Comparative Effectiveness Trial of Tobacco Cessation Treatments Among Cancer Patients Who Smoke
Phase: PHASE4
Conditions: Smoking Cessation, Cancer
Sponsor: University of Wisconsin, Madison

STUDY PROTOCOL 
“Tobacco Treatment Comparison for Cancer Care” 
P.I.: Danielle E. McCarthy, Ph.D. ; UW-CTRI 
 
 
 
 
 
STUDY PROTOCOL 
Version Date: 09/30/2025. 
 
UW HS-IRB # 2023-1025 
NCT 06218823 
“Tobacco Treatment Comparison for Cancer Care” 
Principal Investigator: Danielle E. McCarthy, Ph.D. (608) 265-5949 
Coordinating Center: UW-Center for Tobacco Research and Intervention (UW-CTRI) 
Funding Sponsor: DHHS, PHS, National Institutes of Health (NIH) 

PROTOCOL TITLE: Comparative Effectiveness Trial of Tobacco Cessation Treatments 
among Cancer Patients who Smoke  
 
 
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PROTOCOL TITLE: 
Comparative Effectiveness Trial of Tobacco Cessation Treatments among Cancer 
Patients who Smoke  
LEAD RESEARCHER: 
Danielle E. McCarthy, Ph.D. 
Center for Tobacco Research and Intervention, Department of Medicine, SMPH 
608-265-5949 
demccarthy@ctri.wisc.edu 
Co-Investigators 
Timothy B. Baker, Ph.D. 
Center for Tobacco Research and Intervention, Department of Medicine, SMPH 
503-387-5167 
tbb@ctri.wisc.edu 
  
Michael C. Fiore, M.D., M.P.H., M.B.A.,  
Center for Tobacco Research and Intervention, Department of Medicine, SMPH 
608-262-8673 
mcf@ctri.wisc.edu  
 
Jesse T. Kaye, PhD 
Center for Tobacco Research and Intervention, Department of Medicine, SMPH 
608-262-8885 
jtkaye@ctri.wisc.edu  
 
VERSION NUMBER/DATE: 
Version 6, September 12, 2025 
 
REVISION HISTORY 
 
Revision 
# 
Version Date 
Summary of Changes 
Consent 
Change? 
1 
8/18/2023 
Response to PRMC concerns regarding 
varenicline start date (noting there is a 1-week 
pre-quit run-in period), counseling end date 
(moved to 12 weeks post-quit in enhanced 
care), and adverse event monitoring schedule 
(the 8 week follow-up has now been moved to 
12-weeks post-quit for both conditions).  
Yes, 
regarding 
timing of 
counseling 
contacts and 
follow-up 
assessments 
2 
9/7/2023 
Response to IRB Pre-review comments 
Yes, to add 
a 
comprehensi

PROTOCOL TITLE: Comparative Effectiveness Trial of Tobacco Cessation Treatments 
among Cancer Patients who Smoke  
 
 
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on question 
and data 
sharing 
consent to 
the oral 
consent 
script and to 
update the 
study 
information 
sheet 
#3 
12/18/2023 
Addition of a qualitative substudy that will 
inform tobacco treatment outreach and 
counseling in the parent study.  
 
Clarification of secondary endpoint/outcome 
and exploratory aims. 
 
Additional minor edits for consistency and 
accuracy regarding the following: 
• Biochemical sample collection occurs only 
at the 26-week follow-up (not at 12-weeks) 
• Target windows for counseling calls are 
the same for the first 3 counseling calls in 
both comparative effectiveness trial arms 
• Update section 11.2 to reflect a change in 
personnel who handle medication 
dispensing 
• Add a cover letter that will accompany 
materials mailed to participants who enroll 
in the comparative effectiveness trial  
• Updating the protocol to reflect the step-
down nicotine patch dose schedule for 
people who receive 12 weeks of nicotine 
patches 
• Updating the protocol to note that 
randomization occurs after baseline 
assessment rather than immediately after 
consent 
Yes, 
addition of a 
new oral 
consent 
script for a 
1-time 
qualitative 
interview 
with up to 
32 patients 
with a 
history of 
cancer.  
#4 
2/13/2024 
Updated eligibility criteria to remove exclusion 
of participants of enrolled in another cancer 
clinical trial. 
Added recruitment flier for participating 
clinics. 
No 

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among Cancer Patients who Smoke  
 
 
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#5 
4/25/2024 
Updated medication eligibility criteria to 
require daily smoking, to be consistent across 
medication conditions. 
Separate oral consent and screening materials 
into two separate documents for clarity. Minor 
editorial changes to these documents to 
improve flow. 
Added baseline assessment of current smoking 
cessation medications. 
Updated qualitative interview substudy 
recruitment to include participants enrolled in 
CET at 12- and 26-week follow up. 
Yes 
#6 
5/1/2025 
Revised descriptions of payment delivery 
method to account for the University’s 
retirement of custodial checking account 
payments. After May 16th 2025 participants 
will be sent gift cards in lieu of checks.  
Yes, all 
mentions of 
sending a 
check have 
been 
stricken. 
#7 
7/16/2025 
Added exploratory aim regarding relations 
between treatment engagement and abstinence 
and health and healthcare utilization outcomes. 
Clarified electronic health record (EHR) and 
Cancer Registry data extraction among all 
patients identified as eligible who did not 
actively decline study participation to examine 
cancer care and outcomes, estimate cancer care 
costs, and capture information on 
environmental exposure. Waiver of consent 
and HIPAA waiver justification for EHR data 
extraction for patients who did not actively 
decline study participation. 
 
Added Jesse Kaye, PhD as Co-Investigator 
No 
 
 
 

PROTOCOL TITLE: Comparative Effectiveness Trial of Tobacco Cessation Treatments 
among Cancer Patients who Smoke  
 
 
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Table of Contents 
 
 
1.0 
Study Summary ........................................................................................................ 5 
2.0 
Background .............................................................................................................. 8 
2.2 
Primary Aim............................................................................................................. 9 
2.3 
Exploratory Aims ..................................................................................................... 9 
3.0 
Study Objectives and Endpoints ............................................................................ 14 
3.2 
Primary & Exploratory Aims ................................................................................. 14 
4.0 
Number of Participants .......................................................................................... 17 
5.0 
Inclusion and Exclusion Criteria ............................................................................ 18 
6.0 
Special Populations ................................................................................................ 21 
7.0 
Recruitment Methods ............................................................................................. 23 
8.0 
Consent/Assent Process ......................................................................................... 25 
9.0 
Process to Document Consent in Writing .............................................................. 32 
10.0 Setting .................................................................................................................... 33 
11.0 Study Intervention .................................................................................................. 33 
12.0 Study Timelines ..................................................................................................... 36 
13.0 Procedures Involved............................................................................................... 37 
14.0 Comparison of usual care and study procedures .................................................... 43 
14.1 Alternatives to participation. .................................................................................. 43 
14.2 Standard of care. .................................................................................................... 44 
14.3 Research procedure overlap with standard practice. .............................................. 44 
14.4 Research participation effects on standard clinical care. ....................................... 45 
15.0 Withdrawal of Participants .................................................................................... 45 
16.0 Data Management and Confidentiality .................................................................. 46 
17.0 Provisions to Protect the Privacy Interests of Participants .................................... 51 
18.0 Sharing of Results .................................................................................................. 52 
19.0 Data and Specimen Banking .................................................................................. 53 
20.0 Study Analysis ....................................................................................................... 53 
21.0 Potential Benefits to Participants ........................................................................... 56 
22.0 Risks to Participants ............................................................................................... 57 
23.0 Provisions to Monitor the Data to Ensure the Safety of Participants .................... 59 
24.0 Economic Burden to Participants........................................................................... 61 
25.0 Resources Available............................................................................................... 62 
26.0 Multi-Site Research ............................................................................................... 63 
27.0 References .............................................................................................................. 63 
28.0 Appendices ............................................................................................................. 66 
 
 
 
 
 

PROTOCOL TITLE: Comparative Effectiveness Trial of Tobacco Cessation Treatments 
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1.0 
Study Summary 
 
Study Title 
 
Brief Summary 
This pilot comparative effectiveness trial will compare two 
active smoking cessation treatments in terms of 
effectiveness, equity across patient subpopulations, and 
efficiency among adult patients diagnosed with cancer within 
the past 3 years. An enhanced treatment comprising 12 
weeks of varenicline treatment and 7 smoking cessation 
coaching calls with a cancer focus will be compared against 
an active comparator modeled after standard quitline 
treatments (2 weeks of nicotine patch therapy with 3 phone 
coaching calls). Approximately 50 participants will be 
recruited for this 7-month study to generate estimates of the 
effects, acceptability, costs, and equity of enhanced 
treatment (vs. standard treatment), with the primary outcome 
being abstinence from smoking 12 and 26 weeks after trying 
to quit. Qualitative interviews will be conducted with up to 
32 adult patients with a history of cancer to inform study 
methods and smoking cessation counseling tailored to cancer 
care. 
Number of study sites 
1 health system (3-10 clinical departments) 
Study Design 
2-arm pilot comparative effectiveness trial of enhanced care 
(high-intensity, cancer-targeted smoking cessation treatment) 
versus low-intensity standard smoking cessation treatment. 
Primary Objective 
Generate an effect size estimate for enhanced care intensive 
smoking cessation treatment targeted to cancer patients 
(versus an active standard care control) effects on abstinence 
3 to 6 months following a target quit date. 
Secondary 
Objective(s) 
Compare treatments in terms of patient acceptability, 
completion, adherence, costs, and cost-effectiveness.  
Estimate the extent to which intensive, cancer-specific 
treatment benefits (relative to control) differ across patient 
subpopulations based on demographics (age, race, sex, 
ethnicity, socioeconomic disadvantage); nicotine 
dependence; and cancer site, stage, and treatment phase. 
 
Explore relations between 1) engagement in tobacco 
treatment and 2) quitting smoking and health and healthcare 
utilization outcomes, including cancer outcomes overall 
(among identified patients who did not actively decline 
participation), and as a function of environmental exposures 
and, for those enrolled in the CET, randomly assigned 
treatment condition.  

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among Cancer Patients who Smoke  
 
 
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Research 
Intervention(s)/ 
Investigational 
Agent(s)  
The two active treatments will be 1) standard treatment 
comprising 2 weeks of free nicotine patch therapy, 3 
telephone counseling sessions, and information about 
quitline and National Cancer Institute text messaging support 
services (SmokefreeTXT); and 2) enhanced treatment 
comprising 12-weeks of varenicline therapy, 7 counseling 
sessions targeted to cancer patients, and information about 
quitline and SmokefreeTXT services. Comparative effects 
will be measured in terms of the proportion of patients 
randomized to treatment who achieve biochemically 
confirmed abstinence overall, and across patient 
subpopulations, acceptability and adherence (measured in 
terms of treatment completion, patient satisfaction), costs 
(including intervention delivery costs and patient burden and 
costs), and cost-effectiveness to identify which treatment is 
most effective, efficient, and equitable. 
Drugs/devices used on 
study (including any 
IND/IDE #)  
Transdermal nicotine patches (FDA approved for smoking 
cessation). 
Varenicline (FDA approved for smoking cessation). 
Study Population 
Adults who currently smoke cigarettes and who have been 
diagnosed with cancer in the past 3 years and received 
cancer care from a participating UW Health clinic in the past 
year will be recruited for the comparative effectiveness trial. 
Adult patients with a history of cancer will be eligible for 
qualitative interviews that will inform study procedures and 
interventions. 
Sample Size 
82 
Study Duration for 
individual 
participants 
Up to 8 months 
Study Specific 
Abbreviations/ 
Definitions  
ACS=American Cancer Society 
EC=Enhanced care (intensive, cancer-specific smoking 
cessation counseling and 12 weeks of varenicline) 
CO=carbon monoxide 
CET=Comparative effectiveness trial 
NCI=National Cancer Institute 
NRT=nicotine replacement therapy 
SC=Standard care (low-intensity general smoking cessation 
coaching and nicotine patch starter kit) 
USDHHS=United State Department of Health and Human 
Services 
UW-CCC=University of Wisconsin Carbone Cancer Center 
UW-CTRI=University of Wisconsin Center for Tobacco 
Research and Intervention 

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Note: Include only elements relevant to this study. 
 

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2.0 
Background 
2.1 Prior experience and gaps in current knowledge. 
Smoking causes multiple types of cancer, including cancers of the oral 
cavity and pharynx, larynx, esophagus, lung, stomach, kidney, pancreas, 
liver, bladder, cervix, colon and rectum, and acute myeloid leukemia 
(American Cancer Society (ACS), 2021, US Department of Health and 
Human Services (USDHHS), 2014). Further, patients who smoke at the 
time of their cancer diagnosis have an increased risk of cancer recurrence, 
treatment complications, and mortality due to cancer-related and all-cause 
mortality (USDHHS 2014; National Cancer Institute (NCI), 2022). 
Moreover, evidence is accumulating that smoking cessation after 
diagnosis is associated with significantly reduced all-cause mortality 
(USDHHS, 2014; NCI, 2022).  
While smoking is clearly related to increased risk negative health 
outcomes amongst cancer patients, it is also clear that patients with cancer 
far too rarely receive treatment for their smoking as part of their cancer 
care (Cooley et al., 2018; Croyle et al. 2019; Day et al., 2019; Peters et al. 
2012). Research suggests that rates of undertreatment may be related to 
cancer care clinicians’ beliefs that they are too busy to intervene with 
smoking or that they are not adequately prepared to treat their patients’ 
smoking (Price et al. 2019). 
Unfortunately, we currently know far too little about how to best help 
cancer patients quit smoking. This knowledge gap reflects a lack of 
rigorous trials of smoking cessation interventions for cancer patients (NCI, 
2022). As such, at present the evidence is mixed as to whether smoking 
cessation pharmacotherapy and counseling significantly improve smoking 
cessation rates in cancer patients (NCI, 2022). There are reasons to suspect 
that treatments that effectively promote smoking cessation in general adult 
populations may be less effective in patients with cancer (e.g., those who 
continue smoking after a cancer diagnosis may be especially dependent on 
nicotine, the stress of cancer or its treatment may be a potent trigger to 
smoking lapses or relapses, patients may lack the energy or time to 
complete smoking cessation treatment in the midst of cancer treatment; 
fatalism may undermine motivation to quit). As such, it is important to 
identify treatments that are effective in promoting smoking cessation 
among cancer patients, and in the context of cancer care.  
In addition, evidence regarding the comparative effectiveness of smoking 
treatments that differ in burden and costs is also lacking, particularly in 
cancer care. An intensive treatment that yields slightly better abstinence 
rates, but at greatly increased costs in terms of money or burden, may not 
be efficient or sustainable. Likewise, an intensive treatment that benefits 
only a small subset of patients with cancer who smoke may exacerbate 
health disparities, while also being inefficient. For these reasons, it is 

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important to evaluate smoking cessation treatments along all three of these 
dimensions: effectiveness, efficiency, and equity when determining which 
treatment approaches to disseminate in cancer care settings.  
The proposed small comparative effectiveness trial will be informed by 
qualitative interviews with adult patients who have had cancer, and will 
generate pilot data that will be used to estimate effect sizes regarding the 
comparative effectiveness, acceptability, efficiency, and equity of 
intensive and cancer-specific smoking cessation treatment versus a 
generic, recommended-care, active, control condition. These pilot data 
will serve as preliminary data that will inform the design of a future full-
scale comparative effectiveness trial.  
2.2 
Primary Aim 
The primary aims of the proposed pilot CET are: 
1. To establish the feasibility of the CET protocol and procedures in preparation 
for a full-scale future trial. 
2. To generate estimates of the size of the comparative effects of enhanced, 
cancer-specific smoking cessation treatment versus a generic standard care 
package similar to quitline care in terms of biochemically confirmed 7-day 
point prevalence abstinence (no smoking in the past 7 days) 26 weeks after a 
target quit date. 
 
2.3 
Exploratory Aims 
Exploratory aims of the pilot CET are: 
3.  To estimate differences in CET arms in exploratory outcomes including 
patient acceptability, completion, adherence, costs, and cost-effectiveness. 
4.  To elicit input from patients who have experienced cancer to inform study 
methods and interventions. 
5.  To estimate the extent to which treatment effects on abstinence and 
exploratory outcomes differ across patient subpopulations based on 
demographics (age, race, sex, ethnicity, socioeconomic disadvantage); 
nicotine dependence; and cancer site, stage, and treatment phase. 
6.  To explore relations between 1) engagement in tobacco treatment and 2) 
quitting smoking and health and healthcare utilization outcomes, including 
cancer outcomes overall, and as a function of environmental exposures and, 
for those enrolled in the CET, randomly assigned treatment condition.  
 
