Clinical trial NCT03860077
Conditions: Nicotine Dependence, Cigarettes, Uncomplicated
Sponsor: Brown University
Start date: 2019-10-10; Completion date: 2022-03-23
Enrollment: 57 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Adolescents are an important vulnerable population to consider as the FDA moves toward a nicotine reduction policy. Such a policy, which would mandate a reduction of nicotine in all commercially available cigarettes, has the potential to transform public health and greatly reduce the toll of tobacco-related death and disease. Yet, data on the effects of such a policy on cigarette use among adolescents are lacking. Further, the advent of e-cigarettes and the popularity of alternative tobacco products have fundamentally altered the current landscape of nicotine delivery, and these products are widely used by adolescents. Although adolescent cigarette use is at an all-time low in the U.S., this reduction has been mirrored by an increase in e-cigarette use, and multiple tobacco product (MTP) use is the most common pattern of use in youth. Adolescent MTP users are more likely to be dependent on nicotine and to have begun using tobacco earlier than their single-product using peers. Thus, MTP-using youth differ from youth who solely smoke cigarettes in meaningful ways that have implications for responses to a nicotine reduction regulatory policy. In adults, longer-term studies have demonstrated that very low nicotine content (VLNC) cigarette exposure results in fewer cigarettes smoked and reduced toxicant exposure; however, increased use of alternative tobacco products has also been reported. No studies to date have examined the effects of VLNC cigarettes on MTP use or toxicant exposure in youth. This study will use real-time, smartphone-based ecological momentary assessment (EMA) and laboratory-based assessments to: (1) investigate the effects of cigarette nicotine reduction on cigarette and MTP use, (2) assess the influence of cigarette nicotine reduction on the harms associated with tobacco use, including nicotine and toxicant exposure, respiratory symptoms, perceived health risk and nicotine dependence, and (3) use a combination of laboratory and real-time assessment to investigate the effects of nicotine reduction on changes in withdrawal, craving, and the reinforcing efficacy of cigarettes to characterize the mechanisms by which VLNC use may affect behavior. Overall, this project will help determine the effects of VLNC cigarettes on real-world tobacco use behavior and indices of tobacco-related harm in adolescents, and examining the mechanisms through which nicotine reduction in cigarettes may effect such changes.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Very Low Nicotine Content Cigarettes intervention 2: Normal Nicotine Content Cigarettes
Intervention descriptions: intervention 1: Very Low Nicotine Content Cigarettes intervention 2: Normal Nicotine Content Cigarettes

Protocol documents:
ICF_002.pdf: 
Cover page for 18+ Consent Form 
NCT03860077 
Grant number: R01DA047356 
Grant Title: Impact of Nicotine Reduction on Adolescent Cigarette Use, Alternative Tobacco Use, and 
Harm From Tobacco 
Consent Document Approval Date: 9/28/20 


 
 
1 
                         
Consent Ver. 9.28.20 
 
BROWN UNIVERSITY 
CONSENT FOR RESEARCH PARTICIPATION 
 
Impact of nicotine reduction on adolescent cigarette use, alternative tobacco use,  
and harm from tobacco 
 
 Version 10, 9.28.20 
 
KEY INFORMATION: 
 
You are invited to take part in a Brown University research study. Your participation is voluntary. 
 
• 
PURPOSE: To look at the effect of different levels of nicotine in cigarettes on teen smoking 
behavior. 
• 
PROCEDURES: We will ask you to come to our lab a total of  4 times (including today), to 
complete two virtual check-ins via Zoom, and complete several questionnaires each day on your 
smartphone for 5 weeks. You will also be asked to switch from using your usual brand cigarette 
to using a study cigarette that we will provide to you. You will be asked for a breath sample, 
urine sample, and pregnancy test, if able to get pregnant. You will also be asked to complete a 
questionnaire about your experiences related to COVID-19.  
• 
TIME INVOLVED: You will be in this study for 5 weeks and completing the surveys will take up 
to 10-15 minutes per day. Lab visits will take between 45 minutes and 2 hours. Virtual check-ins 
will take up to 40 minutes. 
• 
COMPENSATION: You will receive up to $523 for your time and effort, depending on how many 
surveys you respond to, cigarettes you return, and lab/virtual visits you complete.  
• 
RISKS: Some of the questions may be about drug use or mental health, but you are free not to 
answer any questions you do not wish to answer. You may also experience nicotine withdrawal, 
but the study does not restrict your use of other nicotine-containing products that aren’t 
cigarettes. If able to get pregnant and become pregnant during the study, you may experience 
emotional distress and you may be in need of a medical professional.  
• 
BENEFITS: There are no direct benefits to you from participating in this research study. 
 
1. Researchers:  
Questions about the study should be directed to Dr. Rachel Cassidy at 401-863-6621 or Dr. Suzanne 
Colby at 401-863-6655.  Questions about the rights of a research participant should be directed to 
the Human Research Protections Program at 401-863-3050.  
 
2. What is this study about? 
This study is investigating the effects of different levels of nicotine in cigarettes on teen tobacco use, 
health, attitudes, mood and other outcomes.  This study is not going to ask you to quit smoking, 
or help you quit smoking.  You are being invited to take part in this research study because you 
are a teen smoker.  
 
3. What will I be asked to do? 
If you agree to participate, you will be asked to attend a total of six individual sessions (including 
today). If you are eligible, we will start your first session (Baseline 1 [BL1]) today after this 
screening session. You will be asked to attend five more sessions. There will be seven days in 


 
 
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between each session. We call these sessions: Baseline 2 (BL2, a lab visit), Week 1 (W1, a virtual 
check-in session), Week 2 (W2, a lab visit), Week 3 (W3, a virtual check-in session), and Week 4 
(W4, a lab visit). This study can be completed in five weeks. Lab sessions will occur in our research 
lab. Virtual check-in sessions will be conducted remotely via Zoom.  
 
On each day of the study, starting tomorrow, you will receive notifications throughout the day 
from the app [PiLR Health] that will ask you to conduct a short survey in the app. The surveys will 
ask you about the cigarettes you smoked, any other tobacco products that you used, and questions 
about how you’re feeling and what you’re doing.  You will also be asked to complete surveys in the 
app several times each day.  We will show you how to download the app onto your phone and how 
to complete the surveys in the app later today if you are eligible. If you do not have a phone, we can 
lend you one to use during the study. You will do several types of surveys on your phone during 
the first two weeks and the last week of the study. During weeks 3 and 4, you will only need to 
complete one survey on your phone per day. 
If you are eligible and consent to participate today, I will then take a breath sample that will show 
me how much you’ve been smoking recently. I’ll also ask you some questions, and you will 
complete some questionnaires about yourself and your history of smoking. You may also be asked 
to provide a urine sample today so we can check to see how much nicotine is in your system.   
If ABLE TO BECOME PREGNANT: Smoking during pregnancy can lead to miscarriage, preterm 
delivery, stillbirth, birth defects, and other problems. To avoid these risks, it is important that you 
are not pregnant during this study.  For that reason, you will be tested for pregnancy at this and 
every lab visit.  If you test positive for pregnancy, we will provide you with a referral to a doctor 
and/or encourage you to seek medical attention from your current primary care physician, if 
applicable. You will also be provided with local pregnancy resources.  You will not be able to be in 
the study if you are pregnant, and if you become pregnant during the study, you will have to 
withdraw from the study. If you are ineligible due to pregnancy today, you will still be paid $25.  
You will be asked to switch from your usual cigarettes to research cigarettes for four weeks. During 
each of your next two in-person study visits, you will receive research cigarettes to last you for the 
following two weeks. You will be asked to smoke only those cigarettes and none of your usual 


 
 
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Consent Ver. 9.28.20 
 
brand or any other brand of cigarettes. However, you may choose to use other tobacco products 
during this time, such as e-cigarettes and little cigars. 
We will ask you to keep track of all your research cigarettes and to bring back any empty packs, 
unopened packs, and unsmoked cigarettes to the lab. Do not share research cigarettes with anyone 
else. They are only for you. You will receive a payment for bringing in your unsmoked cigarettes 
and/or unopened packs of up to up to $5 per week, for a total possible amount of $20.   
You will be randomly assigned to one of two study conditions.  Random assignment is a procedure 
similar to flipping a coin.  You have an equal chance of being in one condition or the other.  If you 
are assigned to one condition, you will be trying cigarettes that contain a different amount of 
nicotine than what is found in most brands. If you are assigned to the other condition, you will be 
trying cigarettes that have levels of nicotine that are similar to cigarettes available in stores. You 
will not be told the nicotine content of your study cigarettes until after the study has been 
completed.  
During lab sessions, you will be asked to complete questionnaires on the computer about any 
recent health changes, recent use of tobacco products, alcohol and marijuana, and about how you 
are feeling. At the BL2 and W2 sessions, we will also ask you to smoke one research cigarette in the 
lab, and to complete questionnaires about how you feel before and after smoking.  You will also be 
asked to give a breath sample before and after smoking, to measure how much smoke you are 
exposed to from the cigarette. We will also ask you to rate the cigarette after smoking it (e.g., how 
much you like the taste, etc.) and to complete some questionnaires that measure your preference for 
the research cigarette compared to other tobacco products. These lab sessions will take about an 
hour and a half to two hours to complete.   
At the BL2 and W4 sessions, you will also be asked to give a urine sample, which we will have 
tested to tell us how much nicotine and other toxicants related to tobacco use you have in your 
system.   
At check-in sessions (W1 and W3), we will take a breath sample to measure your recent smoking, 
ask you about recent changes in your health, and ask your about your recent use of tobacco 
products, alcohol, and marijuana. We will also collect unsmoked research cigarettes and dispense 
new research cigarettes as needed.  
During session W4, the final session, we will collect any remaining research cigarettes from you. 
You will answer some final questions anonymously on your experience in the study, and we will 
schedule a phone call for 30 days from then so we can check in on you and your recent smoking. If 
you feel comfortable, we will also ask you to participate in an open-ended audio interview 
regarding the COVID-19 pandemic where you can share how this pandemic has affected you. This 
audio interview is optional and will be recorded on a device that is stored in a locked drawer that 
only research personnel has access to. The audio file will be transferred from the device and onto a 
secure sever that only the research staff has access to and deleted from the device. There will be no 
personal identifying information obtained in this interview (i.e., you will be referred to as your 
participant ID number and not your first or last name).   


 
 
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It is very important for you to attend your appointments for this study. Throughout the study, if 
you reschedule your sessions more than 3 times for any reason, you may be withdrawn from the 
study.   
The study can be completed in five weeks. The daily surveys will take about 90 seconds per survey 
to complete each day. Each lab session will vary in length but will not take more than two hours. 
4. Will I be paid?  
You will be paid for completing each of the sessions as follows: $25 for today; $50 for BL2; $15 each 
for W1 and W3, $50 each for W2 and W4. You will be paid up to $5.00 for every day that you 
interact with the phone app during weeks 1,2 and 5; and up to $2 for completing one phone survey 
per day during weeks 3 and 4. You will also be eligible to earn up to $40 in random bonuses if you 
interact with the app, for a maximum total of $173. A bonus payment of $50 will be paid if you 
complete 80% or more of the surveys you’re supposed to fill out on your phone app. A completion 
bonus of $75 will be given if you attend all 4 lab sessions. A maximum of $20 possible 
compensation is available for returned cigarettes and packs (up to $5 per week). The total amount 
that you can earn for participating in the study, if you complete all sessions and app surveys, is 
$523. 
 
Payments for each of the sessions will be paid to you at the end of each session. Bonuses will be 
paid to you at the end of the study.  All study payments will be made on a ClinCard. This pre-paid 
card works like a bank debit card. You will receive further information about how to use this card. 
If you decide to withdraw from the study before completing it, we will add the money to your 
ClinCard for the number of sessions and daily app surveys that you completed before stopping. If 
you decide to quit smoking during the study, you may still be paid for any remaining study 
procedures that you complete.   
We will pay for your transportation expenses to in-person lab sessions as follows: If you drive to 
the study, parking in the garage at our research building will be paid for by the study.  If you prefer 
to take a bus, bus tickets will be provided to you at each visit. We can also pay if you take Uber to 
your appointment if you send us the receipt from your phone. If none of these options works for 
you, we can arrange for a taxi bring you to the study and back; when you schedule your 
appointment the study staff will also schedule a taxi.  
Completion of the surveys using the app will incur normal data and texting rates from your phone 
service provider that the study does not specifically compensate for.  
5. What are the risks?  
Discomfort from nicotine withdrawal: You may experience nicotine withdrawal symptoms during 
this study. Symptoms can include irritability, frustration, anxiety, sadness, craving to smoke, 
difficulty concentrating, muscle pain, fatigue or difficulty sleeping, and increased hunger.   These 
feelings can be uncomfortable, but they are normal, temporary, and are usually mild.   
 
Discomfort from interview procedures: We will ask you questions about whether you are 
experiencing psychological symptoms and about your background and smoking/drug use history. 
Answering these questions could cause you some minor discomfort.  However, the questions we 
ask are commonly used in research and clinical practice and you will not be required to answer any 
question you are not comfortable answering. All answers to these questions will be kept 
confidential.  


 
 
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Consent Ver. 9.28.20 
 
Risks related to smoking cigarettes: All cigarettes are bad for a person's health and can lead to 
heart disease, lung diseases, cancer, and death.  However, exposure to smoke and nicotine in this 
project is not significantly more than what you are exposed to on a daily basis. You do not have to 
smoke more than you normally would. Nicotine is an addictive chemical. All products containing 
nicotine can become addictive and lead to longer-term use in the future. Symptoms of too much 
nicotine include headache, dizziness, shakiness, nausea, vomiting or diarrhea, weakness, and fast 
heartbeat.  
The study cigarettes do not provide any less risk than your usual brand cigarette. Only those 
teenagers who smoke cigarettes daily, and have smoked this much for 6 months or longer, will be 
allowed to participate. Because some of the cigarettes in the study may have less nicotine in them, 
you may use other nicotine-containing products in response. The type of product you choose to use 
may result in increased risk. 
Potential Discomfort Related to Electronic Cigarette Use: The FDA has not regulated electronic 
cigarettes to date and electronic cigarettes have not been fully studied. We currently don’t know all 
risks of electronic cigarettes when used as intended, how much potentially harmful chemicals are 
being inhaled during use, or whether there are any benefits associated with using these products. 
The studies to date indicate that electronic cigarettes are likely less harmful than regular cigarettes. 
The most common discomfort from electronic cigarettes is that some people find the vapor 
irritating. The most frequently reported discomforts are mouth irritation, throat irritation, and dry 
cough. Other possible effects may include: nausea, sore throat, or headache. No serious health 
effects have been clearly due to electronic cigarettes in any study. When used as intended, serious 
risks related to electronic cigarettes are rare but it is important to use the electronic cigarette and e-
liquid provided by the study as intended and to not alter the device or e-liquid. It is important to 
follow all the study instructions regarding the electronic cigarette and e-liquid, since there have 
been cases of serious injury, including burns and explosions. The FDA has become aware that some 
people have experienced seizures, with most reports involving teens or young adult users. Seizure 
activity is a known potential side effect of nicotine toxicity. There are no known interactions of 
electronic cigarettes with any medications. 
What are the benefits? 
There are no immediate benefits from participating in the study.  You will have the chance to learn 
more about the effects of smoking.  Also, you will help us learn more about how nicotine in 
cigarettes affects teen smoking.  
 
6. How will my information be protected? 
Participation in this study and information gathered from the study will be kept confidential to the 
extent allowable by law.  All information that you give us will be identified only by a code number, 
not your name.  Your answers and test results are confidential and will not be shared with your 
parents, or anyone else who is not involved in conducting, overseeing, or monitoring the research.  
There are two exceptions to this. The first is if you report any plans to hurt yourself or anyone else. 
The second is if you report any physical or sexual abuse of yourself, other minors, or elderly people.  
If you report these things, then we are ordered by law to report them to the proper agency, to help 
keep you and other people safe. Also, if you report plans to harm yourself, we will share that 
information with our medical provider, who will talk with you about it, to help keep you safe.   
 


 
 
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Participation in this study may require a sign-in or download for using Zoom and will require 
that you have internet access or access to WiFi. You should schedule your interviews with 
appropriate times to ensure privacy. 
 
