UW Withdraw From Tobacco Study: Enhancing and Evaluating Tobacco Withdrawal Assessment Psychometrics and Validity
Phase: PHASE2
Conditions: Tobacco Dependence
Sponsor: University of Wisconsin, Madison

 
 
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SCIENTIFIC PROTOCOL 
 
Version January 21, 2022 
NCT04969198 
Principal Investigator: Timothy B. Baker, PhD 
Study Director: Jesse T. Kaye, PhD 
Center for Tobacco Research and Intervention 
University of Wisconsin, School of Medicine and Public Health 
 
 
Title: UW Withdraw from Tobacco Study: Enhancing and Evaluating Tobacco Withdrawal 
Assessment Psychometrics and Validity 
  
 
Specific Aims 
 
Specific Aim 1: To enhance and evaluate the validity of a self-report assessment of tobacco 
withdrawal, the revised Wisconsin Smoking Withdrawal Scales-2 (long: WSWS2-L; brief: 
WSWS2-B), in terms of their sensitivity to smoking abstinence in initially unmedicated 
individuals making a quit smoking attempt. 
 
Specific Aim 2: To compare the validity of the WSWS2-L and the WSWS2-B with alternative 
withdrawal scales on the bases of psychometric criteria. 
 
Specific Aim 3: To determine factors that most accurately predict withdrawal severity (peak, 
average, variability, and duration), including contextual factors, personality factors, lifestyle 
factors, pharmacologic factors, precessation symptomatology, reward sensitivity/response, and 
affective processing dimensions.  
 
 
Significance 
 
The Wisconsin Smoking Withdrawal Scale (WSWS) was developed over two decades ago to 
provide researchers and clinicians with a psychometrically sound, validated self-report 
assessment of nicotine withdrawal (Welsch et al., 1999). This 28-item scale includes a total 
symptom scale and 7 subscales addressing components of the tobacco withdrawal syndrome 
(e.g., anxiety, anger, sadness, craving, concentration difficulties, hunger, and sleep problems). 
The original scale has reasonable psychometric properties, is sensitive to smoking abstinence, 
related to tobacco dependence measures, and has moderate predictive validity regarding 
smoking cessation outcomes. The WSWS has been a valuable assessment instrument that has 
been used by numerous researchers worldwide for investigating the nature and correlates of 
tobacco withdrawal. However, the field’s understanding of tobacco withdrawal has advanced in 
recent years and the population of smokers has changed substantially (e.g., reduced smoking 
heaviness; Jamal et al., 2018). Thus, there is a clear need to update and improve the 
assessment of withdrawal.  
 
It is of considerable scientific and clinical importance to assess tobacco withdrawal accurately 
since withdrawal severity is highly determinant of smoking cessation success. In addition, 
smoking cessation pharmacotherapy produces its effects on smoking abstinence by 
suppressing such symptoms (Bolt et al., 2012). The current study aims to validate, and possibly 
enhance, a revised WSWS for use in research and clinical settings. We have recently 

 
 
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developed a psychometrically robust, revised version of the WSWS based on several recent 
smoking cessation trials conducted by UW-CTRI (WSWS2, Smith et al., in press). However, 
most previous research, including our own, has occurred within the context of the 
pharmacological treatment of smoking. In order to ensure that a measure of tobacco withdrawal 
is sensitive to severe withdrawal, it is essential to examine unmedicated smokers. Unmedicated 
smokers display withdrawal symptoms that vary greatly in severity, which will allow us to 
determine which WSWS2 items are sensitive to both mild and severe withdrawal 
symptomatology. Assessment of unmedicated withdrawal is rarely done and therefore this 
research will yield unusual and valuable data on withdrawal amongst today’s smokers. It is also 
important to assess withdrawal amongst smokers who are using smoking medications since 
treatment guidelines (Fiore et al., 2008) recommend that virtually all smokers in formal 
treatment programs use such medication. Therefore, data gathered from smokers when they 
begin using medication will be highly relevant to the greater population of treated smokers.  
 
The current study aims to validate a revised WSWS measure (WSWS2-L) in a new sample of 
unmedicated smokers who abstain from smoking for 1 week prior to receiving pharmacological 
smoking cessation treatment. Furthermore, the research will evaluate constructs that have 
emerged primarily in recent years for possible inclusion in the new WSWS (e.g., restlessness, 
anhedonia, pain). Depending on the results of such evaluation, items representing these 
constructs may be included in a future version of the WSWS instrument. Another reason for 
conducting more research on the WSWS is that the previous measure was quite lengthy, which 
reduced its routine use in both clinical and research contexts due to concerns over assessment 
burden. Therefore, the proposed research will validate a psychometrically valid short form of this 
instrument (the Brief WSWS2: the WSWS2-B) in addition to a longer form suited for in-depth 
analysis of withdrawal (WSWS2-L). Developing a short form is especially vital given the 
increasing use of mobile technology for assessment. Such technologies require the use of very 
brief but valid assessment instruments. As such, this study aims to validate both a full yet 
efficient comprehensive WSWS2-L as well as a brief and focused WSWS2-B for use across 
diverse clinical and research settings.  
 
 
Study Overview 
 
We propose recruiting up to 500 daily cigarette smokers who report a desire to quit smoking in 
order to enroll up to 250 participants. This is a treatment-delay, one-group clinical trial that is 
intended to enhance the assessment of tobacco withdrawal amongst participants who try to quit 
smoking with delayed use of cessation medication. In addition, it is intended to identify important 
determinants of withdrawal severity. Participants will not receive any pharmacotherapy during 
the first 1 week of their quit attempt. They will initiate pharmacotherapy 1 week past the target 
quit day (TQD) and continue treatment through 9 weeks past the TQD. This will allow for the 
examination of withdrawal symptoms for 1 week post-TQD in participants who are not using 
pharmacotherapy. Participants will receive 8 weeks of combination nicotine replacement 
therapy (C-NRT: nicotine patch + nicotine mini-lozenge) starting 1 week past the TQD. 
Participants will receive 4 counseling sessions that conform to the US PHS Clinical Practice 
Guideline recommendations (1 prequit, 3 postquit). Participants will complete 4 weeks of 
ecological momentary assessment (EMA) including a 2-week baseline (starting TQD-14) and 2-
week post-TQD (1-week un-medicated, 1-week using C-NRT). Participants will be recruited via 
media (newspaper and television advertisements, and Facebook advertisements) to attend an 
Orientation Visit where the study will be explained and they will provide written informed 
consent. Once consented, the study will include three phases (described below): Orientation, 
Precessation and Cessation. Over the 2-week Precessation and the first 2 weeks of the 

 
 
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Cessation phase, participants will complete intensive daily mobile self-report assessment 
(mobile assessment) of withdrawal and other relevant variables. 
 
The Orientation Phase. This will include an Orientation session for all participants and will entail 
completion of written informed consent, eligibility screening, a self-report assessment battery, 
and physical assessments (e.g., breath CO, urine nicotine/cotinine levels, blood pressure). 
Assessments delivered during these visits will include withdrawal assessment, smoking 
heaviness, use of all nicotine products, and potential mechanisms of treatment (e.g., 
expectations of smoking reinforcement, smoking contexts, affect). Eligible participants will be 
scheduled for a Precessation Call. 
 
