A Comparative Effectiveness RCT of Optimized Cessation Treatments
Phase: PHASE4
Conditions: Smoking Cessation
Sponsor: University of Wisconsin, Madison

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“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
 
 
 
 
 
 
 
PROTOCOL  
 
UW HS-IRB # 2014-1041 
 
“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
 
Principal Investigator: Michael Fiore, Ph.D., (608) 262-8673 
Coordinating Center: UW-Center for Tobacco Research and Intervention (UW-CTRI) 
Funding Sponsor: DHHS, PHS, National Institutes of Health (NIH) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
Study Overview 
 
 
The ultimate goal of this research is to develop a chronic care treatment package for 
smokers that will address the challenges and opportunities of each phase of the cessation 
process – motivation, preparation, cessation, maintenance, and relapse recovery. That is, to 
develop treatments for smokers not yet ready to quit, those who are preparing to quit, those 
actively engaged in the quitting process and those who have tried to quit but relapsed. 
 
To achieve this goal, this research comprises three distinct research studies, each of 
which represent a phase in a comprehensive chronic care treatment model for clinical 
intervention with smokers in the primary care setting: the Motivation Study, the Cessation Study, 
and the Long-term Quitting (LTQ) Study (see Figure 1). The goal of each study is to test and 
identify effective intervention components for distinct phases of the smoking cessation process. 
These components will then be combined for future research on the effectiveness of this chronic 
care treatment package. While the three studies are distinct, they are conceptually integrated, 
rely on the same recruitment mechanism, have similar inclusion/exclusion criteria and use 
similar assessments and treatment. For that reason, we have submitted this as a single protocol 
for IRB review. 
 
In sum, these three studies will allow us to identify experimentally validated intervention 
components that constitute a menu of highly effective interventions for every phase of smoking 
cessation and that can be combined to constitute a comprehensive chronic care treatment for 
smoking. 
 
 
 
 
 
In addition to the three clinical (human subjects) research projects, this research 
includes a randomized control trial testing the use of the EHR as a way to initiate smoking 
cessation intervention as compared to current standard of care.  This is a clinic comparison (not 
human subjects) trial.  The electronic health record (EHR) has the potential to enhance the 
efficiency, consistency, and ascertainment of the delivery of smoking treatment in primary care. 
The main goal of clinic comparison research project is to develop and test new, comprehensive 
EHR enhancements and associated healthcare practices that efficiently guide smoker 
identification, referral to, and engagement in the chronic care treatments for smokers developed 
in the three treatment projects. The EHR enhancements will include: 1) smoker identification 
and documentation aids; 2) a 1-click system to refer primary care patients to the chronic care 
smoking treatments developed in Projects 2-4; 3) a function to provide EHR feedback to 
clinicians on the outcome of those referrals; and 4) communications resources to reach out to 
smokers in the health system (via a query of existing smokers within each clinic), informing 
them of the chronic care smoking treatment options available as part of this Program Project. 
 
Figure 1. Developing Chronic Care Treatment for Smoking Using the Phase-Based Model 
 Motivation  
Preparation     Cessation       Maintenance           Relapse Recovery 
     Motivation Study:  
  Screening Experiment 
Cessation Study: 
RCT 
Long-term Quitting Study: 
Screening Experiment 
 
 
 

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“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
The impacts of the EHR-based enhancements along with the integrated chronic care smoking 
treatment will be evaluated in a randomized clinical trial (RCT) involving up to 28 primary care 
clinics in two healthcare systems in Wisconsin that will serve as recruitment sites for the clinical 
studies. The methodology, data collection and analysis plans for this clinic comparison trial are 
presented at the end of each section of the narrative regarding the treatment studies. 
 
Recruitment & Study Entry 
Up to 2600 participants will be recruited to participate in this research:  512 in the 
Motivation Study, 600 in the Cessation Study and 1000 in the Long-term Quitting Study and an 
estimated 188 additional participants.  These additional participants are necessary in order to 
keep both a quitting and motivational project open enough time to allow full recruitment in all of 
the studies. However, to get a proper balance of participants across the three studies, we may 
need to recruit as many as 2600. Participants will be patients in approximately 18 primary care 
clinics from within 2 Wisconsin clinic systems (Aurora Health Care and Dean Clinic) that serve 
diverse populations. Smokers who express interest in quitting smoking or cutting down during 
the electronic health record (EHR)-guided assessments will have their willingness (verbal 
consent) to share their contact information and be contacted by the study documented in their 
EHR and their contact information electronically sent to the study office.  Alternatively, smokers 
at participating clinics who do not have a scheduled clinic visit will receive direct recruitment 
information via mailings and EHR-specific messaging to other smokers from each clinic who do 
not have scheduled clinic visits. The direct recruitment messages will encourage smokers to 
learn more about the study by contacting the UW-CTRI research office directly. Research 
personnel will call all referred patients, whether they were self-referred or referred via the EHR, 
and assess interest and eligibility.  
 
In either entry method, patients interested in quitting smoking will be eligible for either 
the Cessation Study or the Long-term Quitting Study, and they will be randomized to one of 
these two studies. The amount and level of randomization of those interested in quitting to these 
two projects will be adjusted in order to meet study recruitment goals. This adjustment may 
include assigning subjects to only one of the two quitting studies if necessary to achieve the 
necessary balance and overall recruitment required for the primary analyses.  Smokers 
expressing an interest in cutting down on their smoking will be eligible for the Motivation Study.  
Patients who pass the phone screen will be invited to attend a study session at their referring 
clinic (where all treatment visits will occur), where they will learn more about the study, have 
eligibility confirmed, and provide written informed consent. Records collected in this research 
will allow us to determine the overall reach of the intervention within the clinic (e.g. percentages 
and demographic characteristics of patients who complete each recruitment step) and will allow 
us to complete a full CONSORT diagram. 
 
Communication that includes essential PHI between each participating health system 
clinic and UW-CTRI research staff takes place for two purposes. First, following verbal consent, 
the clinic communicates information about their patients interested in hearing about the study to 
UW-CTRI. This information will include patient name, contact information (phone, address) 
available and responsible clinic provider and MR number (all necessary to contact patients and 
to fully match referred patients and complete the data analysis at the end of the study). (Note: 
Second, UW-CTRI must communicate back specific information about those patients consented 
This information communicated after written consent is obtained and includes the name of the 
enrolled patient and over-the-counter (OTC) medication (dosage and duration) provided by the 

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“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
study to the patient. As described below, these communications will take place without any UW-
CTRI staff having access to any additional patient medical record information and without health 
system staff having access to any additional research information.   
 
At no time will UW-CTRI research staff be able to access any patient information 
contained in the health system EHR.  However, in order to expedite communication between the 
health system and research personnel, we will take advantage of either Epiccare Link, which is 
a secure method of data transmission supported by the health care clinic’s Epic electronic 
health record (EHR), or some comparable secure, HIPAA-compliant email transmission of the 
essential contact information. This secure transmission method will be used to transmit 
information from patients who verbally consent to supply their information to study personnel. 
The contact information will be retrieved by specific UW-CTRI study staff (i.e., among those who 
are part of the IRB-approved study team) who are granted access by each health system who 
will then enter the contact information into the UW-CTRI research study database. As per health 
system requirements, these specific UW-CTRI staff will complete necessary user 
confidentiality/security information. When a patient is enrolled, the same authorized UW-CTRI 
staff will create a return communication using the same secure transmission system to send the 
enrollment information and medication dosage and duration to the responsible clinic provider to 
update the provider’s clinical record (EHR). Only clinic staff authorized by the clinic to view and 
handle PHI will be given access to these return communications. Similarly, the health system 
will not be provided within any non-clinical information from the research study, since clinics and 
their staff are not engaged in research.      
 
At the present time, we are seeking IRB approval to recruit and enroll participants 
contingent upon our submission of confirmation from each health system IRB that they agree 
that their health system is “not engaged in research,” as defined in the UW Human Research 
Protection Program and OHRP 45 CFR part 46. Their activities do not include any study 
intervention and are limited to letting potentially eligible patients know about the study, obtaining 
prospective participants’ permission for investigators to contact them, allowing their facilities to 
be used by study staff to provide intervention, providing other de-identified data necessary for 
the study to ascertain rates of recruitment from the overall pool of smokers, and receiving 
clinical information such as medication being given as part of the study in order to provide 
proper clinical care.  
 
Additional Data Related to Recruitment and the CONSORT Diagram 
 
 
In order to evaluate the reach of the treatments in this study among the general and 
smoking populations in each clinic, and to report the necessary CONSORT information, we will 
collect additional aggregate data from the EHR of each clinic in which we are recruited 
participants. These data will allow us to clearly report patient flow through the clinic (e.g., 
number of patients seen in the clinic, number of patients who are smokers) as well as the 
proportion of smokers who participated in the study and any differences in basic demographic 
characteristics of those who participated and those who did not (See Appendix 1: Sample 
Representativeness/Study Recruitment Aggregate Data Plan for details). No individual data will 
be collected. The data will be aggregated by group depending on the response to the smoking 
identification and study invitation within the EHR. Comparable data will be collected from the set 
of individuals who did not come in for a study visit during the time frame of study recruitment but 
received outreach from the clinic via a letter or myChart message to determine the level of 
response and the demographics of smokers who responded to these forms of recruitment. In 

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“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
sum, this aggregate data collected from clinic EHRs will allow us to determine percentages of 
patients who completed each recruitment step and will allow us to complete a full CONSORT 
diagram (See Appendix 2: Consort Diagram) 
 
Inclusion/Exclusion 
 
 
Inclusion criteria for all 3 studies will be: age (18 years or older); smoking >4 
cigarettes/day for the previous 6 months; able to read, write, and speak English; have reliable 
phone access and agree to respond to Interactive Voice Response (IVR) phone prompts; a 
patient at a clinic currently recruiting in the study; not currently taking bupropion; if currently 
using nicotine replacement therapy (NRT) or varenicline, agreeing to use only study medication 
for the duration of the study; free of medical contraindications to using NRT; no history of stroke, 
mini-stroke, heart attack, TIA (Transient Ischemic Attack) nor an abnormal electrocardiogram in 
the past 4 weeks; no hospitalizations for diabetes or congestive heart failure in the past 4 
weeks; no diagnosis of or treatment for schizophrenia, a psychotic disorder or bipolar disorder in 
the last 10 years; and, if the participant is a woman of childbearing potential, using an approved 
method of birth control during treatment. We will not exclude participants based on their prior 
use of cessation medication or if they use multiple tobacco products in order to enhance real-
world generalization (these will be statistically controlled in analyses). However, we will 
encourage participants to discontinue use of all tobacco products on their target quit date.  
 
Additional inclusion criteria for the individual studies include: 
• 
Motivation Study: not currently attempting to quit smoking; not intending to quit 
smoking (defined as no plans to quit in the next month); and planning to remain in 
the area for at least 12 months. 
• 
Cessation Study: reporting being motivated to quit; and planning to remain in the 
area for at least 12 months. 
• 
Long-term Quitting Study: reporting being motivated to quit; and planning to remain 
in the area for at least 2 years and 2 months. 
 
       Incarcerated individuals will not be enrolled in this study. However, given the longitudinal 
nature of the research, participants could be incarcerated for periods during their participation. If 
study staff learn that a participant is incarcerated at a time point subsequent to enrollment, the 
participant will not be withdrawn unless that incarceration will take them beyond the study 
period.  Staff will not contact the participant while incarcerated and will not provide any 
treatment (counseling or medication) nor conduct any assessments during that 
incarceration.  Services and assessments will be re-initiated if the participant is released at a 
later study time point.   
 
 
Even though we screen out participants who are pregnant, plan to become pregnant, 
nursing, or are unwilling to take steps to avoid pregnancy, there is a chance that a participant 
previously eligible could become pregnant. She would then be considered part of a vulnerable 
group. Given the longitudinal nature of the research, a participant who becomes pregnant after 
enrolling may remain in the study for counseling and other assessments. However, she will be 
advised to immediately stop using study medications and to return any unused medications.  No 
further medications will be given to this study participant while in the study. 
 
 
 

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“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
 
 
Study Design 
           This research utilizes innovative engineering principles and designs. The Motivation and 
Relapse Recovery Studies are screening studies utilizing factorial designs that will allow us to 
evaluate different treatment components and how well they work when combined. The 
Cessation Study is a randomized controlled trial of treatment components that were identified as 
optimal in a previous screening study that used a factorial experimental design. 
 
 
Motivation Study  
This study is a 2x2x2x2 factorial design (see Table 1). Participants will be randomized to 
one of two levels on four different factors: 1) Nicotine Mini-Lozenge vs. No Mini-Lozenge, 2) 
Behavioral Reduction Counseling vs. No Behavioral Reduction Counseling, 3) 5Rs Motivation 
Counseling vs. No 5Rs Motivation Counseling, and 4) Behavioral Activation Counseling vs. No 
Behavioral Activation Counseling. These components have strong theoretical and empirical 
support, but their relative, additive, and interactive effects are unknown.  
 
Table 1.  Motivation Study Treatment Conditions 
Conditions 
Medication Type  
(Mini-Lozenge) 
Behavioral 
Reduction (BR) 
Counseling 
5Rs Motivation 
Counseling 
Behavioral 
Activation (BA) 
Counseling 
1 
Mini-Lozenge 
BR 
5Rs 
BA 
2 
Mini-Lozenge 
BR 
5Rs 
No BA 
3 
Mini-Lozenge 
BR 
No 5Rs 
BA 
4 
Mini-Lozenge 
BR 
No 5Rs 
No BA 
5 
Mini-Lozenge 
No BR 
5Rs 
BA 
6 
Mini-Lozenge 
No BR 
5Rs 
No BA 
7 
Mini-Lozenge 
No BR 
No 5Rs 
BA 
8 
Mini-Lozenge 
No BR 
No 5Rs 
No BA 
9 
No Mini-Lozenge 
BR 
5Rs 
BA 
10 
No Mini-Lozenge 
BR 
5Rs 
No BA 
11 
No Mini-Lozenge 
BR 
No 5Rs 
BA 
12 
No Mini-Lozenge 
BR 
No 5Rs 
No BA 
13 
No Mini-Lozenge 
No BR 
5Rs 
BA 
14 
No Mini-Lozenge 
No BR 
5Rs 
No BA 
15 
No Mini-Lozenge 
No BR 
No 5Rs 
BA 
16 
No Mini-Lozenge 
No BR 
No 5Rs 
No BA 

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“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
*Note.  In factorial designs each main effect is 
tested; within each column, the shaded vs. 
non-shaded rows are compared. 
 
Cessation Study  
 
This study is a 2-arm randomized 
clinical trial (RCT). Participants motivated 
to quit smoking will be randomized to one 
of two treatments: 1) a Modern Usual 
Care (M-UC) vs. 2) Abstinence-Optimized 
Cessation Treatment (AOCT). The 
components for the optimized treatment 
have strong theoretical and empirical 
support from our previous screening 
studies. 
 
Long-term Quitting Study  
This study utilizes a sequential, 
multiple assignment, randomized trial 
(SMART) design—an innovative approach 
aimed at optimizing adaptive treatments. 
In a SMART design, randomization occurs 
at more than one stage, with 
randomization at a later stage based on 
response to treatment at an earlier stage. 
This experiment will test adaptive 
intervention components that are applied at two stages: 1) when a smoker relapses, and 2) 
when a smoker decides to make a new quit attempt (See Figure 2 and Figure 2a). Participants 
will initially receive a Usual Care cessation treatment. If they relapse (smoke for 7 consecutive 
days prior to 6 months after the quit day), they will be randomized to one of three Relapse 
Recovery (RR) Preparation conditions: 1) Preparation Control, 2) Behavioral Reduction 
Counseling + Nicotine Replacement Therapy (NRT with the nicotine mini-lozenge), or 3) 
Recycling Counseling. If they are randomized to the Preparation Control condition, the 
participant will continue to receive the Initial Cessation usual care treatment, but will also be told 
that they can receive additional treatment from the Wisconsin Tobacco Quitline (WTQL). Thus 
participants randomized to the Preparation Control condition will receive at least a usual care 
cessation treatment and will be told how to get more free treatment, but they will not receive any 
further study treatment. If participants are randomized to one of the two active RR Preparation 
conditions, they will be seamlessly transitioned into either Behavioral Reduction Counseling + 
Nicotine Replacement Therapy (NRT with the nicotine mini-lozenge) or Recycling Counseling. If 
participants in either of these active RR Preparation conditions (the “Behavioral Reduction” or 
the “Recycling” conditions) choose to make a new aided quit attempt, they will be randomly 
assigned—stratified for prior type of RR Preparation treatment and gender—to one of two levels 
of each of the 2 RR Cessation treatment factors in a 2x2 factorial design: 1) Supportive 
Counseling & Maintenance vs. Brief Information, and 2) Skill Training Counseling and 
Maintenance vs. Brief Information (See Figure 2, Figure 2a, and Table 2.)   
 
 
 

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“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
Figure 2a. Long-Term Quitting Study Design.  
 
 
   
 
 
Table 2.  Long-term Quitting Relapse Recovery Cessation Treatment Conditions. 
Condition 
Supportive Counseling Intervention 
Skill Training Counseling Intervention  
1 
Supportive 
Skill Training 
2 
Supportive 
Brief Info 
3 
Brief Info 
Skill Training 
4 
Brief Info 
Brief Info 
*Note.  In factorial designs each main effect is tested; within each column, the shaded vs. non-shaded 
rows are compared. 
 
Clinic Randomized Control Trial  
 
 
 
A set of EHR modifications (described in detail below) will be presented sequentially to 
groups of clinics within both healthcare systems as per an RCT design (RCT). Over 36 months, 
and across the two healthcare systems, the EHR enhancements will be introduced into up to 18 
“experimental” clinics. During this time 10 control clinics will also be inducted into the study. It is 
possible that fewer experimental clinics will be used in this design if recruitment for Projects 2-4 
is so successful that not all 18 clinics are required. The experimental clinics will each participate 
in the study for at least 16 months (albeit, unforeseen events could cause us to terminate 
participation earlier in some clinics: e.g., clinic closure, dramatic change in clinic size or 
structure). Experimental clinics will be yoked to a control clinic for the purpose of fixing the 
duration of participation. A variation of the Multiattribute Utility Measurement Matching strategy 
will be used to allocate experimental and control clinics so that they are matched with regard to 
key baseline variables and timing of study induction.  

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“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
 
 
 
The following will serve as dependent variables: 1) rate of smoking status documentation 
among adult patients visiting the primary care clinic; 2) rate of referral of smokers to smoking 
treatment; and 3) rate of engagement in smoking treatment (the primary outcome).  
 
 
 
A set of standard EHR modifications will be implemented in (up to) 18 experimental 
clinics as part of the RCT. Importantly, these 18 clinics will also serve as recruitment sites for 
participants for Projects 2, 3, and 4, consistent with the integration of all projects across the 
P01. The ultimate, specific N for the experimental group may comprise 10–18 clinics depending 
on recruitment rates; we project good power across this range of sample size. The clinics 
participating in the study will be selected based on the following criteria: 1) Size: clinics will be 
fairly large, including at least 3-6 clinicians, to ensure adequate recruitment for the three clinical 
research projects. 2) Location: clinics will be concentrated in Southcentral and Southeastern 
Wisconsin so that case managers from UW-CTRI Madison and Milwaukee research sites can 
provide services at multiple clinics. 3) Diversity: clinics from both of the health systems will 
include both urban and rural location and a range of SES (based on rates of Medicaid and 
uninsured patients). 4) Independence: we will ensure that clinics with high levels of clinic 
integration (e.g., sharing significant numbers of staff) do not participate (i.e., only one of such 
highly linked clinics can participate). And, 5) all clinics will have to have, or be willing to adopt, 
the control or experimental smoker identification and referral routines (either fax referral or the 
enhanced EHR strategies) and be willing and able to collect necessary data.            
 
