Clinical trial NCT04969198
Conditions: Tobacco Dependence
Sponsor: University of Wisconsin, Madison
Start date: 2021-07-13; Completion date: 2022-09-21
Enrollment: 232 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
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. However, in order to ensure that a measure of tobacco withdrawal is sensitive to severe withdrawal, it is essential to examine a period of unmedicated abstinence. The current study aims to validate, and possibly enhance, a revised Wisconsin Smoking Withdrawal Scale long and brief version for use in research and clinical settings.

Two hundred adults who smoke cigarettes daily and report a desire to quit smoking will be enrolled. 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. Participants will not receive any pharmacotherapy during the first 1 week of their quit attempt and will initiate 8 weeks of combination nicotine replacement therapy (C-NRT; nicotine patch + nicotine mini-lozenge) starting 1 week past the target quit day (TQD). Participants will receive 4 counseling sessions as well (1 pre-quit, 3 post-quit). Participants will complete 4 weeks of ecological momentary assessment (EMA) smartphone surveys including a 2-week baseline (starting TQD-14) and 2-week post-TQD (1-week un-medicated, 1-week using C-NRT).

Detailed description:

Arms: arm 1: No medication for 1 Week after Target Quit Day (TQD). Medication started 1 Week after TQD.

Patches (Nicotine): 14 mg Patches for 4 weeks postquit (Week 1-5), then 7 mg patches for 4 weeks (Week 6-9)

Mini Lozenge (Nicotine): 2 mg Mini Lozenges 5x per day (up to 20x day max) for 8 weeks post quit (Week 1-9)
Interventions: intervention 1: Combination nicotine replacement therapy (Nicotine patch + nicotine mini-lozenge)
Intervention descriptions: intervention 1: Nicotine patch and mini-lozenge dosing will be based off the 2008 Public Health Services (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.

Protocol documents:
ICF_002.pdf: 
 
 
 
 
 
 
 
 
 
 
 
UW Withdraw from Tobacco Study 
 
 
NCT04969198 
 
8/26/2021 
 
 


HS IRB #: 2020-0792 
Lead Researcher: Timothy B. Baker (608) 262-8673 
Version: August 10, 2021 
Page 1 of 12 
IRB Approval Date: 8/26/2021 
University of Wisconsin – Madison 
 
 
 
University of Wisconsin-Madison 
Consent to Participate in Research 
and 
Authorization to Use Protected Health Information for Research 
Study Title for Participants: UW Withdraw from Tobacco Study 
 
Formal Study Title: UW Withdraw from Tobacco Study: Enhancing and Evaluating Tobacco 
Withdrawal Assessment Psychometrics and Validity 
 
Lead Researcher: Timothy B. Baker, PhD (608) 262-8673 
 
Where Lead Researcher works: University of Wisconsin-Madison School of Medicine 
and Public Health; Center for Tobacco Research and Intervention 
 
Invitation 
We invite you to take part in a research study about the health effects of tobacco 
withdrawal and how the quit smoking medications nicotine patch and nicotine mini- 
lozenge affect tobacco withdrawal to help people quit smoking. We are inviting you 
because you smoke cigarettes and are interested in quitting. Your participation is 
voluntary. 
 
The purpose of this consent and authorization form is to give you the information you 
need to decide whether to be in the study. It also explains how health information will be 
used for this study and requests your authorization (permission) to use your health 
information. Ask questions about anything in this form that is not clear. If you want to 
talk to your family and friends before making your decision, you can. When we have 
answered all your questions, you can decide if you want to be in the study. This 
process is called “informed consent.” 
 
 
Why are researchers doing this study? 
The purpose of this research study is to 1) identify important health effects of tobacco 
withdrawal and 2) understand how the quit smoking medications nicotine patch and 
nicotine mini-lozenge affect tobacco withdrawal to help people quit smoking. Everyone 
in the study will try to quit smoking without any medication for the first week after their 
quit day. Everyone will receive 8 weeks of quit smoking medications, the nicotine patch 
and nicotine mini-lozenge, starting 1 week after quitting.  We are doing this research to 


HS IRB #: 2020-0792 
Lead Researcher: Timothy B. Baker (608) 262-8673 
Version: August 10, 2021 
Page 2 of 12 
IRB Approval Date: 8/26/2021 
University of Wisconsin – Madison 
 
 
 
understand how people experience tobacco withdrawal symptoms and how to measure 
them accurately. We will do this using data gathered over the first week after quitting 
when people are not using medications and during the following weeks when they are 
using them. The surveys used to evaluate the effects of tobacco withdrawal have not 
been updated in many years and this study is evaluating new and improved surveys. 
 
This study is being done at the Center for Tobacco Research and Intervention, 
University of Wisconsin-Madison (UW-Madison) offices in Madison and Milwaukee, WI. 
A total of about 200 people will participate in this study. 
 
Funding for this study is provided by the National Institutes of Health (NIH). 
 
 
What will happen in this study? 
If you are eligible and decide to participate in this research study, you will receive quit 
smoking medications (nicotine patch and nicotine mini lozenges) and 4 coaching 
sessions to help you quit smoking. You will set a date to quit smoking and try to quit 
without using medications for the first week. You will receive 8 weeks of medications 
starting 1 week after your quit date. 
 
Nicotine patches and mini lozenges are medications that help you quit smoking. They 
are approved by the Food and Drug Administration (FDA) for use in quitting smoking, 
but have not been approved to start after the quit day so its use in this way is 
considered experimental. The quit smoking treatments will be provided at no cost to 
you. You will start using the patch and lozenges 1 week after your quit date. You will 
use the 2 mg mini lozenge at least 5 times per day (but not more than 20 mini lozenges 
per day) until the end of the study. You will use the patch 1 time per day until the end of 
the study. You will start using either the 14 mg or 7 mg patch for 4 weeks (depending on 
if you smoked during the first week after your quit date), followed by 7 mg patch for 4 
weeks. We will give you instructions and written information about how to use the 
patch and mini lozenge (for example: allow the lozenge to slowly dissolve, do not chew 
or swallow it). We ask you not to use any other quit smoking treatments (for example: 
varenicline/Chantix or bupropion/Zyban) or electronic/e-cigarettes/vaping while you are 
using the study medications. 
 
You will be asked to attend 1 study visit and 3 phone calls before your quit day and 
attend 2 visits and 2 phone calls after your quit day. In total, over the course of about 3 
months, study participants will be asked to complete 3 study visits (2 with quit coaching) 
and 5 phone calls (2 with quit coaching). At these visits and calls the researchers will 
ask you complete questionnaires and answer questions about your smoking habits, 
medication use and side effects, withdrawal symptoms, emotions, daily experiences, 
and changes to your physical health or mental health. You may be asked the same 


HS IRB #: 2020-0792 
Lead Researcher: Timothy B. Baker (608) 262-8673 
Version: August 10, 2021 
Page 3 of 12 
IRB Approval Date: 8/26/2021 
University of Wisconsin – Madison 
 
 
 
questions at different study visits/calls and you may skip any question on the 
questionnaire that you do not wish to answer. At each visit you will also complete a test 
to look at the amount of nicotine and carbon monoxide in your body (by a breathing into 
a machine or providing a urine sample) and check your blood pressure. Most study 
visits will last about 1 hour, although some visits may last up to 2 hours (3-5 hours total 
over the whole study). The study assessment calls will last about 25-60 minutes. 
 
You will also be asked to answer questions on your mobile phone several times per day 
(3-6x/day) for 29 consecutive days, starting 2 weeks before the date you plan to quit 
smoking. These questions ask about your smoking, withdrawal symptoms, and daily 
experiences (such as moods, stressors, alcohol use, etc.) and will take less than 10 
minutes to complete. 
 