The Precessation Phase. This will include all participants (n=250) and last 2 weeks, ending at 
the participant’s TQD. Participants will have 3 phone calls during this phase: at around 2 weeks, 
1 week, and 1 to 3 days before the TQD. They will continue their normal ad lib smoking and 
receive no medication during this phase. They will complete 2 weeks of intensive daily mobile 
self-report assessment (via ecological momentary assessment; EMA) of tobacco withdrawal and 
related factors prior to the TQD. Counseling will be provided at 1 week before the TQD. This 
visit will encourage all participants to review their motivation for quitting and ensure that they 
have a good quit plan for their TQD (e.g., abstaining completely on their TQD). Counseling 
sessions will be audio recorded for quality assurance. The extensive withdrawal assessment 
battery will be repeated at the study calls and any EMA problems will be addressed. 
 
The Cessation Phase. This will start on the TQD and will last 9 weeks. Participants will attend 2 
study visits and 1 study call during the first two weeks of this phase: at 1-2 days post-TQD (call), 
7 days post-TQD (visit), and 2 weeks post-TQD (visit). During these calls and visits participants 
will be given cessation counseling (15-20 min) that stresses complete abstinence from 
cigarettes and that is consistent with the PHS Smoking Cessation Clinical Practice Guideline 
(Fiore et al., 2008). Counseling at the 1-week and 2-week visits will also stress adherent 
medication use and ways to deal with medication side effects. Counseling sessions will be audio 
recorded for quality assurance. Extensive withdrawal assessment battery will be repeated at the 
study visit and calls. At the study visits physical assessment will include breath CO, urine 
nicotine/cotinine levels, and blood pressure. Participants will be given their medication at the 
study visit 1-week post-TQD and instructed to start using their medication the next day. At these 
study visits and calls we will assess withdrawal and relevant factors as well as timing of any 
lapses. Participants will receive 1 additional assessment study phone calls during this phase at 
63 days post-TQD (9 weeks). This phone call will assess smoking status, withdrawal, 
medication adherence, and medication side effects. Participants who report abstinence at this 
call will be asked to attend an in-person visit for biochemical verification of abstinence (e.g., 
breath CO). Urine nicotine/cotinine levels will also be measured. 
 
Participants 
 
Two hundred participants (age ≥21; 50% women) who smoke ≥5 cigarettes per day, have a CO 
level ≥5 ppm, and report a desire to quit smoking, will be recruited from Madison and 
Milwaukee, WI. Participants must be willing to attempt to abstain from smoking for 1 week 
without the use of pharmacotherapy treatment or other nicotine use (e.g., e-cigarettes). See 
sections below for details on eligibility criteria, recruiting, and participant compensation 
strategies to enhance retention. 
 
 
Inclusion/Exclusion Criteria 

 
 
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Self-reported inclusion criteria: 
• 
Smoke ≥5 cigarettes per day for past year 
• 
≥21 years old 
• 
Able to read and write English 
• 
Desire to quit smoking 
• 
Not currently engaged in cessation treatment 
• 
Eligible to use combination nicotine replacement therapy 
• 
Willing and able to attend study visits 
• 
Have reliable smartphone access 
• 
Not currently pregnant, trying to get pregnant, or breastfeeding 
• 
Willing to respond to ecological momentary assessment prompts and other study 
activities 
 
Other inclusion criteria: 
• 
Baseline breath carbon monoxide (CO) ≥5 ppm 
 
Self-reported exclusion criteria: 
• 
Used pipe tobacco, cigars, snuff, or chew more than twice in the past week 
• 
Used e-cigarette, vaping, or any other electronic nicotine delivery product more than 
twice in the past week 
• 
Unwilling to try to abstain from all non-medicinal nicotine use (including e-cigarettes) for 
the duration of the Cessation Phase (other than nicotine replacement therapy provided 
by the study) 
• 
Currently taking varenicline or bupropion 
• 
Allergy to adhesive tape 
• 
Previous reaction to the nicotine patch or mini-lozenge that prevented them from 
continuing to use it 
• 
Unwilling to use study approved methods of birth control while taking study medication 
and for 1 month after discontinuing study medication [only for women of child-bearing 
potential] 
• 
Hospitalized for a stroke, heart attack, congestive heart failure, ulcers, or diabetes within 
the last year 
• 
History of seizure within the last year 
• 
Diagnosis of and/or treatment for schizophrenia, other psychotic disorders, or bipolar 
disorder within the last 5 years 
• 
End-stage renal disease 
• 
Suicide attempt or suicidal ideation within the last 12 months 
 
Other exclusion criteria: 
• 
Severe hypertension > 180/100 mmHg 
 
 
Recruitment 
 
Participants will be recruited via media recruitment methods (e.g., social media, UW-CTRI 
website, TV, and earned media) from Madison and Milwaukee, WI. Additionally we will 
proactively ask current participants in this study to recruit their friends with approved fliers and 
business cards. Interested smokers will call the study phone number or click the web links in 

 
 
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recruitment advertisements. Web recruitment will direct to a UW-CTRI website that provides 
basic information about the study goals, treatment offered, participant requirements, and 
financial compensation. Participants may provide their telephone and/or mailing address contact 
information (via voicemail or UW Qualtrics website or REDCap website) for study staff to return 
their calls and screen them for eligibility. Potentially eligible participants will be scheduled to 
attend an in-person, Orientation Visit. Participants who are potentially eligible but do not attend 
the Orientation Visit will be re-contacted to invite them to reschedule if they remain interested. 
 
 
Study Visits and Phone Contacts: Orientation, Precessation, and Cessation Phases 
 
For Study Visit and phone contact schedule and procedures see Table 1 (Orientation, 
Precessation) and Table 2 (Cessation). Participants will receive one visit-reminder (call, email, 
and/or text) prior to each study visit. 
 
Orientation Phase (TQD >-2 weeks)  
 
Orientation Visit 1 (TQD >-2 weeks). Participants will be provided an overview of the study goals 
and procedures in an individual setting. They will then be presented a written consent form and 
their questions will be answered. Interested participants will sign the consent form. Following 
successful consent, participants will be screened for eligibility (e.g., questionnaires, blood 
pressure, expired breath CO sample). Participants will provide urine nicotine/cotinine samples 
and complete a computerized self-report assessment battery (via REDCap and/or Qualtrics, see 
Table 1). Participants will schedule their TQD and the various study visits/calls. Participants will 
be instructed how to complete smartphone ecological momentary (EMA) mobile assessments 
on their own phone. Participants will be asked when they would prefer to receive assessment 
calls and will be given a calendar that shows all the study calls, visits, and assessments 
required by the study as well as contingent incentive amounts. 
 
Precessation Phase (TQD -2 weeks to TQD) 
 
There will be three phone contacts during the Precessation Phase. 
 