 
 
 
The key new EHR functions that will be implemented and tested are: 1) a modified 
“screen for smoking status” to enhance the identification and documentation of all smokers 
visiting targeted primary care clinics; 2) an outreach to smokers, (direct-to-consumer 
communications) about the study availability in their clinic; 3) a 1-click referral system to 
evidence-based smoking treatment with UW-CTRI case managers; 4) a closed-loop feedback 
feature to communicate to the clinician the fate of a referral, documenting receipt of the 
referral and treatment engagement; and 5) EHR-based communication options to inform 
smokers of treatment resources.  
 
 
 
After pre-testing in each healthcare system, the enhanced EHR functionalities will be 
implemented in experimental clinics as they become available for induction into the study 
starting with the two pilot experimental clinics that are identified by the health systems. During 
the 6-month period when the enhanced EHR resources are being developed (anticipated 
completion 1/10/15), candidate clinics will be screened for participation criteria as noted above.   
 
 
 
Assignment to conditions. Clinics will be assigned in sets or groupings using a 
multistage or captive assignment procedure. These sets can vary in size, and not all members 
of a set must be available for assignment at the same time. We propose that assignment may 
start when there are at least 3-6 clinics available for assignment. The clinics in each set will be 
randomly assigned until the set is exhausted, and then clinics within the next set will be 
assigned. Within each set of clinics, a subset will be assigned to the control condition and a 
subset will be assigned to the experimental condition to ensure that assignment to condition is 
not correlated with time and secular events (as the sets will be started at different times as 
additional clinics become available). Finally, we will use an approximation to the MultiAttribute 
Utility Measurement (MAUM) strategy using principal components (PC’s) to stratify clinics with 
regards to possible biasing features: size, mix of Medicaid patients, healthcare system, and 

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“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
rural-urban setting, baseline rate of WTQL referral, and smoker prevalence. These criteria can 
be altered depending upon their pre-assignment availability. Thus, the approach involves: 1) 
Conducting a PC analysis in the pool of potentially available clinics (combined across the 2 
healthcare systems) to identify a small number of uncorrelated PC’s. 2) Integrating the PC’s in a 
way that reflects the hypothesized direction of their impact on outcomes (inflating vs. reducing 
treatment engagement). 3) Locating all clinics available for randomization on a single dimension 
that reflects the hypothesized net impact of the PC’s. 4) Forming two groupings of high and low 
clinics that are set using a cut-score imposed on the dimension composite. 5) The clinics are 
randomly assigned within and across sets in a manner that ensures that approximately an equal 
number of high and low ranking clinics are assigned within each condition. Thus, if a set of 6 
clinics is being used for captive assignment, and this entails assigning 2 of the 6 to the control 
condition, one of the high scoring clinics and one of the low-scoring clinics will be randomly 
assigned to the control condition. Conversely, 2 of the high scoring and 2 of the low-scoring 
clinics must be assigned to the experimental condition (to complete an assignment set), 
exhausting this particular set. Thus, randomization to condition is nested within the high and low 
PC-score groupings. We will assign clinics to the two conditions on a 50/50 basis during early 
recruitment when the ultimate N (and mix of experimental and control clinics is unknown). Note 
that if the set of clinics is quite small (due to limited availability at a given point in time), it might 
be the case that only one clinic can be assigned to a particular condition in that set (e.g., to the 
control condition). In that case, in the next set the clinic assigned to the control condition must 
come from the other end of the PC risk dimension. In this way, the approach is flexible but 
nevertheless increases the likelihood that clinics are assigned to the two conditions at a similar 
rate over time, and that the two conditions are similarly balanced on factors thought to affect the 
dependent variables.    
 
 
Study Procedures, including Visits and Phone Contacts 
 
All participants will attend an initial in-person baseline visit at their primary care clinic 
where they will provide written informed consent, receive information on assigned intervention 
components, complete assessments, provide a breath sample for carbon monoxide (CO) 
assessment, and receive initial treatment based on their treatment condition.  After the initial 
visit, study participation will include phone calls and/or additional in-person visits to provide 
interventions and collect data. 
 
Motivation Study  
This study has two phases:  Motivation and Cessation. While all participants will receive 
Motivation treatment, participation in the Cessation phase of the research depends on whether 
participants decide they would like to quit smoking during the Motivation phase.  
 
Motivation Phase. After the in-person baseline session, all participants in the Motivation 
Study will receive assessment calls at Weeks 12, 26, 39 and 52. They will also receive 11 IVR 
calls over the course of 52 weeks. Participants receiving Behavioral Reduction (BR) Counseling 
and Behavioral Activation (BA) Counseling will receive 1 in-person session at Week 0 followed 
by 9 phone sessions (Table 3). Participants receiving 5Rs Motivation Counseling will receive 1 
in-person session at Week 0 followed by 3 phone sessions (Table 3).  Participants who are 
randomized to receive Nicotine Mini-Lozenge will receive 15 weeks of medication at Week 0. 
Participants who are still using the medication will receive more medication following the 12, 26, 

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“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
and 38-week assessment calls. Medication use and AE assessments will occur either during the 
Week 3 and 5 counseling calls, or alone if the participant is not randomized to receive any 
counseling.  
 
Table 3. Motivation Study Schedule of Study Contacts  
Week 
0 
1 
2 
3 
4 
5 
6 
9 
12 
15 
18 
22 
26 
30 
34 
3
8 39 
43 
47 
52 
Visit 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment 
Call 
 
 
 
X* 
 
X* 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
IVR Calls 
 
 
X 
 
X 
 
X X 
 
X 
X 
X 
 
X 
X 
 
 
X 
X 
 
BR 
counseling 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
BA 
Counseling 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
5Rs 
Counseling 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
Mini-Lozenge 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
*Medication use and AE Assessments only 
 
Cessation Phase. Participants who decide to quit during the first 9 months of the 
Motivation Phase treatment period will receive a cessation treatment. The cessation treatment 
includes in-person counseling sessions at Days -7, 7 and 14, and a counseling phone call on 
the target quit day (TQD).Participants will receive 8 weeks of medication at Day -7 (see Table 
4). Two follow up assessments will occur at 28 and 56 days post TQD to assess for medication 
use and symptoms for the full duration of the medication schedule. Participants who chose to 
receive the cessation treatment will still receive all Motivation Phase phone and IVR 
assessments to permit standardized assessments for all Motivation Phase participants.  
 
Table 4.  Motivation Study Schedule of Treatment Contacts for  
Participants who Choose to Quit Smoking 
Day 
-7 
TQD 
7 
14 
28 
56 
In-Person Counseling 
X 
 
X 
X 
 
 
Phone Counseling 
 
X 
 
 
 
 
Medication 
X 
 
 
 
 
 
Assessment 
 
 
 
 
X 
X 
 
Cessation Study  
After the in-person baseline session, participants assigned to the Modern Usual Care 
(M-UC) will have no other treatment visits or calls, other than the single call from the Wisconsin 
Tobacco Quit Line.  However, participants in this condition will receive the 6 assessment calls at 
Weeks 4, 8, 16, 26, 39 and 52. 
 
 
Participants in the Abstinence-Optimized Cessation Treatment (AOCT) will attend three 
additional visits at 1 week pre-quit, on the Target Quit day (TQD), and 1 week post-quit, during 
which they will receive the in-person counseling (see Table 5). In addition, AOCT participants 
will receive 8 counseling calls at Weeks 3, 4, 6, 8, 10, 14, 18, and 22 as well as 7 or 11 
automated calls that encourage medication adherence at Days 1, 3, 10, 17, 24, 31 and 45 
(those who are still smoking at Week 8 will receive 4 additional automated adherence calls to 
encourage medication use at Days 73, 101, 126 and 154). Participants in AOCT will receive 3 
weeks of pre-quit nicotine mini-lozenges at Visit 1 and will receive nicotine mini-lozenges and 

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“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
nicotine patches 1 week before their quit day.  Participants who are still using the medication will 
receive more medication following the 8-week and 16-week assessment calls.   
 
Table 5.  Cessation Study Schedule of Treatment Contacts for AOCT Participants. 
Day 
-21 
-7 
TQD 
1 
3 
7 
10 
17 
24 
28 
31 
45 
56 
73 
101 
112 
126 
154 
Week 
-3 
-1 
0 
1 
1 
1 
2 
3 
4 
4 
5 
6 
8 
10 
14 
16 
18 
22 
Visit 
1 
2 
3 
 
 
4 
 
 
 
 
 
 
 
 
 
 
 
 
Medication 
X 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
In-Person 
Counseling 
 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Maintenance 
Calls 
 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
Automated 
Calls* 
 
 
 
X 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
IVR Calls** 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Assessment 
Calls† 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
*Automated calls will be discontinued after Week 6 for those who report abstinence at their Week 8 assessment call 
**IVR calls will be daily from 1 week pre-quit through 2 weeks post-quit. 
†Additional assessment calls will occur at Weeks 26, 39 and 52. Further, participants reporting abstinence at 26 weeks will be 
invited to come to the clinic to provide a breath sample for biochemical confirmation of abstinence. 
 
Long-term Quitting Study  
This study has three potential phases:  Initial Cessation (also called the “Quit Phase”), 
Relapse Recovery (RR) Preparation (also called the “Preparation Phase”), and RR Cessation 
(also called the “New Quit Phase”). While all participants will receive the same Initial Cessation 
Treatment, participation in the subsequent phases of the research depends on participant 
response to the prior phase and on what RR Preparation condition they are randomized to.  
 
Initial Cessation Phase. All participants will receive the same Initial Cessation 
Treatment, and includes an in-person counseling session at Day -7 and counseling phone calls 
on Day 7, and Day 14 (see Table 6). There will also be assessment calls from research staff 
(see Table 6).  Initial Cessation Assessments will stop once a participant is randomized to the 
RR Preparation treatment or Control conditions.  
 
Table 6.  Long-Term Quitting Study Initial Cessation Phase Schedule of Treatment Contacts*  
Day 
-7 
-1 
1 
3 
7 
14 
28 
56 
84 
112 
140 
168 
Week 
-1 
 
 
 
1 
2 
4 
8 
12 
16 
20 
26  
Visit 
X 
 
 
 
 
 
 
 
 
 
 
 
Medication 
X 
 
 
 
 
 
 
 
 
 
 
 
In-Person Counseling 
X 
 
 
 
 
 
 
 
 
 
 
 
Phone Counseling 
 
 
 
X 
X 
 
 
 
 
 
 
IVR Calls 
 
X 
X 
X 
 
 
 
 
 
 
 
 
Assessment Calls 
 
 
 
X† 
X† 
X 
X 
X 
X 
X 
X 
*All treatment and assessments will be discontinued for those who relapse between the quit date and 6 months postquit. 
(Relapse criteria can first be met at 6 days after the target quit day.) †These assessment calls will be combined with the 
counseling calls.  

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“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
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Fiore P01 Protocol, Version 10, July 19, 2018  
 
 
RR Preparation Phase. Participants may enter the Relapse Recovery (RR) Preparation 
phase if relapse is detected during the initial cessation treatment for up to 6 months after the 
quit day via either counseling calls or assessment calls. If relapse is detected, the health 
counselor or student assessor will randomize the participant to one of the 3 RR Preparation 
intervention conditions via a dynamic real-time database.  If the participant does not relapse or 
chooses not to enter the preparation phase during this 6 month period, they will not be eligible 
for the RR preparation phase.  
 
If participants are assigned to the Preparation Control condition, they will be encouraged 
to continue the Initial Cessation treatment (if counseling sessions and/or medication remain) 
and to continue taking the study medication, but to contact the WTQL or talk to their referring 
clinician for additional treatment. Participants in the Preparation Control condition will be given 
WTQL contact information only the first time they report relapse. The RR Preparation Control 
participants will complete their RR Preparation baseline assessments at their first Standard 
Assessment Staff call at Week 1. They will also be asked to attend a visit at the 14 month mark 
to provide a CO sample if they claim abstinence at that time (abstinence demonstrated by a CO 
<= 5 ppm). 
 
 
Participants assigned to an “active” RR Preparation condition (either Reduction or 
Recycling) will schedule a visit. At the visit, participants will complete RR baseline assessments, 
the nature of that treatment will be explained, future contacts will be described and scheduled, 
and treatment will be provided (Behavioral Reduction Counseling + nicotine mini-lozenges or 
Recycling Counseling); see Table 7. This first contact, where RR Preparation treatment begins 
for those in non-control conditions, is designated Preparation Day 0. Subsequent treatment 
contacts will be scheduled for such participants for Week 2 and Months 1, 3, 6, 9, & 11 post-
Preparation Day 0. The contacts at Week 0 and Months 1 & 6 will be in-person visits; all other 
RR Preparation contacts will be by phone. However, if a participant cannot attend an in-person 
visit, a phone visit will be conducted instead.  
 
All participants assigned to the non-control (active) RR Preparation conditions will 
receive Standard Assessment Staff calls (at Week 1 and Months 2, 4, 7, & 10) in addition to 
assessments that occur at RR Preparation treatment contacts (at Day 0, Week 2, and Months 1, 
3, 6, 9, & 11). The phone assessments occurring at RR Preparation treatment contacts other 
than the Day 0 and Week 2 contacts will be brief, collecting primarily data on smoking since the 
last treatment contact. Finally, all RR Preparation participants (including those in the control 
condition) will participate in follow-up calls at Month 14; at Month 14 they will be asked to make 
a visit to provide a CO sample should they claim abstinence (see Table 7).   
 
Table 7.  Long-Term Quitting Study RR Preparation Phase Schedule of Treatment Contacts*  
Preparation 
Week 
Preparation 
Day 0 
(Day 0) 
1 
2 
4 
8 
10 
12 
16 
24 
28 
32 
36 
40 
41 
43 
56 
Month 
0 
 
1 
2 
 
3 
4 
6 
7 
8 
9 
10 
 
11 
14 
Visit 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X† 
Reduction or 
Recycling 
Counseling  
X 
 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 

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“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
Quitting Help 
Letter 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
Assessment 
at Prep 
Phase 
treatment 
contacts 
(controls do 
not get this) 
X 
 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
Standard 
Assessment 
Staff Calls  
 
X*** 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
† A visit to biochemically confirm abstinence will follow the Month 14 call for those who claim abstinence. 
*All Preparation medication and treatment content will be discontinued for those who transition to the Cessation Phase. 
Participants in the Cessation Phase will, however, continue to complete the Standard Assessment Staff Calls. All 
participants (including RR Preparation Control participants) will complete the Standard Assessment Staff Calls and the 14 
month assessments listed above. 
**Medication is only for participants in Reduction Counseling. 
***Preparation Control participants get the Standard Assessment Staff Call at Week 0 instead of at Week 1. 
Note.  RR Preparation Control participants will get only the Standard Assessment Staff calls and not other treatment 
elements, assessments, or visits. 
 
RR Cessation Phase.  Participants enter the RR Cessation Phase when they are in the 
active Preparation Phase conditions and indicate they are ready to make a new cessation 
attempt. Participants assigned to the RR Reduction condition will be encouraged to delay their 
new quit attempt (for at least one month or longer) until they have had some experience 
reducing their smoking and building their quitting skills. However, if participants in Reduction 
Counseling strongly wish to quit before 1 month has passed, they will be transitioned into the 
RR Cessation Phase earlier. In both the RR Reduction and Recycling conditions, as soon as 
participants enter RR Cessation treatment (via either a Staff Assessment call, an RR 
Preparation therapy call or visit, or by proactively contacting their counselor/research program), 
they will be randomly assigned to one of the 4 RR Cessation conditions.  
 
All RR Preparation participants (both control and non-control) will complete Standard 
Assessment Staff Calls regardless of entry into RR Cessation treatment. However, once a 
participant has entered RR Cessation treatment, all RR Preparation treatment contacts will end. 
Thus, for those in RR Cessation treatment, all RR Preparation medication and treatment content 
will be discontinued.   
 
The first contact in RR Cessation treatment will be a visit (RR Cessation Day -7). That 
visit will be scheduled during the RR Preparation contact when the participant reports wanting to 
try to quit.  If the RR Preparation contact at which the participant decides to enter RR Cessation 
is an in-person contact, it is possible that the Day -7 Cessation treatment contact will be initiated 
at that Preparation visit.   
 
 Participants assigned to Brief Information only will have 1 RR Cessation visit on Day -7 
when they receive their medication and basic, brief (“generic”) cessation counseling.  They will 
also receive 2 brief phone counseling contacts at the TQD and at Week. 1. If a participant is 
assigned to Skill Training or Supportive Counseling or both, they will receive 2 visits (at Day -7 
and Day +7) and 7 brief phone calls on Day -2, the TQD, and at Weeks 2, 3, 6, 8.5 and 14 (see 

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“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
Table 8).   
 
In addition to the RR Preparation Standard Assessment Staff Calls and 14-month follow-
up call that continue from the RR Preparation phase, participants in the New Quit Phase will 
complete assessment on the first RR Cessation treatment visit, automated assessment calls 
(IVR calls) -4, -1, +1, +3 after initiation of RR Cessation treatment, and RR Cessation Follow-up 
Calls at Days +7, +14, Months 1, 2, 4, and 6 after initiation of RR Cessation treatment.  
 
Table 8.  Long-Term Quitting Study RR Cessation Phase Schedule of Treatment Contacts  
Day 
-7 
-2 
TQD 
7 
14 
21 
28 
42 
60 
70 
98 
112 
182 
Week 
-1 
 
0 
1 
2 
3 
4 
6 
 8.5 
10 
14 
16 
26 
Month 
  
 
0 
  
  
  
1 
  
  
2.5 
 
4 
6 
Visit with assessments 
X 
 
  
X** 
  
  
  
  
  
 
 
 
 
Medication 
X 
 
  
  
  
  
  
  
 
 
 
 
Brief Information  
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
Supportive and/or Skills 
Counseling  
X 
X 
 X 
X 
X 
X  
  
X  
X 
 
X 
 
 
IVR Calls 
Days -4, -1, 1, and 3 
 
 
 
 
 
 
 
 
 
Assessment  
  
 
  
~X  
~X  
  
X 
  
X 
 
X 
X 
 ** This visit at Week 1 is only for participants randomized to Supportive Counseling, Skills Counseling, or both. 
~The assessment occurs during the treatment call wherever possible. 
The Intervention Components 
 
      All 3 studies will use as their primary interventions nicotine replacement therapy for 
treating smokers and one or more specific types of counseling.  They will also employ the same 
research staff (referred to as health counselors) with each health counselor trained to provide all 
types of counseling.  The research will use specific quality/fidelity assurance strategies that 
include: intensive case manager training in counseling and ethical conduct, mock sessions, 
review of audiotapes, and meetings to discuss safety, confidentiality, and treatment fidelity. 
Health counselors will meet every other week for clinical supervision with a clinical psychologist 
investigator to review the study protocol and address treatment issues. A common database 
provides guidance on the counseling content, medication and assessments to be provided at 
each contact. Such procedures have produced excellent treatment delivery fidelity in our recent 
work.  The distinct intervention components are detailed below. 
 
