Clinical trial NCT05367492
Conditions: Vaping Nicotine Dependence
Keywords: Vaping Nicotine Adolescents Cessation Varenicline
Sponsor: Massachusetts General Hospital
Start date: 2022-06-22; Completion date: 2024-05-28
Enrollment: 261 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study will test the hypothesis that varenicline, when added to behavioral and texting support for vaping cessation, will improve vaping abstinence rates in adolescents dependent on vaped nicotine over placebo plus behavioral and texting support for vaping cessation. Approximately 225 adolescents will be randomly assigned to one of three arms (1) varenicline up to 1 mg bid for 12 weeks plus behavioral and texting support for vaping cessation (V+BC), (2) identical appearing placebo plus behavioral and texting support (P+BC) and (3) enhanced usual care (EUC). The primary comparison will be the double-blind, placebo-controlled comparison of vaping cessation rates in those assigned to varenicline vs placebo.

Detailed description:
Up to 300 adolescents, aged 16-25, who vape, do not smoke regularly, and want to quit vaping will be consented; approximately 225 eligible participants will be randomly assigned to a double blind, placebo-controlled intervention consisting of (1) varenicline or (2) identical placebo, up to 1 mg bid for 12 weeks, plus behavioral and texting support for adolescent vaping cessation or to (3) enhanced usual care. The primary comparison of interest is the double blind, placebo-controlled efficacy comparison of those assigned to (1) varenicline vs (2) placebo on vaping abstinence outcomes. The secondary comparison of placebo plus behavioral and texting support vs. EUC will estimate the efficacy of behavioral and texting support for vaping cessation in this population. The secondary comparison of varenicline plus behavioral and texting support vs EUC will estimate of the efficacy of varenicline treatment plus behavioral and texting support for vaping cessation in this population vs no treatment, the most common vaping cessation intervention. All participants will complete enrollment and baseline visits, and six monthly assessment visits. Those assigned to double blind intervention (study arms 1 or 2) will also complete 12 weekly behavioral support sessions. Assessors will be blind to intervention assignment (arm 1 or 2) vs EUC (arm 3) assignment. Among those assigned to the V+BC or P+BC intervention arms, study staff and participants will be blind to active varenicline vs placebo assignment, such that among those assigned to intervention (arm 1 or 2), assignment to study drug will be double blind. For those assigned a double blind intervention arm, study staff will distribute varenicline or identical appearing placebo and give instructions use at weeks 0, 2, 4 and 8. Participants will be asked to bring all empty and unused study medication at each in-person study visit through Week 12. The enrollment visit will consist of questionnaires, diagnostic assessments, vitals, saliva and urine samples. The baseline visit will consist of questionnaires, a saliva sample for cotinine concentration, and randomization. Monthly visits will consist of interviews, questionnaires and a saliva and urine sample. Weekly treatment meetings for participants assigned to arms 1 or 2 will consist of cognitive behavioral support and questionnaires.

Arms: arm 1: Participants will...

* Receive the drug varenicline, in tablet form, up to 1 mg BID for 12 weeks.
* Attend QuitVaping behavioral support sessions, completed in-person or via video-conferencing, once per week for 12 weeks.
* Be encouraged to sign up for This Is Quitting (TIQ), a text message vaping cessation program for adolescents. arm 2: Participants will...

* Receive placebo tablets, identical in appearance to varenicline, up to 1 mg BID for 12 weeks.
* Attend QuitVaping behavioral support sessions, completed in-person or via video-conferencing, once per week for 12 weeks.
* Be encouraged to sign up for This Is Quitting (TIQ), a text message vaping cessation program for adolescents. arm 3: Participants will...

* Receive NO drug intervention.
* Attend NO behavioral support sessions.
* Be encouraged to sign up for This Is Quitting (TIQ), a text message vaping cessation program for adolescents.
Interventions: intervention 1: Double Blind Varenicline intervention 2: Double Blind Placebo intervention 3: QuitVaping intervention 4: This Is Quitting
Intervention descriptions: intervention 1: For participants 16-17 years old, ≤ 55 kg:

* 0.5 mg once daily for 7 days, then
* 0.5 mg twice daily for 11 weeks

For participants 16-17 years old, \>55 kg:

* 0.5 mg once daily or 3 days,
* 0.5 mg twice daily for 4 days
* 1.0 mg twice daily for 11 weeks

For participants 18+ years old:

* 0.5 mg once daily or 3 days,
* 0.5 mg twice daily for 4 days
* 1.0 mg twice daily for 11 weeks intervention 2: For participants 16-17 years old, ≤ 55 kg:

* 0.5 mg once daily for 7 days, then
* 0.5 mg twice daily for 11 weeks

For participants 16-17 years old, \>55 kg:

* 0.5 mg once daily or 3 days,
* 0.5 mg twice daily for 4 days
* 1.0 mg twice daily for 11 weeks

For participants 18+ years old, regardless of weight:

* 0.5 mg once daily or 3 days,
* 0.5 mg twice daily for 4 days
* 1.0 mg twice daily for 11 weeks intervention 3: QuitVaping is a manualized intervention based on the American Lung Association smoking cessation program modified with adolescent appropriate content and language for vaping cessation from the vaping section of teen.smokefree.gov and the Truth Initiative. These behavioral support sessions will be delivered weekly during the 12-week treatment phase via videoconference or in- person. intervention 4: A free, publicly available text message vaping cessation program from Truth Initiative, designed specifically to help adolescents who vape nicotine quit. Participants who set a quit date receive messages for a week preceding it and 30 days afterward that include encouragement and support, skill- and self-efficacy building exercises, coping strategies, and information about the risks of vaping, benefits of quitting and cutting down to quit.

Protocol documents:
ICF_002.pdf: 
Official Title: Randomized controlled trial of varenicline for 
cessation of nicotine vaping in adolescent non-smokers
NCT Number: NCT05367492
Document Date: 10/09/2024


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2019
Page 1 of 27
Subject Identification
Protocol Title: VARENICLINE FOR VAPING CESSATION IN NON SMOKER VAPER 
ADOLESCENTS
Principal Investigator: A. Eden Evins, MD/MPH
Site Principal Investigator: N/A
Description of Subject Population: Adolescents and young adults 16-25 years old
About this consent form
Please read this form carefully.  It tells you important information about a research study.  A 
member of our research team will also talk to you about taking part in this research study.  
People who agree to take part in research studies are called “subjects.”  This term will be used 
throughout this consent form. 
Partners HealthCare System is made up of Partners hospitals, health care providers, and 
researchers.  In the rest of this consent form, we refer to the Partners system simply as 
“Partners.”
If you decide to take part in this research study, you must sign this form to show that you want to 
take part.  We will give you a signed copy of this form to keep.
Some of the people who are eligible to take part in this study may not be able to give consent 
because they are less than 18 years of age (a minor). Instead, we will ask their parent(s) to give 
permission for them to take part in the study and will ask them to agree (give their assent) to take 
part. Throughout the consent form, “you” always refers to the person who takes part in the study.
IRB Protocol No: 2020P002774
IRB Expiration Date: 10/9/2025
Consent Form Valid Date: 10/9/2024
IRB Submission: CR6/AME76


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2019
Page 2 of 27
Subject Identification
Key Information
Taking part in this research study is up to you.  You can decide not to take part.  If you decide to 
take part now, you can change your mind and drop out later.  Your decision will not change the 
medical care you get within Partners now or in the future.  
The following key information is to help you decide whether or not to take part in this research 
study.  We have included more details about the research in the Detailed Information section that 
follows the key information. 
Why is this research study being done?
In this research study we want to learn more about how well varenicline, a medication that helps 
people quit smoking, will work to help young adults stop vaping.
How long will you take part in this research study?
If you decide to join this research study, it will take you about 6 months to complete the study. 
During this time, we will ask you to take part in an enrollment visit, weekly individual 
behavioral vaping cessation sessions or study visits (virtual or in-person), and monthly 
assessment visits. In-person visits will be held at the Center for Addiction Medicine at 101 
Merrimac St. Boston, MA, or in a private room at your school or local library.
What will happen if you take part in this research study?
If you decide to join this research study, the following things will happen: you will be asked 
about your medical and psychiatric history, complete questionnaires about your mood, vaping 
habits, smoking and substance use, and provide urine and saliva samples. If you are eligible and 
choose to participate, you will be randomly assigned to one of three groups. For two of the 
groups, you will take either the study medication (varenicline) or placebo (sugar pill), complete 
weekly in-person or virtual study visits, and attend brief weekly virtual behavioral vaping 
cessation sessions. If you are assigned to the third group (Enhanced Usual Care), you will 
complete weekly virtual or in-person study visits, but you will not take any medication or attend 
the vaping cessation sessions. All participants will complete monthly assessment visits, which 
can be in person or virtual. At the final study visit (week 24), all participants will have the option 
to provide contact information for three friends who will be invited to participate in a one-time 
virtual visit to answer some questionnaires about themselves. Providing contact information is 
voluntary and will not affect your participation in any way. Your information will remain 
confidential and private regardless of whether you provide your friends’ contact information and 
they agree to participate.
IRB Protocol No: 2020P002774
IRB Expiration Date: 10/9/2025
Consent Form Valid Date: 10/9/2024
IRB Submission: CR6/AME76


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2019
Page 3 of 27
Subject Identification
Why might you choose to take part in this study?
We cannot promise you any benefits from taking part in this research study. However, for the 
group that is assigned to receive study medication, it is possible that you may have a good 
response to varenicline and/or the vaping cessation sessions and may be able to quit vaping. 
What we learn from this study may help other people quit vaping in the future.
Why might you choose NOT to take part in this study?
Taking part in this research study has some risks and requirements that you should consider 
carefully.  
For the group assigned to receive varenicline, important risks and possible discomforts to know 
about include risks due to taking varenicline such as nausea, headache and dizziness. You may 
also experience withdrawal symptoms after stopping vaping or experience stress caused by 
behavioral vaping cessation sessions. 
A detailed description of side effects, risks, and possible discomforts can be found later in this 
consent form in the section called “What are the risks and possible discomforts from being in this 
research study?”
What other treatments or procedures are available for your condition?
There are no FDA-approved medications for helping to quit vaping. There are, however, 7 FDA-
approved medications to help people quit smoking: 5 nicotine replacement therapies (patches, 
gum, lozenges, inhaler, and nasal spray), bupropion (Zyban®), and varenicline (Chantix®). They
may be available to you outside of this study. In addition, individual or group counseling is 
available outside this study and can be helpful in stopping vaping. 
If you have questions or concerns about this research study, whom can 
you call?
You can call us with your questions or concerns.  Our telephone numbers are listed below.  Ask 
questions as often as you want. 
Dr. Eden Evins, MD, MPH is the person and physician in charge of this research study. You can 
call her at 617-643-4679, Monday through Friday 9AM to 5PM with questions about this 
research study. If you would like to speak with a clinician, you can contact Dr. Randi Schuster, 
PhD at 617-643-6673, Monday through Friday 9AM to 5PM. If you need to speak to someone 
IRB Protocol No: 2020P002774
IRB Expiration Date: 10/9/2025
Consent Form Valid Date: 10/9/2024
IRB Submission: CR6/AME76


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2019
Page 4 of 27
Subject Identification
after office hours in an emergency, you can call 617-726-2000 and ask the operator to page Dr. 
Evins. 
If you have questions about the scheduling of appointments or study visits, call our study staff at 
617-643-3467.
If you want to speak with someone not directly involved in this research study, please contact 
the Partners Human Research Committee office.  You can call them at 857-282-1900.
You can talk to them about:
▪
Your rights as a research subject
▪
Your concerns about the research
▪
A complaint about the research
▪
Any pressure to take part in, or to continue in the research study
Detailed Information
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the 
website will include a summary of the results. You can search this website at any time.
Why is this research study being done?
The purpose of the study is to learn if varenicline, a medication to help people quit smoking, will 
work to help young adults stop vaping. 
This research study will compare varenicline to placebo to enhanced usual care (EUC). The 
placebo looks exactly like varenicline but contains no varenicline. Placebos are used in research 
studies to see if the results are due to the study medication or due to other reasons. If you decide 
to participate in this study, you will be randomly assigned to one of three groups:
•
Varenicline Group (1): You will receive varenicline, along with behavioral vaping 
cessation sessions, texting support, and daily smartphone assessments.
•
Placebo Group (2): You will receive placebo (a sugar pill), along with behavioral vaping 
cessation sessions, texting support, and daily smartphone assessments.
•
Enhanced Usual Care (EUC) Group (3): You will complete weekly study visits, but 
you will not take the study medication (varenicline or placebo), attend the vaping 
cessation sessions, or complete daily smartphone assessments. You will be advised to set 
a quit date and be introduced to a supportive texting program.
IRB Protocol No: 2020P002774
IRB Expiration Date: 10/9/2025
Consent Form Valid Date: 10/9/2024
IRB Submission: CR6/AME76


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2019
Page 5 of 27
Subject Identification
You will have a one in three chance of being assigned to one of the three groups. Neither you nor 
the study staff can choose your study group. If you are enrolled in this study, you must be willing 
to be randomized to any of the three groups. This is a blinded study. This means if you are 
assigned to the varenicline or placebo group, neither you nor the study team will know whether 
you received varenicline until after the study is over; however, your doctor or the study team can 
get this information quickly if needed. 
The National Institute on Drug Abuse is paying for this study to be done.
Who will take part in this research?
We are asking you to take part in this research study because you are a healthy person between 
the ages of 16 and 25 who vapes nicotine daily or almost daily and you are willing to try 
varenicline to quit vaping. About 300 participants ages 16-25 will take part in this research 
study. We will enroll all of these subjects at Massachusetts General Hospital (MGH).
What will happen in this research study?
If you choose to take part in this study, we will ask you to sign this consent form before we do 
any study procedures. Even if you sign this consent form, you can change your mind at any time 
and stop taking part in the study. Vital signs and carbon monoxide will be collected only at in-
person visits. If you complete all your visit virtually, these measures will not be collected at all, 
and we will ask you to self-report your height and weight. For virtual visits, drug and pregnancy 
screenings will be mailed to you will detailed instructions on how to complete each test on your 
own.
Enrollment Visit (in-person or virtual for all participants)
The enrollment visit will take about 2 hours. During this visit, we will do some tests and 
procedures to see if you qualify to take part in this research study. At this visit, we will:
•
Ask you about your health, lifestyle, medical, and psychiatric history.
•
Take your height, weight, and vital signs (blood pressure and heart rate). 
•
Ask you about current medications you are taking. This is important because if you are 
randomized to the varenicline group, some medications could have a bad reaction with 
the study medication.
•
Measure the carbon monoxide in your breath using a small, hand-held machine to check 
for recent smoking activity. Carbon monoxide is produced by burning materials, like 
cigarettes and exhaust from cars. If this is done virtually, we will not collect this 
information.
IRB Protocol No: 2020P002774
IRB Expiration Date: 10/9/2025
Consent Form Valid Date: 10/9/2024
IRB Submission: CR6/AME76


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2019
Page 6 of 27
Subject Identification
•
Test your urine for certain drugs, THC (marijuana), and illegal drugs. The results of the 
urine drug test will not become part of your medical record. These test results will, 
however, remain part of your study record. 
•
Test your urine for pregnancy if you are biologically female and able to become 
pregnant. Women who are currently pregnant or breastfeeding cannot take part in this 
research study.
•
Test your saliva for cotinine. Cotinine is a substance that can be found in the body up to 
three days after someone has been exposed to tobacco products. Measuring cotinine in 
people’s saliva is a good way to determine exposure to tobacco products for both smokers 
and nonsmokers. We will also teach you how to perform this test at home.
•
Give you questionnaires to fill out about your general health and well-being, mental 
health, mood, vaping and smoking habits, substance use history, and cravings to vape. 
•
Ask you to fill out a form with information about your age, sex, race, marital status, 
employment, and occupation. 
The study doctor will review the results of these tests and procedures to find out if you are 
eligible to continue in the study. 
If you qualify to continue in the study, we will randomly assign you by chance (like a lottery 
chosen by a computer) to either the varenicline group, the placebo group, or the monitoring 
group. If you and another member of your household enroll, you will both be assigned to the 
same study group. Neither you nor the study staff can choose your study group. You will have a 
one in three chance of being assigned to one of the study groups. This is a blinded study. This 
means that if you are randomized to the varenicline or placebo group, you and the study team 
will not know which study group you are in, but the study team can find out if necessary.
If you qualify for the study, we will schedule you to attend weekly behavioral vaping cessation 
sessions (week 1 to week 12) and seven monthly assessment visits (weeks 0, 4, 8, 12, 16, 20, 24). 
All visits can be done virtually if necessary.
Visit Descriptions for Groups 1 and 2: Varenicline Group and Placebo Group 
Week 0 (Baseline) to Week 12: Weekly Behavioral Vaping Cessation Sessions
At the week 0 (baseline, in-person or virtual visit) we will: 
•
Ask about any symptoms, illnesses, or injuries since your last visit. 
•
Ask about any medications you are taking or any non-drug treatment you are receiving.
•
Ask you to complete questionnaires about your overall mental health and well-being, 
depression, aggression, and suicidal thoughts and feelings.
IRB Protocol No: 2020P002774
IRB Expiration Date: 10/9/2025
Consent Form Valid Date: 10/9/2024
IRB Submission: CR6/AME76


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2019
Page 7 of 27
Subject Identification
•
Ask you about nicotine cravings and withdrawal symptoms.
•
Ask you to take a saliva cotinine test (see ‘Saliva Testing for Cotinine’ on page 12). 
•
Test your urine for pregnancy if you are biologically female and able to become 
pregnant.
•
Ask you to participate in weekly vaping cessation sessions to stop vaping. 
•
Teach you how to take the study medication. You will be asked to start the study 
medication the day after the week 0 (baseline) session.
•
Collect vitals
•
Set you up for daily REDCap surveys via emocha.. Daily REDCap surveys are estimated 
to take 1-5 minutes each.
•
Teach you how to use emocha. The emocha Mobile Health app is a smartphone 
application that we will use to remind you about attending your vaping cessation sessions 
and study visits, as well as notify you to take your study medication. In this app, you will 
record yourself taking the study medication and record any side effects you may 
experience. You will receive daily micropayments for recording yourself taking your 
medication in the emocha app and completing your surveys ($1 per daily video and 
survey completion, up to $2 daily).
•
Teach you how to use the “This is Quitting” (TIQ) text messaging program to quit 
vaping.
Week 1 to week 12 visits will be either in-person or virtual. During these visits, we will: 
•
Ask about any symptoms, illnesses, or injuries since your last visit. 
•
Ask about any medications you are taking or any non-drug treatment you are receiving.
•
Ask you to complete questionnaires about your overall mental health and well-being, 
depression, aggression, and suicidal thoughts and feelings.
•
Ask you about nicotine cravings and withdrawal symptoms.
•
Ask you to take a saliva cotinine test if you report not using nicotine since the last visit.
•
Ask you to count your unused study medication from the previous week. At the week 12 
visit, you will stop taking the study medication.
•
Ask you to report any recent vaping.
Weeks 0, 4, 8, 12, 16, 20, 24: Monthly Assessment Visits
The monthly assessment visits will take place in-person or virtually at weeks 0, 4, 8, 12, 16, 
20, and 24. At these visits we will:
•
Ask about any symptoms, illnesses, or injuries since your last visit. 
•
Ask about any medications you are taking or any non-drug treatment you are receiving.
IRB Protocol No: 2020P002774
IRB Expiration Date: 10/9/2025
Consent Form Valid Date: 10/9/2024
IRB Submission: CR6/AME76