At the end of today’s Orientation study visit, you will be asked to schedule your 
remaining study visits and calls approximately along this timeline: 
Call 1 (12 days before your quit day, 0.5 hour) 
Call 2 (1 week before your quit day, 1 hour) 
Call 3 (1-3 days before your quit day, 0.5 hour) 
Call 4 (1-2 days after your quit day, 1 hour) 
Visit 2 (1 week after your quit day, 1-2 hours) 
Visit 3 (2 weeks after your quit day, 1 hour) 
Call 5 (9 weeks after your quit day, 1 hour) 
Visit 4 (>9 weeks after your quit day, 0.5 hour, only if you are not smoking at Call 5) 
 
 
Protected health information (PHI) used in this study 
 
Protected health information, also called PHI, is information about your physical or 
mental health that includes your name or other information that can identify you, like 
your date of birth or medical record number. To do this study, we will use the following 
kinds of PHI: 
  
Your answers to questionnaires and interviews about your smoking and other 
tobacco use, demographics, emotional and physical health, your use of alcohol, 
your use of study medications, withdrawal symptoms, and your mood. 
  
The names, addresses, and phone numbers of 3 people who will know how to 
contact you during your participation in this study. If we have been unable to get 
in touch with you (for example, if mail is returned or your phone is disconnected 
or no longer in use), we will ask these people how to contact you – we will not 
share anything about your participation in the study with these contacts. 
  
Audio recordings of your counseling/coaching sessions. 
  
Urine and/or carbon monoxide breath tests to verify nicotine abstinence. 


HS IRB #: 2020-0792 
Lead Researcher: Timothy B. Baker (608) 262-8673 
Version: August 10, 2021 
Page 4 of 12 
IRB Approval Date: 8/26/2021 
University of Wisconsin – Madison 
 
 
 
How long will I be in this study? 
You will be part of the study starting about 2 weeks before your quit day and for about 9 
weeks after your quit day while you are taking study medication and coming in for study 
visits or calls. The total amount of time you’ll be in the study is about 3 months. 
The researchers may take you out of the study, even if you want to continue, if 
● your health changes and the study is no longer in your best interest 
● you do not follow the study rules or no longer meet the requirements to be in the 
study 
● the study is stopped by the sponsor or researchers 
 
How is being in this study different from my regular health care? 
People wanting treatment to quit smoking from health care providers usually receive 
either brief coaching and a single prescription for medicine lasting 8-12 weeks or a 
referral for brief coaching and a starter package of medication from a telephone quitline. 
During this study, you will receive medication for up to 8 weeks, complete in-person pre- 
and post-quitting study visits, complete pre-and post-quitting phone calls, and complete 
questionnaires. 
 
Do I have to be in the study? What if I say “yes” now and change my 
mind later? 
No, you do not have to be in this study. Taking part in research is voluntary. This 
means that you decide if you want to be in the study. If you decide now to take part, 
you can choose to leave the study at any time. 
If you decide to be in the study, the researchers will tell you about new information or 
changes in the study that may affect your willingness to continue in the study. 
Let the researchers know if you choose to leave the study. 
If you decide not to take part in the study, or if you choose to leave the study, your 
choice will not affect any treatment relationship you have with healthcare providers at 
UW-Madison, UW Health or any affiliated organizations, or any services you receive 
from them. No matter what decision you make, and even if your decision changes, 
there will be no penalty to you. You will not lose medical care or any legal rights. 


HS IRB #: 2020-0792 
Lead Researcher: Timothy B. Baker (608) 262-8673 
Version: August 10, 2021 
Page 5 of 12 
IRB Approval Date: 8/26/2021 
University of Wisconsin – Madison 
 
 
 
Your authorization for researchers to use your protected health information (PHI) does 
not have an end date. However: 
● You can choose to take back your authorization for researchers to use your 
health information. You can do this at any time before or during your 
participation in the research. 
● If you take back your authorization, information that was already collected may 
still be used and shared with others, but the researchers will no longer be able 
to collect NEW information about you. 
● If you take back your authorization, you will not be able to take part in the 
research study. 
● To take back your authorization, you will need to tell the researchers by 
writing to the Project Director, Jesse T. Kaye, PhD, at 1930 Monroe St # 200, 
Madison, WI 53711. 
 
 
What are my other choices if I do not take part in this study? 
You do not have to participate in this study to get help with quitting smoking. If you 
decide not to participate in this study, you can get help from your primary care provider 
at your health clinic. Also, you can receive help from the Wisconsin Tobacco Quit Line 
by calling the toll-free number 1-800-QUIT-NOW (1-800-784-8669). 
 
 
Will being in this study help me in any way? 
The nicotine patch and nicotine mini lozenge are FDA-approved smoking cessation 
treatments and have been shown to help people quit smoking, especially when used in 
combination. Quit smoking counseling has also been shown to help people quit. We 
don’t know if being in this study will make it easier for you to quit smoking, but it may. All 
participants in this study will receive free quit-smoking medication and 4 counseling 
sessions to help them quit smoking. 
 
 
What are the risks? 
The most common side effects associated with the nicotine patch are headache, skin 
irritation, difficulty sleeping, vivid dreams, nausea, upset stomach, and dizziness. The 
most common side effects associated with nicotine mini-lozenge are heartburn, hiccup, 
nausea, upper respiratory tract infections, coughing, and sore throat. If you are taking a 
prescription medicine for depression or asthma you should talk to your doctor or 
pharmacist because your prescription dose may need to be adjusted. Study staff will be 
checking your physical and mental health symptoms at every visit. You should notify 


HS IRB #: 2020-0792 
Lead Researcher: Timothy B. Baker (608) 262-8673 
Version: August 10, 2021 
Page 6 of 12 
IRB Approval Date: 8/26/2021 
University of Wisconsin – Madison 
 
 
 
study staff immediately and stop taking the study medication if you experience any 
significant emotional or heart-related symptoms, a seizure, symptoms of an allergic 
reaction (such as difficulty breathing), or symptoms of nicotine overdose (such as 
nausea, dizziness, rapid heartbeat). You should notify study staff and stop taking the 
medication if skin redness caused by the patch does not go away after four days, or if 
you skin swells, or you get a rash. If you experience symptoms of nicotine overdose, the 
study staff may recommend you stop the study medications or make adjustments to the 
dose or how often you use the medications. If you do report significant, unresolved 
emotional issues or thoughts of suicide, you will be asked to speak to a licensed 
psychologist or medical doctor who will evaluate your symptoms and help connect you 
to appropriate psychiatric services. 
 
According to the FDA and the manufacturer of the nicotine patch and nicotine mini- 
lozenge these medications should not be used by pregnant women. The risks of this 
medication to an unborn child are not fully known. We ask female study participants 
who are able to get pregnant or who believe that it is possible to get pregnant to agree 
to the statement below about avoiding pregnancy while taking study medication. 
 
People who quit smoking may experience unpleasant symptoms as part of the nicotine 
withdrawal syndrome. These symptoms may include the following: anger, frustration, 
irritability, craving for nicotine, anxiety, difficulty concentrating, restlessness, decreased 
heart rate, increased appetite or weight gain. Since you will not start using nicotine 
patches or mini-lozenges until one week after your quit day, you may experience more 
severe withdrawal symptoms. In addition, smoking cessation can increase the likelihood 
of depression in some individuals, and this is the reason we ask about depression and 
thoughts of hurting yourself during the study. Coaching received in the study may help 
you cope with symptoms such as these. 
 