Motivation Study 
Participants in the Motivation Study may receive treatment during 2 phases:  Motivation 
and Cessation. While all participants will receive Motivation treatment, participation in the 
Cessation phase of the research depends on whether participants decide they would like to quit 
smoking during the Motivation phase.  
 
 
      Motivation Phase. All participants will start the study in the Motivation Phase. 
 
Nicotine Replacement Therapy (NRT). Participants randomly assigned to the Mini-
Lozenge condition will use either the 2- or 4-mg doses (smoke within 30 min of waking = 4mg; 
smoke more than 30 min after waking = 2mg—as per package insert). Starting Spring 2018 we 
started to screen individuals who would be prescribed mini-lozenges for soy allergens prior to 

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“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
dissemination to prevent allergic reaction AEs - per the ML new package insert. Participants will 
be instructed to use the product for 12 months and to use it in a scheduled manner consistent 
with the 2008 PHS Guideline; they will be instructed to use one Mini-Lozenge every 1-2 hours 
and up to 12 daily, with a goal of using at least 5 daily. Participants will receive 12-weeks of 
medication at Visit 1 and will be sent additional medication after the assessment calls at Weeks 
12, 26, and 39. The case manager will provide use instructions, teach participants to detect 
symptoms of nicotine toxicity, and encourage them to reduce smoking and/or NRT use to avoid 
these symptoms. All participants will be given an information sheet that conveys all medication 
instructions as well as a phone number to call if they have concerning side effects or other 
questions about their medication. All participants will be told to promptly report any difficulty, 
side effects or allergic reactions, and we will consult with participants as per good clinical 
practice to address any problems they have with NRT use. In some cases we may counsel 
participants to stop using NRT if they develop significant side effects (e.g., vomiting). The case 
manager will refer the patient to their primary care physician should the patient require medical 
consultation.  
 
Behavioral Reduction Counseling (BR). We will deliver BR in 10 (10-15 minute) sessions 
over a 52-week period, with an in-person session at Visit 1 followed by nine phone counseling 
sessions (see Table 3). Sessions are front-loaded to enhance acquisition of new behaviors. BR 
Counseling will emphasize the development of smoking control skills via feasible, specific, and 
graded assignments of smoking reduction activities that will be tracked over time. BR will also 
emphasize competence and self-efficacy, both which will be directly linked to the practice of 
smoking reduction skills and success in smoking control. The health counselor will provide 
rationales for the reduction intervention, why reduction (e.g., eliminating smoking contexts) 
should help the smoker, and provide the participant with specific exercises and goals. The 
health counselor will explicitly address pragmatic issues such as work contexts, smoking 
policies, and habits that interfere with smoking reduction efforts. The health counselor will 
suggest the strategic use of medication to help achieve reduction goals (as appropriate with 
NRT treatment assignment). The health counselor will not pressure the smoker to quit. Smoking 
reduction will be presented as an important and worthwhile goal, and participants will be told 
that they are in the best position to decide when they are ready to make a quit attempt.  
 
Behavioral Activation (BA). The BA treatment will be delivered in 10 (10-15 minute) 
sessions over a 52-week period starting with Visit 1 followed by nine phone counseling sessions 
(see Table 3). This BA treatment will be modeled after Behavioral Activation for quitting 
smoking, but made relevant for smoking reduction. Treatment goals focus on helping 
participants engage in positively reinforcing activities while not smoking. The treatment includes: 
1) a rationale for the BA exercises as they relate to smoking (e.g., engaging in non-smoking 
reinforcers will provide other sources of pleasure and assist with cutting down); 2) assessment 
of the participant’s goals, values, and reinforcing value of current nonsmoking activities; 3) 
training in self-monitoring using an activity log; 4) ongoing assignments of activities that should 
significantly increase the participant’s nonsmoking reinforcement and create broader lifestyle 
and cue exposure changes; and 5) problem-solving to address obstacles to goal attainment. BA 
fosters a collaborative, problem-solving relationship between the health counselor and 
participant, and will be front-loaded (a dense schedule of sessions early in treatment) since BA 
activity assignments depend on the early assessment of the participant’s reinforcing activities 
and feedback on success in assignment completion.  
 

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“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
5Rs Motivation Counseling. The 5Rs Motivation Counseling will be delivered in four (10-
15 min) sessions over a 52-week period starting at Visit 1 and followed by three phone 
counseling sessions (see Table 3). Participants in the "on" condition will receive three brief 
phone sessions over the year to prompt processing of motives for smoking reduction or 
cessation. This light schedule of sessions is a reasonable burden even when paired with the 
other counseling conditions. The same health counselor will conduct these sessions and any 
other counseling interventions components (e.g., BR Counseling) with the participant. 5Rs 
Motivation Counseling will be similar to that described in the 2008 PHS Guideline. The health 
counselor and smoker will discuss: 1) Relevance of smoking to the individual; 2) Risks of 
continued heavy smoking; 3) Rewards of quitting and significant reduction; and 4) Roadblocks 
to success; and will do so on a 5) Repeated basis. The discussion will follow the general 
principles of MI: counselors will use strategies that are nonauthoritarian, nonconfrontational, 
supportive, and use open-ended questions. At the 2nd-4th sessions, the health counselor will first 
ask the patient to discuss his/her current feelings about smoking and then will review the 
patient’s thoughts and attitudes shared in previous sessions. The participant will be asked to 
discuss any changes that have occurred over time and their relevance to making a behavior 
change—towards both smoking reduction and cessation goals. If a participant has stopped 
smoking, the call will be directed at reinforcing cessation.  
 
Cessation Phase.  Motivation Phase participants who decide to quit smoking during the 
9 months of the intervention period will receive a smoking cessation treatment, delivered by 
their same health counselor with whom they have been working. This cessation treatment will 
involve 2 in-person counseling sessions and 2 phone counseling sessions (see Table 4). 
Participants will also receive 8 weeks of the Nicotine Patch and Nicotine Mini-Lozenge.  
 
Medication.  Participants will receive 8 weeks of nicotine patch (participants who smoke 
>10 cigs/day: 4 weeks of 21 mg, 2 weeks of 14 mg, and 2 weeks of 7 mg nicotine patches; 
participants who smoke <=10 cigs/day: 6 weeks of 14 mg and 2 weeks of 7 mg nicotine 
patches) at the Day -7 counseling session (see Table 4) and will be instructed to begin using the 
patch on the TQD. Participants will also receive 8 weeks of the Mini-Lozenge, and use either the 
2- or 4-mg doses (smoke within 30 min of waking = 4mg; smoke more than 30 min after waking 
= 2mg—as per package insert). Starting Spring 2018 we started to screen individuals who 
would be prescribed mini-lozenges for soy allergens prior to dissemination to prevent allergic 
reaction AEs - per the ML new package insert. Participants will be instructed to use it in a 
scheduled manner consistent with the 2008 PHS Guideline; they will be instructed to use one 
Mini-Lozenge every 1-2 hours and up to 12 daily, with a goal of using at least 5 daily. All 
participants will be given complete instructions on proper patch and Mini-Lozenge use, including 
an information sheet and contact information if they want to ask questions regarding their 
medication, and/or symptoms they experience. We will recommend dosage/use alterations as 
per good clinical practice if the participant experiences any medication side effects. The case 
manager will refer participants to their primary care physician should they require medical 
consultation. Participants will be asked to take the medication for the full 8 weeks, regardless of 
whether they return to smoking.  
 
Counseling. Participants who decide to quit smoking will receive a 20 minute in-person 
counseling session at Day -7 that will involve preparing for the TQD (e.g., reinforce motivation, 
remove cigarettes and smoking paraphernalia from the environment, plan for the quit day), 
develop techniques to cope with withdrawal symptoms and smoking triggers, including negative 

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“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
affect and withdrawal, and provide support (see Table 4). A 20-minute phone counseling 
session will occur on the TQD, followed by 2, 20-minute in-person counseling sessions on Days 
7 and 14. These sessions will focus on maintaining abstinence, coping with withdrawal 
symptoms and smoking triggers, encouraging requitting following a lapse, and providing support 
(see Table 4 for counseling schedule). 
 
Cessation Study  
Modern Usual Care (M-UC).  We developed the Modern Usual Care (M-UC) to serve as 
a control condition to demonstrate that the abstinence-optimized cessation treatment would 
result in improved cessation compared to what would typically happen in a primary care 
practice. However, we wanted a control condition that was sufficiently effective to serve as a 
reasonable control condition.  Therefore, while “usual care” in primary care may not extend 
beyond advice to quit smoking, participants assigned to the M-UC will receive 8 weeks of 
nicotine patch, a single brief, in-person counseling session, a faxed referral to the Wisconsin 
Tobacco Quit Line (WTQL), and will be signed up for either the QUITNOW app or the Web 
Coach (both provided by Alere Wellbeing, the vendor that provides the WTQL services).   
 
Medication.  M-UC participants will receive 8 weeks of nicotine patch (participants who 
smoke >10 cigs/day: 4 weeks of 21 mg, 2 weeks of 14 mg, and 2 weeks of 7 mg nicotine 
patches; participants who smoke <=10 cigs/day: 6 weeks of 14 mg and 2 weeks of 7 mg 
nicotine patches) at their first clinic visit and will be instructed to begin using the patch on the 
TQD. All participants will be given complete instructions on proper patch use, including an 
information sheet and contact information if they want to ask questions regarding their 
medication, and/or symptoms they experience. We will recommend dosage/use alterations as 
per good clinical practice if the participant experiences any medication side effects. The case 
manager will refer participants to their primary care physician should they require medical 
consultation. Participants will be asked to take the medication for the full 8 weeks, regardless of 
whether they return to smoking. 
 
Counseling and Technology.  Participants in the M-UC condition will receive a brief (10 
minute) counseling session that will involve setting a quit date, identifying motivation for quitting 
and preparing for the quit date.  Participants will then complete a fax-to-quit referral form for the 
WTQL, which will be faxed to the WTQL and result in the WTQL calling the participant to 
provide cessation counseling at the time of the participant’s choosing. Finally, the health 
counselor and the participant will review a handout that educates the participant about the 
QUITNOW app and the Web Coach feature from the WTQL. The handout will review how the 
app will provide access to evidence-based tools to help the smoker quit and for the first 2 weeks 
post-quit will provide active support and how to complete the 3 set-up screens for the app: 1) 
entering the quit date; 2) entering the number of cigs/day they smoke and the cost/pack; and 3) 
entering the reasons for quitting. The handout will also remind participants to mention their 
interest in the Web Coach feature to the Quit Line caller, who will then send them the link and 
password so that they can access the Web Coach after their Quit Line call.  The handout will 
also provide the link to a brief 4-minute video about the Web Coach site, which will illustrate how 
they can enter their quit date and medication into their quit plan and access the different tools 
and support from the website through quit coaches or other quitters in the web community.  
 
Abstinence-Optimized Cessation Treatment (AOCT). In our prior research using the 
Phase-Based Model and MOST, we conducted two screening experiments and experimentally 

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19 
“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
evaluated 19 different intervention components delivered during the Preparation, Cessation, or 
Maintenance Phases. Based on the results, we identified 5 particularly effective intervention 
components to include in the AOCT package: 1) Preparation Nicotine Mini-Lozenges; 2) 26-
week postquit Combination NRT (nicotine patch + nicotine mini-lozenges); 3) Intensive In-
Person Cessation Counseling; 4) Extended Maintenance Counseling Calls; and 5) Automated 
Adherence Calls. Earlier research supports the individual intervention components identified by 
our screening experiments but no research has evaluated how well these components work 
together as an integrated treatment package, one assembled based upon experimental 
evidence that these components exert additive and synergistic effects when used together (as 
per MOST). Because our earlier screening experiments show that each of these components 
produces especially great benefit at the phase of smoking intervention at which it is used, we 
hypothesize that these components will constitute a particularly effective treatment package. 
Moreover, because the screening experiments occurred in real-world healthcare settings, and 
the intervention components were designed for this context, we believe that they will easily 
translate to real-world use.  
 
Medication. The 3 weeks of Preparation nicotine mini-lozenge use will begin the day 
after Visit 1 (Week -3), during which most participants will likely continue to smoke regularly, 
albeit at a reduced rate. Participants will use 2- or 4-mg mini-lozenges, depending on how soon 
they smoke after waking, as per package insert (smoke within 30 min of waking = 4mg; smoke 
more than 30 min after waking = 2mg). Starting Spring 2018 we started to screen individuals 
who would be prescribed mini-lozenges for soy allergens prior to dissemination to prevent 
allergic reaction AEs - per the ML new package insert. Participants will be instructed to use the 
product in a scheduled manner consistent with the 2008 PHS Guideline; they will be instructed 
to use one Mini-Lozenge every 1-2 hours and up to 12 daily, with a goal of using at least 5 daily. 
Participants will be advised to try to cut down on their smoking, stop smoking in different places, 
and substitute mini-lozenges for cigarettes in preparation for quitting. Preparation use of NRT is 
safe and accepted by the FDA.  
 
 
Starting on the TQD, participants will be instructed to use both the nicotine patch and the 
nicotine mini-lozenges. Patch dosing and mini-lozenge dosing will be consistent with the 2008 
PHS Guideline and package inserts (smoke within 30 min of waking = 4-mg mini-lozenge; 
smoke more than 30 min after waking = 2-mg mini-lozenge; smoke >10 cigs/day = 22 weeks of 
21-mg, 2 weeks of 14-mg, and 2 weeks of 7-mg nicotine patches; smoke <=10 cigs/day = 24 
weeks of 14-mg and 2 weeks of 7-mg nicotine patches). Participants will be told to try to use a 
mini-lozenge every 1-2 hours until 2 weeks before treatment termination at which time 
participants should cut down until they are down to no mini-lozenge use by the end of 26 weeks. 
Participants will also be told that they may not be able to take a full, recommended dose of mini-
lozenges given their conjoint use of the patch. Participants will be urged to use an average of 9 
mini-lozenges/day, unless this amount of use produces negative (toxic) effects—instructions 
which have been shown to be effective in prior research; it reduces the potential for side effects, 
and research shows that very few people use ≥9 pieces of oral NRT, whether alone or in 
combination with other NRT, regardless of instructions. All participants will be given complete 
instructions on proper NRT use, including an information sheet and contact information if they 
want to ask questions regarding their medication, and/or symptoms they experience. We will 
recommend dosage/use alterations as per good clinical practice if the participant experiences 
symptoms of nicotine toxicity or other side effects. The case manager will refer participants to 
their primary care physician should they require medical consultation. Participants will be asked 

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“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
to take the medication for the full 26 weeks, regardless of whether they return to regular 
smoking.  Additional medication will be mailed to those still using the medication, following the 
assessment calls at Weeks 8 and 16.   
 
Counseling and Automated Calls. Participants in the AOCT will receive In-Person 
Cessation Counseling which will be supportive and focus on skill development and problem-
solving, as recommended by the 2008 PHS Guideline. The goals of Cessation-phase 
counseling are to prepare for the TQD (e.g., reinforce motivation, remove cigarettes and 
smoking paraphernalia from the environment, plan for the quit day), develop techniques to cope 
with withdrawal symptoms and smoking triggers, including negative affect and withdrawal, and 
provide support. There will be three 20-min In-person Cessation Counseling sessions (Week -1, 
TQD, Week 1). The timing and counseling content of the three sessions is consistent with the 
2008 PHS Guideline recommendations. AOCT participants will also receive 8 Maintenance-
phase smoking cessation counseling sessions.  These 15-minute calls emphasize content 
similar to that provided in the In-Person counseling, namely support and problem-solving.  
 
Finally, participants will receive 11 brief, automated calls reminding them to use their 
medications properly at Days 1, 3, 10, 17, 24, 31, 45, 73, 101, 129, and 157. However, if 
participants report that they are not smoking during the Week 8 assessment call, they will not 
receive any further automated adherence messages (i.e., they would get 7 automated calls 
during the first 6 weeks of their quit attempt).  This decision was based on data from our prior 
study that suggested that smokers who were able to achieve abstinence early in the quit 
attempt, appeared to have less long-term cessation success if they got the automated 
adherence calls. 
 
 
 
 
 
Long-term Quitting Study  
 
Initial Cessation Treatment. The Initial Cessation Treatment, which meets the standard 
of care, will include 3 counseling contacts: one 10-minute in-person counseling session 1 week 
prior to the quit day, and 5 min counseling calls 1 and 2 weeks post-quit. The counseling 
content will be supportive and will include some skill development as recommended by the 2008 
PHS Guideline (Fiore et al., 2008). The counseling will include encouragement and will also 
emphasize the importance of taking the medication and how to use it, and provide information 
about side effects/safety and what to do in case of problems. Participants will receive 8 weeks 
of nicotine patch (participants who smoke >10 cigs/day: 4 weeks of 21 mg, 2 weeks of 14 mg, 
and 2 weeks of 7 mg nicotine patches; participants who smoke <=10 cigs/day: 6 weeks of 14 
mg and 2 weeks of 7 mg nicotine patches). Participants will receive their medication at Visit 1 
(i.e., 1 week before the quit day).  
 
Relapse Recovery Phase.  If participants relapse within 6 months of their Initial 
Cessation treatment quit day, they will be eligible to receive RR Preparation treatment unless 
they have been randomized to the RR Preparation Control condition. Relapse will be defined as 
7 consecutive days of smoking at any point after the quit day. Relapse will be detected via 
counseling calls and Initial Cessation phase assessment calls (see Table 6). Participants will 

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21 
“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
also be asked to call the program office if they return to daily smoking. Participants in the 
Relapse Recovery Preparation Phase (and not in the RR Preparation Control condition) will be 
randomized to one of two treatments:  Behavioral Reduction Counseling + Nicotine 
Replacement Therapy (NRT with the nicotine mini-lozenge) or Recycling Counseling.  
 
Table 9.  Counseling contacts for the Relapse Recovery Preparation Phase Components. 
Note: C = Calls  V = VisitsRR Reduction Counseling and Nicotine Replacement Therapy. 
Participants randomized to this treatment will receive manual-based counseling calls and visits 
over the course of 11 months (see Table 9). The ultimate goal will be smoking that is reduced in 
amount and location. Case managers and participants will collaboratively identify a set of steps 
to progressively reduce smoking (e.g., make the house smoke-free). The primary vehicles for 
change are to encourage substitution of the nicotine mini-lozenge for cigarettes and to reduce 
the contexts in which smoking occurs (including making the home smoke free). Counseling will 
counter post-lapse demoralization by emphasizing participants’ progress, the value of smoking 
reduction as a transitional goal, and the critical value of ongoing treatment engagement.  
Evidence of progress in reduction of smoking, and smoking contexts will be used to build self-
efficacy. Case managers will monitor the outcomes of these tasks, provide feedback to patients 
on their status over time and help participants attribute their success to their own efforts. 
  
