Centralized Health System Interventions to Enhance Reach: A Factorial Screening Experiment
Phase: PHASE4
Conditions: Smoking, Cigarette, Smoking Cessation
Sponsor: University of Wisconsin, Madison

 
 
          
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Study Protocol 
 
Official Title: Health Systems Reach Interventions Project 
 
NCT Number: NCT04199117 
 
Document Date: 10/12/2023 
 

 
 
          
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Title: Research Plan and Protocol: Breathe 2 Project 2: Centralized Health System Interventions 
to Enhance Reach: A Factorial Screening Experiment (HS Reach Interventions) 
 
Principal Investigator: Danielle E. McCarthy (University of Wisconsin School of Medicine and 
Public Health, Department of Medicine, Center for Tobacco Research and Intervention) 
 
Protocol Version: October 12, 2023 
 
Funding Sponsor: National Cancer Institute, National Institutes of Health, Grant 2P01CA180945 
 
 
 

 
 
          
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Research Plan and Protocol: Health System Reach Interventions Study 
 
August 2, 2021 Update:  Parts of the protocol pertaining to provision of varenicline to 
participants randomly assigned to have access to intensive treatment will be modified due to 
recent problems with the supply of varenicline.  These problems are related to the recent 
discovery of a novel nitrosamine, N-nitroso-varenicline, at levels above the recommended FDA 
acceptable daily intake (ADI) threshold for human drugs.  Although this novel nitrosamine is not 
known to be carcinogenic, it is being treated as a possible carcinogen similar to other complex 
nitrosamines. This prompted the manufacturer of varenicline (Pfizer) to recall several lots of 
varenicline in which the novel nitrosamine exceeded their ADI level.  As of 7/22/2021, 
discrepancies between the FDA ADI (37 ng) and the ADI that Pfizer advocates and used as the 
basis of its voluntary recall (185 ng) have not been resolved. Details regarding this issue are 
provided in FDA alerts accessible at https://www.fda.gov/drugs/drug-safety-and-availability/fda-
updates-and-press-announcements-nitrosamine-varenicline-chantix.  
This issue prompted the investigators to suspend recruitment for the study beginning on June 
25, 2021 and to modify the protocol to ensure we do not dispense varenicline from lots that 
have not yet been tested to ensure they are at or below the acceptable daily intake (ADI) level 
for nitrosamines set by the FDA.  We are now seeking IRB approval to modify consent scripts 
and documents, and other scripts and letters pertinent to varenicline treatment, so we can 
resume study activities. At this time, we seek to resume recruitment, enrollment, intervention, 
and follow-up activities with modifications as noted below.   
We want to alert participants to the possible unavailability of varenicline due to a possible safety 
concern, as we will not dispense varenicline until we are sure that the medication we have in 
stock is below the FDA ADI.  That is, we will NOT resume dispensing varenicline to participants 
in this study until we are assured that the medication is within FDA guidelines for nitrosamines. 
The global pause on distribution of varenicline has caused shortages of the medication, so we 
may not be able to get new deliveries of varenicline known to be below the FDA ADI for some 
time (likely months).  To convey this to participants, scripts and letters that describe the 
treatments available to participants eligible for intensive treatment with varenicline (due to 
randomization and passing screening for intensive medication eligibility) will be amended to 
note that recent problems with the supply of varenicline due to a possible safety concern have 
occurred and that varenicline availability cannot be guaranteed. 
The one participant in the study who was dispensed varenicline prior to the June 2021 recall of 
varenicline has already been called and informed about possible exposure to nitrosamines in 
varenicline, and advised to stop using the medication. This participant will also be offered 
alternative treatment (combination NRT) because their varenicline treatment was disrupted, as 
described in CP012. 
I. 
SIGNIFICANCE 
Despite a large decline in smoking prevalence, 15% of US adults (~37 million people) continue 
to smoke1. Healthcare settings are excellent places to engage smokers in evidence-based care 
that can double or triple abstinence rates2, as most smokers (roughly 70%) visit primary care 
clinics each year2. Epidemiological and healthcare system data show that smoking cessation 

 
 
          
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interventions are rarely offered in healthcare settings, however3-16(<40% of patients report the 
being offered assistance quitting smoking, <15% report being offered follow-up for smoking by 
their primary care provider6,17). Long-term access to treatment and follow-up are critical to the 
treatment of tobacco use as a chronic, relapsing condition18,19. At the population level, only 
about 5% of smokers who try to quit use Public Health Service Guideline-recommended 
treatment each year (both counseling and pharmacotherapy20). Healthcare systems have 
unrealized potential to improve treatment reach markedly, given their existing intervention 
infrastructure. 
Healthcare systems are adopting care-management, population-health approaches to manage 
common chronic conditions (e.g., diabetes, hypertension)21-23, but still undertreat smoking24. 
Similar infrastructure, expertise, and personnel can be used to treat smoking as a chronic 
condition, however. Proactive approaches to promoting smoking cessation treatment and 
treating tobacco use as a chronic condition have shown promise in recent years18,19. Repeated 
proactive outreach to patients who smoke may be one good way to leverage the reach of 
healthcare systems among smokers to address the chief limitation on the impact of smoking 
treatments, their very low rates of use. Although researchers have explored ways to extend 
smoking treatment reach in healthcare25-28, rates of treatment use remain low29-32. Thus, there is 
a pressing need to effectively and efficiently increase smoking treatment reach in healthcare.  
Data support care management25,33-35, periodic telephone outreach36-38, and warm handoffs that 
immediately connect those interested in quitting with treatment39 as ways to enhance the reach 
of chronic disease management interventions, but we do not yet know which chronic 
interventions for smoking work best to connect smokers with evidence-based cessation 
treatment, alone or in combination (and which are to be avoided due to antagonistic 
interactions). We also do not yet know how can we best promote use of the most effective 
treatments (vs. less intensive cessation treatment). This project will address these questions 
and generate new data on healthcare system interventions that effectively and efficiently 
increase treatment reach among outpatients who smoke.  
This project will use a factorial experiment (Table 1) to test the main and interactive effects of 3 
centralized, healthcare system-delivered intervention components designed to enhance use of 
either standard care or more 
intensive, evidence-based 
cessation treatments. Standard 
care comprises referral to a toll-
free state tobacco quitline 
offering a starter kit of nicotine 
replacement therapy and a 
single proactive counseling call 
to all Wisconsin residents who 
smoke, and/or referral to a 
primary care provider for brief 
smoking cessation 
advice/counseling and 
medication. More intensive 
treatment comprises varenicline 
or combination nicotine 
replacement therapy (NRT) with 
three counseling calls. Access to 
more intensive treatment 
(among those who meet medical 
eligibility criteria for varenicline 
and/or combination NRT use) 
will be randomly assigned on a 
Table 1. Study Design: 2x2x2x2 Factorial Screening Experiment 
Participants: Adult daily smokers in primary care not willing to quit 
within the next 30 days 
• Experimental sample: Target sample size of 300 patients eligible 
to use C-NRT* and/or varenicline and willing to be randomized to 
4th factor below 
• ~416 patients eligible for neither C-NRT nor varenicline 
Intervention Components:  
1. Incentives ($40 for each 1st counseling call in up to 4 rounds of 
treatment over 2 years, maximum $160) vs. none 
2. Semi-annual automated, tailored mailed and electronic-health-record 
outreach promoting treatment vs. generic letters 
3. Semi-annual proactive telephone-delivered care management 
(outreach and motivational intervention) vs. none 
4. Access to intensive care (12 weeks of either C-NRT or varenicline, 
with 3 counseling calls) vs. standard care (counseling and 
medication from quitline and/or patient’s primary care provider)  
Outcome: Any use of smoking cessation treatment in the 1st year of 
enrollment and over 2 years of enrollment (primary) and abstinence 
(secondary) 
Final Product: Optimized reach interventions to promote smoking 
cessation treatment utilization that will be evaluated in an RCT 
*C-NRT= Combination Nicotine Replacement Therapy (patch + mini-lozenge) 

 
 
          
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4th experimental factor (see Table 1). The factorial design will allow us to determine how well 
each intervention (incentives for initiating smoking cessation treatment, automated tailored 
outreach via letter and electronic message, and proactive telephone-delivered care manager 
motivational support) works overall (i.e., the main effects), and to identify particularly promising 
combinations of reach-focused interventions for both standard and more intensive smoking 
cessation treatment (i.e., interaction effects) in real-world healthcare settings. The intervention 
components selected for this experiment target patients directly and can be implemented 
centrally and remotely by chronic care management specialists, with minimal disruption to 
routine clinical care. In this way, these patient-level interventions have strong potential for 
adoption and effectiveness in healthcare settings, as supplements to primary care efforts to 
address tobacco use. 
The proposed study was designed with dissemination in mind, and will be implemented in a 
pragmatic manner, but with appropriate controls to protect human subjects and permit strong 
inferences regarding the success and impact of the experimental manipulations. Overall, the 
objective is to conduct pragmatic and dissemination-ready research about effective, efficient, 
and acceptable ways to enhance the reach of stop-smoking treatments by enhancing access to 
and promotion of treatments. 
 
II. 
GOALS/AIMS 
 
This project will use an efficient 2x2x2x2 factorial design (Table 1) to identify reach-focused 
intervention components that either singly, or in combination, increase patient use of evidence-
based smoking cessation treatment over 2 years of availability and, by extending treatment 
reach, reduce smoking prevalence 2 years after enrollment. All adult patients who smoke daily, 
but who are not willing to enter smoking cessation treatment at the time of enrollment (the 
vast majority of smokers40) will be eligible to participate, with no obligation to quit smoking or 
use treatment. Participants (N=240-300) will be recruited in 4-12 primary care clinics in 2 
healthcare systems by system staff using an opt-out strategy41 to maximize inclusion and 
enhance dissemination and the generalizability of results. (Roughly 60 additional patients who 
do not meet eligibility criteria for intensive counseling and medication with either combination 
NRT or varenicline will be included in the study but will not be part of the experimental sample.) 
This will be the first factorial experiment in healthcare settings to test interventions designed to 
extend the reach of varied smoking cessation treatments in primary care patients who are not 
initially willing to make an aided quit attempt (see Table 1). This rigorous and efficient factorial 
design will address the following aims:  
Primary Aims 
1. To create an optimized reach intervention package by identifying intervention 
components that increase cessation treatment reach especially well, at low cost, at 1-year 
follow-up. 
2. To estimate the main and interactive effects of the intervention components on cumulative 
treatment reach over 2 years of treatment access.   
Secondary Aims  
1. To estimate the main and interactive effects of intervention components on abstinence at 2-
year follow-up. 
2. To identify the degree to which intervention component effects on 2-year abstinence are 
mediated by increases in cessation treatment reach.  
3. To assess the cost-effectiveness of intervention components in promoting reach and 
abstinence. 
4. To identify patient and clinic moderators of intervention component effects on reach and 
abstinence.  
 