In addition to the investigators listed on the first page of this consent form and their research staff, 
organizations that oversee this research may ask to review information we collect that may identify 
you. These organizations include the Brown University Research Protections Program and the 
National Institute on Drug Abuse. The findings of the study may be published but individual 
participants will not be identified.  
 
Additionally, authorized representatives from any governmental agency that regulates the study may 
also have access to your identifiable information.  Agencies include the Food and Drug 
Administration (FDA), the U.S. Department of Health and Human Services (DHHS) and Office for 
Human Research Protections (OHRP). 
 
A description of this trial will be available on http://www.ClinicalTrials.gov as required by U.S. 
Law. This website will not include information that can identify you.  At most, the website will 
include a summary of the results. You can search this Website at any time. 
 
Certificate of Confidentiality 
To help us protect your privacy, we have received a Certificate of Confidentiality from the National 
Institutes of Health. We can use this certificate to legally refuse to provide information about you, 
even if there is a court subpoena, in any federal, state, or local civil, criminal, administrative, 
legislative, or other proceedings.  
 
The Certificate cannot be used to refuse to provide information to the U.S. Government or the 
Federal Food and Drug Administration (FDA). The U.S. Government or the FDA can require us to 
provide information so that they can audit or evaluate this federally funded research project.  
You should understand that a Certificate of Confidentiality does not prevent you or a family member 
from voluntarily releasing information about you and your involvement in the research.  If an 
insurer, employer or other person obtains your written consent to receive research information, then 
we may not use the Certificate to withhold that information. 
The Certificate of Confidentiality will not be used to prevent us from contacting state or local 
authorities if you report child or elder abuse, or plans to hurt yourself or others. 
 
The medical monitors of this study may decide to withdraw you from the study if they feel it is 
necessary to protect your health.  
 
 
7. What if I want to stop? 
Your decision whether to be in this study is completely up to you.  Participation is voluntary.  If 
you decide now to participate, you will be able to change your mind and withdraw from the project 
at any time without any consequences.  We will keep the data and specimens we collected from you 
prior to your withdrawal.  
 
8. Who can I talk to if I have questions about this study? 
Please ask any questions you have now. You can email us at ProjectSiren@brown.edu with any 
general study questions, or call Jasmine at 401-863-6645 (jasminette_dilorenzo@brown.edu). Any 


 
 
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Consent Ver. 9.28.20 
 
further questions about the study should be directed to Dr. Rachel Cassidy at 401-863-6621 
(Rachel_cassidy@brown.edu) or Dr. Suzanne Colby at 401-863-6655 (Suzanne_Colby@brown.edu).   
 
9. Who can I talk to if I have questions about my rights as a participant? 
If you have questions about your rights as a research participant, you can contact Brown 
University’s Human Research Protection Program at 401-863-3050 or email them at 
IRB@Brown.edu. 
 
10. Consent to Participate 
Your signature below shows that you have read and understood the information in this document, and 
you agree to volunteer as a research participant for this study. You will be offered a copy of this form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant's Signature and Date 
 
/  
 
 
PRINTED NAME  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Staff Signature and Date 
 
/ 
 
  
PRINTED NAME  
 
Optional 
 
The researcher may contact me in the future to see whether I am interested in being in other studies by 
researchers working at the Center for Alcohol and Addiction Studies at Brown University. 
 
 
 
I agree ______  
I disagree ______ 
 

ICF_003.pdf: 
Cover page for Parental Consent Form 
NCT03860077 
Grant number: R01DA047356 
Grant Title: Impact of Nicotine Reduction on Adolescent Cigarette Use, Alternative Tobacco Use, and 
Harm From Tobacco 
Consent Document Approval Date: 9/28/20 


 
 
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Consent Ver. 9.28.20 
BROWN UNIVERSITY 
PARENTAL CONSENT FOR RESEARCH PARTICIPATION 
 
Impact of nicotine reduction on adolescent cigarette use, alternative tobacco use,  
and harm from tobacco 
 
Version 10, 9.28.20 
 
KEY INFORMATION: 
 
Your child is invited to take part in a Brown University research study.  Participation is voluntary. 
 
• 
PURPOSE: To look at the effect of different levels of nicotine in cigarettes on teen smoking 
behavior. 
• 
PROCEDURES: We will ask your child to come to our lab a total of  4 times (including today) to 
complete two virtual check-ins via Zoom and complete several questionnaires each day on their 
smartphone for 5 weeks. Your child will also be asked to switch from using their usual brand 
cigarette to using a study cigarette that we will provide to them. They will be asked for a breath 
sample, urine sample, and pregnancy test, if able to get pregnant. Your child will also be asked to 
complete a questionnaire about their experiences related to COVID-19.  
• 
TIME INVOLVED: Your child will be in this study for 5 weeks and completing the surveys will 
take up to 10-15 minutes per day. Lab visits will take between 45 minutes and 2 hours. Virtual 
check-ins will take up to 40 minutes. 
• 
COMPENSATION: Your child will receive up to $523 for their time and effort, depending on how 
many surveys they respond to, cigarettes they return, and lab/virtual visits they complete.  
• 
RISKS: Some of the questions may be about drug use or mental health, but your child is free not 
to answer any questions they do not wish to answer. Your child may also experience nicotine 
withdrawal, but the study does not restrict their use of other nicotine-containing products that 
aren’t cigarettes. If able to get pregnant and become pregnant during the study, your child may 
experience emotional distress and may be in need of a medical professional. 
• 
BENEFITS: There are no direct benefits to your child from participating in this research study. 
 
 
1. Researchers:  
Questions about the study should be directed to Dr. Rachel Cassidy at 401-863-6621 or Dr. Suzanne 
Colby at 401-863-6655.  Questions about the rights of a research participant should be directed to 
the Human Research Protections Program at 401-863-3050.  
 
2. What is this study about? 
This study is investigating the effects of different levels of nicotine in cigarettes on teen tobacco use, 
health, attitudes, mood and other outcomes.  This study is not going to ask your child to quit 
smoking, or help your child quit smoking.  Your child is being invited to take part in this research 
study because he or she is a teen smoker.  
 
3. What will my child be asked to do? 
If you agree to your child’s participation, your child will be asked to attend a total of six individual 
sessions. The first session has two parts: screening and (if your child is eligible based on the 
screening), the Baseline 1 [BL1] assessment will be completed on the same day. Your child will be 


 
 
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Consent Ver. 9.28.20 
asked to attend five more sessions. There will be seven days in between each session. We call these 
sessions: Baseline 2 (BL2, a lab visit), Week 1 (W1, a virtual check-in session), Week 2 (W2, a lab 
visit), Week 3 (W3, a virtual check-in session), and Week 4 (W4, a lab visit). This study can be 
completed in five weeks. Lab sessions will occur in our research lab. Virtual check-in sessions will 
be conducted remotely via Zoom. 
 
On each day of the study, starting tomorrow, your child will receive notifications throughout the 
day from the app [PiLR Health] that will ask him or her to conduct a short survey in the app. The 
surveys will ask your child about the cigarettes he or she smoked, any other tobacco products that 
he or she used, and questions about how your child is feeling and what he or she is doing.  Your 
child will also be asked to complete surveys in the app several times each day.  We will show your 
child how to download the app onto his or her phone and how to complete the surveys in the app if 
he or she is eligible. If your child does not have a phone, we can lend him or her a phone to use 
during the study. Your child will do several types of surveys on their phone during the first two 
weeks and the last week of the study. During weeks 3 and 4, your child will only need to complete 
one survey on their phone per day. 
If you consent to your child’s participation, they will be scheduled for an in-person screening 
session. At that session, after we have explained the study to your child we will then take a breath 
sample that shows how much they’ve been smoking recently. We will also ask your child some 
questions, and he or she will complete some questionnaires, including about his or her history of 
smoking. Your child may also be asked to provide a urine sample so we can check to see how much 
nicotine is in his or her system.   
If able to become pregnant: Smoking during pregnancy can lead to miscarriage, preterm delivery, 
stillbirth, birth defects, and other problems. To avoid these risks, it is important that your child not 
be pregnant during this study.  For that reason, your child will be tested for pregnancy at this and 
every in-person lab visit.  If your child tests positive for pregnancy, we will provide your child with 
a referral to a doctor and/or encourage your child to seek medical attention from your current 
primary care physician, if applicable. Your child will also be provided with local pregnancy 
resources. Your child will not be able to be in the study if they are pregnant, and if they becomes 
pregnant during the study, they will have to withdraw from the study. If your child is ineligible 
due to pregnancy at the screening visit, they will still be paid $25.  


 
 
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Consent Ver. 9.28.20 
Your child will be asked to switch from his or her usual cigarettes to research cigarettes for four 
weeks. During each of his or her next two in-person study visits, your child will receive research 
cigarettes for the following two weeks. Your child will be asked to smoke only those cigarettes and 
none of his or her usual brand or any other brand of cigarettes. However, your child may choose to 
use other tobacco products during this time, such as e-cigarettes and little cigars. 
We will ask your child to keep track of all research cigarettes and to bring back any empty packs, 
unopened packs, and unsmoked cigarettes to the lab. Your child must not share research cigarettes 
with anyone else. They are only for your child. Your child will receive a payment for bringing in his 
or her unsmoked cigarettes and/or unopened packs of up to up to $5 per week, for a total possible 
amount of $20.   
Your child will be randomly assigned to one of two study conditions.  Random assignment is a 
procedure similar to flipping a coin.  Your child has an equal chance of being in one condition or 
the other.  If your child is assigned to one condition, he or she will be trying cigarettes that contain a 
different amount of nicotine than what is found in most brands. If your child is assigned to the 
other condition, he or she will be trying cigarettes that have levels of nicotine that are similar to 
cigarettes available in stores. Your child will not be told the nicotine content of his or her study 
cigarettes until after the study has been completed.  
During lab sessions, your child will be asked to complete questionnaires on the computer about any 
recent health changes, recent use of tobacco products, alcohol and marijuana, and about how he or 
she is feeling. At the BL2 and W2 sessions, we will also ask your child to smoke one research 
cigarette in the lab, and to complete questionnaires about how he or she feels before and after 
smoking.  Your child will also be asked to give a breath sample before and after smoking, to 
measure how much smoke he or she is exposed to from the cigarette. We will also ask your child to 
rate the cigarette after smoking it (e.g., how much he or she likes the taste, etc.) and to complete 
some questionnaires that measure your child’s preference for the research cigarette compared to 
other tobacco products. These lab sessions will take about an hour and a half to two hours to 
complete.   
At the BL2 and W4 sessions, your child will also be asked to give a urine sample, which we will 
have tested to tell us how much nicotine and other toxicants related to tobacco use he or she has in 
his or her system.  During these two sessions, your child will also be asked to blow into a device 
that measures lung function. 
At virtual check-in sessions (W1 and W3), we will ask about recent changes in your child’s health, 
and ask your child about recent use of tobacco products, alcohol, and marijuana. 
During session W4, the final session, we will collect any remaining research cigarettes from your 
child. He or she will answer some final questions anonymously on his or her experience in the 
study, and we will schedule a phone call for 30 days from then so we can check in on your child 
and his or her recent smoking. If your child feels comfortable, we will also ask to participate in an 
open-ended audio interview regarding the COVID-19 pandemic where you can share how this 
pandemic has affected your child. This audio interview is optional and will be recorded on a device 
that is stored in a locked drawer that only research personnel has access to. The audio file will be 
transferred from the device and onto a secure sever that only the research staff has access to and 
deleted from the device. There will be no personal identifying information obtained in this 


 
 
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Consent Ver. 9.28.20 
interview (i.e., you will be referred to as your participant ID number and not your first or last 
name).   
 
It is very important for your child to attend his or her appointments for this study. Throughout the 
study, if your child reschedules his or her sessions more than 3 times for any reason, he or she may 
be withdrawn from the study.   
The study can be completed in five weeks. The daily surveys will take about 90 seconds per survey 
to complete each day. Each in-person lab session will vary in length but will not take more than two 
hours. 
4. Will my child be paid?  
Your child will be paid for completing each of the sessions as follows: $25 for Screening/BL1; $50 
for BL2; $15 each for W1 and W3, $50 each for W2 and W4. Your child will be paid up to $5.00 for 
every day that he or she interacts with the phone app, during weeks 1,2 and 5; and up to $2 for 
completing one phone survey per day during weeks 3 and 4. Your child will also be eligible to earn 
up to $40 in random bonuses if they interact with the app, for a maximum total of $173.  A bonus 
payment of $50 will be paid if your child completes 80% or more of the surveys on the phone app. 
A completion bonus of $75 will be given if your child attends all 4 lab sessions. A maximum of $20 
possible compensation is available for returned cigarettes and packs (up to $5 per week). The total 
amount that your child can earn for participating in the study, if he or she completes all sessions 
and app surveys, is $523. 
 
Payments for each of the sessions will be made at the end of each session. Bonuses will be paid at 
the end of the study.  All study payments will be made on a ClinCard. This pre-paid card works 
like a bank debit card. Your child will receive further information about how to use this card. If you 
or your child decide to withdraw from the study before your child completes it, we will add the 
money to your child’s ClinCard for the number of sessions and daily app surveys that he or she 
completed before stopping. If your child decides to quit smoking during the study, he or she may 
still be paid for any remaining study procedures that he or she completes.   
We will pay for your child’s transportation expenses to in-person lab sessions as follows: If your 
child drives to the study, parking in the garage at our research building will be paid for by the 
study.  If your child prefers to take a bus, bus tickets will be provided at each visit. We can also pay 
if your child takes Uber to appointments if he or she sends us the receipt from his or her phone. If 
none of these options works for your child, we can arrange for a taxi bring him or her to the study 
and back; when your child schedules his or her appointment, the study staff will also schedule a 
taxi.  
Completion of the surveys using the app will incur normal data and texting rates from the phone 
service provider that the study does not specifically compensate for.  
 
5. What are the risks?  
Discomfort from nicotine withdrawal: Your child may experience nicotine withdrawal symptoms 
during this study. Symptoms can include irritability, frustration, anxiety, sadness, craving to 
smoke, difficulty concentrating, muscle pain, fatigue or difficulty sleeping, and increased hunger.   
These feelings can be uncomfortable, but they are normal, temporary, and are usually mild.   


 
 
5 
                         
Consent Ver. 9.28.20 
 
Discomfort from interview procedures: We will ask your child questions about whether he or she 
is experiencing psychological symptoms and about your child’s background and smoking/drug 
use history. Answering these questions could cause your child some minor discomfort.  However, 
the questions we ask are commonly used in research and clinical practice and your child will not be 
required to answer any question he or she is not comfortable answering. All answers to these 
questions will be kept confidential.  
Risks related to smoking cigarettes: All cigarettes are bad for a person's health and can lead to 
heart disease, lung diseases, cancer, and death.  However, exposure to smoke and nicotine in this 
project is not significantly more than what your child is exposed to on a daily basis. Your child does 
not have to smoke more than he or she normally would. The study cigarettes do not provide any 
less risk than your child’s usual brand cigarette. Only those teenagers who smoke cigarettes daily, 
and have smoked this much for 6 months or longer, will be allowed to participate. Because some of 
the cigarettes in the study may have less nicotine in them, your child may use other nicotine-
containing products in response. The type of product your child chooses to use may result in 
increased risk, while others may reduce risk relative to cigarette use. Nicotine is an addictive 
chemical. All products containing nicotine can become addictive and lead to longer-term use in the 
future. Symptoms of too much nicotine include headache, dizziness, shakiness, nausea, vomiting or 
diarrhea, weakness, and fast heartbeat.  
Potential Discomfort Related to Electronic Cigarette Use: The FDA has not regulated electronic 
cigarettes to date and electronic cigarettes have not been fully studied. We currently don’t know all 
risks of electronic cigarettes when used as intended, how much potentially harmful chemicals are 
being inhaled during use, or whether there are any benefits associated with using these products. 
The studies to date indicate that electronic cigarettes are likely less harmful than regular cigarettes. 
The most common discomfort from electronic cigarettes is that some people find the vapor 
irritating. The most frequently reported discomforts are mouth irritation, throat irritation, and dry 
cough. Other possible effects may include: nausea, sore throat, or headache. No serious health 
effects have been clearly due to electronic cigarettes in any study. When used as intended, serious 
risks related to electronic cigarettes are rare but it is important to use the electronic cigarette and e-
liquid provided by the study as intended and to not alter the device or e-liquid. It is important to 
follow all the study instructions regarding the electronic cigarette and e-liquid, since there have 
been cases of serious injury, including burns and explosions. The FDA has become aware that some 
people have experienced seizures, with most reports involving teens or young adult users. Seizure 
activity is a known potential side effect of nicotine toxicity. There are no known interactions of 
electronic cigarettes with any medications. 
What are the benefits? 
There are no immediate benefits from participating in the study.  Your child will have the chance to 
learn more about the effects of smoking.  Also, your child will help us learn more about how  
nicotine in cigarettes affects teen smoking.  
 