Some of the topics discussed in interviews or in questionnaires may cause temporary 
embarrassment or emotional discomfort for some people. If this happens to you, please 
let study staff know about your discomfort. You may choose not to answer any 
questions that make you uncomfortable. This study involves asking questions about 
illegal substance use (e.g., cannabis use). There is a chance that someone outside the 
study could find out about answers to your questions or your study information. If this 
happens, this could expose you to legal risks or damage your reputation, which could 
also affect your relationships with family and friends, affect your employment, or make it 
harder to get insurance or a job. We will try to keep others from getting this information 
by asking these questions in private and storing your information securely (see section 
on confidentiality below). 
 
Pregnant people who abuse illegal drugs or alcohol may be reported by members of the 
research team to county social services under Wisconsin state law. Although this rarely 


HS IRB #: 2020-0792 
Lead Researcher: Timothy B. Baker (608) 262-8673 
Version: August 10, 2021 
Page 7 of 12 
IRB Approval Date: 8/26/2021 
University of Wisconsin – Madison 
 
 
 
happens, county social services may decide to place pregnant people found abusing 
drugs or alcohol to a severe degree in custody to protect the fetus. 
 
 
Will being in this study cost me anything? 
The study medication (nicotine patch and nicotine mini-lozenge), all clinic visits, physical 
tests, and quit smoking coaching will be provided at no cost to you. You will have to pay 
for basic expenses like any childcare, food, parking, or transportation related to study 
activities. If you need treatment for side effects while you are on the study, you or your 
insurance will need to pay for this treatment. 
 
 
Will I be paid or receive anything for being in this study? 
You will receive up to $280 for participating in this study. You will receive $20 for 
completing today’s visit ($20 total). You will receive $30 for completing each study visit 
during the first 2 weeks after your quit day ($60 total). You will receive $10 for 
completing each study phone call ($50 total). If you are asked to come for the in-person 
visit at Week 9 (Visit 4), you will receive $50 if you attend this visit. If you complete 80% 
or more of the mobile/cell phone surveys, you will receive $100. We will issue checks in 
the following schedule: 
 
Visit Number: 
Call 1 
Visit 2 
Visit 3 
(Smartphone 
Survey Bonus) 
Call 5 
Visit 4 
Weeks from your quit 
day: 
-2 
week 
+1 
week 
+2 week 
+9 week 
>9 week 
Maximum Payment: 
$30 
$60 
$30-130 
$10 
$50 
 
 
What happens if I am injured or get sick because of this study? 
If you are injured or get sick because of this study, medical care is available to you 
through UW Health, your local provider, or emergency services, as it is to all sick or 
injured people. 
  
If it is an emergency, call 911 right away or go to the emergency room. 
  
For non-emergency medical problems, contact your regular health care provider 
first. Then contact the study team to discuss possible changes to your study 
medication use and/or study participation. 
  
Call the Project Director, Jesse T. Kaye, PhD, at (608) 262-8673 to report your 
sickness or injury. 


HS IRB #: 2020-0792 
Lead Researcher: Timothy B. Baker (608) 262-8673 
Version: August 10, 2021 
Page 8 of 12 
IRB Approval Date: 8/26/2021 
University of Wisconsin – Madison 
 
 
 
 
 
Here are some things you need to know if you get sick or are injured because of this 
research: 
  
If the sickness or injury requires medical care, the costs for the care will be billed 
to you or your insurance, just like any other medical costs. 
  
Your health insurance company may or may not pay for this care. 
  
No other compensation (such as lost wages or damages) is usually available. 
  
UW-Madison and UW Health do not have a program to pay you if you get sick or 
are injured because of this study. 
  
By signing this consent form and taking part in this study, you are not giving up 
any legal rights you may have. You keep your legal rights to seek payment for 
care required because of a sickness or injury resulting from this study. 
 
How will researchers keep my research information confidential? 
We have strict rules to protect your personal information and protected health 
information (PHI). We will limit who has access to your name, address, phone number, 
and other information that can identify you. We will protect your confidentiality by 
assigning a participant number to most of the information that you provide. We will also 
store this information securely. The study team has a Certificate of Confidentiality from 
the National Institutes of Health for this study. A Certificate of Confidentiality prohibits 
researchers from disclosing information that may identify you in a legal proceeding or in 
response to a legal request without your consent. 
 
However, we cannot promise complete confidentiality. Federal or state laws may permit 
or require us to show information to university or government officials responsible for 
monitoring this study. This includes access to your medical records so that study 
monitors, auditors, the Institutional Review Board and regulatory authorities can verify 
study procedures and/or data. These groups will maintain your confidentiality. By 
signing this consent form, you are authorizing this access to your records. We may also 
have to tell appropriate authorities, such as child protective services or health care 
providers, if we learn during the study that you or others are at risk of harm (for 
example, due to child or elder abuse, or suicidal thoughts). 
 
Authorizing the research team to use your PHI means that we can release it to the 
people or groups listed below for the purposes described in this form. Once your health 
information is released outside UW-Madison or UW Health it may not be protected by 
privacy laws and might be shared with others. Also, with appropriate institutional 
permissions and confidentiality protections, we might use information and biospecimens 
that we collect during this study for other research or share with other researchers 


HS IRB #: 2020-0792 
Lead Researcher: Timothy B. Baker (608) 262-8673 
Version: August 10, 2021 
Page 9 of 12 
IRB Approval Date: 8/26/2021 
University of Wisconsin – Madison 
 
 
 
without additional consent or authorization from you or your legally authorized 
representative. 
 
 
Who at UW-Madison can use my information? 
  
Members of the research team 
  
Offices and committees responsible for the oversight of research 
  
Accounting and billing personnel at the UW-Madison 
 
Who outside the UW-Madison may receive my information? 
  
U.S. Office for Human Research Protections 
  
The National Heart, Lung and Blood Institute (NHLBI; the study sponsor) 
  
The U.S. Food and Drug Administration (FDA) 
  
The OSF (Open Science Framework) 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site 
at any time. 
 
As required by the study sponsor, after the conclusion of the study, ALL information that 
can identify you will be removed from the health information collected in this study and 
the data will be deposited in the NHLBI data repository. At that time, it is no longer PHI 
and this authorization will no longer limit how the remaining information can be used. 
This means the information without anything that identifies you could be used or shared 
for reasons other than the ones described in this form (for example, use by a researcher 
from another university). 
 
While there will probably be scientific publications and presentations as a result of this 
study, your name or identity will not be used. Some of the information you provide may 
be shared publicly on the OSF (https://osf.io) to support open and transparent science 
practices. This will not include any information that can identify you. Data shared with 
OSF will be totally de-identified, meaning this information will not be linked to your name 
or identity. 
 
Will information from this study go in my medical record? 
 
None of the information we collect for this study will be put in your medical record. 
 
 
What if I have questions? 


HS IRB #: 2020-0792 
Lead Researcher: Timothy B. Baker (608) 262-8673 
Version: August 10, 2021 
Page 10 of 12 
IRB Approval Date: 8/26/2021 
University of Wisconsin – Madison 
 
 
 
If you have questions about this research, please contact the Project Director, Jesse T. 
Kaye, PhD, at (608) 262-8673. 
 
We are requesting your email address and text message number so we can send you 
reminders and instructions for your study visits and reschedule your study visits, if 
necessary. Email and texting is generally not a secure way to communicate about your 
health as there are many ways for unauthorized users to access email and text 
messages. You should avoid sending sensitive, detailed personal information by email 
or text. Email and text messages should also not be used to convey information of an 
urgent nature. If you need to talk to someone immediately, please contact the Project 
Director, Jesse T. Kaye, PhD, at (608) 262-8673. You do not have to provide your email 
address to participate in this study. 
 