 
 
          
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III. 
METHODS 
 
Design Overview. In this factorial experiment (see Table 1), participants (not willing to enter 
cessation treatment at the time of enrollment) recruited by phone after initial outreach or primary 
care visits in or telemedicine appointments with participating clinics in UW Health and 
AdvocateAurora Health will be screened, consented, and randomized over the phone to one of 
16 conditions resulting from the crossing of the 4 experimental factors in this 2 (incentives on vs. 
off) x 2 (tailored vs. generic outreach letters) x 2 (care manager calls on vs. off) x 2 (access to 
intensive treatment on vs. off) design. Participants who request treatment for smoking cessation 
over the next 2 years will do so through a Tobacco Care Manager who will coordinate referrals 
to a tobacco quitline (the Wisconsin Tobacco Quit Line (WTQL) for Wisconsin residents) and/or 
the patient’s primary care provider, as preferred by the patient in the standard care conditions. 
Tobacco Care Managers will also coordinate scheduling with a UW-CTRI Health Counselor for 
intensive smoking cessation treatment. Participants will have access to either standard or 
intensive smoking cessation treatment for 24 months, and will receive outreach promoting 
smoking cessation twice per year from enrollment to 22 months post-enrollment. Participants 
will be asked to complete brief (10-20-minute) follow-up telephone interviews 6, 12, 18, and 24 
months after enrollment. Those claiming abstinence at the 12- and 24-month post-enrollment 
phone interviews will be asked to return to their primary care clinic to complete breath, urine, 
and/or saliva testing to verify abstinence from combustible tobacco. This will entail providing 
breath samples for carbon monoxide testing and/or a urine or saliva sample for immediate 
cotinine/anabasine testing (no samples will be stored). Participants may also be asked to collect 
a saliva sample at home and return it in the mail. If a participant sets a target stop-smoking date 
as part of a smoking cessation treatment episode (either standard or intensive treatment), the 
participant will be asked to complete telephone follow-up interviews 3, 12, and 26 weeks post-
target-quit-day, as well. Participation in the study will last 24 months (27 months maximum, if 
the person is not reached immediately for the final 24-month post-enrollment telephone follow-
up or visit). In addition, data on health status and healthcare utilization for participants who do 
vs. do not use stop-smoking treatment and quit smoking will be extracted from the EHR for up to 
1 year pre-enrollment, and 4 years post-enrollment to inform economic analyses for Aim 3 and 
moderation analyses for Aim 4.  
 
A. Recruitment, inclusion and exclusion 
 
Up to 2600 adult participants will be recruited from 4-12 participating primary care clinics over 6-
15 months. First, all patients who meet criteria for the smoking registry in the electronic health 
record (EHR) will be notified that the clinic is offering help in quitting smoking. The notification 
will be sent by mail and supplemented by secure EHR patient portal (e.g., MyChart) message 
just prior to the launch of recruitment in each clinic. This message is a way to let patients know 
that tobacco care management is starting, that treatments (study-related and standard care) for 
quitting smoking are available, and to give patients a way to opt out of future Tobacco Care 
Manager phone outreach. All study notifications will provide the name and number of a Tobacco 
Care Manager to contact if interested in quitting, and the number to call to opt out of future 
Tobacco Care Manager outreach. Tobacco Care Managers will be healthcare system 
employees who are also members of the study team who have completed all relevant human 
subjects research, HIPAA, and good clinical practice trainings and been added to the study 
team in ARROW.  
Second, all patients on the smoking registry or identified as current cigarette smokers at 
clinician visits (whether face-to-face, video visits, or telemedicine visits) at participating adult 
primary care clinics (which adds the patient to the smoking registry) will be told by clinic staff 
that they can expect a call from the care management outreach program within a few business 
days of their visit. All patients will have the right to opt out of such outreach. Medical Assistants 

 
 
          
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will be trained to record such patient requests to opt out in the EHR to suppress outreach at 
least until the next clinic visit or patient-initiated contact with the Tobacco Care Manager. 
Offering advice to quit smoking and assistance in quitting and follow-up are the current 
recommended standard of care in outpatient care. The introduction of the Tobacco Care 
Manager who will provide phone follow-up to all adult patients who smoke is new, however, and 
is not part of standard clinical practice and is new to this study. Although the Tobacco Care 
Manager role as the centralized means of offering smoking cessation treatment is new, the 
process of advising patients to quit, assessing interest in quitting, and offering assistance in 
quitting is the recommended standard clinical practice at UW Health, AdvocateAurora and 
elsewhere. In addition, posters about Breathe2 will be posted in clinics to encourage patients to 
talk to their primary care team about stop-smoking resources, including Breathe 2 studies. 
Next, a Tobacco Care Manager, who is a healthcare system employee, will make at least 3 
phone call attempts to reach each smoker (who did not opt out) beginning within 3 business 
days of the visit, at the patient telephone numbers in the EHR. When the Tobacco Care 
Manager reaches a smoker, s/he will explain that the healthcare system is reaching out to all 
smokers to offer support and resources to help them protect their health. The Tobacco Care 
Manager will advise all patients who smoke to quit, will let them know that s/he can offer help in 
quitting, and will ask if patients are interested in quitting within the next 30 days. If patients 
answer yes, they will be routed to cessation resources and invited to screen for a smoking 
cessation study (UWHSIRB Protocol #2019-0054) and will be ineligible for the Health System 
(HS) Reach Interventions Study described in the present protocol. Patients who are not ready to 
quit within 30 days will be given a brief description of this study and invited to complete a brief 
screening for the study (See uploaded Recruitment Call Script) for the following 
inclusion/exclusion criteria: 
Inclusion criteria for study participation: 
• 
Age > 17 years. 
• 
On smoking registry at a participating clinic 
• 
Smoked cigarettes every day in the past 30 days (with or without other forms of tobacco 
or nicotine). 
• 
Able to participate in informed consent activities (e.g., reports understanding the nature 
of the study and consent) 
• 
Able to speak and read English. 
Exclusion criteria for study participation: 
• 
Opted out of recruitment at the most recent clinic visit, or by patient-initiated contact. 
• 
Willing to quit smoking within the next 30 days at recruitment call (these patients are 
referred for treatment or invited to be in a cessation study IRB# 2019-0054). 
• 
Activated healthcare power of attorney or cognitive impairment that would preclude 
informed consent. 
Those who agree to and pass the screening for the inclusion/exclusion criteria for study 
participation will be asked to complete an oral consent and HIPAA authorization process next. 
Those who decline the screening invitation, do not meet eligibility criteria, or do not provide oral 
consent for study participation will be advised to quit smoking and offered standard smoking 
cessation treatment (referral to their primary care provider and/or to the Wisconsin Tobacco Quit 
Line or other tobacco quit line, as appropriate given state of residence).  
Those who consent to the study will then be asked to complete a baseline assessment, 
including screening for initial eligibility for intensive treatment medication regimen, as shown 
below. Of the up to 2600 participants in this study, we anticipate that up to 1800 (target N=300) 
will meet additional criteria for randomization to access to intensive treatment with either 
varenicline or combination nicotine patch and mini-lozenge treatment. To be randomized to 
intensive vs. standard treatment access, a participant needs to meet medical eligibility criteria 

 
 
          
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for one of the intensive treatments (varenicline or combination nicotine patch and mini-lozenge), 
not both. Those who are eligible for both will be able to choose which regimen they want to use 
to quit smoking (pending approval of that regimen by a primary care provider at the time 
treatment is requested). Initial inclusion/exclusion criteria for randomization to access to 
intensive treatment or standard care are: 
Inclusion criteria for access to intensive treatment (randomization on 4th factor):  
• 
Smoke at least 5 cigarettes per day on average for at least 6 months at enrollment. 
• 
Ability to meet screening criteria for one or both of the enhanced medication regimens, 
varenicline and/or combination NRT. 
Exclusion criteria for access to intensive treatment (randomization on 4th factor):  
• 
Among women with childbearing potential: pregnancy, breastfeeding, or unwillingness to 
use an approved method of birth control (these include: abstinence, condoms, 
diaphragm, birth control pills or injectable contraceptive (e.g., Depo-Provera), IUD, 
hysterectomy, tubal ligation, sterilization, vasectomy, or being more than 2 years post-
menopausal) while receiving study medication. This will be assessed via self-report at 
the time a participant requests intensive treatment and participants who report this will 
not be eligible for study-provided varenicline or combination NRT.In addition, Tobacco 
Care Managers will look for pregnancy indicators in the patient’s chart at the time a 
request is sent to the primary care provider to review patient eligibility for varenicline 
and/or combination NRT. If a Tobacco Care Manager sees that a patient is currently 
pregnant, s/he/they will not place the order. 
• 
Contraindications to both varenicline and nicotine patch and mini-lozenge. These 
contraindications are listed by agent below. To be excluded, a person would have to 
have a contraindication in both the 2nd and 3rd columns below. 
Table 2. Exclusion criteria for access to intensive treatment 
Contraindication 
Varenicline Nicotine patch 
& mini-
lozenge 
Severe renal disease 
X 
 
Allergic or severe adverse reaction to varenicline 
X 
 
Allergic or severe adverse reaction to nicotine patch 
 
X 
Allergic or severe adverse reaction to nicotine lozenges or 
mini-lozenges 
 
X 
Suicide attempt in past 10 years 
X 
X 
Current treatment for schizophrenia or a psychotic disorder 
X 
X 
 
Because we seek to evaluate interventions that will promote use of evidence-based treatment, 
and thereby abstinence from smoking, from the full range of adult daily smokers who are not 
immediately ready to quit, we will not exclude members of vulnerable populations, including 
pregnant women (for whom quitting smoking is an important goal for the health of both mother 
and child) or those on parole or probation (this will not be assessed, as it is not directly relevant 
to the study and does not materially alter the risk to benefit ratio of participation). Individuals 
who are in institutional living situations (e.g., in assisted living facilities) will also be eligible, if 
they are adults, smoke daily, present at the host clinics for primary care, and are considered 
competent to make healthcare decisions according to existing healthcare system protocols and 
procedures. Tobacco Care Managers will be trained to check this information and to only seek 
oral consent from those capable of providing fully informed oral consent.  
None of these vulnerable populations will be specifically targeted in recruitment. The proposed 
reach interventions, assessments, and compensation schedule should pose no more risk for 

 
 
          
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pregnant women, those on parole or probation, or those in institutionalized settings than for the 
general population, as study procedures confer minimal risk, are informational in nature, and are 
entirely voluntary. The risks of intensive treatment will be addressed in the informed consent 
process for those who agree to randomization to treatment intensity and are eligible for this 
(pregnant and breastfeeding women will be ineligible for intensive treatment).  
In addition, the compensation offered for completing assessments ($20 for the baseline 
assessment and $10-$20 for each semi-annual and post-cessation follow-up assessment (not 
counseling) call and $50 for 12- and 24-month post-enrollment visits for biochemical validation 
of abstinence from smoking), which is available to all enrolled participants, regardless of 
assigned experimental condition, are modest. Likewise, the incentives for completing an initial 
counseling session ($40) available to half the enrolled participants on the basis of random 
assignment to an incentive condition are modest and unlikely to be undue inducements to 
participation, even in vulnerable populations. Excluding members of these vulnerable 
populations is not warranted for their protection, would instead unjustly prevent their 
involvement in a minimal-risk program offering benefit (information about and the opportunity to 
connect with evidence-based smoking treatment at no personal cost, apart from telephone 
charges where applicable) to all participants. In addition, while the study does not target 
incarcerated individuals, some participants may be incarcerated during the period of study 
involvement. All study outreach, treatment provision, and assessment will be suspended during 
a participant’s period of incarceration.  
 
B. Consent 
 
For this study, a two-tiered consent process will be used. First, all prospective participants who 
meet inclusion criteria and who do not endorse exclusion criteria for study participation will be 
read an oral consent script by a healthcare system Tobacco Care Manager (see uploaded 
Recruitment Call script). The consent script read to participants over the phone conveys the key 
points regarding study procedures; risks; and participant rights, protections, and benefits in 
accessible, lay language. Prospective participants will be given an opportunity to ask questions 
and raise concerns during this process, which will be addressed prior to assessing participant 
consent to participate in the study. Informed consent for study participation will be formally 
documented electronically in a REDCap database. Following enrollment for those who consent, 
study staff will send out a letter in hard copy to the participant at the address provided (see 
uploaded Study Information Sheet). This letter will remind the participant of study procedures 
and will include a detailed study information sheet containing all required elements of informed 
consent and HIPAA authorization.  
 
For those participants randomized to intensive treatment access upon enrollment, their 
enrollment packet will also contain an Intensive Treatment Information Sheet (see upload) 
containing required additional elements of consent and HIPAA authorization relevant to 
intensive study treatment. This will serve as an additional resource for those participants who 
elect to initiate intensive smoking cessation treatment at some future point during the study.  
 
