daily 
calendar using timeline follow-back); use of alternative nicotine products (e.g., e-cigarettes); 
study medication use in the last 7 days; and withdrawal, self-efficacy, and adverse events (if 
using study medication). Calls 7, 9, and 10 will also assess the impact of Covid-19 on their life 
and their beliefs about Covid-19 and smoking. These assessment calls will not include 
counseling. If participants do not complete the 26 or 52-week assessment calls, we will send a 
brief assessment to them in the mail with a return envelope for them, and/or via text/email if the 
participant has consented to text/email communications, to report their smoking status. If 
participants report a serious adverse event or if they discontinue their study medication due to 
an adverse event, that information will be emailed to their primary care provider in the EHR by 
the Care Manager to enhance clinical care. 
Table 1. Schedule of Cessation Screening Project Assessments and Interventions 
Assessments 
 
 
Wk  
-1 
Day 
2 
Wk 
2 
Wk 
4 
Wk 
12 
Wk 
20 
Wk 
26 
Wk  
52 
 
C1* 
C2 
C3 
C4 
C5 
C6 
C7 
C8 
C9 
C10 
Eligibility screening 
X 
 
 
 
 
 
 
 
 
 
Verbal consent and info sheet mailed 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Smoking history 
 
X 
 
 
 
 
 
 
 
 
Covid-19 questions 
 
X 
 
 
 
 
X 
 
X 
X 
Self-efficacy/ motivation 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Random assignment to treatment 
 
X 
 
 
 
 
 
 
 
 
Tobacco dependence 
 
X 
 
 
 
 
 
 
 
 
Health, alcohol use 
 
X 
 
 
 
 
 
 
 
 
Withdrawal 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Smoking status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Use of other tobacco products 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cannabis use 
 
X 
 
 
 
X 
X 
 
X 
 
Medication use† 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events† 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Patient satisfaction 
 
X 
 
 
 
 
X 
 
X 
 
Medication education and mailing 
 
X 
 
 
 
 
 
 
 
 
Set target quit day** 
 
X 
 
 
 
 
 
 
 
 
Intensive counseling (phone/video) 
 
 
X 
X 
X 
X 
 
 
 
 
Minimal counseling (phone/video) 
 
 
X 
X 
 
 
 
 
 
 
Cotinine/anabasine 
 
 
 
 
 
 
 
 
Xa 
Xa 
*C1 will be conducted by the healthcare system Care Manager.  All other calls will be conducted by 
research Health Counselors or other research staff 
**The TQD will be set either 5 weeks from C2 to allow a week for medication to be delivered and 4 
weeks for prequit medication use for those in the prequit medication condition, or 2 weeks from the C2 to 
allow a week for medication to be delivered and 1 week for prequit medication if the participant is in the 

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Month 6 and 12 Biochemical Confirmation. Participants who report 7-day point-prevalence 
abstinence at the Month 6 and 12 follow-up call will be mailed a saliva collection kit with 
instructions on how to collect a saliva sample and mail it back to the Center. These saliva 
samples will be sent to a lab to assess the level of cotinine (a metabolite of nicotine and 
biomarker for smoking and other sources of nicotine). Please note, if participants have a 
detectable level of anabasine (a biomarker specific for combustible tobacco), we will also collect 
those results. Participants who report abstinence in the last 7 days at this visit but have a 
cotinine level >10ng/mL or who do not have provide a cotinine result will be considered to be 
smoking. When a participant demonstrates biochemically confirmed abstinence, that information 
will be conveyed to the primary care provider by the Care Manager via either email in the 
electronic health record or by changing the electronic health record smoking status.  
Satisfaction Assessments. All participants will evaluate their treatment in terms of burden, 
acceptability, and perceptions of the healthcare system, using measures based on previous 
research on patient satisfaction assessments. At Weeks 12 and 26 we will assess satisfaction 
with research staff, clinic staff for referring the smoker to the study, and the healthcare system 
for providing the treatment. Up to 110 participants will also be offered up to an additional $20 
($10 for Call 2 assessment and $10 for Call 7 assessment) for completing a brief (5 minute) 
interview related to burden, acceptability, and perceptions of telehealth modality (i.e., Webex 
versus telephone). This additional interview is supplementary, will occur at Call 2 and Call 7 with 
the first 110 smokers in the study who agree to participate, and will not affect their eligibility in 
the study or care provided. These interviews will be recorded and transcribed. 
Healthcare Utilization. Data on health status and healthcare utilization for participants who do 
and do not quit smoking will be extracted from the EHR for up to 1 year pre-enrollment, and 4 
years post-enrollment to inform economic analyses for the Secondary Aims. 
 
Interventions 
Participants will be told their treatment condition at Call 2, set a target quit date (TQD), and 
instructed how to use their study medications. Medications will be mailed following this call, 
along with a handout that describes: 1) when to begin taking study medication; 2) the type and 
doses involved; 3) how and when to obtain the next month’s medication; and 4) complete 
instructions on proper medication use, including information from the package insert and contact 
information if they have questions regarding their medication and/or symptoms they experience. 
Participants will be mailed all Preparation Medication as well as one month of post-quit study 
medication after Call 2. They will need to call in to a study line to request that more medication 
be mailed to them (Standard Duration participants will call one time to receive their final 2 
months of medication; Extended Duration participants will call once to get 2 additional months of 
medication and again to get the remaining 3 months of study medication). Participants will also 
receive a counseling handout with their medications; those randomized to intensive counseling 
will receive a Quit Plan listing their target quit day and when they start the medications and 
those randomized to minimal counseling will receive the mHealth handout. 
 
 
varenicline no-pre-quit medication condition 
†Medication use and adverse events will be assessed for participants currently receiving study 
medication (this will vary by treatment condition) 
aAll participants who report 7-day point-prevalence abstinence will be asked to provide a saliva sample to 
biochemically confirm abstinence.  