2.4 Preliminary data. 
The opt-out referral model to be adapted in this project has increased the 
reach of smoking cessation treatment in primary care and inpatient 
contexts (Creswell et al., 2022; McCarthy et al., 2022). In this approach, 
referral to or connection with treatment is the default for all adults whose 
EHR records suggest they currently smoke, unless a patient actively opts 
out of such referral. We are currently employing a similar opt-out referral 

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approach in 22 clinics in 2 health systems (UW IRB Protocol #: 2019-
0054, 2019-0939, 2022-0124, and especially 2022-0973) with great 
success. Over the past 2.75 years, this referral strategy has led to the 
enrollment of more than 1300 adult patients who smoke in smoking 
treatment trials. All of these protocols involve mailing patients who meet 
initial eligibility prerequisites based on information in their EHR a study 
launch letter that offers them an opportunity to opt out of study 
recruitment, and then proactive telephone outreach to patients who have 
not opted out of such contact to offer both standard tobacco treatment and 
the opportunity to enroll in a tobacco treatment trial.  
The design of the proposed CET is similar to a CET that we recently 
completed with primary care patients (Piper et al., 2018, UW HS IRB 
Protocol # 2014-1041). This 2-arm CET compared an even more intensive 
treatment (26 weeks of varenicline with 11 counseling contacts) with a 
recommended usual treatment comparator that comprised 8 weeks of 
nicotine patch therapy, a single 10-minute counseling call, and referral to 
the Wisconsin Tobacco Quitline and a smoking cessation app. Participants 
were 623 adult primary care patients whose EHR indicated they currently 
smoked cigarettes and who either contacted the research team after 
receiving an outreach letter alerting them to the study opportunity or 
agreed to be referred to the treatment team when they presented for 
primary care.  Results indicated that optimized care nearly tripled rates of 
biochemically verified 7-day point-prevalence abstinence 26 weeks after 
participants’ target quit dates (Odds ratio=2.94, 95% Confidence 
Interval=1.69, 5.14; Piper et al., 2018).  
The proposed project seeks to conduct a similar CET of an enhanced 
treatment targeted to cancer-related challenges and concerns and offering 
12 weeks of varenicline treatment with an active comparator representing 
standard care (2 weeks of nicotine patch, 3 counseling sessions, and 
information about digital and quitline cessation support, not targeted to 
cancer).  
2.5 Scientific background, rationale, and significance. 
Combustible cigarette smoking is a leading preventable cause of cancer 
(USDHHS, 2014; NCI, 2022), and continued smoking after diagnosis is 
associated with poor clinical outcomes. Evidence synthesized from the 2014 and 
2020 Surgeon General’s Reports shows a causal relationship in patients with 
cancer between smoking and adverse health outcomes, increased all-cause 
mortality, increased cancer-specific mortality, and increased risk of second 
primary smoking-related tumors (USDHHS, 2014, 2022). Evidence also suggests 
that smoking in cancer patients is associated with risk of cancer recurrence, 
reduced efficacy of cancer treatment, and increased cancer treatment-related 
toxicity (NCI, 2022). 

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Despite compelling evidence that smoking increases risks for negative outcomes, 
many patients with cancer continue to smoke after diagnosis, and cessation 
treatment is not consistently integrated into cancer care, particularly for 
minoritized groups (Cooley et al., 2018; Croyle et al., 2019; Ramaswamy et al., 
2016; D’Angelo et al., 2021). Research suggests that while many patients with 
cancer are advised to stop smoking, fewer than half of cancer patients receive 
treatment to help them do so (Borger et al., 2022; Price et al., 2019). Importantly, 
evidence shows that many cancer patients are interested in trying to quit and the 
majority of cancer patients try to quit following their diagnosis (Gritz et al., 
2020). However, such quit attempts are very often unsuccessful with at least half 
of patients with cancer continuing to smoke after diagnosis (Gritz et al., 2020; 
Sharp et al., 2014).  Even with strong motivation to quit, only half of head and 
neck cancer patients in a recent study abstained from smoking for at least 24 
hours, and only 10% were able to quit for at least 30 days (Borger et al., 2022).  
Given the known risks of smoking in cancer patients, it is imperative that 
accessible, evidence-based smoking cessation treatment be offered consistently to 
patients receiving cancer care. Opt-out approaches to referring patients to 
treatment have shown promise in broader populations (Creswell et al., 2022; 
McCarthy et al., 2022), including patients receiving cancer care (D’Angelo et al., 
2022). In an opt-out referral system, patients are automatically referred to a 
proactive smoking treatment service that offers quitting assistance, unless the 
patient has specifically requested that they not receive such offers. This opt-out 
referral process does not burden front-line cancer care teams. Instead, tobacco 
treatment offers are extended by tobacco treatment specialty teams directly to 
patients identified based on reports extracted from EHR data who do not opt out 
of such outreach. Importantly, this approach seems to enhance the equity of 
smoking treatment reach among historically underserved populations that have 
been disproportionately affected by tobacco use (e.g., minoritized individuals; 
Creswell et al., 2022; McCarthy et al., 2022). As such, an opt-out referral to a 
centralized smoking treatment outreach program may be a promising way to 
equitably engage more people with cancer in effective smoking cessation 
interventions while imposing little to no burden on clinic staff or providers.  
Important unanswered questions in the literature include which cessation 
interventions are effective in patients with cancer and whether more intensive 
intervention improves abstinence outcomes relative to less intensive treatment in 
this population. There are few rigorous controlled clinical trials of smoking 
cessation treatments in patients with cancer (NCI, 2022). Some studies of patients 
with cancer have shown that relatively intensive counseling and pharmacotherapy 
can improve cessation rates more than less-intensive treatment (Duffy et al., 2006; 
Park et al., 2020; Rettig et al., 2018). However, other studies show little or no 
benefit of more intense treatment (Schnoll et al., 2010, 2019; NCI, 2022). A 
recent meta-analysis also failed to find consistent evidence that cessation 
intervention improves smoking abstinence rates amongst cancer patients (Sheeren 

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among Cancer Patients who Smoke  
 
 
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et al., 2019). One reason for the uncertainty in this area is that too few randomized 
controlled trials have been done with cancer patients; most of the available 
evidence comes from studies that are small and underpowered (NCI, 2022).   
Currently, clinicians must rely on more general treatment research and guidelines 
(e.g., NCCN, 2022) when offering cessation care to people with cancer. The 
general cessation intervention literature and guidelines support 2 first line 
pharmacotherapies: varenicline, a selective nicotine acetylcholine receptor partial 
agonist; and the combination of nicotine patches with fast-acting nicotine 
replacement therapies (NRT) such as nicotine gum or lozenges (Cahill et al., 
2013). Research suggests that varenicline is well tolerated in patients with cancer 
(Crawford et al., 2019; Schnoll et al., 2019). Some recent guidelines have also 
promoted varenicline as the preferred first line therapy for smoking cessation 
based on evidence of its superiority to NRT (Leone et al., 2020). The study will 
generate much needed evidence on the effectiveness of varenicline treatment in 
patients with cancer. 
Importantly, the proposed study will also evaluate an opt-out referral mechanism 
for people receiving cancer care to address the critical undertreatment of smoking 
in cancer care. Patients receiving cancer care at UW-CCC will be referred to 
smoking cessation treatments facilitated or delivered by centralized staff at UW-
CTRI. Patients will be automatically referred via quarterly UW Institute for 
Clinical and Translational Research (ICTR) Clinical Research Data Service 
(CRDS) reports to the UW-CTRI cessation study coordinators who will first send 
patients letters to inform them of the proactive outreach program and give them a 
chance to opt out. Then, UW-CTRI study coordinators will call patients who have 
not opted out to invite them to enroll in either the current standard of care at UW 
Health (connection with the Wisconsin Tobacco Quitline (WTQL) and/or referral 
to their primary care provider) or to randomized smoking treatment delivered in a 
comparative effectiveness trial of 2 smoking cessation interventions:  
1) Standard treatment comprising a 2-week supply of transdermal nicotine 
patches; 3 brief telephone smoking cessation counseling sessions; and mailed 
information about standard care resources (NCI-sponsored resources 
including the 8-week SmokefreeTXT program, WTQL services, and primary 
care or oncology support). 
2) Enhanced treatment comprising 12 weeks of varenicline, 7 remote counseling 
sessions adapted for cancer patients from the Park et al., 2020 counseling 
protocol, and information about SmokefreeTXT and WTQL services. 
These 2 treatments will be compared in terms of smoking abstinence rates, 
but also in terms of costs, patient burden, adherence, and side effects to 
gauge the value of intensive smoking treatment in terms of patient 
acceptability, engagement, effectiveness, and cost-effectiveness and 
efficiency. Equity in treatment effects across patient subpopulations will 

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also be examined. As such, the project will evaluate both an opt-out 
referral method designed to make offering smoking treatment the default 
rather than the exception for patients with cancer and the effects of 2 
highly distinct smoking treatment packages in cancer care. 
An opt-out treatment referral mechanism that has shown promise in primary care 
(McCarthy et al., 2022) will be adapted to the cancer care context. This is 
innovative and important, given the elevated risks of continued smoking and 
critical benefits of smoking cessation in patients with cancer, and current low 
rates of evidence-based treatment use among cancer patients (Borger et al., 2022; 
NCI, 2022). In addition, the proposed project will compare an intensive, tailored 
smoking cessation intervention with a less intensive treatment similar to quitline 
services. This comparison will demonstrate to cancer care programs the extent to 
which their patients would benefit from enhanced smoking cessation treatment 
that has cancer focused content versus a treatment that is similar to a quitline 
intervention. Such evidence does not currently exist.  
The cancer-focused smoking cessation counseling protocol that will be used in the 
intensive treatment will be based on the counseling used in the recent randomized 
controlled trial conducted by Park and colleagues (Park et al., 2020), and 
informed by the qualitative interviews completed with patients in the qualitative 
substudy. The Park et al. study was conducted in patients with a variety of cancer 
diagnoses and showed that such intensive treatment produced higher smoking 
abstinence rates at 6 months post-treatment than did a less intense treatment 
(34.5% vs. 21.5%). However, few studies of smoking treatment in cancer patients 
have manipulated pharmacotherapy intensity, and results to date have been 
inconclusive (Schnoll et al., 2010, 2019). In addition, the Park et al., (2020) did 
not systematically vary pharmacotherapy treatment across the two experimental 
conditions; thus, it may underestimate the effectiveness of more intensive 
treatment.  
In addition to addressing a novel research question, the research methods for the 
CET are also innovative in their integration of patient self-report data on 
treatment utilization, acceptability, burden, tolerability, adherence, and success (in 
terms of abstinence rates) with treatment cost data and EHR-extracted data on 
healthcare utilization, complications, and clinical outcomes to facilitate a multi-
dimensional comparison of the 2 treatment conditions (i.e., a comparison of 
treatment not just in terms of abstinence, but also in terms of likely population 
impact and efficiency). This work is much needed given the dearth of rigorous 
trials of smoking treatments in this high-priority population.  
We anticipate that the proposed feasibility pilot test will demonstrate that 
automatic, opt-out referral of cancer patients who smoke to centralized, low-
barrier smoking cessation treatment resources is feasible. We anticipate that at 
least 12% of patients eligible for referral will enter evidence-based smoking 
treatment, the rate we observe in primary care settings. We also anticipate that 

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reach may be stronger in historically underserved populations most adversely 
affected by tobacco use, including African-American patients and those who are 
uninsured or eligible for Medicaid. If recruitment of minoritized individuals is 
slow, we will reach out to partners at Wisconsin Oncology Network to enhance 
sample diversity. We will elicit patient input through qualitative interviews to 
enhance the design of outreach materials and counseling protocols in an effort to 
enhance acceptability for patients, as well.  
The study will accelerate progress in an important but neglected facet of cancer 
care. Identifying ways to connect more patients with cancer to evidence-based 
treatments that show particular promise in this population is critically important 
and can lead to significant improvement in the lives of people with cancer. 
3.0 
Study Objectives and Endpoints 
3.1 Study objectives. 
The objectives of the proposed study are: 
1) To evaluate the feasibility and acceptability of a proactive tobacco 
treatment referral model for patients who use tobacco after diagnosis 
with cancer. 
2) To generate estimates of the reach, effectiveness (in terms of 
abstinence up to 6 months after a target quit day), efficiency (i.e., cost-
effectiveness), and equity of enhanced smoking treatment relative to a 
lower-intensity standard care comparator. 
The primary endpoints in this feasibility pilot will be the reach of smoking 
treatment among adult patients diagnosed with cancer who continue 
smoking after diagnosis and 7-day point-prevalence abstinence from 
smoking 26 weeks after a target day to quit smoking (as a measure of 
effectiveness). Additional important endpoints include: patient 
perspectives on smoking treatment outreach and counseling (elicited in 
qualitative interviews), retention in and completion of treatment activities 
(as additional measures of feasibility and acceptability), costs and cost-
effectiveness (to assess relative efficiency of the two active treatments), 
and differences in comparative treatment effects across patient 
subpopulations (to assess equity in treatment outcomes). Given the limited 
sample size in this pilot CET, these endpoints will be used to generate 
estimates of effects and sample size needs for a future full-scale CET.  
3.2 
Primary & Exploratory Aims 
Primary Aims 
Aim 1: To establish the feasibility of the CET protocol and procedures in 
preparation for a full-scale future trial. 
Aim 2: To generate estimates of the size of the comparative effects of intensive, 
cancer-specific smoking cessation treatment versus a generic, lower-

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intensity recommended smoking cessation treatment in terms of 
biochemically confirmed 7-day point prevalence abstinence (no smoking 
in the past 7 days) 26 weeks after a target quit date. 
 
 
Exploratory Aims 
Aim 3: To estimate differences in CET arms in exploratory outcomes including 
patient acceptability, completion, adherence, costs, and cost-effectiveness. 
Aim 4. To elicit input from patients who have experienced cancer to inform study 
methods and interventions. 
 
Aim 5. To estimate the extent to which treatment effects on abstinence and 
exploratory outcomes differ across patient subpopulations based on 
demographics (age, race, sex, ethnicity, socioeconomic disadvantage); 
nicotine dependence; and cancer site, stage, and treatment phase. 
 
Aim 4. To explore relations between 1) engagement in tobacco treatment and 2) 
quitting smoking and health and healthcare utilization outcomes, including 
cancer outcomes overall, and as a function of environmental exposures 
and, for those enrolled in the CET, randomly assigned treatment 
condition.  
 
3.3 Study hypotheses. 
The primary hypothesis to be tested for Aim 1 is that at least 12% of 
eligible adult patients who have cancer and smoke cigarettes and are 
referred to the tobacco treatment outreach team will initiate an 
evidence-based form of smoking treatment (either Wisconsin 
Tobacco Quit Line care or treatment offered in the CET).  
The primary hypothesis to be tested for Aim 2 is that more-intensive, 
cancer-specific smoking cessation treatment will increase the log 
odds of achieving 7-day abstinence 26 weeks after a target quit date 
by at least 50% over the comparator condition (predicted odds ratio 
>=1.50). 
Exploratory hypotheses include the following: 
For Aim 3, we hypothesize that the majority of patients assigned to 
each condition will initiate treatment and will receive at least some 
counseling and use at least some of the provided medication. We 
also hypothesize that patient ratings of acceptability and satisfaction 
will be favorable. We also expect retention, adherence, and 
satisfaction with treatment to be higher in enhanced care relative to 
the standard care control condition. We anticipate that the more-
intensive treatment, although more costly, will be cost-effective in 
terms of the incremental cost effectiveness ratio per additional 

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patient who quits smoking, relative to the comparator condition and 
to other preventive health interventions. 
For Aim 4, we are not testing a specific hypothesis. Instead, we are 
seeking patient input to enhance the acceptability of tobacco 
treatment outreach and the relevance of smoking cessation 
counseling for participants in the CET. 
For Aim 5, we expect treatment reach to be especially high among 
historically undertreated populations (including African-American, 
Medicaid-eligible patients, and those from disadvantaged 
neighborhoods), and for the effects of enhanced care (vs. the 
standard care comparator) to be similar across patient subgroups. 
 
3.4 Study endpoints.  
Primary endpoints: 
1. Reach of smoking treatment, defined as the proportion of eligible 
patients who initiate evidence-based smoking treatment through 
the opt-out referral program. (Aim 1) 
2. Biochemically verified 7-day point-prevalence abstinence 26 
weeks after a target quit date (confirmed by expired carbon 
monoxide and/or a cotinine urine or saliva sample test). (Aim 2) 
Secondary endpoint:  
1. Self-reported 7-day point-prevalence abstinence 12 weeks after a 
target quit date. (Aim 2). 
Exploratory endpoints: 
1. Treatment acceptability and feasibility indicators including 
treatment retention (at each treatment contact/milestone) and 
completion, medication adherence, patient satisfaction, and 
patient ratings of burden. (Aim 3). 
2. Treatment costs from payer and patient perspectives. (Aim 3). 
3. Incremental cost-effectiveness ratios for each additional patient 
who quits smoking with higher-intensity treatment versus lower-
intensity treatment. (Aim 4). 
4. Differences in rates of treatment reach, retention, and completion 
by patient factors (demographics, nicotine dependence, smoking 
history). (Aim 5). 
5. Moderation of treatment effects (high- vs. low-intensity) by 
patient factors. (Aim 5). 