6. How will my child’s information be protected? 
Participation in this study and information gathered from the study will be kept confidential to the 
extent allowable by law.  All information that your child gives us will be identified only by a code 
number, not your child’s name.  Your child’s answers and test results are confidential and will not be 
shared with you, or anyone else who is not involved in conducting, overseeing, or monitoring the 


 
 
6 
                         
Consent Ver. 9.28.20 
research.  There are two exceptions to this. The first is if your child reports any plans to hurt himself 
or herself, or anyone else. The second is if your child reports any physical or sexual abuse of 
him/herself, other minors, or elderly people.  If your child reports these things, then we are ordered 
by law to report them to the proper agency, to help keep your child and other people safe. Also, if 
your child reports plans to harm himself or herself, we will share that information with our medical 
provider, who will talk with your child about it, to help keep him or her safe.   
 
Participation in this study may require a sign-in or download for using Zoom and will require 
that your child has internet access or access to WiFi. Your child should schedule their interviews 
with appropriate times to ensure privacy. 
 
In addition to the investigators listed on the first page of this consent form and their research staff, 
organizations that oversee this research may ask to review information we collect that may identify 
you. These organizations include the Brown University Research Protections Program and the 
National Institute on Drug Abuse. The findings of the study may be published but individual 
participants will not be identified.  
 
Additionally, authorized representatives from any governmental agency that regulates the study may 
also have access to your child’s identifiable information.  Agencies include the Food and Drug 
Administration (FDA), the U.S. Department of Health and Human Services (DHHS) and Office for 
Human Research Protections (OHRP). 
 
A description of this trial will be available on http://www.ClinicalTrials.gov as required by U.S. 
Law. This website will not include information that can identify your child.  At most, the website 
will include a summary of the results. You and your child can search this Website at any time. 
 
Certificate of Confidentiality 
To help us protect your child’s privacy, we have received a Certificate of Confidentiality from the 
National Institutes of Health. We can use this certificate to legally refuse to provide information 
about your child, even if there is a court subpoena, in any federal, state, or local civil, criminal, 
administrative, legislative, or other proceedings.  
 
The Certificate cannot be used to refuse to provide information to the U.S. Government or the 
Federal Food and Drug Administration (FDA). The U.S. Government or the FDA can require us to 
provide information so that they can audit or evaluate this federally funded research project.  
You and your child should understand that a Certificate of Confidentiality does not prevent you or 
your child from voluntarily releasing information about your child’s involvement in the research.  If 
an insurer, employer or other person obtains your written consent to receive research information, 
then we may not use the Certificate to withhold that information. The Certificate of Confidentiality 
will not be used to prevent us from contacting state or local authorities if your child reports child or 
elder abuse, or plans to hurt himself/herself or others. 
 
The medical monitors of this study may decide to withdraw you from the study if they feel it is 
necessary to protect your health.  
 
7. What if my child wants to stop participating? 
 Your child does not have to be in this study if you do not want them to be, or if he or she does not 
want to. Even if you decide to consent to let your child be in this study and he or she assents to 


 
 
7 
                         
Consent Ver. 9.28.20 
participate, you can change your mind and withdraw them, or they can stop participating at any 
time.  We will keep the data and specimens we collected from your child prior to your withdrawal.  
 
If you do not consent to your child’s participation or if your child leaves the study, your child’s 
current or future relationship with Brown University will not be affected. 
 
8. Who can I talk to if I have questions about this study? 
Please ask any questions you have now. You can email us at ProjectSiren@brown.edu with any 
general study questions, or call Jasmine at 401-863-6645 [jasminette_dilorenzo@brown.edu). 
 
Any further questions about the study should be directed to Dr. Rachel Cassidy at 401-863-6621 
(Rachel_cassidy@brown.edu) or Dr. Suzanne Colby at 401-863-6655 (Suzanne_Colby@brown.edu).   
 
9. Who can I talk to if I have questions about my child’s rights as a participant? 
If you have questions about your child’s rights as a research participant, you can contact Brown 
University’s Human Research Protection Program at 401-863-3050 or email them at 
IRB@Brown.edu. 
 
 
10. Consent to Participate 
Your signature below shows that you have read and understood the information in this document, and 
you agree that your child can volunteer as a research participant for this study. You will be offered a 
copy of this form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parent's Signature and Date  
/  
 
 
PRINTED NAME  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Staff Signature and Date 
 
/ 
 
  
PRINTED NAME  
 

Prot_000.pdf: 
Cover page for Protocol 
NCT03860077 
Grant number: R01DA047356 
Grant Title: Impact of Nicotine Reduction on Adolescent Cigarette Use, Alternative Tobacco Use, and 
Harm From Tobacco 
Includes changes approved as of: 9/28/20 


Impact of nicotine reduction on adolescent cigarette use, alternative tobacco use, and harm from tobacco 
 
PIs: Cassidy & Colby 
 
1 
 
1. Lay Summary:  Adolescents are an important vulnerable population to consider as the FDA moves 
toward a nicotine reduction policy. Such a policy, which would mandate a reduction of nicotine in all 
commercially available cigarettes, has the potential to transform public health and greatly reduce the toll 
of tobacco-related death and disease. Yet, data on the effects of such a policy on cigarette use among 
adolescents are lacking. Further, the advent of e-cigarettes and the popularity of alternative tobacco 
products have fundamentally altered the current landscape of nicotine delivery, and these products are 
widely used by adolescents. Although adolescent cigarette use is at an all-time low in the U.S., this 
reduction has been mirrored by an increase in e-cigarette use, and multiple tobacco product (MTP) use is 
the most common pattern of use in youth. Adolescent MTP users are more likely to be dependent on 
nicotine and to have begun using tobacco earlier than their single-product using peers. Thus, MTP-using 
youth differ from youth who solely smoke cigarettes in meaningful ways that have implications for 
responses to a nicotine reduction regulatory policy. In adults, longer-term studies have demonstrated that 
VLNC cigarette exposure results in fewer cigarettes smoked and reduced toxicant exposure; however, 
increased use of alternative tobacco products has also been reported. No studies to date have examined 
the effects of VLNC cigarettes on MTP use or toxicant exposure in youth. This study will use real-time, 
smartphone-based EMA and laboratory-based assessments to: (1) investigate the effects of cigarette 
nicotine reduction on cigarette and MTP use, (2) assess the influence of cigarette nicotine reduction on 
the harms associated with tobacco use, including nicotine and toxicant exposure, respiratory symptoms, 
perceived health risk and nicotine dependence, and (3) use a combination of laboratory and real-time 
assessment to investigate the effects of nicotine reduction on changes in withdrawal, craving, and the 
reinforcing efficacy of cigarettes to characterize the mechanisms by which VLNC use may affect 
behavior. Overall, this project will help determine the effects of VLNC cigarettes on real-world tobacco 
use behavior and indices of tobacco-related harm in adolescents, and examining the mechanisms through 
which nicotine reduction in cigarettes may effect such changes. Such knowledge will contribute to the 
science base that may inform future policy decisions. 
 
2. Protocol Narrative 
a. Aims & Methodology 
a) Aim 1: To determine the effects of VLNC vs. NNC cigarettes on cigarettes smoked per 
day and frequency of alternative tobacco product use in adolescent cigarette smokers. 
We hypothesize that use of VLNC cigarettes will be associated with a decrease in 
combustible cigarettes smoked per day and an increase in the number of days of 
alternative combustible and noncombustible tobacco product use.  
b) Aim 2: To determine the effects of VLNC cigarettes on nicotine and toxicant exposure, 
perceived health risk of tobacco products, respiratory symptoms and dependence. We 
will test the hypothesis that use of VLNC cigarettes will lead to reduced nicotine and 
toxicant exposure, dependence, and respiratory symptoms in adolescent MTP users. 
c) Aim 3: To leverage real-time EMA assessment to determine the effects of VLNC 
cigarettes on withdrawal and craving, and to determine whether these momentary 
changes influence alternative tobacco use. We hypothesize that VLNC cigarette 
exposure may influence momentary changes in withdrawal and craving; and that these 
will vary both within and across individuals. 


Impact of nicotine reduction on adolescent cigarette use, alternative tobacco use, and harm from tobacco 
 
PIs: Cassidy & Colby 
 
2 
 
3. Overall Study Design:  A 2-group randomized between-subjects design will be used. Following a 
phone screening and informed consent procedure, adolescent tobacco users (ages 15-19, N=120) who 
report smoking cigarettes on at least 28 out of the last 30 days and use of one or more alternative 
tobacco products in the past 30 days, will complete their first laboratory session (Baseline Session 1 or 
BL1). After a one-week usual-brand baseline period during which all participants smoke as usual, a 
second laboratory session will be completed (BL2). At the end of that session, participants will be 
randomized to switch to either NNC (15.8 mg/g; n = 60) or VLNC (0.4 mg/g) cigarettes (n=60). During 
the 4-week experimental period, participants will be provided with study cigarettes each week and 
instructed to smoke only those cigarettes. They will also be told that they may choose to use other 
nicotine-containing products, such as e-cigarettes and little cigars, during the study. Daily, we will 
assess all cigarette smoking and use of all other tobacco products (as well as any non-compliant use of 
non-study cigarettes), and craving, withdrawal, and other factors using a smartphone-based app.  
Weekly, participants will come to the laboratory to complete assessments of dependence and respiratory 
symptoms, and behavioral economic assessments. Thirty days after the end of the protocol, participants 
will be contacted via phone and asked about their use of tobacco products and any changes in their 
overall health as a safety check. The flow of the protocol is depicted in Figure 1. All laboratory 
measures are shown in Table 1. 
Figure 1. Protocol Timeline. 
 
a.  Research Cigarettes. All cigarettes tested will be Spectrum research cigarettes (22nd Century 
Group, Inc.), which are produced for the National Institute on Drug Abuse (NIDA; NOT-DA-14-
004). The two cigarette types tested in the current study will contain 15.8 mg nicotine/g tobacco 
(normal nicotine content, NNC) or 0.4 mg nicotine/g tobacco (VLNC), both with tar yields of 9 
± 1.5 mg. Cigarettes are available in both menthol and non-menthol versions and participants 
will be assigned the flavor that they prefer based on their usual menthol preference. 


Impact of nicotine reduction on adolescent cigarette use, alternative tobacco use, and harm from tobacco 
 
PIs: Cassidy & Colby 
 
3 
 
b.  Advertising & Recruitment: We will contact schools to receive permission to set up 
informational tables during lunchtime that will provide information about the study. Interested 
adolescents will be read a short script with information about the study and if they remain 
interested will be screened for eligibility. We will also advertise the study on regional buses, in 
local and school newspapers, on Craigslist.org, on Facebook and Instagram, on the Center for 
Alcohol and Addiction Study’s (CAAS) website, other places online and on social media, via 
direct mail, and at local events. To reach adolescents outside of high school, we will also 
promote the study at GED classes and youth job training programs, and/or social service 
agencies such as community action programs, using flyers and information sessions. Interested 
adolescents can self-administer a screening interview via iPad, provide contact information to 
receive a follow up phone call, or call the research office to complete a brief, confidential 
telephone screening interview to establish eligibility.  
c. Phone Screen (Provided as attachment): The screening questionnaire will query past 6-month 
cigarette use, past 30-day frequency of other tobacco/nicotine, alcohol, and other drug use, 
motivation for smoking cessation, and other items required to establish preliminary eligibility 
(see Adolescent Phone Screen). The screening will remain the same whether or not it is 
administered via iPad or over the phone.  The screening questionnaire is used only to determine 
eligibility and will not be used as research data. 
d. Informed consent procedure: Adolescents who meet initial eligibility criteria, and who remain 
interested after hearing a more detailed description of the study, will provide contact information 
for their parent or legal guardian (minors only) so that parental informed consent can be 
obtained; 18-19 year olds can provide their own informed consent (see 18+ Consent 
attachment). Research staff will call the minor’s parent/guardian and provide the study 
information and answer any questions that they have (see Parent Phone Script attachment). If 
parents are willing to consent to their child’s participation, we will mail or email them a consent 
form to sign (and one to keep), which the adolescent participant will bring to the first session 
(see Parental Consent attachment). Eligible interested adolescents (with verbal parental consent 
if minors) will be scheduled for the initial in-person session and transportation arranged if 
necessary (see Adolescent Assent attachment). 
4. Screening 
a. During the initial in-person screening, participants will complete several questionnaires and have 
their CO taken to confirm eligibility to enroll. Female participants will also submit a urine 
sample to test for pregnancy. Urine will be sampled for cotinine levels if necessary. The 
Timeline Follow back, stages of change, and MINI suicide subscale will be used to determine 
eligibility. We estimate that we may need to consent up to 200 adolescents to result in a final 
sample of N=120. 
 
b. Inclusion Criteria 
1) Ages 15-19 20 inclusive 
2) Male and female current daily smokers 
a. Defined as self-reported daily cigarette smoking at phone screening AND 


Impact of nicotine reduction on adolescent cigarette use, alternative tobacco use, and harm from tobacco 
 
PIs: Cassidy & Colby 
 
4 
 
b. a breath carbon monoxide (CO) criterion of 5 ppm or higher; if this is not met, urine 
cotinine levels, detected by a NicAlert cotinine screening device, must indicate recent 
smoking (level 3 or higher) 
3) Current users of alternative tobacco product(s) 
a. Defined as any self-reported use of at least one non-cigarette tobacco product (e.g., e-
cigarettes, little cigars, cigarillos, hookah, etc.) in the past 30 days  
4) Participants must speak and comprehend English well enough to complete study procedures. 
a. Participant will be asked to read aloud first few lines of informed consent and then 
summarize the contents aloud to check for competency 
 
Exclusion Criteria 
1) Unwilling to use research cigarettes as part of the study 
2) Self-reported binge drinking of alcohol (> 4/5 drinks within a 2-hour period for female/male 
participants respectively) or use of illicit or non-prescribed drugs (excluding marijuana) > 10 
days in the past 30 daysdaily use of alcohol 
a. We will ask about daily alcohol and drug use in the phone screen, and we will use the 
Timeline Follow-Back to assess current and recent marijuana and alcohol use. 
3) Currently seeking treatment to quit smoking, and/or intending to quit smoking for good in the 
next 30 days 
a. This information corresponds to questions 2 & 3 of the Stages of Change measure 
which will be administered at the in-person screening. 
b. These participants will be excluded, and provided with referral information for 
cessation services in the community. 
4) Suicidal ideation in the past month or any past-year suicide attempts 
a. Suicidal ideation determined by the MINI suicide subscale at the in-person screening 
(Questions 4 and 5) 
b. Suicide attempt in the past year determined by MINI question 6.a. (If participant has a 
lifetime history of suicide attempt between 1 and 10 years ago, licensed medical 
monitor approval required) 
c. If a participant indicates that he/she currently has suicidal ideation during this or any 
future session, the Emergency Protocol will be followed in which a Licensed 
Clinician will be contacted immediately, and participants will speak with the clinician 
over the phone and the clinician will determine the appropriate action to take to keep 
the child safe. 
5) Pregnant or breastfeeding 
a. Determined by urine test at in-person screening; tested again at each in-person visit; 
participant will be excluded or withdrawn if test indicates pregnancy 
b. Self-reports current breastfeeding at in-person screening 
6) Any medical or psychiatric conditions in which participation is likely to pose a significant 
threat to health or for which the condition could interfere with the ability of the participant to 
fully participate (as determined by LMP). 
7) Having participated in another research study during the past year in which they were 
switched to research cigarettes for longer than one week.  
 