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Medication Type: Varenicline vs. C-NRT. Half of participants will be assigned to receive 
varenicline and half to receive nicotine patch + mini-lozenge (C-NRT). Unless participants are 
assigned to Preparation or Extended Duration, they will receive the standard dosing and 
duration of pharmacotherapy (e.g., 12 weeks of varenicline starting 1 week prequit or 12 weeks 
of C-NRT starting on the TQD; see Table 2). 
Preparation 
Medication: 4 weeks 
vs. Standard. Half of 
participants will be 
assigned to receive 
the Preparation 
Medication (“ON” 
condition); they will be 
instructed to use their 
assigned medication 
type (varenicline or 
nicotine patch) for 4 
weeks prior to their 
TQD (see Table 2). 
Participants will use a 
lower dose of NRT 
(14-mg patches) while 
they are still smoking 
to reduce the risk of 
adverse events. Our 
prior research found 
no significant 
increases in adverse 
events among 
smokers who used 
NRT prior to the TQD 
and prior research has 
shown that use of 
varenicline up to 35 days prior to the quit day is safe and effective. Participants assigned to the 
“OFF” level start their C-NRT use on their TQD or the standard Preparation varenicline, which 
starts 1-week pre-TQD (see Table 2). 
Medication Duration: Extended vs. Standard. After Call 2, all participants will be mailed 
enough medication to get through the first month post-TQD and instructed to call a toll-free 
study number to have their refills mailed to them. Half of participants will be assigned to the 
Extended Duration (i.e., the “ON” condition); these participants will be able to use varenicline for 
23 weeks post-TQD (24 weeks post-TQD if also randomized to preparation meds) or use C-
NRT for 24 weeks post-TQD (see Table 2). The other half of participants will have varenicline 
for 11 weeks post-TQD (12 weeks post-TQD if also randomized to preparation meds) or C-NRT 
for 12 weeks post-TQD. We will urge all participants to use all of their study medication, 
regardless of whether they are abstinent or not. 
Counseling: Intensive vs. Minimal. Half of the participants will be assigned to the Intensive 
Counseling condition and will receive four 15-20-minute counseling sessions occurring 1 week 
prequit, during the first week post-TQD and during Weeks 2 and 4 (see Table 1). During the first 
counseling call, the HC and participant will create a quit plan that the HC will then mail to the 
participant following the call. The counseling will be provided either via HIPAA-secure WebEx 
Table 2. Medication Dosing 
 
 
Cessation Medication: 
Standard Duration (12 Weeks) 
Cessation Medication: 
Extended Duration (24 Weeks) 
Varenicline 
No Preparation Meds: 
 Days 1-3: 0.5 mg pill QD  
 Days 4-7: 0.5 mg pill BID  
 Day 8 (TQD)-Week 11: 1 mg 
pill BID  
Preparation Meds: 
 Days 1-3: 0.5 mg pill QD  
 Days 4-7: 0.5 mg pill BID  
 Day 8-Week 16: 1 mg pill BID 
(TQD in Week 4) 
No Preparation Meds: 
 Days 1-3: 0.5 mg pill QD  
 Days 4-7: 0.5 mg pill BID  
 Day 8 (TQD)-Week 23: 1 mg 
pill BID  
Preparation Meds 
 Days 1-3: 0.5 mg pill QD  
 Days 4-7: 0.5 mg pill BID  
 Day 8-Week 28: 1 mg pill BID 
(TQD in Week 4) 
Combination NRT* 
Nicotine Patch 
Smoke ≥10 cigs/day: 
 Weeks 1-8: 21 mg  
 Weeks 9-10: 14 mg  
 Weeks 11-12: 7 mg 
Smoke 5-9 cigs/day: 
 Weeks 1-10: 14 mg  
 Weeks 11-12: 7 mg  
Smoke ≥10 cigs/day: 
 Weeks 1-20: 21 mg  
 Weeks 21-22: 14 mg  
 Weeks 23-24: 7 mg 
Smoke 5-9 cigs/day: 
 Weeks 1-22: 14 mg  
 Weeks 23-24: 7 mg 
Nicotine 
Mini-
lozenges 
 2 mg  
 Weeks 1-6: 1 ML/1-2 hrs  
 Weeks 7-9: 1 ML/2-4 hrs  
 Weeks 10-12: 1 ML/4-8 hrs  
 2 mg  
 Weeks 1-20: 1 ML/1-2 hrs  
 Weeks 21-22: 1 ML/2-4 hrs  
 Weeks 23-24: 1 ML/4-8 hrs  
*Participants randomized to Preparation C-NRT will receive 14-mg patches for the 4 
weeks prior to the TQD. QD = daily, BID = twice a day, ML = mini-lozenge 