If and when a patient requests stop-smoking treatment, the Tobacco Care Manager or a UW-
CTRI staff member will go through the Treatment Initiation Screen and Consent script over the 
phone. Those randomly assigned to the standard care condition will be offered referral to the 
Wisconsin Tobacco Quit Line (WTQL) and/or referral to their primary care provider. Those 
randomly assigned to the incentive condition will be reminded that they can earn $40 by 
completing a first counseling call with the WTQL.  Participants randomized to standard care are 
free to choose whatever treatment the WTQL or their primary care providers recommend, or 
that they choose to pursue outside of the treatment study (e.g., over the counter medication). 

 
 
          
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For example, a participant randomized to standard care in the study who gets a prescription for 
varenicline from their primary care provider will still be retained in the study, but the medication 
will not be provided by the study (it will be accessed, and paid for, in the usual means in clinical 
practice).  
 
For those randomized to access to intensive treatment, the Tobacco Care Manager or UW-
CTRI staffer will obtain oral assent to screen for current eligibility for varenicline and/or 
combination NRT (depending on their initial eligibility at enrollment—only the medications(s) for 
which the person met prerequisites at enrollment will be considered as options), will conduct this 
screening, and will then obtain oral consent to begin intensive treatment over the phone (see 
uploaded Treatment Initiation Screen and Consent). Those who were randomly assigned to 
receive incentives for treatment initiation will be reminded that they can earn $40 by completing 
a first counseling call with a UW-CTRI quit coach. Medication and UW-CTRI health-counselor 
delivered telephone counseling will not be dispensed to patients unless they provide oral 
consent for intensive treatment. Medications also will not be dispensed until the patient’s 
primary care provider has had a chance to review and decline a request for the patient to begin 
the medications for which they are eligible according to the study protocol. Because we: 
anticipate that not all participants will request smoking cessation treatment during the study, 
want medication screening to be done at the time of the smoking cessation attempt, and want to 
minimize burden on primary care providers, medication requests for combination NRT or 
varenicline will be sent to primary care providers only after a participant has requested intensive 
treatment, assented to and passed eligibility screening, and consented to intensive treatment 
over the phone.  Those in the intensive treatment condition who are not eligible for either 
combination NRT or varenicline will still have access to 3 sessions of UW-CTRI quit coach 
counseling, as will those who are eligible but decline to use combination NRT or varenicline.  
Access to counseling is not dependent on medication eligibility or election. Adverse events will 
be assessed among all those who initiate stop-smoking treatment at phone follow-up interviews 
3, 12, and 26 weeks post-target quit date. In addition, adverse events will be assessed among 
those in intensive treatment during the quit coach counseling calls 1 week pre-quit, 1 day post-
quit, and 1 week post-quit.  
 
Access to medication is not limited to those in the conditions receiving incentives; all the study 
manipulations including access to incentives and access to intensive treatment are independent 
and fully crossed in this factorial design. 
 
Given the remote nature of the outreach and treatment access interventions to be evaluated in 
this study, an oral consent process is the most likely to protect the external validity of the 
findings by ensuring that they resemble real-world practices in wellness and prevention 
interventions. Collecting consent over the phone also reduces the risk that we will inadvertently 
bias the sample toward the most motivated, stable, or affluent members of the target population 
by requiring face-to-face or mailed consent processes. Mailing a written consent form and 
waiting for this to be returned would result in an evaluation study sample that is less 
representative of the target population (i.e., selecting for those most motivated or most stably 
motivated, which is particularly problematic given the focus of this project on trying to engage 
adult patients who are not initially motivated in smoking cessation). Attempting to collect 
electronic or written consent at clinic visits would be a major challenge in terms of training and 
human subjects research training certification of clinic staff, and in terms of integration of the 
consent process into clinic workflows. A clinic-based consent process could also yield a biased 
sample (e.g., those who can least afford to miss work may be least likely to agree to hear about 
the study at a clinic visit). As such, introducing a delay or logistical barriers in the consent 

 
 
          
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process for the sole purpose of documenting written informed consent would undercut the 
knowledge to be gained by this minimal risk study without substantially enhancing subject 
protections. Requiring written informed consent and HIPAA authorization for study participation 
would reduce the real-world relevance of this study designed to evaluate real-world remotely 
delivered outreach interventions to increase smoking cessation quit attempts and success. We 
will, however, supplement the oral process with written documents (a Study Information Sheet 
mailed to enrollees after providing oral consent for the randomized reach interventions and 
standard treatment, plus an Intensive Treatment Information Sheet for enrollees randomized to 
this condition. The latter will be reviewed with participants if they request intensive treatment 
prior to delivery of that treatment), and primary care providers will review patient medical 
eligibility for combination NRT and varenicline treatment before any study medication is 
dispensed. 
 
For these reasons, we also propose to use an altered HIPAA authorization because it would be 
impracticable to obtain authorization with all elements required under the HIPAA Privacy Rule 
over the phone to conduct our research study. We also seek to waive some of the required 
elements of consent and HIPAA authorization over the phone in order to reduce participant 
burden and to enhance comprehension of the material read to participants, without omitting any 
key information pertinent to risks, rights, or protections. Consent and HIPAA authorization over 
the phone will cover the collection of data from the electronic health record and the Wisconsin 
Tobacco Quit Line for research purposes. The mailed Study Information Sheet that will follow 
the telephone enrollment and oral consent process will include all required elements of consent 
and HIPAA authorization (including a statement regarding how long permission to use the PHI 
will last, how to withdraw permission for PHI use, and the mandatory statement that the PHI 
could be redisclosed without subjects' permission in the consent/authorization and enrollment 
process). The study information sheet also details how to withdraw from the study and revoke 
authorization to use PHI, without penalty or punishment. Likewise, the Intensive Treatment 
Information Sheet mailed to participants in the intensive treatment condition at enrollment (prior 
to intensive treatment delivery) will similarly cover all required elements of consent and HIPAA 
authorization. 
 
Other considerations also support the use of oral consent to participate in this study and to 
extract data from the electronic health record (EHR) for intervention and research purposes. For 
those receiving tailored outreach letters, the tailoring will be based on demographic information 
and administrative data on clinic and assigned primary care provider from the EHR. The level of 
risk involved is also low, and the study will evaluate ways to enhance minimal risk reach-
focused interventions to increase the number of patients who smoke who attempt to quit and 
use available smoking cessation treatments. The intensive treatment medication and counseling 
regimens are also minimal risk. These are not experimental treatments; they are good clinical 
practice shown to be safe and effective in previous studies. First, 12 weeks of combination NRT 
or varencline are FDA-approved regimens that are the recommended standard of clinical care 
for smoking cessation. The UW Health Sciences IRB has previously deemed nicotine 
replacement therapy, including combination NRT as minimal risk. Varenicline has a similar risk 
profile to NRT. Among adults with or without psychiatric conditions, a large multi-site trial of 
varenicline, bupropion, nicotine patch therapy, and placebo demonstrated that varenicline has 
superior efficacy without increased rates of neuropsychiatric adverse events or serious adverse 
events of any kind, relative to placebo, even among those with psychosis, anxiety, or mood 
disorders42-43. Previous studies at UW conducted by Dr. Fiore and colleagues have similarly 
shown that both combination NRT and varenicline are well tolerated. In a randomized clinical 
trial of 12 weeks of pharmacotherapy in 1086 adult smokers (N=241 who received nicotine 

 
 
          
12 
 
patches only, N=421 who received nicotine patches and nicotine lozenges, and N=424 who 
received varenicline), only one serious medication-related adverse event (an allergic reaction to 
varenicline) occurred44. This is 0.24% of those assigned to varenicline, and 0.12% of all those 
assigned to varenicline or combination NRT. In an ongoing trial of the effects of extending 
varenicline treatment to 26 weeks and adding nicotine patch therapy to varenicline (IRB protocol 
#: 2017-0404), only 2 out of 1251 (0.15%) consented participants who initiated 12 weeks of 
varenicline treatment have experienced serious adverse events possibly related to study 
medication. In the current study, to ensure that varenicline can be safely used, we will use the 
same inclusion/exclusion criteria used in IRB protocol #: 2017-0404 to determine eligibility for 
varenicline at the time of treatment request, and will additionally require approval of the primary 
care provider prior to dispensing either combination NRT or varenicline to study participants 
who consent to intensive treatment. In addition, the data to be collected are not particularly 
sensitive and will be securely transmitted and stored.   
 
With regard to compensation and incentives, the Consent Script and mailed Study Information 
Sheet will make clear distinctions between compensation for completing study follow-up 
assessments (available in all conditions), and incentives for treatment engagement (available to 
those in only half of conditions). This is important for the sake of transparency, but also to 
prevent attrition among those randomized to conditions that offer no incentives for using 
smoking cessation treatments. 
 
C. Baseline assessment 
 
Following oral consent, a healthcare system Tobacco Care Manager will: conduct a brief 
baseline assessment (see uploaded Baseline Assessment) and collect information on 1-3 
contacts who could help study staff get in touch with participants who move or experience 
phone interruptions (with participant consent). Participants will receive $20 for completing this 
assessment. 
 
The Care Manager will also ask if the participant gives the study permission to stay in touch with 
them and send them reminders about upcoming study contacts during the study via email 
and/or text message. The Care Manager will remind them that email and text messaging are 
generally not a secure way to communicate about their health as there are many ways for 
unauthorized users to access email and text messages. The Care Manager will also inform 
them that they do not have to provide their email address or text message number to participate 
in this study.  
 
D. Randomization  
 
Randomization will occur immediately after oral consent and baseline data are collected and will 
be conducted by healthcare system Tobacco Care Managers using randomization tables 
developed at UW-CTRI. Randomization will be blocked by clinic, patient-identified gender, and 
eligibility for randomization to intensive treatment access to ensure equitable distributions 
across conditions. Enrollees who meet initial eligibility for intensive treatment will be randomized 
to 1 of 16 conditions (see Table 3), while those who do not meet these criteria (e.g., those with a 
history of severe renal disease and allergic reaction to NRT) will be randomized to 1 of the first 
8 conditions shown below (because the 4th factor, access to intensive treatment, will not apply to 
them; they will have access to counseling and medication, if appropriate, from the quitline 
and/or their primary care provider). No placebo will be used in this pragmatic trial. Every 
enrollee will receive advice to quit smoking and information about resources available to help 

 
 
          
13 
 
them quit smoking no less than 2 times per year for 2 years. All enrollees who want stop-
smoking treatment at some point in the 2-year study will have access to no less than a single 
smoking cessation counseling session and a 2-week supply of a single nicotine replacement 
therapy (if medically eligible for nicotine medication).  
 
Following randomization, healthcare system Tobacco Care Managers will describe the stop-
smoking treatments available to participants over the next 2 years (as determined by eligibility 
for and randomized access to intensive treatment condition), and will give instructions about 
how to contact him/her when ready to initiate smoking treatment. Those randomized to the 
incentive conditions will be told that they will receive $40 for completing a first smoking 
cessation counseling session if/when they decide to enter treatment (they can earn the incentive 
up to twice per year [four times maximum] over the 2-year study). The Tobacco Care Manager 
will also remind the participant that the study team will be reaching out in 6 months to conduct a 
brief follow-up assessment interview and the healthcare system will reach out again via letter in 
6 months to provide information about resources and support available to quit smoking. If the 
person is randomized to a care management condition, the Care Manager will also schedule a 
15-minute phone call for a motivational intervention within the next 2 weeks (with the option to 
complete the call immediately, if the participant is interested in doing so). 
 