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2019
Page 8 of 27
Subject Identification
•
Ask you to complete questionnaires about your overall mental health and well-being, 
depression, aggression, and suicidal thoughts and feelings.
•
Ask you about nicotine craving and withdrawal symptoms.
•
Ask about your recent use of alcohol, marijuana, opioids, cigarettes and other tobacco 
products and vaping use.
•
(Week 0) Test your saliva for cotinine (after week 0, we will only test your saliva for 
cotinine if you report not using nicotine).
•
Ask you to provide a urine sample for a drug test.
•
Collect your vitals.
•
(Weeks 0, 4, 8 and 12) Ask you to provide a urine sample for a pregnancy test.
•
(Weeks 0, 12, and 24) Collect your urine for THC (marijuana) and NNAL testing, a 
substance that identifies if you smoked tobacco products in the past 2 months.
•
(Week 12) Ask you to bring all unused or empty study medication materials to the in-
person visit.
Study Medication: Study staff will distribute and/or send via priority mail a 2-week or 4-week 
supply of varenicline or identical placebo according to the following schedule:
•
Week 0: a 2-week supply
•
Week 2: a 2-week supply
•
Weeks 4 & 8: a 4-week supply
You will be instructed to start taking the study medication the day of your baseline visit (week 0) 
according to the following schedule:
If you are > 55kg (> 121 lbs; regardless of age)
•
Week 1: For the first three days, you will take one 0.5 mg tablet every day in the evening. 
Then for the next 4 days, you will take one 0.5 mg tablet in the morning and one 0.5 mg 
tablet in the evening.
•
Weeks 2-12: Starting at the beginning week 2, you will take one 1 mg tablet in the 
morning and one 1 mg tablet in the evening until the end of week 12.
If you are ≤ 55kg (≤ 121 lbs and between the ages of 16 and 17)
•
Week 1: You will take one 0.5 mg tablet every day in the evening. 
•
Weeks 2-12: You will take one 0.5 mg tablet in the morning and one 0.5 mg tablet in the 
evening until the end of week 12.
IRB Protocol No: 2020P002774
IRB Expiration Date: 10/9/2025
Consent Form Valid Date: 10/9/2024
IRB Submission: CR6/AME76


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2019
Page 9 of 27
Subject Identification
Please make sure no one else uses your study medication and keep it out of reach of children. 
Please keep the study medication away from your other medication(s). The study medication 
should be stored at room temperature. Before taking your study medication, you should eat a 
small snack or meal. Swallow the pills whole with a full glass of water. Do not chew, crush, or 
split the pills. There should be at least 8 hours between your morning dose and your evening 
dose. It is important for you to follow our instructions about how to take the study medication.
QuitVaping Sessions (in-person or virtual): From week 1 to week 12 you will attend weekly 
individual QuitVaping behavioral therapy sessions. QuitVaping sessions will be video recorded 
for quality control. These sessions will last about 15 minutes. These sessions will teach you ways 
to become a “non-vaper,” how to deal with cravings and withdrawal, how to deal with triggers in 
difficult situations, and how to help you stay quit. At each meeting, we will ask you about your 
vaping and ask you to take a saliva cotinine test to measure any exposure to nicotine. 
Medication Adherence: During this study, you will use a smartphone application created by a 
company called emocha Mobile Health Inc. (“emocha”). 
Before using emocha, you will be instructed on how to set up the application to confirm your 
identity and register your preferred settings. You will also learn how to use it.
You may use your personal smartphone by downloading the app with assistance from the study 
staff. If you do not have a suitable smartphone, a device will be provided by the study site. If you 
are provided with a device, you will not be able to make general phone calls, respond to SMS 
(text) messages, or use the device to access the internet. You are required to return the device at 
the end of the study.
How you will interact with the application:
•
The application will remind you when it is time to take your study medication. You will 
be required to use the application to record yourself taking each dose of study 
medication. The app is used to visually confirm that the same person uses the device each 
time, and that the study medication is properly administered. It is important that you use 
the application every time you take your study medication.
•
The application will prompt you to report any side effects you may experience as a result 
of taking the study medication. 
•
You will receive micropayments for recording yourself taking the study medication in the 
emocha app and completing your REDCap surveys ($1 per daily emocha video and 
survey completion, up to $2 daily), for a maximum payment of $168.
IRB Protocol No: 2020P002774
IRB Expiration Date: 10/9/2025
Consent Form Valid Date: 10/9/2024
IRB Submission: CR6/AME76


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2019
Page 10 of 27
Subject Identification
During the registration process, you will be sent an email from noreply@emocha.com with the 
subject: “Welcome to emocha!” The email will house a link to create a username and password. 
Upon creation of your account, you will download the emocha app on the App Store or Google 
play. If you are registering on a computer, you will have an option to enter your phone number. 
The option to enter your personal telephone number(s), is voluntary. By submitting your number, 
you grant emocha permission to SMS (text) message or call you by phone if:
•
You are not responding to the prompts or reminders in the application.
•
The study staff needs to reach you regarding the study.
•
The study device requires updates or alterations.
The information emocha will collect on or through their website or app may include:
•
Information that you provide by filling in forms on their website or app. This includes 
information provided at the time of registering.
•
Personally identifiable information such as: your name, password, age, gender, email 
address, and home/mobile telephone number that you may provide when you register for 
an account.
•
Records and copies of your correspondence (including e-mail addresses) if you contact 
emocha.
•
Your study ID and time-stamped videos of you (including audio) when you use the 
application to record yourself taking the study medication. 
All of your video recordings and data are encrypted by the application and will be automatically 
forwarded to a secure server. The encrypted recordings are only accessible by authorized staff of 
emocha and study staff through a website that is password protected.
The video recordings and identifiable data will be deleted at the end of the study. If you 
withdraw from the study, your videos will be kept until the conclusion of the study.
The privacy of the individually identifiable health information emocha collects is protected by 
federal law (the Health Insurance Portability and Accountability Act or HIPAA).
Visit Descriptions for Group 3: EUC Group
At the week 0 (baseline, in-person or virtual visit) we will: 
•
Ask about any symptoms, illnesses, or injuries since your last visit. 
•
Ask about any medications you are taking or any non-drug treatment you are receiving.
•
Ask you to complete questionnaires about your overall mental health and well-being, 
depression, aggression, and suicidal thoughts and feelings. 
IRB Protocol No: 2020P002774
IRB Expiration Date: 10/9/2025
Consent Form Valid Date: 10/9/2024
IRB Submission: CR6/AME76


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2019
Page 11 of 27
Subject Identification
•
Ask you about nicotine cravings and withdrawal symptoms.
•
Collect vitals.
•
Ask you to take a saliva cotinine test (see ‘Saliva Testing for Cotinine’, pg 12).
•
Test your urine for pregnancy if you are biologically female and able to become 
pregnant.
•
Ask about your recent use of alcohol, marijuana, opioids, cigarettes and other tobacco 
products, and vaping use.
•
Teach you how to use the “This is Quitting” (TIQ) text messaging program to quit 
vaping.
Week 1 to week 12 visits will be either in-person or virtual and have the same procedures 
as week 0 (baseline), with the exception that we will:
•
Ask about your recent vaping use only.
Weeks 0, 4, 8, 12, 16, 20, 24: Monthly Assessment Visits
The monthly assessment visits will take place in-person or virtually at weeks 0, 4, 8, 12, 16, 
20, and 24. At these visits we will:
•
Ask about any symptoms, illnesses, or injuries since your last visit. 
•
Ask about any medications you are taking or any non-drug treatment you are receiving.
•
Ask you to complete questionnaires about your overall mental health and well-being, 
depression, aggression, and suicidal thoughts and feelings.
•
Ask you about nicotine cravings and withdrawal symptoms.
•
Ask about your recent use of alcohol, marijuana, opioids, cigarettes and other tobacco 
products and vaping use.
•
Test your saliva for cotinine (after week 0, we will only test your saliva for cotinine if 
you report not using nicotine).
•
Ask you to provide a urine sample for a drug test.
•
Collect your vitals.
•
(Weeks 0, 4, 8, and 12) Ask you to provide a urine sample for a pregnancy test.
•
(Weeks 0, 12, and 24) Collect your urine for THC (marijuana) and NNAL testing, a 
substance that identifies if you smoked tobacco products in the past 2 months.
For All Groups:
At any time during the study, if your answers to the questions about mental health require more 
follow-up, you may be referred for a psychiatric evaluation.
IRB Protocol No: 2020P002774
IRB Expiration Date: 10/9/2025
Consent Form Valid Date: 10/9/2024
IRB Submission: CR6/AME76


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2019
Page 12 of 27
Subject Identification
“This is Quitting” Text Message Vaping Cessation Program (TIQ): “This is Quitting” is a 
free, publicly available text message vaping cessation program from Truth Initiative, designed 
specifically to help people quit vaping nicotine. As part of this program, you will receive 
messages for a week preceding your quit date and 30 days afterwards that include 
encouragement and support, skill and self-efficacy building exercises, coping strategies, and 
information about the risks of vaping, benefits of quitting, and cutting down to quit. Keywords 
“CRAVE,” “STRESS,” or “SLIP” provide on-demand support. You will be introduced to TIQ at 
your baseline visit (week 0), and be asked about your use of TIQ at each visit until week 12. 
Texting: Text messages by mobile/cell phones are a common form of communication. This 
research study utilizes a third-party service, Google Voice, which we will use to send reminder 
de-identified text messages asking participants to confirm their appointments the day before the 
scheduled appointment. 
Below are some important points about texting in this research study. 
•
Text messages are not encrypted, and therefore carry security risks. This research study 
and Partners Healthcare are not responsible for any interception of messages sent through 
unencrypted text message communications.  
•
You will be responsible for all fees charged by your carrier’s service plan for text 
messaging. This research study and Partners Healthcare are not responsible for any 
increased charges, data usage against plan limits or changes to data fees from the 
research texts. 
•
You may decide to not send or receive text messages with staff associated with this 
research study at any time. You can do this in person or by sending the research email a 
message that says, “Stop Research Text.” 
•
Your agreement applies to this research study only. Agreeing to other texts from Partners 
Healthcare, for example appointment reminders, is a separate process. Opting out of other 
texts from Partners Healthcare is a separate process as well.
•
It is your responsibility to update your mobile/cell phone number with this research study 
in the event of a change.
Do we have your permission to send you text reminders to your cell phone?
  YES
 NO
Initials_________________
Urine Drug Screen: Before study procedures are initiated, we will perform a urine drug screen 
that will test for THC (marijuana) and illicit substances. The test will be administered by a 
trained research coordinator. 
IRB Protocol No: 2020P002774
IRB Expiration Date: 10/9/2025
Consent Form Valid Date: 10/9/2024
IRB Submission: CR6/AME76


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2019
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Subject Identification
Urine Pregnancy Test: At the enrollment visit before any study procedures are initiated and at 
baseline, weeks 4, 8, and 12, we will perform a urine pregnancy test for females who are able to 
become pregnant. The test will be administered by a trained research coordinator.
Saliva Testing for Cotinine: At enrollment and Week 0, we will collect your saliva to see if you 
have cotinine in your body. We will collect saliva at each visit after Week 0 where you report not 
having used nicotine. For in-person sessions, we will collect saliva during the visit. For virtual 
sessions, we will give you a handout with instructions, materials, and barcoded kits unique to 
you to perform the test during the session.
Stopping the Study Early: Taking part in this research study is up to you. You may choose not 
to take part, or you can change your mind and withdraw (drop out) later. If you want to stop 
taking part in this study, you should tell us. We will make sure you end the study in the safest 
way. We will also talk to you about follow-up care, if needed.
The study doctor may take you out of the study without your permission if:
•
You do not follow the directions of the study team.
•
The study doctor decides that the study is not in your best interest.
•
The study is stopped by the study sponsor, the institutional review board (IRB) or 
independent ethics committee.
•
You become pregnant, want to become pregnant, or are nursing a child during this study.
If you no longer want to continue in the study, we may ask you to come in for a final clinic visit.
The visit may take about 1.5 hours. During this final visit, the same procedures that are done at 
week 24 will happen. 
During this study, it is important that you:
•
Do not use tobacco products (including, cigarettes, pipe tobacco, cigars, snuff, chewing 
tobacco, and hookah). 
•
Do not use nicotine patches, bupropion and other aids used to quit smoking or vaping. 
•
Take the study medication as prescribed and return all unused pills and study medication 
packaging at the week 12 in-person visit.
•
Use an appropriate form of birth control during the study if you are female and able to 
become pregnant.
•
Do not take part in another research study.
If you turn 18 years of age while you are taking part in this study, we will ask you to sign a new 
consent form at that time.
IRB Protocol No: 2020P002774
IRB Expiration Date: 10/9/2025
Consent Form Valid Date: 10/9/2024
IRB Submission: CR6/AME76


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2019
Page 14 of 27
Subject Identification
Partners Alert System: Partners has an electronic system that lets your study doctors know 
if you are admitted to a Partners Hospital, or if you visit a Partners Hospital Emergency 
Department. We want to make sure the study doctors know about any possible problems or 
side effects you experience while you are taking part in the study. A member of the study 
staff may contact you if they receive an alert to ensure your safety in continuing forward in 
our study.
Partners Medical Record Information: A notation that you are taking part in this research 
study may be made in your electronic medical record.  For this study, only a study number, 
and NOT the title of the study, will be in your record: for example, Study #123.  Information 
from the research that relates to your general medical care may be included in the record (for 
example: list of allergies, results of standard blood tests done at the hospital labs).
Please ask your study doctor if you have any questions about what information will be included 
in your electronic medical record.
(Optional) Saliva Samples for Genetic Testing: The collection of a saliva sample for genetic 
research is optional (not required). You can still take part in the main study even if you do not 
want to take part in the genetic study. Giving a DNA sample involves filling one small plastic 
container with your saliva. This will be done at your first visit and should take less than 5 
minutes. Usually, researchers study just a few areas of genetic code that are linked to a disease or 
condition. Instead, we may perform a whole genome analysis on your DNA sample. In the whole 
genome analyses, all or most of the genes are looked at and used by researchers to study links to 
substance use and mental health. These whole genome analyses will be conducted by 
investigators at the Broad Institute. Samples shared with investigators at the Broad Institute will 
be labeled with a code number and not with your name or other identifying information. 
Research using whole genome information is important for the study of virtually all diseases and 
conditions. Therefore, the anonymized samples will provide study data for researchers working 
on any disease.
It is not intended to provide important genetic information about your health. We have no plan to 
return any research results to you or your doctor. The results of the genetic testing will not be 
placed in your medical record. Consenting to take part in this additional genetic study is 
voluntary, and you may decide to withdraw from the study at any time or decide not to join the 
study. If you change your mind and want to withdraw your saliva sample from further genetic 
research, you can do so at any time by contacting Dr. Evins (617-643-4679; 
AEEVINS@MGH.HARVARD.EDU) or Dr. Schuster (617-643-6673; 
RSCHUSTER@MGH.HARVARD.EDU). Any information obtained from the sample will also 
be withdrawn except to the extent to which the information has already been used in analyses. 
IRB Protocol No: 2020P002774
IRB Expiration Date: 10/9/2025
Consent Form Valid Date: 10/9/2024
IRB Submission: CR6/AME76


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2019
Page 15 of 27
Subject Identification
All information and samples obtained for this study will be assigned a code number. No names 
or important numbers that could be used to identify you, like hospital medical record numbers or 
social security numbers, will be kept on samples. Only MGH study staff will keep the link 
between your subject number and your name on a computer protected by a personal password.
Would you like to provide a saliva sample to be used for genetic testing as described above?
Please mark your choice below.
  YES
 NO
Initials_________________
How may we use and share your samples and health information for 
other research?
The samples and information we collect in this study may help advance other research.  If you 
join this study, we may remove all information that identifies you (for example, your name, 
medical record number, and date of birth) and use these de-identified samples and data in other 
research.  It will not be possible to link the information or samples back to you.  Information 
and/or samples may be shared with investigators at our hospitals, at other academic institutions 
or at for-profit, commercial entities.  You will not be asked to provide additional informed 
consent for these uses.
Will you get the results of this research study?
No. The research study we are doing is only a steppingstone in understanding how to help 
participants to quit vaping. Therefore, no information about the results of this research study or 
the results of your individual participation in the research study will be given to you or your 
doctor. Tests done for the research using your samples will not be useful in directing your 
medical treatment. The results of the tests will not be placed in your medical record.   
What are the risks and possible discomforts from being in this research 
study?
All drugs have some risks and side effects. Some side effects may make you sick, make you feel 
uncomfortable, or hurt you. You will be watched carefully during the study for any side effects.
Risks of Varenicline
Common side effects:
IRB Protocol No: 2020P002774
IRB Expiration Date: 10/9/2025
Consent Form Valid Date: 10/9/2024
IRB Submission: CR6/AME76


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2019
Page 16 of 27
Subject Identification
Nausea: Nausea is the most common adverse reaction reported with varenicline treatment. 
Nausea is generally described as mild or moderate and often transient; however, for some 
patients, it is persistent over several months. 
Other frequent side effects are:
•
Headaches
•
Sleep disturbances (difficulty in sleeping, abnormal dreams)
•
Dizziness
•
Constipation
•
Flatulence (gas)
•
Diarrhea
•
Vomiting
Even though these side effects are expected to occur in some people, most people have not had to 
stop taking varenicline because of side effects. 
Less common side effects are:
•
Changes in mood (depression and mania) 
•
Agitation psychosis (loss of contact with 
reality)
•
Hallucinations (seeing or hearing things 
that are not there)
•
Paranoia (feeling people are against you)
•
Delusions (false beliefs)
•
Homicidal ideation (thoughts of killing 
others)
•
Hostility (aggression)
•
Changes in behavior
•
Anxiety
•
Panic (sudden fear that takes over or 
replaces normal thinking)
•
Somnambulism (sleep walking)
•
Suicidal ideation (suicidal thoughts)
•
Suicide attempt
•
Completed suicide
Smoking cessation with or without treatment is associated with nicotine withdrawal symptoms 
and the worsening of underlying psychiatric illness. Not all patients reporting these events had 
psychiatric illnesses before and not all had stopped smoking. The role of varenicline in these 
reports is not known.
Interaction with Alcohol: There have been postmarketing reports of patients experiencing 
increased intoxicating effects of alcohol while taking varenicline. Some cases described unusual 
and sometimes aggressive behavior and were often accompanied by amnesia for the events.
 