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video conference or phone, depending on the participant’s preference. A web link for the video 
conferences will be sent to participants via Outlook email to the participant’s email address they 
have provided the HC. The counseling sessions will be designed to produce intra-treatment 
support and skill training and problem-solving.  
The other half of the participants receive a brief (15-30 minute) phone/video counseling session 
1 week prior to the TQD to promote engagement with free mobile health (mHealth) resources: 
smokefree.gov and/or the Wisconsin Tobacco Quit Line, mHealth resources developed and 
maintained by the National Cancer Institute and the Wisconsin Department of Health Services. 
This will include a fax referral to the Wisconsin Tobacco Quit Line, which will then fax back to 
the research office what services the participant received (i.e., did they complete the counseling 
call, were they sent any smoking cessation medications). Smokefree.gov allows participants to 
develop a quit plan and access different quit smoking resources. The Quit Line is an interactive 
program that involves one-on-one telephone coaching sessions with a trained Quit Line coach 
to encourage smoking cessation, offer personalized advice on how to quit, information on 
medications, and assistance with choosing a quit date and creating a plan. This counseling will 
include informing participants about the features of the resources and encouraging them to sign 
up during their counseling session and a mailing that describes the mHealth resources. 
Participants will then receive a brief (10-20 minute) follow-up phone/video session during the 
first week post-TQD to mimic a nurse or clinician follow-up after a quit attempt and to provide 
additional mentoring around the use of the mHealth resources (e.g., has the participant signed 
up/used these resources, recommendation for specific pages that would be appropriate).  
All participants will receive the medication conditions as outlined above, regardless of their 
counseling condition. Regular team meetings will discuss safety, confidentiality, and fidelity to 
the counseling manual. Health counselors (HCs) will also meet for 2 hours/month for clinical 
supervision with the Project Leader, Dr. Piper, a licensed clinical psychologist, to review the 
study protocol and address treatment issues.  
Promoting Continued Experimental Participation 
We will utilize participant retention strategies that were effective in our prior research, including 
strategies such as scheduling flexibility, calling participants’ cell phones if they request that, and 
continued interaction with the same health counselor. In addition, consented participants who 
we are not able to reach using contact information obtained at the baseline and subsequent 
calls, the CM will check in the EHR for updated contact information. If there is no updated 
information, we will call and/or send a letter to the alternate contacts provided by the participant, 
designated as a contact for this specific situation. 
 
Compensation: Participants will be compensated for completing assessments: $20 for Call 2; 
$10/assessment for Calls 3-8 (1 week pre-quit, Weeks 1, 2, 4, 12, and 20); $20/assessment call 
at Weeks 26 and 52; and $50/Month 6 and 12 returning the saliva sample for cotinine analysis. 
This would result in a total potential compensation of $220. If participants are unable to 
complete the assessment calls at Weeks 26 and 52, return the assessment letter or complete it 
online, they will receive $15. Up to 110 participants will also be offered an additional $10 for 
completing a brief (5 minute) interview related to of burden, acceptability, and perceptions of 
telehealth modality (i.e., Webex versus telephone) at Calls 2 and 7 (total of $20). 
Analytic Approach       
Primary Aim 1: Identifying Main and Interactive Effects. The primary outcome is 
biochemically confirmed, point-prevalence abstinence at 12-months post-TQD. We will also 

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examine the main and interactive effects on cost-effectiveness. The secondary outcome is cost 
effectiveness in which the costs of implementing each intervention (minus research-related 
costs) will be computed from a payer perspective. Costs will be combined with the intent-to-treat 
biochemically verified 7-day point prevalence abstinence at 12 months post-TQD to determine 
the cost per quit. 
Effectiveness. We will conduct logistic regression analyses with predictors corresponding to the 
four factors using effect coding. The logistic regression models will include main and all 
interactive effects. Main effects will reflect the degree to which participants in the “ON” condition 
of a factor have significantly higher 1-year point-prevalence abstinence, relative to participants 
in the “OFF” condition for each factor, averaged across the other factors. These analyses will 
allow us to identify optimized treatments based upon main effects and interactions as they 
provide effect sizes (standardized regression coefficients) for the various intervention 
components and their combinations. Interactions between Medication Type and other factors 
could potentially yield distinct optimized treatment regimens for C-NRT and varenicline, 
especially given the frequency of meaningful interactions amongst smoking intervention 
components. A priori we have decided to identify two optimized treatments to allow for patient 
choice, provide flexibility for patients who may have contraindications, and provide an 
opportunity for strategic assignment depending on smoker characteristics (algorithm-based 
personalized medicine). On the other hand, if we obtain a strong main effect for one of the 
medications (e.g., varenicline), this would be important clinically and would identify one of these 
agents as the preferred basis for optimized treatment.  
The question of primary interest is how treatments affect abstinence amongst diverse smokers 
amidst the variety of other factors that also influence smokers’ ability to maintain abstinence, not 
whether such effects occur in a statistically adjusted sample. Therefore, the primary analyses 
will first be conducted without covariate adjustment, to ensure that covariate adjustment does 
not cloud interpretation or reduce external validity for various reasons. In additional analyses, 
we will statistically control for covariates such as healthcare system and clinic, and important 
smoker characteristics known to affect either treatment response or abstinence likelihood 
(biological variables: e.g., sex and age, as well as other key variables such as living with a 
smoker, educational attainment) to explore how treatment effects are related to such variables.  
Cost-effectiveness. Cost-effectiveness analyses will focus on the intervention components and 
combinations of components per se and on the entire program costs more globally, including 
implementation costs related to recruitment, medication screening, and CM time. We will use 
methods recommended by the US Panel on Cost-Effectiveness in Health and Medicine, 
consistent with our prior research. We will measure costs from a societal perspective using data 
on smoking cessation benefits from publicly available Medicare and Medicaid reimbursement 
rates. Cost estimates will be converted to a common year and QALYs will be computed, using a 
rate of 3% to discount future outcomes and costs to present value. We will also conduct 
probabilistic sensitivity analyses to account for uncertainty. We will determine net monetary 
benefit (NMB), cost per quit, and incremental cost-effectiveness ratios (ICERs). The 
components of NMB will be the added costs of the treatments and the monetized value of the 
QALYs added by the treatments. We will convert the increased effectiveness of the treatments 
from quits to added QALYs. Total program costs will be compared to program costs of the usual 
care approach to tobacco (MA offer, fax-to-quit referral) in place prior to the research 
implementation. These cost-effectiveness outcomes will be computed for all intervention 
conditions for all projects. To generate stable estimates of short and longer-term costs and 
savings, we will extract data on healthcare utilization from 1 year pre-enrollment to up to 4 years 
post-enrollment (maximum of 5 years total). 
Primary Aim 2: Comprehensive Optimization of Treatment. The results of the analyses for 
Primary Aim 1 will be used to optimize two treatment packages: varenicline-based treatment 