Precessation Call 1 (TQD -2 weeks). Participants will engage in mobile assessments daily for 2 
weeks during the Precessation Phase (EMA starting TQD-14d) while smoking ad libitum and 
prior to any pharmacotherapy treatment. The Precessation Call 1 will occur approximately 2 
days after the start of EMA (TQD-12 days) to address any EMA problems (e.g., adherence or 
technical troubleshooting). Participants will complete a brief self-report assessment battery 
during this call. 
 
Precessation Call 2 (TQD -1 week). Participants will receive smoking cessation counseling and 
complete self-report assessments at this phone call. This call will also involve dealing with any 
smartphone data assessment issues that arise during the Precessation Phase and instruction to 
continue mobile assessment for the next 1 week until the TQD. 
 
Precessation Call 3 (TQD -1 to -3 days). This call will focus on preparing the participants for the 
TQD, reminding them of its date, and stressing the importance of complete abstinence after the 
TQD. Participants will complete the self-report assessments. This call will also address any 
EMA problems (e.g., adherence or technical troubleshooting). 
 
Cessation Phase (TQD to +10 weeks) 

 
 
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Participants will attend 2 study visits and 3 study calls during this phase. 
 
Cessation Call 4 (TQD Day +1-2). Participants will receive smoking cessation counseling, 
complete self-report assessments including any smoking since their TQD. Participants will be 
reminded to attempt to completely abstain from smoking and use of all nicotine products. Mobile 
assessment data will be reviewed and problems with collection of such data will be addressed. 
 
Cessation Visit 2 (TQD Day +7). Participants will receive smoking cessation counseling, 
complete self-report assessments including any smoking since their last visit, and provide 
breath CO and urine nicotine/cotinine samples. Participants will be reminded to attempt to 
completely abstain from smoking and all nonmedicinal nicotine products. Participants will be 
provided with an 8-week supply of C-NRT including nicotine patches and nicotine mini-lozenges 
with instructions on how to use them (through TQD +9 weeks). Participants will be encouraged 
to start the medication the following day and to use their medication adherently. Mobile 
assessment data will be reviewed and problems with collection of such data will be addressed. If 
a participant is unable to attend Visit 2 or Visit 3 (2 weeks post-quit; described below) we will 
conduct the appointment over the phone. Most study activities can be conducted remotely (self-
report assessments, quit smoking counseling, medication education) with the exception of 
medication dispensation and physical tests (breath/urine smoking bioverification and blood 
pressure). In these cases, we will mail participants their study medication so they can still 
receive their nicotine replacement medication as soon as possible rather than delaying their 
medication dispensation until they are able to attend an in-person visit. 
 
Cessation Visit 3 (TQD Day +14). Participants will receive smoking cessation counseling and 
complete self-report assessments including any smoking since their last visit, and provide 
breath CO and urine nicotine/cotinine samples. Participants will be reminded to attempt to 
completely abstain from smoking and use of all nonmedicinal nicotine products. Participants will 
be encouraged to use their medication adherently and any medication problems such as side 
effects will be addressed. Participants will be reminded of the follow-up phone contact planned 
for 9 weeks post-TQD and the incentives for taking the call. 
 
Cessation Call 5 (TQD + Week 9). Participants will receive a call on their final scheduled day of 
pharmacotherapy to assess smoking status, medication adherence, and assess any medication 
side effects. Participants will complete self-report assessments. 
 
Cessation Visit 4 (TQD > Week 9). Participants who report abstinence from smoking at their Call 
5 will be asked to attend an in-person visit for biochemical verification of abstinence (e.g., breath 
CO). Urine nicotine/cotinine levels will also be measured. 
 
 
 

 
 
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Table 1. Study Visit Schedule and Procedures: Orientation and Precessation Phases 
 
 
 
Study Schedule, Assessment, and Procedures 
Visit 1 
Call 1 
Call 2 
Call 3 
Study Phase 
 Orientation 
Precessation 
Days +/- Target Quit Day: TQD 
> -14 
-12 
-7 
-3 to -1 
Sign Informed Consent and HIPAA 
X 
 
 
 
Inclusion/exclusion interview 
X 
 
 
 
Smoking Status & Timeline Follow Back 
X 
X 
X 
X 
Revised Wisconsin Smoking Withdrawal Scale 
(WSWS2-L) 
X 
X 
X 
X 
Minnesota Tobacco Withdrawal Scale – Revised 
(MTWS-R) 
X 
X 
X 
X 
Questionnaire of Smoking Urges (QSU) 
X 
 
 
 
Demographics 
X 
 
 
 
Smoking History 
X 
 
 
 
Brief Wisconsin Inventory of Smoking Dependence 
Motives (Brief WISDM) 
X 
 
 
 
Fagerström Test of Cigarette Dependence (FTCD) 
X 
 
 
 
Wisconsin Predicting Patients’ Relapse (WI-
PREPARE) 
X 
 
 
 
NIAAA Recommended Alcohol Questions 
X 
 
 
 
Pain Numeric Rating Scale (PNRS) 
X 
 
X 
 
Graded Chronic Pain Scale (GCPS 2.0) 
X 
 
 
 
Depression, Anxiety, Stress Scale (DASS21) 
X 
 
 
 
Snaith-Hamilton Pleasure Scale (SHAPS) 
X 
 
X 
 
Distress Tolerance Scale (DTS) 
X 
 
 
 
CO Breath & Blood Pressure 
X 
 
 
 
Urine Collection 
X 
 
 
 
Feedback Survey 
X 
 
 
 
 
 
 
 
 
Interventions 
 
 
 
 
Counseling (in minutes) 
 
 
15-25 
 

 
 
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Table 2. Study Visit Schedule and Procedures: Cessation Phase 
Study Visit Schedule, 
Assessment, and 
Procedures 
Call 
4 
Visit 2 
Visit 3 
Call 5 
Visit 4 
Study Phase 
Cessation 
 
Days +/- Target Quit Day: TQD 
+ 1-2 
+ 7 
+ 14 
+ 63 (9w) 
> 64 (>9w) 
Smoking Status & Timeline Follow 
Back 
X 
X 
X 
X 
X 
Revised Wisconsin Smoking 
Withdrawal Scale (WSWS-2) 
X 
X 
X 
X 
X 
Minnesota Tobacco Withdrawal 
Scale – Revised (MTWS-R) 
X 
X 
X 
X 
X 
Questionnaire of Smoking Urges 
(QSU) 
X 
X 
X 
 
X 
Pain Numeric Rating Scale (PNRS) 
X 
X 
X 
X 
X 
Depression, Anxiety, Stress Scale 
(DASS21) 
 
X 
 
 
 
Snaith-Hamilton Pleasure Scale 
(SHAPS) 
X 
X 
X 
X 
X 
CO Breath & Blood Pressure 
 
X 
X 
 
X 
Urine Collection 
 
X 
X 
 
X 
Feedback Survey 
 
X 
X 
 
 
 
 
 
 
 
 
Interventions 
 
 
 
 
 
AE/Safety assessment 
 
 
X 
X 
 
Counseling (in minutes) 
15 
15 
15 
 
 
C-NRT Adherence assessment 
 
 
X 
X 
 
 
Self-Report Measures 
 
WSWS-2. At all study visits participants will complete a newly revised set of Wisconsin Smoking 
Withdrawal Scale (WSWS2-L) items (Smith et al., in press). This 18-item assessment is 
intended to evaluate 6 subscales of craving, negative affect, difficulty concentrating, sleep 
difficulties, hunger, and restlessness. This assessment will provide data to validate a full version 
of the WSWS2-L. The brief 6-item version, the WSWS2-B, will be administered during EMA 
(see below). 
 