If you have any questions about your rights as a research subject or have complaints 
about the research study or study team, contact UW Health Patient Relations at 
(608)263-8009. The Patient Relations Representatives work with research subjects to 
address concerns about research participation and assist in resolving problems. 


HS IRB #: 2020-0792 
Lead Researcher: Timothy B. Baker (608) 262-8673 
Version: August 10, 2021 
Page 11 of 12 
IRB Approval Date: 8/26/2021 
University of Wisconsin – Madison 
 
 
 
 
 
 
Agreement to participate in the research study 
 
You do not have to sign this form. If you refuse to sign, however, you cannot take part in 
this research study. 
 
If you sign the line below, it means that: 
● You have read this consent and authorization form. 
● You have had a chance to ask questions about the research study, and the 
researchers have answered your questions. 
● You want to be in this study. 
● You give authorization for your protected health information to be used and 
shared as described in this form. 
 
 
 
Printed Name of Research Participant 
 
 
Signature of Research Participant 
Date 
 
 
Signature of Person Obtaining Consent and Authorization 
Date 
 
 
 
 
 
 
 
 
 
**You will receive a copy of this form** 


HS IRB #: 2020-0792 
Lead Researcher: Timothy B. Baker (608) 262-8673 
Version: August 10, 2021 
Page 12 of 12 
IRB Approval Date: 8/26/2021 
University of Wisconsin – Madison 
 
 
 
VOLUNTARY STATEMENT OF INTENT TO AVOID PREGNANCY 
 
According to the FDA and the manufacturer of the nicotine patch and nicotine mini- 
lozenge these medications should not be used by pregnant women. The risks of this 
medication to an unborn child are not fully known. We ask female study participants 
who are able to get pregnant or who believe that it is possible to get pregnant to agree 
to the statement below about avoiding pregnancy while taking study medication. 
Women who are menopausal and have not have a menstrual period in more than one 
year are not required to sign. Male participants are not required to sign this statement. 
 
 
I,  
(print name), agree to attempt to avoid 
pregnancy while I am taking study medication. I will continue to employ medically 
acceptable means to avoid pregnancy that have been approved by study staff. These 
methods 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, vasectomy of sex partners, or are more 
than 2 years post-menopausal. I will immediately contact study staff if pregnancy is 
suspected. I am aware that I may decline to sign this statement and my refusal to sign 
will have no effect on my further relationship with the University of Wisconsin; however, 
I cannot participate in this research study. 
 
 
 
 
 
Signature of Participant 
Date 

Prot_001.pdf: 
 
 
1 
 
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 


 
 
2 
 
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 


 
 
3 
 
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 


 
 
4 
 
 
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 


 
 
5 
 
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) 


 
 
6 
 
 
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. 
 
 
 


 
 
7 
 
 
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 
 


 
 
8 
 
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 & 


 
 
9 
 
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) 


 
 
10 
 
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) 
 


 
 
11 
 
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 
 
References 
 
Aczel, B., Szaszi, B., Sarafoglou, A., Kekecs, Z., Kucharský, Š., Benjamin, D., Chambers, C. D., 
Fisher, A., Gelman, A., Gernsbacher, M. A., Ioannidis, J. P., Johnson, E., Jonas, K., 
Kousta, S., Lilienfeld, S. O., Lindsay, D. S., Morey, C. C., Monafò, M., Newell, B. R., … 
Wagenmakers, E.-J. (2019). A consensus-based transparency checklist. Nature Human 
Behaviour, 1–3. https://doi.org/10.1038/s41562-019-0772-6 
Anthenelli, R. M., Benowitz, N. L., West, R., St Aubin, L., McRae, T., Lawrence, D., Ascher, J., 
Russ, C., Krishen, A., & Evins, A. E. (2016). Neuropsychiatric safety and efficacy of 
varenicline, bupropion, and nicotine patch in smokers with and without psychiatric 
disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. Lancet 
(London, England), 387(10037), 2507–2520. https://doi.org/10.1016/S0140-
6736(16)30272-0 
Bolt, D. M., Piper, M. E., McCarthy, D. E., Japuntich, S. J., Fiore, M. C., Smith, S. S., & Baker, 
T. B. (2009). The Wisconsin Predicting Patients’ Relapse questionnaire. Nicotine & 
Tobacco Research: Official Journal of the Society for Research on Nicotine and 
Tobacco, 11(5), 481–492. https://doi.org/10.1093/ntr/ntp030 
Bolt, D. M., Piper, M. E., Theobald, W. E., & Baker, T. B. (2012). Why two smoking cessation 
agents work better than one: role of craving suppression. Journal of Consulting and 
Clinical Psychology, 80(1), 54–65. https://doi.org/10.1037/a0026366 
Fagerström, K. (2012). Determinants of tobacco use and renaming the FTND to the Fagerstrom 
Test for Cigarette Dependence. Nicotine & Tobacco Research, 14(1), 75–78. 
https://doi.org/10.1093/ntr/ntr137 
FDA, C. for D. E. and. (2019). FDA Drug Safety Communication: FDA revises description of 
mental health side effects of the stop-smoking medicines Chantix (varenicline) and 
Zyban (bupropion) to reflect clinical trial findings. FDA. http://www.fda.gov/drugs/drug-


 
 
22 
 
safety-and-availability/fda-drug-safety-communication-fda-revises-description-mental-
health-side-effects-stop-smoking 
Fiore, M. C., Jaén, C. R., Baker, T. B., Bailey, W. C., Benowitz, N., & Curry, S. J. (2008). 
Treating Tobacco Use and Dependence: 2008 Update U.S. Public Health Service 
Clinical Practice Guideline Executive Summary. Respiratory Care, 53(9), 1217–1222. 
Hsieh, F. Y., Bloch, D. A., & Larsen, M. D. (1998). A simple method of sample size calculation 
for linear and logistic regression. Statistics in Medicine, 17(14), 1623–1634. 
https://doi.org/10.1002/(sici)1097-0258(19980730)17:14<1623::aid-sim871>3.0.co;2-s 
Hughes, J. R. (n.d.). Minnesota Tobacco Withdrawal Scale. Retrieved February 3, 2020, from 
http://www.med.uvm.edu/behaviorandhealth/research/minnesota-tobacco-withdrawal-
scale 
Jamal, A., Phillips, E., Gentzke, A. S., Homa, D. M., Babb, S. D., King, B. A., & Neff, L. J. 
(2018). Current Cigarette Smoking Among Adults — United States, 2016. Morbidity and 
Mortality Weekly Report, 67(2), 53–59. https://doi.org/10.15585/mmwr.mm6702a1 
MacCallum, R. C., Widaman, K. F., Preacher, K. J., & Hong, S. (2001). Sample Size in Factor 
Analysis: The Role of Model Error. Multivariate Behavioral Research, 36(4), 611–637. 
https://doi.org/10.1207/S15327906MBR3604_06 
MacCallum, Robert C., Widaman, K. F., Zhang, S., & Hong, S. (1999). Sample size in factor 
analysis. Psychological Methods, 4(1), 84–99. https://doi.org/10.1037/1082-989X.4.1.84 
Meyer, M. N. (2018). Practical Tips for Ethical Data Sharing. Advances in Methods and 
Practices in Psychological Science, 1(1), 131–144. 
https://doi.org/10.1177/2515245917747656 
NIAAA. (2003). Recommended Alcohol Questions. National Institute on Alcohol Abuse and 
Alcoholism (NIAAA). https://www.niaaa.nih.gov/research/guidelines-and-
resources/recommended-alcohol-questions 


 
 
23 
 
Smith, S. S., Piper, M. E., Bolt, D. M., Fiore, M. C., Wetter, D. W., Cinciripini, P. M., & Baker, T. 
B. (2010). Development of the Brief Wisconsin Inventory of Smoking Dependence 
Motives. Nicotine & Tobacco Research, 12(5), 489–499. 
https://doi.org/10.1093/ntr/ntq032 
Smith, S. S., Piper, M. E., Bolt, D. M., Kaye, J. T., Fiore, M. C., & Baker, T. B. (in press). 
Revision of the Wisconsin Smoking Withdrawal Scale: Development of Brief and Long 
Forms. Psychological Assessment. 
Snaith, R. P., Hamilton, M., Morley, S., Humayan, A., Hargreaves, D., & Trigwell, P. (1995). A 
scale for the assessment of hedonic tone the Snaith-Hamilton Pleasure Scale. The 
British Journal of Psychiatry: The Journal of Mental Science, 167(1), 99–103. 
https://doi.org/10.1192/bjp.167.1.99 
Welsch, S. K., Smith, S. S., Wetter, D. W., Jorenby, D. E., Fiore, M. C., & Baker, T. (1999). 
Development and validation of the Wisconsin Smoking Withdrawal Scale. Experimental 
and Clinical Psychopharmacology, 7(4), 354–361. 
 