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and C-NRT-based treatment. We will select component packages that are especially effective 
and low in cost, to constitute optimized treatments. The primary criteria we will use for this 
project are abstinence at 12 months post-TQD and cost. We will attempt to balance cost and 
effectiveness in this effort, so that the selected components hit a “sweet spot” on a synthesis of 
the two criteria.  
We will use multiple criteria decision analysis (MCDA), which focuses on how to weight and 
combine such criteria to support meaningful decisions and to decide on the optimal treatment 
packages. We will follow recommendations of the International Society for Pharmacoeconomics 
and Outcomes Research (ISPOR) Best Practices Task Force139,140 with respect to problem 
definition, criteria selection, use of the value measurement approach, criteria weighting, 
sensitivity analyses, and so on. We will synthesize cost and effectiveness scores for groupings 
of intervention components via an additive model with weights for the scores being derived from 
data generated by assessments of key healthcare system and clinical stakeholders (e.g., 
physicians, healthcare system administrators; see Implementation Project). The optimized 
packages will be those that perform best with regard to stakeholder-based preference 
weightings.  
Secondary Aims Analyses. Exploratory analysis of moderators of abstinence outcomes will 
use complementary logistic regression analyses with appropriate model-fitting techniques141 and 
regression tree analyses that can identify differential treatment responses142,143 in 6- and 12-
month abstinence. Candidate moderators of treatment effects on abstinence will include 
tobacco dependence and psychiatric history, contextual factors such as household smoking, 
and biological variables such as sex. In the logistic regression analyses, moderators will be 
evaluated with regard to their interactions with treatment main effects and interactions. With a 
similar sample size, we were able to detect moderation in our prior factorial research. 
Additional Exploratory Analyses. Seven-day point-prevalence abstinence at Weeks 12 and 
26 will be analyzed using similar methods to those used for the primary outcome. These 
analyses will allow us to examine the stability or robustness of the intervention component 
effects. These findings may also be used in future research to optimize cessation treatments 
based on longer-term outcomes. In addition, we will examine the occurrence of adverse events 
and its relation with adherence. Logistic and linear regression will be used for categorical and 
continuous variables, respectively, with appropriate transformations of continuous variables 
and/or adoption of generalized regression modeling techniques as necessary. Analyses of these 
exploratory outcomes will achieve scientific rigor by controlling for experiment-wise error in 
families of related tests using the Benjamini-Hochberg approach148-150.  
Sample Size and Power Considerations 
This study was designed to have sufficient power to detect a clinically significant (i.e., 10 
percentage point increase) difference between the two levels of a factor (i.e., the main effects) 
in 52-week biochemically confirmed abstinence. In other words, the sample size was chosen to 
ensure that the Primary Aim comparisons of ON vs OFF levels of a factor would have sufficient 
power to detect clinically meaningful increases in abstinence. It should also be noted that 
because this is a balanced factorial design, we will have the same power to detect 2-way 
interactions that we have to detect main effects. To address the Primary Aim, we assume that 
the base rate (participants who get Standard Preparation Medication and Standard Duration) of 
52-week biochemically confirmed abstinence will be 20%. This is consistent with our prior 
research that found a self-reported 52-week abstinence rate of 26.8% among primary care 
smokers who received 8 weeks of C-NRT13 and our efficacy trial that showed biochemically 
confirmed 52-week abstinence rates of approximately 20% for smokers who received either 12 
weeks of varenicline or 12 weeks of C-NRT43. If we assume that abstinence rates among real-
world primary care patients might be somewhat lower (e.g., 15%), then with a sample size of 

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608 (304 in the ON and 304 in the OFF levels of each factor with no missing data because 
missing=smoking) and α=.05, we are powered at .87 to detect a difference between 15% and 
25% in 52-week biochemically confirmed abstinence; we also have sufficient power (.81) to 
detect a difference between 20% and 30% in 52-week biochemically confirmed abstinence. 
Treatment optimization will be based on the effect size estimates of the main and interactive 
effects on 12-month abstinence, rather than statistical significance, consistent with our prior 
research15.  
Protection of Human Subjects   
Human Subjects Involvement and Characteristics. All EHR-identified smokers in a clinic will 
receive an invitation (in their preferred modality: mail, MyChart messages from the EHR, text) to 
find out more about smoking treatment by calling a healthcare system Care Manager. In 
addition, Medical Assistants (MAs), using an EHR-guided prompt, will inform all smokers 
attending in-person or tele-health visits that they will be getting a call from their clinic’s Care 
Manager, using an opt-out approach. The Care Manager will call the smoker and assess their 
interest in quitting smoking. Smokers who are interested in quitting in the next 30 days will be 
offered a variety of cessation treatment options, including the opportunity to participate in this 
smoking cessation study.  
Specific eligibility requirements for this project are: age >17 years; smoking >4 cigarettes/day for 
the previous 6 months; able to read, write, and speak English; not currently taking bupropion or 
varenicline; if currently using NRT, agreeing to use only study medication for the duration of the 
study; medically eligible to use study medications (e.g., no severe renal disease, no allergic 
reactions to tested agents); and, if the participant is a woman of childbearing potential, using an 
approved method of birth control during treatment.  
Those who agree to and pass the screening for the inclusion/exclusion criteria for study 
participation will be asked to complete an oral consent and HIPAA authorization process next. 
During this process, participants will be read a consent script that conveys the key points 
regarding study procedures; risks; and participant rights, protections, and benefits in accessible, 
lay language. Prospective participants will be given an opportunity to ask questions and raise 
concerns during this process, which will be addressed prior to assessing participant consent to 
participate in the study. Informed consent for study participation will be formally documented 
electronically in a REDCap database. Following consent, study staff will send the participant the 
Study Information Sheet that will remind the participant of study procedures and will include 
detailed information including all required elements of informed consent and HIPAA 
authorization. 
 