E. Welcome mailing 
 
Following the enrollment call, study staff will mail enrollees a welcome package containing the 
following (samples of which are uploaded with the application): 
1. A study Welcome Letter and a Treatment Offer Letter with information about: 
a. Available smoking cessation treatments and evidence of their effectiveness. In 
the tailored letter condition, this information will be tailored and personalized. 
b. Instructions about ways to contact the Care Manager to request treatment. 
c. Incentives available, how to earn them, and how and when they will be paid (if 
Table 3. Conditions (cells) to which participants will be randomized* 
Cell 
Incentives for 
treatment initiation 
Automated tailored 
letters 2x/year 
Care Manager 
Outreach 2x/year 
Access to Intensive 
Treatment 
1. 
Off 
Generic 
Off 
Off 
2. 
On 
Generic 
Off 
Off 
3. 
Off 
Tailored 
Off 
Off 
4. 
On 
Tailored 
Off 
Off 
5. 
Off 
Generic 
On 
Off 
6. 
On 
Generic 
On 
Off 
7. 
Off 
Tailored 
On 
Off 
8. 
On 
Tailored 
On 
Off 
9. 
Off 
Generic 
Off 
On 
10. 
On 
Generic 
Off 
On 
11. 
Off 
Tailored 
Off 
On 
12. 
On 
Tailored 
Off 
On 
13. 
Off 
Generic 
On 
On 
14. 
On 
Generic 
On 
On 
15. 
Off 
Tailored 
On 
On 
16. 
On 
Tailored 
On 
On 
* Those meeting initial criteria for access to intensive treatment will be randomized to all 16 
cells; those ineligible for intensive treatment will be randomized to only the first 8 cells. 

 
 
          
14 
 
applicable, as randomly assigned on the incentives factor). 
d. A reminder that the Tobacco Care Manager will call within 2 weeks of enrollment 
and again 5, 10, 16, and 22 months post enrollment to talk about smoking, 
quitting, and available resources (if applicable, as randomly assigned on the 
Care Manager outreach factor). 
e. A reminder that participants will receive a letter about stop smoking resources at 
enrollment (with enrollment packet) and at months 6, 12, 18, and 22 (in all 
conditions).  
f. A reminder that participants will be called by UW-CTRI research staff every 6 
months to complete follow-up interviews regarding smoking and quitting, and that 
$20 in compensation will be offered for completing each of these calls. 
2. A copy of the study information sheet containing all the information agreed to over the 
phone, and additional details covering all required elements of consent and HIPAA 
authorization (see uploaded Study Information Sheet). 
3. A copy of an Intensive Treatment Information Sheet for varenicline and/or combination 
nicotine patch and nicotine mini-lozenge treatment for those randomly assigned to have 
access to intensive treatment when ready to quit. 
4. A business card and a magnet showing how to contact the Tobacco Care Manager if 
participants decide they would like to quit (see uploaded Care Manager Magnets Cards). 
 
F. 
Study treatments and experimental conditions  
All enrollees in the study will receive a minimum of 5 outreach contacts in the form of letters 
describing available stop-smoking resources (at enrollment, 6, 12, 18, and 22 post-enrollment) 
to promote utilization of available evidence-based smoking cessation treatments offered at no 
cost to the participant (apart from possible cell phone minute charges if the participant receives 
study- or treatment-related calls on a cell phone). Every participant will be offered some form of 
evidence-based treatment, as even those who are not eligible for or randomized to access to 
intensive treatment will be offered referral to a tobacco quit line that, in Wisconsin, offers 
proactive counseling and (for those medically eligible) a 2-week starter-kit supply of a nicotine 
replacement therapy. Tobacco Care Managers will also offer to alert enrollees’ primary care 
providers when enrollees are interested in quitting (i.e., coordination of care).   
Some participants will receive additional or modified outreach, as randomly assigned. Some will 
receive incentives to use smoking cessation counseling, some will receive automated tailored 
letters and MyChart messages (if MyChart active) promoting smoking cessation treatment use, 
and some will receive a motivational intervention and care management delivered by phone. 
These experimental interventions are described in detail below. 
Incentives. In 2 of our recent studies45,46, incentive-driven increases in counseling use 
mediated incentive effects on abstinence in Medicaid-insured smokers. Given the significant 
savings associated with smoking cessation47, modest incentives to use treatment may well be 
cost-effective if they drive increased quitting. Modest incentives ($25 or $50) also improve 
attendance at primary care visits48. Thus, evidence supports modest, utilization-contingent 
incentives for use of both smoking cessation and primary care treatment. The proposed project 
will be the first to examine incentives to use smoking treatment (rather than achieve abstinence) 
in primary care.  
Half of participants will be assigned to receive incentives while the other half will not. Incentives 
will be tied to readily observable initiation of treatment (i.e., completion of a quitline or health 
counselor counseling call). A single $40 incentive per round will be offered to spur treatment 
initiation. The $40 incentive was selected based on the promising results of earlier work that 

 
 
          
15 
 
used $30 incentives to improve counseling completion, and through this pathway, abstinence 
rates among low-income smokers. A slightly larger incentive will be used here due to the greater 
diversity in socioeconomic status of the proposed sample, and because only 1 incentive is 
available per treatment round. Participants will be limited to 2 rounds of treatment per year (as 
per Affordable Care Act guidelines49), for a maximum of $160 over the 2-year study. Participants 
will be paid by mailed check or gift card. Incentives are not contingent on medication use, as 
medication use is subject to medical eligibility and too difficult to verify. Those in the incentive 
condition will be told of these incentives at enrollment and reminded of them at months 6, 12, 
18, and 22 post-enrollment. 
Automated Tailored Outreach. Repeated, proactive outreach to patients who smoke increases 
use of smoking-cessation treatment18,50-53. A recent proactive campaign based on a smoker 
registry yielded a 30% response rate52, markedly higher than population treatment use rates54-56. 
One promising strategy to improve receptivity to treatment invitations is tailoring and 
personalizing content57-61. Tailoring involves crafting messages for specific individuals based on 
their characteristics (e.g., age, gender62). Personalization involves identifying the source of the 
message (i.e., the provider, team, or system sending the message62). Tailoring and 
personalization increase smoking abstinence among healthcare system patients interested in 
quitting62, but the degree to which these approaches enhance treatment reach is less clear and 
will be evaluated in this study.  
Half of participants will be assigned to receive proactive outreach tailored to sex, age, assigned 
primary care provider, and assigned clinic, as recorded in the EHR and confirmed at enrollment. 
Messages will be tailored to only these variables to foster dissemination. This outreach, 
personalized with pictures and messages from the Tobacco Care Manager, clinic, and primary 
care provider will promote the use of available interventions (as determined by eligibility and 
random assignment). Those in the mailing-only (“Off”) control condition will receive non-tailored 
mailed letters noting available treatments and how to access them twice per year (at enrollment, 
month 6, month 12, month 18, and month 22). Participants in the “On” condition will receive 
communications on the same schedule, via both mail and MyChart (if MyChart active). Each 
letter/message will have a different theme, but all will provide information about available 
treatments and how to access them, as shown in the uploaded Sample Letters.  
Care Management. Healthcare systems are increasingly adopting disease/care management 
approaches to improve the clinical management of costly chronic conditions such as diabetes 
and depression36-38,63. Care management involves continuing (i.e., longitudinal) care with 
proactive outreach, patient education and support, and coordination of care61,62. In this study, a 
Tobacco Care Manager will provide a manual-guided motivational enhancement intervention 
known to increase motivation to quit smoking66. Tobacco dependence Care Management 
models have been tested in 2 RCTs18,19, both of which suggested that proactive chronic disease 
management improves both treatment use and abstinence over at least 18 months.  
In the current study, half of the sample will be assigned to care management and receive live 
phone calls from the Tobacco Care Manager within 2 weeks of enrollment and again at 5, 10, 
16, and 22 months post-enrollment. Tobacco Care Managers will be healthcare system 
employees and study team members trained in tobacco dependence treatment and certified in 
human subjects research and HIPAA training. Training manuals and documentation templates 
will be provided to enhance real-world implementation potential and quality 
assurance/intervention fidelity. Tobacco Care Managers will follow a protocol to provide support, 
information, and motivational interviewing strategies, delivered via phone (see uploaded Care 
Management Counseling Protocol) comprising 5 10-15-minute sessions (within 2 weeks of 
enrollment and at months 5, 10, 16, and 22). Treatment options and ways to initiate treatment 
and seek Care Manager support will be discussed at every call. We will strive to keep patients 
with the same Care Manager for 2 years to foster rapport and trust. Care Managers will 
document contact attempts and a random sample of phone sessions will be audiotaped for 

 
 
          
16 
 
fidelity coding (among those who consented to such recording, see consent for audio recording 
in the Study Recruitment Call Script). The half of the sample assigned to the “off” condition will 
receive no Care Manager outreach beyond enrollment.  
Access to Intensive Treatment. Half of the participants who meet initial eligibility for intensive 
treatment will be randomized to have access to intensive treatment, with patient choice among 
intensive treatments (if eligible for both standard dosing of a 12-week regimen of varenicline and 
combination nicotine patch and mini-lozenge). At the time a patient requests treatment, the 
Tobacco Care Manager will send a medication order for the patient’s primary care provider to 
review and order, if the primary care provider considers this a safe and appropriate medication 
for the patient. Intensive treatment will involve three 15-minute phone counseling sessions 
delivered 1 week prequit, on the day after the target quit day, and 1 week postquit, following a 
standard protocol (see uploaded Cessation Counseling Protocol). These sessions will be 
offered by bachelor’s level UW-CTRI Health Counselors. The remaining half of the experimental 
sample will be randomly assigned to standard care (referral to the Primary Care Provider and 
referral to a tobacco quit line, which for Wisconsin residents comprises a single 20-minute 
proactive cessation counseling call from a trained quit coach and, if medically eligible, a 2-week 
supply of a nicotine monotherapy dispensed by the quit line, at no cost to the smoker). Data 
from the WTQL will note the patient’s quit date, counseling use, and medications dispensed for 
those referred to the WTQL. Quit line use will also be assessed via self-report at semi-annual 
follow-ups. 
Dosing for the medication regimens will follow standard dosing procedures as follows: 
Participants approved to take varenicline will receive one 0.5 mg pill for the first 3 days, starting 
7 days prior to the target quit day (TQD). They will then use one 0.5 mg pill twice daily for the 
next 4 days. After the first week of study medication ramp up, participants will use one 1 mg pill 
twice daily until 11 weeks post-TQD. Participants approved to take combination nicotine patch 
and nicotine mini-lozenge treatment will receive 12 weeks of nicotine patches and nicotine mini-
lozenges starting on the target quit day (TQD). Consistent with standard dosing and package 
insert instructions, Participants who smoke 10 or more cigarettes/day will start with a 21 mg 
patch for 8 weeks, and then titrate down to a 14 mg patch for 2 weeks and then a 7 mg patch for 
2 weeks. Participants who smoke 5-9 cigarettes/day will be given 10 weeks of 14 mg patches 
and then 2 weeks of 7 mg patches. To reduce the risk of adverse effects, all participants 
receiving combination NRT will receive 2 mg mini-lozenges. This is a lower dose of nicotine 
mini-lozenges than used in standard dosing in which those who smoke within 30 minutes are 
given 4 mg mini-lozenges. Participants who smoke fewer than 5 cigarettes per day will not be 
eligible for intensive treatment with either varenicline or combination NRT. 
 
Adverse events associated with stop-smoking treatment will be assessed at every post-
cessation follow-up (3, 12, and 26 weeks post-target quit date) and at every intensive treatment 
quit coach counseling call with a UW-CTRI quit coach (1 week pre-quit, 1 day post-quit, 1 week 
post-quit). Follow-up assessors and UW-CTRI quit coaches will follow the uploaded adverse 
event protocol and will notify the Tobacco Care Manager of adverse events that may be study 
related so that the Tobacco Care Manager can inform the primary care provider of this and 
coordinate care as needed.  
 