Accidental Injury: There have been postmarketing reports of traffic accidents, near-miss 
incidents in traffic, or other accidental injuries in patients taking varenicline. In some cases, the 
patients reported somnolence, dizziness, loss of consciousness or difficulty concentrating that 
IRB Protocol No: 2020P002774
IRB Expiration Date: 10/9/2025
Consent Form Valid Date: 10/9/2024
IRB Submission: CR6/AME76


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2019
Page 17 of 27
Subject Identification
resulted in impairment, or concern about potential impairment, in driving or operating 
machinery. You should use caution driving or operating machinery or engaging in other 
potentially hazardous activities until you know how varenicline may affect you.
Rare (but serious) side effects: 
•
Hypersensitivity reactions (swelling of face, mouth, extremities [arms, legs], and neck 
that can make breathing difficult)
•
Skin reactions (rash, swelling, redness)
•
Peeling of the skin that can sometimes be life-threatening)
•
Seizures: There have been reports of seizures in patients treated with varenicline. Some 
patients had no history of seizures, whereas others had a history of seizure disorder that 
was remote or well-controlled. In most cases, the seizure occurred within the first month 
of therapy. You should discontinue study medication and contact a healthcare provider 
immediately if you experience a seizure while on treatment.
If you have cardiovascular disease, taking varenicline may increase your risk of certain 
cardiovascular adverse events. You should contact your health care provider if you experience 
new or worsening symptoms of cardiovascular disease, such as chest pain, shortness of breath, 
calf pain when walking, or sudden onset of weakness, numbness, or difficulty speaking. 
If there are any concerns that you are in need of clinical attention, the Physician Investigator (A. 
Eden Evins, MD, MPH) will be made aware of the issue immediately to determine appropriate 
steps. The Physician Investigator and another medically trained co-investigator will assess the 
needs of the subject and offer the subject either prompt treatment or medical referral, whichever 
is appropriate for the situation. 
If you think you are having an allergic reaction and having trouble breathing, or other life-
threatening events, call 911 immediately. It is important that you report all symptoms and side 
effects that you experience as soon as they occur, whether or not you think they are caused by 
the study medication.
Placebo Risk: You may receive a placebo. Taking a placebo may be similar to not taking any 
medication. If you receive a placebo, your vaping habit may stay the same or get worse, or you 
may spontaneously quit vaping just as you may have done without additional treatment.
Nicotine Withdrawal Symptoms: Decreased nicotine consumption, with or without treatment, 
may result in nicotine withdrawal symptoms (e.g., irritability, anxiety, restlessness, depressed 
mood, increased appetite, fatigue, insomnia/sleep problems, impatience, headache, difficulty 
IRB Protocol No: 2020P002774
IRB Expiration Date: 10/9/2025
Consent Form Valid Date: 10/9/2024
IRB Submission: CR6/AME76


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2019
Page 18 of 27
Subject Identification
concentrating). Your withdrawal symptoms will be monitored throughout the study. The study 
doctors will help you to get appropriate treatment for any severe symptoms.
Pregnancy/Birth Control: The effects of varenicline on an embryo or fetus (developing baby 
still in the womb), or on a nursing infant are not known and may be harmful. If you are pregnant 
or breastfeeding, you cannot participate in this study. All female subjects must have a negative 
pregnancy test before starting the study drug. If your pregnancy test is positive at the visits it is 
collected at, then you cannot join the study. For this reason, we ask that women of child-bearing 
potential agree to use adequate contraception prior to study entry and during the study. 
Acceptable birth control methods include: birth control pill plus a condom, spermicide plus a 
condom, diaphragm plus spermicidal jelly, subcutaneous contraceptive medication (birth control 
medication). 
If you are the parent of a 16- or 17-year-old subject, the results of your child’s urine screen will 
not become part of your child’s medical record, and the result will not be shared with you. 
However, if your daughter has a positive pregnancy test, we will inform her and encourage her to 
share those results with you, and she will be withdrawn from the study.  
Risks of the Carbon Monoxide Test: The carbon monoxide test might cause only slight 
discomfort. The carbon monoxide test requires that you take a deep breath, hold it for 15 seconds 
and exhale (blow out) one large breath into a machine that will measure the amount of carbon 
monoxide in your lungs.
Saliva Collection: Using a collector to obtain saliva can be uncomfortable. We are going to give 
you all the tools and material such as gloves, etc. 
Questionnaires: It is possible that some of the questions in the questionnaires may make you 
feel uncomfortable. You can skip any questions you do not want to answer. However, we hope 
that you will answer all questions.
Confidentiality and Loss of Privacy: Information collected from you will be stored in a 
password-protected research database on a password-protected computer. This information will 
not become part of your medical record. Your information may be kept for several decades.
We will assign all information a unique code. The key to the code will be kept on a password-
protected computer. Only the researchers from our research study will be able to use the 
computer. The code linking test results to subject identity will only be accessible to study staff.
We will not share your identity with anyone outside the Partners institutions. However, we 
cannot guarantee your confidentiality.
IRB Protocol No: 2020P002774
IRB Expiration Date: 10/9/2025
Consent Form Valid Date: 10/9/2024
IRB Submission: CR6/AME76


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2019
Page 19 of 27
Subject Identification
Confidentiality will be strictly enforced and is only limited in ways mandated by the law, which 
will be detailed below. 
•
Your research results will not be shared with you or entered into your medical record. 
This is because the research results cannot currently be used to guide your medical care. 
•
Through regular clinical interviews, questionnaires and conversations, we will monitor 
your mental health closely over the course of the study visits and you will meet regularly 
with Dr. Schuster who is a clinical psychologist at Massachusetts General 
Hospital/Harvard Medical School. If you indicate that you are having many feelings of 
depression or anxiety and/or we notice an elevation in symptoms during the study, we 
will tell you about these results and recommend that you get follow-up from a counselor, 
therapist, psychologist or psychiatrist. We have carefully collected the names and phone 
numbers of local mental health professionals who are trusted in the community and will 
provide you with their contact information. All study staff will be properly trained on 
assessment, monitoring and intervention of mental health issues and all study staff will be 
prepared to discuss counseling options. 
•
If you indicate concern about substance use, we will provide you with resources for local 
treatment/support options. 
•
We are obligated by law to report any suspicion of intention to cause harm to self or 
others. If at any time, any of the completed questionnaires or interviews reveal any such 
concerning information, we will notify you of our concerns and, if necessary, contact the 
appropriate officials. Specifically, if you tell us that you have intent and/or a plan to harm 
yourself or someone else, we will call 911. 
There may be other risks that are currently unknown. Our study staff will update individuals of 
any new potential risks or discomforts as they arise.
What are the possible benefits from being in this research study?
You may not benefit from taking part in this study. If you are assigned to the groups that receive 
study medications (Groups 1 and 2), you may have a good response to varenicline and/or the 
vaping cessation sessions may be able to quit vaping. However, there is no guarantee that you 
will benefit in any way. Information from this study may help other people quit vaping in the 
future.
What other treatments or procedures are available for your condition?
Your study doctor will discuss with you the good points and bad points of taking part in this 
study and your options for quitting vaping if you do not take part in this study. 
IRB Protocol No: 2020P002774
IRB Expiration Date: 10/9/2025
Consent Form Valid Date: 10/9/2024
IRB Submission: CR6/AME76


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2019
Page 20 of 27
Subject Identification
There are no FDA-approved medications for helping to quit vaping. There are, however, 7 FDA-
approved medications to help people quit smoking: 5 nicotine replacement therapies (patches, 
gum, lozenges, inhaler and nasal spray), bupropion (Zyban®), and varenicline (Chantix®). All 
reduce nicotine withdrawal symptoms. These treatments are often combined with individual or 
group counseling and some supportive intervention. 
Varenicline is approved by the FDA for individuals aged 18 and older, but not for individuals 
under age 18 so it may not be available outside of a research study if you are 16 or 17 years of 
age. 
In addition, individual or group counseling is available outside this study and can be helpful in 
stopping smoking. Talk with the study doctor if you have questions about any of these treatments 
or procedures.
Can you still get medical care within Partners if you don’t take part in 
this research study, or if you stop taking part?
Yes.  Your decision won’t change the medical care you get within Partners now or in the future.  
There will be no penalty, and you won’t lose any benefits you receive now or have a right to 
receive.
We will tell you if we learn new information that could make you change your mind about taking 
part in this research study.
What should you do if you want to stop taking part in the study?
If you take part in this research study, and want to drop out, you should tell us.  We will make 
sure that you stop the study safely.  We will also talk to you about follow-up care, if needed.
Also, it is possible that we will have to ask you to drop out of the study before you finish it.  If 
this happens, we will tell you why.  We will also help arrange other care for you, if needed.
Will you be paid to take part in this research study?
Independent of your group assignment, you will have the chance to earn $1188 by participating 
in our study. You will be paid for the completion of each study visit. You will be paid $30 for 
completing the enrollment visit and all subsequent weekly and follow-up visits.  For each 
monthly assessment visit you will be paid $50 if you are in the varenicline or placebo group, and 
$100 if you are in EUC. If you complete all study visits from enrollment through week 24, you 
IRB Protocol No: 2020P002774
IRB Expiration Date: 10/9/2025
Consent Form Valid Date: 10/9/2024
IRB Submission: CR6/AME76


Partners HealthCare System
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Certificate of Confidentiality Template
Version Date: January 2019
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Subject Identification
will earn $738 if you are in the varenicline or placebo group, and $720 if you are in Enhanced 
Usual Care.
All participants who complete the study will have a chance to win a study completion bonus. For 
participants in the varenicline or placebo groups, the bonus is $450, and for the EUC group, it is 
$468. Including this bonus, all participants can make up to $1188 for participating in our study. 
For every ten people who complete the study (through week 24), one participant will be drawn as 
a winner.
If you are assigned to the varenicline or placebo group (Groups 1 and 2), you can receive 
micropayments of up to $2 per day for emocha medication adherence and REDCap survey 
completions, for a maximum of $168. If you are randomized to the EUC group (Group 3) you 
will not receive any micropayments. 
If you come in for the enrollment visit but are found to be ineligible, you will still be paid for the 
enrollment only ($30). Payment will be provided in between visits. If you want to stop being in 
the study, you can stop at any time, but you will be paid only for the visits you have completed. 
Please refer to the table below for a complete breakdown of study payments:
Visit/Week
Varenicline/Placebo
EUC
Enrollment
30
30
Weeks 0, 1, 2, 3
30
30
Week 4
50
100
Weeks 5, 6, 7
30
30
Week 8
50
100
Weeks 9, 10, 11
30
30
Week 12
50
100
Week 16, 20, 24
30
30
Emocha + surveys
168
0
Total
738
720
Bonus
450
468
Grand Total
1188
1188
You will be reimbursed up to $15 for necessary travel for in-person visits.
We will use an approved, outside vendor (Advarra), or checks to make study visit payments to 
you via a reloadable credit card-based system, called Advarra Participant Payments. This secure 
system is similar to a gift card. You will be given an Advarra Payments Visa card when you 
enroll in the study. Once the card is activated, the study team will add your payment your card 
after you complete each visit. The payment should be available to you within a day, and you may 
IRB Protocol No: 2020P002774
IRB Expiration Date: 10/9/2025
Consent Form Valid Date: 10/9/2024
IRB Submission: CR6/AME76


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Subject Identification
use the card anywhere Visa cards are accepted, such as at a grocery store. If you cannot be paid 
via Advarra or checks because you do not have a social security number or individual taxpayer 
identification number, we will pay you via gift card.
We will need to collect your Social Security number to make these payments, and it will be 
shared securely with Advarra, the company that runs the card-based system. If you are under 18 
and would like to be paid through Advarra, you need to provide us with your parent or 
guardian’s social security number, date of birth, and address to make these payments.  Payments 
are considered taxable income. If you receive more than $600 a year from Partners HealthCare, 
Partners will issue a 1099 form to you and to the Internal Revenue Service for income reporting 
purposes. After you sign this consent form, you will be asked to sign an agreement form or 
provide a verbal agreement of Advarra procedures, acknowledging your understanding of the 
Advarra payment system. 
We may use your samples and information to develop a new product or medical test to be sold.  
The Sponsor, hospital, and researchers may benefit if this happens. There are no plans to pay you 
if your samples or information are used for this purpose.
What will you have to pay for if you take part in this research study?
There is no cost to you for taking part in this study. The cost of all the tests and procedures done 
for research will be paid for by study funds.
What happens if you are injured as a result of taking part in this 
research study?
We will offer you the care needed to treat any injury that directly results from taking part in this 
research study. We reserve the right to bill your insurance company or other third parties, if 
appropriate, for the care you get for the injury. We will try to have these costs paid for, but you 
may be responsible for some of them. For example, if the care is billed to your insurer, you will 
be responsible for payment of any deductibles and co-payments required by your insurer.
Injuries sometimes happen in research even when no one is at fault. There are no plans to pay 
you or give you other compensation for an injury, should one occur. However, you are not giving 
up any of your legal rights by signing this form.
If you think you have been injured or have experienced a medical problem as a result of taking 
part in this research study, tell the person in charge of this study as soon as possible. The 
researcher's name and phone number are listed in the beginning of this consent form.
IRB Protocol No: 2020P002774
IRB Expiration Date: 10/9/2025
Consent Form Valid Date: 10/9/2024
IRB Submission: CR6/AME76


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Version Date: January 2019
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Subject Identification
If you take part in this research study, how will we protect your privacy?
Federal law requires Partners to protect the privacy of health information and related information 
that identifies you.  We refer to this information as “identifiable information.”
In this study, we may collect identifiable information about you from:
•
Past, present, and future medical records
•
Research procedures, including research office visits, tests, interviews, and 
questionnaires
Who may see, use, and share your identifiable information and why:
•
Partners researchers and staff involved in this study
•
The sponsor(s) of the study, and people or groups it hires to help perform this research or 
to audit the research
•
Other researchers and medical centers that are part of this study
•
The Partners ethics board or an ethics board outside Partners that oversees the research
•
A group that oversees the data (study information) and safety of this study
•
Non-research staff within Partners who need identifiable information to do their jobs, 
such as for treatment, payment (billing), or hospital operations (such as assessing the 
quality of care or research)
•
People or groups that we hire to do certain work for us, such as data storage companies, 
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Federal agencies (such as the U.S. Department of Health and Human Services (DHHS) 
and agencies within DHHS like the Food and Drug Administration, the National 
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Certificate of Confidentiality
A federal Certificate of Confidentiality (Certificate) has been issued for this research to add 
special protection for information and specimens that may identify you.  With a Certificate, 
IRB Protocol No: 2020P002774
IRB Expiration Date: 10/9/2025
Consent Form Valid Date: 10/9/2024
IRB Submission: CR6/AME76


Partners HealthCare System
Research Consent Form
Certificate of Confidentiality Template
Version Date: January 2019
Page 24 of 27
Subject Identification
unless you give permission (such as in this form) and except as described above, the researchers 
are not allowed to share your identifiable information or identifiable specimens, including for a 
court order or subpoena. 
Certain information from the research will be put into your medical record and will not be 
covered by the Certificate.  This includes records of medical tests or procedures done at the 
hospitals and clinics, and information that treating health care providers may need to care for 
you.  Please ask your study doctor if you have any questions about what information will be 
included in your medical record.  Other researchers receiving your identifiable information or 
specimens are expected to comply with the privacy protections of the Certificate.  The Certificate 
does not stop you from voluntarily releasing information about yourself or your participation in 
this study.
Even with these measures to protect your privacy, once your identifiable information is shared 
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Because research is an ongoing process, we cannot give you an exact date when we will either 
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The results of this research may be published in a medical book or journal, or used to teach 
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Your Privacy Rights
You have the right not to sign this form that allows us to use and share your identifiable 
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You have the right to withdraw your permission for us to use or share your identifiable 
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continue to take part in the study.
If you withdraw your permission, we will not be able to take back information that has already 
been used or shared with others, and such information may continue to be used for certain 
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IRB Protocol No: 2020P002774
IRB Expiration Date: 10/9/2025
Consent Form Valid Date: 10/9/2024
IRB Submission: CR6/AME76


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Research Consent Form
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Subject Identification
You have the right to see and get a copy of your identifiable information that is used or shared 
for treatment or for payment.  To ask for this information, please contact the person in charge of 
this research study.  You may only get such information after the research is finished.
Informed Consent and Authorization
Statement of Person Giving Informed Consent and Authorization
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This research study has been explained to me, including risks and possible benefits (if 
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identifiable information to be used and shared as described above.
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IRB Protocol No: 2020P002774
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Subject Identification
Statement of Person Giving Assent 
•
 This research study has been explained to me, including risks and possible benefits (if 
any), other possible treatments or procedures, and other important things about the study.
•
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Signature of Child: 
I agree to take part in this research study and agree to allow my health information to be used 
and shared as described above. 
Child, Ages 16-17 
Date 
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IRB Protocol No: 2020P002774
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Subject Identification
Signature of Study Doctor or Person Obtaining Consent:
Statement of Study Doctor or Person Obtaining Consent
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Consent Form Version Date:  11/08/2023
IRB Protocol No: 2020P002774
IRB Expiration Date: 10/9/2025
Consent Form Valid Date: 10/9/2024
IRB Submission: CR6/AME76

Prot_000.pdf: 
Official Title: Randomized controlled trial of varenicline for cessation 
of nicotine vaping in adolescent non-smokers
NCT Number: NCT05367492
Document Date: 01/10/2024


Version 2024.01.10 
1 
PARTNERS HUMAN RESEARCH COMMITTEE DETAILED PROTOCOL 
VARENICLINE FOR VAPING CESSATION IN NON SMOKER VAPER ADOLESCENTS 
Includes: 
NCT04602494: Varenicline for Nicotine Vaping Cessation in Non Smoker Vaper Adolescents 
(Pilot) 
NCT05367492: Varenicline for Nicotine Vaping Cessation in Adolescents (ViVA) 
I. BACKGROUND
a. Background
The rapid rise in popularity of electronic nicotine delivery devices or ENDS (i.e., e-
cigarettes) used to inhale vaporized nicotine solutions has effectively reversed 5 decades of 
denormalization of nicotine use among youth. While adolescent use of combusted tobacco 
products (cigarettes) has declined dramatically, vaping prevalence is on the rise and since 2014 
has been the most popular form of nicotine use in youth. In 2018, 21% of U.S. high-school 
seniors reported vaping in the past month, a 10-point increase from 2017, which was the largest 
one-year increase in any substance used over the 44 years that Monitoring the Future has tracked 
adolescent substance use.1 In 2019, over 25% of high-school and 11% of middle-school students 
nationally had vaped in the past 30 days. In many areas, over a third of high-school seniors use 
regularly. Most adolescents who vape have never smoked; an estimated 5.4 million middle- and 
high-school students in the U.S. recently used a vaping device, according to a federal survey 
released in December 2019, over 400% more than used cigarettes.2 It is estimated that a million 
adolescents have become addicted to vaped nicotine.3  
Health Consequences of Nicotine Vaping in Adolescent Non-Smokers: Empiric evidence 
supports that e-cigarette use should be discouraged among novice tobacco users.4 Reduced 
nicotine exposure in adolescence is a benefit in itself, as nicotine exposure in adolescence 
induces lasting changes in brain function.5–8 In a study in a Kaiser Permanente electronic medical 
record, among never-smokers, ENDS use was associated with greater odds of initiating smoking 
(OR = 7.41, 95% CI = 3.14-17.5).9 There is also a growing consensus that ENDS increase risk of 
subsequent use of cannabis, alcohol, and other substances.10 Therefore, cessation of ENDS use 
will reduce the risk for combusted tobacco use in this population11,12 and probably reduce the 
risk for other problem drug use.7,8,13,14 In addition, nearly a third of adolescents who vape have 
used an e-cigarette to vape cannabis, often high potency cannabis oils and concentrates.15 
Regular vaping has been associated with heavy metal and carcinogen exposure,16 wheezing,17 
pulmonary inflammation,18 impaired pulmonary gas exchange, and e-cigarette or vaping 
associated lung injury (EVALI).19,20 A recent review concluded that it is not clear whether the 
respiratory health effects of ENDS are less than those of cigarettes.21 ENDS cessation will 
reduce exposure of youth to these and other acute and long-term health risks.22,23  
Desire to Quit: The prevalence of quitting smoking among youth is lower than adults.24 
The 2015 National Youth Risk Behavior Survey (YRBS) found that among 9–12 grade current 
cigarette smokers, 45.4% had tried to quit smoking during the prior year.25 The National Youth 
Tobacco Survey found that, in 2015, the prevalence of having a past-year quit attempt among 
students in grades 9–12 was 57.8%, 4% higher than YRBS.26 Among long-term vapers, 88% of 
whom were former smokers in a 2017 European survey, few intended to quit vaping.27 In 