SAP_000.pdf: 
1 
 
December 8, 2022 
Project Title 
UW Withdraw from Tobacco Study: Enhancing and Evaluating Tobacco Withdrawal 
Assessment Psychometrics and Validity 
 
Principal Investigator 
Timothy B. Baker, PhD 
 
Project Director 
Jesse T. Kaye, PhD 
 
Institution 
University of Wisconsin Center for Tobacco Research and Intervention (UW-CTRI), School of 
Medicine and Public Health 
 
Study Purpose & Aims 
The objectives of this project are to examine the assessment and nature of cigarette smoking 
withdrawal among adults who attempt to quit smoking without using medication initially. The 
objectives are to: 1) evaluate the validity and psychometric properties of the Wisconsin Smoking 
Withdrawal Scale-2 (Long Form: WSWS2-L; Brief Form: WSWS2-B); and, 2) understand the 
characteristics of smoking withdrawal and factors that relate to withdrawal severity in 
unmedicated individuals.  
 
Objective 1: WSWS2 Assessment Validation 
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 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 an alternative 
withdrawal scale, the Minnesota Tobacco Withdrawal Scale – Revised (MTWS-R), on the bases 
of psychometric criteria. 
 
Objective 2: Characterize the Dynamics and Predictors of Withdrawal Severity 
Specific Aim 3: To characterize the dynamic features of withdrawal symptoms and determine 
factors that most accurately predict withdrawal severity (peak, trajectory, average, variability, 
and duration), including contextual factors, personality factors, lifestyle factors, pharmacologic 
factors, other substance use, pain, pre-cessation symptomatology, reward sensitivity/response, 
and affective processing dimensions. 
 
Study Registration 
We completed this registration of our data analysis plan on December 8, 2022. Enrollment in 
this study occurred between July 14, 2021, and May 26, 2022. Follow up data collection for this 
study was completed by September 21, 2022. This study was registered at clinicaltrials.gov 
(NCT04969198). We completed this complementary pre-registration to provide a greater level of 
detail regarding our data analysis plans. At the time of this registration, we have only reviewed 
data for the purposes of routine monitoring of study management and oversight (e.g., 
appointment attendance, adverse events). We have not yet examined any data that would 
inform our analysis plans. We describe the primary aims of this study and analyses in this 
registration. Given the scope of this study, this information will likely appear in multiple 
complementary manuscripts and/or presentations. 
 


2 
 
December 8, 2022 
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 good 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 people who smoke has changed substantially (e.g., reduced 
smoking heaviness; Jamal et al., 2018; increased psychiatric comorbidity, Weinberger, Funk, 
Goodwin, 2016; Prochaska, Das, Young-Wolff, 2017). In addition, new components of 
withdrawal have been proposed (e.g., anhedonia; Cook et al., 2015; Hughes, Klemperer, 
Peasley-Miklus, 2020). Moreover, we believed that it was important to validate a short-form of 
this instrument in a contemporary sample of adults who smoke, one that would be suitable for 
situations where a long form would be impractical (e.g., population based studies, clinical use). 
These considerations motivated this effort to update and improve the assessment of withdrawal 
and validate a short-form scale. 
 
We have recently developed a psychometrically robust, revised version of the WSWS (Smith et 
al., 2021), based on several recent smoking cessation trials conducted by UW-CTRI (Baker et 
al., 2016, Piper et al., 2018, Baker et al., 2021). This revised self-report assessment includes a 
long and brief version (Long: WSWS2-L; Brief: WSWS2-B) and comprises a revised stem, item 
wording, and response scale. The WSWS2-L is a 19-item scale that includes a total symptom 
scale and 6 revised subscales (i.e., negative affect, craving, concentration difficulties, hunger, 
restlessness, and sleep problems). The WSWS2-B is a 6-item scale that includes one item per 
symptom domain and may be useful in clinical or research contexts in which time or 
assessment burden is of high importance. 
 
Most previous research, including our own (e.g., initial development and validation of the 
WSWS2), occurred in individuals who were using smoking cessation medication, which can 
significantly affect tobacco withdrawal symptoms. Cessation medication can reduce withdrawal 
severity and affect some symptoms (e.g., cigarette cravings) more than others. It is important, 
therefore, to examine individuals attempting to quit smoking during unmedicated withdrawal. For 
instance, the sensitivity of assessment items might be obscured amongst medicated individuals. 
While withdrawal scales will often be used in clinical contexts with individuals who are using 
medication, it is vital to determine for substantive reasons, the severity of different symptoms 
and their trajectories in unmedicated individuals. Assessment of unmedicated withdrawal is 
rarely done even though the majority of people who try to quit smoking still do so without any 
medication. It is of considerable scientific and clinical importance to assess tobacco withdrawal 
accurately since withdrawal severity is hypothesized to be a key motivator of smoking lapses 
and relapses (Baker et al., 2004; Bolt et al., 2012; McCarthy et al., 2008; Piasecki et al., 2000; 
Piper, 2015). In addition, smoking cessation pharmacotherapy may produce its effects on 
smoking abstinence by suppressing such withdrawal symptoms (Bolt et al., 2012).  
 
Study Overview 
Adults who smoked cigarettes daily and desired to quit smoking enrolled in this study (N=232). 
This treatment-delay, one-group clinical trial was intended to validate and/or enhance the 
assessment of tobacco withdrawal amongst participants who try to quit smoking without using 


3 
 
December 8, 2022 
medication early in the course of their quit attempt. Participants attempted to quit smoking and 
were instructed not to use any smoking cessation pharmacotherapy during the first week of their 
quit attempt. They initiated pharmacotherapy 1 week past the target quit day (TQD) and 
continued pharmacotherapy 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 received 8 weeks of combination nicotine replacement therapy 
(C-NRT: nicotine patch + nicotine mini-lozenge) starting 1 week past the TQD. Participants 
received 4 counseling sessions (1 pre-TQD, 3 post-TQD) that conform to the US PHS Clinical 
Practice Guideline recommendations (Fiore et al., 2008). Participants completed 4 weeks of 
ecological momentary assessment (EMA) including a 2-week baseline (starting TQD -14d) and 
2-week post-TQD (1-week un-medicated, 1-week using C-NRT). Enrolled participants 
completed an Orientation Phase, Pre-cessation Phase, Cessation Phase, and Follow-up Phase 
(Visit 4 only if self-reported 7d point prevalence abstinence). See Tables 1-3 below for timing of 
assessment and study activities. 
 