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6. Health outcomes (e.g., cancer mortality, cancer progression, new 
cancer diagnoses, treatment side effects). 
 
3.5 Primary safety endpoints. 
1. Adverse events, by treatment condition. 
2. Serious adverse events, by treatment condition. 
 
4.0 
Number of Participants 
4.1 Total number of participants to be accrued. Up to 82 adult 
participants will be enrolled in the clinical trial by UW-CTRI staff 
from UW Carbon Cancer Center clinic referrals over 12-30 months. 
We will continue enrolling within each clinic until we reach 
saturation in qualitative data analysis of patient interviews 
(maximum N=32) and until we reach our target enrollment for the 
CET (N=50).   
4.2 Number of participants needed to complete the research 
procedures.  We anticipate that we will engage 12% of participants 
in some form of evidence-based treatment, and that 50 will enroll in 
the proposed comparative effectiveness study while another 50 will 
opt for the Wisconsin Tobacco Quit Line.  As such, we anticipate 
that we will need to reach out to approximately 833 patients who 
meet criteria to be included on the quarterly CRDS reports that will 
guide proactive outreach letters and calls. We anticipate that the 
remaining 733 participants will either opt-out of smoking treatment 
outreach, will not be reached by the outreach team, will decline 
tobacco treatment, will elect to pursue treatment via their primary 
care provider or other means (e.g., over-the-counter) rather than to 
use formal treatment, or will not complete the treatment enrollment 
process for other reasons.  
Among the 50 participants who enroll in the CET, we will use an 
intent-to-treat approach to data analyses so that all randomized 
participants will be included in key analyses of feasibility, 
acceptability, and abstinence rates, even if lost to follow-up. In 
primary analyses of abstinence outcomes, missing cases will be 
treated as still smoking. This will be supplemented by sensitivity 
analyses under varying assumptions regarding censored data (i.e., 
that 5%, 10%, or 20% of missing data are abstinent). 
For the qualitative interviews, even 2-5 interviews could inform and 
enhance study methods. We anticipate that we could reach thematic 
saturation in qualitative data coding with fewer than 32 interviews, 
and have set 32 as an upper limit for recruitment. 

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4.3 Criteria for considering participants “enrolled.” Individuals will 
be considered enrolled in the study at the point of randomization to a 
study arm in the CET. Randomization will occur after oral consent to 
participate and completion of baseline assessments. People who do 
not complete oral consent and randomization will not be considered 
fully enrolled and will be replaced until 50 people are randomized in 
the CET (25 in each arm).  
5.0 
Inclusion and Exclusion Criteria 
5.1 Eligibility screening and retention. Adult, living patients 
potentially eligible for the CET based on their current tobacco use 
status (as recorded in Health Link), a diagnosis of cancer within the 
past 3 years, receipt of care in a participating cancer clinic in the past 
year, and not having a preferred language other than English 
recorded in the EHR, will be identified by UW Health CRDS reports 
sent securely to UW-CTRI on a quarterly basis through ICTR 
REDCap.  
This list of potentially eligible patients will guide UW-CTRI study 
coordinators who will first send letters notifying patients that they 
have been identified as potentially eligible for the CET and 
Wisconsin Tobacco Quit Line treatment.  
The study letters sent to participants will include all required 
elements of such recruitment tools, and will inform patients that they 
will receive phone calls inviting them to learn more about smoking 
treatment options, unless they elect to opt-out of such outreach. The 
letter will direct patients who wish to opt out of such calls and future 
mailings to call UW-CTRI to request that they be removed from 
future outreach efforts. Patients will also have the opportunity to opt 
out of future outreach at any outreach calls, as well (if they have not 
already opted out after receiving the letter).  
All opt-out requests will be respected throughout the duration of the 
project. In order to ensure that such opt-outs are respected, we will 
need to maintain a list of people who opted out until the project ends, 
as they may appear on future quarterly reports that will guide 
outreach, and we will need to maintain a cumulative list of patients 
who opted out to ensure we do not contact them against their stated 
wishes. This list will need to contain enough information to identify 
patients (name, phone numbers, date of birth, and MRN), along with 
their study status (i.e., opted out of all contact). These identifiers will 
be stripped from the data after the close of recruitment/outreach 
activities. Basic demographics (age, sex, gender, race, ethnicity) and 
insurance type will also be collected, and this will be maintained 
after the close of recruitment/outreach in de-identified manner (i.e., 
age will be truncated at 90 and recoded into 5-year bins) for analyses 

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of the representativeness of tobacco treatment reach of both 
Wisconsin Tobacco Quit Line standard care and comparative 
effectiveness trial treatment.  
Recruitment fliers will also be placed in participating clinics and/or 
distributed by cancer care teams so that patients may proactively 
contact the study team to learn about tobacco treatment options. 
For patients who do not opt-out of tobacco treatment outreach, UW-
CTRI study coordinators will make up to 5 phone call attempts to the 
patient telephone numbers in the EHR over 12 weeks. When a study 
coordinator reaches a patient, s/he will explain that UW-CTRI is 
reaching out to patients who smoke and receive cancer care at UW 
Health/Carbone to offer support and resources, including both 
standard care (e.g., Wisconsin Tobacco Quit Line referral) and the 
opportunity to screen for eligibility for a UW-CTRI study.  
Patients who are interested in treatment from their care teams or the 
Wisconsin Tobacco Quit Line (WTQL) (or the quit line in their 
home state, if outside of Wisconsin) will be given the appropriate 
referrals. Patients who are interested in the UW-CTRI study will be 
given a brief description of this study and invited to complete a brief 
screening for the study (See uploaded Recruitment Call Script) to 
determine study eligibility.  
Please note that being medically eligible to use study medication is 
not required for study entry. Participants will be screened for 
medication eligibility if they elect to enter treatment, but participants 
who are medically ineligible to use study medications will still 
receive smoking cessation counseling as part of study treatment.   
For the one-time qualitative interviews, eligibility criteria are 
minimal. Participants will be adults with a history of cancer. Past 
tobacco use is not a criterion for interview eligibility.  
Actively declining study participation by notifying the study team 
that patients would like to be removed from the list of potentially 
eligible patients will be exclusionary in EHR data extraction. As 
such, deidentified EHR data will not be gathered from patients who 
stated they did not want to be included in the study. 
5.2 Inclusion criteria. The following criteria will be used to identify 
patients eligible for initial outreach based on data recorded in Health 
Link. 
• 
Alive. 
• 
Age 18 years or older. 
• 
Diagnosed with cancer in the past 3 years.  

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• 
Received care from a participating oncology clinic in the 
past year. 
• 
Has a current tobacco use status. 
• 
Does not have a preferred language other than English 
(missing language preference will be included). 
• 
Valid address that is not a correctional facility or residential 
treatment/care facility. 
• 
No flag for patient cognitive impairment, activated health 
care power of attorney, or other health care agent (e.g., 
legally authorized representative) in the EHR. 
The following additional inclusion criteria must be met for 
inclusion in the CET 
• 
Smoked combustible cigarettes in the past month. 
• 
Able to speak and understand English. 
• 
Willing to set a date to quit smoking in the next 60 days. 
• 
Willing to receive smoking treatment information. 
• 
Willing to complete study activities. 
For qualitative interviews, the only inclusion criteria are: 
• At least 18 years of age. 
• Have a history of cancer. 
• Willing to participate in an audio-recorded interview about their 
experiences and perspectives. 
5.3 Exclusion criteria. The following exclusion criteria apply to the 
CET: 
• 
Current suicidal ideation. 
• 
Suicide attempt in the past year. 
• 
Currently receiving treatment for bipolar disorder, 
schizophrenia, schizoaffective disorder, or psychotic 
disorder. 
• 
Incarceration. 
• 
Unable to provide informed consent to treatment (i.e., 
cannot answer questions about study procedures or risks 
after hearing about the study). 
Those who decline the screening invitation or do not meet eligibility 
criteria will be advised to quit smoking and offered standard 
smoking cessation treatment (referral to their primary care provider 

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and/or to the Wisconsin Tobacco Quit Line or other tobacco quit 
line, as appropriate given state of residence). 
The only exclusion criterion for qualitative interviews is not being 
able to provide informed consent due to difficulty understanding the 
consent information. 
5.4 Target populations. We will not target specific subpopulations in 
the proposed study, but hope instead to enroll a broad and 
representative sample by reaching out to all adult patients who 
smoke and meet the prerequisites listed above. The proactive 
outreach approach to be adapted in this project has increased the 
reach and equity of smoking cessation treatment in primary care and 
inpatient contexts (Creswell et al., 2022; McCarthy et al., 2022). In 
this approach, proactive outreach regarding smoking treatment 
options is the default for all adults whose EHR records suggest they 
currently smoke, unless they opt out of such outreach. Such 
proactive outreach processes have especially strong reach in 
historically underserved populations (e.g., African-American, 
Hispanic, and/or Medicaid-eligible patients; Creswell et al., 2022; 
McCarthy et al., 2022) and we anticipate this will hold in population 
of patients with cancer that will be the focus of this project.  
6.0 
Special Populations 
6.1 Special population inclusion, justification, and safeguards. 
☐ Children/Minors (HRP-416 - CHECKLIST - Children) 
☒ Pregnant persons / fetuses (HRP-412 - CHECKLIST - Pregnant 
Persons; HRP-413 - CHECKLIST - Non-Viable Neonates; HRP-414 - 
CHECKLIST - Neonates of Uncertain Viability) 
☐ Prisoners (HRP-415 - CHECKLIST - Prisoners) 
☐ Participants with impaired decision-making capacity (HRP-417 - 
CHECKLIST - Adults with Impaired Decision-Making Capacity) 
 
 
 
Although pregnant persons will be eligible for CET inclusion and smoking 
cessation counseling, they will not be eligible for any study medication 
while pregnant or breastfeeding. Quitting smoking has important health 
benefits for both pregnant persons and their fetuses, so we will not 
withhold smoking cessation counseling for pregnant persons. We will not 
dispense study medications during pregnancy or breastfeeding, however, 
to prevent any adverse effects of medication on fetuses. 
 
We will not target special populations for qualitative interviews. Adult 
patients with a history of cancer will be referred to the study team if 
interested in participating in an interview by their cancer care team, 
without targeting to special populations. 

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6.2 Vulnerable population inclusion, justification, and safeguards. 
☒ Individuals who are receiving inpatient or outpatient services for mental 
illness, developmental disability, or alcohol and other drug abuse (AODA) 
☐ Individuals who are protectively placed by a court in a treatment facility 
☒ Veterans/Military Personnel 
☐ Emancipated minors 
☒ Anyone especially vulnerable to manipulation or inducements for 
participation as a result of their illness or socioeconomic condition 
 
We will not target any vulnerable populations in the proposed recruitment 
strategy, but we anticipate that our broad approach in which proactive 
outreach regarding smoking treatment is the default will reach members of 
some special populations, as these populations have especially high smoking 
rates (e.g., veterans, socioeconomically disadvantaged people, and people 
with mental health and substance use smoke at higher rates than the general 
population). We will not assess all special population status (i.e., we will not 
ask if participants are veterans or ask about current mental health or 
substance use treatment).  
 
Special and vulnerable populations are disproportionately affected by 
tobacco use and its devastating effects. As such, we will not exclude them 
from participation in the study if they meet all other eligibility criteria. We 
seek to evaluate interventions that will promote abstinence from smoking 
from the full range of adult smokers receiving oncology care.  
 
Study coordinators will reach out to the PCP (if at UW Health) and UW 
Health oncologist of patients who consented to the CET to ask them to 
review the randomly assigned medication regiment, and to disapprove the 
medication within 5 business days if they have any concerns about study 
medications for their patients. Study medications will be sent to participants 
who have provided informed consent for CET participation only after 
providers have had this opportunity to review and disapprove study 
medications. Patients whose providers disapprove varenicline, but not patch, 
will receive nicotine patches (for 2 weeks in the recommended usual care 
control condition or for 12 weeks in the intensive treatment condition). 
Patients whose providers disapprove nicotine patches will receive 
psychosocial treatments, but no study medications.  
 
We will not reach out to patients flagged in quarterly CRDS reports as 
having cognitive impairment, an active power of attorney for health care, or 
other active health care agent.  
 
Vulnerable populations will not be targeted for qualitative interviews.  

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6.3 Consent considerations in particular populations. We anticipate 
recruiting at least some participants from the groups checked below: 
☐ Non-English speaking participants  
☐ Illiterate or Low Literacy participants 
☒ Participants with visual or hearing impairments 
☐ Status Relationship: Individuals with a status relationship with the PI or 
other study team members (e.g., employees, students, family members) 
 
To avoid enrolling people incapable of consent we will not reach out to 
patients flagged in quarterly CRDS reports as having cognitive impairment, 
an active power of attorney for health care, or other active health care agent.  
Second, an audio version of the letter sent to patients will be available via 
QR code for patients who would prefer to hear the information about 
proactive outreach rather than read it. This accommodation is offered to 
address concerns about low literacy among some patients. In addition, in the 
CET, we will only include people who speak and understand English so we 
can obtain informed consent and administer study treatments and surveys 
orally over the phone. We will use oral means of communication as our 
primary modality in CET consent, treatment, and assessment procedures. 
This will be supplemented by a written study information sheet and 
medication instructions, but all information will be presented orally to 
eliminate literacy-related barriers to participant understanding.  These 
accommodations will also reduce barriers to understanding or participation 
among patients with visual impairments.  Patients with hearing impairments 
who have TTY technology will still be able to communicate by phone with 
study coordinators and smoking cessation counselors, as well.  
 
7.0 
Recruitment Methods 
7.1 Source(s) of participants. 
Prospective participants in the tobacco treatment outreach and CET 
will be patients identified via health records at UW Health. We will 
adapt the process that we have used in primary care (IRB protocols 
2019-0054, 2019-0939, 2022-0973) that similarly identifies UW 
Health patients eligible to receive smoking treatment outreach based 
on health records. As in those studies, patients identified in CRDS 
reports will receive study recruitment letters and tobacco treatment 
outreach offering both standard treatment and research participation 
opportunities unless they opt out of such outreach. This study will 
focus on adult patients receiving oncology care rather than primary 
care, however. Fliers will also be placed in participating clinics or 
cancer care team members may share the flier with patients. 