Assessment Battery. Participants will complete a battery of self-report questionnaires using 
REDCap or Qualtrics on a computer or tablet at the Orientation Visits (see Table 1). A smaller 
assessment battery will be re-administered at subsequent study visits and calls (see Tables 1-
2). Participants will complete several questionnaires designed to evaluate factors related to 
smoking experiences, nicotine dependence, and relapse risks. These questionnaires include the 
Minnesota Tobacco Withdrawal Scale-Revised (MTWS-R, (Hughes, n.d.), Smoking History 
Questionnaire, Brief Wisconsin Smoking Dependence Motives (Brief WISDM; Smith et al., 
2010), Fagerström Test of Cigarette Dependence (FTCD; Fagerström, 2012), and Wisconsin 
Predicting Patients’ Relapse (WI-PREPARE; Bolt et al., 2009). Participants will be asked a brief 
series of questions regarding menthol cigarette use, inhaled agents, noncombustible tobacco 
use, and e-cigarette use. Participants will complete a battery of assessments of affective and 
other personality traits, chronic pain, alcohol use, and psychiatric symptoms. These 
questionnaires include the Distress Tolerance Scale (DTS), Snaith-Hamilton Pleasure Scale 
(SHAPS; Snaith et al., 1995), Depression, Anxiety, and Stress Scale (DASS21; Lovibond & 

 
 
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Lovibond, 1995), Graded Chronic Pain Scale (GCPS 2.0), Pain Numeric Rating Scale (PNRS), 
and the NIAAA Recommended Alcohol Questions (NIAAA, 2003). 
 
Ecological Momentary (mobile) Assessment (EMA). Participants will provide daily ecological 
momentary assessment data (meaning data that has been collected “in the moment”) for 4 
weeks total during the study (over 2 weeks of Precessation and 2 weeks of Cessation). Mobile 
online surveys technology using smartphones will be used to acquire data. For most of the EMA 
portion of the study, participants will complete 3 assessments per day (morning, midday, and 
evening). Daytime EMA prompts will be brief (10 min) to include the brief WSWS2-B focused on 
motivationally relevant affective/cognitive features of withdrawal (e.g., excluding sleep which will 
only be assessed at the evening EMA) and smoking (# cigarettes since last assessment). The 
evening assessment will include a larger battery of questionnaires to include the WSWS2-B and 
additional targeted assessments (see below). Versions of these EMA protocols have been used 
effectively in multiple large scale smoking cessation clinical trials over the past two decades with 
very high completion rates (~80%). The frequency of EMA will be increased for 5 days from 1-
day pre-TQD to 3-days post-TQD in order to provide intensive monitoring of withdrawal 
symptoms on a more fine-grained time course during the early period of abstinence. During 
these 5 days participants will complete 6 EMA reports/day at within 2 hours of waking, waking + 
3 hours, waking + 5 hours, waking + 7 hours, waking + 9 hours, and retiring. Participants will 
complete the full 18-item WSWS2-L (rather than the WSWS2-B) during the evening EMA during 
these 5 days (1x/day). 
 
In addition to the WSWS2-B items, at each evening assessment (1x/day) or when a participant 
reports his/her first 3 post-TQD smoking events, they will also complete an expanded battery of 
EMA assessments regarding smoking, person-related, and contextual factors that day. These 
will include smoking (# cigarettes since last assessment), cessation self-efficacy, location (e.g., 
home, work, vehicle), activity (job, school, household), social context (e.g., social, work, 
stressful interaction), eating or drinking (e.g., eating, drinking caffeine, drinking alcohol), 
cigarette cues (e.g., lighter, ashtray, others smoking, tobacco ads), other inhaled substances 
(yes/no), cigarette availability (e.g., easy, hard, not available), medication use, pain (e.g., 
average, worst), smoking restrictions (e.g., home restriction, work restriction, public place 
restriction), with whom (e.g., friends, family, partner, co-worker), smoking triggers (e.g., 
see/smell cigarettes, stress, drink alcohol), tempted to smoke, coping strategies (e.g., cognitive, 
behavioral, none), and pre-coping intention. 
 
Table 3. Intensive Longitudinal Data Collection Schedule (Ecological Momentary 
Assessment: EMA)  
 
 
 
EMA and 
Medication 
Schedule 
 
Total: 5 weeks 
 
Precessation  
TQD 
Cessation 
TQD -14 
to -2 
 
TQD-1 
to TQD+3 
TQD +4 
to TQD+14 
TQD +15 
to TQD+21 
13 days 
 
5 days 
11 days 
7 days 
# Daily Assessments 
3/d 
6/d 
3/d 
 
Medication Status 
no medication 
C-NRT  
(Start TQD+8) 

 
 
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Bio-verification Measures  
 
Carbon monoxide Assessment. At all study visits, participants will provide expired breath 
sample of carbon monoxide (CO; Smokelyzer) for biochemical verification of abstinence. CO is 
used as both a measure of smoking heaviness at baseline as well as to confirm self-reported 
abstinence from smoking following the TQD. The higher of two samples recorded will be used 
as the value for data analysis. A cutoff of ≤5 ppm will be used as the criteria to be considered 
abstinent.  
 
Nicotine/Cotinine Assessment. At all study visits, participants will provide a urine sample to 
assess nicotine/cotinine levels, which can be used to estimate smoking heaviness and 
environmental smoke exposure. Trained study staff at UW-CTRI will collect the participants’ 
urine within the same day. All samples and test results will be labeled with the date of collection 
and the participant’s numerical ID. Urine will be disposed of after nicotine/cotinine levels are 
read and recorded. 
 
 
Smoking Cessation 
 
Pharmacotherapy. An 8-week supply of nicotine patch and nicotine mini-lozenges will be 
distributed at the visit 1-week post-TQD (Visit 2). Participants will be instructed to initiate C-NRT 
following the study visit on TQD +8-days. Nicotine patch and mini-lozenge dosing will be based 
off the 2008 PHS Clinical Practice Guideline and package insert with adjustments to account for 
the delayed start 1-week post-TQD. All participants will receive 2mg mini-lozenge due to the 
superior palatability of the 2mg lozenges. Participants are encouraged to use at least 5 mini-
lozenges per day for the full 8 weeks. Participants who report any smoking or nicotine use (e.g., 
even a cigarette puff, e-cigarette use) in the 3 days before C-NRT distribution will receive 4 
weeks of 14mg and 4 weeks of 7mg nicotine patches. Participants who report complete 
abstinence from smoking and nicotine in the 3 days before C-NRT distribution will receive 8 
weeks of 7mg nicotine patches. This dosing schedule based on abstinence status is determined 
to balance the goals to ensure participants receive a sufficient dose of nicotine replacement 
while minimizing the likelihood of experiencing nicotine toxicity. The study staff will recommend 
dosage/use alterations as per good clinical practice if the participant experiences side effects.  
 