 
Participants will also receive up to 11 months of mini-lozenges as part of this treatment 
(dosing based on their nicotine dependence as measured when they started the study: 4 mg if 
they smoked within 30 minutes of waking and 2 mg if they smoked more than 30 minutes after 
waking, as per the package insert), along with instructions for use. Starting Spring 2018 we 
started to screen individuals who would be prescribed mini-lozenges for soy allergens prior to 
dissemination to prevent allergic reaction AEs - per the ML new package insert. Participants will 
receive 2 months of mini-lozenges at the Week 0 visit, 2 months of mini-lozenges at the Month 1 
visit, 3 months of mini-lozenges following the counseling call at Month 3, and the last 4 months 
of mini-lozenges at the Month 6 visit. If participants don’t attend the RR Reduction Counseling 
V1, V2, or V3 but they indicate that they want mini-lozenges, we will mail the mini-lozenges to 
them.  Participants will be able to switch to a lower dose of mini-lozenges over the course of 
Reduction Therapy if the Medication Safety Assessment suggests this could be helpful. 
Participants will be encouraged to use around 9 lozenges/day for the duration of time they are in 
Reduction therapy. If adherence data suggest low usage, the health counselor will work with the 
participant to identify barriers to use. Participants will also be asked about the occurrence of 
side effects. Participants will be told that if they are using the mini-lozenge regularly and are 
smoking in only a limited number of contexts, they are building success for their quit attempt. 
The intent is to convey a realistic and positive appraisal of participants’ increasing ability to 
control their smoking.  
   
 
After 1 month of treatment, at every RR Reduction Counseling contact case managers will 
offer participants the option of beginning RR Cessation treatment.  However, care will be taken 
 
Wk 0 
Wk 2 
Mo 1 
Mo 3 
Mo 6  
Mo 9 
Mo 11 
RR Reduction Counseling
  
 (All calls 15 min; 30 min Visit 1; 
20 min at Visit 2 and 3) 
V1 
C1 
V2 
C2 
V3 
C3 
C4 
RR Recycling Counseling 
(20 min at V1; 15 min at V2, 10 
min at V3; all others are 5-10 min) 
V1 
C1 
V2 
C2 
V3 
C3 
C4 

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“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
to ensure that participants do not feel pressured to make a quit attempt before they are ready.  
 
 
 
RR Recycling Counseling. Participants assigned to this treatment condition will also have 
7 treatment contacts (see Table 9) and will be encouraged to commit to a quit date as soon as 
they feel ready. As in prior recycling efforts, participants will be encouraged to discuss reasons 
for quitting, concerns and barriers, and to view abstinence as the primary treatment goal.  
 
 
 
To ensure all participants remember they can make a quit attempt with study help at any 
time, participants in both the RR Reduction and Recycling Conditions will receive letters, emails, 
or text messages (depending on the preferred delivery route they selected at the start of the 
study and depending on what is feasible) at Weeks 10, 32, and 41 encouraging them to make a 
quit attempt and providing information on how to contact study staff to receive RR Cessation 
treatment.    
 
 
RR Cessation or “New Quit” Phase.  When participants opt to make a new quit attempt 
within 11 months of entering the RR Preparation Phase, they will be transitioned to RR 
Cessation treatment. RR Cessation Phase participants will be randomized to one of 4 treatment 
conditions (a 2x2 factorial design) comprising 2 active intervention components: 1) Skill-Based 
Training vs. Brief Information; and 2) Supportive Counseling vs. Brief Information. Each form of 
counseling is designed to boost cessation success through the incorporation of medication 
adherence content: i.e., the importance of using medication despite lapsing, inculcating positive 
beliefs about medication, and so on. Participants will receive skill-based, supportive counseling 
or both prior to and after discontinuation of study medication, including supportive maintenance 
phone calls. Elements of this counseling will be designed to ease the transition off medication.   
 
 
The delivery of each active counseling component (i.e., Skill-Based Training or Supportive 
Counseling) will take 15-20 minutes at Visit 1, 15 minutes at Visit 2 and 10-15 minutes/call. The 
RR Cessation Brief Information intervention will take about 5 minutes/contact and occur at Visit 
1 and 2 and the Target Quit Day. When a participant receives both of the active components the 
net delivery time will be 35-45 minutes for each visit and 20-25 min/call to ensure that the Brief 
Information content is also covered (see Table 10).   
Table 10. Long-Term Quitting Study RR Cessation (“New Quit”) Phase Counseling  
Week 
-1 
Day -2 
0 
(TQD) 
1 
2 
3 
6 
8.5 
14 
Total 
Contact 
Time 
Visit or Call 
V 
C 
C 
V* 
C 
C 
C 
C 
C 
 
# Minutes Brief Info 
Only 
5 
 
5 
5 
 
 
 
 
 
15 
# Minutes Support or 
Skill Training + Brief 
Info 
20-25 
10-15 
15 
20 
10 
10 
10 
10 
10 
115-125 
# Minutes Support + 
Skill Training + Brief 
Info 
35-45 
20-25 
25 
35 
20 
20 
20 
20 
20 
215-230 
*This is a call for the Brief Info Only Group. TQD = Target Quit Day 
 
 
Brief Information. All participants will receive brief (generic) information about the 
importance of taking the medication and how to use it, information about side effects/safety and 
what to do in case of problems, and will also be given encouragement.  
 

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23 
“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
 
 
Skill Training Therapy.  Skill training therapy will: 1) carefully assess smoking cue contexts 
and opportunities to smoke, concentrating especially on problems encountered in the 
participant’s prior quit attempt; 2) develop specific plans for avoiding such contexts and skills for 
coping with them; 3) help participants develop plans for negotiating with critical others who 
smoke (e.g., housemates, co-workers); 4) develop lifestyle changes to reduce future smoking 
opportunities and contexts; and 5) assign homework and assess execution of assigned skills.  
Participants will also receive coping menus that the counselor fills out with the patient that 
provide personalized coping/avoidance options and “coping reports” that assess coping 
execution over time and troublesome contexts and cues around which counseling will be 
focused. These will be handed to participants after sessions or emailed or mailed to participants 
(based on the participant’s preference) after some calls. While the emphasis will clearly be on 
skill acquisition and execution, the targeting of skills for individual participants will be done in a 
collaborative manner. There will be praise for any progress and a collaborative determination of 
barriers to skill execution. Thus, coping and avoidance plans will be: 1) collaboratively 
developed, 2) given/ sent to patients immediately after any contact where plans are developed, 
and 3) reviewed carefully at future contacts to refine coping plans. The key elements of this 
counseling will be specific, individualized coping plans, monitoring of plan execution and effects, 
and on-going modification of plans.  
 
 
Supportive Therapy. This intervention will comprise elements and content consistent with 
the characterization of intra-treatment support as contained in the PHS Clinical Practice 
Guideline (Fiore et al., 2008). Thus, it will involve encouragement (e.g., information that 
previous failure to quit is often positively related to subsequent success), a focus on short-term 
goals (e.g., go without smoking for 2 hours, communication of belief in the participant’s ability to 
quit), discussion of participant values (what the participant feels would be good and healthy for 
them in the long run) and how these values are congruent with cessation, emphasis on the 
patient and the counselor being a team, encouragement for the participant to generate a quitting 
strategy with the message that smokers often have a good sense of what will work for them (a 
client centered approach), and prompts for the participant to explore his/her feelings about 
quitting and feelings of optimism and concern; i.e., to use the counselor as a sounding board.  
Therefore, the Skill Training approach emphasizes explicit training while the Supportive 
intervention does not. Because these two forms of therapy may co-occur, counseling manuals 
will be carefully prepared so as to permit their effective integration. For instance, while the Skill 
Training intervention will recommend coping skills for the participant, when the participant also 
receives Supportive counseling s/he will be encouraged to discuss his/her feelings about the 
quit plan and reflect on its “fit” for his/her life.  
 
 
 
Medication.  All participants will receive 8-weeks of combination NRT (nicotine patch + 
nicotine mini-lozenge). Nicotine patch dosing will be based on current cigarettes smoked per 
day, per package insert: for those who currently smoke >10 cigs/day=4 weeks of 21 mg, 2 
weeks of 14 mg, and 2 weeks of 7 mg nicotine patches, along with nicotine mini-lozenges; for 
those who currently smoke <=10 cigs/day=6 weeks of 14 mg and 2 weeks of 7 mg nicotine 
patches along with mini-lozenges. Mini-lozenge dosing will be based on how soon participants 
currently smoke after waking before their initial quit attempt and will be consistent with the 
package insert (4 mg for participants who smoke within 30 minutes of waking and 2 mg for 
participants smoke more than 30 minutes after waking). 
 

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“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
 
Clinic Randomized Control Trial  
 
 
 
Implementation. The clinics assigned to the experimental condition will have the EHR 
enhancements introduced by methods we have used previously to introduce healthcare 
upgrades into clinics (including EHR enhancements). These procedures include staff training 
visits, follow-up calls, and feedback on EHR use and treatment referral. Importantly, clinic 
training will be standardized across clinics. The great majority of the clinics assigned to the 
control condition will already be participating in the Fax-to-Quit (F2Q) program. However, all 
clinics (including those already using the F2Q program) will be given implementation training to 
ensure that all clinics start with similar implementation support. The minimum implementation 
training will be one initial staff meeting and a second meeting at six months to provide feedback, 
encouragement, and promote problem solving). Also, as per good clinical practice, if notable 
problems are observed in smoker identification and referral data coming from a clinic, ad hoc 
problem solving via phone calls or meetings will be undertaken with the clinic to resolve 
obstacles. Such ad hoc problem solving will occur with clinics in both conditions and will be 
recorded so as to permit comparison of needed implementation support.  
 
 
 
Certain additional procedures will be used in the active (non-control) clinics.  Prior to the 
EHR modifications and initiation of participant recruitment in a given clinic, an in-service training 
will take place, attended by UW-CTRI research staff, clinic physicians, and other clinical and 
support staff. These trainings will be scheduled during one of the clinic's existing staff meetings. 
Trainings will include a description of the study protocol relevant to clinic staff and an overview 
of the goals of the project and the role of the clinic personnel in achieving these goals. Past 
experience has demonstrated the importance of both Dr. Fiore (as study PI) and the clinic 
Medical Director attending these launch training meetings for each clinic (i.e., 18 meetings in the 
proposed Program Project). Their joint attendance at the meetings increases staff attendance 
and highlights how important the project is to the clinic and healthcare system. These launch 
meetings will include a walk-through of the new EHR functions (including EHR screen-shots), 
emphasizing their ease of execution and how they will enhance patient care. The training will 
also clearly describe the roles of clinic personnel in the research/treatment project and explain 
how their activities benefit the patient and the project. We will then answer any questions and 
address concerns. Because the roomers will play a pivotal role in using the enhanced EHR 
functions (e.g., smoking documentation, referral), we will arrange additional meetings with these 
key clinic staff members to continue training, answer questions and enhance their commitment. 
These additional trainings with roomers often involve a lunchtime meeting where the UW-CTRI 
research staff brings lunch. UW-CTRI staff will conduct the research interventions for the clinical 
projects at the clinic sites and therefore will be available throughout the study, providing 
refresher training once every other month and regular quality/progress reports to the clinic. 
 
 
 
About a week after this introduction and launch of the EHR enhancements in each clinic, 
UW-CTRI research staff assigned to the clinic will follow-up with the clinic manager to address 
questions, problem solve, provide early performance feedback on smoker identification and 
recruitment, and reinforce proper EHR use. Over the next 3 weeks, UW-CTRI research staff will 
work with each clinic manager, as well as healthcare system database personnel, to examine 
de-identified data to ensure that clinic staff are using the new EHR resources properly. We will 
record all instances where we intervene and train with clinics in order to identify and document 
best practices training recommendations. When problems come to light, we will work 

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25 
“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
collaboratively with the clinic manager and roomers (and occasionally the Medical Director and 
other medical staff) to support proper EHR use and smoker referral. These training and 
feedback systems have been used successfully by UW­CTRI research staff in more than a 
dozen prior NIH studies and by UW-CTRI staff who have trained over 10,000 clinicians across 
Wisconsin in tobacco intervention as part of the Center’s statewide outreach mission. 
 
 
 
Smoker identification and referral in clinics. Therefore, in control clinics, clinic 
personnel will use methods consistent with good clinical practice, and that very similar to those 
currently in use in such clinics, to identify smokers, document their smoking status, and refer 
them to the WTQL (and possibly to other resources such as the patient’s primary care 
physician). These methods include using existing EHR resources to identify smokers (e.g., the 
expanded vital signs) and to document their smoking status, and then use the standard paper 
fax-to-quit methods to refer patients to the WTQL. As is typical of current practice (and distinct 
from a chronic care approach) only those patients who are interested in cessation will be 
referred to the WTQL (not those interested in reducing their smoking). These methods will be 
compared with the EHR methods that will be used in the experimental clinics and that are 
described above, with both the F2Q and EHR methods having comparable levels of 
implementation support. 
 
Data Collection: Questionnaire, Interview, and Behavioral Assessments for the 
Clinical Studies and Data Collection for the Clinic Randomized Control Trial 
 
 
Part of the synergy of this research arises from the use of consistent assessments across 
all three research studies. This consistency will allow us to compare participants and events 
across all three samples – including allowing us to compare smokers who are and are not 
motivated to quit and smokers who do and do not relapse.  Assessments, which have good to 
excellent psychometric characteristics, will include: 1) individual difference variables related to 
outcome; 2) potential mediators of intervention component effects; and 3) proximal and distal 
outcomes.  At Visit 1 participants in all 3 studies will complete a standard baseline assessment 
that includes: tobacco use history, demographic assessments, exhaled carbon monoxide 
assessment, height and weight assessment, tobacco dependence assessed via the Brief 
Wisconsin Inventory of Smoking Dependence Motives (WISDM-34) and the Fagerström Test of 
Nicotine Dependence (FTND), affect assessed using the well-validated Positive and Negative 
Affect Scale (PANAS), withdrawal assessed using the Wisconsin Smoking Withdrawal Scale 
(WSWS), and motivation and self-efficacy assessed using Likert scale items used in previous 
research. Participants will also evaluate the treatment provided in terms of burden and 
acceptability as well as their perceptions of the healthcare system for providing such treatment, 
using measures developed for this study based on previous research on patient satisfaction 
assessments. Specifically, we will assess constructs such as satisfaction with study staff, clinic 
staff for referring the smoker to the study, and the healthcare system for providing the treatment. 
Consistent mediators assessed across the 3 projects include motivation, self-efficacy, and 
withdrawal.  There will also be study-specific baseline and follow-up assessments, as described 
below. 
 
Motivation Study  
At Visit 1 participants will complete the standard baseline assessment (see above). 
Participants will also complete the 15-item Snaith-Hamilton Pleasure Scale and confidence 
assessments using Likert scale items used in previous research. Participants will also complete 

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26 
“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
a Decisional Balance Questionnaire about smoking, assessments about whether they have 
been encouraged to quit, and assessments of recent quit attempts and plans for future quitting. 
Participants will complete 4 assessment calls at Weeks 12, 26, 39 and 52 (see Table 11). Only 
selected items from the above scales will be used for the subsequent assessment calls. 
Medication usage and side effects will be assessed at every study contact for participants using 
Nicotine Mini-Lozenge. NRT use and smoking will be assessed at each contact using the 
timeline follow back procedures.  
 
Intensive Longitudinal Data (ILD).  Participants will receive 11 brief, automated 
assessment calls over 52 weeks after Visit 1 (see Table 3 for schedule). The assessment 
schedule will continue even if a participant receives the cessation treatment to permit 
standardized assessments for all participants. The 3-4 min calls will occur shortly before 
bedtime, based on participants’ self-reported sleep times. This has resulted in acceptable call 
times in our previous research. The calls will assess: withdrawal symptoms (selected items from 
the Wisconsin Smoking Withdrawal Scale, including craving); positive and negative affect 
assessed via items from the PANAS; time to first cigarette in the morning; any smoking and use 
during the day of the call and during the preceding 7 day period; alcohol use, quit attempts and 
plans for quitting; pleasure from events; medication use; intrinsic motivation to quit or reduce 
smoking; and self-efficacy. Missed or deferred calls will be reinitiated in 15-minute intervals. 
Eligible participants must have access to a phone (either cell or land line). This assessment 
burden is much less than has been used successfully in many other studies, and research has 
shown that ILD/ecological momentary assessment produces modest assessment reactivity. Our 
prior experience shows that IVR systems yield high quality information with response rates 
exceeding 80%, even among primary care patients.  
 
 
 
 
 
 
 
Table 11.  Schedule of Motivation Study Assessments 
Assessments 
V1 
Call  
Wk 12 
Call  
Wk 26 
Call  
Wk 39 
Call  
Wk 52 
Sign informed  
consent  and HIPAA 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Tobacco use history 
X 
 
 
 
 
Tobacco dependence 
X 
 
 
 
 
Medication beliefs  
X 
 
 
 
 
Height, weight 
X 
 
 
 
 
Carbon Monoxide 
X 
 
 
 
 
Tobacco dependence  
X 
X 
X  
X 
X  
Current tobacco use 
X 
X 
X 
X 
X 
Current alcohol use  
X 
X 
X 
X  
X  
Motivation, self-efficacy, and confidence  
X 
X 
X 
X 
X 
Dual Use 
 
X 
X 
X 
X 

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27 
“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
* Participants will receive 11 IVR calls over the course of 52 weeks (see Table 3).  
 
Cessation Study  
At Visit 1 participants will complete the standard baseline assessment (see Table 12).  It 
should be noted that we will assess use of all tobacco and nicotine products (e.g., electronic 
cigarettes, smokeless tobacco), but the primary outcome for this study is abstinence from all 
combustible tobacco products. Participants will complete 6 assessment calls at Weeks 4, 8, 16, 
26, 39 and 52 (see Table 12). Only selected items from the above scales will be used for the 
subsequent assessment calls. In addition, participants will complete assessments of cessation 
fatigue and confidence in quitting. Medication usage and side effects will be assessed at all 
appropriate assessment calls. NRT use and smoking will be assessed at each contact using the 
timeline follow back procedures. We will ask participants reporting abstinence at Week 26 to 
come to their primary care clinic to provide a breath sample for carbon monoxide biochemical 
confirmation of abstinence. The timeline follow back smoking assessment will allow us to 
determine the key clinical outcomes: 1) initial cessation; 2) latency to lapse (smoking their first 
postquit cigarette) and relapse (the first day of smoking on 7 consecutive days); and 3) 
consistent with the recommendations of the Society for Research on Nicotine and Tobacco 
(SRNT) Workgroup on Biochemical Confirmation, 6- and 12-month continuous abstinence (no 
smoking or other tobacco use between the quit day and a specified follow-up time-point). This 
selection of outcomes is consistent with the Phase-Based Model’s recommendation that 
researchers use outcomes appropriate for the smoking cessation phase being studied.  
 