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Participants in qualitative interviews will be referred by cancer care 
team members to the research team, if interested in sharing their 
perspectives and experiences related to cancer. Participants in the 
CET will be offered the chance to participate in the qualitative 
interviews following their 12- and 26-week follow up contacts. 
7.2 Identification of potential participants. Potential participants in 
tobacco treatment outreach and the CET will be identified based on 
private/protected records (medical records) at UW Health. Records 
will be accessed by requesting CRDS reports regarding eligible 
patients on a quarterly basis. These reports will be transferred from 
UW Health to UW CTRI securely via ICTR REDCap to a secure 
UW-CTRI REDCap database that will guide study coordinator 
outreach to patients, and track all patients who opt out of future 
outreach. Patients may also proactively call the UW-CTRI study 
team to learn more about their treatment options if they see or 
receive a recruitment flier in their cancer care clinic. 
Participants in qualitative interviews will be identified by cancer care 
providers who will refer interested patients to the study team. The 
study team will offer all participants who are enrolled in the CET the 
opportunity to complete the qualitative interview substudy following 
their 12- and 26-week follow up contacts.     
7.3 Recruitment process. Potential tobacco treatment outreach and 
CET participants will first receive a mailed letter. This letter will 
inform patients that they have been identified based on their health 
records for tobacco treatment outreach from UW-CTRI, and will tell 
them how to opt out of such outreach by calling study coordinators 
at UW-CTRI. Letters will be sent no more frequently than once per 
quarter. 
Patients who do not opt out of outreach in response to letters will 
receive up to 5 phone calls per quarter from UW-CTRI study 
coordinators who will offer tobacco treatment options including both 
standard care and the CET as available options. Patients can opt out 
of future outreach at all such phone calls, as well. 
Recruitment fliers will also be placed in participating cancer care 
clinics and/or cancer care providers may give these study invitation 
fliers to patients interested in participating. These patients may call 
the study team to learn more about their tobacco treatment options. 
Recruitment for qualitative interviews will be conducted by cancer 
care providers who will have study invitation fliers to give to 
patients interested in participating. Cancer care providers may also 
send Health Link InBasket messages to study lead McCarthy to 
indicate that the patient is interested and has agreed to receive a call 
about participating in interviews. In addition, people who are not 

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interested in or eligible for the CET will be asked if they would be 
interested in participating in the one-time qualitative interview. 
Participants in the CET will be offered the chance to participate in 
the qualitative interviews following their 12- and 26-week follow up 
contacts. 
7.4 Recruitment materials. The tobacco treatment outreach and CET 
recruitment letter and an audio version of the recruitment letter is 
uploaded with the application. These letters will be sent no more 
frequently than once per quarter during the recruitment period 
(anticipated to last 2.5 years). The clinic recruitment flier is uploaded 
with the application. 
The script for outreach calls from UW-CTRI study coordinators is 
also uploaded with the application. Although study coordinators may 
make up to 5 attempts to reach participants over 12 weeks, this script 
will be completed only once per quarter with participants. 
Participants may be eligible for a new round of call attempts in 
future quarters if they appear on a subsequent quarterly CRDS report 
(and have not already opted out of such calls).  
The patient flier and template for Health Link InBasket messages to 
be used in recruitment for qualitative interviews are uploaded with 
the application. The script that will be used during interview 
recruitment calls for referred patients and those who decline or do 
not meet criteria for the CET is also uploaded with the application. 
7.5 Compensation. Participants who enroll in the CET will receive 
pharmacotherapy at no cost (if medically eligible) and will be compensated 
for completing study assessments according to the following schedule: 
Baseline phone survey ($50), 8-week phone follow-up ($50), 26-week 
phone follow-up ($50), biochemical verification of abstinence ($75 via visit 
to UW-CTRI for carbon monoxide breath test or urinary cotinine test, or 
mailed saliva sample kit for cotinine testing). As such, the maximum 
compensation available to participants will be $225.  
Participants in qualitative interviews will be paid $40 for completing 
the interview. 
8.0 
Consent/Assent Process 
 
8.1 Informed consent process. 
Those who assent to and pass the phone screening for CET 
participation will be asked to complete an oral consent and HIPAA 
authorization process in accordance with UW-Madison HRP-090-
SOP. This will be completed by phone at the screening call, or at a 
subsequent call, if necessary. During the phone consent process, a 

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UW-CTRI study coordinator will follow the phone screen and 
consent script uploaded with the application. These study 
coordinators will not be involved in patients’ ongoing care at UW 
Health (i.e., this is consent for research and occurs outside of clinical 
care at UW Health). The consent process will be facilitated by a 
REDCap database that will conduct automatic validation checks 
regarding eligibility and will both prompt and document completion 
of the informed consent process. Participants will have the 
opportunity to ask questions and to request more information before, 
during, or after the informed consent process, and they can take time 
to consider their decision after hearing about the study. They can 
also elect to receive a written copy of the study information sheet 
that contains the information covered in the oral consent script 
before making a decision about participation. Even if they decide to 
consent without receiving this information in writing, it will be sent 
to them after the consent is completed by phone. As such, all 
participants will receive a written study information sheet covering 
all required elements of informed consent after hearing this 
information over the phone.   
After presenting oral informed consent information, study 
coordinators will ask a comprehension question to ensure 
participants understand key components and risks of the study (see 
uploaded Screening and Consent Script).  If participants are still 
unable to answer these questions correctly after the study coordinator 
reviews key aspects of the study with them over the phone, the 
participant will be considered unable to consent. In addition, study 
coordinators will be trained to monitor for participant understanding 
during phone contacts and to stop the informed consent process if 
they have concerns about the participant’s mental status or level of 
comprehension. 
If we learn of new risks or alternative treatments that participants 
need to know (as determined by the study team, DSMC, and/or 
IRB), we will re-consent participants at the next scheduled study 
contact, or as needed.  We do not anticipate that such changes will 
occur, however.  
Participants in the one-time qualitative interviews will also complete 
an oral consent process before completing the interviews. 
We are proposing an alteration of informed consent to omit certain 
required elements of consent so we can use an oral consent process 
for the comparative effectiveness trial and for the qualitative 
interviews, and a waiver of informed consent for the initial outreach 

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activities so we can reach out to patients identified based on medical 
record review without their prior affirmative consent for such 
contact.  We request these alternatives due to the following 
considerations (as outlined in CHECKLISTS HRP-410 and 411): 
8.2 Alteration of consent justification. 
We are requesting an alteration of consent to abbreviate certain elements 
of informed consent. The oral consent script includes most required 
elements of consent but does not include all the recommended template 
language to streamline and shorten the oral consent script. These 
abbreviated elements are included in the written information sheet that all 
participants in the CET will receive. Omitting these elements from the oral 
script allows us to focus the script on information most important to 
deciding whether to participate in the study activities. 
• Participation in qualitative interviews or the CET poses no 
more than minimal risk to subjects. Study procedures involve 
answering phone survey questions; completing smoking 
cessation treatments that are known to be safe and effective in 
adult patients who smoke combustible cigarettes; and possibly 
providing a breath, urine, or saliva sample for biochemical 
verification of smoking status at the end of the study. The study 
medications to be administered to participants are FDA 
approved for smoking cessation and are recommended as first-
line medications to help patients quit smoking (Fiore et al., 
2008), including patients with cancer (NCCN, 2022). In 
addition, risks of adverse effects from these medications will 
be reduced by screening participants for medication eligibility 
and giving their primary care providers (if at UW Health) and 
oncologists at UW-CCC the opportunity to review and 
disapprove study medications for participants before study 
medication is dispensed. These strategies will ensure that the 
proposed study procedures pose minimal risk to participants, 
particularly compared to the known risks of continued 
smoking.  
• Altering informed consent for study participation will not 
adversely affect the rights and welfare of subjects because 
subjects will be informed of the risks, benefits, and alternatives 
prior to providing oral consent to join the CET or participate in 
interviews. Participants will receive this information over the 
phone and will have the option to request a written study 
information sheet about the CET prior to consent, or to view 
this CET information online, if they would like additional time 
to review this material before making a consent decision. 

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• The clinical investigation could not practicably be carried 
out without this alteration of consent because including all 
required elements of informed consent in the oral consent 
script in greater detail would increase participant burden and 
may bias the sample toward those with the greatest motivation 
to join a smoking treatment study and/or the greatest tolerance 
for receiving lengthy and detailed information over the phone. 
Because the proposed research seeks to identify strategies that 
cancer treatment programs can use to equitably increase the 
rates at which their patients who smoke use evidence-based 
smoking treatment and achieve lasting abstinence from 
tobacco, it is vital that we not impose barriers to participation 
that would restrict representativeness of the sample in these 
ways. 
• Subjects will be provided with additional pertinent 
information before, during, or after participation.  All those 
who provide oral consent for the CET will be mailed a detailed 
study information sheet containing all required elements of 
consent and HIPAA authorization. 
 
 
8.3 
Waiver of informed consent 
 
We are requesting a waiver of informed consent for the proactive outreach 
calls and outreach mailings that will occur up to once per quarter for 
patients identified as eligible based on record review. We are requesting a 
full waiver of informed consent for the creation of a de-identified data set 
from health records and cancer registry data to examine cancer care 
outcomes, estimate cancer care costs, and capture information on 
environmental exposure, among the patients initially identified as eligible 
for outreach who did not actively decline study participation. The 
justification for this waiver of informed consent for this FDA-regulated 
study is as follows (using criteria outlined in CHECKLIST HRP-410): 
 
• The proposed outreach involves no more than minimal risk 
to subjects as the primary study activities include receiving 
written and oral information about readily available standard 
treatments for quitting smoking, in addition to information 
about the comparative effectiveness trial. The risk is minimal 
due to the informational nature of the outreach and the fact that 
only standard care and FDA-approved over-the-counter 
medications and publicly sponsored psychosocial treatments 
for smoking (e.g., through the Wisconsin Tobacco Quit Line 
and Smokfree.gov) will be promoted in the study.  

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• Waiving informed consent for proactive outreach will not 
adversely affect the rights and welfare of subjects because 
subjects will be informed in writing of their right to opt out of 
proactive outreach at study initiation; any and all requests to 
opt out of proactive outreach mailings and letters will be 
honored; subjects may choose to decline or dispose of letters or 
decline to take calls, without any penalty, punishment, or 
alteration in their treatment in their host health system. 
• The clinical investigation could not practicably be carried 
out without this waiver of consent because only including 
patients who proactively volunteer or agree to receive 
information about their smoking treatment options would bias 
the sample toward patients with the greatest interest in smoking 
treatment. Results of such a study would not address the 
critical gaps in the research literature on ways to better engage 
patients with cancer who smoke in EBST, and would not 
provide clear guidance to health systems about how best to 
reach or treat the cancer patients who are not initially or 
intrinsically interested in smoking treatment. 
• Subjects will be provided with additional pertinent 
information during or after outreach.  In the initial launch 
letter, patients will be provided basic information about the 
study (e.g., who is leading the study, why the patient was 
included, why the study is being done and what it entails), and 
what smoking treatments are available through either standard 
care or the comparative effectiveness trial. In addition, the 
launch letter will direct patients to research staff who can 
provide additional information, answer any questions patients 
may have, address any concerns raised by patients (in 
consultation with the study team and/or DSMC or IRB, as 
needed), and can honor any patient requests to cease smoking 
treatment outreach activities. Oral versions of the same 
information will be available to all letter recipients, either via 
the web or via phone call to a research team member.   
• A full waiver of consent is necessary for the creation of a de-
identified data set from health records and cancer registry data 
to examine cancer care outcomes, estimate cancer care costs, 
and capture information on environmental exposure among 
identified patients who did not actively decline study 
participation. The medical record is the best source of the PHI 
and critical data source to examine study outcomes. If consent 
was required for this retrospective data analysis it could 
significantly bias the results and reduce value of the research as 
a goal is to examine how tobacco treatment relates to clinical 
outcomes captured in the medical record. For example, the 

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sociodemographic and cancer diagnosis elements are needed to 
assess the representativeness of the recruited clinical trial 
sample and equity in the reach of smoking treatment among 
eligible patients (relative to all patients who were initially 
identified as potentially eligible per EHR eligibility criteria). 
For this reason, it is critical to the representativeness and 
generalizability of these study aims that de-identified health 
record data is included from all patients who were initially 
eligible for proactive outreach (excluding those who actively 
declined to participate in further outreach or the comparative 
effectiveness clinical trial). 
We also seek a waiver of HIPAA authorization for the medical 
record review and proactive (mailed and telephone) outreach for 
recruitment and conduct of the CET, and an alteration of HIPAA 
authorization for the CET (as signatures will not be required and 
not all elements of HIPAA authorization will be covered during the 
oral consent process). We seek a waiver of HIPAA authorization 
for the creation of a de-identified data set from health records and 
cancer registry data to examine cancer care outcomes, estimate 
cancer care costs, and capture information on environmental 
exposure, among the patients initially identified as eligible for 
outreach (excluding those who actively declined study 
participation). All required HIPAA authorization information will 
be included in mailed information sheets that will be sent to 
participants who consent to the CET, and this will be available 
online or in writing by request prior to consent, as well. The 
justification for this request is as follows (using CHECKLIST 
HRP-441 as a guide): 
• The PHI needed for recruitment and for study conduct is 
described in the protocol and is limited to information 
needed to mail outreach letters and to make outreach calls to 
adult patients who smoke and meet eligibility requirements 
for both standard treatment options and study recruitment. 
Data collected about patients prior to consent will include: 
MRN, name, DOB, date visited a participating clinic, care 
team members who treat the patient (at the most recent clinic 
and for primary care), address, phone numbers, preferred 
language, preferred communication modality, tobacco use 
status, insurance, and demographics).  
• The use or disclosure of PHI involves no more than 
minimal risk to privacy because there are thorough plans in 
place to: protect identifiers from improper use and disclosure 
(e.g., secure data transfer and storage practices; tight access 
controls, with access limited to study coordinators and those 
who maintain the databases or oversee their outreach; 

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logging of record access); destroy identifiers at the earliest 
opportunity after achievement of the study aims; prevent 
reuse or disclosure of PHI (except as required by law or 
authorized oversight bodies).   
• The research is not practicable without a waiver and 
alteration of HIPAA authorization due to the sampling bias 
and reduced generalizability that would result.  
• The research could not practicably be conducted without 
access to PHI because outreach letters must be mailed to 
eligible patients, and study coordinators must have access to 
phone numbers to call patients to offer them smoking 
treatment (both standard treatment and the CET) to assess the 
reach and equity in reach of such proactive outreach in 
cancer care at UW Health.   
• A full waiver of HIPAA authorization is necessary for the 
creation of a de-identified data set from health records and 
cancer registry data to examine cancer care outcomes, 
estimate cancer care costs, and capture information on 
environmental exposure. The medical record is the best 
source of the PHI and critical data source to examine study 
outcomes. If consent was required for this retrospective data 
analysis it could significantly bias the results and reduce 
value of the research as a goal is to examine how tobacco 
treatment relates to clinical outcomes captured in the medical 
record. For example, the sociodemographic and cancer 
diagnosis elements are needed to assess the 
representativeness of the recruited clinical trial sample and 
equity in the reach of smoking treatment among eligible 
patients (relative to all patients who were initially identified 
as potentially eligible per EHR eligibility criteria). For this 
reason, it is critical to the representativeness and 
generalizability of these study aims that de-identified health 
record data is included from all patients who were initially 
eligible for proactive outreach (excluding those who declined 
to participate in further outreach or the comparative 
effectiveness clinical trial). 
 
Non-English Speaking Participants 
We do not plan to enroll participants who do not speak or understand 
English.  We will reach out only to patients who have not designated 
a language other than English as their preferred language in the 
EHR, and we will only enroll participants who speak and understand 
English in the CET. 
Participants who are not yet adults (infants, children, teenagers) 

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Individuals under the age of 18 will not be included in tobacco 
treatment outreach efforts and will not be eligible for the CET or 
qualitative interviews. Being an adult is a criterion for inclusion on 
the CRDS reports that will guide tobacco treatment outreach and 
study recruitment efforts, and for participation in qualitative 
interviews.  
 
Adults with Impaired Decision-Making Capacity 
 
Process to determine whether an individual is capable of 
consent. We will first filter out patients with evidence of 
impaired decision-making capacity in their EHR by excluding 
patients with an EHR flag for cognitive impairment, an active 
power of attorney for health care, or another active health agent 
(e.g., legally authorized representative). Patients meeting these 
exclusion criteria will not be on the CRDS reports that will 
guide tobacco treatment outreach calls and CET recruitment 
efforts. 
Next, study coordinators will be trained to monitor for 
comprehension problems during the consent process and will 
not accept consent from participants who are unable to 
correctly answer questions about the study after hearing the 
consent script.   
Process for individuals with impaired decision-making 
capacity who are capable of consent. We will not enroll 
participants who we know to have impaired decision-making 
capacity. 
Adults Unable to Consent 
We will not attempt to secure consent from designated 
representatives of participants with impaired decision-making 
capacity due to the level of engagement and decision-making 
that would be required of participants during the treatment 
selection (pre-CET) and smoking cessation counseling 
processes (in the CET), or in qualitative interviews. 
9.0 
Process to Document Consent in Writing 
 
9.1 Waiver of written documentation of consent.  Consent for 
participation in the opt-out tobacco treatment outreach component of 
the study will not be documented in writing, as this will occur on an 
opt-out basis (patients who are sent notices of such outreach who do 

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not opt out will be enrolled in proactive outreach without 
documented consent).  
 
For the CET, study participation will not be documented in writing 
by the participant, but the study coordinator will document that oral 
informed consent was obtained using a time-stamped field in the 
CET REDCap database. This consent will be obtained using an IRB-
approved script and will be followed with a mailed version of the 
IRB-approved study information sheet (which will also be available 
online before and during the consent process).  
 
For the qualitative interviews, interviewers will obtain oral consent 
prior to beginning the interview, as guided by the oral consent script, 
and will document this in a securely stored interview tracking sheet. 
 
Documentation of informed consent via other means (wet signature 
or e-consent) would be impracticable due to the bias that would 
result in the study samples if in-person contact or access to e-consent 
computing resources were required to opt into tobacco outreach or to 
consent to smoking cessation treatment in the CET or to 
participation in qualitative interviews. The consent scripts and 
written study information sheet are uploaded with the application. 
 
The proposed research will use an oral consent process, as it presents 
no more than minimal risk of harm to participants and involves no 
procedures for which written documentation of consent is normally 
required outside of the research context, as health systems routinely 
accept oral consent for smoking cessation treatment initiation. 
Although we will not collect participant signatures to demonstrate 
consent, we will document consent obtained orally or online using 
scripts uploaded with the application.  
 