Initial eligibility determination will be made by the RA based on the above criteria. If the 
participant is deemed initially eligible, the BL1 session will immediately being. Eligibility 


Impact of nicotine reduction on adolescent cigarette use, alternative tobacco use, and harm from tobacco 
 
PIs: Cassidy & Colby 
 
5 
 
criteria will be reviewed by the medical monitor (Dr. Cioe) and the PI to confirm final eligibility 
for the study prior to randomization (BL2). 
5. Baseline 1 Session  
a. Purpose: If the participant is eligible after screening procedures, the first baseline session (BL1) 
will immediately begin. Participants who are ineligible will be paid $25 and will not complete 
the BL1 procedures. The RA will make the initial determination of eligibility; final eligibility 
will be confirmed by the study clinician and PI prior to BL2 (randomization). 
b. Procedure: BL1 will consist of an initial battery assessing baseline characteristics (see measures 
schedule). After these assessments, participants will be oriented to the EMA procedures. 
Research staff will help participants download the app to their smartphones, and then train them 
on how to complete the assessments. EMA surveys will begin the next day (see Table 2 and 
section on EMA Procedures below). During the 1-week baseline EMA period, participants will 
be instructed to smoke and use other tobacco products as they normally would.  
6. Baseline 2 (BL2) Laboratory Session  
a. Purpose: During this session, participants will be randomized to their study cigarette. Using 
multiple laboratory-based measures, this session establishes the acute effects of study cigarettes 
on craving, withdrawal symptoms, and subjective reinforcement value of the participant’s 
randomly assigned study cigarette.  
b. Procedure: At the beginning of the session, participants will provide a breath CO sample, 
complete a timeline follow-back measure for the interim week (i.e., between BL1 and BL2) 
which will query their use of cigarettes, alcohol, marijuana, and alternative tobacco products, 
complete a delay discounting task, and complete measures of craving (QSU), withdrawal 
(MNWS) and mood (PANAS). They will then smoke one study cigarette in the laboratory (while 
being observed by a research assistant in an adjoining room). Female participants will also 
provide a urine sample for a pregnancy test. Next, they will provide a post-smoking CO sample, 
repeat the QSU, MNWS, and PANAS, and then complete measures of cigarette subjective 
effects (CES), and perceived health risks of smoking. Then, they will complete a cigarette 
purchase task (CPT), a behavioral economics-based measure of cigarette reinforcement, which 
assesses hypothetical demand for cigarettes across a range of prices. They will complete the 
Experimental Tobacco Marketplace task which is described in detail under the Measure section.  
Participants will also complete a Health Changes Questionnaire to assess any adverse events. 
Participants will also complete an objective assessment of respiratory function using a 
Spirometer to measure their breath volume, and then provide urine samples for biomarker 
assessment. 
c. Product Dispensing: Participants will be randomized to switch from smoking their usual brand 
cigarettes to smoking either NNC or VLNC cigarettes over a subsequent four-week experimental 
period.  After all BL2 assessments are completed, study cigarettes will be dispensed to the 
participant at 125% of their weekly (between BL1 and BL2) consumption of cigarettes. Extra 
cigarettes are provided, as is typical in studies of this type (e.g., Donny et al., 2015; Hatsukami et 
al., 2010), to accommodate potential increases in smoking that may occur, and to allow any 
compensatory smoking (e.g., with VLNC cigarettes) to be detected. Participants will be 
instructed to smoke only the research cigarettes provided to them by the study rather than their 
usual brand cigarettes or any other cigarettes. They will also be told that they may choose to use 


Impact of nicotine reduction on adolescent cigarette use, alternative tobacco use, and harm from tobacco 
 
PIs: Cassidy & Colby 
 
6 
 
other nicotine-containing products (not provided by the study), such as e-cigarettes and little 
cigars, during the study. This distinguishes the proposed trial from past work with adolescents, 
which excluded most poly-tobacco users and prohibited non-cigarette product use during the 
experimental period. Participants will be dispensed cigarettes for a 714-day period; however; if 
their session is scheduled earlier or later (e.g., due to school holiday or vacation), then the RA 
may dispense up to a 14-day supply.. Participants will also be informed that if they run out of 
study cigarettes prior to their next scheduled visit, they can schedule a time to pick up more at an 
Unanticipated Visit, which will follow the same visit protocol as W1/W3 Check-In Visit. If such 
an Unanticipated Visit occurs, the RA will dispense product for the number of days until their 
next scheduled visit (e.g., if they have two days until their next visit, then the RA will dispense 
two days’ worth of study product). 
d. Product Compliance and Accountability: Participants will be required to keep track of all the 
cigarettes provided to them.  Each week, they will return all unused cigarettes and empty or 
unopened cigarette packs to the research staff, and will receive incentives for doing so. 
Participants will be asked if they have decided to quit smoking at each lab visit. If they wish to 
quit, they will be asked if they still want to receive study cigarettes. If not, no cigarettes will be 
dispensed. The participant will be retained in the study with no penalty and will continue to 
complete all subsequent EMA and other self-report assessments. In an ongoing study 
(IRB#1404001032), we dispense research cigarettes in this manner to 15-19-year-old daily 
smokers with approvals from the FDA, Brown University IRB and permission (waiver) from the 
Rhode Island Attorney General (K01CA189300, PI Cassidy). We are in the process of obtaining 
such a waiver for the current study as well. We will provide incentives for study cigarette 
accountability, which we have found to increase study cigarette compliance in our prior trials. 
The incentive will be a payment at each in-person session, which encourages participants to keep 
track of their study cigarettes, minimizes hoarding of study cigarettes, and discourages sharing of 
study cigarettes with other people. The payment schedule for returning unsmoked cigarettes is as 
follows: 50-74% returned, $5; 25-49% returned, $2.50; and 0-24% returned, $0. Returned empty 
packs will receive $1. At each session, participants will be reminded that if they do not like their 
study cigarettes, they can use alternative products that are not cigarettes, as the goal of the study 
is to model a scenario in which a nicotine reduction policy applies only to cigarettes. Honest 
reporting will be encouraged throughout the study. The total possible incentive for 
cigarette/empty pack return is $5. 
e. Randomization: Using procedures similar to our current study, a double-blind randomization 
procedure will be used. We will stratify on the following four variables to optimally balance 
conditions on factors that might influence responses to study cigarettes:  
a) Gender  
b) Average cigarettes per day in past month (CPD; < 8 cigarettes vs. > 8 cigarettes)  
c) frequency of past-month alternative combustible tobacco product use (< 10 days vs. > 
10 days). 
d) frequency of past-month non-combustible tobacco product use (< 10 days vs. > 10 
days). 


Impact of nicotine reduction on adolescent cigarette use, alternative tobacco use, and harm from tobacco 
 
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7 
 
Each participant will be assigned a randomization code which will be associated with blind codes 
for cigarette cartons. The research assistant dispensing the cigarettes to each participant will be 
blind to the cigarette nicotine content, and will dispense cigarettes based on the blind code linked 
to each individual’s randomization code. The randomization schedules and the link between the 
randomization code, blind codes and treatment assignment will be maintained securely by the 
CAAS Data Core (Suzanne Sales and Tim Souza). 
f. EMA Platform: All EMA assessments will be conducted via a smartphone app designed for this 
purpose, PiLR EMA (MEI Research, Edina, Minnesota; http://pilrhealth.com/), which was 
developed and made available by MEI Research, Inc. The app is fully customizable for 
conducting time-based, event-based, contingent and random surveys, and supports logic 
branching to ask follow-up questions only when certain events are noted.  The app uses a cloud-
based infrastructure to store data securely, and this software has been used successfully in other 
smoking studies conducted here in vulnerable populations (Allen, Tosun, Carlson, & Allen, 
2017) and in ongoing research on other health behaviors at our Center (for further information 
about ongoing behavioral health projects using the app, see http://pilrhealth.com/projects/). The 
app uses a mobile-friendly interface to capture data, including options for ‘slider’ visual analog 
scales (VAS) to input Likert scale items, text-based data entry, and check boxes to indicate the 
presence of certain environmental features. The app will be downloaded onto participants’ 
phones at the BL1 session. As we have done in prior EMA studies, if participants do not have a 
smartphone, they will be loaned one for the duration of the study. Further detailed information 
about the security and data transmission of the app are included as an attachment to this protocol. 
During the BL1 session, participants will be given detailed instructions on how to use the app, 
including information on when the app will notify them to complete a survey and when they 
should initiate a survey themselves (e.g, after each cigarette or use of any other tobacco product). 
Participants will be provided with a ‘hotline’ phone number to call for general questions and 
technical support. Further information about app data safety and confidentiality is included as an 
attachment.  
g. EMA Procedures: Each assessment will take approximately 90 seconds to complete.  EMA 
report types will include: 1) Interval-contingent wake-up reports whereby participants will be 
signaled to record the number of cigarettes and other nicotine and tobacco products they used the 
day before; 2) Event-contingent tobacco use reports wherein participants will initiate a report 
each time they smoke a cigarette or use an alternative tobacco product; each such report will 
query social context, withdrawal, mood and other factors; and 3) Signal-contingent random 
prompts whereby adolescents respond to an app-initiated audible signal which will prompt a 
report with the same questions as the event-contingent tobacco use report to determine non-
tobacco levels of mood and other factors for comparison purposes. Random prompts will be 
signaled 4 times per day, once per 3-hour block: 8am-11am; 12pm-3pm; 3-6pm; 4-7pm, 8-11pm] 
The purpose of the random prompts is to assess non-tobacco levels of withdrawal, craving, and 
other variables in order to compare these with the variables reported during tobacco reports. 
Variables such as mood, location sett and peer context will be included as these may also affect 
adolescent smoking and can be explored as potential moderators of effects. Random prompts will 
also ask participants if they smoked cigarettes or used any other tobacco products since their last 


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report, and if so, they will be prompted to record it in order to capture any missed product use. 
The minimum number of surveys to be completed per day is five (one interval-contingent 
morning report and four random prompts). Cigarette reports can be compared directly with 
reports on other forms of tobacco to identify common and unique antecedents, and contextual 
factors for use of each type of product use can be compared to those during random prompts. 
During Weeks 2 and 3, to reduce participant burden, only the morning report will be required. 
The schedule of EMA assessments and question wording is included as an attachment.  
7. Week 1 Safety & Product Dispensation Check-In  
a. Purpose: This check-in visit can occur either at our research lab or in the community at the 
participant’s preference and convenience. The purpose of this check-in is to check on safety/any 
adverse events, check CO level, and dispense product; allowing participants to meet us in the 
community will help reduce the burden of travel time for participants and is designed to reduce 
study attrition, particularly among participants for whom the logistics of scheduling and 
transportation may be challenging.  
b. Procedures: Participants will provide breath CO, complete a timeline follow-back measure for 
the interim week which will query their use of study and non-study cigarettes, alcohol, 
marijuana, and alternative tobacco products. Participants will also complete a Health Changes 
Questionnaire to assess any adverse events, and the RA will follow-up on any ongoing medical 
events. Note: These sessions were conducted virtually post-COVID. 
8. Week 2 Laboratory Session 
a. Purpose: This laboratory session will evaluate mid-point responses to study cigarettes. 
b. Procedures: At the beginning of the session, participants will provide a breath CO sample, 
complete a timeline follow-back measure for the interim week which will query their use of 
study and non-study cigarettes, alcohol, marijuana, and alternative tobacco products, and 
complete measures of craving (QSU), withdrawal (MNWS) and mood (PANAS). Female 
participants will provide a urine sample for a pregnancy test. They will then smoke one of their 
study cigarettes. Next, they will provide a post-smoking CO sample, repeat the QSU, MNWS, 
and PANAS, and then complete measures of cigarette subjective effects (CES). Participants will 
also complete a Health Changes Questionnaire to assess any adverse events, and the RA will 
follow-up on any ongoing medical events. 
9. Week 3 Safety & Product Dispensation Check-In 
a. Purpose: As described above (Week 1 Check-In), this check-in visit can occur either at our 
research lab or in the community; the purpose is to check on safety/any adverse events, check 
CO, and dispense product.  
b. Procedures: Participants will provide breath CO, complete a timeline follow-back measure for 
the interim week which will query their use of study and non-study cigarettes, alcohol, 
marijuana, and alternative tobacco products. Participants will also complete a Health Changes 
Questionnaire to assess any adverse events, and the RA will follow-up on any ongoing medical 
events. Note: These sessions were conducted virtually post-COVID. 
10. Week 4 Session 
a. Purpose: This laboratory session will evaluate end-point responses on behavioral economic 
measures and allow for collection of final biomarkers and cigarette collection. 


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b. Procedures: At the beginning of the session, participants will provide a breath CO sample, 
complete a timeline follow-back measure for the interim week which will query their use of 
study and non-study cigarettes, alcohol, marijuana, and alternative tobacco products. Female 
participants will provide a urine sample for a pregnancy test. Then, they will complete the 
cigarette purchase task (CPT), a behavioral economics-based measure of cigarette reinforcement, 
which assesses hypothetical demand for their usual brand and study cigarettes across a range of 
prices. Finally, they will complete the Experimental Tobacco Marketplace task again. 
Participants will also complete a Health Changes Questionnaire to assess any adverse events, and 
the RA will follow-up on and close any ongoing medical events. Should any adverse events be 
left open at this time, they will be re-assessed at the 30-day call. Participants will also complete 
an assessment of respiratory health and provide urine samples for biomarker assessment. 
Participants will also administer and anonymous debriefing survey which will ask them about the 
honest of their reporting. At the end of the week 4 session, following return of all products, 
participants will be debriefed on products used during the study. Health risk information will be 
presented for combusted cigarettes, e-cigs, and other tobacco products, using a handout drawn 
from CDC Fact Sheet. 
b.c. Post-Session COVID survey and qualitative interview: Following the last sessions, participants 
will be asked if they would like to participate in a short survey and interview. They will first 
complete a brief survey of their COVID-19 experiences. Then, the researchers will conduct a 
recorded qualitative interview about their experiences with the EMA app in order to improve 
future app use.  
11. Outcomes, Measures Justification, Descriptions, and Schedule 
Primary Outcomes 
 
 Cigarettes smoked per day 
 Amount of total alternative product (ATP) use  
 
Secondary Outcomes 
 
 Amount of combustible and amount of noncombustible ATP use 
 Toxicant exposure (total nicotine equivalents and NNAL) 
 FEV outcomes 
 
Exploratory Outcomes 
 
 ATSQ score 
 Perceived Health Risk Questionnaire 
 Nicotine dependence score 
 Differences in craving across time and product type  
 Differences in withdrawal across time and product type  
 Measures of reinforcing efficacy/cigarette demand from the Cigarette Evaluation Scale 
 Hypothetical Purchasing in the Experimental Tobacco Marketplace 
 


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a. Background/Descriptive Measures: A modified version of the PATH Demographics and 
Tobacco Use History (Adolescent version) will be used to assess participant characteristics and 
lifetime history of tobacco product use (using a comprehensive list of combusted and non-
combusted products), including ages of initiation and progression through smoking milestones 
such as daily use. The Vaping History Questionnaire will be used to assess lifetime use of e-
cigarettes, including e-cigarette characteristics. Social and Environmental Influences (tobacco 
use by parents and peers; perceived norms for cigarettes and e-cigs) will be assessed using a 
modified Interpersonal Influences Questionnaire (Colby et al., 2005. We will use the reliable and 
valid Smoking Stage of Change (Velicer, Hughes, Fava, Prochaska, & DiClemente, 1995) to 
assess readiness to change at baseline and week 4. The Center for Epidemiological Studies-
Depression Scale (CES-D; Radloff, 1991) is a widely used and validated 20-item questionnaire 
assessing depressive symptoms in the past week.  This measure will be used for sample 
description given the high co-occurrence of smoking and depression. Respiratory symptoms will 
be assessed using the American Thoracic Society Questionnaire (ATSQ; Comstock, Tockman, 
Helsing, & Hennesy, 1979). Participants report the frequency of experiencing each of 8 
respiratory symptoms (e.g., morning cough, wheezing, shortness of breath when walking). We 
recently validated this scale for assessing the severity of respiratory symptoms associated with 
smoking in adolescents (Cassidy, Roberts & Colby, 2015). Nicotine Dependence will be 
assessed using the modified Fagerstrom Tolerance Questionnaire (Heatherton, Kozlowski, 
Frecker, & Fagerström, 1991). Scores on this measure will be evaluated as an outcome at Week 
4 as an index of changes in dependence as a function of VLNC exposure.  
b. Safety: Pregnancy tests will be performed for all female participants at Screening/BL1, BL2, and 
both lab visits (weeks 2 and 4).  The suicide subscale from the Mini International 
Neuropsychiatric Interview (MINI; Sheehan et al., 2010) will be used at Screening to evaluate 
suicide risk. CO level will be obtained at every session to evaluate level of exposure to smoke; a 
large increase in CO (i.e., CO > 80 ppm) can be a reason for withdrawing a participant from the 
study. Brief Medical History (Screening/BL1) assesses physical and emotional health to 
establish eligibility for participation (determined by the medical monitors). In subsequent 
sessions, the Health Changes Questionnaire asks whether the participant experienced any 
changes in his/her physical or emotional health since their last visit, including whether they have 
visited the doctor, the hospital, or whether they have had a change in any of their medications. 
Any endorsement of a negative health change will be tracked as an adverse event.  
c. Frequency of tobacco and other drug use measures: Past 30-day tobacco product use will be 
comprehensively assessed using a Timeline Follow-Back (TLFB), a reliable calendar-assisted 
interview validated for estimating daily use of tobacco and other substances in adolescents 
(Lewis-Esquerre et al., 2005). The TLFB will determine: # cigarettes per day; frequency of e-cig 
use (including nicotine concentration in e-liquid) and use of all other tobacco products; use of 
alcohol (# standard drinks/day); and frequency of marijuana use and other illicit or recreational 
drug use. The TLFB will also be used to assess tobacco, alcohol, marijuana and other drug use 
between sessions to evaluate use over the course of the study.  
d. Biomarkers. Expired breath CO level is a reliable and valid assessment of recent smoking and 
will be measured using a Vitalograph CO Monitor. CO will be assessed at BL to confirm 