Participants will be given the package insert use instructions and verbal guidance on medication 
use. Medication use will be assessed via evening EMA reports and at study phone calls. We will 
monitor adverse events at all study calls/visits as well as gather additional data on medication 
use. All participants will be given a phone number to call in case of medication issues or any 
other significant problems related to their participation. 
 
Table 4. Combination Nicotine Replacement Therapy (C-NRT)  Schedule 
Medication Schedule 
 
 
Precessation  
Cessation 
TQD -14 
to -1 
 
TQD 
to TQD+7 
TQD +8 
to TQD+63 
2 weeks 
 
1 week 
8 weeks 
Medication 
No medication 
C-NRT (8 weeks) 
 

 
 
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Counseling. Participants will receive counseling at 1 Precessation call and 3 Cessation 
calls/visits (≈15 min, see Table 1-2). Counseling will conform to the US PHS Clinical Practice 
recommendations for an intensive counseling intervention (motivational, supportive, and skill 
training elements). Counseling will not explicitly focus on psychoeducation regarding withdrawal 
symptoms. Counselors will be bachelors-level health educators supervised by licensed 
psychologists. Quality/fidelity assurance strategies developed by our prior work will include 
intensive training in counseling techniques and ethical conduct, practice sessions, regular 
supervision including review of audiotapes, and quarterly team meetings to discuss safety, 
confidentiality, and counseling fidelity. Participants will be paired with a single counselor 
whenever possible. 
 
 
Participant Compensation Strategy 
 
Participants will receive free evidence-based smoking cessation treatment including both 
counseling and 8 weeks of C-NRT. In addition, participants will be compensated financially for 
completing study activities and EMA/mobile assessments. Participants will receive $20 for the 
Orientation Visit. Participants will receive $30 for each study visit and $10 for each telephone 
call in the Precessation Phase ($30), and Cessation Phase ($80). Participants who report 
abstinence at Call 5 and complete Visit 4 will receive $50 for this visit. Participants will be 
compensated for completing > 80% of the EMA assessments ($100). Thus, the total 
compensation available to participants is $130 (visits) + $50 (calls) + $100 (EMA bonus) = $280. 
Importantly, payments will be linked to visit/assessment completion, but not to smoking status 
so as not to induce participants to incorrectly report their smoking status. This is essential to 
encourage participants’ accurate and honest reporting, particularly as lapse will be an important 
outcome for evaluating WSWS-2 validity. Compensation will be delivered via checks mailed to 
participants’ residence or distributed at study visits. 
 
 
Analytic Plan 
 
Specific Aims: WSWS-2 and WSWS-2BR Validation 
Psychometric analyses of the 18 item pool will be conducted to validate a full and brief version 
(6 items) of the WSWS2 in this sample of medicated and unmedicated smokers. The aims 
include clarifying the dimensional structure and the best-performing items to construct the final 
scales. Subscales will be evaluated with respect to internal consistency (e.g., Cronbach’s alpha 
≥.8), item-analysis (response distributions, item-to-total correlations, IRT analyses), and 
confirmatory factor analyses (CFA) and measurement invariance (e.g., across at least 2 post-
TQD time points).  
 
Concurrent, discriminant, and predictive validity will be considered in evaluating and 
constructing the final scale. The WSWS2-L should demonstrate meaningful relations with 
measures of tobacco dependence (WISDM-PDM, FTCD, time to first cigarette), other published 
withdrawal scales (Minnesota Withdrawal Scale), and prediction of cessation outcomes (e.g., 
time to lapse/relapse, survival analyses). In analyses predicting cessation outcomes both pre-
post increase in withdrawal symptoms and post-TQD symptoms per se will be used in prediction 
models. In addition, such models will be tested with and without (primary) covariates (gender, 
and race). The WSWS2-L should demonstrate a characteristic time-course of a withdrawal 
syndrome including sensitivity to abstinence (rise over first 12-24 hours and 2-4 days) and 
decrease over time following a peak in post-TQD. The time course will be examined with growth 
curve models that evaluate different trajectory components (i.e., linear, quadratic) with time 

 
 
12 
 
varying covariates for smoking lapse occurrence, exposure to temptation events, dependence 
level. The WSWS2-L should also be sensitive to medication use (e.g., decrease with C-NRT). 
This will be tested by determining the effects of C-NRT during Cessation on WSWS2-L scores 
versus precessation and unmedicated cessation levels. The WSWS2-L will be correlated with 
variables that assess relevant person factors such as affective disorder, distress tolerance, and 
the various measures of tobacco dependence.  
 
We will conduct parallel set of psychometric and validation analyses of the WSWS2-B as we do 
with the WSWS2-L, except when not possible due to constraints placed on single-item 
subscales (e.g., subscale internal consistency, CFA). 
 
 
Exploratory Analyses: 
This study will produce a rich data set for exploratory analyses to both examine the robustness 
of the primary aims as well as hypothesis generation for future studies. We provide a brief 
summary of planned theory-driven exploratory analyses, but it is likely that further avenues of 
analysis will be applied to the data set. We will report all analyses transparently as hypothesis-
testing versus exploratory in presentations and published manuscripts. We will examine 
candidate predictors and moderators of smoking cessation treatment effects in secondary 
analyses. 
 
Candidate predictors of cessation treatment effects, gathered from EMA and follow-up phone 
assessments will be: medication use and side effects, withdrawal symptoms (e.g., craving, 
negative affect), anticipatory pleasure from smoking, adverse events, nicotine reward, nicotine 
anticipation, and reports of cue-elicited urges. The occurrence of smoking during the quit 
attempt will be statistically controlled. One-week abstinence will be the primary outcome, which 
will be modeled via a weighted least squares approach in Mplus. We will attempt to characterize 
orthogonal routes to outcome change and also examine how certain events such as stressor 
occurrence or exposure to smoking cues affect withdrawal symptoms via time varying effects 
modeling.   
 
Analysis of moderators of abstinence outcomes will use both logistic regression with model-
fitting techniques and regression tree analyses that reflect differential treatment responses in 1-
week abstinence. The logistic regression and regression tree approaches are complementary 
since the former fits interactions in the entire sample whereas the latter identifies the most 
robust interactions amongst subpopulations of a sample (groups of participants nested within 
levels of another predictor, which could include either a covariate or treatment condition. 
Candidate moderators of treatment effects on abstinence will include tobacco dependence, 
contextual factors such as household smoking, and biological variables such as sex. In the 
logistic regression analyses moderators will be evaluated with regards to their interactions with 
treatment effects. 
 