10.0 Setting 
 
10.1 Research sites. 
All research procedures will be performed at UW-CTRI, including 
telephone qualitative interviews, telephone outreach regarding tobacco 
treatment and CET recruitment, screening, enrollment, treatment, and 
follow-up activities.  Participants will be recruited from oncology clinics of 
the UW Carbone Cancer Center (UW-CCC) that treat diverse populations of 
patients with cancer. The UW-CCC treats more than 30,000 people annually 
for diagnosis, therapy, follow-up care or consultations.   
 
11.0 Study Intervention 
 

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11.1 Description. 
The outreach strategy that is being evaluated in terms of reach and reach 
equity comprises mailings (no more than quarterly) and proactive telephone 
calls offering smoking treatment information and access.  
 
The smoking cessation treatment strategies being evaluated in terms of 
comparative effectiveness, efficiency, and equity are 2 treatment packages 
that vary in terms of intensity, cancer-specificity, costs, and burden on 
patients. These interventions are described below. 
 
• Standard treatment  
o 3 counseling calls (each 10-15 minutes in length) on the 
following schedule (an outline of the counseling protocol is 
uploaded with the application): 
 Pre-quit call (1 week before the target quit date they 
selected at enrollment) 
 Post-quit call 1 (target quit date or next day) 
 Post-quit call 2 (1 week after the target quit date). 
o Nicotine patch starter kit (1 14-count box of transdermal 
nicotine patches) for use starting on the target quit date, at the 
following dosing schedule (medication instructions to be 
mailed to participants are uploaded with the application): 
 For those who smoke 10 or more cigarettes per day at 
enrollment, 21-mg patches. 
 For those who smoke 5-9 cigarettes per day, 14-mg 
patches. 
 For those who smoke 1-4 cigarettes per day, 7-mg 
patches. 
 Those who smoke less frequently than daily will not 
be eligible for patches. 
 Those whose clinicians disapprove of nicotine patch 
therapy for their patients will not receive patches. 
o Mailed information about smoking cessation treatments 
available from the Wisconsin Tobacco Quit Line (or state 
quit line in patient’s state of residence) and SmokefreeTXT, 
two publicly funded, remotely delivered treatment services 
available to the general public. 
• Enhanced treatment  
o 7 counseling calls (each 10-15 minutes in length) on the 
following schedule (an outline of the intensive counseling 
protocol is uploaded with the application): 
 Pre-quit call (1 week before the target quit date they 
selected at enrollment). 
 Post-quit call 1 (target quit date or next day). 
 Post-quit call 2 (1 week after the target quit date). 

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 Post-quit call 3 (2 weeks after the target quit date). 
 Post-quit call 4 (4 weeks after the target quit date). 
 Post-quit call 5 (8 weeks after the target quit date). 
 Post-quit call 6 (12 weeks after the target quit date). 
o Varenicline starting 7 days before the target quit date (0.5 mg 
once per day for 3 days, 0.5 mg twice per day for 4 days, 1 
mg twice per day for 11 weeks), as per the package insert 
(medication instructions for patients are uploaded with the 
application). Those who smoke less frequently than daily will 
not be eligible for varenicline.  
 If patients in high-intensity treatment are ineligible 
for varenicline (due to contraindications reported at 
initial medication screening or clinician disapproval 
of varenicline for the patient), patients will instead be 
offered 12 weeks of nicotine patch therapy for use 
starting on the target quit date, at the following dosing 
schedule: 
• For those who smoke 10 or more cigarettes 
per day at enrollment, 21-mg patches (week 1-
8), 14-mg patches (week 9-10), 7-mg patches 
(week 11-12). 
• For those who smoke 5-9 cigarettes per day, 
14-mg patches (week 1-10), 7-mg patches 
(week 11-12). 
• For those who smoke 1-4 cigarettes per day, 
7-mg patches. 
• Those who smoke less frequently than daily 
will not be eligible for patches. 
• Those whose clinicians disapprove of nicotine 
patch therapy for their patients will not receive 
patches. 
o Mailed information about smoking cessation treatments 
available from the Wisconsin Tobacco Quit Line (or state 
quit line in patient’s state of residence) and SmokefreeTXT, 
two publicly funded, remotely delivered treatment services 
available to the general public. These information sheets are 
uploaded with the application.  
11.2 Drug/Device Handling. 
• Study medications (nicotine patches, varenicline) will be received at 
the Center for Tobacco Research and Intervention by the Study 
Coordinator or  designees in the Madison office. 
• Nicotine patches will arrive in commercially packaged boxes of 14 
patches each (two weeks of 21mg, 14mg, or 7 mg patches).  

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• Varenicline will arrive in commercially packaged 28-day starter packs 
that clearly designate when and how to start the medication run-in 
period (beginning 1 week before the target quit day), or 28-day 
continuation packs (standard commercial packaging sizes). 
• Study medications will be stored in designated locked drug cabinets in 
Madison until processed for dispensing.   
• Dissemination mailings containing processed study medication will be 
labeled with Study ID and subject initials and stored in secure, locked 
cabinets, closets, or rooms in Madison.   
• Medication will be mailed to participants. Due to the need to match 
nicotine patch dose to smoking heaviness at enrollment and potential 
changes in medication based on clinician disapproval of varenicline, 
medication mailings will be assembled to order rather than 
preassembled.  
• Medications returned by mail will NOT be recirculated.  
11.3 IND status. 
No investigational drugs will be used. Both varenicline and 
transdermal nicotine patches are currently FDA approved for use to 
treat smoking and are broadly available. Both medications will be 
used as directed in the package inserts. This use of varenicline and 
nicotine patches in this study is considered IND exempt under 
category 1 (21 CFR 312.2(b)(1)). 
 
12.0 Study Timelines 
12.1 CET Timeline. 
1. The duration of an individual participant’s participation in 
the study. Participants will be in the outreach component of 
the study in which they may receive mailings and calls 
regarding tobacco treatment options up to once per quarter for 
up to 30 months if they continue to meet inclusion criteria for 
the reports that guide such outreach.  
Participants who consent to the CET will be in the study for up 
to 8 months (up to 2 months before a target quit date and to 6 
months post-quit-date. 
Participants in qualitative interviews will participate in one 
hour-long interview (with the option to break this interview up 
over multiple calls if they prefer not to do it all at one call). 
The total duration of the interview will be about one hour. 
2. The duration anticipated to enroll all study participants. 
We anticipate completing recruitment in 30 months. 

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3. The estimated date for the researchers to complete this 
study (complete primary analyses). We will need 1 year after 
completion of recruitment to complete the study (8 months to 
complete follow-up data collection and 4 months to complete 
primary analyses), and thus anticipate completing this study by 
mid 2027). 
13.0 Procedures Involved 
13.1 Study Procedures. 
Tobacco treatment outreach. Patients who meet criteria for inclusion on 
quarterly CRDS reports will first receive a mailed letter informing them 
that tobacco treatments are available and that quitting smoking has 
important benefits during cancer care. Patients will also be informed in the 
letter that they will receive phone outreach from UW-CTRI regarding their 
tobacco treatment options over the next 12 weeks unless they prefer to opt 
out of such outreach by calling UW-CTRI to ask that they not receive 
future tobacco treatment outreach. UW-CTRI study coordinators will 
make up to 5 attempts to reach patients who do not opt of such calls over 
12 weeks. The outreach letter and phone outreach script are uploaded with 
the application.  
Tobacco treatment facilitation. When they reach patients on the phone, 
UW-CTRI study coordinators will talk with patients about the benefits and 
challenges of quitting smoking during cancer care and will describe 
available treatment options (enrolling in Wisconsin Tobacco Quit Line (or 
other applicable quit line) services; working with their primary or 
oncology care team; enrolling in the CET) and ask which, if any, 
treatments the patient would prefer. Patients who decline any treatment 
will be offered the number of the WTQL/national quit line number. A 
script for these treatment offers is uploaded with the application. 
CET screening. Patients who express interest in the CET will be given 
information about screening and enrollment procedures and then asked if 
they assent to eligibility screening. Those who do will complete a brief 
eligibility screen during the same phone call. Those who do not meet 
eligibility criteria to continue will be offered quit line services and 
reminded that their care teams may be able to help them quit smoking, as 
well. Ineligible participants will also be asked if they would like to 
participate in a sub-study that involves one phone interview. Those who 
pass the screening will move on to the oral informed consent process. 
Interviews. Up to 32 people, including those who are not eligible or do not 
enroll in the CET, will be offered an additional $40 to complete a one-
hour telephone interview to gather information that will help improve the 
way tobacco treatment is offered to people who have had cancer. 
Participants will first complete an oral consent procedure (uploaded with 

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the application). The interview will address the participants’ cancer 
experiences, tobacco use history, smoking and supportive care outreach, 
and smoking treatment. The interview outline is uploaded with the 
application. These interviews will be recorded and transcribed without 
participant identifying information. 
Oral consent. In the oral consent process, UW-CTRI study coordinators 
will read the oral informed consent script to participants and will then ask 
if they have any questions. The study coordinator will answer questions 
during the call, or will schedule a follow-up call if the patient needs more 
time to make a decision about the study or if the study coordinator needs 
to consult with the PI or other team member to address the patient’s 
concerns or questions. Once the patient’s questions have been fully 
addressed, the patient will be asked questions to assess their 
comprehension of key CET study features. People who are unable to 
answer these questions correctly, even after review of key points by the 
study coordinator, will be considered unable to consent and will be 
referred to their care team and given information about WTQL services. 
Those who pass the comprehension screening will be asked if they consent 
to participate in the CET study.  
Baseline assessment.  Next, participants will complete a baseline 
assessment (see uploaded survey) of their tobacco use history, nicotine 
dependence, quitting motivation, quitting confidence, stress, mood, 
wellbeing, quality of life, support system, symptom burden, and 
demographics. Participants will also select a target date to quit smoking 
within the next 60 days at this call.  These activities will occur during the 
enrollment phone call if participants are willing and able to stay on the 
call. If they are not, the UW-CTRI study coordinator will schedule this 
assessment call within the following 1-2 weeks.  
Randomization. Participants will next be randomized to treatment. 
Participants will be considered fully enrolled once consented, baseline 
assessment is complete, and randomized. Study coordinators and 
participants will be informed of the randomly assigned condition after the 
baseline assessment is completed. 
Treatment procedures. These are described in section 13.1 above. 
Follow-up assessments. UW-CTRI follow-up assessors will call CET participants 
12 and 26 weeks after their target quit dates to collect outcome data (see uploaded 
follow-up surveys) including: tobacco use; quitting motivation and confidence; 
stress, mood, wellbeing, quality of life, support, and symptom burden; and 
treatment utilization, satisfaction, and adverse events. In addition to these self-
report measures, counseling utilization and medication refill data will be used to 
track smoking treatment adherence; EHR data on healthcare utilization and 
diagnoses will be extracted (with patient consent provided at enrollment); and 
biochemical verification of abstinence claims at the 6-months post-quit follow-up 

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will be obtained via carbon monoxide breath samples and urinary cotinine 
samples, or mailed saliva samples (as participants are able to provide them).  
 
13.2 CET procedure schedule. 
Study Phase 
Enroll-
ment 
Treatment/Intervention Calls 
Follow 
Up 
Calls 
FU 
Visit 
Study Contact 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Week relative to target 
quit day (tqd, day 0) 
-8 to -3 
-1 
0  
tqd 
1 
2 
4 
8 
12 
12 
26 
26-
29 
Eligibility screening 
 
 
 
 
 
 
 
 
 
 
 
Oral informed consent & 
HIPAA Authorization 
 
 
 
 
 
 
 
 
 
 
 
Clinician(s) given 5 
business days to 
disapprove study 
medication; medications 
dispensed if not 
disapproved 
 
 
 
 
 
 
 
 
 
 
 
Tobacco, alcohol, and 
cannabis history 
 
 
 
 
 
 
 
 
 
 
 
Nicotine dependence 
 
 
 
 
 
 
 
 
 
 
 
Motivation to quit 
 
 
 
 
 
 
 
 
 
 
 
Quitting confidence 
 
 
 
 
 
 
 
 
 
 
 
Stress, mood, and 
withdrawal 
 
  
 
 
 
 
 
 
 
 
 
Wellbeing and quality of 
life 
 
 
 
 
 
 
 
 
 
 
 
Social support 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
 
 
 
 
Welcome mailing packet 
with study information 
sheet sent 
 
 
 
 
 
 
 
 
 
 
 
Standard care (SC) 
counseling (10-15 
minutes) 
 
SC 
SC 
SC 
 
 
 
 
 
 
 
Standard care nicotine 
patch treatment (2 weeks) 
 
 
SC 
SC 
 
 
 
 
 
 
 
Enhanced care (EC), 
cancer-specific counseling 
 
EC EC EC EC EC EC 
EC 
 
 
 
Enhanced care varenicline 
treatment (12 weeks 
 
EC EC EC EC EC EC 
EC 
 
 
 

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beginning with run-in 
period 1 week pre-quit 
followed by 11 weeks at 
full dose post-quit, as per 
package insert) 
Recent tobacco, alcohol, 
and cannabis use 
 
 
 
 
 
 
 
 
 
 
 
Treatment use 
 
 
 
 
 
 
 
 
 
 
 
Treatment satisfaction 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event 
Assessment (all 
participants will be 
assessed through 26 weeks 
post-target-quit date; those 
in enhanced care will have 
additional assessments at 
counseling contacts 
specific to that arm) 
 
 
 
 
EC EC EC 
EC 
 
 
 
Biochemical verification 
via CO and urine cotinine 
(or mailed saliva cotinine) 
 
 
 
 
 
 
 
 
 
 
 
 = applies to both treatment arms 
SC = applies only to standard care arm 
EC = applies only to enhanced care arm 
 
13.3 Research procedures: 
1. Safety monitoring and risk prevention. 
To reduce risks to CET participants, we will first screen them 
for eligibility prior to enrollment, will ask their clinicians to 
review and disapprove study medications that raise safety 
concerns for them, and then we will monitor for adverse events 
at all study contacts following the initiation of smoking 
cessation treatments in the trial. The schedule for these 
activities is presented above. Please note that follow-up 
contacts will occur for all study participants 12 and 26 weeks 
after their target quit date (i.e., after the end of 
pharmacotherapy in both conditions, which will end 2 weeks 
after a target quit date in the control condition and 11 weeks 
after the target quit date in the enhanced care condition for 
varenicline). The final counseling contact in the enhanced care 
condition will also occur at the 12-week post-quit time point. 

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For qualitative interviews, interviewers will monitor for 
distress or confusion during the interview and will stop the 
interview and address the distress or confusion, as needed. 
2. Biospecimens. 
The only biospecimens to be collected in the study will be 
collected directly from CET participants at the follow-up visit 
6 months after a participant’s target quit date, if the participant 
reported no use of tobacco products at the 26-week post-quit-
date follow-up call.  These participants reporting abstinence 
from tobacco will be asked to provide a breath sample for CO 
testing and a single urine sample for cotinine testing at either 
the UW-CTRI Madison office or at their oncology clinic (if 
willing to schedule this so it coincides with a clinic visit). 
Breath samples cannot be stored and urine samples will be 
tested immediately after collection and then discarded the same 
day. If patients are unable to travel to Madison for biochemical 
verification of abstinence, they will be given the option of 
providing a saliva sample in the mail using a kit supplied by 
the research team. These kits would be retained only until 
testing by a lab is complete and would then be destroyed.  
3. Drugs. 
The medications to be used in this study include transdermal 
nicotine patches and varenicline. Both medications are 
approved by the FDA for use as smoking cessation aids. No 
other medications or devices will be used in the research. 
 
13.4 Data Collection. 
• List of data elements. 
The following data elements will be extracted from EHR data via 
CRDS reports. These data elements are needed to enable 
preparation of initial study recruitment mailings that will let 
patients know they have been identified for the study and that they 
can opt out of recruitment calls and letters.  
o MRN 
o Name 
o Phone numbers (with preferred number flagged) 
o Address 
o City 
o State 
o ZIP code 
o Communication preferences (MyChart, mail, phone) 
o Tobacco use status (must be smoking currently) 

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o Preferred language (must be English or missing) 
o Use of smokeless tobacco 
o Use of e-cigarettes 
o Date of birth (must be at least 18 years old) 
o Sex 
o Gender 
o Race 
o Ethnicity 
o Insurance type 
o Assigned primary care provider 
o Oncologist 
o Clinic department (where seen in the past year to 
achieve eligibility) 
o Cancer diagnosis (diagnosis in past 3 years that 
conferred eligibility)  
 
• Additional de-identified data elements will be extracted from 
the EHR data and Cancer Registry for patients who were 
initially identified as potentially eligible for the study per 
EHR eligibility criteria, but excluding those who actively 
declined study participation. The sociodemographic and 
cancer diagnosis elements are needed to assess the 
representativeness of the recruited sample and equity in the 
reach of smoking treatment among eligible patients. The data 
regarding healthcare utilization, cancer care outcomes, and 
environmental exposures are needed to assess care outcomes 
and estimate cancer care costs (overall and between Standard 
and Enhanced care conditions) from participants in the CET. 
Specific data fields are listed in supplemental documents. 
These data will be extracted with identifiers only for 
participants who enrolled in the CET and provided informed 
consent for EHR data use.  
• In addition, self-reported data regarding the constructs shown 
in the study schedule above will be collected directly from 
participants over the phone or at the final follow-up visit. 
Participant responses will be documented in REDCap. 
• Completion of study counseling sessions and medication 
refill requests and dispensing will also be tracked in REDCap 
to assess treatment utilization and adherence.  
• Fidelity to counseling protocols will be assessed by 
reviewing a subset of audio-recorded counseling sessions and 
coding for fidelity using a checklist.  
• Qualitative interviews will be transcribed and thoroughly 
deidentified prior to review of transcripts for interviewer 
feedback and for thematic analysis. 