G. Detailed study procedures: recruitment and retention  
As noted in the flow diagram in Figure 1, recruitment will occur in healthcare systems. We will 
recruit participants via 2 routes. First, at the launch of recruitment in each clinic, and quarterly 
thereafter, we will alert all adult patients on the EHR smoker registry at participating clinics that 
a Tobacco Care Manager will be available to offer information and resources to any and all 
patients who want to quit smoking, and that opportunities to participate in research studies 

 
 
          
17 
 
offering compensation also exist. This 
notice will be delivered in the patient’s 
preferred communication modality 
(mailed letter and in the secure EHR 
message portal MyChart; see the 
uploaded Recruitment Letter and 
MyChart Message content). These 
notices will also instruct patients to call 
or MyChart message the Care Manager 
if they would like to opt out of future 
Care Manager outreach. 
Second, for all adult primary care 
patients on the smoker registry who 
present at participating primary care 
clinics or participate in primary care 
video visits or telemedicine calls with a 
primary care provider affiliated with a 
participating clinic, an EHR alert will 
prompt clinic staff assessing tobacco 
use and vital signs (typically this is a 
Medical Assistant or Licensed Practical 
Nurse) to advise all smokers to quit and 
tell the patient to expect a call within the 
next few days from a Tobacco Care 
Manager who will offer information about 
resources available to help them quit 
smoking now or in the future. Clinic staff 
will be trained how to respond to the 
EHR alert, present information on Care 
Manager outreach to the patient, answer 
patient questions about Care Manager 
outreach, and note if the patient opts out 
of telephone outreach from the Care 
Manager.  
For clinic patients who do not opt out of 
Care Manager outreach, the Care 
Manager will proactively call the patient 
at the numbers listed in the EHR 
(beginning with the patient’s preferred 
number) and will leave messages 
according to their consent for voicemail 
messages on file (see uploaded 
Recruitment Call Script for sample 
messages). Care Managers will make  
attempts to call the patient on varying 
days and at varying times of day, over 
no more than 30 days. The first call will 
typically occur within 3 days of the most 
recent visit to a participating clinic. 
Figure 1. Recruitment & Enrollment Process 
At study launch 
in each clinic, 
all patients on 
smoker registry 
are notified via 
mail (and 
MyChart if 
active) of 
program and 
how to enroll or 
opt out 
At Clinic Visits/Calls, Medical 
Assistant (MA) or other roomer:  
• Documents smoking status 
(current practice) 
• EHR alert prompts MA to: 
• Tell all smokers about program 
to promote smoker health that 
begins with CM phone call  
• Note with 1 click if patient opts 
out (otherwise, smoker is 
referred to CM by default) 
Care Manager (CM; employee of healthcare 
system): 
• Calls patient within 3 business days of visit or 
receives incoming request from interested patient  
• Introduces program, advises all smokers to quit 
• Assesses readiness to quit 
Ready to 
quit within 1 
month? 
Standard Care Only 
Sample (~N=25-60, 
max=300) 
• Randomized to 1st 3, 
reach-focused 
factors only 
• Offered quitline & 
PCP referral only 
Intensive Treatment 
Sample (~N=240-300, 
max=300) 
• Randomized to all 4 
factors 
• Offered standard vs. 
intensive care, as 
randomly assigned; 
eligibility reassessed 
prior to dispensing 
Directed to Cessation 
Project (IRB# 2019-0054) 
or, if ineligible/ declines 
study, to quitline & primary 
care provider (PCP) for 
counseling & medication 
Directed to Reach 
Interventions Project 
(this project), invites to 
screen for and consent 
to study  
Eligible for 
study & 
consents? 
Eligible for 
C-NRT or 
varenicline?
Offer quitline and PCP 
as resources to quit 
Screen for intensive 
medication eligibility 

 
 
          
18 
 
Healthcare system Tobacco Care Managers will deliver the reach-focused interventions in this 
study. For those who tell the Care Manager that they are ready to quit within 30 days at any 
point during the 24-month follow-up period, the Care Manager will coordinate access to either 
standard care (quit line and/or primary care provider referral) or intensive smoking cessation 
treatment depending on experimental condition. Coordinating standard care means providing 
referral to a state quit line (typically the Wisconsin Tobacco Quit Line), for patients who agree to 
this, and/or sending a message to the patient’s primary care provider in the EHR to let the 
provider know the patient wants help in quitting smoking. Coordinating intensive treatment 
means screening for current eligibility for varenicline or combination NRT and obtaining oral 
consent for intensive treatment. For those who consent, the Care Manager will schedule a first 
session with an UW-CTRI health counselor and send a request for Primary Care Provider 
review for varenicline or combination NRT.  
UW-CTRI personnel will be responsible for: conducting telephone follow-up interviews 6, 12, 18, 
and 24 months post-enrollment; conducting in-clinic visits with patients to verify claimed 
abstinence 12- and 24-months post-enrollment via biochemical  testing (breath CO, urine, 
and/or saliva testing without biobanking); delivering three sessions of telephone counseling to 
those in the intensive cessation treatment conditions who initiate treatment; and conducting 
telephone follow-up interviews 3, 12, and 26 weeks after a patient’s target quit day (for those 
who set a quit day during the study).   
Personnel from both the healthcare systems and UW-CTRI will therefore have contact with 
study participants and/or their data. Coordination of all activities will be led by UW-CTRI and 
UW-CTRI will perform all data analyses. All data transmissions to UW-CTRI will occur via 
secure, HIPAA-compliant means via capture in REDCap or SFTP or Box file transfers. Data 
about study participation shared by UW-CTRI with health system primary care teams will occur 
via similar secure means or manual electronic health record (EHR) entry by Tobacco Care 
Managers who are both health system employees and study personnel. Tobacco Care 
Managers will have security templates in the EHR that permit them to enter research records, 
update smoking status, enter telephone encounters regarding study medications and route 
these to primary care providers, and/or exchange secure inbasket messages with primary care 
providers regarding medication requests, serious adverse events, or medication discontinuation 
due to side effects. 
Assessment Plan 
 
1. Baseline assessment (See uploaded Baseline Assessment and uploaded List of EHR Data 
to Be Extracted). At enrollment, Care Managers will assess patient age, sex, race, ethnicity, 
contact information, communication preferences, educational attainment, self-reported 
psychiatric history, tobacco use history and smoking cessation history, motivation and self-
efficacy related to quitting smoking, attitudes about and beliefs regarding smoking cessation 
treatments, and self-assessed health. EHR data regarding chronic medical conditions and 
healthcare utilization over the past year will be extracted, as well. Participants will earn $20 
for completing the baseline assessment. 
 
2. Semi-Annual assessment (See uploaded Semi-Annual Follow-Up and List of EHR Data to 
Be Extracted). At these follow-ups, patient self-report of smoking, treatment use, and 
quitting attitudes, beliefs, and experiences (including withdrawal and social support related 
to quitting) will be assessed and EHR and pharmacy data on healthcare utilization and 
smoking status changes will be extracted. Participants will earn $20 for each of 4 10-20-
minute semi-annual follow-up phone interviews assessing smoking status, treatment use, 

 
 
          
19 
 
and candidate mediators of intervention effects on treatment initiation and abstinence (e.g., 
extrinsic/intrinsic motivation, self-efficacy, perceived social support, and treatment use). Self-
reported satisfaction with healthcare and with the interventions provided in the study and 
any smoking cessation treatments used during the study will be assessed, as well. In 
addition, participants who report no smoking in the past 7 days at the 12- and 24-month 
post-enrollment interviews will be asked to return to a participating primary care clinic to 
complete a brief visit to assess smoking, tobacco, and smoked marijuana use since the 
telephone interview and to provide breath, urine, and/or saliva samples for biochemical 
testing to verify abstinence from smoking. Breath testing will be completed using the 
commercially available Micro+Smokerlyzer® from Bedfont Scientific Ltd. This biochemical 
verification procedure presents minimal risk, as it requires only that participants hold their 
breath for 15 seconds before blowing into a CO detector and that the participant provide a 
urine or saliva sample for immediate testing for cotinine/anabasine via NicAlert® (Nymox 
Corporation, Hasbrouck Heights, NJ) test strip in an effort to verify self-reported abstinence 
from nicotine. Participants who do not come into the clinic may be asked to collect a saliva 
sample at home and mail it back to the study team instead. In order to achieve a high level 
of abstinence verification, and in light of participant travel involved, participants will receive 
$50 for completing this visit. If we are unable to reach participants, we will send letters and 
emails or texts (if they have given permission for this) reminding them about these follow-
ups. At 12 and 24 months post-enrollment, if we cannot reach people by phone, we will send 
a letter with a form to return in a self-addressed stamped envelope to indicate their smoking 
status and any use of treatment in the past 6 months.  
 
3.  Post-quit attempt assessment (See uploaded Post Treatment Follow-Up assessment). Those 
who request smoking cessation treatment through a Care Manager will be asked to 
complete 10-20 minute telephone interviews 3, 12, and 26 weeks post-target-quit day and 
paid $10 for these calls (this payment is low to avoid interfering with the incentive 
manipulation). At these follow-ups, patient self-report of smoking, treatment use, and quitting 
attitudes, beliefs, and experiences (including withdrawal and social support related to 
quitting) will be assessed, along with any adverse events that occurred since the beginning 
of cessation treatment. In addition, participant utilization of treatment will be assessed by 
tracking how many calls or visits the participant completed and how much medication they 
report using. 
 
To enhance intervention fidelity, intervention delivery will be assessed via supervisory review of 
recorded motivational interventions by the Care Manager and smoking cessation counseling 
calls delivered by UW-CTRI Health Counselors, with feedback regarding performance to 
enhance fidelity, as needed.  
To enhance follow-up interview and visit completion rates, participants will be texted, mailed, 
sent MyChart reminders or automated phone calls (depending on their communication 
preferences as noted in the EHR and during enrollment).  
Data management, transmission and storage 
Data will be transferred from the EHR to research databases for use in tailoring and 
personalizing outreach (as randomly assigned) and tracking recruitment, participant healthcare 
utilization, smoking cessation treatment, and changes in smoking status, insurance type, or 
health status over the course of the 2-year study. Both healthcare systems maintain secure, 
HIPAA-compliant electronic health records for their operations and have mechanisms and 
processes in place to extract and encrypt data from the EHR for research purposes. Staff at 
UW-CTRI will receive data on enrollees who have provided consent for such data sharing as 

 
 
          
20 
 
part of the oral consent process. The data to be extracted from the EHR for the purposes of 
reach-focused interventions and assessment are shown in the uploaded List of EHR Data to Be 
Extracted. The research office will also receive data from the Wisconsin Tobacco Quit Line 
regarding services those in Standard Care received (i.e., did they complete the counseling call, 
were they sent any smoking cessation medications). 
Although this program will evaluate interventions delivered by healthcare system personnel 
(Tobacco Care Managers), delivery of intensive treatment and follow-up data collection 
procedures and collation of data from multiple sources/sites necessary for thorough program 
evaluation are the responsibility of the UW-CTRI study investigators. To achieve the study aims, 
UW-CTRI investigators require access to identifiable patient data. At UW-CTRI, all study data 
will be stored in a HIPAA-compliant and secure manner on Department of Medicine servers with 
UW-CTRI-controlled password access. Staff trained in human subjects research and HIPAA 
compliance will link these datasets using a random subject identifier and will then de-identify the 
data for analyses.  
Treatment procedures description 
The reach-focused interventions to be evaluated in this study will be delivered by healthcare 
system Tobacco Care Managers and/or UW-CTRI personnel. In addition to recruiting, 
screening, consenting, randomizing, and informing enrollees about available treatments at 
enrollment, healthcare system Care Managers will be responsible for live outreach via 
telephone to provide motivational interventions to promote cessation and treatment use (as 
randomly assigned), and to coordinate care for participants who request smoking cessation 
treatment during the study (including seeking approval of medications by primary care providers 
and updating patient records to reflect treatment use and changes in smoking status). UW-CTRI 
personnel and health system Care Managers will work together to prepare and disseminate 
automated semi-annual mailed/electronic outreach materials (e.g., UW-CTRI personnel will mail 
letters, but Care Managers who have access to the EHR patient message portal will need to 
send MyChart messages). UW-CTRI personnel will be responsible for conducting follow-up 
interviews, including semi-annual interviews and post-target-quit-date follow-up interviews, and 
will alert Care Managers to any requests for treatment that occur during these telephone 
interviews. UW-CTRI Health Counselors will track completion of intensive treatment counseling 
calls and use of quit line services to determine whether or not a patient in the incentive condition 
is owed a $40 incentive. UW-CTRI staff will process incentive payments and letters (see 
uploaded Incentive Letter). 
Standard (vs. intensive) treatment procedures will involve an offer of referral to standard quit 
line (e.g., Wisconsin Tobacco Quit Line, or WTQL) care. The WTQL offers all Wisconsin 
residents who smoke and want to quit within 30 days a single 20-minute counseling call (plus ad 
hoc calls as initiated by the participant) and a 2-week supply of an over-the-counter nicotine 
replacement therapy (for those who meet WTQL eligibility criteria for this medication, or have 
documented approval for the medication from their own physician). The WTQL mails 
medications to the participant’s home, with instructions in proper use. This is the standard 
treatment protocol for the WTQL and will not be modified for this study. Another option for 
standard treatment is for the Care Manager to notify the participant’s primary care provider that 
the participant has set a quit date and would like to talk about medication and support to help 
them quit. Participants may elect to accept one or both of these interventions, and the Care 
Manager will make the quit line referral and/or send an electronic message to the primary care 
provider via the EHR, as requested by the participant. 
Requests for intensive treatment that come in from participants randomly assigned to have 
access to such treatment will be handled initially by the health system Tobacco Care Manager, 