 
Power and Sample Size Justification 
 
Based on the average expected communalities and the variables-to-factors ratio (factor 
overdetermination) of the proposed analyses, we believe the sample sizes proposed will provide 
good power the exploratory factor analyses and other covariance structural modeling (R. C. 
MacCallum et al., 2001; Robert C. MacCallum et al., 1999). A key prediction concerns the 
relation between a dichotomized scoring of the WSWS-2B and likelihood of abstinence at 
follow-up. We propose that those with low withdrawal scores will have an abstinence likelihood 

 
 
13 
 
of .40 while those with a high score will have an abstinence likelihood of .20. Assuming p=.05 
and B=.80, the N for a regression of .20 = 95 (Hsieh et al., 1998). Therefore, we believe the 
design is adequately powered for the expected results, which would be of clinical significance.  
 
 
 
 

 
 
14 
 
Protection of Human Subjects 
 
Risks to the Participants   
 
Human Subjects Involvement and Characteristics: Up to 400 adult smokers will be 
consented from the community in order to enroll at least 250 participants. Participants must: 
have the ability to read and write in English, smoke ≥5 cigarettes per day, be ≥21 years old, 
desire to quit smoking but not be engaged currently in cessation treatment, expired breath 
carbon monoxide ≥5 ppm, willing to use nicotine patch and nicotine lozenge, willing and able to 
attend study visits, have reliable smartphone access, willing to respond to EMA prompts and 
other study activities, and if female, not be pregnant, trying to get pregnant, or breastfeeding. 
Exclusion criteria include: use of pipe tobacco, cigars, snuff, chew, e-cigarettes/vaping, or other 
electronic nicotine delivery product more than twice in the past week, unwilling to try to abstain 
from all nicotine use (including e-cigarettes) for the duration of the Cessation Phase (other than 
study-provided NRT), currently taking varenicline or bupropion, diagnosis of and/or treatment for 
schizophrenia, other psychotic disorder, or bipolar disorder within the last 5 years; suicide 
attempt or suicidal ideation in the past 12 months; severe hypertension (>180/100 mmHg), on 
dialysis or being told you have severe kidney disease; hospitalization for a stroke, heart attack, 
congestive heart failure or uncontrolled diabetes mellitus within the past year; currently 
participating in a smoking cessation study, or unwilling to use study approved methods of birth 
control while taking study medication and for 1 month after discontinuing study medication (only 
for women of child-bearing potential). Study approved methods of birth control include 
abstinence from sex with men, condoms, diaphragm, birth control pills, injectable contraceptive 
(e.g., Depo-Provera), contraceptive implant (e.g., Implanon), IUD, have had hysterectomy or 
tubal ligation, or are more than 2 years post-menopausal. 
 
Sources of Materials:  Participants will provide data for the express purpose of research. Data 
will consist of answers to questionnaires and interviews assessing smoking history, 
demographics, nicotine dependence, personality, affect and psychiatric history, disease status 
and health history. These will include provision of urine samples that will later be used for 
nicotine/cotinine tests. Breath tests and a brief questionnaire will be used to assess exhaled 
carbon monoxide. Counseling sessions will be recorded for purposes of clinical supervision and 
quality assurance. 
 
Potential Risks: None of the medical, physiologic, self-report, or behavioral assessments 
constitute a significant risk. The use of cessation medications poses a risk of side-effects. 
Participants will be made aware of the common nicotine replacement side effects before they 
consent to participate in the study. It should be noted that the nicotine patch and nicotine mini-
lozenge are available over the counter. The Food and Drug Administration (FDA) has approved 
using a combination of two forms of NRT (e.g., nicotine patch + nicotine mini-lozenge) for 
smoking cessation. These interventions have also been studied and used safely in multiple 
clinical trials, are used by clinicians in clinical practice, are available over-the-counter, and are 
reviewed in the 2008 PHS Guideline. The PHS Guideline, in fact, recommends combination 
NRT as a particularly effective treatment. The nicotine patch is generally well tolerated, but up to 
50% of participants may have a local skin reaction, and rarely, individuals may have a more 
systemic allergic reaction. The most likely side effects associated with the nicotine mini-lozenge 
are heartburn, hiccup, nausea, upper respiratory tract infections, coughing, and sore throat. 
Although most smokers have tolerance to nicotine, symptoms of acute nicotine toxicity (nausea 
and vomiting) are possible. Participants will be informed that NRT is typically initiated on or 
before the TQD rather than 1 week after quitting. To reduce the risk of nicotine toxicity by over-
dosing after the 1 week period of reduced or no nicotine use: 1) initial nicotine patch dose will be 

 
 
15 
 
determined based on smoking/nicotine abstinence status in the 3 days prior to patch 
distribution; and, 2) submaximal dosages of both NRT products are used (e.g., no 4mg mini-
lozenge or 21mg patch). Finally, individuals often attempt to stop smoking without the use of 
medication. As the 2008 PHS Guideline shows, this method is considerably less likely to 
produce long-term cessation and for this reason C-NRT is provided to increase participants’ 
likelihood of achieving abstinence. Those not successful in quitting bear the health risks 
associated with continued smoking. 
 
There is always a remote, but existing, possibility that sensitive or personal information about a 
participant could be divulged as a function of his/her research participation. Other than cannabis 
use no additional information about illegal behavior will be collected by research staff or entered 
into research data bases. Finally, 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 before and are familiar with these phenomena. Though unpleasant, 
smoking withdrawal symptoms pose minimal health risk. Participants will be informed about the 
possible effects of smoking withdrawal. Individuals who elect not to participate in this research, 
or are eliminated due to screening failure, will be given a list of alternative smoking cessation 
programs at any point during the pre-consent process. 
 
Adequacy of Protection Against Risks   
 
Recruitment and Informed Consent: As in our previous research, participants will be recruited 
via TV, print, flyers, referral cards, other studies, social media such as Facebook, and earned 
media (e.g., press releases and conferences). 
 
Participants will be recruited in the Milwaukee and Madison metro areas. Advertisements and 
publicity will contain a phone number for interested individuals to call and/or link to UW 
recruitment website to contact study personnel. Study staff will call potential participants and 
conduct an initial phone screening to rule out those with clear contraindications. The study will 
be briefly described, questions answered, and potentially qualifying individuals will be invited to 
attend an Orientation Visit. Participants will provide verbal consent to complete the initial phone 
screen. Participants identifying contact information will be stored securely and retained until 
study completion and the CONSORT diagram is created. Without this altered authorization, it 
would not be feasible to keep track of who has tried to screen into the study and failed because 
staff would not be able to identify these renewed attempts to enroll in a study that might not be 
appropriate based on answers to the phone screen. 
 