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• Questionnaires. 
Questionnaires to be administered as structured interviews to 
collect participant self-report data following the schedule 
shown above are uploaded with the application.  
 
• Source records: 
☑ UW Health medical or billing records via ICTR’s Clinical 
Research Data Service (CRDS) 
☑ UW Health HealthLink Records (study team will directly 
access)  Study team members will access HealthLink directly 
to communicate with providers about patient medication 
eligibility and to document study medication dispensing in 
patient records for care teams). 
☐ Data from departmental QA or QI database 
☐ Data from UW Health Enterprise Data Warehouse (EDW) 
☐ Data from PACS (Picture Archiving and Communication 
System); specify whether study will use the clinical or research 
instance in the Radiology Department’s warehouse: 
___________ 
☐ Data from Center for Medicare/Medicaid Services 
☐ Data from publicly available datasets (e.g., U.S. census data) 
☐ Data from outside institutions or organizations (specify: 
______________) 
☐ Other (specify: ____________________________________) 
13.5 Long-term follow-up.  
There are no plans for long-term follow-up.  
13.6 Regulatory status of study drugs. 
Both varenicline and transdermal nicotine patches are currently FDA 
approved for use to treat smoking and are broadly available. This use 
of varenicline and nicotine patches in this study is considered IND 
exempt under category 1 (21 CFH 312.2(b)(1)). 
 
14.0 Comparison of usual care and study procedures 
14.1 Alternatives to participation. 
The current standard of care for treating tobacco use at UW Health is to 
electronically refer patients to the Wisconsin Tobacco Quit Line if patients 
consent to such referral.  Clinicians are also able to prescribe smoking 
cessation pharmacotherapies, including nicotine patches, varenicline, other 

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forms of nicotine replacement therapy, and/or bupropion and to provide 
smoking cessation counseling to patients. 
 
The proposed study will proactively offer patients both these standard forms 
of care available at UW Health and will present the option to screen for and 
possibly enroll in the proposed CET. These alternatives will be presented on 
an even footing to prospective participants, with all options presented before 
asking patients to choose among them.  
 
Proactive outreach will occur because evidence suggests that existing 
standard care options (Quit Line referral, UW Health clinician intervention) 
are delivered rarely to patients. The proactive model of treatment offers 
seeks to address this issue that limits the reach of evidence-based smoking 
treatment by making outreach regarding tobacco treatment options the 
default, unless the patient opts out of such contacts.  
 
The CET recruitment and consent process will highlight differences between 
standard care and the treatments offered in the CET, and will clearly identify 
procedures that are just for research (e.g., assessments, biochemical 
verification). The CET has also been designed so that participants in both 
arms will receive treatment that meets the current standard of care available 
through the Wisconsin Tobacco QuitLine. In addition, participants in both 
CET arms will receive information about available QuitLine and NCI-
sponsored text messaging program (SmokefreeTXT) resources available to 
them. As such, no patients will be assigned to a condition that offers less 
than standard care to address their smoking, and participating in the study 
will not inhibit participants’ ability to take advantage of publicly funded 
smoking cessation treatment resources.  
 
The alternative to participating in the qualitative interview is simply not to 
participate, and this will not affect the care the patients receive or any other 
aspect of their relationships with UW Health, UW CCC, or UW more 
broadly. 
14.2 Standard of care.  
The current standard of care for treating tobacco use at UW Health is to 
electronically refer patients to the Wisconsin Tobacco Quit Line if patients 
consent to such referral.  Clinicians are also able to prescribe smoking 
cessation pharmacotherapies, including nicotine patches, varenicline, other 
forms of nicotine replacement therapy, and/or bupropion and to provide 
smoking cessation counseling to patients. Quitline reports and past projects 
suggest that this standard of care is not being applied consistently, and that 
relatively few patients are receiving such care.  
 
14.3 Research procedure overlap with standard practice. 

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As noted above, the current standard of care for addressing tobacco use at 
UW Health is to refer patients to the Wisconsin Tobacco Quit Line, and 
there is an order set clinicians can use to place orders for pharmacotherapies 
to help patients stop smoking. These tools are rarely used, however. All 
patients contacted by UW-CTRI will hear about these standard care options, 
and will still have these options, and more (e.g., SmokefreeTXT, no-cost 
pharmacotherapies) available to them if they enroll in the CET. To ensure 
that study treatments do not interfere with standard care, UW Health 
primary care providers and oncologists of patient care teams will be able to 
review and disapprove study medications, and UW Health prescribers will 
be able to see which study medications were dispensed to patients in Health 
Link. No other research procedures (e.g., assessments, counseling calls) 
overlap with standard care activities, and none should interfere with 
standard care. 
 
14.4 Research participation effects on standard clinical care.   
Participation in this research will not affect standard clinical care. Patients 
will remain eligible for standard smoking cessation treatment, and standard 
cancer treatment, without delay or disruption. 
 
 
15.0 Withdrawal of Participants 
15.1 Withdrawal from the research without participant consent. 
Participants will be withdrawn from the study without their consent 
if they are found to have diminished capacity to consent to ongoing 
participation, or if, in the judgment of the lead investigators, 
continued participation would not be in the best interest of the 
participant (i.e., if participation is causing distress or dysregulation 
in the participant). Participants may also be withdrawn from the 
study without consent if they are no longer willing or able to fulfill 
their responsibilities as study participants. 
15.2 Orderly termination. 
For patients in the medical records review portion of the study, 
termination will simply entail excluding records from withdrawn 
participants in CRDS reports and/or outreach efforts. For patients 
who consent to the CET, termination will be accomplished by 
cessation of all proactive outbound communications to the 
participant and by not fulfilling medication or treatment requests that 
are deemed not in the patient’s best interests (e.g., if a patient has 
developed a contraindication to a study medication). For participants 
who consent to qualitative interviews, termination will mean ending 

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the interview early and may also involve referrals to supportive care 
resources, as needed. 
15.3 Withdrawal procedures. 
Participants who withdraw from the medical records portion of the study 
and opt out of tobacco treatment outreach will have this change of status 
noted in both the REDCap project that guides outreach activities and CET 
recruitment, and in OnCore (to prevent inclusion in future CRDS reports). 
Participants who withdraw from the CET will have this status change noted 
in the REDCap project that study team members use to guide 
communication, treatment, and assessment activities in the CET.  
 
Previously collected data from people who consent to the CET and later 
request to withdraw will be retained in study datasets, in keeping with HRP-
314 criteria for approval for FDA-regulated research. Removal will not be 
possible once deidentification has occurred; it will not be possible to 
identify and delete records for specific participants.  
 
Participants who are incarcerated during the study or who request temporary 
suspensions of outreach, treatment, or communication will be given a 
temporary suspension status until they are able to resume participation 
because their incarceration or inability to participate has ended (e.g., they 
have been released or transitioned to parole or probation).  
 
Patients withdrawn from the due to safety risk related to their health or 
wellbeing will be notified by the research team and advised if any safety 
procedures are recommended. This will be documented in study records, 
and adverse and serious adverse event reporting guidelines will be followed.  
 
People who choose to withdraw during the qualitative interview will have 
the option to request that none of the information they shared will be used in 
the study. In that case, the interview recording will be destroyed and no 
transcript will be created. 
 
16.0 Data Management and Confidentiality 
16.1 Quality control. 
Both an internal quality improvement team and an external Data 
Safety and Monitoring Committee will help to monitor and ensure 
data quality. The project will follow a thorough Data and Safety 
Monitoring Plan (DSMP). Under this DSMP, the Lead Researcher 
will develop and implement protocols for assuring UW-CTRI data 
collection accuracy and protocol compliance, with the support of the 
UW-CTRI staff including the Director of Information Technology 
(IT) and the Regulatory and Compliance Coordinator, among others 

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(e.g., our database and implementation teams and study 
coordinators). Study protocols will include data verification and 
protocol compliance checks. The Lead Researcher will also be 
responsible for ensuring that the data for the project are securely 
transferred from UW Health and securely stored at UW-CTRI, in 
compliance with University and federal regulations, and that no 
unauthorized persons have access (electronic or physical) to any 
participant-identifiable data. HIPAA regulations and guidelines are 
currently implemented at UW-CTRI, and all study staff must 
complete approved human subjects and HIPAA training programs. 
In addition, the Department of Medicine employs extensive data 
backup and server redundancy procedures and performs full backups 
weekly of all servers, along with incremental and daily backups to 
prevent loss of data.  
16.2  Data security. 
 
As specified in the DSMP, the Lead Researcher will be responsible for 
ensuring that the data for the project are securely transferred from UW 
Health and securely stored at UW-CTRI, in compliance with University and 
federal regulations, and that no unauthorized persons have access (electronic 
or physical) to any participant-identifiable data. HIPAA regulations and 
guidelines are currently implemented at UW-CTRI, and all study staff must 
complete approved human subjects and HIPAA training programs. Inter-site 
data transfers are accomplished via secure UW REDCap or file transfer 
protocols (SFTP) using an internet server maintained by the UW School of 
Medicine and Public Health (UWSMPH) Department of Medicine. To 
protect the privacy of database records and the integrity of the network, this 
server is firewall-protected and is stored in a locked server room with a 
numeric keypad to restrict entry. The server is continuously scanned for 
viruses. A complete virus scan of all workstations also takes place once a 
week. Server system log files are scanned for unusual activity, which is 
immediately investigated. Network and server administration staff members 
apply critical and non-critical patches as needed. In addition, UW-CTRI and 
UWSMPH Department of Medicine also have multiple mechanisms for 
preserving confidentiality of research participants and providing data 
security in the transfer of data from participant machines to the SFTP server. 
The Department of Medicine web servers use Secure Socket Layer (SSL or 
https) technology to encrypt data exchanged between the client and the 
server. In addition, all online and offline components of data systems will be 
accessible only through a login and password unique to each user. The 
security access levels for these login accounts are tiered and the features and 
privileges given to each staff member will be determined by the PI and UW-
CTRI Director of Information Technology (IT). To further protect 
confidentiality, only the UW-CTRI Director of IT will be permitted to 
transmit data to the SFTP server. Additional measures include: 

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☑ Data will be coded, and the “key” linking identities to codes will 
be kept separately from the data. 
☐ Data will be coded, and the “key” linking identities to codes will 
be kept on paper only. The study data will be stored electronically 
and labeled only with codes. 
☐ Only those listed as key personnel will have access to the “key.” 
☑ Access to the “key” will be limited to the following people (e.g., 
Database Administrator): Database Administrators, Saliva Sample 
Collection Coordinator.  
☑ This study is funded by the National Institutes of Health 
and is covered by a Certificate of Confidentiality. 
☐ This study is NOT funded by the National Institutes of 
Health but because it will collect sensitive information, the 
research team will apply for a Certificate of Confidentiality 
to protect data from being requested without the subject’s 
consent as part of a legal proceeding. 
☐ Other: _______________________________________________ 
A unique study ID will be used to store all data on individual 
participants and information linking that study ID to participant 
identifying information will be accessible only to Database 
Administrators. Data being used for analysis will be identified with the 
study ID only. Participant contact information will only be available to 
study staff having direct contact with participants, and only when 
needed to complete such contacts, as per protocol.  
For qualitative interview data, a random ID will be assigned to each 
transcript, and all transcripts will be thoroughly deidentified. 
If a saliva sample is needed from a participant, a separate unique 
identifying code will be used to label the saliva collection kit. Only the 
person coordinating saliva sample data collection will have the key to 
that code.  
Participant study data will be collected by UW-CTRI research 
personnel through REDCap and will be stored on secure, password 
protected servers.  Data will be accessible only to assigned study staff 
for their study function; computer workstations will be password-
protected, and thus secured from unauthorized use. Healthcare systems 
will transmit identifying information to UW-CTRI via secure, HIPAA 
compliant means. A Certificate of Confidentiality will be issued for 
the study. 
 

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16.3 Data storage: 
☑ Online Collaborative Research Environment (OnCore) 
Biospecimen Management 
☑ Research Electronic Data Capture (REDCap) Specify which 
instance you will be using (e.g., ICTR’s, Department of 
Medicine’s): UW-CTRI Instance________________ 
☐ Other software option that will be stored on departmental 
server. Specify the department: _UW-CTRI_____________ 
☐ Locked filing cabinet or drawer inside a locked room. 
Specify the building: ____________________________ 
☑ Other (describe): _Saliva samples returned via mail by 
participants will be stored in a locked cabinet in a locked office 
until ready to be shipped to a lab for testing. Samples will be 
identified by a code number only. 
☐ Data will not be stored or accessed on portable devices. 
☑ Portable devices such as laptops will be used to access 
secure web-based data collection sites such as REDCap. No 
data will be stored locally on the devices. 
☐ Data stored on portable devices will be coded with the key 
stored separately. No identifiers will be stored on portable 
devices. 
☐ Data stored on portable devices and therefore only 
encrypted devices will be used. 
 
16.4 Management of Identifiers: 
☐ Identifiers will be destroyed after all data has been 
collected. 
☑ Identifiers will be destroyed at study closure. 
☐ Identifiers will be destroyed at study closure or at the time 
of publication. 
 
16.5 Data and specimen handling: 
1. 
Data associated with specimens. 
A subset of participants in the CET who report no smoking in 
the past 7 days 26 weeks after their target date to quit smoking 
and who are unable to come to Madison to provide a breath and 
urine sample for biochemical verification of abstinence will be 
sent saliva collection kits identified by a unique code number 
specific to saliva tests kits. These kits will include instructions 
for home collection of saliva using the passive drool method, 
collection materials, and a stamped, addressed return envelope 
to return samples to the study team. Only the team member 

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coordinating saliva sample collection will have the key to this 
code, and they will be responsible for entering results from the 
saliva testing in the REDCap database. This unique key will be 
destroyed on study closure. No other biospecimens (breath or 
urine samples) will be banked. These samples will instead be 
tested immediately and recorded in the REDCap database. 
2. 
Where and how data or specimens will be stored. 
Saliva samples will be stored in a locked cabinet in a locked 
office until ready to ship to the lab that conducts the testing and 
returns results identified only by the unique sample identifier to 
the saliva collection coordinator for the study.  
3. 
How long will the data or specimens will be stored. 
Saliva samples will be stored until ready to ship to the testing 
lab (within 3 weeks of sample collection). The samples will be 
destroyed by the testing lab after testing is complete and a 
study team member has received testing results via a secure 
portal maintained by the lab.  
4. 
Who will have access to the data or specimens. 
The Lead Researcher will designate a Research Manager to 
serve as the Saliva Sample Collection Coordinator for this 
project. This person will be the only one to have access to the 
samples, and will be responsible for transcribing the results 
into the REDCap project. The Lead Researcher will serve as 
backup to this Coordinator if he/she is unable to fulfill these 
duties. 
5. 
Who is responsible for receipt and transmission of the data 
or specimens. 
The Lead Researcher and the Research Manager designated to 
serve as the Saliva Sample Collection Coordinator will be 
responsible for receipt and transmission of data or specimens, 
and transcription of results in REDCap. 
6. 
How data or specimens will be transported. 
The saliva sample collection kit is designed to collect and store 
samples at room temperature for up to 23 days. As such, 
regular mail or shipping methods (e.g., USPS, UPS, FedEx) 
will be used to transport specimens. 
16.6 Sharing of data or specimens. 
1. What data and/or specimens will be shared. 
No specimens will be shared with those outside the research 
team and testing laboratory. Self-report data, treatment 
utilization data, and biochemically confirmed abstinence data 
will be shared with other researchers in a fully deidentified 
manner via the BioLINCC repository (rather than directly to 
other researchers), under approved and fully executed data use 

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agreements (the BioLINCC RMDA), in accordance with the 
policy on resource sharing at NIH, the funder of this research. 
2. Identifiers.  
Data shared will be stripped of all identifiers and assigned a 
random ID code rather than remaining linked to participant 
identifiers in any way. 
3. Transmission. Data transfers will occur via secure means (e.g., 
SFTP, secure BOX) in accordance with University policy. 
4. The study will NOT share large-scale genomic data. 
5. Repository.  
The study will use the BioLINCC repository. 
6. Limitations on the sharing of data. 
Data will be shared with controlled access in BioLINCC for general 
research use, as allowed by the participant’s informed consent and 
Institutional Certification.. We will submit a future change of protocol 
to request Institutional Certification when we have draft materials 
(e.g., data dictonaries, explanation of coded variables) ready for 
submission to the BioLINCC repository.   
 