The Care Manager will notify the patient’s primary care provider (PCP) that the patient has 
volunteered for a study with C-NRT or varenicline and that the PCP should notify the Care 
Manager that the patient is medically eligible to receive either agent. The PCP will notify the CM 
that the patient is medically eligible to receive either agent (e.g., no severe renal disease, no 
psychiatric concerns), as required by the collaborating healthcare systems. This will occur within 
5 business days. The PCP will be notified of the patient’s treatment assignment, and of study-
related serious adverse events or adverse events that prompt medication discontinuation that 
may occur. Care coordination with the PCP will occur via Tobacco Care Manager entry of data 
in the patient EHR.  
Patients who are eliminated due to screening failure or elect not to participate in this research 
program will be given a list of alternative smoking cessation programs, including the Wisconsin 
Tobacco Quit Line (1-877-QUIT-NOW) and told to make an appointment with their PCP to 
discuss smoking cessation treatment. 

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A total of 608 participants will be recruited for this project. No special vulnerable populations will 
be recruited (pregnant women will be specifically screened out due to medication safety 
concerns and no persons under the age of 18 will be allowed to participate because the 
medications we are using have not been approved by the FDA for individuals less than 18 years 
old). Eligible participants will be randomized following provision of oral informed consent and 
PCP verification of eligibility (stratified by clinic, gender, and race [white vs. non-white]). 
Nicotine patch and varenicline dosing will be consistent with the 2008 PHS Guideline3 and 
package inserts. All participants in the C-NRT group will receive 2mg mini-lozenges due to the 
superior palatability of the 2mg lozenges. 
• 
Nicotine patches: ≥10 cigs/day = 8 [or more, depending on treatment condition] weeks of 21 
mg, 2 weeks of 14 mg, and 2 weeks of 7 mg nicotine patches; 5-9 cigs/day = 8 [or more, 
depending on treatment condition] weeks of 14 mg, and 4 weeks of 7 mg nicotine patches;  
o Participants assigned to Preparation NRT will receive 14 mg patches 
• 
Nicotine mini-lozenges: 2mg mini-lozenges;  
• 
Varenicline .5 mg once/day for 3 days, then .5 mg bid for 3 days and then 1 mg bid for the 
remainder of the regimen. 
The study will recommend dosage/use alterations as per good clinical practice if the participant 
experiences side effects. The Health Counselor will refer participants to their primary care 
physician should they require medical consultation. Medication is provided to participants in 
dosage periods defined within each treatment condition (e.g., participants may start their 
medication 4 weeks prior to the TQD; participants may receive medication for 12 or 24 weeks 
post-quit). 
This project involves collaboration with staff of the two health systems (Aurora Health Care, UW 
Health). In prior research of similar scope, MAs at referring clinics have been determined to be 
not involved in research since their role is limited to providing information about the availability 
of a study and sending contact information to the study to the Care Manager. The Care 
Manager, who will be a clinic employee but also engaged in research procedures, will complete 
the necessary Human Subjects training. The only study data shared by the Tobacco Care 
Managers with clinic teams will be interest in or enrollment in the study, study medications that 
may be and are given to study participants, study-related serious adverse events or adverse 
events that prompt medication discontinuation, and changes in smoking status. 
Sources of Materials. Contact information on all smokers interested in hearing more about 
smoking programs will be sent to the clinic Care Manager. The Care Manager will reach out to 
patients by phone and invite them to learn more about stop-smoking resources, including 
standard care (fax referral to the Wisconsin Tobacco QuitLine and/or their PCP) and the 
research study.  Those interested in the research study will then be told that this research is 
being conducted with Dr. Piper at the University of Wisconsin and asked if they would be willing 
to spend 10 minutes learning about the study and see if they qualify for it. Those who assent to 
this will then be told how their information will be used and stored, and asked if they would like 
to continue. If they assent again, and confirm that they smoke cigarettes, then then are read a 
detailed description of the study and asked if they are interested in participating in the study and 
if they assent to sharing their contact information and screening responses with the University of 
Wisconsin research team. If they provide oral assent to this, then the Care Manager completes 
eligibility screening in a UW instance of REDCap. For those who pass the eligibility screening, 
Care Managers (CM) will provide more information about the study, allow the patient to ask 
questions, and then patients will provide verbal consent. Finally, participants will complete a 