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smoking status and for sample description. CO will be evaluated pre- and post-cigarette in each 
labs session, and as an outcome at Week 4 as a biomarker of changes in effects of changes in 
combustible product use.  Urine samples will be analyzed for the tobacco-specific nitrosamine 4-
methylnitrosamineo-1-(3-pyridyl)-1-butanol (NNAL), a biomarker of tobacco smoke carcinogen 
that decreases upon combustible tobacco cessation or reduction (Benowitz et al., 2012; Hecht et 
al., 2014) and total nicotine equivalents (TNEs), which is a measure of total nicotine exposure 
(i.e., from all nicotine-containing products). Both TNEs and NNAL will be analyzed from 
samples collected at baseline (BL2) and at the end of the product use period (W4). Samples will 
be shipped twice per year for analysis to the University of Minnesota and will be analyzed by 
Sharon Murphy, Ph.D. (see letter of support included in grant application). Scores on this 
measure will be evaluated as an outcome at Week 4. Forced Expiratory Volume (FEV) is a 
measure of how much air a person can exhale during a forced breath. Cigarette smoking is 
associated with reduced lung function in adolescents, indicating mild airway obstruction, and 
with slowed lung growth during adolescence (Gold et al., 1996) whereas quitting smoking leads 
to improvement in lung function and slows reductions in lung function associated with aging in 
later adulthood (Kohansal et al., 2009). Forced vital capacity (FVC) is the total volume of breath 
exhaled during the test; FEV1 is the volume exhaled within the first second. FEV will be 
measured with a water-filled recording spirometer. Research assistants will be trained by Co-
Investigator Cioe, who has experience measuring FEV in clinical settings, to take these 
measurements. Each participant will perform three forced expirations; FVC and FEV1 means 
will be calculated for each expiration judged acceptable by the RA.  
e. Assessments of Potential Mechanisms. The Brief Questionnaire on Smoking Urges (Brief 
QSU; (Cox, Tiffany, & Christen, 2001) assesses craving for cigarettes. Factor 1 assesses desire 
to smoke/positive reinforcing aspects of smoking, and Factor 2 assesses relief from 
withdrawal/negative reinforcing aspects of smoking.  The Minnesota Nicotine Withdrawal 
Scale (MNWS; Hughes & Hatsukami, 1986) asks individuals to rate their experience of 
withdrawal from nicotine using a four-point scale across 7 items reflecting DSM-IV criteria for 
nicotine withdrawal syndrome. The Positive and Negative Affect Scale (PANAS; Watson, 
Clark, & Tellegen, 1988) asks participants to rate how they are feeling at the moment, using a 
series of adjectives, on a 5-point scale (from “not at all” to “extremely”); its items form two 
factors tapping positive affect and negative affect.  All of these measures have been validated for 
use in adolescent smokers and shown to be sensitive to smoking abstinence effects (Colby et al., 
2010) and effects of VLNC cigarettes (Kassel, Evatt, et al., 2007). Each participant will rate how 
much he/she enjoyed the cigarette they just smoked using the Cigarette Evaluation Scale, 
which assesses subjective characteristics such as enjoyment on a 7-point Likert scale (CES; 
(Arger et al., 2017; Cappelleri et al., 2007). Participants will report their perceptions of the health 
risks associated with both their usual brand and their study cigarette brand using the Perceived 
Health Risks Assessment (Hatsukami et al., 2010).  
f. Behavioral Economic Assessments of Reinforcing Efficacy. The Cigarette Purchase Task 
(Jacobs & Bickel, 1999; MacKillop et al., 2008) will be used to assess demand for both their 
usual brand cigarette which may change as a function of VLNC exposure (Smith, et al., 2016). 
Participants will be asked how many cigarettes of their usual brand and their study cigarette they 


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would purchase per day at increasing costs per pack, starting with how many they would 
consume when cigarettes are free (zero price). This measure has been validated for use in 
adolescents in a study directed by primary mentor Colby (Murphy, MacKillop, Tidey, Brazil, & 
Colby, 2011). Participants will also complete the CPT for their study cigarette. Similarly, the 
Juul Purchase task will be administered to those participants who report past 30-day Juul use.. 
Delay discounting is a measure of impulsivity which asks participants to make hypothetical 
choices between a fixed amount of money now and larger amount of money after a delay. This 
measure has been widely used in substance abuse research, and correlates with smoking status in 
adolescent smokers (Quisenberry et al., 2016) and is included for descriptive and exploratory 
purposes.  The Experimental Tobacco Marketplace (Bickel et al., 2018) will be used to assess 
effects of cigarette price on consumption of cigarettes and alternative products. In the task, 
participants are shown a virtual marketplace of tobacco products, including both noncombustible 
and combustible alternative products, as well as cigarettes. Participants are instructed to make 
hypothetical purchases of tobacco products that they would use for the week. Participants are 
given an experimental budget of money which can be used in the marketplace and are instructed 
that they can ‘save’ unspent money. The costs for the other products will reflect average prices in 
RI and will not change across conditions. For each iteration of the task, participants will receive 
account balances approximately equal to the money they would spend on three days’ worth of 
tobacco. They can purchase as many or few tobacco products as their account balance allows 
(only packaged products, e.g., whole cigarette packages, can be purchased). For example, if a 
participant smokes a pack of cigarettes each day, then she is spending ~$10.00 per day on 
tobacco, as this is the price of a pack of cigarettes in RI. During each iteration of the ETM task, 
she will have an account balance of $30.00 to spend on tobacco for a 3-day period. The 
hypothetical cigarette available will be their study cigarette. Across trials, the price of cigarettes 
increases while the prices of alternative products remain the same. On each trial, participants can 
choose to purchase any combination of tobacco products that they choose, as long as they stay 
within their experimental budget. Across four trials, the price of cigarettes will increase ($0.12, 
$0.25, $0.50, and $1.00, $2.00, $4.00, $8.00, and $16.00 per cigarette). The following 
tobacco/nicotine products will be available on the ETM: 
a) Study cigarettes – menthol OR non-menthol flavors depending preference; 
b) Little cigars (e.g., Winchester, Cheyenne) – menthol and tobacco flavors; 
c) Cigarillos (e.g., Black and Mild; Swisher Sweets) – menthol and tobacco flavors; 
d) E-cigarettes (e.g., cigarette-like systems such as Juul and tank-like systems such as 
NJOY prefilled tanks) – menthol and tobacco flavors;  
e) Snus (e.g., Camel and Marlboro snus) – menthol and tobacco flavors; 
f) Conventional smokeless tobacco products (e.g., Copenhagen) – menthol and tobacco 
flavors; 
g) Non-prescription medicinal nicotine (e.g., 2mg and 4mg nicotine gum; 7, 14 and 21 mg 
nicotine patch) – menthol and regular flavors; 
This task will first be administered at Baseline 2 following acute cigarette exposure to assess 
intentions to purchase alternative products following initial exposure to study cigarettes, and at 
Week 4 to assess effects of extended exposure to study cigarettes on intentions to purchase 


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alternative products across groups. This measure will be compared with patterns of product use 
generated from EMA assessment in the field.  
g. Laboratory Measures schedule (Table 1) 
 
 
Measure 
Screening 
Baseline 1 
Baseline 2 Week 1 
Week 2 
Week 3 
Week 4 
Demographics/Tobacco Use 
History and Exposure 
X 
 
  
  
  
  
 
Brief Medical History  
X 
 
 
  
  
 
 
Smoking Stages of Change 
X 
 
 
 
 
 
X 
MINI Suicide Subscale 
X 
 
 
 
 
 
 
Pregnancy Test 
X 
X 
X 
X 
X 
X 
X 
Timeline Follow Back (TLFB) 
X 
 
 X 
X 
X  
X 
X 
Breath Carbon Monoxide  
X 
 
X 
X 
X 
X 
X 
Dependence (mFTQ) 
 
X 
 
 
X 
 
X 
ASTQ Respiratory Questionnaire 
 
 
X 
 
X 
 
X 
Delay Discounting 
 
X 
 
 
 
 
X 
Environmental Tobacco 
Smoke/Social Influences 
 
X 
 
 
 
 
 
Depressive Symptoms (CESD) 
 
X 
 
 
 
 
 
Quit Intentions Questionnaire 
 
 
X 
X 
X 
X 
X 
Health Changes Questionnaire 
 
X 
X 
X 
X 
X 
Craving (Brief QSU) (pre/post cig) 
 
X 
 
X 
 
 
Withdrawal (MNWS) (pre/post 
cig) 
 
X 
 
X 
 
 
Affect (PANAS) (pre/post cig) 
 
X 
 
X 
 
 
Cigarette Evaluation Scale (post 
cig) 
 
X 
 
X 
 
 


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Perceived Health Risks (UB) 
 
X 
 
 
 
 
Perceived Health Risks (Study) 
 
X 
 
 
 
X 
Cigarette Purchase Task (UB) 
 
X 
 
X 
 
X 
Cigarette Purchase Task (Study) 
 
X 
 
X 
 
X 
Juul Purchase Task 
 
X 
 
X 
 
X 
Experimental Tobacco 
Marketplace 
 
X 
 
 
 
X 
Respiratory Health Outcomes 
(FEV) 
 
X 
 
 
 
X 
Urine NNAL/TNEs 
 
  
X 
  
  
 
X 
Debriefing Questionnaire 
 
 
 
 
 
 
X 
 
 
12. 30-Day Follow Up Call: Participants will be contacted after 30 days by telephone to assess current 
tobacco use, quit status, and to assess overall safety. Participants who have not quit will be advised to do 
so. 
13. Compensation: The following payment schedule for in-person session attendance will be used: 
a.  $25 for BL1; $50 for BL2; $15 each for W1 and W3, $50 each for W2 and W4. If a participant 
comes in for the in-person screening but is ineligible, they will still be paid $25 for their time 
provided they meet the CO or NicAlert inclusion criteria. Participants will be paid $25.00 per 
day that they ineracted with the phone accorign to the intrsucrions given in Weeks 1, , and 5; in 
Weeks 3 and 4, they that theycan  complete at least one EMA assessment for $2.00 daily for a 
possible maximum total of $17370. A completion bonus of $75 will be given to participants who 
attend all laboratory sessions. A bonus payment of $50 will be paid to participants who complete 
80% or more of their EMA surveys. Participants will be eligible to earn up to $40 in random 
bonuses if they interact with the app  A completion bonus of $75 will be given to participants 
who attend all laboratory sessions. A maximum of $20 possible compensation is available for 
returned cigarettes. Bonus payments are included because study procedures involve considerable 
time commitments and five sessions, thus attrition is a potential issue. Participants are free to 
discontinue at any time and will receive full compensation for the sessions they complete. The 
total possible compensation will be $523420. Participants will be paid using ClinCard.  
 
14. Risks and Benefits. Potential risks and benefits for participants 
a. Subjective discomfort (survey questionnaires): The protocol includes survey questions about medical 
history, drug and alcohol use, and questionnaires about mood.  Answering these personal questions 
could make the participant feel uncomfortable.  However, the questions we ask are commonly used 
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in research and clinical practice and the participant will not be required to answer any question 
he/she is not comfortable answering. Answers to these questions will be kept confidential. 
b. Subjective discomfort (biological samples): The participant may feel some discomfort about 
providing breath and/or urine samples for analysis. This probability of this risk is low, based on our 
past experience using these measures.  Interactions with participants will be conducted in private 
rooms. Urine sample collection is private (i.e., unsupervised); the participant will provide the sample 
in a private bathroom within the laboratory suite. Discomfort will be further minimized by 
employing trained staff to conduct all procedures and emphasizing that study participation is 
voluntary.  
c. Breach of Confidentiality: A risk of the interview is loss of privacy if other people find out the 
results. We will work to ensure that the participant’s confidentiality is kept. Research data without 
identifiers will be maintained in a locked file cabinet and on password-protected computers in the 
research staff workplace, with only code numbers identifying participants. Study consent forms and 
the linkage between the participants’ names and codes will be stored in a locked file cabinet in the 
Contact PI’s office, on a separate floor of the building. 
d. Smoking Cigarettes: The participant will smoke a single cigarette in the laboratory on 2 separate 
occasions.  Study participation is restricted to established daily smokers so that this limited exposure 
will present no increased risk of harm than their current smoking status incurs.   
e. Smoking Withdrawal: The participant may experience some discomfort related to nicotine 
withdrawal as a function of switching to VLNC cigarettes over an extended period.  Symptoms can 
include irritability, frustration, anxiety, depressed mood or sadness, desire or craving to smoke, 
difficulty concentrating, and increased appetite or hunger. These feelings can be uncomfortable but 
they are normal, temporary, and usually mild. Participants are not prohibited from using other 
nicotine-containing products, which would prevent or reduce these symptoms. 
f. Coercion: Coercion is a possible risk due to monetary compensation for participation; however, the 
likelihood of this risk is low because the compensation is commensurate with time and effort 
required for this study.   
g. Compensatory smoking: The possibility exists that use of VLNC cigarettes over an extended period 
may lead to compensatory smoking (i.e., more intense or frequent smoking in an attempt to derive 
more nicotine from study cigarettes). However, research to date indicates that this outcome is 
unlikely. We will monitor the participant’s weekly cigarette use and CO levels to evaluate the extent 
to which compensatory smoking is occurring, and will make changes to the protocol to reduce this as 
necessary. 
h. Lower perceived risk of harm: The possibility exists that use of VLNC cigarettes over an extended 
period may lead to perceiving a reduced risk associated with VLNC cigarettes; we will debrief the 
participant post-study on risks associated with smoking. All cigarettes are harmful to a person’s 
health. Smoking can lead to severe or fatal medical problems including heart disease, respiratory 
(breathing) problems and diseases, cancer, diabetes, and other health risks.  The study cigarettes do 
not provide less risk than the participant’s usual brand cigarette. 
 