Table 1. Study Visit Schedule and Procedures: Orientation and Pre-cessation Phases 
Study Phase 
Orientation 
Pre-cessation 
 
Visit 1 
Call 1 
Call 2 Call 3 
Days +/- Target Quit Day: TQD 
> -14 
-12 
-7 
-3 to -
1 
Consent, HIPAA, Eligibility Screening 
X 
 
 
 
CO Breath, Urine, & Blood Pressure 
X 
 
 
 
Smoking Status & Timeline Follow Back (TLFB) 
X 
X 
X 
X 
Wisconsin Smoking Withdrawal Scale - Long 
(WSWS2-L) 
X 
X 
X 
X 
Minnesota Tobacco Withdrawal Scale – Revised 
(MTWS-R) 
X 
X 
X 
X 
Questionnaire of Smoking Urges (QSU) 
X 
 
 
 
Snaith-Hamilton Pleasure Scale (SHAPS) 
X 
 
X 
 
Pain Numeric Rating Scale (PNRS) 
X 
 
X 
 
Depression, Anxiety, Stress Scale (DASS21) 
X 
 
 
 
Smoking History 
X 
 
 
 
Fagerström Test of Cigarette Dependence (FTCD) 
X 
 
 
 
Brief Wisconsin Inventory of Smoking Dependence 
Motives (WISDM) 
X 
 
 
 
Wisconsin Predicting Patients’ Relapse (WI-
PREPARE) 
X 
 
 
 
NIAAA Recommended Alcohol Use 
X 
 
 
 
Graded Chronic Pain Scale (GCPS 2.0) 
X 
 
 
 
Distress Tolerance Scale (DTS) 
X 
 
 
 
Demographics 
X 
 
 
 
  
 
 
 
 
Interventions 
 
 
 
 
Counseling (in minutes) 
 
 
15-25 
 
 
 


4 
 
December 8, 2022 
Table 2. Study Visit Schedule and Procedures: Cessation Phase 
Study Phase 
Cessation 
 
Call 4 Visit 2 
Visit 3 Call 5 Visit 4 
Days +/- Target Quit Day: TQD 
+1-2 
+7 
+14 
+63 
(9w) 
>64 
(9w) 
CO Breath, Urine, & Blood Pressure 
 
X 
X 
 
X 
Smoking Status & Timeline Follow Back (TLFB) 
X 
X 
X 
X 
X 
Revised Wisconsin Smoking Withdrawal Scale - 
Long (WSWS2-L) 
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 
X 
Snaith-Hamilton Pleasure Scale (SHAPS) 
X 
X 
X 
X 
X 
Pain Numeric Rating Scale (PNRS) 
X 
X 
X 
X 
X 
Depression, Anxiety, Stress Scale (DASS21) 
 
X 
 
 
 
  
 
 
 
 
 
Interventions 
 
 
 
 
 
Counseling (in minutes) 
15 
15 
15 
 
 
Medication Education/Dispensing 
 
X 
 
 
 
Medication Adherence/AEs 
 
 
X 
X 
 
 
 
Ecological Momentary Assessment (EMA) 
Participants provided daily ecological momentary assessment data (meaning data that has been 
collected “in the moment”) for 4 weeks total during the study. Participants were sent a text 
message that contained a link to an online survey that they could complete on their mobile 
smartphone. For most of the EMA portion of the study, participants were sent 3 assessments 
per day (morning, midday, and evening). Daytime EMA assessments were brief (<5 min) to 
include the brief WSWS2-B (and exploratory items: anhedonia, pain) and additional items 
focused on understanding the motivationally relevant affective/cognitive subjective states 
associated withdrawal and craving (e.g., wanting to reduce stress, to feel a high or buzz), 
smoking (# cigarettes), and smoking triggers since the last EMA survey. The evening 
assessment included a larger battery of questionnaires to include the WSWS2-B and additional 
targeted assessments regarding smoking, person-related, and contextual factors in the last 24 
hours. These evening assessments (1x/day) included smoking (# cigarettes), e-cigarette use 
(yes/no), alcohol use (yes/no, quantity), cannabis use (yes/no, mode of use, tobacco co-
administration), pain (worst), cessation confidence and self-efficacy, smoking triggers (e.g., 
stressful events, cigarette access, others smoking) and coping strategies, future smoking 
likelihood/prediction, and NRT medication use (e.g., yes/no, mini lozenge quantity, subjective 
effects). The frequency of EMA increased to 6 reports/day 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. Participants completed the full 
WSWS2-L (rather than the WSWS2-B) during the evening EMA during these 5 days (1x/day). 
Participants were compensated $100 for completing >80% of the EMA assessments. Payments 
were linked to assessment completion, but not to smoking status so as not to induce 
participants to incorrectly report their smoking status. 
 


5 
 
December 8, 2022 
Table 3. Ecological Momentary Assessment (EMA) & Combination Nicotine Replacement 
Therapy (C-NRT) Schedule 
 
 
Data Analysis Plan 
 
WSWS2 & MTWS-R Scoring: 
The WSWS2-L (Smith et al., 2021) is a 19-item scale scored via one total score (mean) and 6 
subscale scores (means). The WSWS2-B is a 6-item scale scored as one total score (mean). 
The WSWS2-L was assessed at all study phone calls and in-person visits (see Table 1-2 for 
assessment timeline). The brief version (WSWS2-B) was assessed at all EMA reports (3-
6x/day), with the exception of TQD -1d through TQD +3d, while the long version (WSWS2-L) 
was assessed at the evening report (the WSW2-L comprises the WSWS-B items). Also see 
Exploratory Withdrawal Symptoms section below. 
 
The MTWS-R is a 17-item scale with one item per symptom domain and no subscales. We will 
score one total score (mean) of the first 8-items that are DSM-5 symptoms as our primary 
MTWS-R score. We will score an exploratory MTWS-R including all 17-items (mean) that 
includes ‘other possible symptoms’ of smoking withdrawal. The MTWS-R and related 
information was derived from John Hughes UVM website describing the scale: 
http://www.med.uvm.edu/behaviorandhealth/research/minnesota-tobacco-withdrawal-scale  
 
 
Sensitivity to Abstinence: 
The WSWS2 (-L and -B) should demonstrate a sensitivity to abstinence from smoking. We will 
examine whether WSWS2 total and subscale scores display significant increases from pre-quit 
to post-quit using a series of linear models. First, using EMA data (evening report) we will use 
piecewise models that allow for discontinuity (pre- vs post-quit day) to examine within-person 
changes in WSWS2 (-L and/or -B) from pre- to post-quit. We will examine differences in mean 
withdrawal severity during the week before vs after the quit-day, modeling the TQD jump (e.g., 
from 1w pre-quit mean to TQD) and post-TQD trajectory (e.g., slope, quadradic) over the first 3 
days (WSWS2-L and WSWS2-B) and first week (WSWS2-B). Using study call/visit data we will 
examine within-person changes in WSWS2-L from an averaged baseline (averaged across pre-
TQD calls/visits) to TQD +1-2d (Call 4) and TQD +1w (Visit 2). For EMA and Call data, we will 
examine the stability of baseline scores with and without approximately 1-3 days pre-quit to 
determine if there are anticipatory increases in withdrawal shortly before the TQD (and therefore 
exclude that rise from mean baseline calculations). We will examine sensitivity of WSWS2 to 
detect effects of smoking abstinence on withdrawal severity among the entire study sample as 
well as only among participants who self-report smoking no more than 2 cigarettes in the past 
24 hours during the post-TQD timepoints as these individuals should still be experiencing 
significant withdrawal. We will examine several cigarettes/day cutoffs in sensitivity analyses to 
determine the robustness of results as function of this exclusion criterion (see below for 
Sensitivity Analyses). We hypothesize that both the WSWS2-L and the WSWS2-B will increase 
 
Pre-cessation 
TQD 
Cessation 
EMA Assessments  
(29 days) 
3/d  
(13 days) 
TQD -14 to -2 
6/d  
(5 days) 
TQD -1 to +3 
3/d  
(11 days) 
TQD +4 to +14 
No EMA 
TQD ≥15 
Medication Status 
No Medication 
C-NRT 
TQD ~+8 to 63 
(Start Day After Visit 2) 


6 
 
December 8, 2022 
significantly during the first 3 days and first week post-quit relative to pre-quit baseline values. 
Further, we expect increases to vary across the WSWS2-L subscales; we expect to see 
especially large increases in WSWS2-L subscales assessing craving, hunger, and 
concentration difficulties.  
 