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2 
contrast, responses to the 2019 National Youth Tobacco Survey administered by the Centers for 
Disease Control and Prevention suggest there is widespread youth interest in quitting e-
cigarettes. Over half (54.5%) of middle- and high-school students who currently use e-cigarettes 
reported seriously thinking about quitting, and 52.9% reported trying to quit in the past year. 
Similarly, in a recent Truth Initiative survey, almost half of 15- to 24-year-olds who vape say 
quitting e-cigarettes is a 2020 resolution.28 
Treatments Available but Not Yet Tested for Youth Vaping Cessation: Effective clinical 
interventions are clearly needed to help young non-smokers who vape to quit vaping. There are 
no controlled trials of vaping cessation interventions in the literature to date to our knowledge, 
though there are case reports of successful tapering with behavioral and pharmacologic 
support.29,30 The Truth Initiative launched a free e-cigarette text message quit program, ‘This is 
Quitting’ (TIQ), for youth over age 13 years that has reportedly been used by 70,000 youth.31 
TIQ delivers tailored messages via text that give age-appropriate advice for quitters age 13 and 
older, including information about pharmacotherapy. Additionally, teen.smokefree.gov contains 
a section on vaping cessation.32  
There are 7 FDA-approved medications for tobacco cessation: 5 nicotine replacement 
therapies (NRT), bupropion, and varenicline. All reduce nicotine withdrawal symptoms, which 
appear earlier and more frequently in youth than adults,14 and include headaches, irritability, 
sleep difficulty, difficulty concentrating, and increased appetite.33 Withdrawal symptoms, or fear 
of experiencing them, can be an important obstacle to quitting.34 Cases of successful vaping 
cessation have been reported with varenicline,29 and a preliminary case series in our group 
yielded more promising results with varenicline and behavioral support than NRT and behavioral 
support or behavioral support alone for adolescent vapers with nicotine dependence. Varenicline, 
a partial α-4 β-2 nicotinic receptor agonist that decreases nicotine withdrawal symptoms and 
craving, has been shown to be superior to placebo, NRT and bupropion for smoking cessation in 
multiple studies and populations,35–37 and is well tolerated in adolescents over age 12.38–40  
 
b. Prior clinical studies supporting the proposed research  
Persistence of Adolescent Nicotine Vaping Despite Statewide Ban on All Vape Sales: In 
the fall of 2019, during a total ban on all vaping products in Massachusetts in response to the 
rapidly evolving EVALI public health crisis, we screened 7519 students in grades 6-12 in 11 
schools in Greater Boston for tobacco, alcohol, and cannabis use and identified 422 students who 
reported daily nicotine vaping despite the ban. Amongst middle-school students surveyed, 14 of 
2253 (0.6%) reported daily vaping, among those in grades 9-12, 408 of 5266 (7.7%) students 
surveyed reported daily vaping, and an additional 1228 (23.3%) reported vaping at least weekly 
in the prior 30 days. Thus, over 31% of high-school students in this sample of 11 schools in 
greater Boston reported frequent vaping, and 7.7% report daily vaping during a full ban on 
vaping in the state.41  
High Desire to Quit but Low Success Rates with Conventional Behavioral Treatment: 
High school administrators at the 11 schools we surveyed in late 2019 reported vaping is a crisis 
in their schools and that disciplinary approaches are ineffective for reducing vaping in school. 
Those who have implemented behavioral interventions by school counselors report high uptake 
by students but low abstinence rates. 
School Administrations Highly Motivated to Help Find Treatment to Mitigate Vaping 
Crisis in Schools: An email request was sent in December 2019 to school administrators 
statewide asking about interest in supporting vaping intervention studies we may propose. In the 


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3 
next 2 days, just before winter recess, we received 170 letters of support from schools offering 
space and staff resources to assist with recruitment for and implementation of projects aiming to 
test and identify effective interventions for adolescent nicotine vaping cessation. Student health 
services in college settings similarly need guidance on vaping cessation treatment options. 
Pharmacotherapeutic Treatment of Adolescents with Dependence to Vaped Nicotine, 
Open case series: A marked increase in treatment seeking amongst adolescents who vape 
nicotine, particularly among daily vapers with symptoms of nicotine dependence followed the 
statewide ban on all vape sales. We at the MGH Center for Addiction Medicine and colleagues at 
the Boston Children’s Hospital Adolescent Substance Abuse Program (ASAP) have attempted to 
meet this increased demand with open label clinical treatment. To date, in an open case series, 
we have used a mobile telephone app for vaping cessation for adolescents who do not endorse 
nicotine withdrawal symptoms. For adolescent vapers with nicotine withdrawal symptoms, we 
have had success with varenicline and NRT combined with behavioral support. From Dec 2019-
Jan 2020, we have treated 25 adolescents with varenicline and 24 with NRT. To date 18 of those 
treated with varenicline (72%) and 5 treated with NRT (21%) have stopped vaping. 
Adolescent Non-Smokers Who Use ENDS have Significant Risk for Negative Outcomes: 
In 2018, we surveyed 1,628 students at two high schools in greater Boston on lifetime and 
current combusted tobacco, oral tobacco, and ENDS use, and past 3-month cannabis and alcohol 
use. Lifetime, past month, and daily ENDS use was endorsed by 29%, 21%, and 6% of students 
while 4%, 2% and 1%, respectively, endorsed combusted tobacco use. 70% of students who used 
tobacco, initiated use with vaped tobacco, and 9% of lifetime ENDS users reported subsequent 
regular cigarette use. Additionally, current frequent tobacco (ENDS or cigarette) use was 
strongly associated with frequent cannabis and alcohol use (ORs = 23.5 - 40.0; p’s<0.0001), with 
no significant difference between ENDS and combusted tobacco users. This is consistent with 
prior reports that that onset of ENDS use before 9th grade increased the strength of the 
association between ENDS use and cigarette smoking, and cannabis, alcohol, and non-medical 
prescription drug use.42 Overall, the health effects of prolonged nicotine vaping are unknown, 
which is why their use is discouraged among non-smokers,42,43 particularly in adolescents whose 
risk for addiction is at a lifetime high. 
Retention of School Recruited Adolescents in Abstinence Trials: In the past 2 years, we 
have enrolled 265 students from Greater Boston middle and high schools into a longitudinal 
investigation of the impact of a month of cannabis abstinence on neurocognition. Our retention 
rate of >85% demonstrates ability of our investigative team to recruit and retain a longitudinal 
cohort of adolescents with comparable research methods employed in a school-based setting, 
e.g., onsite drug testing, diagnostic interviews. Similarly, we enrolled 1169 smokers with 
schizophrenia in a community-based pragmatic smoking cessation trial, with retention rates of 
80% at 3-year follow-up, further highlighting our team’s strength in recruiting and retaining high 
risk cohorts in community settings. 
 
c. Rationale and potential benefits to patients and/or society  
There is no known benefit of ENDS in this population. Even among adult cigarette 
smokers from high-risk populations, there is debate and concern regarding the risk to benefit 
ratio of ENDS use. Moreover, youth who do smoke tobacco often engage in dual use of 
combusted cigarettes and ENDS.44 Although e-cigarette vapor may be less hazardous than 
tobacco smoke, many recent reports challenge the idea that e-cigarette vapor is safe. Eighteen to 
20% of EVALI patients report only using nicotine vapes prior to developing the idiopathic 


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4 
vaping related serious pulmonary illness. Many volatile organic compounds identified in 
vaporized nicotine e-liquids are carcinogenic.16 In addition, adolescent exposure to nicotine in 
animals has been shown to increase the addictive potential of other substances.14 In our 
preliminary studies, adolescent vapers have elevated risk for use of alcohol and cannabis over 
those who do not use nicotine, not different from tobacco smokers. Although effective 
interventions are urgently needed to aid the estimated million adolescents in the US who have 
already developed nicotine addiction with daily ENDS use, to date, there are no published 
studies reporting effective treatments for nicotine vaping in adolescents. 
 
II. SPECIFIC AIMS  
We aim to test the hypothesis that varenicline added to behavioral and texting support 
will be well tolerated and improve vaping cessation rates over behavioral treatment and texting 
support and over enhanced usual care only in nicotine dependent adolescents who vape, do not 
smoke regularly, and are willing to try treatment to stop vaping. To do so, we propose to enroll 
up to 300 adolescents and randomize up to 240 in Greater Boston meeting these criteria into a 3-
arm randomized, placebo-controlled, parallel-group study of varenicline up to 1 mg bid for 12 
weeks added to behavioral and texting support specifically designed for teen vaping cessation 
compared with (1) behavioral and texting support and placebo and (2) enhanced usual care 
(EUC; i.e., monitoring and TIQ only). 
 
Aim 1 (primary): To evaluate the efficacy of varenicline, added to behavioral and texting 
support, for cessation of vaped nicotine in adolescents with nicotine dependence. 
Hypothesis 1.1: Those assigned to varenicline will have a higher rate of cotinine-verified, 
continuous nicotine vaping abstinence from study week 9 to end of treatment (weeks 9-12) 
(primary) and end of follow-up (weeks 9-24) (secondary) than those assigned to placebo, as 
operationalized by self-report of no nicotine vaping since the last study visit and salivary cotinine 
<30ng/ml at each study visit in the time frame designated. 
Hypothesis 1.2 (secondary): Those assigned to varenicline will have a higher rate of 
cotinine-verified, seven-day point-prevalence nicotine vaping abstinence at end of treatment 
compared to placebo. Point prevalence abstinence is operationalized as self-report of no nicotine 
vaping since the last study visit and salivary cotinine <30ng/ml at study visit 12. 
Hypothesis 1.3 (secondary): Those assigned to varenicline will have a higher rate of 
cotinine-verified, continuous nicotine vaping abstinence from study week 9 to end of treatment 
(weeks 9-12) and end of follow-up (weeks 9-24) than those assigned to EUC. 
Hypothesis 1.4 (secondary): Those assigned to placebo will have a higher rate of 
cotinine-verified, continuous nicotine vaping abstinence from study week 9 to end of treatment 
(weeks 9-12) and end of follow-up (weeks 9-24) than those assigned to EUC. 
Hypothesis 1.5 (secondary): Those assigned to varenicline will have a higher rate of 
cotinine-verified, seven-day point-prevalence nicotine vaping abstinence at end of treatment 
compared to EUC.  
Hypothesis 1.6 (secondary): Those assigned to placebo will have a higher rate of 
cotinine-verified, seven-day point-prevalence nicotine vaping abstinence at end of treatment 
compared to EUC. 
Hypothesis 1.7 (exploratory): Those assigned to varenicline will have an earlier onset of 
abstinence, longer latency to first lapse, longer latency to relapse, longer duration of abstinence, 
and greater total number of days of vaping abstinence than those assigned to placebo or EUC as 


Version 2024.01.10 
5 
determined by using data ascertained daily with the emocha Mobile Health app (emocha) or 
REDCap surveys. 
 
Aim 2 (secondary): To establish the safety and tolerability of varenicline in adolescents 
attempting to quit vaping nicotine. 
Hypothesis 2.1: Nicotine withdrawal symptoms, craving, and negative mood symptoms 
will be less frequent and severe in the varenicline group than the placebo or EUCgroups.  
Hypothesis 2.2: Those assigned to varenicline will have no greater incidence or severity 
of adverse events (AE) compared with those assigned to placebo or EUC during treatment and 
follow-up. 
 
Aim 3 (exploratory): To assess if there are between group differences (based on intervention 
status and peer group vape use) in consumption of alcohol, combusted tobacco, cannabis, and 
non-medical prescription drugs during the treatment and follow-up periods. 
 
Exploratory Hypothesis 3.1: Those assigned to varenicline will have less consumption of 
alcohol, combusted tobacco, cannabis, and non-medical prescription drugs and greater reduction 
in severity of nicotine dependence as assessed with the ECDI during the treatment and follow-up 
periods than those in the placebo or EUC groups. 
 
Exploratory Hypothesis 3.2: Peer vape use and intervention status will interact. 
Participants enrolled in QuitVaping and involved in peer groups that endorse lower rates of vape 
use (as reported by their three closest friends) will endorse lower vape use at study conclusion. 
 
Exploratory Hypothesis 3.3: Participants in the QuitVaping intervention will have more 
accurate perceptions of peers’ vape use (as assessed by the correlation between participants’ 
report and peers’ report of peers’ vape use).  
 
PILOT STUDY 2020P002774-Pilot - NCT04602494 
In 2021, during the national recall of varenicline in the US, the FDA provided temporary 
authorization for importation of apo-varenicline from the Canadian company, Apotex. A pilot 
vaping cessation trial was conducted using apo-varenicline or identical placebo in 4 study 
participants who met inclusion and exclusion criteria below except that the age range was limited 
to 18-25. In this pilot trial, all study procedures listed below were piloted, including the emocha 
platform for study medication adherence and daily report of vaping behavior and adverse effects 
and the novel, brief lay-counselor behavioral vaping cessation intervention.  
Note: No IND was sought to enroll children into the trial with the apo-varenicline study 
medication, as it was being used under temporary FDA authorization. When US-made, generic 
varenicline was FDA approved (August 2021) and available for purchase through PAR 
Pharmaceuticals (November 2021), an IND was sought (December 2021) to enroll children ages 
16 and 17 into the trial. This trial was deemed exempt in March 2022. When IND exemption was 
granted for enrolling children ages 16 and 17, IRB approval was sought for the main trial which 
will uses generic US made varenicline in participants ages 16-25.  
 
III. SUBJECT SELECTION  
a. Inclusion/exclusion criteria  
 
Inclusion Criteria:  
- 
Ages 16-25, inclusive; 


Version 2024.01.10 
6 
- 
Self-report of daily or near daily nicotine vaping for the prior ≥ 3 months and semi-
quantitative saliva screening for cotinine positive for recent nicotine use;  
- 
Nicotine dependence as defined by a score ≥4 on the 10-item E-cigarette Dependence 
Inventory (ECDI), or report of persistent use despite negative consequences, or prior 
failed quit attempts; 
- 
Self-report of no regular combusted tobacco use in the past 2 months at enrollment and 
exhaled CO <10 ppm; 
- 
Total body weight at enrollment ≥35 kg (77 lbs); 
- 
Report willingness to try varenicline to stop vaping; 
- 
Able to understand study procedures and read and write in English; 
- 
Have a parent or legal guardian who is able and willing to provide written informed 
consent (if under the age of 18); 
- 
Competent and willing to provide written informed consent (if age 18+) or assent (if 
under 18);  
- 
For participants who could become pregnant: negative urine pregnancy test at enrollment 
and agreement to use effective contraception (e.g., abstinence, hormonal contraception, 
intra-uterine device, sterilization, or double barrier contraception) during the study. 
 
Exclusion Criteria:  
- 
Use of a smoking cessation medication in the prior month (nicotine patch, gum, nasal 
spray, or inhaler, varenicline, bupropion); 
- 
Unwilling to abstain during the study from using smoking cessation aids other than those 
provided by the study; 
- 
Unstable medical condition, epilepsy, severe renal impairment; 
- 
Inpatient psychiatric hospitalization in the prior 6 months, serious suicidal ideation or 
suicide attempt within 6 months of enrollment, recent active suicidal ideation or suicidal 
behavior identified at enrollment or baseline visits; 
- 
Evidence of active problem substance use severe enough to compromise ability to safely 
participate, in the investigator’s opinion; 
- 
Prior adverse drug reaction to varenicline; 
- 
Unwilling to provide urine samples; 
- 
Any condition or situation that would, in the investigator’s opinion, make it unlikely that 
the participant could adhere safely to the study protocol;  
- 
Ward of the state. 
 
Source of subjects and recruitment methods  
Participants will be recruited via: 1) annual high school screenings conducted as part of 
the protocol, School Screening for Substance Use and Related Risk Factors PI: Schuster, 
Protocol #2021P001873, 2) direct physician referral from local MGH clinics and the MGB 
Healthcare network, 3) teacher, counselor, administrator, parent/guardian referral, 4) response to 
postings online, flyers, streaming services, through social media advertisements, and through 
traditional advertisements, 5) identification via research databases, such as the Research Patient 
Data Registry (RPDR) and Research Match. The MGB RPDR is a clinical data registry that can 
identify patients for clinical trials through EPIC records. We will run RPDR queries to find 
patients in the target age range with frequent vaping who are likely to be eligible for the current 
study. Research Match is a database of research volunteers developed by Vanderbilt University 


Version 2024.01.10 
7 
and approved for use by the MGB IRB. Participants in high school will be identified through 
both school-based screening processes and non-school-based procedures. All potential 
participants, regardless of recruitment source, will complete a REDCap-based screener and/or 
telephone screen for eligibility. All participants will have the option to consent to receiving text 
messages from study staff. Text messages will be sent using Google Voice, and will be used to 
send deidentified study visit reminders to participants.  
 
Ancillary Cohort 
An ancillary cohort (N = up to 150) of participants’ nominated top three peers will be recruited 
to participate in a single, remote visit after participants' study protocol is completed. Primary 
participants will be invited to provide the contact information (telephone number) of their top 
three peers at the week 24 visit (final study visit), as part of the Peer Network Structure measure. 
Participants will be informed that providing the contact information is voluntary, they are free to 
decline, and including contact information will not affect their participation in any way. 
Ancillary cohort recruitment will begin after the nominating participant completes the study. 
 
Ancillary cohort participants will be recruited by blinded study staff via telephone (recruiting 
staff will only have access to the ancillary peer’s name and phone number, they will not have 
access to information about the primary participant who provided their contact information or 
any data collected about that participant). Rates of ancillary participation will in no way 
influence the primary cohort’s participation.  
 
Inclusion criteria for the ancillary cohort: 
- 
Able to understand study procedures and read and write in English; 
- 
Have a parent or legal guardian who is able and willing to provide written informed 
consent (if under the age of 18); 
- 
Competent and willing to provide written informed consent (if age 18+) or assent (if 
under 18). 
 
Exclusion criteria for the ancillary cohort: 
- 
Any condition or situation that would, in the investigator’s opinion, make it unlikely that 
the participant could adhere safely to the study protocol;  
- 
Ward of the state. 
  
IV. SUBJECT ENROLLMENT  
a. Methods of enrollment 
School-Based Screening and Enrollment: Potential participants may be identified through an 
ongoing school screening process, School Screening for Substance Use and Related Risk Factors 
(PI: Schuster, Protocol #2021P001873), that involves school-wide assessments of all students in 
participating schools who were not opted out by their parents/guardians.  
 
This assessment includes general demographic items and basic questions related to health 
behavior and psychological functioning. All students who are not withdrawn from the school-
wide assessment by their parents/guardians and who wish to complete the questionnaire will also 
complete a separate form where they may provide their contact information and indicate their 
interest in being contacted for research studies. Questionnaires will be reviewed by MGH study 
staff, and all students who meet the criteria to participate in the study based on this initial 


Version 2024.01.10 
8 
screening and who provided contact information will be contacted by MGH study staff to 
conduct a telephone screener or will be provided a link to complete the screener as a REDCap 
survey. The telephone screener will involve an explanation of study procedures as well as 
questions to screen for eligibility for the trial. 
 
Students who express interest in participating in the study and are eligible based on the 
telephone screen will be scheduled for an in-person or virtual enrollment visit to sign consent 
(assent if under the age of 18) and complete eligibility screening procedures. A member of study 
staff will conduct informed consent procedures with at least one parent/guardian of participants 
under the age of 18 either in-person or via telephone/zoom prior to initiating study procedures. 
Parents/guardians will have the option to sign the ICF electronically if that is their preference.  
 
Non-School-Based Screening and Enrollment: Participants identified through data registries 
like RPDR will receive a recruitment letter via Patient Gateway or by mail from study staff. The 
letter will not be sent to those who have opted out of receiving research invitations. MGB 
Research invitations will only be used to recruit participants aged 18 and older. Interested 
participants will reach out to study staff to complete a REDCap screener and/or telephone 
screener. Participants referred by self or other (e.g., in response to flyers, social media posting, 
clinic or school referral) will also complete a screener over the phone or via REDCap. The 
screener will involve an explanation of study procedures as well as questions to screen for 
eligibility for the trial. Potentially eligible participants interested in enrolling will be scheduled 
for an in-person or virtual enrollment visit to sign consent (assent if under the age of 18) and 
complete eligibility screening procedures. A member of study staff will conduct informed 
consent procedures with at least one parent/guardian of participants under the age of 18 either in-
person or via telephone/zoom prior to initiating study procedures. Parents/guardians will have 
the option to sign the Informed Consent Form (ICF) electronically if that is their preference.  
  
b. Procedures for obtaining informed consent  
Waived Parental Consent for Phone Screening Only (for participants under age 18): We 
request a waiver of parental consent for those under age 18 for phone screening only, which is 
justified given the following: 
 
The proposed phone screening involves no more than minimal risk to participants. During 
the phone screening, we will provide details about the study and ask potential participants if they 
have any questions or concerns about the study protocol. We will also ask participants basic 
demographic information as well as brief questions related to symptoms of psychopathology to 
assess eligibility. They will be told that all information will be kept strictly confidential and 
answers to screening questions will be stored separately from any identifying information. 
Participants are free to refuse to answer any questions. Participants will also have the option to 
complete the initial screening via a REDCap survey that will be accessible through the study’s 
approved Massachusetts General Hospital Rally page. If participants are interested in the study 
and are eligible, we will collect parents/guardian’s contact information so that we can obtain 
written parental consent for study enrollment. No study procedures will occur before written 
parental consent is obtained. We will also obtain written assent from the participant prior to the 
initiation of any study procedures. 
 