Intensive Longitudinal Data. The Cessation Study will collect intensive longitudinal data 
(ILD) to examine the impact of the two treatment packages on potential treatment mediators and 
outcomes. ILD will be collected via automated calls and will assess constructs posited to 
mediate treatment effects and/or influence cessation success. Participants will complete daily 
ILD assessments for a 3-week period (1 week prequit and 2 weeks postquit). The 3-4 min calls 
will occur shortly before bedtime, based on participants’ self-reported sleep times. This has 
resulted in acceptable call times in our previous research. The calls will assess: withdrawal 
symptoms (selected items from the Wisconsin Smoking Withdrawal Scale, including craving); 
positive affect assessed via items from the PANAS; stressors; any smoking during the day; 
temptation events; urges; pleasure from events; medication use; cessation fatigue; and self-
efficacy over the day. Missed or deferred calls will be reinitiated in 15-minute intervals. Eligible 
participants must have access to a phone (either cell or land line). The brief assessment 
items—tailored for ILD collection—have been shown to sensitively reflect treatment effects, 
Smoking Environment 
X 
X 
X 
X 
X 
Withdrawal 
X 
X 
X 
X 
X 
Quit attempts, Plans for quitting 
X 
X 
X 
X  
X  
Affect and pleasure 
X 
X 
X 
X 
X 
Stress  
X 
X 
X  
X  
X  
Decisional Balance 
X 
X 
X  
X  
X  
Self-report of 
medication adherence 
 
X 
X 
X 
X 
Safety assessment 
 
X 
X 
X 
X 
Healthcare system evaluation 
X 
X 
 
X 
 
Treatment acceptability 
 
 
 
 
X 
IVR* 
 
X 
X 
X 
X 

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28 
“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
predict relapse, and reveal treatment mediation. This assessment burden is much less than has 
been used successfully in many other studies, and research has shown that ILD/ecological 
momentary assessment produces modest assessment reactivity. Our prior experience shows 
that IVR systems yield high quality information with response rates exceeding 80%, even 
among primary care patients.  
 
Table 12.  Schedule of Cessation Study Assessments 
*Participants who report abstinence at the 26-week call will be asked to come to the clinic to provide a 
breath sample to biochemically verify abstinence.  
**Participants will self-report weight at Weeks 26 and 52. 
 
 
 
Long-term Quitting Study  
 
Assessments will be gathered during the three phases of the proposed research: 1) Initial 
Cessation, 2) RR Preparation, and 3) RR Cessation (see Figure 2). The Initial Cessation 
assessments will be gathered at baseline and during the 6-month Initial Cessation treatment 
(see Table 13). Participants who relapse from Initial Cessation treatment and who are 
randomized to the active RR Preparation treatment conditions (Reduction and Recycling 
Counseling), will complete assessments during the Standard RR Assessment Staff Calls across 
the RR treatment (at Week 1 and Months 2, 4, 7, & 10), at the treatment contacts at RR 
Preparation Day 0, Week 2, and Months 1, 3, 6, 9, & 11, and at the 14-month RR follow-up 
period contact (which may include a visit at 14 months if the participant claims abstinence at 
that time). Participants who enter RR Cessation treatment will continue to receive the Standard 
RR Assessment Staff Calls but RR Preparation treatment and associated contacts will be 
discontinued. The RR Preparation Control subjects will complete the RR Preparation Standard 
Staff Assessment calls (at Week 1 and Months 2, 4, 7 & 10) and will also provide assessment 
information at the Month 14 follow-up call/visit.   
 
 
Assessments 
V1 
TQD† 
Call  
Wk 4 
Call  
Wk 8 
Call  
Wk 16 
Call 
Wk 26 
Call 
Wk 39 
Call  
Wk 52 
Sign informed  
consent  and HIPAA 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Tobacco use history 
X 
 
 
 
 
 
 
 
Tobacco dependence 
X 
 
 
 
 
 
 
 
Medication beliefs 
X 
 
X 
X 
 
 
 
 
Height, weight 
X 
 
 
 
 
X** 
 
X** 
Carbon monoxide  
X 
 
 
 
 
X* 
 
 
Current tobacco use 
X 
 
X 
X 
X 
X 
X 
X 
Motivation, self-efficacy and 
confidence  
X 
 
X 
X 
X 
X 
X 
X 
Withdrawal 
X 
 
X 
X 
X 
X 
X 
X 
Affect and pleasure 
X 
 
X 
X 
X 
X 
X 
X 
Self-report of 
medication adherence 
 
 
X 
X 
X 
X 
 
 
Safety assessment 
 
X 
X 
X 
X 
X 
 
 
IVR assessment 
X 
X 
 
 
 
 
 
 

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“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
 
Initial Cessation Phase. Participants will complete core baseline assessments at Visit 1 
(Week -1). Participants will also complete assessments during phone calls using selected items 
from the baseline scales (see Table 13) and 4 brief evening automated IVR assessments (Days 
-4, -1, 1, and 3). These staff assessment calls will assess medication use, reasons for 
nonadherence, exposure to contextual risk factors, withdrawal symptomatology, and smoking 
over the past week (to detect relapse). The IVR calls will assess: withdrawal symptoms 
(selected items from the Wisconsin Smoking Withdrawal Scale, including craving); positive 
affect assessed via items from the PANAS; stressors; any smoking during the day; temptation 
events; urges; use of coping skills; pleasure from events; medication use; cessation fatigue; and 
self-efficacy over the day. Initial Cessation Phase assessments will stop once a participant is 
randomized to RR Preparation treatment.  
 
Table 13.  Schedule of Long-Term Quitting Study Quit Phase (Initial Cessation) Assessments 
Day 
-7 
-1 
1 
3 
7 
14 
28 
56 
84 
112 
140 
182 
Week 
-1 
 
 
 
1 
2 
4 
8 
12 
16 
20 
26  
Contact 
V 
I 
I 
I 
C 
C 
C 
C 
C 
C 
C 
C 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Sign informed  
consent  and HIPAA 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Tobacco use history  
X 
 
 
 
 
 
 
 
 
 
 
 
Tobacco dependence 
X 
 
 
 
 
 
 
 
 
 
 
 
Health, mental health, 
and health behaviors  
X 
 
 
 
 
 
 
 
 
 
 
 
Height, weight 
X 
 
 
 
 
 
 
 
 
 
 
 
Carbon monoxide  
X 
 
 
 
 
 
 
 
 
 
 
 
Current tobacco use  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Other tobacco and 
medication use 
X 
 
 
 
 
 
X 
 
 
 
 
X 
Motivation, self-efficacy, 
and fatigue  
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
Demoralization 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
Withdrawal  
X 
X 
X 
X 
X 
 
X 
 
 
 
 
X 
Pleasure 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
Coping skills  
X 
 
 
 
X 
 
 
 
 
 
 
 
 Smoking context 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
Positive Affect  
X 
X 
X 
X 
X 
 
X 
 
 
 
 
X 
 Stressors 
X 
 
 
 
 
 
X 
 
 
 
 
 
 Medication adherence 
and beliefs 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Medication safety 
assessment 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
Adherence Factors 
question 
 
 
 
 
 
 
 
 
 
 
 
 

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“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
V = Visit; I = IVR assessment; C = Call 
 
 

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“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
Relapse Recovery Phase. All participants who relapse and are randomized to RR 
Preparation treatment (both control and non-control participants) will complete Standard RR 
Assessment Staff Calls during the 11-month RR Preparation period (see Table 14). In addition, 
the non-control participants will complete assessments at each RR Preparation treatment 
contact (i.e., at Day 0, Week 2, and Months 1, 3, 6, 9, and 11). Both control and non-control 
participants will complete the 14 Month Follow-up (and an associated visit if the participant 
claims abstinence at that time).  These calls will assess smoking status, self-efficacy at 
controlling smoking, and exposure to smoking cues and contexts. Participants will also be 
queried about NRT/medication use, “intentional” quit attempts (conscious attempts to quit 
regardless of success/length of abstinence), number of “meaningful” quit attempts (that led to 
more than one day of abstinence), use of other cessation aids/treatments, and estimated 
amount of smoking/day for the past 7 days. We will assess use of all tobacco and nicotine 
products (e.g., electronic cigarettes, chew), but the primary outcome will be abstinence from 
combustible tobacco products.  Finally, we will assess desire to enter an RR Cessation Phase 
treatment (the latter only for non-control RR Preparation participants). All participants will 
complete the Standard RR Assessment Staff Calls, regardless of entry into RR Cessation 
treatment.  
Table 14.  Long-Term Quitting Study RR Preparation Phase Assessments  
 
 
Month 
Baseline 
Wk 1 
Wk 2 
Wk 4 
2 
3 
4 
6 
7 
9 
10 
11 
14 
Visit or Call 
V (C for 
Control) 
C 
C 
V 
C 
C 
C 
V 
C 
C 
C 
C 
C 
Reduction motivation 
and self-efficacy 
X 
 
X 
X 
X 
 
 
X 
 
 
X 
X 
 
Cessation motivation 
and self-efficacy 
X 
 
X 
X 
X 
 
 
X 
X 
 
X 
X 
X 
Time to first cigarette 
X 
 
 
X 
 
 
X 
X 
 
 
X 
X 
X 
FTND 
++ 
 
 
 
 
 
 
X 
 
 
 
 
X 
Withdrawal 
X 
 
X 
X 
X 
 
X 
X 
 
 
X 
X 
X 
Coping skills 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Smoking context 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Current smoking 
X 
++ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Smoking status and 
quit attempts 
X 
++ 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
Dual use 
X 
 
 
X 
 
 
X 
X 
 
 
 
X 
X 
Plans to quit  
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Demoralization, 
fatigue 
X 
 
 
X 
X 
 
 
X 
 
 
 
X 
X 
Positive Affect  
++ 
 
 
X 
 
 
 
X 
 
 
 
 
 
Self-compassion  
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Medication safety 
assessment  
 
+++ 
+++ 
+++ 
 
+++ 
 
+++ 
 
+++ 
 
+++ 
 
Mini-lozenge use  
 
+++ 
+++ 
+++ 
 
+++ 
 
+++ 
 
+++ 
 
+++ 
 
Adherence factors 
form  
 
 
 
+++ 
 
 
 
+++ 
 
 
 
 
 
Carbon monoxide 
++ 
 
 
X 
 
 
 
X 
 
 
 
 
X** 
Use of other 
cessation treatments 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Ask if want to switch 
to New Quit Phase 
+ 
 
+ 
++ 
 
++ 
 
++ 
 
++ 
 
++ 
 

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“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
Note. Grey columns are for active RR Preparation participants only.  + = for Recycling participants only; 
++ = for Reduction and Recycling participants; +++ Reduction participants only.     **All participants 
claiming abstinence at the Month 14 Follow-up will be asked to take a CO test to confirm their self-report.     
 
        RR Cessation Phase.  When participants decide to make a new quit attempt and are 
randomized to RR Cessation treatment, they will also receive RR Cessation Phase 
assessments (see Table 15). The RR Cessation Assessments will involve assessment on the 
first RR Cessation treatment visit, IVR calls -4, -1, +1, and +3 days after initiation of RR 
Cessation treatment, and RR Cessation Follow-up Calls at Days +7, +14, Months 1, 2, 4, and 6 
months after initiation of RR Cessation treatment  
 
The RR Cessation Assessments will typically elicit information on smoking heaviness 
and potential mechanisms (e.g., demoralization, pleasurable activities, exposure to smoking 
cues, self-efficacy, coping execution, medication use, medication side-effects, perceived 
treatment support, smoking heaviness, and craving; see Table 15). Participants will also 
complete a smoking calendar for the duration of the RR Cessation treatment to establish time to 
lapse and time to relapse.  
 
Table 15.  Schedule of Long-Term Quitting Study New Quit Phase (RR Cessation Phase) 
Assessments 
Day 
-7 
-4 
-1 
1 
3 
7 
14 
28 
70 
112 
182 
 
Week 
-1 
 
 
 
 
1 
2 
4 
10 
16 
26 
 
 Contact 
V 
I 
I 
I 
I 
V/C 
C 
C 
C 
C 
C 
 
Time to first cigarette 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Tobacco dependence  
X 
 
 
 
 
 
 
 
 
 
 
 
Carbon monoxide  
X 
 
 
 
 
X** 
 
 
 
 
 
 
Current tobacco use 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Number of alcoholic 
drinks  
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Relapse context 
questionnaire as needed 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
Mental health and alcohol 
use 
X 
 
 
 
 
 
 
 
 
 
 
 
Non-study med use 
 
 
 
 
 
X 
 
 
 
 
X 
 
Dual use 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Motivation, self-efficacy, 
and fatigue  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Demoralization 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Withdrawal  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Stressors 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Pleasure 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
Coping skills  
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Positive affect  
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
Medication adherence  
and beliefs 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Self-Compassion 
X 
 
 
 
 
X 
 
 
 
 
 
 

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33 
“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
Day 
-7 
-4 
-1 
1 
3 
7 
14 
28 
70 
112 
182 
 
Week 
-1 
 
 
 
 
1 
2 
4 
10 
16 
26 
 
 Contact 
V 
I 
I 
I 
I 
V/C 
C 
C 
C 
C 
C 
 
Questionnaire  
Avoidance and Inflexibility 
Questionnaire  
X 
 
 
 
 
X 
 
X 
 
 
 
 
Medication safety  
X 
 
 
 
 
X 
X 
X 
 
 
 
 
 Smoking context 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
V = Visit; I = IVR assessment; C = Call;  
* = This visit is only for participants claiming abstinence. 
. 
 
Data Collection for the Clinic Randomized Control Trial  
 
 
 
Baseline data. Baseline data will be used for assigning clinics to the experimental 
conditions: e.g., using WTQL referral rates and smoker prevalence data as matching criteria in 
the MAUM method. Second, baseline data will be used as pretreatment covariates in outcome 
analyses. Again, WTQL referral and smoker documentation data would be useful for this 
purpose. We anticipate being able to derive the smoker documentation rates from the clinic’s 
EHR records. Documentation of smoking status per visit will be assessed by determining the 
percentage of time that known smokers at a clinic are asked about their smoking status. The 
denominator (“known” smoking status) will be determined by search of the EHR smoking 
relevant ID fields. We will query the WTQL records to obtain baseline rates of WTQL referral for 
the various control and experimental clinics.   
 
 
 
Post-intervention data. Post-intervention data (i.e., once training and implementation 
have occurred in a clinic) will be gathered from the control clinics using the same methods as 
were used in the baseline period. In the experimental clinics, smoker documentation will be 
assessed via the same method as used during baseline (i.e., comparing per visit smoker 
documentation with EHR smoker identification fields). However, in the experimental condition 
clinics, treatment referral will be ascertained not only from the EHR records but also from 
records from the chronic care research program. The clinic’s EHR records should reveal referral 
to the research program and the research program’s records will reveal receipt of clinic referral 
to it, and also referral from the research program to the WTQL. The latter will occur because the 
research program will refer the patient to the WTQL if the patient is not interested in the 
research program, is screened out from that program, or decides that s/he prefers WTQL 
referral. The EHR records will be cross checked with both the research program records of 
referral and with WTQL records to examine agreement. Treatment engagement for the 
experimental clinics will be derived from the research program records and from WTQL records. 
Treatment engagement will be defined as receipt of any clinical contact with either the WTQL or 
the chronic care research program: e.g., a counseling phone call, medication receipt, use of the 
WTQL website or text messaging service (if available on a cost-effective basis). Further, for 
both control and experimental clinics there will be an attempt to gather data on clinician billing 
for smoking cessation counseling, and prescription issuance for a smoking cessation medication 
(with a special focus on varenicline and nicotine replacement therapy, given that bupropion is 
also used in treating depression). These latter two measures will not be included in the primary 

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34 
“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
treatment engagement dependent variable because of their expected low rate of occurrence 
and because the EHR changes do not target these outcomes. They will be used merely to 
ascertain whether the experimental and control conditions differ in rates of referral to auxiliary 
treatment resources. In this way the design can reflect increases in the three identified 
dependent variables due to the EHR enhancements and chronic care treatment availability. In 
addition, the WTQL, e-prescriptions for smoking medications, and clinician counseling are the 
only documentable smoking treatment options currently available in both healthcare systems 
(e.g., there are no in-house or other cessation programs). Therefore, the list of measures for 
smoking treatment referral and engagement are exhaustive; they should capture all clinic-based 
smoking-related intervention during the baseline period.  
 
 
 
It is important to note that other outcome measures will be collected during the post-
intervention period. For example, we will also track: the rate at which patients referred to chronic 
care treatment complete treatment and quit smoking successfully. These are not dependent 
variables, however, since data on these outcome classes will not be available from control 
clinics. In addition, we will determine the number of calls to the dedicated smoking treatment 
information call-line that follow Smoker Registry communications to seek smoking treatment 
information. (Note: Within Epic, the Registry function allows patients with similar diagnosis or 
other characteristics to be readily identified.  Typically, the function is used for health 
maintenance or health promotion.  Smoker Registry in this document refers to the use of that 
functionality to allow Dean Clinic staff to identify adult smokers connected with a particular clinic 
to perform these recruitment functions.) Finally, quality assurance methods will be used to 
examine the consistency of EHR functions: e.g., 1) the percentage of patients referred to 
treatment for whom closed loop feedback is entered into their EHR’s (based on WTQL or 
research treatment referral or the healthcare pharmacy database); and 2) the proportion of 
smokers in the Smoker Registry who are identified as smokers or recent quitters on an index 
clinic visit.    
 
Promoting Continued Experimental Participation 
We will utilize participant retention strategies that were effective in our prior research, 
including strategies such as scheduling flexibility, calling participants’ cell phones if they request 
that, continued interaction with the same health counselor, and providing medication contingent 
upon visit attendance/call completion. If participants appear to have dropped out of the study 
(they miss appointments and do not reschedule, or they do not answer our phone calls, but they 
have not formally withdrawn from the study), we may write them (via standard mail or email) to 
encourage their renewed participation.   
 
Motivation Study  
For the Motivation Study, participants will be reimbursed $25 each for completing Visit 1. 
They will receive $10 for completing each of the assessment calls at Weeks 12, 26, 39, and 52. 
Participants will also be reimbursed $25 for completing at least 75% of their IVR calls. Thus, 
participants will be compensated up to $90 for assessments but not for therapy participation.  
 
Cessation Study  
For the Cessation Study, participants will be reimbursed $20 for completing Visit1, $20 
for completing at least 75% of their IVR calls, and $10 for completing each of the assessment 
calls at Weeks 4, 8, 16, 26, 39, and 52.  Participants who report 7-day point-prevalence 
abstinence at 26 weeks and attend a visit to provide CO-confirmation of abstinence will be 

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“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
reimbursed $25. Participants will not be compensated for participating in treatment visits. The 
maximum compensation would be $125.  Participants will be paid after the Week 4 call, after the 
Week 16 call, and then after the 26, 39 and 52 week calls. 
 
Long-term Quitting Study  
For the Long-term Quitting Study, participants will be reimbursed $10 for completing the 
Initial Cessation Phase Visit 1 assessments plus $5/call for the 6 Initial Cessation Follow-up 
assessment calls that do not include phone counseling ($30) plus $5 if they complete the 3 
scheduled IVR calls for a maximum of $45 for the Initial Cessation Phase.  
 
If participants relapse and are randomized to one of the active RR Preparation 
conditions, they will be paid $25 for attending the initial RR Preparation visit at Day 0, $5/call for 
the 5 Standard RR Assessment Staff Calls ($25), $10 for completing the Month 14 Follow-up 
Call, and $40 for attending the Month 14 Visit if they claim abstinence for a maximum of $100. 
Participants randomized to the RR Preparation Control condition will receive $25 for the first 
Standard Assessment Staff Call and $5/call for the next four ($20), $10 for the Month 14 Follow-
up Call and $40 for attending the Month 14 Follow-up Visit if needed for a total potential 
compensation of $95. 
 
Participants who choose to make a new quit attempt and are randomized to the RR 
Cessation conditions will be paid $10 for completing the New Quit Phase baseline assessment, 
and $5/call for the 5 RR Cessation assessment calls ($25) plus $10 for completing the Month 6 
Follow-up Call and $5 for completing at least 3 of the 4 IVR scheduled calls for a maximum 
compensation of $50. 
 