15. Adverse Events 
a. Collection and reporting of AEs and SAEs 
While participating in the trial, adverse events and changes in medications will be assessed at 
every study visit and carbon monoxide will be obtained.  Medical events will typically be 


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identified during the administration of the Health Changes Questionnaire. Other events may be 
identified by spontaneous reports during non-scheduled assessments.  
b. Questionnaire items that will be reviewed: 
Health Changes Questionnaire  
1) Have you noticed that your physical health or mental health have gotten worse since your 
last visit? If Yes, please describe. 
2) Have you had any changes in medication since your last visit? If Yes, please describe:  
3) Since your last visit, have you gone to the doctor? If Yes, please describe:  
4) Since your last visit, have you gone to the hospital? If Yes, please describe: 
No new AE required if one or more conditions below are met and the description does not 
otherwise meet the definition of an AE. 
1) Existing AE already open for reported symptom 
2) Pre-existing condition without increase in severity or frequency of symptoms (brief 
medical history will be updated if not previously reported). 
3) Received preventative or follow-up medical care. 
4) Other (explain). 
For the participant’s protection, participants will be withdrawn immediately from the 
study if any of the following occur: 
1) Cardiovascular disease (CVD) event: Typically includes MI (heart attack), PTCA 
(angioplasty/stenting), bypass surgery, stroke, peripheral vascular disease (arterial 
blockages in arms or legs leading to procedure or surgery).  Less common CVD problems 
would be new cardiac arrhythmias (e.g., new atrial fibrillation) or new valvular disease 
(e.g., mitral or aortic regurgitation). 
2) DVT/PE (deep vein thrombosis/pulmonary embolism, i.e., blood clots in the venous 
system). 
3) Suicide Attempt:  A participant will be withdrawn if he/she attempts suicide at any time 
during participation in the study. 
4) Psychiatric Hospitalization: A participant will be withdrawn if he/she is hospitalized for 
psychiatric reasons at any time during participation in the study. 
5) Pregnancy: If a participant indicates she is pregnant or has a positive pregnancy test at 
any session, she will be withdrawn from the study, and this event will remain open until 
delivery.  At that time the license medical monitor will contact the participant to ask a 
few questions about the baby’s health and will update the open ‘Adverse Event Form’.   
The following will be monitored and can lead to the participant being withdrawn by the PI 
or Licensed Medical Monitor: 
1) Expired breath Carbon Monoxide >80 ppm 
2) Any hospitalization or debilitation in which participation in the study could be 
detrimental to the recovery process. This will be self-reported by the participant and will 


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be reviewed by the MPIs and medical monitor to determine whether continued 
participation in the study is appropriate.   
3) If a participant is behaving in an inappropriate or threatening manner, admits to lying 
about eligibility criteria, including omitting previous medical diagnoses and medications, 
is participating in other smoking research studies that could affect the primary outcome 
measures, does not follow study instructions, etc., then an MPI can withdraw him/her 
from the study at her discretion.  
Serious adverse events (SAEs): Information about all serious adverse events will be collected 
and recorded on a standard Serious Adverse Event Report Form. To ensure participant safety, 
each study-related serious adverse event will also be reported to the IRB office within 72 hours 
of learning of its occurrence. A serious adverse event is an undesirable sign, symptom or medical 
condition which: 
1.is fatal or life-threatening 
2. requires or prolongs hospitalization 
3. results in persistent or significant disability/incapacity 
4. constitutes a congenital anomaly or a birth defect 
5. is medically significant, in that it may jeopardize the subject and may require medical 
or surgical intervention to prevent one of the outcomes listed above. 
A hospitalization would not be considered to be a serious adverse event if it was elective, pre-
planned, or for a pre-existing condition that did not worsen since starting the study; or for 
treatment on an outpatient basis for an event not fulfilling any of the definitions of serious given 
above and not resulting in hospital admission.  
Any SAE occurring after the participant has signed the informed consent and until the participant 
has stopped study participation must be reported. Investigator responsibilities for notification of 
SAEs are described above. 
c. Management of SAEs and Other Study Risks 
The medical monitor will review all AEs. A study participant may be discontinued from the 
study if a medical monitor and/or an MPI determines it is the best decision in order to protect the 
safety of a participant. In the event that a participant either withdraws from the study or the 
investigator decides to discontinue a participant due to an AE/SAE, the participant will have 
appropriate follow-up medical monitoring. The participant experiencing an AE/SAE will be 
followed until the problem resolves, stabilizes, or is clearly unrelated to the study cigarettes. Any 
AE that remains open will be reviewed and closed during the 30-day follow-up phone call.   
d.  Medical Monitor Contact information: 
Robert Swift, M.D., Ph.D. 
Email: robert_swift_md@brown.edu  


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Phone: 401-863-6643  
Patricia Cioe, Ph.D., R.N.P. 
Email: patricia_cioe@brown.edu 
Phone: 401-863-6638 
16. Research Involving Minors. Adolescents who meet initial eligibility criteria during the phone screen, 
and who remain interested after hearing a more detailed study description, will provide contact 
information for their parent/guardian (minors only) so that parental informed consent can be obtained; 
18-19 year olds can provide their own consent. Minors will not be scheduled without research staff first 
talking directly to a parent/guardian. Research staff will call the parent or guardian, describe the study, 
and answer any questions. Consent forms will be mailed or emailed to the parent (with a copy to 
keep/option to print for their records). Adolescents will then be scheduled for the initial in-person 
session and transportation arranged if necessary. The adolescent (if a minor) will bring the signed 
consent form to the in-person screening session, or the RA will ensure that the participants’ parent has 
electronically signed the consent form. Participants will complete informed assent (minors)/consent at 
the in-person screening session. A researcher will review the assent/consent form in detail, review all 
study procedures, and answer questions. Participants will receive a copy of their consent/assent form. 
Participants over 18 will need to provide an ID that indicates their age in order to participate. 
 
 


H:\Project SIREN\Clinical Trials Results Reporting\OTHER DOCS\Codebook_Highlighted.Changes.docx 
 
Morning Report 
First Random Prompt 
Report of the Day (FR) 
Random Prompt Report 
(RR) 
Usual Brand Smoke 
Report (UR) 
Study Cig Smoke 
Report (SR.) 
Alternative Product 
Report (AR) 
Item 
Response Format 
Logic 
MR1 
 
 
 
 
 
What time did you go to bed last night? 
Enter hour (text entry) 
 
MR1A 
 
 
 
 
 
What time did you wake up today? 
Enter hour (text entry) 
 
MR1B 
 
 
 
 
 
Please rate how well you slept. 
1 Not well at all  
to  
10 Very well 
(categorical) 
 
MR2 
 
 
 
 
 
Think about the time since the last report 
you completed yesterday and when you 
went to sleep. Did you forget to enter 
any smoke reports? 
0=No 
1=Yes 
If “Yes”, proceed 
to MR2B. If 
“No”, skip to 
MR3. 
MR2A 
 
 
 
 
 
What time did you last use tobacco? 
1=15 mins ago 
2=30 mins ago 
3=45 mins ago 
4=1 hour ago 
5=2 hours ago 
6=3 or more hours ago 
 
MR2B 
 
 
 
 
 
What did you use? Select all that apply 
 
 
1=Non-study cigarette 
2=Study cigarette 
3= E-cigarette/vape 
4= Cigar/cigarillo (Black & 
Mild, Swisher Sweets) 
5= Smokeless tobacco (chew, 
dip, snuff, snus) 
6=Hookah 
7=Pipe (tobacco) 
 
MR3 
 
 
 
 
 
How many study cigarettes did you 
smoke yesterday? 
Numeric (integer) entry (0-
200) 
 
MR4 
 
 
 
 
 
How many non-study cigarettes did you 
smoke yesterday? 
Numeric (integer) entry (0-
200) 
 


H:\Project SIREN\Clinical Trials Results Reporting\OTHER DOCS\Codebook_Highlighted.Changes.docx 
 
Morning Report 
First Random Prompt 
Report of the Day (FR) 
Random Prompt Report 
(RR) 
Usual Brand Smoke 
Report (UR) 
Study Cig Smoke 
Report (SR.) 
Alternative Product 
Report (AR) 
Item 
Response Format 
Logic 
MR5 
 
 
 
 
 
Select all alternative tobacco products 
you used yesterday. 
0=None 
1= E-cigarette/vape 
2= Cigar/cigarillo  (Black & 
Mild, Swisher Sweets) 
3=Smokeless tobacco (chew, 
dip, snuff, snus) 
4=Hookah 
5=Pipe (tobacco) 
Each endorsed 
choice brings up 
data entry for 
quantity (6A-6E) 
MR6A 
 
 
 
 
 
About how many puffs of E-
cigarette/vape do you think you took? 
Numeric (integer) entry (0-
200) 
Show only if “E-
cigarette/vape” is 
selected in MR5 
MR6A1 
 
 
 
 
 
Did you finish a Juul pod or refill your 
vape tank? 
0=No 
1=Yes 
Show only if “E-
cigarette/vape” is 
selected in MR5 
MR6B 
 
 
 
 
 
About how many cigars did you smoke? 
Numeric (integer) entry (0-
200) 
Show only if 
“Cigar/cigarillo) 
is selected in 
MR5 
MR6C 
 
 
 
 
 
About how much smokeless tobacco did 
you use? 
Text entry 
Show only if 
“smokeless 
tobacco” is 
selected in MR5 
MR6D 
 
 
 
 
 
About how much hookah did you use? 
Text entry 
Show only if 
“hookah” is 
selected in MR5 
MR6E 
 
 
 
 
 
About how much pipe (tobacco) did you 
use? 
Text entry 
Show only if 
“pipe (tobacco)” 
is selected in 
MR5 
 
 
 
 
 
 
 
 
 


H:\Project SIREN\Clinical Trials Results Reporting\OTHER DOCS\Codebook_Highlighted.Changes.docx 
 
Morning Report 
First Random Prompt 
Report of the Day (FR) 
Random Prompt Report 
(RR) 
Usual Brand Smoke 
Report (UR) 
Study Cig Smoke 
Report (SR.) 
Alternative Product 
Report (AR) 
Item 
Response Format 
Logic 
 
FR0A 
RR0A 
 
 
 
Have you used tobacco in the last 30 
minutes? 
0=No 
1=Yes 
If “Yes”, proceed 
to R0B. If “No”, 
proceed to R1. 
 
FR0B 
RR0B 
 
 
 
Did you do a smoke report? 
0=No 
1=Yes 
If “Yes”, proceed 
to R1. If “No”, 
proceed to R0C. 
 
FR0C 
RR0C 
 
 
 
Please do a smoke report now. 
(Instruction) 
All – random 
survey end. 
 
FR1 
 
 
 
 
Think about the time since you woke up 
this morning. Did you forget to enter any 
smoke reports? 
0=No 
1=Yes 
If “Yes”, proceed 
to FR1B. If 
“No”, proceed to 
FR2. 
 
 
RR1 
 
 
 
Think about the time since you last 
completed a report. Did you forget to 
enter any cigarette or tobacco reports? 
0=No 
1=Yes 
If “Yes”, proceed 
to R1B. If “No”, 
proceed to R2. 
 
FR1A 
RR1A 
 
 
 
What time did you last use tobacco? 
1=15 mins ago 
2=30 mins ago 
3=45 mins ago 
4=1 hour ago 
5=2 hours ago 
6=3 or more hours ago 
 
 
FR1B 
RR1B 
 
 
 
What did you use? (Select all that apply) 
1=Non-study cigarette 
2=Study cigarette 
3= E-cigarette/vape 
4= Cigar/cigarillo (Black & 
Mild, Swisher Sweets) 
5= Smokeless tobacco (chew, 
dip, snuff, snus) 
6=Hookah 
7=Pipe (tobacco) 
IF 3,4 OR 5 show 
FR1C/R1C 
(flavor Q) 


H:\Project SIREN\Clinical Trials Results Reporting\OTHER DOCS\Codebook_Highlighted.Changes.docx 
 
Morning Report 
First Random Prompt 
Report of the Day (FR) 
Random Prompt Report 
(RR) 
Usual Brand Smoke 
Report (UR) 
Study Cig Smoke 
Report (SR.) 
Alternative Product 
Report (AR) 
Item 
Response Format 
Logic 
 
FR1C 
RR1C 
 
 
 
What flavor was your product? 
1=Tobacco 
2=Menthol/Mint 
3=Fruit 
4=Candy 
5=Vanilla 
6=Desserts/Sweets 
9=Other 
 
 
 
 
 
 
 
Think about how you are feeling right 
now. Do you feel… 
 (NWQ header) 
 
 
FR2 
RR2 
 
 
 
Desire or craving to smoke a cigarette? 
0=None 
1=Slight 
2=Mild 
3=Moderate 
4=Severe 
 
 
FR3 
RR3 
 
 
 
Angry, irritable, or frustrated? 
 
0=None 
1=Slight 
2=Mild 
3=Moderate 
4=Severe 
 
 
FR4 
RR4 
 
 
 
Anxious or nervous? 
0=None 
1=Slight 
2=Mild 
3=Moderate 
4=Severe 
 
 
FR5 
RR5 
 
 
 
Difficulty concentrating? 
 
0=None 
1=Slight 
2=Mild 
3=Moderate 
4=Severe 
 


H:\Project SIREN\Clinical Trials Results Reporting\OTHER DOCS\Codebook_Highlighted.Changes.docx 
 
Morning Report 
First Random Prompt 
Report of the Day (FR) 
Random Prompt Report 
(RR) 
Usual Brand Smoke 
Report (UR) 
Study Cig Smoke 
Report (SR.) 
Alternative Product 
Report (AR) 
Item 
Response Format 
Logic 
 
FR6 
RR6 
 
 
 
Impatient or restless? 
0=None 
1=Slight 
2=Mild 
3=Moderate 
4=Severe 
 
 
FR7 
RR7 
 
 
 
Hungrier than usual? 
 
0=None 
1=Slight 
2=Mild 
3=Moderate 
4=Severe 
 
 
FR8 
RR8 
 
 
 
 Depressed? 
 
0=None 
1=Slight 
2=Mild 
3=Moderate 
4=Severe 
 
 
FR9 
RR9 
 
 
 
Happy? 
 
 
0=Not at all 
1=A little 
2=Moderately 
3=Quite a bit 
4=Extremely 
 
 
FR10 
RR10 
 
 
 
Stressed? 
0=None 
1=Slight 
2=Mild 
3=Moderate 
4=Severe 
 
 
FR11 
RR11 
 
 
 
Bored? 
0=None 
1=Slight 
2=Mild 
3=Moderate 
4=Severe 
 
 
 
 
 
 


H:\Project SIREN\Clinical Trials Results Reporting\OTHER DOCS\Codebook_Highlighted.Changes.docx 
 
Morning Report 
First Random Prompt 
Report of the Day (FR) 
Random Prompt Report 
(RR) 
Usual Brand Smoke 
Report (UR) 
Study Cig Smoke 
Report (SR.) 
Alternative Product 
Report (AR) 
Item 
Response Format 
Logic 
 
FR12 
RR12 
 
 
 
Where are you now? 
0 Home/Dorm 
1 Other's Home/Dorm 
2 Work/School 
3 Party/Bar/Club 
4 Public Place (Outside) 
5 Public Place (Inside) 
6 Car/Bus/Other 
Transportation 
99 Elsewhere 
 
 
FR12O RR12O 
 
 
 
You chose other location.  Please 
describe where you are now: 
Text entry 
Show if 
‘Elsewhere’ is 
selected in R12 
 
FR13 
RR13 
 
 
 
Who are you with? (Select all that apply) 
1 Friend(s)  
2 Parent(s) 
3 Sibling(s) 
4 Boy/girlfriend 
5 Teacher 
6 Co-workers 
7 Other persons 
0 No one, I was alone 
 
 
FR14 
RR14 
 
 
 
Are any of these people using tobacco 
products? (Select all that apply) 
1=Cigarettes 
3=E-cigarette/vape 
4=Cigar/cigarillo 
5=Smokeless tobacco 
6=Hookah 
7=Pipe (tobacco) 
0=No other people are using 
tobacco 
Do not show if 
only ‘No One’ is 
selected in R13 
 
(code 2 
intentionally 
skipped “study 
cig” to keep 
values consistent 
with similar 
fields) 


H:\Project SIREN\Clinical Trials Results Reporting\OTHER DOCS\Codebook_Highlighted.Changes.docx 
 
Morning Report 
First Random Prompt 
Report of the Day (FR) 
Random Prompt Report 
(RR) 
Usual Brand Smoke 
Report (UR) 
Study Cig Smoke 
Report (SR.) 
Alternative Product 
Report (AR) 
Item 
Response Format 
Logic 
 
FR15 
RR15 
 
 
 
What are you doing? (Select all that 
apply) 
 
 
1 Drinking Alcohol 
2 Using Marijuana 
3 Using other Drugs 
4 Socializing 
5 Exercising/Walking/Sports 
6 Studying/Reading/Working 
7 
Game/Movie/Video/TV/Music 
8 Social Media/Texting/On 
Phone 
9 Resting 
10 Eating/Drinking 
99 Other 
 
 
FR15A RR15A 
 
 
 
You chose Eating/Drinking.  What are 
you eating or drinking? Select all that 
apply. 
1 Meal 
2 Snack 
3 Caffeine drink 
9 Other beverage 
Show if 
‘Eating/drinking’ 
is selected in R15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AR0 
What type of product did you use 
1= E-cigarette/vape 
2=Cigar/cigarillo (Black & 
Mild, Swisher Sweets) 
3=Smokeless tobacco (chew, 
dip, snuff, snus) 
4=Hookah 
5=Pipe (tobacco) 
IF 1,2 OR 3 show 
AR1B (flavor Q) 
 
 
 
UR1 
SR1 
AR1 
What time did you last use 
[PRODUCT]? 
1=15 mins ago 
2=30 mins ago 
3=45 mins ago 
4=1 hour ago 
5=2 hours ago 
6=3 or more hours ago  
Should be piped 
text 
To replace 
[PRODUCT] 
from item AR0. 