 
 
          
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who will help the participant select a quit day within the next 30 days and then schedule a first 
phone counseling session with an UW-CTRI Health Counselor for one week prior to the target 
quit day. The Care Manager will record this quit date in a study database and will conduct a 
brief medication eligibility interview to determine whether the patient meets eligibility criteria for 
varenicline and/or combination nicotine patch and mini-lozenge therapy, and to determine what 
dose of nicotine patch is appropriate for those eligible for combination nicotine replacement 
therapy, at the time of the call. Care Managers will facilitate treatment for participants during 
their first 98 weeks (22.5 months) of enrollment and will provide standard treatment referral 
information to those who request treatment after that time or who request treatment more than 2 
times per year or 4 times total during the study. See the uploaded Treatment Initiation Screen 
and Consent document. The Care Manager will collect oral consent for intensive treatment and 
ask those who consent and are eligible for both medications which medication they would 
prefer. The Care Manager will then draft a pending order for all the medications for which the 
consented participant meets eligibility criteria and will note in a message to the primary care 
provider which medication the participant would prefer. Primary care providers will be asked to 
review these medication orders (both the preferred medication and the alternative, if the 
preferred medication is deemed unsuitable for the patient by the provider) within 3 business 
days. Only patients with primary care providers in an active BREATHE 2 clinic will be eligible for 
intensive treatment medication, as the Tobacco Care Manager will not be able to seek approval 
for medication orders outside these clinics. Participants who have switched to an external 
primary care provider will be offered standard care instead. When a primary care provider 
approves a medication order, the Care Manager will note this in the study database and the 
UW-CTRI team will mail a starter medication kit and instructions to the participant’s preferred 
mailing address (see uploaded medication instructions). Care Managers or UW-CTRI staff will 
notify the participant whether or not the medication has been approved by their provider and is 
being mailed to them. If a participant is eligible and approved for both varenicline and 
combination NRT, the participant’s preferred treatment will be dispensed (so long as both 
regimens are available at the time treatment is initiated; see the 8/2/2021 update above). If a 
participant reports a soy allergy at the time of treatment request, soy-free mini-lozenges will be 
dispensed. Medication instructions mailed with medications will note how to request refills (as 
medications will be mailed in one-month supplies). In addition, either automated calls or text 
messages (for those who consent to receive text messages in the study) will be sent to alert 
participants when they can request medication refills. 
Additional telephone counseling will be provided by UW-CTRI Health Counselors on the day 
after the target quit day, and one week following the target quit day. Health Counselors will be 
trained and supervised by licensed psychologists. Audio recordings of at least 10% of sessions 
will be reviewed and coded for fidelity. See the uploaded Cessation Counseling Protocol. 
 
Analysis Plan 
Ongoing study monitoring. Ongoing analyses to monitor study progress, patient flow, retention, 
and fidelity will be conducted for quality assurance. Patient flow through the recruitment process 
will be tracked carefully and descriptive statistics will be used to characterize the subsamples of 
participants who are fully enrolled and those who are lost at each step in the process, and 
whether this differs by clinic, Care Manager, or demographics. This will allow us to identify, and 
if need be, adjust for differences in retention due to patient-, clinic-, or Care Manager-level 
factors. Fidelity in telephone sessions delivered by Care Managers and Health Counselors will 
be monitored. Adverse events will be assessed and queried (see Adverse Event Protocol in the 
Post-Treatment Follow-Up assessment). Analyses will be conducted by UW-CTRI personnel 
using data collected from the EHR and data collected from the health system Care Manager (to 

 
 
          
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determine the number of patients eligible for referral to the Care Manager, the number and 
proportion who opt out, and the proportion retained through each step of the enrollment 
process, and the representativeness of the enrolled sample). Data collected via telephone 
interview by the Care Manager and UW-CTRI Health Counselor will be used to track retention 
and intervention delivery and fidelity. 
Aim 1. To develop an optimized package of health system interventions to promote smoking 
cessation treatment reach among patients not initially willing to quit, logistic regression analyses 
will be conducted with binary treatment initiation over 1 year of study enrollment as the primary 
outcome, in the primary sample randomized on all 4 experimental factors. Effect size estimates 
will be generated and all main and all 2-way, 3-way, and 4-way interactive effects will be tested 
as predictors in the logistic regression model. In addition, the magnitude of the difference in 
treatment initiation rates between the most promising intervention conditions and the cell in 
which all the intervention components are off will be used to generate an upper limit estimate of 
optimized reach intervention package effects. Exploratory analyses will be conducted adjusted 
for covariates known to be predictive of treatment use. Exploratory sensitivity analyses will be 
conducted to estimate intervention component effects across a range of assumptions regarding 
missing outcome data. We anticipate that 25% of follow-up data will be missing and will 
examine the robustness of results across intent-to-treat and less stringent assumptions 
regarding missingness (i.e., that 90%, 80%, or 70% of missing cases are smoking) in sensitivity 
analyses. We may also use multiple imputation and examine the consistency of results across 
multiply imputed datasets and those imputed using the simple methods already described. This 
analysis will use data collected via UW-CTRI staff during follow-up telephone interviews 
supplemented by data regarding smoking cessation attempts and treatment utilization extracted 
from the EHR and the WTQL. 
Aim 2. To assess the cumulative main and interactive effects of each intervention component 
on binary treatment initiation over 2 years of study enrollment, logistic regressions predicting 
any treatment initiation (defined as completing a first counseling session, the primary outcome 
at a more distal endpoint) will address this aim, first in the ~240-300 patients (max 300) eligible 
for intensive treatment to examine all 4 intervention components, and then, separately, in the 
~30-60 (max 60) participants who do not meet criteria for access to intensive treatment. As in 
the analyses for Aim 1, effect coding will be used to ensure the independence of the main and 
interactive effects in this balanced design, exploratory analyses will be conducted with 
adjustment for covariates, and exploratory sensitivity analyses will examine the robustness of 
results across a range of missing data assumptions.  
In addition to the binary logistic regression described above, exploratory logistic regression 
models will estimate intervention component main and interactive effects on treatment 
completion (all 3 counseling sessions and medication initiation) among those randomly 
assigned to have access to intensive treatment with C-NRT or varenicline and counseling. This 
exploratory analysis will quantify the effects of the informational/motivational intervention 
components on the dose of evidence-based treatment received by participants over 2 years. 
Effect coding, covariate adjustment, and sensitivity analyses will be used, as described above. 
Exploratory descriptive analyses of the frequency and temporal patterns of treatment use will 
also be conducted (e.g., to explore whether C-NRT use tends to follow varenicline more often 
than the reverse, to see whether C-NRT is more likely to be repeated than varenicline use). As 
for Aim 1, this analysis will use data collected via UW-CTRI staff during follow-up telephone 
interviews supplemented by data regarding smoking cessation attempts and treatment 
utilization extracted from the EHR. 
Secondary Aim 1. Although the primary outcome in this study is treatment reach, the ultimate 
objective of this project is to help more smokers stop smoking. A key secondary binary logistic 
regression analysis in this project will estimate reach-focused intervention component effects on 
end-of-study 7-day point-prevalence abstinence confirmed by CO testing, and, if CO is elevated, 

 
 
          
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salivary cotinine/anabasine testing, among those claiming abstinence. This analysis will 
estimate the main and interactive effects of the intervention components on end-of-study (2-
year) 7-day point-prevalence abstinence rates (as ascertained by self-report and biochemically 
confirmed). The primary analysis will be an unadjusted, intent-to-treat analysis, but this will be 
followed by exploratory adjusted models and sensitivity analyses. This analysis will use data 
collected by personnel during the final semi-annual follow-up telephone interview plus the 
biochemical confirmation visit (for those claiming abstinence), supplemented by data on 
smoking status extracted from the EHR. 
Additional, exploratory analyses will examine the 7-day point-prevalence abstinence rates at 3 
time points following each round of treatment initiated with the Tobacco Care Managers (3, 12, 
and 26 weeks post-target-quit-day), for up to 4 rounds of treatment. Exploratory descriptive 
analyses will summarize abstinence rates at each time point, and the effects of intervention 
components on these abstinence rates will be explored, both within and across rounds of 
treatment. This analysis will use data collected by UW-CTRI personnel during the post-quit 
follow-up telephone interviews. 
Secondary Aim 2. The degree to which intervention component effects on abstinence are 
mediated by treatment use will be examined via formal mediation analysis. These tertiary 
outcome models will examine the extent to which intervention component effects on 7-day point-
prevalence abstinence after 2 years of enrollment are mediated by initiation of treatment in the 
preceding 2 years. Enrollees eligible for intensive treatment will be the primary sample for these 
analyses, with exploratory replication in those not eligible for intensive treatment. To examine 
mechanisms of specific intervention effects on the primary outcomes of interest, additional, 
exploratory models will examine the extent to which intervention components affect quitting 
motivation, self-efficacy, and perceived intra-treatment social support, and the degree to which 
these candidate mediators are associated with treatment initiation and point-prevalence 
abstinence at the end of the study. Within each treatment episode, the degree to which short-
term abstinence (3-, 12-, or 26-weeks postquit) is mediated by reductions in withdrawal will also 
be explored. 
Secondary Aim 3. We will attempt to estimate total (service, administrative, medication, 
utilization, patient out-of-pocket) costs of implementing the reach interventions in the study (e.g., 
costs related to administration, training, supervision, recruitment, medication screening) and 
each specific intervention component (and combination thereof) as tertiary outcomes for the 
project, without including any costs related only to research activities. First-year and second-
year costs will be estimated separately in order to generate cost estimates after 1 year of 
implementation (and compare these with program costs of the usual fax-to-quit care approach in 
place prior to study launch), and to separately estimate program maintenance costs. To 
generate stable estimates of short and longer-term costs and savings, we will extract data on 
healthcare utilization from 1 year pre-enrollment to up to 4 years post-enrollment (maximum of 5 
years total). These tertiary analyses will inform optimization of health system reach interventions 
and provide healthcare systems that may adopt reach interventions estimates of both initial and 
maintenance costs, overall, and by intervention component. We will compute total costs, and 
costs by category, and then use these cost data to compute cost per treatment initiation (the 
primary outcome of this study), cost per quit (the secondary, abstinence outcome), and costs 
per Quality Adjusted Life Years gained (QALYs67) by each intervention component. These 
analyses will help to assess intervention component efficiency in terms of promoting reach, 
abstinence (effectiveness), and quality of life. We may also conduct exploratory analyses to 
estimate net monetary benefit (NMB) when considering the added costs of the reach 
intervention components, and the monetized value of their QALYs gains. In addition, we may 
use incremental cost-effectiveness ratios (ICERs)68,69 to assess intervention component 
efficiency in promoting reach, and, separately, abstinence. These exploratory cost-effectiveness 
methods will be computed in the primary sample of participants eligible for intensive treatment 
access, where the costs of standard care and both forms of intensive treatment will be 