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brief series of questions and then the CM will schedule a call with the study staff (i.e., a Health 
Counselor) in the REDCap database to initiate treatment and complete study assessments. 
Care Managers will also contact potentially eligible patients’ PCP to finalize eligibility via EHR 
records and communication. Final PCP approval will be documented and participants’ 
randomized treatment assignment will be conveyed to the PCP as well as study-related serious 
adverse events or adverse events that prompt medication discontinuation that may occur. Care 
coordination with the PCP will occur via Tobacco Care Manager entry of data in the patient EHR 
Data will be transferred from the EHR to research databases for tracking recruitment, participant 
healthcare utilization, smoking cessation treatment, and changes in smoking status, insurance 
type, or health status over the course of the study. Both healthcare systems maintain secure, 
HIPAA-compliant electronic health records for their operations and have mechanisms and 
processes in place to extract and encrypt data from the EHR for research purposes. Staff at 
UW-CTRI will receive data on enrollees who have provided consent for phone screening. The 
data to be extracted from the EHR for the purposes of assessment are shown in the uploaded 
List of EHR Data to Be Extracted. The research office will also receive data from the Wisconsin 
Tobacco Quit Line regarding which services the participants in the Minimal Counseling condition 
received. 
Data collected from participants in this program will primarily be used for research. Data will 
consist of answers to questionnaires and interviews assessing smoking history, demographics, 
nicotine dependence, medication usage, medication side effects and satisfaction surveys. A 
small subset of participants will also complete interviews about telemedicine preferences. 
Participants will also provide saliva samples for cotinine assays that reflect smoking status. All 
data are retained in the research database. The research database access is limited to the clinic 
Care Managers and those staff members and investigators directly involved in the study and all 
under the supervision of the UW IRB. 
Potential Risks. Risks associated with this research are judged to be minimal. Smoking 
withdrawal is associated with a number of unpleasant symptoms such as sleep disturbance, 
hunger, craving, and negative mood. Most smokers have tried to quit in the past and are familiar 
with these phenomena. Participants will be informed about the likely effects of smoking 
withdrawal.  
With respect to the pharmacotherapies, participants will be made aware of the common side 
effects before they consent to participate in the study. It should be noted that the nicotine patch 
and nicotine mini-lozenge are available over the counter. The Food and Drug Administration 
(FDA) has approved using a combination of two forms of NRT (e.g., nicotine patch + nicotine 
mini-lozenge) for smoking cessation and using NRT prior to cessation151. These interventions 
have also been studied and used safely in multiple clinical trials, are used by knowledgeable 
clinicians in clinical practice, and are reviewed in the 2008 PHS Guideline3 and in a recent 
review in the New England Journal of Medicine29. The PHS Guideline, in fact, recommends 
combination NRT as a particularly effective treatment. The nicotine patch is generally well 
tolerated, but up to 50% of participants may have a local skin reaction, and rarely, individuals 
may have a more systemic allergic reaction. The most likely side effects associated with the 
nicotine mini-lozenge are heartburn, hiccup, nausea, upper respiratory tract infections, 
coughing, and sore throat. Although most smokers have tolerance to nicotine, symptoms of 
acute nicotine toxicity (nausea and vomiting) are possible. The most common side effects 
associated with varenciline are nausea and sleep disruption. It is also important to note that 
some individuals may experience worsening of psychiatric conditions or symptoms such as 
anger, agitation, depression, or suicidal thoughts. Varenicline may be associated with a small, 

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increased risk of certain heart problems in people with heart and blood vessel disease. Finally, 
individuals often attempt to stop smoking without the use of medication. As the 2008 PHS 
Guideline3 shows, this method is considerably less likely to produce long-term cessation. Those 
not successful in quitting bear the health risks associated with continued smoking. 
Finally, there is a small risk of loss of confidentiality. This could occur through a number of 
possible avenues, all highly unlikely due to the data security measures in place. UW-CTRI’s 
computer system is linked to the UW network through a firewall, which is managed by the 
School of Medicine and Public Health network team, via a fiber link which is maintained by the 
UW Division of Information Technology. No data are stored on individual computer hard drives. 
All data are transmitted from the point of collection to the UW-CTRI server through secure, 
encrypted web connection. There are rare occasions when, due to a loss of internet access or 
computer hardware failure, data are collected in paper forms, which could be taken or lost. In 
addition, consent forms are obtained in paper copy; these forms contain the participant name 
and signature. Finally, the University of Wisconsin and the National Cancer Institute may inspect 
the signed consent forms. Because of this possible need to release information to these parties, 
we cannot guarantee absolute confidentiality.    
Adequacy of Protection Against Risks 
Recruitment and Informed Consent. To ensure that our findings are maximally relevant to 
real-world healthcare application, we will screen smokers presenting to 8 primary care clinics in 
two participating health systems located throughout Southern Wisconsin. All EHR-identified 
smokers in a clinic will receive an invitation (in their preferred modality: mail, MyChart messages 
from the EHR, text) to find out more about smoking treatment by calling a Care Manager (CM). 
In addition, clinic roomers (e.g., Medical Assistants) will be prompted by the electronic health 
record (EHR) to invite all smokers attending primary care clinic in-person or tele-health visits. 
The MA will then send the contact information of interested patients to the CM. We have 
developed and used this successfully in our past research. The CM will call patients and offer 
interested patients an opportunity to participate in this smoking cessation study. The CM will 
then screen the participant to verify eligibility. If the patient is eligible and interested, the CM will 
complete an oral consent and HIPAA authorization process. During this process, participants 
will be read a consent script that conveys the key points regarding study procedures; risks; and 
participant rights, protections, and benefits in accessible, lay language. Prospective participants 
will be given an opportunity to ask questions and raise concerns during this process, which will 
be addressed prior to assessing participant consent to participate in the study. Informed consent 
for study participation will be formally documented electronically in a REDCap database. 
Following consent, study staff will send the participant the Study Information Sheet that will 
remind the participant of study procedures and will include detailed information including all 
required elements of informed consent and HIPAA authorization.  
 
After the patient provides oral consent, the CM will notify the patient’s primary care physician 
(PCP) that the patient has indicated they are interested in a study with C-NRT or varenicline and 
that the PCP should notify the CM if the patient should not receive either agent, as required by 
the collaborating healthcare systems. This will occur within 5 business days.  
 