H:\Project SIREN\Clinical Trials Results Reporting\OTHER DOCS\Codebook_Highlighted.Changes.docx 
 
Morning Report 
First Random Prompt 
Report of the Day (FR) 
Random Prompt Report 
(RR) 
Usual Brand Smoke 
Report (UR) 
Study Cig Smoke 
Report (SR.) 
Alternative Product 
Report (AR) 
Item 
Response Format 
Logic 
 
 
 
 
 
AR1A 
What flavor was your product? 
1=Tobacco 
2=Menthol/Mint 
3=Fruit 
4=Candy 
5=Vanilla 
6=Desserts/Sweets 
9=Other 
 
 
 
 
 
 
 
Think about how you felt just before 
[SMOKED/VAPED/you used tobacco]. 
Did you feel… 
IF FIRST REPORT WITHIN 
A 2 HOUR BLOCK (i.e. the 
long survey); ELSE go to 
UT1/ST1/AT1 
Should be piped 
text 
for [tobacco 
PRODUCT] 
from item AR0. 
 
 
 
UR2 
SR2 
AR2 
Desire or craving to smoke a cigarette? 
0=None 
1=Slight 
2=Mild 
3=Moderate 
4=Severe 
 
 
 
 
UR3 
SR3 
AR3 
Angry, irritable, or frustrated? 
 
0=None 
1=Slight 
2=Mild 
3=Moderate 
4=Severe 
 
 
 
 
UR4 
SR4 
AR4 
Anxious or nervous? 
0=None 
1=Slight 
2=Mild 
3=Moderate 
4=Severe 
 
 
 
 
UR5 
SR5 
AR5 
Difficulty concentrating? 
0=None 
1=Slight 
2=Mild 
3=Moderate 
4=Severe 
 


H:\Project SIREN\Clinical Trials Results Reporting\OTHER DOCS\Codebook_Highlighted.Changes.docx 
 
Morning Report 
First Random Prompt 
Report of the Day (FR) 
Random Prompt Report 
(RR) 
Usual Brand Smoke 
Report (UR) 
Study Cig Smoke 
Report (SR.) 
Alternative Product 
Report (AR) 
Item 
Response Format 
Logic 
 
 
 
UR6 
SR6 
AR6 
Impatient or restless 
 
0=None 
1=Slight 
2=Mild 
3=Moderate 
4=Severe 
 
 
 
 
UR7 
SR7 
AR7 
Hungrier than usual? 
 
0=None 
1=Slight 
2=Mild 
3=Moderate 
4=Severe 
 
 
 
 
UR8 
SR8 
AR8 
 Depressed? 
 
0=None 
1=Slight 
2=Mild 
3=Moderate 
4=Severe 
 
 
 
 
UR9 
SR9 
AR9 
Happy? 
 
0=Not at all 
1=A little 
2=Moderately 
3=Quite a bit 
4=Extremely 
 
 
 
 
UR10 
SR10 
AR10 
Stressed? 
0=None 
1=Slight 
2=Mild 
3=Moderate 
4=Severe 
 
 
 
 
UR11 
SR11 
AR11 
Bored? 
0=None 
1=Slight 
2=Mild 
3=Moderate 
4=Severe 
 
 
 
 
UR12 
SR12 
AR12 
Where were you when you used 
tobacco? 
0 Home/Dorm 
1 Other's Home/Dorm 
 


H:\Project SIREN\Clinical Trials Results Reporting\OTHER DOCS\Codebook_Highlighted.Changes.docx 
 
Morning Report 
First Random Prompt 
Report of the Day (FR) 
Random Prompt Report 
(RR) 
Usual Brand Smoke 
Report (UR) 
Study Cig Smoke 
Report (SR.) 
Alternative Product 
Report (AR) 
Item 
Response Format 
Logic 
2 Work/School 
3 Party/Bar/Club 
4 Public Place (Outside) 
5 Public Place (Inside) 
6 Car/Bus/Other 
Transportation 
99 Elsewhere 
 
 
 
UR12O 
SR12O 
AR12O 
You chose other location.  Please 
describe where you were: 
Text entry 
Show if 
_R12=Elsewhere 
 
 
 
UR13 
SR13 
AR13 
Who were you with when you used 
tobacco? Select all that apply. 
1 Friend(s)  
2 Parent(s) 
3 Sibling(s) 
4 Boy/girlfriend 
5 Teacher 
6 Co-workers 
7 Other persons 
0 No one, I was alone 
 
 
 
 
UR14 
SR14 
AR14 
Were any of these people using tobacco 
products? (Select all that apply) 
1=Cigarettes 
3=E-cigarette/vape 
4=Cigar/cigarillo 
5=Smokeless tobacco 
6=Hookah 
7=Pipe (tobacco) 
0=No other people were using 
tobacco 
Do not show if 
‘No one’ is 
selected in _R13 
 
 
 
UR15 
SR15 
AR15 
What were you doing just before you 
used tobacco? Select all that apply. 
 
1 Drinking Alcohol 
2 Using Marijuana 
3 Using other Drugs 
4 Socializing 
5 Exercising/Walking/Sports 
6 Studying/Reading/Working 
 
 
 
 


H:\Project SIREN\Clinical Trials Results Reporting\OTHER DOCS\Codebook_Highlighted.Changes.docx 
 
Morning Report 
First Random Prompt 
Report of the Day (FR) 
Random Prompt Report 
(RR) 
Usual Brand Smoke 
Report (UR) 
Study Cig Smoke 
Report (SR.) 
Alternative Product 
Report (AR) 
Item 
Response Format 
Logic 
7 
Game/Movie/Video/TV/Music 
8 Social Media/Texting/On 
Phone 
9 Sleeping 
10 Eating/Drinking 
11 Other 
 
 
 
UR15A 
SR15A 
AR15A 
You chose Eating/Drinking.  What were 
you eating or drinking? Select all that 
apply. 
 
1 Meal 
2 Snack 
3 Caffeine drink 
9 Other beverage 
Show if 
‘Eating/drinking’ 
is selected in 
_R15 
 
 
 
 
 
 
Think about how you felt just after you 
used [tobacco]. 
 
Should be piped 
text 
for [tobacco 
PRODUCT] 
from item AR0. 
 
 
 
UR16 
SR16 
AR16 
Did you feel a desire or craving to smoke 
a cigarette?  
0=None 
1=Slight 
2=Mild 
3=Moderate 
4=Severe 
 
 
 
 
UR17 
SR17 
AR17 
Thinking about the [product] you just 
used. 
 
How pleasurable was your [product]? 
 
0=Not at all 
1=A little 
2=Moderately 
3=Quite a bit 
4=Extremely 
Pipe in text to 
replace [product] 
from item AR0. 
depending on 
product used. 
 
 
 
UR18 
SR18 
AR18 
Thinking about the [product] you just 
used. 
 
How satisfying was your [product]? 
 
0=Not at all 
1=A little 
2=Moderately 
3=Quite a bit 
4=Extremely  
Pipe in text to 
replace [product] 
from item AR0. 
depending on 
product used. 


H:\Project SIREN\Clinical Trials Results Reporting\OTHER DOCS\Codebook_Highlighted.Changes.docx 
 
Morning Report 
First Random Prompt 
Report of the Day (FR) 
Random Prompt Report 
(RR) 
Usual Brand Smoke 
Report (UR) 
Study Cig Smoke 
Report (SR.) 
Alternative Product 
Report (AR) 
Item 
Response Format 
Logic 
MRT1 
FRT1 
RRT1 
URT1 
SRT1 
ART1 
Thank you for reporting this! 
(Instruction) 
 
End of all reports 
 
 
 

ICF_004.pdf: 
Cover page for Adolescent Assent Form 
NCT03860077 
Grant number: R01DA047356 
Grant Title: Impact of Nicotine Reduction on Adolescent Cigarette Use, Alternative Tobacco Use, and 
Harm From Tobacco 
Consent Document Approval Date: 9/28/20 


 
 
1 
                         
Assent Ver. 9.28.20 
 
BROWN UNIVERSITY 
ASSENT FOR RESEARCH PARTICIPATION 
 
Impact of nicotine reduction on adolescent cigarette use, alternative tobacco use,  
and harm from tobacco 
 
 Version 10, 9.28.20 
 
KEY INFORMATION: 
 
You are invited to take part in a Brown University research study. Your participation is voluntary. 
 
• 
PURPOSE: To look at the effect of different levels of nicotine in cigarettes on teen smoking 
behavior. 
• 
PROCEDURES: We will ask you to come to our lab a total of 4 times (including today), to 
complete two virtual check-ins via Zoom, and complete several questionnaires each day on your 
smartphone for 5 weeks. You will also be asked to switch from using your usual brand cigarette 
to using a study cigarette that we will provide to you. You will be asked for a breath sample, 
urine sample, and pregnancy test, if able to get pregnant. You will also be asked to complete a 
questionnaire about your experiences related to COVID-19. 
• 
TIME INVOLVED: You will be in this study for 5 weeks and completing the surveys will take up 
to 10-15 minutes per day. Lab visits will take between 45 minutes and 2 hours. Virtual check-ins 
will take up to 40 minutes. 
• 
COMPENSATION: You will receive up to $523 for your time and effort, depending on how many 
surveys you respond to, cigarettes you return, and lab/virtual visits you complete.  
• 
RISKS: Some of the questions may be about drug use or mental health, but you are free not to 
answer any questions you do not wish to answer. You may also experience nicotine withdrawal, 
but the study does not restrict your use of other nicotine-containing products that aren’t 
cigarettes. If able to get pregnant and become pregnant during the study, you may experience 
emotional distress and you may be in need of a medical professional. 
• 
BENEFITS: There are no direct benefits to you from participating in this research study. 
 
 
1. Researchers:  
Questions about the study should be directed to Dr. Rachel Cassidy at 401-863-6621 or Dr. Suzanne 
Colby at 401-863-6655.  Questions about the rights of a research participant should be directed to 
the Human Research Protections Program at 401-863-3050.  
 
2. What is this study about? 
This study is investigating the effects of different levels of nicotine in cigarettes on teen tobacco use, 
health, attitudes, mood and other outcomes.  This study is not going to ask you to quit smoking, 
or help you quit smoking.  You are being invited to take part in this research study because you 
are a teen smoker.  
 
3. What will I be asked to do? 
If you agree to participate, you will be asked to attend a total of six individual sessions (including 
today). If you are eligible, we will start your first session (Baseline 1 [BL1]) today after this 


 
 
2 
                         
Assent Ver. 9.28.20 
 
screening session. You will be asked to attend five more sessions. There will be seven days in 
between each session. We call these sessions: Baseline 2 (BL2, a lab visit), Week 1 (W1, a virtual 
check-in session), Week 2 (W2, a lab visit), Week 3 (W3, a virtual check-in session), and Week 4 
(W4, a lab visit). This study can be completed in five weeks. Lab sessions will occur in our research 
lab. Virtual check-in sessions will be conducted remotely via Zoom.  
 
 
On each day of the study, starting tomorrow, you will receive notifications throughout the day 
from the app [PiLR Health] that will ask you to conduct a short survey in the app. The surveys will 
ask you about the cigarettes you smoked, any other tobacco products that you used, and questions 
about how you’re feeling and what you’re doing.  You will also be asked to complete surveys in the 
app several times each day.  We will show you how to download the app onto your phone and how 
to complete the surveys in the app later today if you are eligible. If you do not have a phone, we can 
lend you one to use during the study. You will do several types of surveys on your phone during 
the first two weeks and the last week of the study. During weeks 3 and 4, you will only need to 
complete one survey on your phone per day. 
If you are eligible and assent to participate today, I will then take a breath sample that will show me 
how much you’ve been smoking recently. I’ll also ask you some questions, and you will complete 
some questionnaires about yourself and your history of smoking. You may also be asked to provide 
a urine sample today so we can check to see how much nicotine is in your system.   
 IF ABLE TO BECOME PREGNANT: Smoking during pregnancy can lead to miscarriage, preterm 
delivery, stillbirth, birth defects, and other problems. To avoid these risks, it is important that you 
are not pregnant during this study.  For that reason, you will be tested for pregnancy at this and 
every in-person lab visit.  If you test positive for pregnancy, we will provide you with a referral to a 
doctor and/or encourage you to seek medical attention from your current primary care physician, 
if applicable. You will also be provided with local pregnancy resources. You will not be able to be 
in the study if you are pregnant, and if you become pregnant during the study, you will have to 
withdraw from the study. If you are ineligible due to pregnancy today, you will still be paid $25.  
You will be asked to switch from your usual cigarettes to research cigarettes for four weeks. During 
each of your next two in-person study visits, you will receive research cigarettes to last you for the 


 
 
3 
                         
Assent Ver. 9.28.20 
 
following two weeks. You will be asked to smoke only those cigarettes and none of your usual 
brand or any other brand of cigarettes. However, you may choose to use other tobacco products 
during this time, such as e-cigarettes and little cigars. 
We will ask you to keep track of all your research cigarettes and to bring back any empty packs, 
unopened packs, and unsmoked cigarettes to the lab. Do not share research cigarettes with anyone 
else. They are only for you. You will receive a payment for bringing in your unsmoked cigarettes 
and/or unopened packs of up to up to $5 per week, for a total possible amount of $20.   
You will be randomly assigned to one of two study conditions.  Random assignment is a procedure 
similar to flipping a coin.  You have an equal chance of being in one condition or the other.  If you 
are assigned to one condition, you will be trying cigarettes that contain a different amount of 
nicotine than what is found in most brands. If you are assigned to the other condition, you will be 
trying cigarettes that have levels of nicotine that are similar to cigarettes available in stores. You 
will not be told the nicotine content of your study cigarettes until after the study has been 
completed.  
During lab sessions, you will be asked to complete questionnaires on the computer about any 
recent health changes, recent use of tobacco products, alcohol and marijuana, and about how you 
are feeling. At the BL2 and W2 sessions, we will also ask you to smoke one research cigarette in the 
lab, and to complete questionnaires about how you feel before and after smoking.  You will also be 
asked to give a breath sample before and after smoking, to measure how much smoke you are 
exposed to from the cigarette. We will also ask you to rate the cigarette after smoking it (e.g., how 
much you like the taste, etc.) and to complete some questionnaires that measure your preference for 
the research cigarette compared to other tobacco products. These lab sessions will take about an 
hour and a half to two hours to complete.   
At the BL2 and W4 sessions, you will also be asked to give a urine sample, which we will have 
tested to tell us how much nicotine and other toxicants related to tobacco use you have in your 
system.  During these two sessions, you will also be asked to blow into a device that measures your 
lung function. 
At virtual check-in sessions (W1 and W3), we will ask you about recent changes in your health, and 
ask your about your recent use of tobacco products, alcohol, and marijuana.  
During session W4, the final session, we will collect any remaining research cigarettes from you. 
You will answer some final questions anonymously on your experience in the study, and we will 
schedule a phone call for 30 days from then so we can check in on you and your recent smoking. If 
you feel comfortable, we will also ask you to participate in an open-ended audio interview 
regarding the COVID-19 pandemic where you can share how this pandemic has affected you. This 
audio interview is optional and will be recorded on a device that is stored in a locked drawer that 
only research personnel has access to. The audio file will be transferred from the device and onto a 
secure sever that only the research staff has access to and deleted from the device. There will be no 
personal identifying information obtained in this interview (i.e., you will be referred to as your 
participant ID number and not your first or last name).   
 


 
 
4 
                         
Assent Ver. 9.28.20 
 
It is very important for you to attend your appointments for this study. Throughout the study, if 
you reschedule your sessions more than 3 times for any reason, you may be withdrawn from the 
study.   
The study can be completed in five weeks. The daily surveys will take about 90 seconds per survey 
to complete each day. Each lab session will vary in length but will not take more than two hours. 
4. Will I be paid?  
 