 
 
          
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computed and analyzed. We will conduct an exploratory replication of these cost-effectiveness 
analyses in the sample of patients eligible only for standard care who may differ systematically 
from those eligible for intensive treatment. In addition, we will use EHR-extracted data on 
healthcare utilization for participants who do vs. do not use smoking cessation treatment, and 
those who do vs. do not quit smoking to estimate potential savings resulting from 
implementation of each reach intervention (and combination of interventions) in exploratory 
analyses. We may also conduct probabilistic sensitivity analyses across a range of assumptions 
to account for uncertainty70,71. Healthcare system budget impact analyses may be conducted to 
help healthcare systems gauge the affordability of the most promising, cost-effective reach 
interventions72. This analysis will use data extracted from the EHR and from UW-CTRI research 
databases regarding intervention delivery and external estimates of Medicaid costs of 
healthcare system staff time and procedures. 
Secondary Aim 4. To explore moderators of reach intervention responses, we will introduce 
individual differences (sex, age, race/ethnicity, education, insurance type, time-to-first-cigarette, 
quitting history, chronic conditions, healthcare utilization in the year prior to enrollment, and 
mental illness history) to the models described above for Aims 1-3. In addition to testing 
interactions between candidate moderators and reach intervention component main and 
interactive effects in logistic regression models of treatment use and abstinence, we may 
conduct regression tree analyses to identify subpopulations of smokers defined by compound 
characteristics that differ maximally on treatment initiation and abstinence outcomes and 
subgroups that vary in intervention response. These exploratory analyses can help to identify 
patients that may benefit especially from particular reach intervention components or 
combinations thereof. These analyses will use data collected at baseline, follow-up, and via the 
EHR. 
Supplemental Models. Exploratory GEE models may examine intervention component effects 
on the pattern of treatment initiation and abstinence across the 4 semi-annual follow-up waves. 
Additional, exploratory latent class analyses may examine patterns of engagement and 
abstinence in 6-month epochs over 2 years, conditional on intervention components and 
combinations. These supplemental analyses will be exploratory and hypothesis generating. 
Their results may facilitate interpretation of interaction effects in the primary analyses and inform 
refinement of optimized combinations of reach-focused system interventions.  
Covariates. All models described above will be conducted and reported with and without 
adjustment for healthcare system or clinic and factors known to be associated with treatment 
engagement (e.g., sex, age, medical comorbidities related to smoking, healthcare utilization73-
77). Covariates will be removed from final adjusted models if not significantly related to the 
dependent variable to enhance model parsimony.  
Power and Sample Size  
The target sample size for participants eligible for randomization to intensive treatment access 
(N=1664) was selected based on estimates of the flow of patients through clinics in a 9-month 
period and the number needed to detect at least an 8% increment in both treatment reach 
(defined here as initiation or completion of treatment) and 2-year abstinence rates, as we 
consider 8% to be a clinically meaningful increment in both reach and abstinence. Power 
estimates for main effects of each intervention component across a range of possible base rates 
in treatment use (from 5 to 65%) and abstinence (from 5 to 30%) exceed .9 (at alpha .05) with a 
sample of 1664 participants. Power to detect simple main effects (i.e., to interpret interactions) 
exceeds .7 for all but one combination of base rates and effect sizes at N=1664.  
Power will be lower in the sample of smokers who do not meet all eligibility criteria for 
randomization to intensive treatment access (we estimate this to be roughly 416 participants, 
but may be as high as 800 participants), but this sample will be sufficiently large to generate 

 
 
          
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upper-bound estimates of effect sizes for intervention component, component-by-component 
interaction, and mediator and moderator effects. 
July 2022 update to sample size based on recruitment challenges 
Initially, the sample size was N=1664 to provide adequate power to detect hypothesized effects 
(8% increments in treatment reach, or initiation of assisted quit attempts, and 8% increments in 
abstinence 2-years after enrollment). Given difficulties in recruitment using the current model, 
we recognize that this sample size is not feasible to achieve during the study period. As such, 
we have now revised our goals for this study and now propose a sample of 240-300 
participants. This will ensure that at least 15 participants are in each cell of the experimental 
design, sufficient to yield stable estimates of effect sizes in this factorial design.  Although this 
sample size will not provide adequate power to test hypothesized effects, it will be sufficient to 
generate effect size estimates and ranges, and to identify interventions and intervention 
combinations with promising effect sizes for future study.   
 
H. Human Subjects Protections and Data Sharing 
Describe any potential direct benefits to subjects. If there are no direct benefits, state 
this. 
Every participant in the study will be given information about ways to access at least 1 
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 and care management). Although smokers could access this care 
outside of the study, we know that only about 1-2% of smokers use a quit line and only about 
5% use both medication and counseling. As such, the proposed study will offer all participants 
the benefit of information about treatment options and a low-barrier method of initiating 
treatment (i.e., by phone). 
Describe the potential benefits of this research to society.  
The proposed research also has the potential to benefit other smokers by identifying highly 
effective health system reach interventions that expand the reach of existing lower- and higher-
intensity treatments and are feasible, cost-effective, and potentially sustainable in primary care 
settings. This work has the potential to accelerate the translation of clinical research on smoking 
interventions into healthcare practice and thereby reduce morbidity and mortality associated 
with smoking.  
To promote public access to the results of this research, and thus its potential benefits, the 
study will be registered as a clinical trial at ClinicalTrials.gov, with information about the study 
purpose, experimental design, outcomes, and analyses available to the general public (with 
results posted within one year of study closing, as required). 
Describe any potential psychosocial risks to subjects, such as psychological stress or 
confidentiality risks (including risk to reputation, economic risks, and legal risks). 
This project poses minimal risk to participants, as it entails only 1) limited data collection (up to 5 
semi-annual phone assessments with two possible 5-minute visits over 2 years for all enrollees, 
plus 3 brief (10 to 20 minute) treatment-initiated assessments for each of up to 4 rounds of 
treatment among those who elect to initiate treatment) and 2) minimal-risk, non-invasive 
informational and supportive interventions to promote smoking cessation and use of FDA-
approved smoking treatments that meet or exceed the current standards of care.  
The chief risks involved are loss of privacy and breach of confidentiality. Although we will take 
several steps to protect participant privacy (including, importantly, honoring patient requests not 

 
 
          
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to be contacted), we cannot guarantee that patients may not experience an invasion of privacy. 
Some patients may perceive tailored outreach letters from the health system (tailored on 
demographics such as sex and age, and on primary care provider and clinic) as violating 
privacy, for example. Likewise, we cannot guarantee the confidentiality of the information 
collected directly from participants. Although we will not collect sensitive data directly aside from 
asking about marijuana use, some data (i.e., substance use disorder diagnoses) may be 
included in deidentified extracted EHR data.  
The outreach messages and motivational support given to participants in this project are 
unlikely to induce psychological distress, as they will be positive in tone and will focus on 
resources available to participants to support their efforts to change. The treatments provided 
are FDA-approved. The intensive pharmacotherapies will be administered only after patients are 
authorized by their PCPs to receive such treatment, patients provide oral informed consent for 
such treatment, and monitoring for adverse effects is in place. Providing breath samples for 
carbon monoxide and/or providing saliva or urine for cotinine/anabasine testing carries minimal 
risk, as these are minimally invasive procedures.  
It is important to note that all patients will have access to evidence-based smoking cessation 
treatment at no cost (through their primary care provider and/or a quit line that offers evidence-
based cessation treatment no cost to callers) and that receiving such treatment is not contingent 
on consenting to this study. It is also important to note that all patients will have the ability to 
decline or withdraw from the study and any study activities at any time. Risks associated with 
use of intensive treatments will be addressed by screening for contraindications prior to 
administering medications and by explaining these risks in the informed consent process for 
those who consent to such treatment. The risks associated with nicotine replacement distributed 
by a tobacco quit line or smoking cessation treatments provided by primary care providers will 
be addressed according to standard quit line or healthcare system protocols and procedures. 
Describe how ALL the risks of the study will be minimized. 
To protect against breach of confidentiality or violations of privacy, we will ensure that data are 
stored on secure, encrypted servers at all participating sites, and that transfer of data between 
clinics and the UW-CTRI research team are conducted via HIPAA-compliant means. 
Communication with patients via the MyChart patient portal will likewise be conducted in HIPAA-
compliant ways that conform to healthcare system standards. 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 maintained by the data manager. 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. Data will be stripped of direct identifiers (limited 
datasets) or completely de-identified prior to sharing with others outside the IRB-approved 
research team.  
To protect against violations of privacy, patients will first have the option to opt out of the 
program, at study launch and quarterly thereafter, at the clinic. Those who opt out will not 
receive a call from a Tobacco Care Manager for recruiting and offers of smoking cessation 
treatment. In addition, potentially sensitive information from the EHR (e.g., depression or 
substance use status) will not be used to tailor automated outreach letters among those who 
consent to participation in this study. Only demographic and care team information will be used 
for tailoring and personalization.  
If, in the course of the study, participants reveal important clinical information to their Tobacco 
Care Manager (e.g., during motivational intervention calls), the Care Manager, who will be an 
employee of the healthcare system, will be able to communicate directly with the patient’s 

 
 
          
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primary care team (e.g., if a patient notes that they are coughing up blood) via the EHR and will 
advise the patient to seek care from their care team or emergency care, as appropriate. 
Routine adverse event assessment will not occur in this study, except in the context of smoking 
cessation treatment episodes, given the minimal and informational nature of the health system 
reach interventions and research assessments. Adverse events that occur during smoking 
cessation treatment will be assessed during post-quit-day follow-ups (3, 12, and 26 weeks post-
quit day). Adverse events reported by patients will be assessed fully and reported to the IRB, 
the host healthcare system, and if appropriate (i.e., if serious or necessitating a change in the 
protocol) to the study sponsor and FDA, in a timely manner, as specified by pertinent guidelines 
and regulations. 
To minimize adverse events, study medications will be administered only to those who meet 
eligibility criteria at the time they request treatment and set a quit day in the next 30 days. In 
addition, study medications will be dispensed in a manner fully consistent with product labels, 
clear patient instructions will be provided, and standard dosing regimens will be used. Patients 
who elect to use combination NRT (nicotine patch + mini-lozenges) and who smoke 5-9 
cigarettes per day will receive a lower dose regimen of nicotine patches (14-mg for 10 weeks, 7-
mg for 2 weeks) than those who smoke 10 or more cigarettes per day (21-mg for 8 weeks, 14-
mg for 2 weeks, 7-mg for 2 weeks). Those who smoke fewer than 5 cigarettes per day will not 
have access to combination NRT at all. The nicotine mini-lozenge dose dispensed to 
participants who initiate C-NRT will be the lower, 2-mg, dose to minimize side effects of mini-
lozenge use. Mini-lozenge use frequency recommendations will also follow labeling (1 mini-
lozenge every 1-2 hours for 6 weeks, every 2-4 hours for 3 weeks, and every 4-8 hours for 3 
weeks). Varenicline will be dispensed in 1-week packs (rather than as loose pills) to facilitate 
proper dosing and will start with 0.5 mg per day for 3 days, 0.5 mg twice per day (8 hours apart) 
for 4 days, and then 1 mg twice per day for the following 11 weeks. 
Participants will be alerted to possible withdrawal effects in the mailed welcome packet sent 
after enrollment and again at the time they consent to smoking cessation treatment (among 
those who request such treatment during the 2 year study) and will be offered medication to 
manage these symptoms (if medically eligible), and will be advised that these symptoms are 
typically mild and temporary. Both Wisconsin Tobacco Quit Line counseling and the counseling 
delivered by UW-CTRI Health Counselors in the intensive treatment condition address ways to 
manage withdrawal. 
Explain why the risks to the subjects are reasonable in relation to the anticipated 
benefits. 
This study carries minimal risk. None of the reach-focused interventions to be deployed poses 
significant risk above and beyond standard treatment and every participant will be offered 
access to at least one form of evidence-based smoking cessation treatment. Those who receive 
FDA-approved medication in the course of the study will be screened for contraindications and 
will provide consent for treatment prior to medication dispensing (even at the Wisconsin 
Tobacco Quit Line). No information about illegal behavior except for marijuana use will be 
entered in databases. The risk of someone's identity becoming known to unauthorized persons 
is low. This risk is outweighed by the benefits of quitting smoking for any individual, and the 
benefit to society of having fewer people use tobacco products. This research has the potential 
to benefit smokers in the future by helping to identify optimal combinations of remotely delivered 
interventions to promote use of smoking cessation treatments for broader dissemination. The 
proposed project will accelerate refinement of treatments with broad reach and low barriers to 
access using an efficient factorial research design. The risks associated with the use of nicotine 
replacement therapy and varenicline are minor relative to the risks of continued smoking , 