At the Orientation Visit the general requirements for participation will be reviewed (e.g., session 
attendance, participation in assessments). In addition, participants will be informed of the nature 
of the interventions involved. They will be told about the pharmacotherapy and counseling 
interventions that will be provided. Everyone will be told that they will receive counseling 
designed to aid them in their cessation attempt. The risks of taking C-NRT will be described 
including the most common side effects. All participants will be informed as to the various parts 
of the study and what will be entailed in each part. After answering any participant questions 
about research participation and intervention, participants will be given a combined 
HIPAA/consent form to review, ask additional questions, and sign the consent form. Individuals 
will then be screened for any remaining exclusion factors. Should eligible smokers decide not to 
participate in the research at the Orientation Visit, the personally identifying information 
collected at the Orientation Visit and the screening phone call will be de-identified following 
study completion (i.e., at the point that data for a study CONSORT diagram have been cleaned 

 
 
16 
 
and analyzed). Participants will be encouraged to ask any further questions about the study 
protocol throughout the study.  
 
Protection Against Risk:  As noted above, participants will be screened by study staff to ensure 
that they are medically and psychiatrically fit to use C-NRT. Study staff (bachelor-level health 
counselors or undergraduate students) are trained to administer eligibility screening questions 
that are entered into a database. The determination of eligibility is based on a computer 
algorithm that is driven by participants’ responses to these questions. UW-CTRI Study 
Physician and Study Clinical Psychologists will be available for consultation should any 
additional unexpected eligibility questions or concerns arise during this process. Study 
participants will be closely monitored in accordance with current FDA recommendations  as well 
as the consensus recommendations of the 2008 Guideline Panel (Fiore et al., 2008), which 
provides additional, detailed instructions for clinicians regarding all FDA-approved cessation 
medications. In addition, we will make appropriate changes in study procedures if the FDA 
issues updates on nicotine patch or nicotine mini-lozenge. We will recommend dosage/use 
alterations including stopping medication treatment as per good clinical practice if the participant 
experiences troublesome side effects once they begin medication treatment. If a participant 
reports using non-study quit smoking medications (varenicline, bupropion, or nicotine 
replacement therapy) after we have distributed the study medications (>1 week after target quit 
day) – we will instruct participants stop using study-provided medications, and counsel 
participants not to combine medications or exceed recommended dosage. However, we will not 
withdraw these participants from the study (e.g., for follow up data collection). Thus, we will take 
extraordinary care to ensure the safety of study participants. 
 
Face-to-face research activity will be conducted according to institutional policy at the time in-
person visits begin, should COVID-19 related restrictions continue to be in place. 
 
Study participants will be carefully monitored for side effects. Monitoring for these symptoms or 
conditions will be accomplished through assessment of adverse events (AEs) and serious 
adverse events (SAEs) at each study visit and phone contact during which the participants are 
receiving study medication. For all AEs and SAEs, study staff will take appropriate action to 
ensure the safety of the participant as follows: 1) Non-urgent AEs will be reported in a timely 
manner to study clinical staff (MDs); and 2) SAEs or AEs that raise concerns (e.g., allergic 
reaction; severe, unresolved changes in mood or any suicidal ideation) will be immediately 
reported to the study physician who will determine an appropriate course of action. In addition, 
participants will be given a telephone number to contact study staff in the event that participants 
have questions or concerns about study medication or medical/psychiatric reactions that may be 
related to study medication or participation, as well as instructions on when to seek emergency 
medical assistance. Individuals who report any significant mood change or suicidal ideation will 
be contacted immediately by a licensed staff psychologist or physician who will assess the level 
of risk and provide referrals as needed. 
 
Pregnant women will not intentionally be recruited to the study. However, due to the longitudinal 
nature of the study, someone who was originally eligible for the study (not pregnant and agreed 
to take measures to avoid pregnancy) when they enrolled and then becomes pregnant will be 
allowed to continue participation (their choice) with the assurance that regardless, we will take 
actions to make sure she is permanently taken off study medication. She will still be allowed, if 
she chooses, to continue counseling and assessments for her remaining time in the study. 
Because the risks of the study medications to an unborn child are unknown, should a participant 
report that she has become pregnant, she will be advised to immediately stop using study 

 
 
17 
 
medications and to return any unused medications as safety precautions. No further 
medications will be given to this study participant while in the study. Study team members will 
be trained to respect and carry out the participant's wishes to stay or leave the study as they 
would any other participant. 
Protecting the privacy and confidentiality of participant information during the pre-enrollment and 
consent process (phone screening and Orientation Visit) will be accomplished in several ways. 
However, we cannot guarantee absolute confidentiality. Over the phone, participants will be told 
about the study, provide oral consent to participate in the phone screen, and will then answer 
questions to assess eligibility and willingness to participate.  
 
Data generated through study participant and data obtained on medical history from participants 
will be stored in secure databases under protections and procedures consistent with the 
guidelines and regulations of the UW School of Medicine and Public Health (UW-SMPH). 
Outside access is available only via an encrypted connection to the Department of Medicine 
Citrix server located at the UW Clinical Science Center in Madison.  
 
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 at UW-CTRI. No 
identifying data other than a participant ID number is entered on any data form. Any data 
collected on paper are entered into the computer 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 UW-CTRI office, where they are 
securely stored. 
All UW-CTRI staff members have completed HIPAA/human subjects training and are aware of 
the sensitivity of study-related data. The UW SMPH has developed school-wide data security 
policies and procedures. UW-CTRI data security policies and procedures conform to those of 
the SMPH. UW-CTRI will use an enterprise-level database that supports audit trails such as 
access, change logging, and more sophisticated access control for managing and tracking user 
access privileges. In addition, this project has a Certificate of Confidentiality, related to the 
collection of baseline information on substance abuse and information on sexual orientation. No 
publications or presentations resulting from this research program will contain identifying 
Protected Health Information (PHI) about individual participants. We will make de-identified 
participant data publicly available online on the NHLBI database and OSF (Open Science 
Framework or similar platform) in accordance with UW and NIH policy and principles of 
transparent science practices (Aczel et al., 2019; Meyer, 2018). 
 
Potential Benefits of the Proposed Research to the Participants and Others  
 
The potential benefits for smokers participating in this study is the increased chances of 
successfully quitting smoking and the associated health benefits of smoking cessation. The 
risks of this research are chiefly associated with the provision of C-NRT as the 

 
 
18 
 
pharmacotherapy. These risks are reasonable because these medications have been shown to 
be safe in numerous large clinical trials as well as the consensus recommendations of the 2008 
Guideline Panel (Fiore et al., 2008). Because the health risks associated with continued 
smoking dramatically outweigh those associated with C-NRT use, and because it is likely that 
many participants will successfully quit smoking as a result of their participation in this research, 
the potential risks to participants are acceptable compared to the potential benefits. The 
availability of consultation with the research program, including physician consultation, also 
decreases the likelihood of adverse consequences from C-NRT use. In addition, this research 
has the potential to provide improved treatment strategies for clinicians trying to help patients 
quit smoking. This could result in more efficient provision of maximally efficacious intervention 
for smokers. 
 
Importance of the Knowledge to be Gained   
 
The results from this study will provide important data to validate a revised assessment of 
smoking withdrawal for use in research and clinical settings. Further, this study will provide a 
description of the course of unmedicated withdrawal in today’s smoker. This information will be 
gathered in a contemporary population of smokers so the results will be highly relevant to 
today’s smokers and clinicians, and can be used to motivate clinicians to intervene and to 
motivate smokers to use evidence-based treatments to stop smoking. 
 