In sum, participants who complete all assigned study activities could be reimbursed $45 
if they never move beyond the Initial Cessation Phase. Those who relapse could receive $140 if 
they relapse and are randomized to the RR Preparation Control group or $145 if they are 
randomized to an active RR Preparation condition. Then for those who go on to the New Quit 
Phase, they could earn $195. 
 
Analytic Plans  
 
      Each study has a distinct analytic plan to address the unique specific aims of that study. 
 
Motivation Study  
Primary Aim 1: Determining the main and interactive effects of the intervention 
components on primary outcomes. Our primary outcomes, assessed at both 6 months (end of 
treatment) and 12 months, are: 1) making a serious quit attempt (defined as ≥ 48 hours of 
nonsmoking as part of an intentional effort to quit); and 2) cessation success (defined as 7-day 
point-prevalence abstinence (PPA)—self-reported abstinence from smoking, even a single puff). 
With each of the components, we hypothesize that the "on" condition will produce higher quit 
attempts and cessation success than the "off" condition. Data for these aims come from phone 
assessments over the 12 months. We will model abstinence longitudinally via a mixed-effects 
logistic regression model including the main effects of treatment106. Longitudinal models will 
include the effects of time, condition, and a random subject effect to account for the correlation 
of repeated assessments within subjects. We will also identify any interaction effects that 
emerge from the combinations of intervention components. For example, we will examine 
whether the combination of the BR and 5Rs has a larger or smaller effect than their additive 

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36 
“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
effects would predict. Although we will examine all possible interactions of the intervention 
components, we do not anticipate significant effects beyond 2-way interactions. In sum, the 
proposed analyses will determine whether the tested intervention components, either via main 
or interaction effects, increase meaningful quit attempts and long-term abstinence rates. In 
addition, we will use logistic regression analyses with effects-coding to examine the effect of 
each intervention component on the occurrence of the binary outcomes of quit attempt 
occurrence and PPA at different follow-up points. Models will include only main effects and two-
way interactions; no higher-order interactions are expected. Following the intent-to-treat 
principle, all 512 participants randomized to treatment will be included; missingness will be 
investigated in other analysis  
 
Secondary Aim 1: Determining the main and interactive effects on secondary outcomes. 
We will use generalized linear mixed models to test main and interactive effects of components 
on smoking reduction. Entry into Cost-Optimized cessation treatment will be analyzed via 
logistic regression models that include main effects and two-way interactions. Cost for each 
treatment component will be tracked and used to identify optimal intervention components for 
further study and to aid decision making.  
 
Secondary Aim 2: Mediational analyses. We will use a Bayesian multi-mediator 
approach, with the longitudinal data collected during the automated phone assessments to 
examine whether quit attempts and cessation success are predicted by treatment effects on key 
putative mediators: craving, self-efficacy, number of cigarettes smoked per day, tobacco 
dependence, intrinsic motivation, anhedonia, medication use, and contextual restrictions of 
smoking. Multi-mediator models will comprise mediators that are significant in univariate 
mediational analyses and allow us to address questions such as whether BR Counseling, 
relative to no BR, increases strength of participants’ self-efficacy, their use of reduction skills, or 
their magnitude of smoking reduction, and whether these increases result in increased quit 
attempts, and/or cessation rates. Or, does assignment to the Nicotine Mini-Lozenge condition, 
relative to assignment to No Nicotine Mini-Lozenge, increase participants’ self-efficacy, or 
decrease their craving, or amount of smoking reduction, and do these changes result in 
increased quit attempts, and/or cessation rates?    
 
Secondary Aim 3: Moderation analyses. Potential moderators (e.g., age, gender, 
dependence) will be tested in moderated logistic regression models. These models will include 
main effects for all treatments and the moderator (e.g., gender) as well as two-way interactions of 
each treatment effect and the moderator. 
 
Cessation Study  
Primary Aim 1: A primary aim of Project 3 is to compare Abstinence-Optimized 
Cessation Treatment (AOCT) with Modern Usual Care (M-UC) on 7-day point-prevalence 
abstinence evaluated at 8, 16, 26, 39 and 52 weeks postquit. We will use GLMM implemented 
via SAS PROC GLIMMIX (SAS Institute Inc., Cary, North Carolina) to test the group effects in 
longitudinal models. Specifically, we hypothesize that participants receiving AOCT will have 
higher cessation rates at each timepoint than those receiving M-UC.  We will also analyze other 
clinical outcomes because they provide complementary information about outcome (e.g., initial 
cessation, 6- and 12- month point-prevalence abstinence, latency to lapse and relapse, and 
treatment engagement and adherence) as recommended by SRNT Workgroup and others. We 
will evaluate initial cessation (did or did not establish 24 hours of abstinence in the first 2 weeks 

PROTOCOL   
 
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“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
following the quit day) and 6- and 12-month abstinence rates using logistic regression and 
latency to lapse and relapse using Cox proportional-hazards regression. We will also examine 
cessation outcomes controlling for treatment adherence in secondary analyses. The 
distributions of the adherence data (percentage of days using nicotine replacement; number of 
mini-lozenges used per day; percentage of counseling sessions completed) will be examined to 
inform decisions about transformation and analysis options.  
 
Primary Aim 2:  Another primary aim is to compare AOCT and M-UC on outcomes 
important to healthcare systems: net monetary benefit (NMB), incremental cost-effectiveness 
ratio (ICER), cost per long-term quit, and patient ratings of treatment and healthcare system 
quality. All of these will inform decision-making with regard to the efficient allocation of 
healthcare resources. Specifically, we hypothesize that, relative to M-UC, AOCT will produce an 
NMB higher than zero. Net monetary benefit analyses will convert the long-term relapse rates to 
Quality-Adjusted Life Years added (QALYs) and then monetize the QALYs added using a range 
of willingness to pay values. NMB analyses will allow us to compute confidence intervals and 
report whether these confidence intervals overlap for the AOCT relative to M-UC. For the ICER 
analyses, we will compare the additional cost of the AOCT to M-UC costs. Participants’ quality 
ratings will be analyzed using ANOVAs. We will examine the role of cessation success in 
satisfaction ratings and control for cessation success as needed. 
 
Secondary Aim: The secondary aim is to understand better the underlying treatment 
mechanisms of the Abstinence-Optimized Cessation and Modern Usual Care treatments and to 
determine which effects mediate cessation success. We will use mediational models similar to 
those used in our previous research to estimate the extent to which treatment-related change in 
the mediator (e.g., change in self-efficacy, craving, negative affect, or perceived support) leads 
to improved outcomes (initial cessation, latency to relapse). The EMA data on daily urges, 
smoking, treatment-related support, withdrawal, cue exposure, coping, etc. will be combined 
with the other phone assessments and studied using latent growth curve models. For example, 
we will examine whether AOCT’s use of a Combination NRT component results in greater 
withdrawal suppression and thereby reduced likelihood of relapse, relative to the M-UC 
treatment and whether the counseling in the optimized treatment produces greater 
intratreatment social support and coping skills and thereby reduces the likelihood of relapse 
relative to M-UC treatment. We will use procedures from our prior work to reduce error and 
ensure temporal ordering of causal modeling. Parameters of the growth models (e.g., intercept 
and trajectory parameters) will be studied as mediators of short-term outcomes such as initial 
cessation and lapse or relapse. We will also examine orthogonal mediation paths via multiple 
mediator analyses. Mediational analyses will be conducted using Mplus, which offers flexibility 
in the handling of outcome variables (e.g., continuous, categorical counts, censoring).  
 
We will also conduct exploratory analyses to determine whether individual difference 
variables such as gender, race, educational attainment, and baseline nicotine dependence 
moderate treatment effects using chi-square analyses and by modeling interaction effects in 
Cox Regression. We will also examine moderated mediation to determine whether any of these 
individual difference variables moderate specific treatment effects. 
 
 
 
 

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“Breaking Addiction to Tobacco for Health (BREATHE) Study” 
PI: Michael Fiore, MD, MPH, MBA; UW-CTRI Center Grant: 1P01CA180945-01. 
 
 
Fiore P01 Protocol, Version 10, July 19, 2018  
 
 
Long-term Quitting Study  
The analytic plan reflects that the treatments will be delivered in sequence (i.e., analyses 
will accommodate the transition of participants across the RR Preparation and RR Cessation 
treatments) as is recommended for SMART designs.  
 
Primary Aim. To determine the effects of the RR Preparation treatment on abstinence at 
the Month 14 Preparation assessment time point amongst participants randomized to RR 
Preparation treatment (“active” and “control”). This analysis will be conducted using generalized 
linear models (GLM) with point-prevalence abstinence data as the outcome variable. Potential 
covariates will include: race, gender, tobacco dependence (e.g., before initial cessation 
treatment) and duration of abstinence in the initial cessation attempt. The main model will not 
control for RR Cessation factors; rather it will focus on the question of whether long-term 
differences in abstinence rates emerge from the RR Preparation treatment. These analyses will 
be done in several ways: 1) by comparing each active RR Preparation component with the 
Preparation Control condition, and 2) by conducting a GLM analysis comprising only the RR 
Reduction vs. Recycling Preparation participants. The former will address the issue of whether 
the active Preparation components, and any consequential access to RR Cessation treatment, 
affects the long-term smoking outcomes of participants. Results will be examined to determine 
the extent to which differences are related to the use of RR Cessation treatments. The second 
type of analysis will focus on the active RR Preparation components, when participants in each 
component have an equal chance of being assigned to any of the RR Cessation intervention 
components. RR Cessation factors will be used as covariates in supplementary analyses of the 
active components and the interactions of these factors with Preparation treatment condition will 
be examined. Marginal frequencies will be examined to determine the rate at which participants 
elect to be randomized to RR Cessation treatment. 
 
Secondary Aim 1. We hypothesize that RR Reduction Counseling will lead to a greater 
likelihood of meaningful quit attempts and that these will occur at shorter latencies than RR 
Recycling Counseling. Even though Reduction participants will be encouraged to delay their quit 
attempts for 1 month of treatment, we predict they will be more successful than Recycling 
participants in sustaining early abstinence. All participants randomized to the non-control, active 
RR Preparation factors will be included in the following two analyses. First, we will use logistic 
regression to test for differences, due to Preparation factor, in the probability of a meaningful 
quit attempt during the 12 months after they enter RR Preparation treatment. Second, to 
examine latency to a new meaningful quit attempt, Cox Proportional Hazard models will be used 
to determine the hazard rate, with those not making a meaningful quit attempt treated as 
censored observations. Potential covariates will include: race, gender, tobacco dependence 
(e.g., before initial cessation treatment) and duration of abstinence in the initial cessation 
attempt (in subsequent analyses the type of RR Cessation treatment used will also be modeled 
as a covariate). These analyses will reflect Preparation effects comprehensively because they 
will reflect meaningful quit attempts that occur both with and without use of RR Cessation 
treatments. Then, only Preparation participants using RR Cessation interventions will be 
included in analyses of relations between RR Preparation and RR Cessation components as 
they influence meaningful quit attempts. This analysis will focus on whether type of RR 
Preparation treatment affects initial success (more than 1 day of abstinence at the start of the 
quit attempt) in an aided quit attempt, and whether this effect depends on type of RR Cessation 
treatment.  We hypothesize that RR Reduction Counseling will produce stronger effects than 

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RR Recycling Counseling with regard to both the probability and latency of meaningful quit 
attempts, and we hypothesize that these effects will not interact with the RR Cessation factors.  
 
Secondary Aim 2. To determine the main and interactive effects of the 2 RR Cessation 
factors on smoking abstinence following a quit attempt, and to determine whether these effects 
differ as a function of the RR Preparation factor. One analytic strategy will involve a 2x2 factorial 
analysis via a longitudinal generalized linear mixed-effects model (GLMM) with the 2 RR 
Cessation factors as independent variables, and RR Preparation factor as a covariate.  Several 
outcomes will be analyzed.  One outcome will be longitudinal abstinence across the 4 RR 
Cessation Follow-up time points ( Weeks 4, 10, 16, 26).  A second will focus on survival 
analyses after the start of the participants’ course of RR Cessation treatment. Finally, a logistic 
regression analysis will be used to analyze abstinence reports at 26 Weeks post-RR Cessation 
treatment initiation. Only those who choose to make an aided quit attempt and are randomized 
to the RR Cessation factors will be included in these analyses, and all tests will be two-sided 
with p=.05. Additional potential covariates in the longitudinal models will include race, gender, 
and time since the initiation of the RR Preparation treatment (for the analysis examining long-
term effects of RR Cessation treatment).  We predict significant main effects for the enhanced 
level of each RR Cessation factor, but we predict no significant interaction effects between RR 
Preparation and RR Cessation factors; that is, we predict the RR Cessation factors will exert 
similar effects across the Preparation factor but we will test these relations. Because some 
participants randomized to Preparation treatment will not be included in this analysis (since they 
will not make aided quit attempts), this analysis will not capture the comprehensive effects of the 
Preparation factor. We are aware that the Preparation factor may cause different numbers or 
types of smokers to make aided quit attempts with the RR Cessation treatments. Such effects 
might moderate effects of the Preparation factor on the RR Cessation factors. However, this is 
not a limitation because this would be present in the real-world clinical effects of a Preparation 
treatment; e.g., such treatments could influence outcomes by better preparing smokers for 
cessation or by sending different types of smokers to an RR Cessation treatment.   
 
Supplemental analyses will examine correspondence between CO levels at the 6 and 14 
Month Preparation Phase follow-up and abstinence self-report at those and other time points 
(e.g., 10 months into the Preparation Phase).  Adherence analyses will use Preparation Phase 
data and RR Cessation treatment contact data to analyze both patch and mini-lozenge use.  
Adherence will be evaluated with regards to both the RR Preparation phase (amongst 
Reduction participants) and in the RR Cessation Phase.  
 
Secondary Aim 3. We will also examine “transition rates” across the phases of 
treatment: 1) To what extent do participants who relapse in response to Initial Cessation 
treatment, enter the RR Preparation treatment? 2) To what extent do participants who enter RR 
Preparation treatment remain in that treatment for 11 months? and 3) To what extent do 
participants who enter RR Preparation treatment decide to enter RR Cessation treatment?  In 
other words, we will examine the extent that “chronic care” treatment “works” amongst 
relapsers, and the extent that this is related to type of “chronic care” provided. Do relapsers 
transition into chronic care and use its various resources?  Such pragmatic analyses will be 
complemented by cost analyses regarding the various treatments analyzed.  
 
Secondary Aim 4. We will also identify moderators and mediators of the effects of the 
RR Preparation and RR Cessation treatment factors. In keeping with the secondary aims of a 

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Fiore P01 Protocol, Version 10, July 19, 2018  
 
SMART trial, these moderator and mediator analyses will be useful for identifying candidate 
tailoring variables. For instance, a key mediator of RR Preparation Reduction treatment might 
be amount and persistence of smoking reduction.  We will examine the relation between such 
reduction and success in RR Cessation treatment and also success as measured by outcome at 
the 7-, 10-, and 14-month Preparation phase assessment time points. Of course, smoking 
reduction will be analyzed as an outcome in its own right.  All those assigned to RR Preparation 
conditions, including Control participants, can be included in such analyses, with outcomes 
assessed across the RR Preparation phase and at Month 14 follow-up. 
 
For RR Cessation treatment moderation and mediation models, the outcome will be 
abstinence at 6 months after the RR Cessation target quit day. Mediation models (including 
multiple mediators) will use methods developed for use with dynamic mediator assessments 
(maximum likelihood estimation using hierarchical linear modeling: HLM 5.04, using RR 
Cessation treatment assessments and possibly data derived from Standard Assessment Staff 
calls) with binary outcomes (via a weighted least squares model in Mplus). Candidate mediators 
will include: demoralization, medication use, coping, smoking cue/trigger density, self-efficacy, 
craving, and smoking heaviness. Mediation effects will be tested using statistically powerful 
approaches (e.g., the joint significance test). Care will be taken to preserve mediator/outcome 
temporal priority, and the occurrence of smoking during the quit attempt will be statistically 
controlled when appropriate. Analysis of moderators will use both logistic regression (with model 
fitting techniques) and regression tree analyses to identify predictors of differential response to 
the RR Cessation components. Candidate moderators will include factors such as tobacco 
dependence and gender, and contextual factors such as household smoking.  
 
Finally, while not a formal aim, we will also compare all possible types of “embedded 
adaptive treatments” on abstinence rates at the 7, 10, and 14 Month outcome time points. That 
is, we will compare the abstinence outcomes of groups of participants receiving the different 
unique combinations of RR intervention components. Logistic regression will be modified to 
weight for the fact that data for each participant are consistent with more than one adaptive 
intervention (an individual will receive multiple intervention components) and to accommodate 
the over/under-representation of outcomes based on the sequential randomization scheme. 
Embedded comparisons are typically underpowered in SMART designs but can be highly 
informative (viz. to check consistency with the factorial analyses).  
 
Clinic Randomized Control Trial 
 
 
 
Primary Aim: Using a multiple baseline design, determine the effects of a healthcare 
intervention package comprising a comprehensive set of EHR-based enhancements and a 
chronic care treatment for smoking, on rates of documentation of smoking status, referral to 
smoking treatment, and engagement in smoking treatment as compared to a usual care fax-to-
quit referral to the Wisconsin Tobacco Quit Line.  
 
Power for Primary Outcomes in the three clinical studies and the clinic 
randomized control trial 
 
Power for each of the three studies was calculated based on the sample size and 
hypothesized effect sizes for each of the individual studies. 
 
Motivation Study  

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 We will enroll 512 participants. We will use an intent-to-treat principle for the primary 
abstinence analyses. Our factorial design takes advantage of all cells and participants, allowing 
us to analyze the entire sample for main effects. With two levels of each factor (e.g., BR 
Counseling or no BR), we will have 256 participants per group for analyses. We have based our 
power estimates on effect sizes found in our prior studies.  
 
For cessation success, we conducted longitudinal power analyses. We computed power 
for the mixed effects longitudinal analysis using a SAS macro111 with the following parameters: 
N=256 per group; smoking status assessed at 6 points (months 1, 2, 3, 4, 6, and 12); a drop-out 
rate of 10% at each successive time-point (higher than in Preliminary Study 1); a 10% versus 
18% abstinence treatment effect modeled as a consistent effect over time; random effects 
variance=1; and within-subject correlation=0.6. We consider the targeted treatment effect (i.e., 8 
percentage point difference: 10% vs. 18% among participants receiving an “on” intervention 
component) to constitute a clinically meaningful effect. Power for this scenario is 0.94 with a 
compound symmetry (CS) within-subject covariance structure; power is 0.99 with a first-order 
autocorrelation (AR(1)) within-subject covariance structure and correlation. Thus, the study is 
powered adequately to yield statistically significant treatment effects in the mixed effects 
analyses.  
 
For quit attempts, we conducted single endpoint power analyses. We expect 
approximately 60% of participants to make a quit attempt on minimal treatment, as suggested 
by our Preliminary Study data. With a total N=512, there is adequate power (.81) to detect at 
least a 12 percentage point increase, a clinically meaningful increase, in quit attempts in the 
“on” treatment condition (72%) relative to the “off” condition (60%).  
 