Version 2024.01.10 
9 
The waiver of consent for phone screening will not adversely affect the rights and welfare 
of subjects. The waiver of parental consent for screening only will not adversely impact an 
adolescent’s access to or the nature of any ongoing health services or primary care in any way 
nor adversely affect his/her rights or welfare. The study will be explained in detail to potential 
participants before any screening questions are asked, giving them a chance to decline screening 
if they are not interested in the study. They are also free to refuse to answer any screening 
questions that make them feel uncomfortable. They will be clearly told that written parental 
consent and adolescent assent will be required for enrollment in the active study phase and that 
answers to phone-based questions are for screening purposes only.  
 
The research could not practicably be carried out with the waiver or alteration. This study 
could not practicably be carried out without a waiver of consent for phone screening to 
determine eligibility due to the burden that would be imposed on parents/guardians of potential 
participants that are not yet even known to be eligible and interested in study participation. This 
study utilizes a brief telephone screen to assess whether the potential participant is interested and 
eligible for the study. Specifically, obtaining written consent would significantly increase the 
time requirement for this brief screener. In our experience, the consent process generally takes 
approximately 30 minutes, while the brief screener should only take about 5-10 minutes for most 
participants. Requiring consent for screening would thus dramatically increase parent burden, 
and in many cases, this imposed burden would be unnecessary because it is not guaranteed that 
their child is interested or eligible for the study. Due to this increased parent/guardian burden, we 
expect that requiring consent for screening would greatly reduce enrollment and compromise the 
representativeness of the sample.  
 
Participants and parents will be provided with additional pertinent information after 
participation. Prior to the first study visit, written parental consent will be obtained and 
parents/guardians will be provided with copies of the consent form which will fully detail the 
study protocol as well as any associated risks and benefits. They will be given contact 
information of key study staff. Similarly, study participants will be given a copy of the signed 
parental consent/study assent form. 
  
The research involves no more than minimal risk to the privacy of the participants. This 
research involves no more than minimal risk to the privacy of participants. During the phone 
screening, only basic demographics and information to determine eligibility will be collected. 
The protocol fully details our plan to protect any identifying information from improper use and 
disclosure.  
Written Parental Consent for Study Enrollment (<18 years of age): Parent/guardian contact 
information will be collected from potential participants who expressed interest in participating, 
who were found to be likely eligible via the initial screener (telephone or REDCap), and who are 
under the age of 18. After a participant under the age of 18 is determined to be likely eligible, 
study staff will reach out to the parent/guardian to obtain written informed consent. 
Parents/guardians can electronically sign the consent form and send the document back to study 
staff if they would prefer. For participants whose parent(s)/guardian only speak Spanish or 
Portuguese, written informed consent will be obtained using professionally translated Spanish or 
Portuguese consent forms. The opportunity to meet with study staff in person, virtually via video 


Version 2024.01.10 
10 
conferencing, or over the phone will be encouraged and made available to all parents. 
Parents/guardians may reach out to MGH study staff with any questions or concerns prior to or 
after signing informed consent. Consent by parents or guardians will be documented. No 
participant under the age of 18 will be enrolled in the study until written parental informed 
consent is obtained. 
 
Written Participant Consent (18+ years of age) or Participant Assent (<18 years of age) for 
Study Enrollment: Participant consent/assent procedures will occur at the enrollment visit, in 
which there will be a discussion of study procedures, potential adverse events, confidentiality, 
and voluntary participation. All participants will have the opportunity to ask questions regarding 
the study to study staff and/or doctoral-level member of the study staff. Participants must 
demonstrate understanding of the nature of this study, its potential risks, discomforts, and 
benefits before signing consent. All participants will have the ability to sign informed 
consent/assent electronically. No other study procedures will occur until informed consent/assent 
documents are signed. All participants as well as parents/guardians for participants under the age 
of 18 will be provided with a copy of their signed consent/assent documents and the Partners 
Privacy Statement. Minors who turn 18 while enrolled in the study will be re-consented to 
continue participation.  
 
Ancillary cohort members will follow the same participant consent (if 18+) and parental 
consent/participant assent (if under 18) protocols as primary participants. Ancillary cohort 
members will sign the Ancillary Cohort consent form. 
 
c. Treatment assignment, and randomization  
Eligible participants will be randomly assigned in a 1:1:1 ratio, in blocks of 6, to varenicline, 
identical appearing placebo prepared by the MGH research pharmacy, or EUC (i.e., TIQ and 
monitoring with assessments only). Study staff and participants will both be blind to drug for 
those randomized to the varenicline and placebo arms. Randomization will be stratified by 
secondary or post-secondary school status. The randomization scheme will be computer 
generated by the MGH Research Pharmacy by personnel with no other interactions with study 
staff or participants. There will be separate randomization codes for apo-varenicline, imported 
from Canada under a provisional FDA allowance, and domestic generic varenicline with full 
FDA approval. The randomization codes will be held in the MGH research pharmacy, and 
available to study PIs only in the case of urgent medical need. Assessments will be conducted by 
study staff who are blind to study intervention. Treatment will be assigned according to study 
number, assigned sequentially to eligible participants who enroll in the trial and attend the 
baseline visit. 
 
Special considerations for individuals living in the same households: More than one 
household member or family member will be allowed to participate in the study. Since there is a 
possibility that participants from the same household, voluntarily or not, share study medication, 
participants from the same household will be yoke randomized, eg assigned to the same 
intervention. Yoked randomization will ensure members of the same household or family 
members receive the same intervention and will reduce the risk for contamination. 
 


Version 2024.01.10 
11 
Ancillary cohort participants will not be randomized. Protocols will be identical for all ancillary 
cohort members. 
 
V. STUDY PROCEDURES  
Participants will be randomly assigned to receive a 12-week course of varenicline, an identical 
placebo, or EUC only. Participants assigned to receive varenicline or identical placebo will 
receive individual behavioral vaping cessation sessions (held virtually by videoconferencing or 
in-person), and a digital platform to report vaping behavior, study medication adherence, and 
tolerability. Participants in EUC will be provided with explicit advice to quit and non-directive 
support. Participants in all three arms will complete assessments, conducted by raters blinded to 
study arm assignment, and will include samples for cotinine assays and self-reports of vaping 
and other drug use. Participants in all three arms will receive an introduction to TIQ and receive 
weekly monitoring of TIQ use from study staff. 
 
a. Study visits and parameters to be measured  
The enrollment visit will be conducted in person and will include a detailed description of the 
study, informed consent/assent, assessments to confirm eligibility, assessments of vaping and 
other drug use behavior, and medical and psychiatric diagnostic and symptom assessments. 
Eligible, consented participants will then be scheduled for a baseline assessment visit where they 
will receive study medications (for those randomized to varenicline or placebo arms), weekly 
visits which will include assessments (all participants) as well as the behavioral vaping cessation 
sessions (for those randomized to varenicline or placebo arms), and monthly assessment visits. 
Following completion of the 12-week intervention period, participants will be scheduled for 
follow-up visits at weeks 16, 20, and 24. Study visits will be conducted at our MGB location, or 
in a private room at a participant’s local library or current school. When conducting a study visit 
at a site external to MGH, study staff will obtain verbal permission from library/school 
administrators to conduct study visits at a given location. When obtaining permission to conduct 
a visit, no identifying or specific information regarding the participant or the study will be 
mentioned. All study visits can be conducted in person or virtually. We have piloted procedures 
and have a standard operating procedure for sending materials to conduct urine drug and 
pregnancy screening during virtual visits. Study staff will include instructions for participants to 
perform the tests and hold the assays up to their device’s camera so study staff can record urine 
screening results. Height and weight will be recorded per participant’s report for remote visits. 
Carbon monoxide will not be recorded for virtual visits, and we will rely on participant reported 
combusted tobacco use. Medication will be shipped via priority mail if a visit where medication 
is distributed is done virtually. Blood pressure and heart rate will not be collected if a visit is 
virtual, as these are not necessary measures in prescribing varenicline or part of our primary 
outcomes.  
Time and Events Table 


Version 2024.01.10 
12 
Time and Events 
 
 
Intervention period 
Follow-up period 
Assessments 
 
Enrollment 
BL  
(Wk0) 
Wk 
1-3 
Wk 
4 
Wk 
5-7 
Wk 
8 
Wk 
9-11 
Wk 
12 
 
Wk 
16 
Wk 
20 
Wk 
24 
Screening 
Consent 
 
X 
- 
- 
- 
- 
- 
- 
- 
 
- 
- 
- 
Demographics, Vaping history 
 
X 
- 
- 
- 
- 
- 
- 
- 
 
- 
- 
- 
Primary outcomes 
Salivary cotinine*** 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Timeline followback (TLFB) 
 
X 
X 
X* 
X 
X* 
X 
X* 
X 
 
X 
X 
X 
Daily vaping exposure y/n via 
REDCap (for those not 
randomized to EUC) 
 
- 
X 
X 
X 
X 
X 
X 
X 
 
- 
- 
- 
Secondary/exploratory outcomes 
MNWS 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
- 
- 
- 
QVC 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
- 
- 
- 
MASQ-D30 
 
X 
X 
- 
X 
- 
X 
- 
X 
 
X 
X 
X 
NAEI 
 
X 
X 
- 
X 
- 
X 
- 
X 
 
X 
X 
X 
Adverse events 
 
- 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Other biomarkers 
Urine NNAL 
 
- 
X 
- 
- 
- 
- 
- 
X 
 
- 
- 
X 
THC-COOH 
 
- 
X 
- 
- 
- 
- 
- 
X 
 
- 
- 
X 
CO 
 
X 
- 
- 
- 
- 
- 
- 
- 
 
- 
- 
- 
Pregnancy test 
 
X 
X 
- 
X 
- 
X 
- 
X 
 
- 
- 
- 
Drug screen 
 
X 
X 
- 
X 
- 
X 
- 
X 
 
X 
X 
X 
Vital signs 
 
X 
X 
- 
X 
- 
X 
- 
X 
 
- 
- 
- 
Height and weight 
 
X 
- 
- 
- 
- 
- 
- 
- 
 
- 
- 
- 
Saliva (genetics) 
 
X 
- 
- 
- 
- 
- 
- 
- 
 
- 
- 
- 
Descriptions, effect modifiers, covariates 
Medical History 
 
X 
- 
- 
- 
- 
- 
- 
- 
 
- 
- 
- 
Concomitant medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
ECDI 
 
X 
- 
- 
- 
- 
- 
- 
X 
 
- 
- 
X 
AUDIT 
 
X 
- 
- 
- 
- 
- 
- 
X 
 
- 
- 
X 
CUDIT 
 
X 
- 
- 
- 
- 
- 
- 
X 
 
- 
- 
X 
BRIEF-SR 
 
X 
- 
- 
- 
- 
- 
- 
X 
 
- 
- 
- 
C-SSRS 
 
X 
- 
- 
- 
- 
- 
- 
- 
 
- 
- 
- 
WTAR 
 
X 
- 
- 
- 
- 
- 
- 
- 
 
- 
- 
- 
UPPS-P 
 
X 
- 
- 
- 
- 
- 
- 
- 
 
- 
- 
- 
CHRT 
 
- 
X 
- 
X 
- 
X 
- 
X 
 
-X 
-X 
-X 
Flavor preferences 
 
X 
- 
- 
- 
- 
- 
- 
- 
 
- 
- 
- 
Peer and family influence on 
vaping 
 
X 
- 
- 
- 
- 
- 
- 
- 
 
- 
- 
- 
PATH Instruments: 
Vaping and substance use 
history, modified WTQ, MTQ  
 
X 
- 
- 
- 
- 
- 
- 
- 
 
- 
- 
- 
YSS 
 
- 
- 
- 
- 
- 
- 
- 
X 
 
- 
- 
- 


Version 2024.01.10 
13 
 
Ancillary cohort recruitment will begin after the nominating participant completes the study. 
Ancillary cohort contact information will be collected at participant’s Wk 24 visit. Ancillary 
cohort members will participate one time in a remote, questionnaire-only visit. They will not 
receive any intervention (behavioral, medication, or placebo). The remote visit will follow 
existing study protocols to ensure participant and data safety and privacy. 
 
b. Drugs to be used varenicline or identical placebo (for participants randomized to 
varenicline or 
placebo arms)  
Varenicline is a selective nicotinic acetylcholine receptor partial antagonist that binds primarily 
to the α4β2 receptor subtype, thereby reducing both nicotine withdrawal and the reinforcing 
effects of nicotine. Due to its mixed agonist-antagonist properties, varenicline is effective at 
relieving nicotine craving and withdrawal during abstinence while blocking the reinforcing 
effects of nicotine in those who lapse.45 The approved regimen of varenicline in adult smokers is 
1 mg bid for 12 weeks, starting with a 1-week titration period (12-week course at 2 mg daily 
recommended).46 A study in adolescents aged 12-17 years old (inclusive) found that steady-state 
systemic exposure in adolescent patients of body weight >55 kg, as assessed by AUC (0-24), was 
comparable to the adult population on the same dose.39 When 0.5 mg bid was given, steady-state 
daily exposure of varenicline was, on average, higher (by approximately 40%) in adolescent 
patients with bodyweight ≤ 55 kg compared to the adult population.39  
 
The dosing schedule is as follows:  
 
For participants 16-17 years old, ≤ 55 kg: 
- 
0.5 mg once daily for 7 days, then 
- 
0.5 mg twice daily for 11 weeks 
  
For participants 16-17 years old, >55 kg: 
- 
0.5 mg once daily for 3 days, 
- 
0.5 mg twice daily for 4 days 
- 
1 mg twice daily for 11 weeks 
  
For participants 18+ years old, regardless of weight: 
- 
0.5 mg once daily for 3 days, 
- 
0.5 mg twice daily for 4 days 
TIQ 
 
- 
X 
X 
X 
X 
X 
X 
X 
 
- 
- 
- 
Treatment assignment 
 
- 
- 
- 
- 
- 
- 
- 
X 
 
- 
- 
- 
Peer Network Stability 
 
- 
X 
- 
- 
- 
- 
- 
X 
 
- 
- 
X 
Additional study procedures 
Randomization 
 
- 
X 
- 
- 
- 
- 
- 
- 
 
- 
- 
- 
Drug distribution 
 
- 
X 
X** 
X 
- 
X 
- 
- 
 
- 
- 
- 
Quit Vaping Intervention 
 
- 
- 
X 
X 
X 
X 
X 
X 
 
- 
- 
- 
*Modified TLFB of past 7-day vaping during weekly visits **Week 2 only *** For weeks 1 thru 24, only administered to 
verify abstinence. 


Version 2024.01.10 
14 
- 
1 mg twice daily for 11 weeks 
 
Medications will be adjusted to a lower dose if 1 mg bid is not well tolerated. Efficacy of doses 
lower than 1.0 mg per day have not been reported to our knowledge, thus participants who do not 
tolerate well the dose of varenicline or placebo 1.0 mg per day in single or divided doses will be 
discontinued from the study. 
Due to a shortage of varenicline in the US, the study medication in the Pilot study was provided 
by Apotex, Canada, apo-varenicline, which was on a temporary importation allowance from the 
FDA. US-made generic varenicline was FDA approved in August of 2021, made available for 
purchase in November 2021, and is currently used for the main study protocol. 
 
Medication Distribution: Study staff will distribute or send via priority mail varenicline or 
identically appearing placebo with instructions on how to take the study medication on the 
following schedule: 
 
Baseline/Week 0: a 2-week supply 
Week 2: a 2-week supply 
Weeks 4 & 8: a 4-week supply 
 
In the case of having participants who are traveling or experience unforeseen circumstances, we 
will coordinate with the research pharmacy to adapt the current distribution schedule to the 
participant’s needs to ensure they receive enough study medication. 
 
Medication adherence: As part of the virtual weekly visit, participants will be asked to show their 
used and unused study medication each week to complete a weekly medication count to assess 
compliance. Missed doses will be discussed to try to ascertain the reason(s). Reasons for missed 
doses and/or patterns of missed doses will be incorporated into the vaping cessation sessions and 
every effort will be made to ensure proper subject dosing. Text messaging will encourage 
participants to take study medications as instructed. Participants will be instructed to bring all 
empty and unused study medication to in-person study visits. Unused medication will be 
cataloged by site staff to verify data reported by the subjects. 
 
The emocha smartphone app will be used during the treatment period to remind participants via 
text message to take their study medication, document medication adherence and medication 
identification, and record daily assessments. Emocha will also be used for appointment 
reminders. When emocha is not available, participants will use REDCap to upload a time-
stamped photo to confirm use of study meds. Recorded dosing will be incentivized with 
micropayments. Emocha and REDCap have embedded privacy protections. 
 
Daily surveys are estimated to take 1-5 minutes each. To maximize compliance, we will adhere 
to best practice guidelines including training on the software at baseline and as needed 
throughout the study, ongoing compliance monitoring and follow-up with participants who 
demonstrate low adherence. Micropayments will be made to incentivize each survey completed 
($1 per emocha video and survey completion, up to $2 daily). 
 


Version 2024.01.10 
15 
c. Devices to be used: N/A 
 
d. Interventions (for participant randomized to varenicline or placebo arms) 
 
i. 
QuitVaping behavioral support sessions will be delivered weekly during the 12-week 
treatment phase via videoconference or in-person. QuitVaping is a manualized 
intervention based on the American Lung Association smoking cessation program47 
modified with teen friendly content and language for adolescent vaping cessation from 
the vaping section of teen.smokefree.gov32 and the Truth Initiative, including: 
 
- 
How to quit vaping: includes setting a quit date and standard quit date preparation 
modified for teen vaping;  
- 
Your first day without vaping; 
- 
Dealing with vape cravings, with standard behavioral methods for nicotine cravings 
and a prompt to call 1-800-QUIT-NOW or 1-877-44U-QUIT, or chat with an expert 
online using the National Cancer Institute’s LiveHelp service;  
- 
Understanding your vaping triggers;  
- 
Vaping addiction and nicotine withdrawal;  
- 
Anxiety, stress, depression and vaping; 
- 
How does vaping affect the environment? Your health?;  
- 
Your likelihood of using other drugs or smoking;  
- 
How to say no to vaping with friends; 
- 
Information on the corporate exploitation of youth through the marketing of addictive 
products for profit, corporate support for vaping memes and corporate funding of 
social media influencers to promote vaping. 
 
Before behavioral intervention sessions, participants will fill out assessments of vaping 
craving and collect saliva for cotinine testing (the latter only occurring if the participant 
self-reports nicotine abstinence since the last weekly visit). To refine and tailor these 
interventions to be maximally appealing to and effective for adolescents who vape, we 
will ask participants for weekly feedback on the appeal, relevance, and effectiveness of 
the educational topics and skills covered in the program. For participants randomized to 
the EUC arm, weekly sessions will only consist of non-directive support and assessments 
noted in the Time and Events Table, including saliva samples for cotinine (collected only 
to bio-verify self-reported nicotine abstinence). 
 