17.0 Provisions to Protect the Privacy Interests of Participants 
17.1 Steps to protect participants’ privacy interests. If any of the 
following apply, check the box for convenience: 
☑ Procedures will be performed in a private area where others 
cannot see the procedures being performed or overhear the 
conversation between subjects and researchers.  
☑ All members of the study team are up to date on their institutional 
HIPAA training. 
☑ The study is not collecting information that could pose 
legal or reputational risks to participants.  
 
Almost all study activities (apart from biochemical verification 
visits) will occur by phone. To protect participant privacy, 
study coordinators will encourage participants to move to 
private spaces during recruitment and study calls, and will offer 
to reschedule calls if participants are unable to do so. 
Biochemical verification tests will happen in private spaces, as 
well (CO tests will be conducted in private rooms and urine 
samples will be self-collected by participants in private 
restrooms, without staff observation).  
17.2 Sensitive information.  
The only sensitive information to be collected in the study is self-
reported use of cannabis. This information is needed to assess 
concurrent use of cannabis that may influence smoking cessation 
success and to interpret carbon monoxide and cotinine tests that 

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could be influenced by use of combustible cannabis (in the case of 
CO) and use of cannabis in tobacco leaf wrappers (in the case of CO 
and cotinine).  
17.3 Steps to make the participants feel at ease. 
Collection of sensitive information about subjects will be limited to 
the amount necessary to achieve the aims of the research and to 
interpret biochemically verified abstinence data correctly. 
Participants will be informed that they have the right to decline to 
answer any question they prefer not to answer, without penalty or 
punishment, and that the study has a Certificate of Confidentiality.  
17.4 Authorized access to UW Health records. 
UW Health records will be accessed to identify patients eligible for 
tobacco treatment outreach by the UW-CTRI team only with 
authorization from UW Health. UW Health EHR and Cancer 
Registry data of identified potentially eligible patients who did not 
actively decline study participation will be extracted and de-
identified to examine the representativeness of the patients who 
enrolled in the CET. A list of the specific data elements is available 
in a protocol supplement document. 
In the CET, participants will provide informed consent for UW-
CTRI study coordinators to coordinate care with their care teams in 
Health Link (i.e., to give providers an opportunity to review and 
disapprove study medications prior to their dispensing, and to update 
patient medication lists to reflect study medications dispensed).  This 
will be covered during the informed consent process. UW Health 
records of CET participants will be accessed and EHR data and 
Cancer Registry data will be extracted to examine preliminary 
treatment utilization, complications, clinical outcomes, and cost-
effectiveness. A list of the specific data elements is available in a 
protocol supplement document. 
 
18.0 Sharing of Results  
18.1 Result sharing with participants or others. 
The only results that will be shared with participants will be CO test 
results, as these results are available immediately upon testing. Study 
coordinators collecting CO samples will congratulate patients whose 
CO tests indicate abstinence from combustible products, and will 
explore sources of exposure to CO (e.g., passive smoke exposure, 
car exhaust, improperly vented or malfunctioning equipment) among 
those whose expired breath contains more than 5 parts per million 
CO. Urine cotinine and salivary cotinine testing results will not be 

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available immediately (urine testing takes at least 15 minutes, saliva 
samples need to be shipped for testing). These results will not be 
captured in participants’ health records, as they capture abstinence at 
a particular time (in the past 1-2 days for CO, and in the past 1-2 
weeks for cotinine), and should not be used to influence ongoing 
healthcare. 
18.2 Plans to share study results with the public. 
Aggregate results from this research will be shared with the 
scientific community and our research collaborators. The findings 
from this research will also be shared upon request with study 
participants.   
19.0 Data and Specimen Banking 
19.1 Data and/or specimens banking for future use. No study 
specimens will be banked for future uses outside of the currently 
described protocol.  Study data and records will be de-identified and 
archived per record retention policy. Fully deidentified/anonymized 
data will be stored for 7 years in case replication, follow-up, or 
sensitivity analyses are necessary.  
19.2 Data to be stored. Data to be stored for additional analyses 
consistent with the original study purpose described to participants 
will be fully deidentified and anonymized and will include EHR-
derived data on smoking status, demographics (in broad categories), 
and REDCap data on smoking cessation treatment utilization, 
experiences, and abstinence. Data from qualitative interviews will be 
anonymized transcripts and thematic codes and sample quotes.  
19.3 Procedures to release data. Data will only be shared under the 
auspices of an approved and executed Data Use Agreement, in 
accordance with university regulations. 
19.4 Participant withdrawal of banked data/specimens from future 
research use. CET participants will not be able to withdraw data 
from the repository, as it will be fully anonymized and it will no 
longer be possible to withdraw data from a particular individual due 
to the lack of identifiers in the data. 
 
 
20.0 Study Analysis 
20.1 Statistical Hypotheses. 
The primary hypothesis to be tested for Aim 1 is that at least 12% of 
eligible adult patients who have cancer and smoke cigarettes and are 
referred to the tobacco treatment outreach team will initiate an 

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evidence-based form of smoking treatment (either Wisconsin 
Tobacco Quit Line care or treatment offered in the CET).  
The primary hypothesis to be tested for Aim 2 is that more-intensive, 
cancer-specific smoking cessation treatment will increase the log 
odds of achieving 7-day abstinence 6 months after a target quit date 
by at least 50% over the comparator condition (predicted odds ratio 
>=1.50 in this superiority comparison). 
Secondary hypotheses include the following: 
For Aim 3, we hypothesize that the majority (>=50%) of patients 
assigned to each condition will initiate treatment and will receive at 
least some counseling and use at least some of the provided 
medication. We expect retention, adherence, and satisfaction with 
treatment to be higher in the enhanced treatment relative to standard 
care. We anticipate that the more intensive, enhanced treatment, 
although more costly, will be cost-effective in terms of the 
incremental cost effectiveness ratio per additional patient who quits 
smoking, relative to the comparator condition and to other 
preventive health interventions. For these superiority hypotheses, the 
null hypotheses are that the two treatments are equally acceptable 
and efficient. 
For Aim 4, we expect to elicit information that will help us better 
communicate with and support patients eligible for tobacco 
treatment outreach and CET counseling by learning more about the 
experiences and perspectives of people who have had cancer. 
For Aim 5, we expect treatment reach to be especially high among 
historically undertreated populations (including African-American, 
Medicaid-eligible patients, and those from disadvantaged 
neighborhoods), and for the effects of enhanced treatment (vs. 
standard care) to be similar across patient subgroups. Thus, we are 
anticipating superior reach in historically underserved patient 
groups, and equivalent effectiveness across patient groups.  
 
20.2 Sample Size Justification. 
In this pilot study, we seek to demonstrate the feasibility and acceptability of 
the proactive outreach model as a way to enhance the reach of smoking 
treatment, and as a feasible way to recruit participants for a CET of 
enhanced vs. standard smoking cessation treatment. We also hope to 
generate estimates of enhanced vs. standard treatment effects on 
biochemically verified 7-day point-prevalence abstinence rates 6 months 
after a target quit date (primary outcome) and other abstinence measures 
(e.g., self-reported prolonged and point-prevalence abstinence 3 and 6 
months post-quit). As such, we selected a sample size of 50 to generate 
stable estimates of the size of treatment effects on these outcomes and costs, 

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and to permit exploration of differences in treatment effects by sex, race, 
ethnicity, and disadvantage. A sample of 50, while too small to sensitively 
test for moderate treatment benefits, is sufficient to pilot test all study and 
treatment procedures and to yield informative effect estimates that will 
guide a future, full-scale CET of standard and enhanced care.  
 
The primary outcome will be analyzed in an intent-to-treat analysis in which 
all randomized participants are included, and missing cases are assumed to 
be non-abstinent. This will be supplemented by sensitivity analyses that 
again use the full sample of randomized participants to examine robustness 
of results across different assumptions regarding missingness. Multiple 
imputation will not be used in this pilot project.  
 
For the qualitative study, we will recruit as many participants as we can 
until we reach thematic saturation in qualitative data coding. We anticipate 
that this will occur with fewer than 32 participants.  
 
20.3 Participant Population(s) for Analysis. 
We will examine reach of the treatment by computing the proportion of all 
participants meeting inclusion criteria for proactive tobacco outreach who 
were referred to WTQL, referred to their PCP, and the proportion who were 
screened for, eligible for, and enrolled/randomized in the CET. As such, the 
pool of participants for Aim 1 includes everyone eligible for inclusion on at 
least 1 CRDS report that guides proactive tobacco treatment outreach. The 
pool of participants included in Aims 2, 3 and 5 will comprise all 
participants who were randomized to treatment in the CET. The pool for 
Aim 4 will include all participants who participated in a qualitative 
interview. 
 
20.4 Statistical Methods. 
Descriptive statistics will be used to characterize smoking treatment reach 
(the proportion of eligible patients who initiate any smoking cessation 
treatment, and the proportion who enroll in the CET. These rates will be 
computed overall, and by patient subpopulation.  
 
Logistic regression will be used to estimate the effects of treatment 
condition on binary outcome data (e.g., abstinence, side effects), overall and 
by patient subgroups (i.e., moderation effects).  Odds ratios and numbers 
needed to treat will be computed to estimate treatment effect sizes.  
 
Analyses of variance will be used to examine condition effects on 
continuous variables such as ratings of treatment satisfaction, burden, and 
treatment effects on ratings of patient experiences and candidate treatment 
mediators (e.g., withdrawal). Treatment effect sizes will be computed. Cost-
effectiveness will be calculated based on the incremental cost-effectiveness 

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ratio of enhanced treatment versus standard treatment per each additional 
case of abstinence.  
 
Thematic analysis of qualitative interview will identify themes that emerge 
in patient interviews in the following areas: cancer experiences, supportive 
care outreach, tobacco history, and tobacco treatment.  
 
20.5 Planned Interim Analysis.  
No formal inferential interim analyses are planned for this pilot study, but 
safety data will be examined on an on-going basis to determine if individual 
participants are at risk or if any treatment element or condition is exerting an 
iatrogenic effect. If any meaningful evidence of this is detected the DSMC 
will be consulted along with the IRB to consider study discontinuation or 
changes. If any danger is deemed likely and significant the study will be 
immediately suspended.  
 
20.6 Handling of Missing Data. The intent-to-treat principle will be applied to 
primary analyses. Patients who do not initiate smoking treatment via a UW-
CTRI study coordinator will be assumed to not have initiated treatment. In 
analyses of abstinence, cases who do not report abstinence and provide 
biochemical evidence of abstinence will be coded as still smoking in 
primary analyses. This will be supplemented by sensitivity analyses to 
estimate treatment effects under different assumptions regarding missing 
data (e.g., if 10%, 20% or 30% of people without verified abstinence are 
abstinent).  
 
21.0 Potential Benefits to Participants 
21.1 
Potential benefits.  
Every participant who uses tobacco in the study will be given information 
about ways to access evidence-based treatment to help them stop smoking 
and will be given access to that treatment at no direct personal cost (apart 
from possible telephone charges for telephone-delivered care such as 
cessation counseling). UW-CTRI study coordinators will proactively offer 
smoking treatment options to patients, including tobacco quitline services 
(the Wisconsin Tobacco Quit Line for Wisconsin residents), referral back 
to their healthcare teams, or either standard or enhanced treatment in the 
CET (as randomly assigned). Given the known efficacy of brief smoking 
counseling and medication (offered by both tobacco quitlines and the 
CET) and the known benefits for quitting smoking for patients with cancer 
(NCI, 2022), offering to connect patients with cancer who smoke to 
evidence-based smoking treatment can benefit them. Patients who enter 
the CET will be offered, at minimum, 2 weeks of nicotine replacement 
therapy, 3 proactive individual counseling calls, information regarding the 
Wisconsin Tobacco Quit Line (which also offers individual counseling, 2 
weeks of free pharmacotherapy, and digital and remote group support) and 

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the NCI-sponsored SmokefreeTXT program. This exceeds the current 
standard of care at UW Health (referral to the Wisconsin Tobacco Quit 
Line). Some participants will be randomly assigned to receive 7 individual 
sessions and 12 weeks of varenicline. As such, all patients will have 
access to both pharmacotherapy (if medically appropriate for them) and 
counseling, whether they enter the CET or elect standard treatment.  
 
For patients who participate in the qualitative interviews and who do not 
use tobacco, there will be no benefits of participation. 
 
 
22.0 Risks to Participants 
22.1 Risks. 
This project poses minimal risk to participants, as it provides only 
FDA-approved, evidence-based smoking cessation treatment to 
patients who continue to smoke after cancer diagnosis, and involves 
minimal risk assessments procedures (providing self-report data and 
possibly a breath, urine, or saliva sample for biochemical 
verification of abstinence).  
The chief risks to participants include:  
• Side effects from medications 
o Nicotine patches can cause skin irritation at the site of 
application, vivid dreams, and insomnia. Severe 
allergic reactions are also possible. 
o Common sides effects of varenicline include nausea 
and sleep disturbances. Some people taking 
varenicline may experience negative moods. 
Varenicline may also be associated with a small 
increase in the risk of heart problems in people with 
heart and blood vessel disease. Rare allergic reactions 
or skin reactions may occur.   
• Psychological discomfort or nicotine withdrawal symptoms. 
This may occur if participants reduce or quit smoking, and 
could include negative moods, cigarette cravings, difficulty 
concentrating, hunger, and problems sleeping. Psychological 
distress may also be triggered by talking about cancer and 
cancer care experiences during qualitative interviews. 
• Loss of privacy or breach of confidentiality. Although we 
will not collect sensitive information about participants (apart 
from cannabis, alcohol, and tobacco use), there is still a risk 
that participant information may become known to someone 

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not involved in the study, and that this could have negative 
social or economic consequences for participants.  
22.2 Risks associated with participants delaying, being withdrawn 
from, or being asked to forgo standard treatment to participate 
in the study.  
All patients will have access to evidence-based smoking cessation 
treatment at no cost (through their primary care provider, oncology 
care team, a state quit line that offers evidence-based cessation 
treatment at no cost to callers), or to no-cost treatment through the 
CET. Receiving treatment is not contingent on consenting to this 
study. To ensure that smoking treatment does not interfere with 
ongoing cancer care, oncology clinicians will have the opportunity to 
review and disapprove medications for patients in the CET. It is also 
important to note that all participants will have the ability to decline 
or withdraw from the study and any study activities at any time 
without jeopardizing access to standard treatment. 
22.3 Currently unforeseeable risks. The minimal risk study procedures 
are unlikely to pose unforeseeable risks to participants. 
22.4 Risks to an embryo or fetus. Medications will not be dispensed to 
people who are pregnant. Smoke cessation counseling poses no risks 
to embryos or fetuses, whereas continued smoking poses known 
risks to fetuses. 
22.5 Risks to others who are not participants. Study procedures pose 
no risks to people in participants’ lives. 
22.6 Strategies to minimize risks of harm or discomfort. Study 
procedures are designed to protect patient choice and safety, and to 
ensure that people with impaired decision making will not receive 
proactive outreach or enrolled in the CET. Participants reached in 
proactive outreach attempts will be presented standard care options 
alongside the CET study invitation to protect patient autonomy and 
choice. Only those who understand and speak English will be 
eligible for the CET, to ensure they can ask questions and understand 
study information before and during study enrollment. To protect 
participant safety, screenings for the CET will exclude people with 
serious mental illness, recent suicidal behavior, and current suicidal 
ideation to reduce the risk of psychological distress among 
participants. Study medications will be dispensed only to people who 
pass inclusion/exclusion criteria screening and whose clinicians do 
not deny approval for the medications.  Study procedures to monitor 
adverse events and safety and to protect participant privacy and 
confidentiality are described elsewhere in this protocol. 
 