For smoking reduction, we conducted longitudinal power analyses. We calculated 
statistical power for a longitudinal mixed effects regression model for the smoking reduction 
outcome with two groups using the RMASS2 sample size program112,113. We specified the 
following parameters for the program: alpha=.05, two-tailed test, 6 time-points (months 1, 2, 3, 
4, 6, and 12), attrition of 10% at each successive time-point (a high rate), within-subject 
correlation=0.6, a mean difference of 1.5 cigarettes (consistent across time), and a standard 
deviation of 7 (consistent across time). With attrition of 10% at each successive time-point, the 
retention rate decreased to 59% by the 12 month follow-up. These specifications yielded a 
composite effect size of .27 adjusted for attrition. With a sample size of 256 per group and 
adjustment for attrition, we have power of at least .85 to detect this effect size with AR(1) within-
subject covariance structure and correlation. 
 
Cessation Study  
 
This study will enroll at least 600 participants to address the primary aims. 
 
Primary Aim 1: We computed power for the GLMM longitudinal analysis of abstinence 
outcomes using a SAS macro developed by Dang and colleagues with the following 
parameters: N=300 per group; 3 time-points; drop-out rate of 20%;  treatment marginal rates 
(over time) of 30% vs 40%; random effects variance=1; and within-subject 
correlation=0.6.  Power for this scenario is 0.91.  Thus, the proposed study appears to be 
powered adequately to yield a statistically significant group difference in point-prevalence 
abstinence in the longitudinal GLMM analyses. 
 

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Power analyses were also computed for 6-month point-prevalence abstinence using 
nQuery Version 7.0 (Statistical Solutions, Cork, Ireland). With sample sizes of Abstinence-
Optimized Cessation Treatment=300, and Modern Usual Care=300 we examined the power to 
detect the primary outcome—biochemically confirmed 7-day point-prevalence abstinence at 6 
months post-target quit day. A previous meta-analysis found that abstinence rates at 6 months 
post-quit were 23.4% of participants receiving 8 weeks of nicotine patch and 28.1% for those 
receiving quitline counseling and medication, as will occur in the M-UC treatment. Given that 
this will be an effectiveness trial with only 1 quitline call, we expect that M-UC will likely produce 
a lower 6-month abstinence rate of approximately 20%. With α=.05, and n=300 for M-UC and 
n=300 for the AOCT, we are powered at .80 to detect a 10% difference in relapse rates of the 
AOCT vs. M-UC. Therefore, we are powered to detect approximately a 10% treatment effect, 
which we consider to be clinically meaningful.   
 
Primary Aim 2: Power analyses for the main systems outcome were computed based on 
the approach described by Glick and implemented in STATA Version 12.1 (StataCorp, College 
Station, TX) programs developed by Glick (http://www.uphs.upenn.edu/dgimhsr/stat-
samps.htm). For purposes of powering cost-effectiveness comparisons, we utilized net 
monetary benefit (NMB) which has benefits over the incremental cost-effectiveness ratio 
(ICER). In contrast to a ratio measure such as the ICER, NMB is a continuous measure with a 
relatively normal distribution; in addition, the variance for NMB is well-defined which permits 
good estimation of confidence intervals, sample size, and power. NMB is computed as the 
difference in effectiveness (ΔQ) minus the difference in costs divided by willingness to pay 
(ΔC/W). Willingness to pay (W) is conceptualized here as the amount society would be willing to 
pay for a health benefit; for our purposes, W is the amount that would result in an additional 
quality-adjusted life year (QALY). Power was computed for two key comparisons: (1) cost-
effectiveness of COT relative to UC, and (2) cost-effectiveness of AOT relative to UC. We made 
the following assumptions for each of these comparisons: sample size of n=300 for the 
Abstinence-Optimized Cessation Treatment and n=300 for the Modern Usual Care treatment; 
two-tailed test; α=.05; standard deviation (SD) for costs=250; SD for effects (i.e., abstinence 
rates)=.42; correlation for the difference in costs and effects=.1; and maximum willingness to 
pay=$50,000. For the AOCT vs. M-UC comparison, we set the difference in abstinence effects 
at .1 (i.e., a 10 percentage point difference; 20% vs. 30%) and a cost difference at $1222 
reflecting a UC cost of $128 and AOCT cost of $1350. Power for this comparison is .60. 
However, we do have sufficient power (.80) to determine cost-effectiveness if there is a 12 
percentage point difference in abstinence rates. This analysis requires a larger abstinence 
difference to establish that it is cost-effective, as well as clinically effective, because of the large 
cost differential.  
 
Secondary Aim: Published estimates of sample sizes for mediational analyses, for 
various types of tests (e.g., the joint significance test and the Sobel test), provide the minimum 
sample size needed for detecting a mediated effect when the size of the effect of an 
independent variable (X; e.g., medication effect) and the size of the mediator effect (M; e.g., 
coping) are jointly considered. Based upon these values, if both the X effect and M effect are 
small/medium, a sample size of 196 would be needed to detect the mediated effect. Thus, we 
feel confident that our sample sizes of 270 per group (n’s=300 with 10% attrition) are sufficiently 
large to detect at least small/medium-sized (7.5% of variance) effects even in the presence of 
measurement error.     
 

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Fiore P01 Protocol, Version 10, July 19, 2018  
 
Long-term Quitting Study  
We have engineered a recruitment strategy that models attrition and subject loss, 
resulting in good power under conservative assumptions. In this project, ~1000 smokers will 
receive a Usual Care cessation treatment. Based on other trials, we anticipate that 72% of the 
N≈1000 smokers will relapse in the first 6 months (i.e., n≈720: see Figure 3); we believe that 
20% will remain abstinent and 8% will attrit. Of the 720 relapsers, we predict that 85% will enter 
RR Preparation treatment (n = 612) at some point in the  6 months after their quit day, while 
15% (n = 108) will stop participating.  The 612 participants who continue in treatment will be 
randomized to the 3 RR Preparation intervention conditions: the Low-Contact control condition 
(n ≈ 150), the Recycling condition (n ≈ 225) and the Reduction condition (n ≈ 225). Of 450 
assigned to the Recycling and Reduction conditions, we believe that 10% (n ≈ 45) will never 
make a new quit attempt, another 30% (n ≈ 135) will quit on their own or attrit without entering 
RR Cessation treatment, leaving 60% (n ≈ 270) who will enter RR Cessation treatment, and be 
randomized to the 2 RR Cessation intervention factors (n ≈ 135/each level of each factor).   
 
We have computed power for Primary Aim 1: to determine the effect of the RR 
Preparation factors on abstinence assessed at 14 months after randomization to RR 
Figure 3. Participant Flow with Estimated Ns
Initial Cessation Treatment(Usual Care)
N = 1000
~20% of the 1000 willremain abstinent
through 6 months
n ≈ 200
~72% of the 1000 will
report relapse on a
follow-up call
n who relapse ≈ 720
~8% of the1000 willnot answer calls
after the quit day
n ≈ 80
~85% of the 720 relapsers will enter
Relapse Recovery Preparation Treatment
by answering a phone call to initiate randomized treatment
n ≈ 612
450 will be randomly assigned to active preparation treatment
(225 to Reduction Counseling and 225 to Recycling Counseling). 150 will be assigned to the control condition.
~15% of the 720 willstop participating in
treatment because of
their relapse or will notanswer follow-up calls
n ≈ 108
~60% of the 450 assigned to
active treatment will decide
within 11 months to quit and
will enter randomized Relapse Recovery Cessation Treatment
n ≈ 270
~10% of the 450will not make anew quit attempt
n ≈ 45
Note: Estimated flow rates are based on past studies.
~30% of the 450 will
make a quit attempt
without study help or
will not answer
follow-up calls
n ≈ 135

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Preparation treatment. We computed power for the GLMM longitudinal analysis using the SAS 
macro developed by Dang and colleagues. We used the following parameters: N=600 in the 
intent-to-treat comparisons involving all 3 RR Preparation conditions (Control n = 150, and n’s = 
225 for each active condition), and N = 450 for comparisons of the two active Preparatory 
conditions. Smoking status will be analyzed at 1 time point (Month 14 after randomization to RR 
Preparation treatment); a 10% attrition rate across follow-up; with the treatment effect modeled 
as consistent over time; random effects variance=1; and within-subject correlation=0.6. We 
hypothesize average abstinence rates to be 15% for the Control condition, 25% for the 
Recycling condition, and 35% for the Reduction condition. We propose that any increase in 
abstinence of 15% or higher would be clinically significant. For the purpose of the power 
analysis we will assume a 15% abstinence rate for the Control condition. Under this scenario, 
there would be insufficient power to detect an effect for the Recycling condition versus the 
Control condition (i.e., 15% vs. 25%), but power would exceed .80 if the Reduction treatment 
produced an abstinence rate of .28 or higher.  If we assume a 10% abstinence rate for the 
Control condition, power would exceed .80 if either the Recycling condition or the Reduction 
condition produced an abstinence rate of .21 or higher. We did not power the study to 
demonstrate a significant difference between the two active conditions.  Therefore, we 
anticipate that only the RR Reduction treatment will significantly increase long-term abstinence 
rates over those produced by the Usual Care control condition.  
 
We also computed power for the Secondary Aim of determining the effect of the RR 
Preparation factor on the likelihood of a meaningful quit attempt characterized by more than one 
day of abstinence (that occurs at some point in the 12 months following entry into RR 
Preparation treatment). For power analyses we will restrict this comparison to the two active RR 
Preparation treatments since they yield the more conservative test.  We predict that 60% of the 
225 participants receiving Recycling Counseling will make a meaningful quit attempt, while 80% 
of the 225 participants receiving Reduction Counseling will make a meaningful quit attempt over 
the 12 months following entry into the RR Preparation treatment. Thus we predict a 20 
percentage point difference (with 60% vs. 80% of participants making a meaningful quit 
attempt); we have power of > .85 to detect this effect. With a 15 percentage point difference 
(e.g., 60% vs. 75% or 65% vs. 80%) power remains > .80.  The estimate of a 60-65% base rate 
of meaningful quit attempts is taken from the rate of quit attempts among smokers in general: 
i.e., with no preparation treatment ~40-45% of smokers a year make a quit attempt. We believe 
that Recycling Counseling will increase this figure by about 40-50% based upon the impact of 
Recycling Counseling on acceptance of pharmacotherapy when it is offered. Therefore, we 
assume that 60% of the Recycling participants will make a meaningful quit attempt, and we 
further propose that a 15-20 percentage point increase in meaningful quit attempts is a clinically 
worthwhile effect, given the strong relation between early quitting success and later abstinence.  
 
 
 
We have not powered this study to detect significant effects for the other data 
comparisons offered as Secondary Aims (e.g., transitions across phases of chronic care 
treatment, the effects of RR Cessation treatments).  Rather, those Aims are included in this 
research so that we can gather additional evidence related to the feasibility of a chronic care 
approach to smoking and so that we can gather additional preliminary data to guide our future 
research and treatment development.      
 
Clinic Randomized Control Trial 
 

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The primary outcome will be treatment engagement and we will analyze this with 
repeated measures analysis of variance (ANOVA) and analysis of covariance (ANCOVA). In 
these analyses we will contrast the experimental and control (F2Q) clinics on the basis of 
treatment engagement means averaged over the periods of clinic participation (which may differ 
somewhat across clinics) pre and post implementation. Since data on the dependent variables 
will be routinely collected pre-implementation, we have opportunity to determine the length of 
the baseline period: we will average data over 6 months to establish a baseline. The analyses 
will, conservatively, use the clinic as the unit of analysis. ANCOVA will use clinic location (rural 
vs. urban), size, SES, and baseline rates of smoker documentation and referral as covariates. 
We will conservatively use ANOVA to estimate power, in part, because it is unclear how much 
this set of covariates will affect error within the ANCOVA. Based on earlier data, we anticipate 
treatment engagement will be 1% for both groups at baseline (for the 6 months pre-
implementation) and 10 and 2% post-implementation for experimental and control clinics, 
respectively. Previous research also suggests that both groups will have the same standard 
deviation (SD = 4). Assuming an SD = 4, and a mean difference of 8 at post-implementation 
(2% vs 10%), power to detect a group by time interaction > .998 with α = .05 and N = 28 (18 
experimental and 10 control clinics). If we are able to recruit adequately with only 10 
experimental clinics (with N = 20, comprising 10 experimental and 10 control clinics), the 
smallest N that we can envision, then power = .887 with a smaller prognosticated post-
implementation group difference (8 vs. 2%). Thus, power appears ample for conservative tests 
of our primary outcome. We will use other analytic strategies to analyze these data (e.g., 
General Estimating Equations) that model patients as the units of analysis, with patients being 
nested within clinics. Only aggregated (non-identifiable) data will be used for these analyses.  
Such approaches should have greater power than the approach described above, which we 
present for purposes of clarity and simplicity. In addition, in secondary analyses we will compare 
subcategories of treatment engagement rates: e.g., comparing WTQL engagement rates in the 
control clinics with engagement rates for cessation treatment in the experimental clinics (i.e., 
removing chronic care engagement data for smokers who wanted to reduce their smoking). We 
will also examine treatment completion rates and 6-month abstinence rates, especially for those 
referred to the chronic care treatment, to determine the “yield” of treatment referral. Such data 
would also allow us to compute cost-effectiveness and cost-benefit analyses.  
 
 
 
The analytic approach that we have described above will also be used for the other 
major outcomes (i.e., smoker documentation and treatment referral). There is adequate power 
for both of these outcomes.  
 
Protection of Human Subjects 
 
Risks to the Subjects 
Human Subjects Involvement and Characteristics.  
This protocol addresses 3 clinical research studies and a clinic-level study comparing 
system enhancements coming from modifications of the EHR to usual care Fax to Quit referral 
of smokers.  The clinic level study has not human subjects. The 3 clinical research studies 
involve human subjects and that involvement is described below.  For the clinic level study, 
necessary data for the intervention clinics will be obtained from the subjects in the clinical 
research as well as from the sample representativeness data described in Appendix 1 below.  
The additional data on non-study participants at the intervention clinics available through these 
aggregate sample representativeness data files will not include any identifiable private 

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information and these individuals are they not considered human subjects.  All data from the 
control clinics (aggregate information on clinic visits and smoker rates obtained from the health 
systems and summary numeric data on the number of referrals received and served reported by 
the Wisconsin Tobacco Quitline for all fax referral sites) will be aggregate data with no 
identifiable private information.  The patients participating in smoking cessation treatment as a 
result of their fax to quit/standard of care referral from the control clinics are therefore not 
considered human subjects and are not discussed further in this section of the protocol.  In 
summary, the remainder of this human subjects section focuses on the human subjects who will 
participate in the clinical interventions as a result of referral from an active clinic assigned to the 
EHR intervention condition within the clinic randomized control trial, since these are the only 
human subjects involved in this set of studies.   
 
Specific eligibility requirements for all 3 clinical studies within the intervention clinics are: 
1) 18 years of age or older; 2) report smoking at least 5 cigarettes per day for the previous 6 
months; 4) able to read and write English; 5) have reliable phone access and agree to respond 
to Interactive Voice Response (IVR) phone prompts 8) free of medical contraindications to NRT; 
and 9), if participant is a woman of childbearing potential, using an approved method of birth 
control during treatment. Participants who are eliminated due to screening failure, or elect not to 
participate in this research medication program, will be given a list of alternative smoking 
cessation programs, including an opportunity to receive usual care from the clinic and a referral 
to the Wisconsin Tobacco Quit Line (1-877-270-STOP).  For the Motivation Study, participants 
also have to be not currently attempting to quit smoking or intending to quit smoking (defined as 
no plans to quit in the next month); and planning to remain in the intervention catchment area 
for at least 12 months.  For the Cessation Study, participants also have to be motivated to quit 
smoking and planning to remain in the intervention catchment area for at least 12 months.  For 
the Long-term Quitting Study, participants also have to be motivated to quit smoking and 
planning to remain in the intervention catchment area for at least 2 years and 2 months.   
 
A minimum of 2112 participants will be recruited to participate in this research:  512 in the 
Motivation Study, 600 in the Cessation Study and 1000 in the Long-term Quitting Study.   
However, to get a proper balance of participants across the three studies, we may recruit as 
many as 2600. No special vulnerable populations will be intentionally recruited (pregnant 
women will be specifically screened out due to medication safety concerns and no persons 
under the age of 18 will be allowed to participate because the medications we are using have 
not been approved by the FDA for individuals less than 18 years old). See the Inclusion/ 
Exclusion section for protocol regarding participants previously eligible who become 
incarcerated or pregnant. 
 
Eligible participants will be randomized at the point of screen passing the phone screen 
(stratified by gender). Those who do not enroll will be unrandomized and the treatment condition 
assigned to them will be reassigned to a new preparticipant. 
 
Medication dosing will be consistent with the 2008 PHS Guideline, other recent clinical practice 
guidelines, and package inserts (smoke within 30 min of waking = 4-mg mini-lozenge; smoke 
more than 30 min after waking = 2-mg mini-lozenge; smoke >10 cigs/day = start with 21-mg 
patch; smoke <=10 cigs/day = start with 14-mg patch). Starting Spring 2018 we started to 
screen individuals who would be prescribed mini-lozenges for soy allergens prior to 
dissemination to prevent allergic reaction AEs - per the ML new package insert. Research 

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personnel will recommend dosage/use alterations as per good clinical practice if the participant 
experiences symptoms of nicotine toxicity or side effects. The health counselor will refer 
participants to their primary care physician should they require medical consultation. Medication 
is provided to participants in dosage periods defined within each protocol. It is important to note 
that study medication use in this research is all in accordance with FDA guidelines, including 
using NRT for longer than 8 weeks, before quitting, and in combinations (e.g., patch + mini-
lozenge). For the Motivation and Long Term Quitting studies, if a medication is discontinued due 
to one or many NRT symptoms, or the patient had a CVD event in the last 4 weeks, that 
medication will not be prescribed at a later phase.   No further medications will be given to this 
study participant while in the study. 
 
The research involves collaborating sites at Penn State University and University of 
Illinois-Chicago. Neither of these sites will collect data. Investigators at these two sites will work 
with cleaned, limited analytic data sets provided by UW-CTRI through secure web access to the 
named investigators. The work of both sites will be overseen by their own institutional IRB’s.  
The data sets provided by UW-CTRI will conform to the rules for a limited data set, including 
dates of service and an identifier that allows for analysis at the individual study participant level. 
The research also involves collaboration with staff of two health systems (Aurora Health Care 
and Dean Health). In prior research of similar scope, their involvement has been determined to 
be not involved in research since their role is limited to providing information about the 
availability of a study and sending contact information to the study staff, as well as providing 
other types of aggregate data. No identifiable research data from UW-CTRI are shared with the 
clinics. 
 
Sources of Materials. Data on those expressing interest in the study within their 
healthcare clinic are gathered by electronic health record (EHR). This statement of interest 
generates an electronic transmission of the person’s contact information (address and phone) to 
a password-protected email account accessed by specifically named study personnel. The 
contact information is entered into the study database. 
 
Data collected from participants in this Program Project will primarily be used for 
research. Data will consist of answers to questionnaires, automated phone assessments, and 
interviews assessing smoking history, demographics, nicotine dependence, personality, affect, 
and breath samples to permit determination of carbon monoxide. Carbon monoxide assays 
reflect smoking status. All data are retained in the study database. The study database access 
is limited to those staff members and investigators directly involved in the study and under the 
supervision of the UW IRB. 
 