CBT Structure 
Time 
Activities 
5 mins 
Check-in on adverse events, vaping exposure, and medication adherence 
3 mins 
New educational content 
7 mins 
Review of education material and skill/behavior goal 
 
Prior to initiating the study intervention, interventionists will complete training conducted 
by Dr. Corinne Cather or other doctoral members of study staff on QuitVaping sessions. 
This will include didactic training on vaping and vaping cessation in adolescents, study 


Version 2024.01.10 
16 
methods, theoretical rationale, and background information on the behavioral and 
pharmacologic interventions. At the end of the training, leaders must achieve a minimum 
score of 80% on the fidelity scale based on their facilitation of two simulated sessions 
before they lead a session.  
 
e. Enhanced Usual Care (EUC) 
 
i. 
TIQ (This is Quitting) is a free, publicly available text message vaping cessation 
program from Truth Initiative, designed specifically to help adolescents who vape 
nicotine quit. The program is grounded in theory-driven and empirically validated 
tobacco cessation treatment strategies for young people,48 national cessation treatment 
guidelines,49 the Mayo Clinic 5-E Model of Wellness Coaching,50 and the Truth Initiative 
qualitative research and social media observations of young e-cigarette users.51 TIQ is 
reported to have been used by over 70,000 youth in the first year after its launch in 
2019.52 TIQ texts messages with young people who have attempted to, or successfully, 
quit e-cigarettes, together with evidence-based tips and strategies to quit and stay quit. 
The language in TIQ is tailored based on the age and products used by the participant to 
give adolescents appropriate recommendations about quitting.  
 
Participants who set a quit date receive messages for a week preceding it and 30 days 
afterward that include encouragement and support, skill- and self-efficacy building 
exercises, coping strategies, and information about the risks of vaping, benefits of 
quitting and cutting down to quit. Keywords “CRAVE,” “STRESS,” or “SLIP” provide 
on-demand support. Users can unsubscribe anytime by texting “STOP.” The teen version 
of the program (ages 13–17) refers to e-cigarettes as JUUL/JUULing, whereas the young 
adult version (YA, ages 18–24) uses several terms (e.g., vaping, e-cigarette).52  
 
Participants in all three arms will be introduced to TIQ in the first session (week 0) and 
encouraged to sign up. Use of digital resources will be discussed and tracked in 
subsequent sessions along with troubleshooting of any problems. Any participant who 
does not have a compatible phone or for whom the texting program would pose a 
financial burden will be given a phone to use for the study.  
 
f. Data to be collected  
Questions derived from the PhenX Toolkit53 will be collected during the phone screen to assess 
for demographics as well as other enrollment criteria, such as vaping and smoking history.  
 
Demographics will be re-assessed by self-report during the enrollment visit. 
 
Medical History will be assessed during the enrollment visit. 
 
Population Assessment of Tobacco and Health (PATH) Study Data Collection 
Instruments54 
The following questionnaires from PATH will be administered at the enrollment visit: Age of 
initiation, lifetime quantity and frequency of tobacco use, prior cessation attempts for vaped 


Version 2024.01.10 
17 
nicotine, other substance vaping, use of other forms of tobacco, cannabis products, alcohol, non-
medical opioids, and other addictive substances. 
 
Willingness to Quit (WTQ) vaping in the next 30 days will be queried at the phone screen and 
enrollment visit with the PATH questionnaire on serious thoughts about quitting all tobacco 
products. 
 
Motivation to Quit (MTQ)55 (PhenX ID=710501) is a single item measuring motivation to quit 
vaping among those who want to quit vaping. It will be administered at enrollment with the 
PATH questionnaire. 
 
The Columbia-Suicide Severity Rating Scale Screener (C-SSRS)56 will be used to assess 
suicidal ideation in the past six months.. This screener will be administered at enrollment and 
will help determine current suicidality incompatible with safe participation in the study. 
 
Flavor Preference57 Youth who vape are far more likely than adults to report using fruit, mint, 
and candy flavored vapes (OR=21(95% CI: 6, 75)).58 This 5-item youth questionnaire will be 
used at enrollment to query e-cigarette flavor use and preference. 
 
The Peer and Family Influence on Smoking59 (PhenX ID=710901) will assess at enrollment 
smoked and vaped tobacco use by those in the participant’s household, dormitory, suite or 
apartment, and perception of use by their immediate social networks. This 5-item measure can be 
self- or interviewer-administered. It is validated for ages 12-22, and its use up to age 26 has been 
recommended as has application of the questions to other tobacco use (e-cigarette and hookah). 
 
The E-Cigarette Dependence (ECDI)60 will be administered at enrollment, baseline, week 12, 
and week 24 to assess the severity of nicotine dependence, which has been reported to correlate 
significantly with cotinine as a biomarker of nicotine exposure. ECDI scores of ≥4, 
corresponding to at least mild nicotine dependence will be required for enrollment. The ECDI 
has been shown to be valid and reliable among e-cigarette users and dual users of e-cigarettes 
and combusted tobacco.  
 
The Alcohol Use Disorders Identification Test (AUDIT)61,62 was developed by the World 
Health Organization (WHO) as a simple screening tool to identify hazardous or harmful alcohol 
use. The AUDIT will be administered at the enrollment visit and at end of the treatment and 
follow-up phases of the study to detect change from baseline in harmful alcohol use. 
 
The Cannabis Use Disorders Identification Test (CUDIT)63 will be administered at the 
enrollment visit and at end of the treatment and follow-up phases of the study to detect change 
from baseline in symptoms of cannabis use disorder. 
 
The Questionnaire of Vaping Craving (QVC)64 is a brief, 10-item, valid and reliable measure 
of vaping craving that queries desire and intent to vape and anticipation of positive outcomes 
related to e-cigarette use that will be administered at enrollment, baseline, and weekly via 
REDCap. 
 


Version 2024.01.10 
18 
Minnesota Nicotine Withdrawal Scale (MNWS)65 is a valid, reliable, 9-item self-rated scale of 
urge to smoke (craving); depressed mood; irritability, frustration or anger; anxiety; difficulty 
concentrating; restlessness; increased appetite; difficulty going to sleep; difficulty staying asleep, 
on an ordinal scale from 0 (not at all) to 4 (extreme). It will be administered at enrollment, 
baseline, and weekly via REDCap. 
 
The Concise Health Risk Tracking Instrument (CHRT-SR)66,67 will be administered to 
provide a sensitive assessment for change in suicidality to supplement open-ended adverse 
events queries at each study visit during the treatment phase. The CHRT-SR is a reliable and 
valid measure for examining severity of suicidal thoughts and associated risk factors and is 
sensitive to change in adolescents. It will be administered at baseline and each monthly 
assessment visit during the treatment and follow-up phases. Clinically trained study staff will 
follow-up on any positive responses.  
 
The Mood and Anxiety Symptoms Questionnaire (MASQ-D30)68 is a 30-item adaptation of 
the 96 item MASQ that is a quick, valid, and reliable assessment of depression and anxiety in 
adolescents that will be administered at enrollment, baseline, and each assessment visit. 
 
Neuropsychiatric Adverse Events Interview (NAEI)36 is a semi-structured interview designed 
to systematically assess the presence and severity of specific neuropsychiatric symptoms and will 
be administered at enrollment, baseline and at each assessment visits. This instrument will be 
asked in regards to the past six months (at enrollment) and since the last assessment visit (all 
other timepoints). 
 
Adverse Events will be assessed weekly by the study staff via REDCap during the treatment 
phase and then monthly during assessment visits to assess the tolerability of the study 
procedures. 
 
Concomitant Medications will be assessed by self-report at each visit. 
 
Peer Network Stability: At baseline, V12, and 3-month follow-up, participants will be asked to 
list and rank up to 10 friends in order of closeness, using a modified version of the “concentric 
circles of closeness” sociometric measure used in. 80, 82 Participants will generate their friends’ 
names by free recall to ensure (1) friends included in the study could come from any context and 
(2) participants designated only individuals whom they truly considered to be friends.81 A 
friendship network instability index will be created by calculating the absolute value of the sum 
of each peer’s rank change divided by the total number of peers the adolescent listed at the 
consecutive time points to account for differences in network sizes.79 At the V24 visit (3-month 
follow-up) only, participants will be invited to provide telephone numbers for their top three 
nominated friends, to be recruited for the ancillary cohort. 
 
Modified Mental Health Youth Satisfaction Survey(YSS) 69 is a 26‐item self-rated survey of 
youth perception of services in 5 domains: access to services; appropriateness of services; 
cultural sensitivity; participation; and treatment outcome whose internal consistency ranges from 
0.70 - 0.94. It has been widely used in state mental health systems to assess youth satisfaction 
with services and will be given at week 12 to assess participant satisfaction with the intervention. 


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The Impulsive Behavior Scale (UPPS-P) – Short70 will be given at enrollment to assess five 
components of impulsivity, including sensation seeking, lack of premeditation, lack of 
perseverance, negative urgency, and positive urgency. Scores on many of these factors have been 
shown to relate to risk behavior. 
 
The Wechsler Test of Adult Reading (WTAR )71 will be used to assess speech and dictation 
and derive an estimated IQ at enrollment. 
 
The Behavior Rating Inventory of Executive Function—Self-Report (BRIEF-SR)72 is a 
standardized 80-item self-report behavior rating scale that assesses impulsivity in cognition, 
behavior, and executive functioning skills. The BRIEF-SR will be administered at enrollment 
and week 12. 
 
emocha Mobile Health is a mobile health platform that uses video technology and human 
engagement to monitor patient behavior and enable remote engagement in clinical trials. The 
emocha platform is globally compliant in terms of data protection standards, including GDPR 
ready, EU-US Privacy Shield certified, and HIPAA compliant. For those randomized to 
varenicline or placebo, emocha will be used to send twice daily reminders to take study 
medication and remotely monitor study medication dosing. Participants will record daily vaping 
either via emocha or REDCap.  
 
Measures of Vaping abstinence: Saliva will be collected weekly during the treatment phase and 
then monthly for semi-quantitative cotinine measurement to verify nicotine abstinence in 
participants who self-report abstinence. Only at enrollment and baseline will cotinine be 
collected despite self-report to verify use. For in-person sessions, saliva will be collected before 
the session. For remote sessions, a handout with instructions, materials, and barcoded kits unique 
to participant will be mailed to participants to perform weekly before their weekly assessment 
visits. We developed SOPs for safe at home collection and mailing of biological specimens, a 
procedure we piloted during the closure of MGH clinical research facilities from March-June 
2020. Semi-quantitative cotinine of <30ng/ml will validate self-reported nicotine vaping 
abstinence since the last visit. Those who report no vaping use since the last study visit but who 
have a cotinine >30ng/ml will be considered non-abstinent at that visit for the analyses. 
 
Measures of smoking abstinence: Carbon monoxide (CO) in expired air will be measured at 
enrollment with a small, hand-held CO monitor. To do so, participants will blow into a straw 
attached to the device, a Bedfont Smokerlyzer II (Kent, England), following a 15-second breath- 
hold to verify self-report of non-smoking status. Expired CO <5 parts per million (ppm) is 
consistent with smoking abstinence. Assays for NNAL will be conducted on urine collected at 
baseline and weeks 12 and 24. NNAL <10pg/ml will be considered a more sensitive verification 
of self-report of no combusted tobacco use in the past 2-3 months. Participants with an NNAL of 
<10pg/ml at baseline and >10pg/ml during the study will be considered to have initiated 
combusted tobacco use during the trial. 
 


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20 
Timeline Follow-Back (TLFB): The TLFB will assess tobacco vaping, smoking, cannabis, and 
alcohol use. It will be administered at enrollment, baseline, monthly, and follow-up visits. A 
modified TLFB of vaping in the past 7 days will be administered at weekly intervention visits. 
 
Pregnancy test: Urine will be collected from biological females at enrollment, baseline, week 4, 
week 8, and week 12 for a pregnancy test. 
 
Drug testing: Urine will be collected at enrollment, baseline, and monthly assessments to screen 
for recent use of cannabis, amphetamines, methamphetamine, cocaine, opiates, barbiturates, 
benzodiazepines, phencyclidine, methadone, and oxycodone. Quantitative assessment of THC 
metabolites in urine will be conducted at baseline, week 12, and week 24 to assess for new 
cannabis use or change in cannabis use during the trial. 
 
Perceived treatment assignment: To assess participants’ guess of their treatment assignment, 
participants will be asked, “what treatment do you think you received? This will be followed by 
one open-ended question: “Why do you think you received that treatment?” No clarifications 
will be asked, nor will participants be probed to expand on their answers. This question will be 
asked either at the end of the week 12 visit or their termination visit. 
 
DNA Collection (saliva) and Analysis: DNA samples will be collected at enrollment using 
Oragene (OGR-500) saliva kits. Participants may be asked to provide a second sample if a 
recollect is recommended after DNA extraction (i.e., there is very little DNA in the sample). 
Participants are not required to provide another sample if they do not wish to do so. Once 
extracted, samples will be transferred to long term storage until genotyping. Samples will be 
stored with a unique participant ID. 
 
GWAS Genotyping: The Broad Institute will perform genotyping (array-based) of subject 
samples and subsequent in-depth analysis of the data, which will allow us to detect alterations in 
the genome including point mutations, small insertions and deletions, chromosomal copy number 
alterations and translocations. These experiments are intended to help identify candidate genes 
involved in the physiopathology of neurological and psychological diseases. The molecular 
information generated from these samples will not be returned to subjects at any time. 
 
Data from this study may result in communications in journals or at scientific meetings. Subjects 
will not be identified in those communications. To facilitate research, the genetic information 
generated may upon publication be deposited in protected databases (such as dbGAP) available 
only to bona fide researchers with specific scientific questions who promise to try not to identify 
individuals. The data will be sent to these banks in a coded manner and again will not contain 
any traditionally used identifiers such as name, address, phone number, or social security 
number. Although we cannot predict how genetic information will be used in the future, there are 
many safeguards in place, and we do not think that there will be further risks to patients’ privacy 
and confidentiality by sharing such information with these banks. 
 
The Broad Institute will not be involved in subject ascertainment. Prior to the transfer of 
biospecimen aliquots to the Broad Institute, samples will be re-encoded at the collaborator's 
institutions. No identifying patient information will be shared with Broad scientists at any time. 


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Some limited clinical data will be obtained from collaborators and only de-identified clinical 
data will be shared with the Broad Institute. 
 
Genetic Data Protection: In addition, steps will be taken to protect the confidentiality of genetic 
data as outlined: 
 
1) All MGH study staff are trained to make confidentiality the first priority. 
2) No genetic research data will be entered into the medical record. 
3) The results of the genetic analyses will not be shared with participants, their family 
member(s), or unauthorized third parties. 
4) Genetic data are encoded using coded identifiers. These codes, rather than personal 
identifiers, are used in any analytic datasets. The code key linking coded identifiers to 
personal identifiers is kept in an access-restricted, password-protected electronic file 
and is not shared with the genetic laboratories. 
5) Consent forms are stored in locked cabinets apart from demographic and diagnostic 
data. 
6) Samples and genetic data stored in the laboratory will be identified only by the code 
numbers and laboratory personnel will not have access to personal identifiers. 
7) The most risk would be identification of individuals in the publicly shared database. 
To prevent this, computerized data files provided to other investigators will not 
include any of the HIPPA-defined personal identifiers. Published material will not 
identify subjects. 
 
Ancillary Cohort Data to be Collected: 
 
Demographics will be assessed by self-report during the enrollment visit. 
 
The Mood and Anxiety Symptoms Questionnaire (MASQ-D30)68 is a 30-item adaptation of 
the 96 item MASQ that is a quick, valid, and reliable assessment of depression and anxiety in 
adolescents. 
 
Timeline Follow-Back (TLFB): The TLFB will assess tobacco vaping, smoking, cannabis, and 
alcohol use. A modified TLFB of vaping in the month prior to associated primary participant’s 
V24 will be administered. 
 
COVID-19 Design Consideration 
This protocol includes data collection and interventions that can be completed either in-
person or virtually. These visits and assessments can be safely conducted in-person with ample 
precautions in place, and standard operating procedures to ensure the safety of the participants 
and staff have been written, reviewed, approved by our institution’s COVID-19 safety officers, 
and are in place for our ongoing research protocols. Remote intervention and assessment visits 
may be required due to COVID-19 safety concerns, and we have piloted procedures for shipping 
study medication and specimen collection kits to participants’ homes.  
 
Early Termination and Relapse 


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Participants will be encouraged to attend all study visits, regardless of vaping status or 
ongoing use of study medication. Participants may voluntarily discontinue study procedures at 
any time for any reason. Participants may be discontinued if their continued participation in the 
study presents an undue risk to their health as determined by the principal investigator or if they 
are unable or unwilling to follow study procedures. For any participant who discontinues 
treatment for any reason, an early termination visit will be conducted to assess vaping outcomes, 
nicotine craving and withdrawal, clinical symptoms, and adverse effects. Every effort will be 
made to contact participants who do not return for a scheduled visit. In any circumstance, every 
effort should be made to document subject outcome. Study staff will inquire about the reason for 
withdrawal, request the participant to return all unused investigational product(s), request the 
participant to return for a final visit, if applicable, and follow-up with the participant regarding 
any unresolved adverse events. Three telephone calls and one letter will be sent to participants 
who are lost to follow-up to schedule the early termination visit. 
 
Participants will be terminated from the protocol if the research team determines that 
their continued participation is unsafe or not in their best interest (e.g., in circumstances where 
there is deterioration in their mental or physical health judged to require a change in medication 
or hospitalization). If a participant is discontinued, we will refer them to clinical resources for 
follow-up care or consultation, and we will ask them if this information that can be disclosed to 
their parents/guardians as applicable to help coordinate and facilitate care. 
 
Study Compensation 
Participants will be compensated $30 for the enrollment visit and all subsequent weekly 
and follow-up visits. Participants will be paid $50 (varenicline and placebo) or $100 (Enhanced 
Usual Care) for completion of monthly visits during the treatment period. Participants will be 
paid up to $2 per day (up to $168 total) for emocha medication adherence and REDCap survey 
completions (for those not randomized to EUC). All participants who complete the study will be 
automatically entered into a raffle for a study completion bonus. For a more detailed description 
of our payment schedule, refer to the table below. Participants will be reimbursed up to $15 for 
necessary travel related to in-person visits. Participants will be compensated for study visits 
either via MGB-issued check or using the MGB Advarra Participant Payment system, a cloud-
based application that provides subjects with a reloadable Visa card that is credited with fixed 
stipends following specified data collection points. Participants will be informed of Advarra 
policy during the consent process. After agreeing to participate in the study, participants will also 
be asked to sign a “Advarra Participant Payment Card Acknowledgement of Receipt” form to 
certify their understanding of Advarra Participant Payment policies. The form will require 
participants to print and sign their name and provide their social security number. If the 
participant is under 18 years old, then parent/guardian information including date of birth, social 
security number, and address will be collected.  Advarra acknowledgment forms will be stored in 
a locked study cabinet. Travel reimbursement as well as emocha/REDCap adherence will issued 
to participants as a lump sum via check at the conclusion of their study participation. Participants 
will be paid using gift cards if they cannot be paid via Advarra/check using a social security 
number/individual taxpayer identification number. 
 
Ancillary participants will be compensated $30 for the one-time remote, questionnaire-based 
visit. All ancillary participants who consent will be compensated in full, regardless of how much 
of the visit they complete. 


Version 2024.01.10 
23 
 
Payment Schedule
Visit/Week 
Varenicline/Placebo 
EUC 
Enrollment 
30 
30 
Weeks 0, 1, 2, 3 
30 
30 
Week 4 
50 
100 
Weeks 5, 6, 7 
30 
30 
Week 8 
50 
100 
Weeks 9, 10, 11 
30 
30 
Week 12 
50 
100 
Week 16, 20, 24 
30 
30 
Emocha + surveys 
168 
0 
Total 
738 
720 
Raffle Bonus 
450 
468 
Grand Total 
1188 
1188 
 
Ancillary cohort: one-time $30 compensation for all participants after primary participants’ 
Week 24 visit. 
 