 
 
          
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particularly with careful medication eligibility screening as proposed here. If successful, this 
treatment approach could be used more broadly to reduce the considerable financial and 
personal costs associated with smoking-related disease. Therefore, the potential gain in 
knowledge regarding treatments and mechanisms of change associated with the proposed 
study outweigh the risks of participation. 
Describe the provisions in place to identify and address unanticipated problems or 
complications. 
The Project Lead and Principal Investigators (PIs) will be responsible for routinely monitoring 
study progress. UW-CTRI has an adverse event monitoring protocol and team in place and will 
alert the study Project Lead and PIs to adverse events among study participants who receive 
smoking cessation treatment. Any data safety concerns will be reported to the Project Lead and 
PIs immediately and addressed. We will report any unanticipated problems to the IRB according 
to posted guidelines. A full data safety and monitoring plan is included at the end of this 
protocol. 
Describe the precautions that will be used to ensure subject privacy is protected 
Collection of sensitive information about subjects will be limited to the amount necessary to 
achieve the aims of the research. Participants will not be asked to disclose any information 
about illegal behavior except for marijuana use.   
Describe the measures that will be implemented by your research team to safeguard the 
identifiable subject information from unauthorized use or disclosure for both paper and 
electronic forms of information. Include how and where data will be stored. 
Participant study data will be collected by Tobacco Care Managers and 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 (either a secure FTP 
site or a secure interface to the EHR). A Certificate of Confidentiality will be issued for the study. 
Required patient identifying data will be stored in a separate file linked to all study data via a 
study identifier. Confidentiality of participant data and information will be accomplished by using 
participant numbers as unique identifiers, allowing us to keep participant data separate from 
identifying information. At UW-CTRI, data generated through study participation and data 
obtained from the EHR or the quit line (with patient consent) will be stored in secure databases 
under protections and procedures consistent with the guidelines and regulations of the UW 
School of Medicine and Public Health (UW-SMPH). Outside access is available only via an 
encrypted connection to the Department of Medicine Citrix server located at the UW Clinical 
Science Center in Madison. The servers at the UW-CTRI Madison office are physically secured 
in a locked room. Data backups are created nightly and stored in a locked safe. Significant 
safeguards have been implemented to protect data including virus and adware protection, 
firewall, access controls and encryption when appropriate such as wireless and remote access. 
All UW-CTRI staff members have completed HIPAA and human subjects training and are aware 
of the sensitivity of study-related data. The UW SMPH has developed school-wide data security 
policies and procedures. UW-CTRI data security policies and procedures conform to those of 
the SMPH. UW-CTRI will use an enterprise-level REDCap database that supports audit trails 
such as access, change logging, and more sophisticated access control for managing and 
tracking user access privileges. No publications or presentations resulting from this research 
program will contain any identifying information about individual participants. Following cleaning 

 
 
          
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and verification of data at the conclusion of the study, all research data will be placed in a de-
identified data set at UW-CTRI. 
Data Safety and Monitoring Plan 
The Data Safety and Monitoring Plan (DSMP) covers all research activities in this proposed 
project. All investigators must agree to comply with the procedures outlined in this DSMP. This 
DSMP does not reduce any investigator’s obligation to comply with the requirements of the 
Institutional Review Board (IRB) at his/her home institution or the IRB of any collaborating 
organizations. 
Monitoring the progress of trials and the safety of participants. The Principal Investigator 
(McCarthy) is responsible for routine monitoring of study progress. This includes scheduled 
meetings with study staff and healthcare system Tobacco Care Managers and their supervisors 
(weekly during the first 2 months of the study, and monthly thereafter); review of deidentified, 
aggregate reports on: patient referral and opt-out rates from clinics, enrollment rates for this 
project, rates of and reasons for ineligibility or declines, accrual rates in both the experimental 
and standard-care-only samples, and rates of allocation to experimental conditions by clinic, 
sex, and eligibility for intensive treatment (to ensure the randomization scheme is coordinated 
and balanced as intended). The PI will also routinely monitor Tobacco Care Manager patient 
contact rates, follow-up assessment completion rates and timeliness, rates of and reasons for 
patient withdrawal from the study, rates of outreach message acknowledgement/acceptance 
(e.g., rates of letters returned, secure EHR messages unopened), and rates of missing data in 
assessments. To verify that incentives are being delivered as intended, the PI will review 
monthly reports on UW-CTRI Health Counselor-delivered counseling session completion and 
quit line referral results (which note the number of counseling sessions completed), and 
compare these against incentive processing records. This will continue throughout the 33-month 
data collection period. Prior to and quarterly following the launch, the PI will review outreach 
materials produced for test patients to make sure that the content, format, and periodicity of 
these tailored outreach materials are implemented as intended. Similar testing with Tobacco 
Care Manager outreach for care management purposes will occur quarterly following launch to 
promote fidelity to the care management protocol and to address drift that may occur over time. 
The PI will troubleshoot difficulties in this area with the Tobacco Care Managers and their 
supervisors, as needed. In addition, the PI will monitor incoming follow-up data to ensure that 
assessors are capturing this data as fully and accurately as possible, and to troubleshoot 
problems with the data collection instruments or procedures, as needed. As such, the PI will 
implement routine monitoring procedures to assess progress and fidelity in terms of recruitment, 
retention, randomization, intervention delivery fidelity, and follow-up. In addition, the PL (a 
licensed Clinical Psychologist) will review all incoming adverse events no less than weekly, and 
will evaluate and address serious adverse events within 24 hours, in consultation with the PI (a 
Physician).  
To facilitate participant safety, all study participants will receive no less than access to standard 
of care smoking cessation care. Those who do not meet eligibility criteria for enhanced 
pharmacotherapy (combination NRT or varenicline) or do not consent to such treatments, will be 
referred to a quit line that administers evidence-based cessation counseling and NRT 
monotherapy. State and national quit lines have standing protocols for screening for medical 
contraindications for nicotine replacement therapy. The Wisconsin Tobacco Quit Line screens 
for pregnancy; recent heart attack, stroke, or transient-ischemic-attack; rapid/irregular heartbeat 
requiring lifestyle modification or medication; severe or worsening angina; and past negative 
reactions to NRT, and has a standard protocol for addressing adverse events. Those who 
initiate intensive C-NRT or varenicline treatment (which is subject to primary care provider 
review) will be counseled in proper use of the medication, monitored for adverse events, and 

 
 
          
30 
 
advised to reduce or stop medication if treatment-related adverse events occur. Any adverse 
events reported during contact with a Tobacco Care Manager or during follow-up assessments 
will be fully assessed, addressed, and reported promptly to the PL and PIs, and, if study-related, 
to the DSMB, the IRB, and, if serious or necessitating protocol changes, NCI. Should either 
excessive risk to study participants and/or convincing evidence of lack of measurable benefit to 
study participants be determined, the study will be stopped and all participants notified in a 
manner appropriate to the nature of the risk and/or lack of benefit. When taking that step, the 
investigators will consult with the IRB and NCI. 
Plans for assuring compliance with requirements regarding the reporting of adverse events. This 
DSMP requires that investigators notify NIH and the University of Wisconsin IRB in a timely 
manner (consistent with IRB and NIH policies) of the occurrence of any SAE or any AE which is 
severe, unexpected, and possibly related to study medication or protocol. Any adverse, study-
related events that come to light 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 
persistent or significant disability/incapacity, or involve congenital abnormality/birth defects. 
Unanticipated problems will be monitored and reported to the DSMC. These are events that 
meet the following criteria: 1) suggest the research places subjects or others at increased risk of 
harm, 2) are unexpected (in terms of nature, severity or frequency) given the research 
procedures that are described in the study-related documents, and 3) possibly related to study 
participation. Any SAE will be queried and reported if it meets the definition of unanticipated 
problem. 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. The PL and PIs 
have 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. 
Plans for assuring that any action resulting in a temporary or permanent suspension of an NIH-
funded clinical trial is reported to the NIH grant program director responsible for the grant. The 
NIH grant program director will be notified within 5 days if the PI deems it necessary to suspend 
the clinical trial. In the case of a temporary suspension, the PI and PL will develop a plan for 
continuation of the study and discuss this plan with the NIH grant program director in a 
reasonable time frame.   
Plans for assuring data accuracy and confidentiality and protocol compliance. The PI will 
develop and implement protocols for assuring UW-CTRI data collection accuracy and protocol 
compliance, with the support of the Administrative and Data Analysis Cores. Study protocols will 
include data verification and protocol compliance checks. The PI will also be responsible for 
ensuring that the data for the project are securely transferred from participating healthcare 
systems 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 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 the presence of viruses. A 

 
 
          
31 
 
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, the 
UW-CTRI and the 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 the data systems 
described in the proposal 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 PIs and UW-CTRI IT Manager. 
To further protect confidentiality, only the UW-CTRI IT Manager will be permitted to transmit 
data to the SFTP server. Finally, the Department of Medicine employs extensive data backup 
and server redundancy procedures and performs full backups to tape weekly of all servers, 
along with incremental and daily backups.  
Data and Safety Monitoring Committee. In addition to the protections outlined in the DSMP 
(above), all research activities conforming to the NIH definition of a clinical trial will also have an 
independent Data Safety and Monitoring Committee (DSMC). This application includes a Phase 
III clinical trial using communication and motivation strategies with strong theoretical rationales 
and promising empirical support in human research, and offering FDA-approved smoking 
cessation therapies prescribed in a manner consistent with FDA-approved labeling. The DSMP 
specifies overall monitoring that will be conducted by the PI, including timely reporting of AEs 
and SAEs. Every 6 months, the DSMC will convene to review the overall safety data, as well as 
data on safety summarized by treatment condition. As per NIH guidelines, the objective of these 
reviews will be to determine whether continued conduct of the trial poses any undue risk for 
participants. 
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 this project’s research activities. Dr. Cleary is joined on the DSMC by Dr. 
James Sosman and Dr. Burke Richmond. Dr. Sosman is Associate Professor of Medicine and 
Medical Director of the HIV/AIDS Comprehensive Care Program at UW Hospital and Clinics 
who has previously collaborated on a clinical trial of smoking cessation with UW-CTRI. Dr. 
Richmond is an otolaryngologist who has served on independent DSMCs for Phase II and III 
trials involving a nicotine vaccine. Neither has direct involvement with any of the proposed 
research. The PI will report to the DSMC; the three DSMC members will be unblinded as to 
treatment conditions and will make the final determinations as to study continuation. 
 
 

 
 
          
32 
 
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