Those who decline the screening invitation, do not meet eligibility criteria, or do not provide oral 
consent for study participation will be advised to quit smoking and offered standard smoking 
cessation treatment (told to make an appointment with their primary care provider and/or referral 
to the Wisconsin Tobacco Quit Line). 
 

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Records collected in this research will allow us to complete a full CONSORT diagram.  
Protection Against Risk. Risks related to medications are minimized through close monitoring. 
The Project Leader, working in consultation with the Program Project’s physician (Dr. Brian 
Williams), will be responsible for routine monitoring of unanticipated health events. This risk 
protection includes procedures for contacting the emergency physician or psychologist and 
monitoring of all events through scheduled biweekly meetings with study staff and review of 
written documentation. Unanticipated health event assessment, recording, reporting and 
investigation will be accomplished through staff training, structured/standardized assessments 
of untoward occurrences/events, and regular monitoring by study physicians and other study 
investigators. The Project Leader and the Program Project Co-Principal Investigators have 
ultimate responsibility for ensuring that unanticipated health events are detected and reported in 
a timely manner. Health events that raise concerns (e.g., allergic reaction, symptoms suggestive 
of nicotine toxicity, significant change in mood) will be immediately reported to the study 
physician who will determine an appropriate course of action.    
To facilitate safety, participants who may not be medically appropriate to use either 
pharmacotherapy will not be included in the study (e.g., no severe renal disease, no allergic 
reactions to tested pharmacotherapies). Once enrolled, follow-up protocols will assess for 
medication side effects and unanticipated health events at all study contacts. We will 
recommend dosage/use alterations as per good clinical practice if the participant experiences 
symptoms of nicotine toxicity or other troublesome side effects once they begin medication 
treatment. We will refer participants their primary care provider as needed. Should either 
excessive risk to study participants and/or lack of measurable benefit to study participants be 
determined, the study will be stopped and all participants notified in a manner appropriate to the 
nature of the risk and/or lack of benefit.  
Participants who are pregnant or planning to become pregnant are not eligible to participate in 
this study. We ask participants who are capable of becoming pregnant to use appropriate 
measures (e.g., abstinence, acceptable birth control) to avoid pregnancy. Should a participant 
become pregnant during the study, they will be told to discontinue all study medications (which 
represents the key risk during pregnancy) but they will be allowed to remain in the study and 
receive any remaining coaching interventions and complete all remaining assessments. If a 
participant becomes pregnant, that is a critical time for them to quit smoking which is something 
that the cessation counseling in this study can support. 
In terms of confidentiality risk, the UW-CTRI Information Technology Administrator, Jonah 
Stankovsky, manages the hardware, data, security, and infrastructure below the firewall. Access 
to the network is limited to only UW-CTRI owned and actively managed devices. All devices 
automatically lock and are password protected after 15 minutes of inactivity. All portable devices 
are encrypted for data security and no PHI is stored on local devices. All data stored on the 
network file server is limited by the principle of least privilege. Healthcare systems will transmit 
identifying information to UW-CTRI via secure, HIPAA compliant means (either a secure FTP 
site or a secure interface to the EHR). 
As stated above, no data are stored on individual computer hard drives. All data are transmitted 
from the point of collection to the UW-CTRI server through secure, encrypted web connection. 
On those rare occasions when, due to a loss of internet access or computer hardware failure, 
data are collected in paper forms, these forms will be stored securely in the clinic and 
transported personally by the case manager to UW-CTRI. No identifying data other than a 
participant ID number is entered on any data form. Any data collected on paper are entered into 

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the computer immediately upon receipt at UW-CTRI and the paper document is disposed of 
securely.  
Finally, no publications or presentations resulting from this research program will contain any 
identifying information about individual participants.   
Potential Benefits of the Proposed Research to the Participants and Others 
The potential benefits for smokers participating in this study include the chance to receive 
smoking cessation counseling and pharmacotherapy, two evidence-based treatments that can 
double a smoker’s odds of quitting successfully, at no cost. Considerable research has 
demonstrated that, at no matter what point a smoker quits successfully, health benefits occur17. 
In addition, quitting smoking reduces the burden of secondhand smoke exposure to others. 
Finally, the benefit of reduced healthcare costs and morbidity and mortality related to smoking is 
a societal benefit from quitting smoking.   
The health and economic benefits to the individual and society greatly outweigh the risks in 
terms of discomfort, side effects of medication, and loss of confidentiality.  
Importance of the Knowledge to be Gained 
This factorial trial will identify the optimal use strategies for varenicline and combination NRT, 
the two most effective smoking cessation pharmacotherapies currently available, and the 
optimal counseling modality for use with these medications.  
As outlined above, the risks of this study are minimal and limited to the discomfort of quitting 
smoking, generally mild side effects of medication, and small risk of breach of confidentiality. 
The potential study impact on increased numbers of smokers across clinical settings nationally 
far outweigh these risks.   
Data and Safety Monitoring Plan 
The Data Safety and Monitoring Plan (DSMP) for this Program Project comprises not only the 
research conducted directly by the University of Wisconsin Center for Tobacco Research and 
Intervention (UW-CTRI) researchers, but also research conducted by other investigators 
collaborating with UW-CTRI-funded projects. All investigators must agree to comply with the 
procedures outlined in this DSMP. This DSMP does not reduce any investigator’s obligation to 
comply with the requirements of the Institutional Review Board (IRB) at his/her home institution 
or the IRB of any collaborating organizations. 
Monitoring the progress of trials and the safety of participants. The Principal Investigators 
of the Program Project are responsible for routine monitoring of the progress of this research. 
This includes scheduled biweekly meetings with study staff and review of written documentation 
of all research projects. Data reviewed at these meetings will include the number and type of 
participants enrolled, the number and reasons for exclusions from enrollment, the number 
treated and the stage of intervention, summary of adverse events (AEs), individual review of 
serious adverse events (SAEs) and study participation, and outcome data. In addition, SAEs or 
AEs that raise concerns (e.g., allergic reaction, significant change in mood or suicidality) will be 
immediately reported to the study physician who will determine an appropriate course of action, 
which may include discontinuation of medication. As data become available, the Director of 
Research Administration, Project Leader and Principal Investigators will review the data on a 
regularly scheduled basis (initially biweekly and later monthly) to determine progress. To 
facilitate participant safety, study participants must meet study inclusion and exclusion criteria. 
Once enrolled, study protocols will assess the presence of AEs and SAEs at all study contacts. 
Should either excessive risk to study participants and/or convincing evidence of lack of 
measurable benefit to study participants be determined, the study will be stopped and all 