VI. BIOSTATISTICAL ANALYSIS  
 
Statistical Design and Power:  
Response estimates are based on 2 studies of the effect of varenicline or placebo plus 
brief weekly individual behavioral treatment for smoking cessation in adolescent smokers with 
nicotine dependence of a similar age range. One reported modest medication adherence (63% 
took 100% of dispensed doses) and high dropout rate (45%) which may underlie low abstinence 
rates (<10%) in both groups. We speculate that this trial under-estimates the therapeutic effect of 
varenicline for adolescent smoking cessation with more optimal treatment adherence. 
Additionally, potentially important participant characteristics, such as the proportion living with 
smokers, was not reported and may significantly impact abstinence outcomes in adolescents. In 
this trial, we will assess smoking and vaping in members of the household (or dorm) and in the 
primary peer group, and daily text message reminders to take medication and remotely observed 
dosing via emocha or REDCap will encourage medication adherence.  
Continuous abstinence rates for weeks 9-12 of a 12-week intervention in the Pfizer report 
to the FDA in the varenicline arm ranged from 10-35%. Lowest abstinence rates (10%) were in 
older adolescents (ages 17-19) assigned to low dose varenicline (0.5 mg bid). In the proposed 
trial, adolescents who weigh >55kg, more likely amongst older adolescents, will be assigned to 
1.0 mg bid as tolerated. Younger adolescents had numerically higher abstinence rates on 0.5 mg 
bid than 1.0 mg bid, regardless of weight, 16-21% versus 35%. This may have been due to 
tolerability issues. While there were no differences between any treatment arm in 
neuropsychiatric adverse events, the high dose group reported numerically more nausea, 
vomiting, and headache than the low dose and placebo groups. Those aged 17-19 with weight 
>55kg had better abstinence rates with 1.0 mg bid. Thus, we propose to dose by weight, not age, 
to employ flexible dosing as follows: All participants will be assessed for tolerability of 0.5 mg 
bid at the end of study week 1. Participants who weigh >55 kg who tolerate 0.5 bid with no 


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complaints will be offered an increased dose of 1mg bid. Other participants will be continued at 
0.5 mg bid.  
 
The primary aim of this trial is to detect whether varenicline added to behavioral 
treatment significantly increases vaping abstinence rates compared with behavioral treatment 
alone. We have computed power over a range of outcomes. It is likely that varenicline will need 
to have a significant effect, such as doubling abstinence rates, to be considered appropriate for 
youth treatment.  Such a significant increase in abstinence with varenicline over that achievable 
with low cost behavioral and digital intervention is clinically important because it would be 
warranted to justify the risk and expense of starting medications in this adolescent population. 
 
Data Analysis:  
 
Missing data:  
Missing or incomplete outcome data from study week 9 to 12 will be imputed 40 times 
using multiple imputation via chained equations (MICE).73 Outcome data will be imputed using 
three predictors collected at the baseline visit: biological sex (male versus female), environment 
(secondary school versus post-secondary school), and severity of nicotine dependence (the Penn 
State Electronic Cigarette Dependence Index, a summed score ranging from 0 – 20).74 
Imputation will be done via fully conditional specification with predictive mean matching using 
linear models for continuous data and logistic regression for binary variables. 
Analyses of safety and efficacy will be conducted separately for participants assigned to 
Canadian manufactured, apo-varenicline or placebo (pilot) and for participants assigned to US 
generic Par Pharmaceutical manufactured varenicline (main trial). Analyses on the combined 
samples of Apo-varenicline and Par pharmaceuticals varenicline will be conducted if 
appropriate. If combined analyses are considered to be appropriate, these will be considered in 
the primary analyses. 
 
Statistical method:  
Hypotheses 1.1-1.6: We will use a logistic regression applied to the binary outcome for 4-week 
continuous abstinence at end of treatment (weeks 9-12; primary) and end of follow-up (weeks 9-
24) (1 = abstinent, 0 = not abstinent). Participants whose status cannot be clearly determined due 
to missing data will have continuous abstinence status determined via imputation (see missing 
data plan). We will include three covariates measured as baseline: sex, environment (secondary 
school versus post-secondary school), and severity of nicotine dependence (the Penn State 
Electronic Cigarette Dependence Index, a summed score ranging from 0 – 20). Covariates will 
be standardized (mean-centered and scaled by the standard deviation). The analysis will be 
intent-to-treat; all subjects randomized at the beginning of the study will be included in the 
analysis, irrespective of whether they receive their assigned behavioral treatment or take their 
assigned medication. Missing data will be imputed per the method specified above. We will then 
apply our logistic regression model to each set of observed and imputed data, and pool the 
regression estimates according to Rubin’s rule. Statistical significance for the contrast between 
varenicline and placebo will be determined using a z-test applied to the pooled mean estimate 
divided by the pooled standard error, where p < 0.05 will indicate that the addition of varenicline 
to behavioral and texting support is more effective than placebo for cessation of vaped nicotine 
in adolescent non-smokers with nicotine dependence. 
 
The same analyses will be applied for secondary hypotheses comparing (1) varenicline to 


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placebo for seven-day point-prevalence nicotine vaping abstinence at end of treatment 
(Hypothesis 1.2), (2) varenicline to EUC for 4-week continuous abstinence at end of treatment 
and end of follow-up (Hypothesis 1.3), (3) placebo with behavioral treatment to EUC for 4-week 
continuous abstinence at end of treatment and end of follow-up (Hypothesis 1.4), (4) varenicline 
to EUC for seven-day point-prevalence nicotine vaping abstinence at end of treatment 
(Hypothesis 1.5), and placebo with behavioral treatment to EUC for seven-day point-prevalence 
nicotine vaping abstinence at end of treatment (Hypothesis 1.6). 
 
Hypothesis 2.1: We will use a linear model applied separately to repeated, continuous weekly 
assessments of nicotine withdrawal symptoms, craving, and negative mood symptoms. The 
linear model will be estimated using generalized estimating equations (GEE), providing 
estimates and standard errors robust to violations of distributional assumptions (e.g., normality), 
and heteroscedasticity. The model will be applied to the summed scores at each time point per 
subject. The analysis will be intent-to-treat with missing data imputed per the method specified 
above. The key confirmatory effect will be a dummy-coded contrast comparing placebo (coded 
as 0) against varenicline (coded as 1). Exploratory analyses will also be conducted to evaluate 
varenicline versus EUC and placebo versus EUC. The model will include covariates for a) 
change over time (two terms encoding linear and quadratic trends), b) baseline levels of the 
given outcome, as well as c) sex, environment (secondary school versus post-secondary school), 
and severity of nicotine dependence. Covariates will be standardized (mean-centered and scaled 
by the standard deviation). P-values will be adjusted to avoid multiple comparison issues using 
the Benjamini-Hochberg method. 
 
Hypothesis 2.2: We will conduct a Fisher’s exact test differences by randomized group in the 
number (%) of participants who endorse an AE at least once in the 12-week treatment period. 
We will evaluate frequent AEs (e.g., that occur in at least 5% of the participants at any point 
between weeks 1 through 12 of the trial). 
 
Sensitivity analyses: We will conduct 3 sensitivity analyses to examine the robustness of our 
conclusion for efficacy. 
1. We will test whether our conclusion on efficacy is robust to the inclusion/exclusion of 
the 3 covariates (biological sex, environment [secondary school vs. post-secondary 
school], and nicotine dependence severity) – we therefore will rerun the analyses 
without the 3 covariates and examine whether the pooled estimate for the contrasts 
between varenicline, placebo, and/or EUC changes in sign and significance. 
2. We will test whether our conclusion on efficacy is robust to the approach for 
imputation of missing data, examining whether the pooled estimate for the contrasts 
between varenicline, placebo, and/or EUC changes in sign and significance. 
a. We will rerun the adjusted (i.e., with covariates) models on the observed data 
only. 
b. We will rerun the adjusted models on a data set with the observed data and all 
missing outcome data imputed as non-abstinent. 
3. We will test whether on conclusion on efficacy is robust to medication adherence by 
conducting a per protocol analysis. We will rerun the analyses only among participants 
who use varenicline on most days in the trial (e.g., 50-75%). 
 


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Software: All analyses will be conducted using the statistical software R (version 4.1.1).75 
Multiple imputation will be carried out using the R package ‘mice’ (version 3.13.0).73 The GEE 
method will be implemented via the R package ‘geepack’ (version 1.3-2).76 
 
VII.. RISKS AND DISCOMFORTS  
 
i. Varenicline Risks: Varenicline has been associated with significant adverse effects, 
including drowsiness and seizures, and must be used with caution while driving. Varenicline was 
previously thought to increase suicidality and neuropsychiatric side effects through similar 
mechanisms as bupropion and other antidepressants; however, the rate of neuropsychiatric 
adverse events has been shown to be no different between varenicline and placebo or bupropion 
or NRT patch in large-scale randomized controlled trial specifically examining these outcomes 
across an array of at-risk and general populations. Varenicline has not been approved for use in 
adolescents aged <18 years. However, recent studies have evaluated the pharmacology, safety, 
and tolerability of varenicline in adolescent smokers. The clinical pharmacology of varenicline in 
adolescent smokers was characterized in 1 single- and 2 multiple-dose pharmacokinetic (PK) 
studies in adolescent smokers. The most frequently reported adverse events in varenicline treated 
adolescent smokers were nausea, headache, vomiting, and dizziness. The incidence of 
nausea/vomiting increased with increasing varenicline exposure. Female adolescent smokers had 
a higher incidence of nausea relative to male adolescent smokers, regardless of dose, consistent 
with observations in adult smokers. Except for 1 case of severe nausea in a subject in the low-
body-weight group (< 55 kg) on varenicline 0.5 mg once daily, all AEs were mild or moderate in 
intensity and resolved during the study. Psychiatric adverse events considered to be treatment-
related were abnormal dreams (n = 2) and mild, transient anger (n = 1). No participants 
discontinued medication or had their dosage reduced due to an adverse event. A 12-week 
varenicline trial from a Pfizer-sponsored multisite study in 307 adolescent smokers (12-19 years 
of age) who were motivated to quit smoking reported no difference in tolerability between high-
dose (1 mg bid) or low-dose (0.5 mg bid) varenicline treatment versus placebo.  
 
To minimize risk of nausea, dosing will be recommended with 240 ml of water, and it is 
recommended that subjects eat prior to dosing. It is recommended that there be at least 8 hours 
between the morning and evening doses. Dosing may be reduced to 0.5 mg bid, temporarily 
discontinued, or stopped for subjects due to adverse events (e.g., nausea).  
 
To minimize risk of rash, there have been rare post-marketing reports of serious rash 
occurring with use of varenicline. To minimize risk of allergic reaction, people with a history 
of hypersensitivity to varenicline will be excluded. 
 
To minimize risk of neuropsychiatric adverse events, participants with a lifetime history of 
schizophrenia or bipolar disorder, an inpatient psychiatric hospitalization in the prior 6 
months, a prior suicide attempt or serious suicidal ideation within 6 months of enrollment, or 
recent active suicidal ideation or suicidal behavior identified at enrollment or baseline visits 
will be excluded (see enrollment criteria). The study team is well prepared to identify and 
address urgent issues that may arise in the setting of new neuropsychiatric adverse events. Our 
investigators and group leaders are well-trained in psychotherapeutic interventions to help 
process and mitigate distress and have significant experience assessing and addressing patient 


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27 
safety. In addition, all study staff will be trained by a licensed psychiatrist (A. Eden Evins, 
MD, MPH) and licensed clinical psychologists (Corinne Cather PhD and Randi Schuster, 
PhD) on identifying and responding to emotional distress in research participants. To ensure 
this process is robust, we have developed an extensive standard operating procedure (SOP) for 
safety monitoring to ensure clinical research coordinators are able to reliably recognize 
emergent suicidal ideation based on a clearly defined pattern of responses on self-report 
inventories. The most updated SOP can be directly accessed using this file path: 
"\\SMBGPA\addnmed5$\CAM SOPs\X. SOP Word Documents". This SOP explicates the 
steps clinical research coordinators will take to report identified distress to the study's trained 
clinical team who may conduct a follow-up safety assessment if indicated. Participants will be 
terminated from the protocol and referred for clinical care if the research team determines that 
their continued participation is unsafe or not in their best interest, (e.g., in circumstances 
where there is deterioration in their mental or physical health judged to require a change in 
medication or hospitalization). For any participant for whom we have concerns about 
emotional wellbeing that do not rise to the severity of an imminent safety risk, we will ask 
them if we can discuss this with their parents/guardians (if 16-17) and/or treater to help 
coordinate a plan for monitoring and treatment. If a participant <18 years of age is 
discontinued due to psychiatric concerns, we will refer them to clinical resources for follow-
up care or consultation and we will ask them if this information can be disclosed to their 
parents/guardians to help coordinate and facilitate care. This procedure will also be used for 
ancillary participants who endorse imminent risk during their study visit. 
 
To minimize exposure to study drug during pregnancy: There are no adequate and well-
controlled studies of varenicline use in pregnant women. In animal studies, varenicline caused 
decreased fetal weight, increased auditory startle response, and decreased fertility in offspring. 
Varenicline should be used during pregnancy only if the potential benefit justifies the 
potential risk to the fetus. To be enrolled in this study, females of childbearing potential must 
be non-pregnant at enrollment and must agree to use effective contraception, such as an oral 
contraceptive agent, an intrauterine device, an implantable or injectable contraceptive, double 
barrier contraception or sexual abstinence for the duration of the study. The study drug will be 
discontinued immediately for any female subject who becomes pregnant during the treatment 
period of the study. These subjects will continue to attend study visits for follow-up. 
 
To minimize abuse liability: Fewer than 1 out of 1,000 patients reported euphoria in clinical 
trials with varenicline. At higher doses (>2 mg/day), varenicline produced more frequent 
reports of gastrointestinal disturbances such as nausea and vomiting. There is no evidence of 
dose-escalation to maintain therapeutic effects in clinical studies, which suggests that 
tolerance does not develop. Abrupt discontinuation of varenicline was associated with an 
incr4ease in irritability and sleep disturbances in up to 3% of patients. This suggests that, in 
some patients, varenicline may produce mild physical dependence, which is not associated 
with addiction. In a human laboratory abuse liability study, a single oral dose of 1 mg 
varenicline did not produce any significant positive or negative subjective responses in 
smokers. In non-smokers, 1 mg varenicline produced an increase in some positive subjective 
effects, but this was accompanied by an increase in negative adverse effects, especially 
nausea. A single oral dose of 3 mg varenicline uniformly produced unpleasant subjective 
responses in both smokers and non-smokers.38,77  


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ii. Nicotine Withdrawal Risks: While it is well known that smoking (and vaping) cessation 
provides a large overall health benefit to patients, there are potential adverse, though transient, 
consequences of quitting smoking (and vaping). Many study participants who successfully 
abstain from nicotine vaping may experience nicotine withdrawal symptoms. Nicotine 
withdrawal symptoms include anxiety, restlessness, anger, irritability, sadness, difficulty 
concentrating, increase in appetite, weight gain, difficulty sleeping and craving for tobacco. 
Withdrawal symptoms begin within a few hours of abstinence, peak 24-48 hours after cessation, 
and may last up to 4 weeks. Nicotine withdrawal can cause slowing on EEG, decrease in cortisol 
and catecholamine levels, sleep EEG changes, and a decline in metabolic rate. In adults, the 
mean heart rate decline is about 8 beats per minute. As with all withdrawal syndromes, the 
severity varies among subjects. Withdrawal symptoms can also mimic or aggravate the 
symptoms of other psychiatric disorders or side effects of medications. Participants who are able 
to quit vaping nicotine are at risk for weight gain. Weight gain following nicotine cessation 
averages 3-5 kg.  
To minimize risk of nicotine withdrawal: Half of participants will receive active varenicline, 
which will likely diminish withdrawal symptoms. All participants will receive written 
materials that list withdrawal symptoms that can be expected. Withdrawal symptoms are 
usually short-lived and never medically dangerous, and most abate after 1-2 weeks. 
 
iii. Psychosocial, Social and Legal Risks: There are no significant psychological, social, or 
legal risks anticipated with participation in this study. There is a slight risk that the 
questionnaires and interviews may contribute to temporary discomfort when participants are 
asked about sensitive behaviors or personal feelings (e.g., drug use, vaping behavior, or mood), 
but, in our experience with similar studies, this risk is minimal. Participants will be reminded by 
study staff that they may omit any questions they do not wish to answer or discontinue their 
participation at any time with no penalty or repercussions. Research staff will provide referral 
information for treaters in the community to participants who request such information. As we 
will be meeting with participants regularly and administering validated mood and substance use 
questionnaires at each visit, we are able to monitor changes in endorsement of mental health 
symptoms. For any participant that experiences significant worsening of symptoms during study 
enrollment, we will share these results with them and will suggest that they seek professional 
support. For any participant for whom we have concerns about emotional wellbeing that do not 
rise to the severity of an imminent safety risk, we will ask them if we can discuss this with their 
parent (if under the age of 18) and/or treater to help coordinate a plan for monitoring and 
treatment.  
 
Psychosocial, Social, and Legal Protections: We will maintain a Certificate of Confidentiality 
(CoC) from the National Institutes of Health for this study. The CoC protects the privacy of 
individuals who are subjects of research by establishing prohibitions on disclosure, in any 
Federal, State, or local civil, criminal, administrative, legislative, or other proceeding, of the 
names of research participants or any information, documents, or biospecimens that contain 
identifiable, sensitive information collected or used in research by an investigator or 
institution. We will use the CoC to resist any demands for information that would identify 
participants, except in the instances of child abuse and neglect, or harm to self or others. 
 


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29 
Protecting the Anonymity of the Schools: Schools will not be identified and only minimal 
information about their characteristics will be released. When the results are published or 
discussed in conferences, no information will be included that would reveal an individual 
participant’s identity or the name of the school at which the research was conducted. All data 
will be analyzed on a group level and not by individual participants.  
 
iv. Confidentiality and Privacy Risks: Protecting the confidentiality and integrity of our 
research participants is a top priority for this and all MGH-based research projects. Data will be 
collected using REDCap (Research Electronic Data Capture)78 tools hosted by MGH and 
Partners HealthCare. REDCap,REDCap Survey systems, and emocha provide secure, HIPAA 
compliant, web-based applications. Confidentiality will be maintained by numerically coding all 
data and by keeping all data in password protected databases. All study staff will be trained in 
protection of privacy of research participants and will be CITI certified. In addition, this study 
will maintain a Certificate of Confidentiality from the National Institutes of Health. 
 
Confidentiality Protections: MGH’s careful consent and data confidentiality procedures 
greatly minimize risk to privacy. Only MGH project investigators and authorized study staff 
will have access to data. Schools will not be provided any information regarding study 
participants, including cannabis use habits. Once collected, an individual’s data will not be 
released to anyone outside of MGH authorized project staff. Confidentiality is further assured 
by assigning a unique identifier to each participant. There will be a restricted-access master 
list of names and other identifying information linked to the identification number. The master 
list will be kept in a locked cabinet and a password-protected computer file, separate from 
other data, along with other materials that have the participant’s name (e.g., consent forms). 
No identifying information is listed on questionnaires or any other materials with data on 
them (e.g., drug tests). Self-report questionnaires will be administered via REDCap on 
Partners encrypted tablets, minimizing the risk of confidentiality breaches. Only authorized 
MGH project members will be allowed access to these tablets. Any data files in electronic 
format will be housed in our network server at the Center for Addiction Medicine at MGH 
and will be password protected so that only authorized project personnel have access to them. 
These files will not have participant names or identifying information attached to them. We 
will follow IRB standard procedures for protection of participant confidentiality in research 
studies that includes sending text messages that are relevant to the research study. 
 