Potential Risks.  Risks associated with this research are judged to be minimal. Smoking 
withdrawal is associated with a number of unpleasant symptoms such as sleep disturbance, 
hunger, craving, and negative mood. Most smokers have tried to quit in the past and are familiar 
with these phenomena. Participants will be informed about the likely effects of smoking 
withdrawal.  
 
With respect to the pharmacotherapies, participants will be made aware of the common 
side effects before they consent to participate in the study. It should be noted that the nicotine 
mini-lozenge and patch are available over the counter. The nicotine patch is generally well 
tolerated, but up to 50% of participants may have a local skin reaction, and rarely, individuals 

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may have a more systemic allergic reaction. The most likely side effects associated with the 
nicotine mini-lozenge are heartburn, nausea, hiccups, and sore throat. Although most smokers 
have tolerance to nicotine, symptoms of acute nicotine toxicity (nausea and vomiting) are 
possible. The two other primary FDA approved alternative medication treatments for smoking 
cessation are bupropion and varenicline. Both have a considerably greater side effect profile 
than nicotine replacement products and require extensive medical monitoring7. Finally, 
individuals often attempt to stop smoking without the use of medication. As the 2008 PHS 
Guideline7 shows, this method is considerably less likely to produce long-term cessation. Those 
not successful in quitting bear the health risks associated with continued smoking. 
 
Finally, there is a small risk of loss of confidentiality. This could occur through a number 
of possible avenues, all highly unlikely due to the data security measures in place. UW-CTRI’s 
computer system is linked to the UW network through a firewall, which is managed by the 
School of Medicine and Public Health network team, via a fiber link which is maintained by the 
UW Division of Information Technology. No data are stored on individual computer hard drives. 
All data are transmitted from the point of collection to the UW-CTRI server through secure, 
encrypted web connection. There are rare occasions when, due to a loss of internet access or 
computer hardware failure, data are collected in paper forms, which could be taken or lost. In 
addition, consent forms are obtained in paper copy; these forms contain the participant name 
and signature. Finally, the University of Wisconsin and the National Cancer Institute may inspect 
the signed consent forms. Because of this possible need to release information to these parties, 
we cannot guarantee absolute confidentiality.    
 
Adequacy of Protection Against Risks 
 
Recruitment and Informed Consent. To ensure that our findings are maximally relevant 
to real-world healthcare application, we will screen smokers presenting to 18 primary care 
clinics (PCCs) in two participating health systems located throughout Southern Wisconsin. 
Participants will be recruited via two methods. 1) Participants will be recruited by the clinic’s 
roomers (e.g., Medical Assistants) with methods similar to methods used in our prior research. 
Prompted by the electronic health record (EHR), roomers will screen all patients for smoking 
status and then will ask all smokers if they are interested in learning about treatments to help 
them quit now or in the future or reduce their smoking. They will also describe standard of care 
services their clinic has available. If the patient is interested, a one-click referral will send an 
EHR-generated Smoker Interest Form, containing patient contact information, to the research 
office. The roomer will also flag the patient’s chart so that the physician will know that the 
patient's smoking has already been addressed and will not offer a smoking cessation 
intervention or study participation in the upcoming clinical encounter. 2) In the second 
recruitment method, smokers at participating clinics will receive direct recruitment information 
via mailings and EHR-specific messaging as part of the Smoker Registry. The direct recruitment 
messages will encourage smokers to learn more about the study by either providing their 
contact information so the study can contact them or by calling the research office directly.  
 
 
 
The EHR-generated messages about interested patients or telephone messages left by 
interested patients will prompt a screening call from our research personnel within 48-72 hours 
to introduce the study options, assess interest and screen for eligibility. If the person is 
interested in one of the studies and is eligible, an in-person appointment at their referring clinic 
with a study staff member is set up. At this visit, the smoker will learn about general 
requirements for participation (e.g., need for follow-up, participation in assessments) as well as 

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risks associated with nicotine toxicity, nicotine withdrawal, and the pharmacotherapies. The 
health counselor will then provide each study candidate with an IRB-approved informed consent 
document corresponding with the study which they have chosen. Study candidates will read the 
informed consent document and be given an opportunity to ask any questions regarding study 
participation. A research staff member will read the consent form to the study candidate if 
needed or desired. The consent form will include necessary HIPAA language. Participants will 
be required to sign the consent form. Case managers will provide participants with a copy of the 
consent form.  
 
Protection Against Risk. Risks related to medications are minimized through close 
monitoring. The leader for each study (Project Leaders), working in consultation with the 
Program Project’s physician (Dr. Fiore), will be responsible for routine monitoring of 
unanticipated health events. This risk protection includes procedures for contacting the 
emergency physician or psychologist and monitoring of all events through scheduled biweekly 
meetings with study staff and review of written documentation. Unanticipated health event 
assessment, recording, reporting and investigation will be accomplished through staff training, 
structured/standardized assessments of untoward occurrences/events, and regular monitoring 
by study physicians and other study investigators. The Project Leaders and the Program Project 
Co-Principal Investigators have ultimate responsibility for ensuring that unanticipated health 
events are detected and reported in a timely manner. Health events that raise concerns (e.g., 
allergic reaction, symptoms suggestive of nicotine toxicity, significant change in mood, suicidal 
ideation) will be immediately reported to the study physician who will determine an appropriate 
course of action.    
 
To facilitate safety, participants who may not be medically appropriate to take NRT will 
not be included in the study (e.g., hospitalized within the past month for a stroke, heart attack, 
congestive heart failure or diabetes). Once enrolled, follow-up protocols will assess for 
medication side effects and unanticipated health events at all study visits and follow-up 
contacts. We will recommend NRT dosage/use alterations as per good clinical practice if the 
patient experiences symptoms of nicotine toxicity or other troublesome side effects once they 
begin medication treatment. We will refer participants to their referring physician as needed. 
Should either excessive risk to study participants and/or lack of measurable benefit to study 
participants be determined, the study will be stopped and all participants notified in a manner 
appropriate to the nature of the risk and/or lack of benefit.  
 
In terms of confidentiality risk, the UW-CTRI Information Technology Administrator 
manages the hardware, data, security, and infrastructure below the firewall. Access to the 
network is limited to only UW-CTRI owned and actively managed devices. All devices 
automatically lock and are password protected after 15 minutes of inactivity. All portable devices 
are encrypted for data security and no PHI is stored on local devices. All data stored on the 
network file server is limited by the principle of least privilege. 
 
As stated above, no data are stored on individual computer hard drives. All data are 
transmitted from the point of collection to the UW-CTRI server through secure, encrypted web 
connection. On those rare occasions when, due to a loss of internet access or computer 
hardware failure, data are collected in paper forms, these forms will be stored securely in the 
clinic and transported personally by the case manager to UW-CTRI. No identifying data other 
than a participant ID number is entered on any data form. Any paper collected data are entered 

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Fiore P01 Protocol, Version 10, July 19, 2018  
 
into the computer immediately upon receipt at UW-CTRI and the paper document is disposed of 
securely. Consent forms are obtained in paper copy; these forms contain the participant name 
and signature. These are retained in secure files at the clinic where they are collected and then 
transported to the UW-CTRI office, where they are securely stored. 
 
Finally, no publications or presentations resulting from this research will contain any 
identifying information about individual participants.   
 
Potential Benefits of the Proposed Research to the Participants and Others 
           The potential benefits for smokers participating in the Motivation Study include the 
chance to reduce their smoking and make a quit attempt sooner than they otherwise would 
have. Benefits for all research participants include the chance to receive smoking cessation 
counseling and pharmacotherapy at no cost—two evidence-based treatments which can double 
a smoker’s odds of quitting successfully. Considerable research has demonstrated that, 
whenever a smoker quits successfully, health benefits occur. In addition, quitting smoking 
reduces the burden of secondhand smoke exposure to others. Finally, the benefit of reduced 
healthcare costs, morbidity and mortality related to smoking is a societal benefit from quitting 
smoking.   
 
 
The health and economic benefits to the individual and society greatly outweigh the risks 
in terms of discomfort, side effect of medication and loss of confidentiality.  
Importance of the Knowledge to be Gained 
These research studies will develop new treatments and determine whether treatment 
packages engineered using Phase-Based intervention components and the MOST approach 
are more effective and more cost-effective than usual care treatment for smoking cessation. 
This information could lead to the provision of tested treatment packages that a health system 
can implement for smoking cessation, as the cornerstone of a chronic care treatment for 
smoking. Further, this research will identify treatment mechanisms via which the treatments 
exert their effects. Such knowledge could be helpful in developing new treatment packages and 
for personalizing treatment based on which treatments work for various groups of smokers. 
Finally, the studies will test methodologies designed to more rapidly develop effective 
interventions, test them and bring them into clinical use, considerably shortening and improving 
the methodology for research translation into practice. 
 
 
As outlined above, the risks of this study are minimal and limited to the discomfort of 
quitting smoking, generally mild side effects of medication and small risk of breach of 
confidentiality. The potential study impact on increased numbers of smokers across clinical 
settings nationally far outweigh these risks.   
 
Data and Safety Monitoring Plan 
The following Data and Safety Monitoring Plan (DSMP) pertains to all research to be 
supported under the National Institute of Health (NIH) Program Project Award. This plan 
comprises not only the research conducted directly by the University of Wisconsin Center for 
Tobacco Research and Intervention (UW-CTRI) researchers, but also research conducted by 
other investigators who are supported by these funds. 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 UW Institutional Review Board (IRB) or the 
IRB of any collaborating organizations. 

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Fiore P01 Protocol, Version 10, July 19, 2018  
 
 
 
Monitoring the progress of trials and the safety of participants. The PIs of the Program 
Project will be responsible for routine monitoring of the progress of the research. This 
monitoring includes scheduled biweekly meetings with study staff and review of written 
documentation of all research projects. Data that are reviewed at these meetings include the 
number and type of participants enrolled, the number and reasons for exclusions from 
enrollment, the number of participants treated and the stage of intervention, a summary and an 
individual review of any unanticipated health events, and outcome data.    
 
To facilitate participant safety, study participants must meet study inclusion and 
exclusion criteria. Once enrolled, follow-up protocols will assess the presence of medication 
side effects and unanticipated health events at all study visits and follow-up contacts. We will 
recommend dosage/use alterations as per good clinical practice if the patient experiences 
symptoms of nicotine toxicity or other troublesome side effects. We will refer patients to the 
study physician and/or their referring physician based on defined, regularly administered 
medication safety protocols. Any unanticipated health events that raise concerns (e.g., allergic 
reaction, symptoms suggestive of nicotine toxicity) will be immediately reported to the study 
physician. Such symptoms typically result in dosage changes or medication stoppage. 
Should either excessive risk to study participants and/or lack of measurable benefit to study 
participants be determined, the study will be stopped and all participants notified in a manner 
appropriate to the nature of the risk and/or lack of benefit.  
 
Plans for the reporting of unanticipated health events. This DSMP requires that 
investigators notify NIH and the University of Wisconsin IRB in a timely manner of the 
occurrence of any unanticipated health events, which are severe, unanticipated, and possibly 
related to study medication or protocol.  
 
Because this study involves pharmaceutical agents, in the event of an unanticipated 
health event that might be related to drug use, both the FDA and the manufacturer will also be 
notified within 5 days of investigators becoming aware of the event. Examples of a serious 
unanticipated health event would be untoward occurrences related to study participation 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 health events would also include less serious problems 
that merit reporting because they are severe, unanticipated, and possibly related to study 
participation. All serious unanticipated health events, including those reported during scheduling 
and follow-up calls, will be examined within 72 hours and reported as required by IRB, NIH 
and/or FDA rules. The PIs will be responsible for the accurate documentation, investigation, and 
follow-up of all study-related unanticipated health events. 
 
Unanticipated health event assessment, recording, reporting, and investigation will be 
accomplished through staff training, structured/standardized assessments of untoward 
occurrences/events, and regular monitoring by study physicians and other study investigators. 
The Project Leaders and the Program Project Co-Principal Investigators have ultimate 
responsibility for ensuring that unanticipated health events are detected and reported in a timely 
manner. Additionally, the IRB will receive an annual report of all serious unanticipated health 
events and unanticipated health events meeting the criteria listed above. 

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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 Program Project PIs 
deem it necessary to suspend a clinical trial. In the case of a temporary suspension, the 
Program Project Co-Principal Investigators and Project Leader 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 
Project Leader, supported by staff, will refine and monitor existing protocols for assuring data 
accuracy and protocol compliance. Data from their compliance reviews will be shared with the 
Program Project PIs. Such protocols will include data verification and protocol compliance 
checks. The Data Manager and IT Manager will also be responsible for ensuring that the data 
for the project are securely stored, that storage is in compliance with University and federal 
regulations and that no unauthorized persons have access (electronic or physical) to any 
participant-identifiable data. The PI’s will ensure that HIPAA regulations and guidelines are 
currently implemented and all study staff have completed approved human subjects and HIPAA 
training programs. The. 
 
Safety Review Committee 
In addition to the protections outlined in the Program Project-wide DSMP (above), all 
three studies conform to the NIH definition of a clinical trial. All of the trials in this P01 
application are Phase IV clinical trials that are not multicenter in nature (the projects are testing 
existing interventions delivered through new methods to determine population effectiveness). 
The DSMP specifies overall monitoring that will be conducted by the PIs for all projects. Their 
responsibilities include timely reporting of unanticipated health events and serious unanticipated 
health events. Every 6 months, the Program Project-wide Safety Review Committee will 
convene to review the overall safety data, as well as data on safety summarized by treatment 
condition. The objective of these reviews will be to determine whether continued conduct of the 
trial poses no undue risk for participants.   
 
The Program Project-wide Safety Review Committee will be chaired by Dr. James 
Cleary, leader of the Palliative Care and Supportive Oncology Group at the UW Carbone 
Cancer Center. Dr. Cleary is a very experienced physician and clinical trial researcher with no 
involvement in any of this P01’s research activities. Dr. Cleary will be joined on the committee 
by Dr. James Sosman and Dr. Burke Richmond. Dr. Sosman is a practicing general internist 
and has collaborated on clinical trials with UW-CTRI in the past. Dr. Richmond has served on 
independent Data and Safety Monitoring Boards for Phase II and III trials involving a nicotine 
vaccine. Neither has direct involvement with any of this P01’s research activities. UW-CTRI’s 
data staff will provide support for these reviews including summaries of safety data by treatment 
condition. The PIs will participate in these reviews and take lead responsibility for implementing 
any recommended changes in procedure or protocol.  
 
 

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Appendix 1:  Sample Representativeness/Study Recruitment Aggregate Data Request* 
* obtained for Active Intervention study clinics only 
Subjects:  
• 
~100000 patients who had visits at clinics during the project recruitment period at each 
participating clinic plus all smokers connected with these clinics who were not seen 
Consent Procedures: 
• 
Patients will not be asked to provide consent or specific HIPAA authorization for this 
anonymous data reporting 
Data Collection for Patients Visiting the Clinic During the Recruitment Period 
• 
Medical Assistants (MAs) complete EMR-recorded tobacco use screening.  The 
following visit record information will be analyzed from the EMR during specified 
recruitment time periods in each clinic: 
o Number of unique adult patients (18 years and older) with visits during the 
recruitment period 
o Number of visits by those unique patients 
o Clinic 
o Smoking status: not asked, never, current, former 
o Study referral: yes/no  
• 
UW-CTRI research staff send the following data to EMR data staff via secure server for 
all those sent for consenting to study participation and contact with their health clinic (by  
clinic subsequent to the close of the recruitment period): 
o Name 
o Date of visit where referral took place 
o MR # 
o Clinic 
• 
EMR data staff sends the following group data to research staff via secure server for 7 
different groups for each clinic participating in the study: (1) those not asked about 
smoking at all visits  (2) those indicating they are a never smoker at any visit; (3) those 
indicating former smoker at any visit, (4) those indicating smoking at any visit but not 
invited to study by attending medical staff  (5) those indicating smoking at any visit not 
interested in being referred at any visit,  (6) those referred but not enrolled in the study 
and (7) those enrolled in the study.   
o Gender distribution 
o Ethnicity distribution (African American, white, other) 
o Age distribution (5 year increments, over 80 as a single group) 
o Types of insurance (commercial, Medicaid, self-pay, etc.) 
o Diagnosis (ICD-9, grouped into categories) 
o Visit type and level 
o Number of clinic visits during the study period (1, 2, 3, 4 or more) 
o Visit at which study invitation was accepted (groups 5 and 6 only) 
 
Data Collection for Patients NOT Visiting the Clinic During the Recruitment Period 
• 
EMR data The following information will be analyzed from the EMR during specified 
recruitment time periods in each clinic for those who had no visits: 
o Number of unique adult patients (18 years and older) with no visits during the 
recruitment period 
o Clinic 
o Smoking status: unknown, never, current, former 

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o Outreach performed: letter, mychart, none 
• 
UW-CTRI research staff send the following data to EMR data staff via secure server for 
all those contacting the study directly.  (Note: the purpose of this transmission is to 
enable the health clinic to differentiate between groups 6 and 7 below.  By providing a 
list of the study participants, the clinic can provide essential aggregate comparative data 
on the group of individuals who they referred but did not enter the study.  
o Name 
o Clinic 
o EMR number 
• 
EHR Data Department staff members at Aurora and Dean Health systems will perform 
necessary database queries that will allow them to send the following group data to 
research staff via secure server for 7 different groups for each clinic participating in the 
study for all those not having a clinic visit: (1) those never asked about smoking  (2) 
those indicating they are a never smoker; (3) those indicating former smoker, (4) those 
indicating smoking at any visit but not receiving any outreach  (5) those indicating 
smoking but not contacting the study,  (6) those referred but not enrolled in the study 
and (7) those enrolled in the study.   
o Gender distribution 
o Ethnicity distribution (African American, white, other) 
o Age distribution (5 year increments, over 80 as a single group) 
o Types of insurance (commercial, Medicaid, self-pay, etc.) 
o Diagnosis at latest visit (ICD-9 [or -10], grouped into categories) 
 
Data Storage: 
• 
Research staff will maintain a cumulative anonymous dataset received from the health 
system EMR provider until 7 years after completion of the study, when the dataset will 
be destroyed 
• 
Health system Data Department staff will securely maintain a record of data provided by 
the study until data verification is performed by the researchers.  Following that time, 
these data will be destroyed in a HIPAA compliant manner in accord with health system 
policies. 
 
 
 

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Appendix 2: Consort Diagram 
Optimized Chronic Care for Smokers: Aggregate Clinic Recruitment Data Needed for Study CONSORT Diagram
All clinic patients
Patients with a visit 
during the study 
recruitment period
Patients not visiting 
the clinic during the 
study recruitment 
period
Non smokers 
and former 
smokers
Non smokers 
and former 
smokers
Smokers 
Smokers 
Not asked 
about study
Asked about 
study and 
declined to 
be referred
Asked about 
the study 
and agreed 
to be 
referred
No response 
to outreach
Responded 
to outreach 
by contacting 
study
Not able to be 
reached by 
study or 
declined
Not able to be 
reached by 
study or 
declined
Entered study
Entered study
In order to just the effectiveness of the study approach, relevant aggregate “demographic” information is 
being sought on each of the groups in the above chart, as outlined in the EMR data summary document 
appended to the protocol
 
 
 
 

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