 
You will be paid for completing each of the sessions as follows: $25 for today; $50 for BL2; $15 each     
for W1 and W3, $50 each for W2 and W4. You will be paid up to $5.00 for every day that you 
interact with the phone app during weeks 1, 2 and 5; and up to $2 for completing one phone survey 
per day during weeks 3 and 4. You will also be eligible to earn up to $40 in random bonuses if you 
interact with the app, for a maximum total of $173. A bonus payment of $50 will be paid if you 
complete 80% or more of the surveys you’re supposed to fill out on your phone app. A completion 
bonus of $75 will be given if you attend all 4 lab sessions. A maximum of $20 possible 
compensation is available for returned cigarettes and packs (up to $5 per week). The total amount 
that you can earn for participating in the study, if you complete all sessions and app surveys, is 
$523. 
 
Payments for each of the sessions will be paid to you at the end of each session. Bonuses will be 
paid to you at the end of the study.  All study payments will be made on a ClinCard. This pre-paid 
card works like a bank debit card. You will receive further information about how to use this card. 
If you decide to withdraw from the study before completing it, we will add the money to your 
ClinCard for the number of sessions and daily app surveys that you completed before stopping. If 
you decide to quit smoking during the study, you may still be paid for any remaining study 
procedures that you complete.   
We will pay for your transportation expenses to in-person lab sessions as follows: If you drive to 
the study, parking in the garage at our research building will be paid for by the study.  If you prefer 
to take a bus, bus tickets will be provided to you at each visit. We can also pay if you take Uber to 
your appointment if you send us the receipt from your phone. If none of these options works for 
you, we can arrange for a taxi bring you to the study and back; when you schedule your 
appointment the study staff will also schedule a taxi.  
Completion of the surveys using the app will incur normal data and texting rates from your phone 
service provider that the study does not specifically compensate for.  
5. What are the risks?  
Discomfort from nicotine withdrawal: You may experience nicotine withdrawal symptoms during 
this study. Symptoms can include irritability, frustration, anxiety, sadness, craving to smoke, 
difficulty concentrating, muscle pain, fatigue or difficulty sleeping, and increased hunger.   These 
feelings can be uncomfortable, but they are normal, temporary, and are usually mild.   
 
Discomfort from interview procedures: We will ask you questions about whether you are 
experiencing psychological symptoms and about your background and smoking/drug use history. 
Answering these questions could cause you some minor discomfort.  However, the questions we 
ask are commonly used in research and clinical practice and you will not be required to answer any 


 
 
5 
                         
Assent Ver. 9.28.20 
 
question you are not comfortable answering. All answers to these questions will be kept 
confidential.  
Risks related to smoking cigarettes: All cigarettes are bad for a person's health and can lead to 
heart disease, lung diseases, cancer, and death.  However, exposure to smoke and nicotine in this 
project is not significantly more than what you are exposed to on a daily basis. You do not have to 
smoke more than you normally would. The study cigarettes do not provide any less risk than your 
usual brand cigarette. Only those teenagers who smoke cigarettes daily, and have smoked this 
much for 6 months or longer, will be allowed to participate. Because some of the cigarettes in the 
study may have less nicotine in them, you may use other nicotine-containing products in response. 
The type of product you chooses to use may result in increased risk.  
Potential Discomfort Related to Electronic Cigarette Use: The FDA has not regulated electronic 
cigarettes to date and electronic cigarettes have not been fully studied. We currently don’t know all 
risks of electronic cigarettes when used as intended, how much potentially harmful chemicals are 
being inhaled during use, or whether there are any benefits associated with using these products. 
The studies to date indicate that electronic cigarettes are likely less harmful than regular cigarettes. 
The most common discomfort from electronic cigarettes is that some people find the vapor 
irritating. The most frequently reported discomforts are mouth irritation, throat irritation, and dry 
cough. Other possible effects may include: nausea, sore throat, or headache. No serious health 
effects have been clearly due to electronic cigarettes in any study. When used as intended, serious 
risks related to electronic cigarettes are rare but it is important to use the electronic cigarette and e-
liquid provided by the study as intended and to not alter the device or e-liquid. It is important to 
follow all the study instructions regarding the electronic cigarette and e-liquid, since there have 
been cases of serious injury, including burns and explosions. The FDA has become aware that some 
people have experienced seizures, with most reports involving teens or young adult users. Seizure 
activity is a known potential side effect of nicotine toxicity. There are no known interactions of 
electronic cigarettes with any medications. 
What are the benefits? 
There are no immediate benefits from participating in the study.  You will have the chance to learn 
more about the effects of smoking.  Also, you will help us learn more about how nicotine in 
cigarettes affects teen smoking.  
 
6. How will my information be protected? 
Participation in this study and information gathered from the study will be kept confidential to the 
extent allowable by law.  All information that you give us will be identified only by a code number, 
not your name.  Your answers and test results are confidential and will not be shared with your 
parents, or anyone else who is not involved in conducting, overseeing, or monitoring the research.  
There are two exceptions to this. The first is if you report any plans to hurt yourself or anyone else. 
The second is if you report any physical or sexual abuse of yourself, other minors, or elderly people.  
If you report these things, then we are ordered by law to report them to the proper agency, to help 
keep you and other people safe. Also, if you report plans to harm yourself, we will share that 
information with our medical provider, who will talk with you about it, to help keep you safe.   
 
Participation in this study may require a sign-in or download for using Zoom and will require 
that you have internet access or access to WiFi. You should schedule your interviews with 
appropriate times to ensure privacy. 


 
 
6 
                         
Assent Ver. 9.28.20 
 
 
In addition to the investigators listed on the first page of this assent form and their research staff, 
organizations that oversee this research may ask to review information we collect that may identify 
you. These organizations include the Brown University Research Protections Program and the 
National Institute on Drug Abuse. The findings of the study may be published but individual 
participants will not be identified.  
 
Additionally, authorized representatives from any governmental agency that regulates the study may 
also have access to your identifiable information.  Agencies include the Food and Drug 
Administration (FDA), the U.S. Department of Health and Human Services (DHHS) and Office for 
Human Research Protections (OHRP). 
 
A description of this trial will be available on http://www.ClinicalTrials.gov as required by U.S. 
Law. This website will not include information that can identify you.  At most, the website will 
include a summary of the results. You can search this Website at any time. 
 
Certificate of Confidentiality 
To help us protect your privacy, we have received a Certificate of Confidentiality from the National 
Institutes of Health. We can use this certificate to legally refuse to provide information about you, 
even if there is a court subpoena, in any federal, state, or local civil, criminal, administrative, 
legislative, or other proceedings.  
 
The Certificate cannot be used to refuse to provide information to the U.S. Government or the 
Federal Food and Drug Administration (FDA). The U.S. Government or the FDA can require us to 
provide information so that they can audit or evaluate this federally funded research project.  
You should understand that a Certificate of Confidentiality does not prevent you or a family member 
from voluntarily releasing information about you and your involvement in the research.  If an 
insurer, employer or other person obtains your parent’s written consent and your written assent to 
receive research information, then we may not use the Certificate to withhold that information. 
The Certificate of Confidentiality will not be used to prevent us from contacting state or local 
authorities if you report child or elder abuse, or plans to hurt yourself or others. 
 
The medical monitors of this study may decide to withdraw you from the study if they feel it is 
necessary to protect your health.  
 
 
7. What if I want to stop? 
Your decision whether to be in this study is completely up to you and your parent.  Participation is 
voluntary.  If you decide now to participate, you will be able to change your mind and withdraw 
from the project at any time without any consequences.  We will keep the data and specimens we 
collected from you prior to your withdrawal.  
 
8. Who can I talk to if I have questions about this study? 
Please ask any questions you have now. You can email us at ProjectSiren@brown.edu with any 
general study questions, or call Jasmine at 401-863-6645 (jasminette_dilorenzo@brown.edu). 
 
Any further questions about the study should be directed to Dr. Rachel Cassidy at 401-863-6621 
(Rachel_cassidy@brown.edu) or Dr. Suzanne Colby at 401-863-6655 (Suzanne_Colby@brown.edu).   


 
 
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Assent Ver. 9.28.20 
 
 
9. Who can I talk to if I have questions about my rights as a participant? 
If you have questions about your rights as a research participant, you can contact Brown 
University’s Human Research Protection Program at 401-863-3050 or email them at 
IRB@Brown.edu. 
 
10. Assent to Participate 
Your signature below shows that you have read and understood the information in this document, and 
you agree to volunteer as a research participant for this study. You will be offered a copy of this form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant's Signature and Date 
 
/  
 
 
PRINTED NAME  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Staff Signature and Date 
 
/ 
 
  
PRINTED NAME  
 
Optional 
 
The researcher may contact me in the future to see whether I am interested in being in other studies by 
researchers working at the Center for Alcohol and Addiction Studies at Brown University. 
 
 
 
I agree ______  
I disagree ______ 
 

SAP_001.pdf: 
Cover page for Data Analysis Plan
NCT03860077 
Grant number: R01DA047356 
Grant Title: Impact of Nicotine Reduction on Adolescent Cigarette Use, Alternative Tobacco Use, and 
Harm From Tobacco 
Document date: 9/1/23


Data Analytic Approach and Power. 
 
Overview and justification. Mixed effects models evaluated change in total cigarette use, 
alternative tobacco product use, study cigarette use, and biomarkers of nicotine exposure from baseline to 
the final study week. All analyses were with SAS V9.4 software (SAS Institute Inc., Cary, NC, USA, 
2016). Due to data-collection disruptions related to the COVID-19 pandemic and intermittent data-
collection challenges with the ecological momentary assessment (EMA) program, we elected to utilize the 
most complete data stream for primary analyses, which was Time Line Follow Back (TLFB) of outcomes 
collected at Week 4 and Baseline. Consistent with our prior work (e.g., 1), aggregated timeline follow-
back (TLFB) data from the final week of study cigarette use (i.e., Week 4) was compared to a one-week 
baseline period during which participants used usual brand cigarettes (i.e., Baseline). The mixed effect 
model using TLFB data was chosen over other possible analytic approaches (e.g., ANCOVA with 
baseline outcome covariates) to reduce bias stemming from (1) pre-randomization group differences in 
baseline outcome levels, and (2) missing outcome data.  
 
Analyses to address project aims. To address primary aims, 2-group (VLNC & NNC) x 2 
repeated measures (Baseline & Week 4) mixed effects models tested the effect of the randomization 
group (VLNC vs. NNC) on change in cigarette use and alternative tobacco product (ATP) use from 
Baseline to Week 4. Similarly, to address secondary aims related to biomarkers of nicotine exposure, 2 x 
2 mixed models tested the effects of VLNC vs. NNC cigarettes on change in biomarkers of nicotine 
exposure (i.e., total nicotine equivalents [TNEs] and cotinine), as well as average number study cigarettes 
smoked per day relative to average number of usual brand cigarettes smoked per day. In all models, 
Group (VLNC = 1; NNC = 0) was a between-subjects predictor, and Time (Baseline vs. Week 4) was the 
repeated measure. Subject was treated as a random effect to account for subject-level differences in 
baseline outcome levels. The focal tests evaluated the difference in change from Baseline to Week 4 (i.e., 
Time) in the VLNC vs. NNC condition (i.e., Group), which is a cross-level interactive effect of Time and 
Group. A p-value < 0.05 was interpreted as meeting statistical significance criteria. For all estimation 


parameters, we report effect estimates, standard errors, and 95% confidence intervals in addition to p 
values. 
 
Consistent with the original statistical analysis plan, demographics and baseline data on 
participant tobacco use history and individual characteristics were summarized using univariate 
descriptive statistics (e.g., means, standard deviations, frequencies). Data visualization and formal 
statistical evaluation of means, standard deviations, skewness, and kurtosis, assessed the distributional 
characteristics of each outcome. Where the assumptions of models implementing a normal (Gaussian) 
outcome distribution were not met, the statistical approach was revised accordingly. The following 
analytic procedures were required to meet model assumptions and account for skewed outcome 
distributions and low frequency events for certain outcomes. 
1. Average cigarettes per day was positively skewed, with a non-normal residual distribution in a 
mixed model analysis specifying a normal (Gaussian) outcome distribution. Therefore, this 
outcome was recoded to integers and modeled as a count with a negative binomial distribution 
and log link.  
2. Frequencies of alternative product use (ATP) were low, particularly for combustible ATP use. 
Therefore, for the primary ATP outcome, combustible and non-combustible ATP use were 
modeled jointly and recoded as a dichotomous outcome (0 = <7 combined days of ATP use; 1 = 
7+ combined days of ATP use), with a binary distribution and log link.  
3. As secondary outcomes and to evaluate sensitivity, combustible and non-combustible ATP use 
were also considered independently as separate outcomes. Frequencies of combustible ATP use at 
Week 4 were too low to allow for model convergence. Frequencies of non-combustible 
alternative product use (ATP) were bimodal with peaks at 0 (no use) and 7 (daily use). Therefore, 
this outcome was recoded as a dichotomous outcome (0 = non-daily non-combustible ATP use; 1 
= daily non-combustible ATP use) with a binary distribution and log link. 
4. The study cigarette secondary outcome was modeled with a normal, Gaussian distribution. 
Baseline (Time = 0) in this analysis was average number of usual brand cigarettes at baseline, 


prior to randomization, and Week 4 (Time = 1) was the average number of study cigarettes at 
Week 4. 
5. Biomarker outcomes (i.e., total nicotine equivalents [TNEs] and cotinine) were modeled with 
normal, Gaussian distributions. 
 
Missing data and sample size considerations. Missing data were assumed missing-at-random2 
(Whittaker, Pituch, & McDougall, 2014). Under the missing-at-random assumption, missing data for each 
focal variable is not expected to be related to that variable itself, e.g., a missed outcome assessment was 
not related to what that value would have been if it were assessed3 (Enders, 2006). The mixed model 
approach utilizing SAS software implemented restricted maximum likelihood estimation (continuous 
outcomes) and pseudolikelihood estimation (count and binary outcomes) to account for missing data. The 
mixed model reduces bias relative to other common approaches, particularly in cases where Group size is 
unbalanced due to attrition and/or baseline outcome levels differ between randomization groups.  
 
Original power analyses suggested a target sample size of 120 participants (60 per Group) yielded 
sufficient power to detect effects of Group (VLNC vc. NNC) on change in cigarettes smoked and 
alternative products used, as measured via ecological momentary assessment (EMA). Specified 
population parameter estimates were based on prior literature 4,5 and previous studies1, and power was 
calculated to reflect a small to medium effect of  VLNC vs. NNC on continuous (i.e., normally 
distributed) outcomes. For the direct effect of Group on primary outcomes, power to detect a small to 
medium direct effect (estimate = .15) with 120 participants (60 per Group) was .74 with 95% coverage, 
where power to detect a slightly larger effect (estimate = .20) was .96, with 95% coverage. Due to 
unforeseeable effects of the COVID-19 pandemic on data collection and unanticipated, intermittent 
challenges with the EMA software, the total number of participants was reduced, as was the degree of 
complete EMA data. As such, TLFB were utilized for an intent-to-treat analysis, thereby retaining all 
participants who provided Baseline outcome data.  
 


1. Cassidy RN, Tidey JW, Jackson KM, et al. The Impact of Reducing Nicotine Content on Adolescent 
Cigarette Smoking and Nicotine Exposure: Results from a Randomized Controlled Trial. Nicotine Tob 
Res Off J Soc Res Nicotine Tob. Published online December 9, 2022:ntac279. doi:10.1093/ntr/ntac279 
2. Whittaker TA, Pituch KA, McDougall GJ. Latent growth modeling with domain-specific outcomes 
comprised of mixed response types in intervention studies. J Consult Clin Psychol. 2014;82(5). 
doi:10.1037/a0036664 
3. Enders CK. A primer on the use of modern missing-data methods in psychosomatic medicine research. 
Psychosom Med. 2006;68(3):427-436. doi:10.1097/01.psy.0000221275.75056.d8 
4. Donny EC, Denlinger RL, Tidey JW, et al. Randomized Trial of Reduced-Nicotine Standards for 
Cigarettes. N Engl J Med. 2015;373(14):1340-1349. doi:10.1056/NEJMsa1502403 
5. Hatsukami DK, Luo X, Jensen JA, et al. Effect of Immediate vs Gradual Reduction in Nicotine 
Content of Cigarettes on Biomarkers of Smoke Exposure: A Randomized Clinical Trial. JAMA. 
2018;320(9):880-891. doi:10.1001/jama.2018.11473