Summary   
 
Given the limited risks of C-NRT the rigorous pre-treatment screening, and the availability of 
both physicians and psychologists to address any adverse effects, we believe that the potential 
risks involved in participating in the study are outweighed by the benefits to both the individual 
study participant and society. 
 
Data Safety Monitoring Plan  
 
The Data Safety and Monitoring Plan (DSMP) for this research comprises not only the research 
conducted directly by the University of Wisconsin Center for Tobacco Research and Intervention 
(UW-CTRI) researchers, but also research conducted by other investigators collaborating with 
UW-CTRI-funded projects. All investigators must agree to comply with the procedures outlined 
in this DSMP.  
 
Monitoring the progress of trials and the safety of participants. The Principal Investigator is 
responsible for routine monitoring of the trial’s progress. This includes scheduled (biweekly 
during the first few months of the study and monthly thereafter) meetings with study staff and 
review of written documentation. Data reviewed at these meetings include the number and type 
of participants enrolled, the number and reasons for exclusions from enrollment, the number 
treated and the stage of intervention, summary of adverse events (AEs), individual review of 
serious adverse events (SAEs) and study participation, and outcome data. In addition, as noted 
above, SAEs or AEs that raise concerns (e.g., allergic reaction, significant change in mood or 
suicidality) will be immediately reported to the study physician who will determine an appropriate 
course of action. As data become available, the Study Director and Principal Investigator will 
review the data on a regularly scheduled basis (initially biweekly and later monthly) to determine 
progress. 
 
To facilitate participant safety, study participants must meet study inclusion and exclusion 
criteria. Once enrolled, study protocols will assess the presence of AEs and SAEs at all study 

 
 
19 
 
visits and follow-up contacts. Should either excessive risk to study participants and/or 
convincing evidence of lack of measurable benefit to study participants be determined, the study 
will be stopped and all participants notified in a manner appropriate to the nature of the risk 
and/or lack of benefit. When taking that step the investigators will consult with the IRB and 
NHLBI.  
 
Plans for assuring compliance with requirements regarding the reporting of adverse events. This 
DSMP requires that investigators notify NIH and the University of Wisconsin IRB in a timely 
manner (consistent with IRB and NIH policies) of the occurrence of any SAE or any AE which is 
severe, unexpected, and possibly related to study medication or protocol. 
 
Because this study involves pharmaceutical agents, if an unexpected SAE might be related to 
study drug use, both the Food and Drug Administration (FDA) and the manufacturer/supplier will 
also be notified within five days of investigators becoming aware of the event. The Principal 
Investigator will assist the study medication manufacturer/supplier in investigating any 
unexpected AE/SAE and will provide any follow-up information reasonably requested by the 
study medication manufacturer/supplier. Examples of SAE would be untoward medical or 
intervention occurrences that result in death, are life-threatening, require hospitalization or 
prolonging of existing hospitalization, create persistent or significant disability/incapacity, or 
involve congenital abnormality/birth defects.  
 
Unanticipated problems will be monitored and reported to the DSMC. These are events that 
meet the following criteria: 1) suggest the research places subjects or others at increased risk of 
harm, 2) are unexpected (in terms of nature, severity or frequency) given the research 
procedures that are described in the study-related documents, and 3) possibly related to study 
participation. Any SAE will be queried and reported if it meets the definition of unanticipated 
problem. The Principal Investigator or designee will also be responsible for the accurate 
documentation, investigation and follow-up of all study-related adverse events. Adverse event 
assessment, recording, reporting, and investigation will be accomplished through staff training, 
structured/standardized assessments of untoward occurrences/events, and regular monitoring 
by study physicians and other study investigators. The Principal Investigator has ultimate 
responsibility for ensuring that SAEs are detected and reported in a timely manner. Additionally, 
the IRB will receive an annual report of all SAEs and AEs meeting the criteria listed above.  
 
Plans for assuring that any action resulting in a temporary or permanent suspension of an NIH-
funded clinical trial is reported to the NIH grant program director responsible for the grant. The 
NIH grant program director will be notified within five days if the Principal Investigator deems it 
necessary to suspend the clinical trial. In the case of a temporary suspension, the Principal 
Investigators 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 UW-CTRI 
Study Director and Principal Investigators will develop plans for assuring data accuracy and 
protocol compliance. Such plans will include data verification and protocol compliance checks. 
The Data Manager and Principal Investigator shall 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. All HIPAA regulations and guidelines will be followed, and all study 
staff must complete approved human subjects and HIPAA training programs. 
 
Data and Safety Monitoring Committee. 

 
 
20 
 
 
In addition to the protections outlined in the DSMP (above), all research activities conforming to 
the NIH definition of a clinical trial will also have an independent Data Safety and Monitoring 
Committee (DSMC). This application includes a Phase IV clinical trial using FDA-approved 
medications. The DSMP specifies overall monitoring that will be conducted by Principal 
Investigators, including timely reporting of AEs and SAEs. Every six months, the DSMC will 
convene to review the overall safety data, as well as data on safety summarized by treatment 
condition. As per NIH guidelines, the objective of these reviews will be to determine whether 
continued conduct of the trial poses any undue risk for participants.  
 
The existing UW-CTRI DSMC is chaired by Dr. James Cleary, leader of the Cancer Control 
Program of the UW Comprehensive Cancer Center. Dr. Cleary is an experienced physician and 
clinical trial researcher with no involvement in any of this project’s research activities. Dr. Cleary 
is joined on the DSMC by Dr. Burke Richmond and Dr. James Sosman. Dr. Sosman is 
Associate Professor of Medicine and Medical Director of the HIV/AIDS Comprehensive Care 
Program at UW Hospital and Clinics who has previously collaborated on a clinical trial of 
smoking cessation with UW-CTRI. Dr. Richmond is an otolaryngologist who has served on 
independent DSMBCs for Phase II and III trials involving a nicotine vaccine. Neither has direct 
involvement with any of the proposed research. The Principal Investigators will report to the 
DSMC; the three DSMC members will be informed as to treatment conditions and will make the 
final determinations as to study continuation. 
 
Data Sharing with the Public 
 
ClinicalTrials.gov Requirements 
This study will be registered at ClinicalTrials.gov prior to its initiation. The UW Office of Clinical 
Trials offers comprehensive support services to UW investigators conducting clinical trials. The 
Principal Investigator and UW-CTRI staff will ensure that this trial conforms to all 
clinicaltrials.gov reporting requirements. 
 
Open Science and NIH Data Sharing Policy 
We value the principles of open science and will take several steps to promote transparency 
and reproducibility. We will preregister our study design and publish the study protocol along 
with the publication of the primary outcome paper. Finally, we will make de-identified data and 
analysis code publicly available on the Open Science Framework (OSF: https://osf.io) or similar 
platform in accordance with NIH policy and principles of transparent science practices (Aczel et 
al., 2019; Meyer, 2018). 
 
 
 

 
 
21 
 
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