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participants notified in a manner appropriate to the nature of the risk and/or lack of benefit. 
When taking that step the investigators will consult with the IRB and NCI. 
Plans for the reporting of unanticipated health events. This DSMP requires that 
investigators notify NIH and the University of Wisconsin IRB in a timely manner (consistent with 
IRB and NIH policies) of the occurrence of any SAE or any AE that is severe, unexpected, and 
possibly related to study medication or protocol. Because this Program Project research 
involves pharmaceutical agents, if an SAE might be related to study drug use, both the Food 
and Drug Administration (FDA) and the manufacturer will also be notified within five days of 
investigators becoming aware of the event. Examples of SAE would be untoward medical or 
intervention occurrences that result in death, are life-threatening, require hospitalization or 
prolonging of existing hospitalization, create persistent or significant disability/incapacity, or 
involve congenital abnormality/birth defects. Unanticipated problems will be monitored and 
reported to the DSMC. These are events that meet the following criteria: 1) suggest the research 
places subjects or others at increased risk of harm, 2) are unexpected (in terms of nature, severity or 
frequency) given the research procedures that are described in the study-related documents, and 3) 
possibly related to study participation. Any SAE will be queried and reported if it meets the definition 
of unanticipated problem. The Project Leader and Principal Investigators will also be responsible 
for the accurate documentation, investigation and follow-up of all study-related adverse events. 
Adverse event assessment, recording, reporting, and investigation will be accomplished through 
staff training, structured/standardized assessments of untoward occurrences/events, and 
regular monitoring by study physicians and other study investigators. The Project Leader and 
Principal Investigators have ultimate responsibility for ensuring that SAEs are detected and 
reported in a timely manner. Additionally, the IRB will receive an annual report of all SAEs and 
AEs meeting the criteria listed above. 
Plans for assuring that any action resulting in a temporary or permanent suspension of 
an NIH-funded clinical trial is reported to the NIH grant program director responsible for 
the grant. The NIH grant program director will be notified within five days if the Principal 
Investigators deem it necessary to suspend a clinical trial. In the case of a temporary 
suspension, the Principal Investigators and Project Leader will develop a plan for continuation of 
the project and discuss this plan with the NIH grant program director in a reasonable time frame.   
Plans for assuring data accuracy and confidentiality and protocol compliance. The 
Project Leader, supported by CTRI analysis staff will develop plans for assuring data accuracy 
and protocol compliance. Such plans will include data verification and protocol compliance 
checks. The Data Manager and IT Manager shall be responsible for ensuring that the data for 
the project are securely stored, that storage is in compliance with University and federal 
regulations and that no unauthorized persons have access (electronic or physical) to any 
participant-identifiable data. All HIPAA regulations and guidelines will be followed, and all study 
staff must complete approved human subjects and HIPAA training programs.  
Data and Safety Monitoring Committee 
In addition to the protections outlined in the DSMP (above), all research activities conforming to the 
NIH definition of a clinical trial will also have an independent Data Safety and Monitoring Committee 
(DSMC). All three proposed clinical research projects (Health System Reach Interventions, 
Cessation Screening, and Optimized Care) in this Program Project conform to the NIH definition of a 
clinical trial. All of the trials in this P01 application are Phase IV clinical trials using FDA-approved 
medications that are not multicenter in nature (the projects are testing existing interventions 
delivered through new methods to determine population effectiveness). The DSMP specifies overall 
monitoring that will be conducted by Principal Investigators for all projects, including timely reporting 
of AEs and SAEs. Every six months, the Program Project-wide DSMC will convene to review the 
overall safety data, as well as data on safety summarized by treatment condition. As per NIH 

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guidelines, the objective of these reviews will be to determine whether continued conduct of the trial 
poses any undue risk for participants. 
The existing Program Project-wide DSMC is chaired by Dr. James Cleary, leader of the Cancer 
Control Program of the UW Comprehensive Cancer Center. Dr. Cleary is an experienced physician 
and clinical trial researcher with no involvement in any of this project’s research activities. Dr. Cleary 
is joined on the DSMC by Dr. James Sosman and Dr. Burke Richmond. Dr. Sosman is Associate 
Professor of Medicine and Medical Director of the HIV/AIDS Comprehensive Care Program at UW 
Hospital and Clinics who has previously collaborated on a clinical trial of smoking cessation with 
UW-CTRI. Dr. Richmond is an otolaryngologist who has served on independent DSMBCs for Phase 
II and III trials involving a nicotine vaccine. Neither has direct involvement with any of the proposed 
research. The Principal Investigators will report to the DSMC; the three DSMC members will make 
the final determinations as to study continuation. 
ClinicalTrials.gov Requirements 
This research project will be registered with clinical trials.gov prior to the enrollment of the first 
subject. Final data (including outcomes and adverse events) will be reported to clinicaltrials.gov 
within 1 year of the conclusion of the trial. 
 
 
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