In order to understand how short periods of abstinence might affect baseline (pre-cessation) 
scores and the pre-to-post jump in withdrawal, additional analyses will be undertaken to select 
pre-withdrawal scores that have occurred within 15 or within 30 minutes of smoking a cigarette 
during the baseline period. These will be used to generate pre-withdrawal or baseline estimates 
and then used in piecewise models to determine the pre-to-post cessation changes in 
withdrawal scale and subscale scores. This may constitute a more sensitive test of abstinence 
related withdrawal than will use of unselected baseline scores (e.g., all evening reports). Also, 
the relations of time-since-smoking data collected in the baseline period will be used as time 
varying covariates to study the relations of this with withdrawal severity in the same baseline 
reporting episode.  
 
Internal Consistency, Temporal Stability, Item Analysis, & Factor Structure: 
WSWS2-L total scale and subscale internal consistency will be assessed with Omega 
(McDonald, 1999) with bootstrap-corrected 95% confidence intervals (CIs). For comparison, we 
will also compute Cronbach’s alpha coefficient (Cronbach, 1951). Ideally, both omega and alpha 
will be > 0.7 for total scale and subscale at all timepoints. Further, we will examine response 
distributions and item-to-total correlations and subscale to total correlations. We will conduct 
parallel analyses for the WSWS2-B total scale (but with no subscale analyses). 
 
We will examine internal consistency pre-TQD and at multiple timepoints post-TQD. We will 
examine internal consistency at Visit 1, which provides the largest sample size of participants 
pre-quit. We will examine internal consistency on the TQD (i.e., EMA evening report), TQD +1 to 
2d (i.e., Call 4), and TQD +1w (i.e., Visit 2). This will provide estimates and comparison of the 
internal consistency at critical time points and assessment modalities (e.g., EMA mobile phone 
self-report, phone call with study staff, in-person tablet self-report) within the first week of the 
quit attempt. 
 
We will examine the idiographic variability or lability of scales and subscales across the pre-
TQD period. This will be compared with such variability in the post-quit period. Regression 
analyses will also be used to determine associations and shared variance during the pre-
cessation period between Visit 1 (TQD >-2w) and Call 1 (TQD -12d) and between Call 1 to Call 
2 (TQD -7d).  
 
We will conduct Confirmatory Factor Analyses (CFA) following the approach we took during the 
initial development and validation of the WSWS2 (Smith et al., 2021). We will conduct CFAs 
with a maximum likelihood (ML) estimator and allow factors to correlate. We will use the 
following model goodness of fit statistics to evaluate CFA models (Hu & Bentler, 1999): a) root 
mean square error of approximation (RMSEA) with values <.06 indicative of good fit, b) 
comparative fit index (CFI) with values >.95 indicative of good fit, c) Tucker-Lewis index (TLI) 
with values >.95 indicative of good fit, and d) standardized root mean residual (SRMR) with 
values <.08 indicative of good fit. Ideally the WSWS2-L will display a simple structure (e.g., 
relatively low cross-loading of items on subscales). We will examine a 6-factor model and a 
single higher-order factor model for the WSWS2-L and a 1-factor model for the WSWS2-B. We 
will examine factor structure both on the TQD (via EMA evening report) and 1-week post-TQD 
in-person assessment (Visit 2). 
 


7 
 
December 8, 2022 
We will conduct similar internal consistency and item analyses on the MTWS scales excepting 
the subscale analyses. 
 
Network Analysis (Exploratory):  
As a complementary perspective on measurement, we will apply Gaussian graphical network 
models to examine possible interactions between individual symptoms of withdrawal, both for 
the WSWS2-B, WSWS2-L, and MTWS-R. We will approach such analyses with the intent of 
evaluating (1) similarities of network structure among WSWS2-B, WSWS2-L, and MTWS-R and 
(2) evaluating possible change in network structure and/or the relations between individual 
symptom pairs (edges) in the presence of abstinence. These analyses will be based on the 
estimated inter-item polychoric correlation matrices of the respective scales and apply LASSO 
regularization in the evaluation of edge weights within the networks. 
 
Convergent and Concurrent Validity: 
We will examine convergent validity using Pearson correlations between two assessment 
instruments, the WSWS2 and MTWS-R, which are both designed to measure the same 
construct: tobacco withdrawal severity. We will examine correlations between these two 
assessments on the same days during the pre-cessation phase (Visit 1, TQD >-2w) and 
cessation phase at TQD +1d to 2d (Call 4) and TQD +1w (Visit 2) when both are delivered at 
the same times and via the same delivery route. We will examine how both the WSWS2-L and 
WSWS2-B relate to the MTWS-R (8 and 17 item versions). Strong positive correlations will be 
supportive of convergent validity. 
 
We will also examine convergent validity using Pearson correlations between the WSWS2 
assessed at study Visits/Calls (Long form) and WSWS2 assessed via EMA (Brief form) for the 
corresponding time window. We will examine correlations between these two assessments on 
the same days during the pre-cessation phase (Call 1 and Call 2) and cessation phase (Call 4 
and Visit 2). Strong positive correlations will be supportive of convergent validity across 
measurement modalities. 
 
We will also examine whether specific WSWS2-L subscales (e.g., craving, negative affect) and 
exploratory subscales (e.g., anhedonia) positively correlate with other assessments that are 
administered at similar times: e.g., QSU total score, QSU factor 1, SHAPS anhedonia, WISDM 
craving subscale, that are designed to measure related constructs. We will examine Pearson 
correlations between WSWS2 subscales (e.g., craving, negative affect) and these other 
measures designed to assess the same/similar constructs at baseline (Visit 1), TQD +1 to 2d 
(i.e., Call 4), and TQD +1w (i.e., Visit 2). Likewise, we will examine whether these assessments 
that are designed to measure related constructs positively correlate with WSWS2 (WSWS2-L 
subscales or WSWS2-B items) assessed via EMA for the same corresponding time period. 
Positive correlations will be supportive of convergent validity for select subscale. 
 
The WSWS2 should demonstrate meaningful positive relations with measure of tobacco 
dependence (e.g., WISDM-PDM, WISDM-SDM, FTCD, time to first cigarette) and possibly 
smoking heaviness (e.g., cigarettes per day, baseline exhaled CO). We will examine Pearson 
correlations between WSWS2 (WSWS2-L and WSWS2-B) on the TQD (via EMA) and baseline 
measures of tobacco dependence (Visit 1).  
 
We will conduct similar measures of convergent validity with the MTWS-R versions. 
 
 
 


8 
 
December 8, 2022 
Discriminant Validity:  
The WSWS2 subscales should demonstrate weaker relations with measures of an unrelated 
construct relative to a related/similar construct either measured with the same method (e.g., 
EMA vs EMA) or different method (e.g., EMA vs. Visit 1 baseline self-report). We will examine 
Pearson correlations between specific WSWS2-L subscales (e.g., EMA TQD craving, negative 
affect) and other measures designed to assess unrelated constructs at baseline (e.g., Visit 1 
WISDM weight control). Smaller correlations (vs. those observed for convergent validity) will be 
supportive of discriminant validity for select subscales.  
 