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23.0 Provisions to Monitor the Data to Ensure the Safety of 
Participants 
 
23.1 Describe: 
1. 
Data review. 
The Lead Researcher (McCarthy) will be responsible for 
routinely monitoring study progress and participant safety, and 
will report on this to the independent Data and Safetry 
Monitoring Committee (DSMC) at least twice per year. The 
existing UW-CTRI DSMC is chaired by Dr. James Cleary, 
Director of Supportive Oncology, Department of Medicine, 
Indiana University, and Simon Cancer Center, Indiana 
University School of Medicine. Dr. Cleary is an experienced 
physician and clinical trial researcher with no involvement in 
any of the proposed research activities. Dr. Cleary is joined on 
the DSMC by Dr. James Sosman and Dr. Burke Richmond. Dr. 
Sosman is an Associate Professor of Medicine and the Medical 
Director of the HIV/AIDS Comprehensive Care Program at 
UW Hospital and Clinics who previously collaborated on a 
clinical trial of smoking cessation with UW-CTRI, but has no 
role in the proposed research. Dr. Richmond is an 
otolaryngologist who served on independent DSMCs for Phase 
II and III trials involving a nicotine vaccine who also has no 
direct involvement in the proposed research. UW-CTRI has an 
adverse event monitoring protocol and team in place and will 
alert the study Lead Researcher to adverse events among study 
participants who receive smoking cessation treatment in the 
CET. Any data safety concerns will be reported to the Lead 
Researcher immediately and addressed. The Lead Researcher 
will meet with the study team no less often than monthly to 
discuss study procedure safety. We will report any 
unanticipated problems to the IRB promptly.  
 
Study investigators will notify NIH and the University of 
Wisconsin IRB in a timely manner (consistent with IRB and 
NIH policies) of the occurrence of any SAE or any AE which 
is severe, unexpected, and possibly related to study medication 
or protocol. Any adverse, study-related events that emerge 
during the study will be assessed fully and reported. If an SAE 
might be related to study drug use, both the Food and Drug 
Administration (FDA) and the manufacturer will be notified 
within 5 days of investigators becoming aware of the event. 
Examples of SAEs would be untoward medical or intervention 
occurrences that result in death, are life-threatening, require 
hospitalization or prolonging of existing hospitalization, create 

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persistent or significant disability/incapacity, or involve 
congenital abnormality/birth defects. Unanticipated problems 
will be monitored and reported to the DSMC. The assessment 
of adverse events will occur via phone calls at all study 
contacts that occur after the initiation of treatment (study 
contacts 2 through 11).  Adverse events 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 an 
unanticipated problem. All study-related adverse events will be 
assessed in a timely manner so that NIH, FDA, and the IRB 
may be notified, as needed. Adverse event assessment, 
recording, reporting, and investigation will be accomplished 
through staff training, structured/standardized assessments of 
untoward occurrences/events, and regular monitoring by the 
study team. Also, any adverse event that affects the patient’s 
ability to receive cancer therapy will be reported to his or her 
oncologic care team as soon as possible. The Lead Researcher 
and PI has ultimate responsibility for ensuring that SAEs are 
reported in a timely manner. Additionally, the IRB will receive 
an annual report of all SAEs and AEs meeting the criteria listed 
above. 
2. 
Safety data, untoward events, and efficacy data review. The 
study team will continuously monitor adverse event data 
collected using a standardized prompt in contacts 2-11 in the 
CET, and any adverse event data that come to light at other 
times (e.g., if a patient or oncologist reports a health event). 
The study team will review this information no less often than 
monthly and the DSMC will review these data at least twice 
per year. 
3. 
Safety data collection. Adverse event data will be collected 
during phone contacts and the final biochemical verification 
visit.  
4. 
Frequency of data collection. In the CET, safety data will be 
collected from study contact 2 (approximately 1 week prior to a 
participant’s target quit date) through the final study visit 
(study contact 11, approximately 6 months after the 
participant’s target quit date). 
5. 
Who will review the data. Safety data will be reviewed by the 
Lead Researcher, study physician, and the DSMC. 

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6. 
The frequency of review of cumulative data. The Lead 
Researcher and study team will review all adverse event data as 
they are collected. The study physician will review any adverse 
events that are unanticipated, severe, and possibly related to 
study procedures, and all serious adverse events among CET 
participants, as they occur. The DSMC will review cumulative 
data no less than twice per year. 
7. 
Analyzing safety data. Given the modest sample size in this 
pilot study, we will focus on effect sizes rather than tests of 
significance when comparing adverse event rates in the two 
CET conditions. Any unanticipated or serious adverse events in 
either condition will be thoroughly assessed and examined.  
8. 
Conditions that trigger immediate suspension of the 
research. The CET will be suspended immediately if data 
suggest there are unanticipated, severe problems associated 
with treatment in the CET. The NIH will be notified within 5 
days if the PI deems it necessary to suspend the study. In the 
case of a temporary suspension, the PI will develop a plan for 
continuation of the study and discuss this plan with NIH in a 
reasonable time frame. 
9. 
How the study team will adhere to reportable event 
reporting requirements. Any reportable events that are 
unexpected, immediately life-threatening or severely 
debilitating, and probably caused by study medication will be 
reported within 1 business day. If new information about study 
medication risks that was not previously known to investigators 
or participants is discovered, investigators will prepare a 
change of protocol with revised study documents or withdraw 
affected drugs from the protocol within 14 business days. 
Likewise, the research team will report to the IRB within 14 
business days any of the following: failures to obtain properly 
informed consent for the CET; dosing errors in medication 
dispensing; unexpected harms to participants or others that are 
probably related to the study procedures; noncompliance that 
could affect participants’ rights, welfare, or safety; reportable 
audit findings; breach of confidentiality; failure to suspend 
study activities during a participant’s known incarceration; and 
unresolved participant complaints. Breaches of confidentiality 
of PHI will also be reported to the HIPAA privacy officer.    
 
24.0 Economic Burden to Participants 
24.1 Costs to participants. 

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The only costs that participants may incur are cell-phone charges for 
minutes spent on phone calls for Wisconsin Tobacco Quit Line (WTQL) 
services, qualitative interviews, or CET counseling or assessment calls. 
Participants may incur co-pays if they elect to receive smoking cessation 
support from their healthcare team, rather than WTQL or CET treatment. 
 
25.0 Resources Available 
 
Will the research be conducted outside 
School of Medicine and Public Health or 
UW Hospitals and Clinics (e.g. the 
researcher does not have an SMPH 
research feasibility attestation for this 
study)?    
☐ YES (complete 25.1) 
☑ NO (remove text below, but retain this 
section) 
 
25.1 Resources available to conduct the research. 
1. 
Recruitment. There are more than 600 living patients with 
head and neck cancer and more than 800 patients with prostate 
cancer who use tobacco receiving care at UW-CCC. Given 
this, it is feasible to recruit 50 patients with cancer who use 
tobacco in to the CET, even if only head and neck and prostate 
cancer clinic patients are recruited. To increase the likelihood 
of recruiting enough people with a history of cancer to achieve 
the aims of the qualitative interviews (maximum 32), those 
without a tobacco use history will also be included.  
2. 
Timeline. We anticipate completing recruitment within 2.5 
years and all data collection within 3 years.  
3. 
Facilities. We have sufficient private office space, secure and 
HIPAA-compliant computing infrastructure, computer 
workstations, and telephone equipment needed to conduct the 
proactive tobacco treatment outreach and the CET counseling 
sessions proposed. We also have locked medication storage 
areas and space and equipment needed to prepare participant 
mailings, including medication mailings, and to conduct 
quality assurance checks on all such mailings. We also have 
private exam rooms for collecting CO samples and a specially 
equipped private bathroom for collecting and cotinine-testing 
urine samples. We have locked cabinet space to store saliva 
samples in need of testing. 
4. 
Medical or psychological resources. A study physician (Brian 
Williams, MD) and psychologist (Danielle McCarthy, Ph.D.) 
will be available to follow-up with participants who experience 

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adverse events of a medical or psychological nature, 
respectively.  
5. 
Process to ensure that all persons assisting with the 
research are adequately informed throughout the study. All 
persons assisting in the research will be informed about the 
protocol during the informed consent process. The oral consent 
process will be supplemented by written information regarding 
the CET. Study personnel who obtain informed consent from 
participants will be trained to mastery of the protocol before 
consenting any participants. They will be guided through the 
oral consent process by a thoroughly tested REDCap database 
that will prompt each step in the consent process, and 
document completion of each step (with timestamping and 
change logging). Thorough quality assurance processes will 
ensure that consent processes are followed as per protocol. 
 
26.0 Multi-Site Research 
Not applicable. 
 
27.0 References 
American Cancer Society (ACS). Cancer facts & figures 2021. 
https://www.cancer.org/content/dam/cancer-org/ 
research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2021/ 
cancer-facts-and-figures-2021.pdf. Accessed July 4, 2023. 
Borger T, Shelton BJ, Valentino J, Ostroff JS, Cummings KM, Studts JL, Carpenter MJ, 
Burris JL. A Daily Assessment Study of Smoking Cessation After a Head and Neck 
Cancer Diagnosis. Nicotine Tob Res. 2022 Oct 26;24(11):1781-8.  
Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking 
cessation: an overview and network meta-analysis. Cochrane Database Syst Rev. 2013 
May 31;2013(5):CD009329.  
Cooley ME, Poghosyan H, Sprunck-Harrild K, Winickoff JP, Edge SB, Emmons 
KM. Tobacco treatment implementation within 28 commission on cancer 
accredited programs in the Northeast region of the USA: a pilot study. Transl 
Behav Med. 2018;8(5):706-13. 
Crawford G, Weisbrot J, Bastian J, Flitter A, Jao NC, Carroll A, Kalhan R, Leone F, 
Hitsman B, Schnoll R. Predictors of varenicline adherence among cancer patients treated 
for tobacco dependence and its association with smoking cessation. Nicotine Tobacco 
Res. 2019 Aug;21(8):1135-9.  
Creswell PD, McCarthy DE, Trapskin P, Sheehy A, Skora A, Adsit RT, Zehner ME, 
Baker TB, Fiore MC. Can inpatient pharmacists move the needle on smoking cessation? 

PROTOCOL TITLE: Comparative Effectiveness Trial of Tobacco Cessation Treatments 
among Cancer Patients who Smoke  
 
 
Page 64 of 66 
Template Revised: February 2, 2023 
Evaluating reach and representativeness of a pharmacist-led opt-out smoking cessation 
intervention protocol for hospital settings. Am J Health Syst Pharm. 2022 Jun 
7;79(12):969-78. 
Croyle RT, Morgan GD, Fiore MC. Addressing a core gap in cancer care—the 
NCI moonshot program to help oncology patients stop smoking. N Engl J Med. 
2019;380(6):512-5.  
D’Angelo H, Webb Hooper M, Burris JL, Rolland B, Adsit R, Pauk D, Rosenblum M, 
Fiore MC, Baker TB. Achieving equity in the reach of smoking cessation services within 
the NCI Cancer Moonshot-funded Cancer Center Cessation Initiative. Health Equity. 
2021;5(1):424-430. PMCID: PMC8237098 
D'Angelo H, Hohl SD, Rolland B, Adsit RT, Pauk D, Fiore MC, Baker TB. Reach and 
effectiveness of the NCI Cancer Moonshot-funded Cancer Center Cessation Initiative. 
Transl Behav Med. 2022 May 26;12(5):688-692. PMCID: PMC9154282. 
Day AT, Tang L, Karam-Hage M, Fkhry C. Tobacco treatment programs at 
National Cancer Institute-designated cancer centers. Am J Clin Oncol. 
2019;42(4):407-10.  
Duffy SA, Ronis DL, Valenstein M, Lambert MT, Fowler KE, Gregory L, Bishop C, 
Myers LL, Blow FC, Terrell JE. A tailored smoking, alcohol, and depression intervention 
for head and neck cancer patients. Cancer Epidemiol Biomarkers Prev. 2006 
Nov;15(11):2203-8.  
Gritz ER, Talluri R, Domgue, JF, Tami-Maury I, Shete S. Smoking behaviors in 
survivors of smoking-related and non-smoking-related cancers. JAMA Netw Open. 
2020;3(7):e209072.  
Gritz ER, Talluri R, Fokom Domgue J, Tami-Maury I, Shete S. Smoking Behaviors in 
Survivors of Smoking-Related and Non-Smoking-Related Cancers. JAMA Netw Open. 
2020 Jul 1;3(7):e209072. 
Leone FT, Zhang Y, Evers-Casey S, et al. Initiating pharmacologic treatment in tobacco-
dependent adults. An official American Thoracic Society Clinical Practice Guideline. Am 
J Respir Crit Care Med. 2020; 202:e5-e31. 
McCarthy DE, Baker TB, Zehner ME, Adsit RT, Kim N, Zwaga D, Coates K, 
Wallenkamp H, Nolan M, Steiner M, Skora A. A comprehensive electronic health record-
enabled smoking treatment program: Evaluating reach and effectiveness in primary care 
in a multiple baseline design. Prev Med. 2022 Dec 1;165:107101. 
National Cancer Institute. Treating Smoking in Cancer Patients: An Essential 
Component of Cancer Care. National Cancer Institute Tobacco Control 
Monograph 23. Bethesda, MD: U.S. Department of Health and Human Services, 
National Institutes of Health, National Cancer Institute; 2022. 

PROTOCOL TITLE: Comparative Effectiveness Trial of Tobacco Cessation Treatments 
among Cancer Patients who Smoke  
 
 
Page 65 of 66 
Template Revised: February 2, 2023 
National Comprehensive Cancer Network. Smoking Cessation (Version 2.2022). 
https://www.nccn.org/professionals/physician_gls/pdf/smoking.pdf. Accessed March 7, 
2023. 
Park ER, Perez GK, Regan S, Muzikansky A, Levy DE, Temel JS, et al. Effect of 
sustained smoking cessation counseling and provision of medication vs shorter-term 
counseling and medication advice on smoking abstinence in patients recently diagnosed 
with cancer: a randomized clinical trial. JAMA. 2020;324(14):1406-18.  
Peters EN, Torres E, Toll BA, Cummings KM, Gritz ER, Hyland A, et al. 
Tobacco assessment in actively accruing National Cancer Institute cooperative 
group program clinical trials. J Clin Oncol. 2012;30(23):2869-75.  
Piper ME, Cook JW, Schlam TR, Jorenby DE, Smith SS, Collins LM, Mermelstein R, 
Fraser D, Fiore MC, Baker TB. A randomized controlled trial of an optimized smoking 
treatment delivered in primary care. Ann Behav Med. 2018 Sep 13;52(10):854-864. 
PMCID: PMC6135958. 
Price SN, Studts JL, Hamann HA. Tobacco use assessment and treatment in cancer 
patients: A scoping review of oncology care clinician adherence to clinical practice 
guidelines in the U.S. Oncologist. 2019;24(2):229-238.  
Ramaswamy AT, Toll BA, Chagpar AB, Judson BL. Smoking, cessation, and cessation 
counseling in patients with cancer: A population-based analysis. Cancer. 2016 Apr 
15;122(8):1247-53.  
Rettig EM, Fakhry C, Hales RK, Kisuule F, Quon H, Kiess AP, Yin LX, Zhang Y, 
Blackford AL, Drummond MB, Gourin CG. Pilot randomized controlled trial of a 
comprehensive smoking cessation intervention for patients with upper aerodigestive 
cancer undergoing radiotherapy. Head Neck. 2018 Jul;40(7):1534-47.  
Schnoll R, Leone F, Veluz-Wilkins A, Miele A, Hole A, Jao NC, et al. A placebo-
controlled randomized clinical trial testing the efficacy and safety of 24-weeks of 
varenicline to treat nicotine dependence among cancer patients. Psychooncology. 
2019;8:561-9.  
Schnoll RA, Martinez E, Tatum KL, Weber DM, Kuzla N, Glass M, et al. A bupropion 
smoking cessation clinical trial for cancer patients. Cancer Causes Control. 
2010;21(6):811-20.  
Sharp L, McDevitt J, Carsin AE, Brown C, Comber H. Smoking at diagnosis is an 
independent prognostic factor for cancer-specific survival in head and neck cancer: 
Findings from a large, population-based study smoking and head and neck cancer 
survival. Cancer Epidemiol Biomarkers Prev. 2014 Nov 1;23(11):2579-90.  
Sheeran P, Jones K, Avishai A, Symes YR, Abraham C, Miles E, et al. What works in 
smoking cessation interventions for cancer survivors? A meta-analysis. Health Psychol. 
2019;38(10):855.  

PROTOCOL TITLE: Comparative Effectiveness Trial of Tobacco Cessation Treatments 
among Cancer Patients who Smoke  
 
 
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Template Revised: February 2, 2023 
U.S. Department of Health and Human Services (USDHHS). The health 
consequences of smoking: 50 years of progress. A report of the Surgeon General. 
Atlanta: U.S. Department of Health and Human Services, Centers for Disease 
Control and Prevention, National Center for Chronic Disease Prevention and 
Health Promotion, Office on Smoking and Health; 2014. 
 
28.0 Appendices 
Not applicable.