We will conduct similar measures of discriminant validity with the MTWS-R versions. 
 
Predictive Validity: 
We will examine prospective predictive validity using logistic regression to evaluate if withdrawal 
severity in the first week post-TQD (via EMA) predicts biochemically confirmed abstinence 1-
week post-TQD (Visit 2). The primary outcome is biochemically confirmed (CO <5ppm) 3d and 
24hr point prevalence abstinence (PPA). We will also examine longer-term predictive validity 
using separate logistic regressions to evaluate if early withdrawal severity (e.g., TQD via EMA, 
TQD +1-2d Call 4, TQD +1w Visit 2) predicts biochemically confirmed 7-day PPA at end of 
treatment (>9w Visit 4). For these analyses we will examine both the linear model estimates of 
TQD jump and post-TQD mean and trajectory (e.g., linear slope, quadratic) as predictors of 
biochemically confirmed PPA. We will examine predictive validity of post-TQD withdrawal 
severity both controlling (primary) and not controlling (secondary) for pre-TQD scores as well as 
controlling for smoking status at time of withdrawal assessment. We will examine the predictive 
validity of both the WSWS2-L and WSWS-B. 
 
We will also use logistic regression and linear model estimates to examine associations of 
individual items and subscales of the WSWS2 forms with abstinence outcomes to identify those 
that are significantly predictive of cessation.  
 
We will also conduct analyses focused on the prediction of 1-week (pre-medication, Visit 2) and 
9-week (end-of-treatment, Visit 4) abstinence using pre-quit WSWS2-L subscale and scale 
scores and WSWS2-B scale scores. These analyses will use dimensions of withdrawal scores 
as used in the piecewise models described above (e.g., capturing trajectory, average, intra-
subject variability). The magnitude of the relations with abstinence outcomes will be compared 
with the magnitude of relations of those dimensions as reflected by pre- to post-withdrawal 
change scores. In addition, regression and regression tree analyses will be used to identify 
person factors that predict strength of withdrawal-abstinence associations using baseline 
withdrawal dimensions and then using withdrawal change dimensions. The intent is to 
determine if different factors may influence trait-like withdrawal symptom elevation versus 
deprivation-induced elevation. 
 
As an exploratory outcome, we will also plan to examine predictive validity using survival 
analysis (e.g., Cox proportional hazards regression models) to determine how withdrawal 
severity (scale and subscales) influence time to first lapse (e.g., any smoking in a 24hr period) 
and progression from first lapse to return to regular smoking (e.g., 7 consecutive days of 
smoking) through end of treatment (Call 5, 9w). 
 
Similar predictive validity analyses will be conducted with the MTWS-R forms. Logistic 
regression analyses will be used to determine if either the WSWS2 or the MTWS-R shows 
significant incremental prediction of abstinence with the alternative assessment statistically 
controlled.  


9 
 
December 8, 2022 
Exploratory Withdrawal Symptoms: 
We included new items with every assessment of the WSWS2-L and WSWS2-B to assess 
symptom domains that have been proposed as possible symptoms of tobacco withdrawal: 
anhedonia (two items) and pain (one item). We will conduct the above analyses with and 
without these new items where possible (e.g., no subscale factor analysis due to limited number 
of items). These analyses may yield recommendations for a revised scale (e.g., WSWS3) or a 
parallel version for research purposes if these new items substantially improve the psychometric 
properties or construct validity of the WSWS2: e.g., improve prediction of abstinence or show 
sensitivity to tobacco abstinence from pre- to post-TQD.  
 
 
Sensitivity to Pharmacotherapy: 
We will examine sensitivity to pharmacotherapy (nicotine patch + mini lozenge), which is 
hypothesized to decrease withdrawal severity. We will calculate residualized change scores 
(adjusting for pre-quit baseline) to quantify the change in WSWS2 total scale and subscale 
scores after 1 week of pharmacotherapy (Visit 3 scores, TQD +2w) relative to immediately prior 
to initiating pharmacotherapy (Visit 2 scores, TQD +1w) and separately, relative to a stable pre-
quit baseline (Mean scores: Visit 1, Call 1, Call 2). We will examine these residualized change 
scores using GLMs to test whether the change significantly differs from zero and the 
corresponding effect size. We will examine unadjusted models as well as models controlling for 
medication dose (e.g., patch 7mg vs 14mg) and medication adherence. A valid assessment of 
withdrawal severity should be sensitive to decreases in symptoms following pharmacotherapy 
use.  
 
We will conduct similar analyses with regard to the MTWS-R forms.  
 
 
Withdrawal Scale Comparison: 
As noted above, we will conduct parallel psychometric and validation analyses for the WSWS2-
L, WSWS2-B, and MTWS-R, except when not possible due to constraints placed on single item-
subscales (e.g., subscale internal consistency, CFA).  
 
 
Idiographic Examination of Withdrawal Waveforms & Prediction of Withdrawal Severity: 
We will examine plots of individual waveforms of withdrawal scores for the WSWS2 forms and 
subscales and the MTWS-R in order to reveal individual variation in withdrawal profiles over the 
pre-TQD and post-TQD assessment periods (e.g., peak, trajectory, average, variability, 
duration). Related to this, changes in symptom volatility and associations with episodic events 
(e.g., stressor occurrence, cue exposure) will also be examined in the pre- and post-TQD 
periods using piecewise linear models. The intent is to determine sensitivity to such events and 
to determine whether such sensitivity changes from pre- to post-TQD. Additionally, we will 
examine baseline factors (e.g., demographics, alcohol/cannabis use, chronic pain, anhedonia, 
anxiety/depression/stress, distress tolerance) that are most strongly associated with withdrawal 
severity during the pre-TQD and post-TQD periods. 
 
 
Craving Construct Exploration: 
We assessed specific motives for smoking occasions that were temporally contiguous with 
craving assessments (e.g., via EMA). Craving is consistently the most informative withdrawal 
symptom with regard to abstinence prediction and the mediation of smoking treatment effects. 
Moreover, there are different theoretical accounts of the nature of motives that may underlie or 


10 
 
December 8, 2022 
instigate craving. The various theories yield somewhat different predictions about the subjective 
states or smoking motives that should be related to craving reports. This research gathered 
EMA reports assessing smoking motives such as smoking to: reduce distress, to escape 
nagging thoughts/interrupts regarding smoking, experience the taste/feel of smoking, 
experience the cigarette high/buzz, enhance pleasure from other activities, and so on. The 
associations of these items with craving self-report will be examined in order to determine which 
relatively specific smoking motives are most highly associated with craving in the pre-quit and 
post-quit periods. This will be done using both zero-order correlations as well as using network 
analytic methods. Further, the associations of such individual craving items with abstinence 
onset and smoking status at 1-week post-TQD (Visit 2) and end of treatment (Call 5 & Visit 4) 
will be determined. 
 
 
Sensitivity Analyses: 
We will conduct all psychometric and validation analyses on the maximum available sample at 
each specified time point as well as on subsets of data to evaluate how the results differ. For 
instance, we will conduct analyses only on the subset of participants who self-report abstinence 
at each post-TQD time point as well as with different cut-offs of maximum number of cigarettes 
smoked per day during each post-TQD period (e.g., <2cpd, <5cpd). We will examine the extent 
to which results vary as a function of including participants who report complete abstinence 
versus significant reductions in smoking (and presumably still may be experiencing significant 
withdrawal symptoms). Likewise, we will examine smoking since the last report as a time-
varying covariate in linear models to determine how results vary when controlling for smoking 
status in this manner.