Limits of Confidentiality on Clinical Information (Emergency Protocol): While we are 
committed to maintaining confidentiality to the extent to which we are able, confidentiality is 
limited when there is a deemed imminent risk to oneself or others or reports of child and elder 
abuse. Study staff will inform participants during the consent process that in emergency 
situations (in which an individual is at immediate risk for harm) we will release information 
about the participant. Specifically, if a participant tells any member of study staff that they 
have intent and/or a plan to cause harm to self or others, study staff will start the Center 
Emergency protocol that includes a psychiatric evaluation by a licensed mental health 
professional and even calling 911. If the participant says that they have recurrent thoughts 
about harming themselves or someone else but does not have intent or plan to do so, study 
staff will ask participant permission to notify appropriate medical or counseling personnel, 
including the guidance counselor or therapist. If study staff learns about mood concerns or 


Version 2024.01.10 
30 
problematic substance use, study staff will provide the participant with referral resources for 
follow-up consultation and care. The PI has prepared a comprehensive list of local and 
national resources for this purpose. 
 
For participants under age 18: Parents and staff members at participating schools, will not be 
provided any information regarding study participants, including substance use habits, unless 
there is imminent risk of harm to self or others in the opinion of the PIs. In the consent/assent 
forms, both parents and participants are informed that only in emergency situations (in which 
an individual is at imminent risk of harm) would we release any information. Specifically, if a 
participant tells us that he/she has intent and/or a plan to cause harm self or other, we will tell 
the parents, and call 911. If the participant says that he/she has recurrent thoughts about 
harming him/herself or someone else but does not have intent or a plan to do so, we may 
notify parents and other appropriate medical or counseling personnel if clinically indicated in 
the opinion of the PIs. Finally, if a participant discusses details about ongoing child abuse, we 
will report such abuse to the Department of Child and Families directly. If we learn about 
mood concerns or problem substance use, we will provide the participant with local and 
trusted resources for follow-up consultation and we will ask him/her if this information can be 
disclosed to his/her parents to help coordinate and facilitate care.  
 
Confidentiality of Drug Tests: The results of the qualitative and quantitative drug testing will 
be confidential. The only individuals who will have knowledge of the results of these tests are 
research staff directly working on the project. Information will be stored in a secure computer 
database that uses participant codes (rather than names) as identifiers. 
 
v. Randomization in Clinical Trials Risk: Participants will be assigned to an intervention by 
chance, using computer generated random allocation code produced by the MGH Research 
Pharmacy. The study arm to which a participant is assigned may prove to be less effective than 
an alternate study arm. 
 
VIII. POTENTIAL BENEFITS  
a. 
Potential benefits to participating individuals  
The study will potentially help individuals to stop vaping or substantially reduce their 
exposure to vaporized nicotine. 
 
b. 
Potential benefits to society  
The goal of this project is to test whether varenicline, the most effective treatment known for 
addiction to smoked tobacco, helps adolescent non-smokers who have developed nicotine 
dependence to quit vaping nicotine. This may benefit other adolescent nicotine vapers in the 
future and increase abstinence rates in this population by informing clinicians and 
adolescents who vape and their families of effective treatment options for nicotine vaping 
cessation. Given the prevalence of vaped nicotine use among adolescents who never smoked 
is rising more rapidly than any prior known drug, putting them at elevated risk for nicotine 
dependence, tobacco smoking, other drug use, and direct negative health effects of vaping, 
we believe that the few potential risks to participants in this research are outweighed by the 
potential benefits 
 


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IX. MONITORING AND QUALITY ASSURANCE  
a. 
Independent monitoring of source data 
All data management will be conducted in the offices of the PI at the MGH Center for 
Addiction Medicine (CAM) in Boston. Standard REDCap data collection forms for all 
proposed clinical rating scales will be used. Tablets with HIPAA compliant REDCap 
capability will be used to capture raw data from clinical rating scales entered by participants 
and study staff and self-reported substance use behavior. A study database will be designed 
by the PI and the data manager and maintained by the PI, the data manager and the research 
coordinators. The data manager will review the data weekly. Access to the database is 
restricted by password. The database will be protected by nightly backup on MGH servers. 
All data will be stored safely for at least 5 years after study completion.  
 
b. 
 Safety monitoring  
An independent Data and Safety Monitoring Board (DSMB) will be appointed for this study, 
to assess the safety of the study by determining whether there is an unacceptable level of risk 
due to study medication, study procedures, and whether an increased number of adverse 
events occur. The DSMB will be established to analyze interim results to assess the safety of 
the study drug at regular intervals for the duration of the study by determining whether an 
increased number of adverse events occur among study participants receiving drug compared 
to participants receiving placebo.  
 
The board will include a statistician, a smoking cessation expert, a pediatrician, and a 
psychiatrist. Each member of the DSMB will not otherwise be associated with the trial. 
Safety data will be reviewed by the Data and Safety Monitoring Board Data every 6 months 
after the recruitment period begins. The DSMB will receive summary reports on recruitment, 
retention and description of all adverse events and review them at each biannual DSMB 
meeting. The DSMB will receive all communication with the IRB and with the FDA. Subject 
information provided to the board will be identified only with study IDs to protect the 
confidentiality of subjects. The DSMB will assess interim results to determine whether the 
active drug treatment is associated with substantial risk, including higher rate of adverse 
outcomes when compared with the placebo group. 
 
c. 
Outcomes monitoring  
A DSMB Report written by the chair and approved by all members will be issued to the IRB, 
FDA, and the NIDA Project Officer after every DSMB meeting. The report will include, but 
may not be limited to, a synopsis of the trials, their progress to date, characteristics of 
participants enrolled, retention and disposition of study participants, quality assurance issues, 
regulatory issues, and reports of AEs and SAEs. 
 
Criteria for trial stopping rules: If serious adverse events occur more frequently in the active 
group compared to the placebo group, at a 2-tailed p value of <0.05, then the DSMB will 
discuss with the PI and co-investigators whether the trial should be stopped 
 
d. 
Adverse event reporting guidelines  


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Study staff, including co-investigators, research coordinators, and data managers, will meet 
weekly with the PIs and the Project Director during a weekly project management meeting to 
review study progress, including any adverse events. 
 
All adverse events volunteered, observed, or solicited will be recorded in the AE CRF from 
the time the subject signs the informed consent up to and including Week 24. The PI will 
meet weekly with all study investigators to review the details of data acquisition and analysis 
as well as any minor problems. AEs will be assessed for each subject at every visit. All 
adverse events will be recorded and will include the dates of occurrence; severity; assessment 
of relationship to study drug; countermeasure(s); specific drug therapy used in 
countermeasure; and outcome. Adverse events will be reviewed by the PI who will complete 
an adverse event report form and submit this to the IRB within the required time frame in 
accordance with the IRB guidelines. 
 
Reporting Adverse Events: The PI will report all adverse events experienced by the study 
subjects in accordance with HRC (Human Research Committee) guidelines to the 
Institutional Review board. Adverse events will also be reported by the principal investigator 
to the funding agency and to the FDA in accordance with IND regulations. The reporting of 
adverse events is the responsibility of the PIs, Drs. Evins and Schuster. 
 
In case of serious adverse events (SAE’s), the PI will report them within 24-hours by 
telephone, fax or email according to HRC guidelines, followed by a written report within 5 
business days. SAEs that occur within 30 days after a subject’s last dose of study medication 
that are categorized as definitely, probably or possibly relate1d to the study will be reported 
to the HRC and FDA. An annual report will be submitted to the HRC and the FDA of the 
progress of the trial. This will include individual study information and information on safety 
reports from the previous year. 
 
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SAP_001.pdf: 
 
1 
 
 
 
 
 
 
Brief Title: Varenicline for Nicotine Vaping Cessation in Adolescents (ViVA) 
Official Title: Randomized controlled trial of varenicline for cessation of nicotine vaping in adolescent 
non-smokers 
NCT Number: NCT05367492 
Document Date: 06/13/2024 
First published: 1/12/2022 
 
 
 
 


STATISTICAL ANALYSIS PLAN 
2 
 
Table of Contents 
Varenicline for Nicotine Vaping Cessation in Adolescents (ViVA) ................................................... 1 
Glossary ........................................................................................................................................... 3 
Study Design .................................................................................................................................... 4 
Participants ................................................................................................................................. 5 
Randomization ............................................................................................................................ 6 
Masking/Blinding ........................................................................................................................ 6 
Analytic Approach ........................................................................................................................... 7 
Primary Outcome ........................................................................................................................ 7 
Covariates ............................................................................................................................... 7 
Missing Data ........................................................................................................................... 8 
Statistical Model and Tests ..................................................................................................... 8 
Secondary Outcomes .................................................................................................................. 9 
Missing Data ......................................................................................................................... 10 
Biochemically-Verified Vaping Abstinence ........................................................................... 10 
Inventory Measures .............................................................................................................. 10 
Statistical Models and Tests ................................................................................................. 10 
Biochemically-Verified Vaping Abstinence ........................................................................... 10 
Inventory Measures .............................................................................................................. 11 
Adverse events ..................................................................................................................... 13 
Sensitivity Analyses ................................................................................................................... 14 
Power ............................................................................................................................................ 15 
Software and Data Management .................................................................................................. 16 
References ..................................................................................................................................... 17 
 
 


STATISTICAL ANALYSIS PLAN 
3 
 
Glossary 
Abbreviation 
Label 
BID 
Two times a day 
BMI 
Body mass index 
ECDI 
E-cigarette Dependence Inventory 
EUC 
Enhanced usual care 
FDA 
U.S. Food and Drug Administration 
MGH 
Massachusetts General Hospital 
MICE 
Multiple imputation via chained equations 
P+BC 
Placebo combined with brief behavioral counseling 
TIQ 
“This is Quitting” vaping cessation program 
V+BC 
Varenicline combined with brief behavioral counseling 
 
 
 
 
 


STATISTICAL ANALYSIS PLAN 
4 
 
Study Design 
We will evaluate the efficacy of a 12-week regime of varenicline, in addition to behavioral 
counseling and texting support, in increasing rates of vaping cessation among nicotine dependent 
adolescents, compared to (a) behavioral treatment and texting support and (b) enhanced usual care and 
monitoring. 
The study will consist of a randomized three-arm, placebo-controlled, parallel-group, double-
blind clinical trial: 
1. [V+BC arm] Participants will receive the drug varenicline, in tablet form, up to 1 mg BID for 
12 weeks. Additionally, participants will (a) attend QuitVaping behavioral support sessions 
(completed in-person or via video-conferencing), once per week for 12 weeks, and (b) be 
encouraged to sign up for This Is Quitting (TIQ), a text message vaping cessation program for 
adolescents. We plan to assign up to 100 participants to this arm. 
2. [P+BC arm]. Participants will receive placebo tablets, identical in appearance to varenicline, 
up to 1 mg BID for 12 weeks. Additionally, participants will (a) attend the QuitVaping 
behavioral support sessions once per week for 12 weeks, and (b) be encouraged to sign up 
for the TIQ program. We plan to assign up to 100 participants to this arm. 
3. [EUC arm] Participants will be assigned to a single-blind monitoring only group and will 
receive no drugs nor attend behavioral support sessions. Participants will receive a brief 
encouragement to enroll in the TIQ program. We plan to assign up to 100 participants to 
this arm. 
All participants will have weekly assessments to monitor vaping behavior, will receive advice to 
quit vaping at the first post-baseline weekly visit and be referred to the TIQ vaping cessation 
app. Other study-related outcomes will be assessed at the monthly visits (weeks 4, 8, 12, 16, 20, 
and 24). 
 
 


STATISTICAL ANALYSIS PLAN 
5 
 
Participants 
 
We will recruit nicotine dependent adolescents who vape, do not smoke regularly, and are 
willing to try treatment to stop vaping. To do so, we plan to enroll up to 300 adolescents (and randomize 
as many as possible) in Greater Boston meeting these criteria. Our inclusion criteria are: 
• 
Ages 16-25 (inclusive); 
• 
Self-report of daily or near daily nicotine vaping for the prior ≥ 3 months, bio-verified by saliva 
cotinine >30 ng/ml. 
• 
Nicotine dependence as defined by a score ≥ 4 on the 10-item E-cigarette Dependence 
Inventory (ECDI), and/or report persistent use despite negative consequences or prior failed quit 
attempts;  
• 
Self-report of no regular combusted tobacco use in the past 2 months at enrollment and exhaled 
CO <10 ppm; 
• 
Total body weight at enrollment ≥ 35 kg (77 lbs);  
• 
Are competent and able to consent (if 18 or older), or have a parent or legal guardian who is 
able and willing to provide written informed consent (if under the age of 18);  
• 
Able to understand study procedures and read and write in English;  
• 
For participants who could become pregnant: negative urine pregnancy test at enrollment and 
agree to use effective contraception (e.g., abstinence, hormonal contraception, intra-uterine 
device, sterilization, or double barrier contraception) during the study. 
Our exclusion criteria are:  
• 
Use of a smoking cessation medication in the prior month (nicotine patch, gum, nasal spray, 
or inhaler, varenicline, bupropion);  
• 
Unwilling to abstain during the study from using smoking cessation aids other than those 
provided by the study;  
• 
Experienced a prior adverse drug reaction to varenicline; 
• 
Report an unstable medical condition, epilepsy, or severe renal impairment;  
• 
Had an inpatient psychiatric hospitalization and/or serious suicidal ideation or suicide 
attempt in the prior six months; 
• 
Have active problem substance use (other than nicotine) severe enough to compromise 
ability to safely participate in the study protocol. 
• 
Evidence of active problem substance use severe enough to compromise ability to safely 
participate, in the investigator’s opinion;  


STATISTICAL ANALYSIS PLAN 
6 
 
• 
Unwilling to provide urine samples;  
• 
Any condition or situation that would, in the investigator’s opinion, make it unlikely that the 
participant could adhere safely to the study protocol;  
• 
Ward of the state. 
 
Randomization 
Eligible participants will be randomly assigned in a 1:1:1 ratio, in blocks of 6, to V+BC (varenicline 
and behavioral counseling), P+BC (identical appearing placebo and behavioral counseling), or EUC 
(enhanced usual care). Randomization will be stratified by secondary or post-secondary school 
status. The randomization scheme will be computer generated by the Massachusetts General Hospital 
(MGH) Research Pharmacy by personnel with no other interactions with study staff or participants. 
Randomization codes will be held in the research pharmacy and made available to study investigators 
only in the case of urgent medical need. There will be separate randomization codes for apo-varenicline, 
imported from Canada under a provisional FDA allowance, and domestic generic varenicline will full FDA 
approval. Treatment will be assigned according to study number, assigned sequentially to eligible 
participants who enroll in the trial and attend the baseline visit. 
 
Masking/Blinding 
Outcome assessors, data managers, and analysts will be blinded to treatment assignments. All 
study staff and participants will be blind to study medication assignment for the primary outcome 
comparing V+BC and P+BC. Interventionists and their clinical supervisors will be unblinded to 
assignment to behavioral counseling and will not be involved in assessments, data management, or data 
analysis.  
 


STATISTICAL ANALYSIS PLAN 
7 
 
Analytic Approach 
Primary Outcome 
The primary outcome for the study will be… 
1. Cotinine-verified self-reported nicotine vaping abstinence from week 9 to week 12 of 
the study. 
a. [Time frame] Self-reported abstinence and urine or saliva samples will be 
collected during (a) the baseline visit, (b) every week from weeks 1 to 12 during 
the randomization interval, and (c) at weeks 16, 20, and 24 during the follow-up 
interval. The primary outcome will then consist of continuous abstinence status 
over weeks 9, 10, 11, and 12 for each participant converted to a binary value (1 
= abstinent across all 4 study visits, 0 = non-abstinent for at least one of the 4 
study visits). 
b. [Biochemical verification] Self-reported nicotine vaping abstinence will be 
considered verified given a semi-quantitative cotinine of less than 30ng/ml. For 
virtual sessions, participants will provide the sample during the 
videoconferencing session and will show results to the assessor. Those who 
report no vaping use since the last study visit but who have a cotinine of 
30ng/ml or higher will be considered non-abstinent. Those who are missing 
cotinine values but self-report vaping will be considered non-abstinent. 
c. [Self-reported abstinence] Self-reported vaping will be assessed at all visits using 
the timeline follow-back (TLFB; Robinson, Sobell, Sobell, & Leo, 2014). The recall 
period will be 60 days at enrollment and for all subsequent visits will be the 
interval between the prior and current visit. 
d. [Randomization groups] The primary analysis will focus on V+BC and P+BC 
groups. 
 
Covariates 
We will use, at a minimum, 2 covariates in our analysis and missing data imputation:  
• 
Biological sex at birth (male [referent] versus female). 
• 
Summed scores from the ECDI (Foulds et al., 2015), a 10-item inventory with scores ranging 
from 0 – 20 (higher scores indicating greater E-cigarette dependence). 
All covariates will be collected during the baseline visit. 


STATISTICAL ANALYSIS PLAN 
8 
 
 
Missing Data 
Missing abstinence data for any of the study weeks 9, 10, 11, or 12 will be imputed 40 times 
using multiple imputation via chained equations (MICE; Azur, Stuart, Frangakis, & Leaf, 2011). 
Abstinence status will be imputed all non-missing time points and using the set of 2 covariates collected 
at the baseline visit described above. Imputation will be done via fully conditional specification with 
predictive mean matching using logistic regression. Following each imputation iteration, the 4 observed 
and/or imputed values per participant across the 4 study visits will be converted into the final binary 
outcome via the rules given above. For instances in which a participant only partially completed the 
baseline ECDI, missing responses to individual questions will be singularly imputed via an item response 
theory model fit to all non-missing responses: a binomial regression with population-level effects for 
items and a participant-varying intercept term. 
 
Statistical Model and Tests 
We will use a logistic regression model to assess continuous cotinine-verified self-reported 
abstinence across study weeks 9 – 12 for participants in the V+BC and P+BC arms (We will exclude 
participants in the EUC arm). Missing data will be imputed per the method specified above. We will then 
apply our logistic regression model to each set of observed and imputed data, and pool the regression 
estimates according to Rubin’s rule. 
Our primary test of interest will be a dummy-coded contrast comparing the P+BC group (coded 
as 0) to the V+BC group (coded as 1). Statistical significance for the contrast between varenicline and 
placebo will be determined using a z-test applied to the pooled mean estimate divided by the pooled 
standard error. We hypothesize that those assigned to V+BC will have significantly higher abstinence 
rates compared to those assigned to P+BC, which will be confirmed with p < 0.05 and an odds ratio 
greater than one. 
The logistic regression model will include the 2 covariates assessed at baseline (biological sex 
and summed scores for the ECDI). Covariates will be standardized (mean-centered and scaled by the 
standard deviation). The analysis will be intent-to-treat; all subjects randomized at the beginning of the 
study will be included in the analysis, irrespective of whether they receive their assigned behavioral 
treatment or take their assigned medication.  
 
 


STATISTICAL ANALYSIS PLAN 
9 
 
Secondary Outcomes 
The secondary outcomes for the study will be… 
1. Cotinine-verified self-reported nicotine vaping abstinence from week 9 to week 24 of the 
study. 
a. [Time frame] Using self-reported abstinence (see primary outcome) and biochemical 
verification based on urine/saliva samples (see primary outcome) collected during 
weeks 9, 10, 11, 12, 16, 20, and 24, the secondary outcome will consist of 
continuous abstinence for each participant converted to a binary value (1 = 
abstinent across all 7 study visits, 0 = non-abstinent for at least one of the 7 study 
visits).  
2. Cotinine-verified self-reported nicotine vaping abstinence at week 12 of the study. 
a. [Time frame] Using self-reported abstinence (see primary outcome) and biochemical 
verification based on urine/saliva samples (see primary outcome) collected during 
week 12, the secondary outcome will consist of 7-day point-prevalence abstinence 
for each participant converted to a binary value (1 = abstinent over 7 days ending at 
week 12, 0 = otherwise). 
3. Summed scores on the Minnesota Nicotine Withdrawal Scale (MNWS; Cappelleri, 
Bushmakin, Baker, Merikle, Olufade, & Gilbert, 2005), a 9-item inventory with scores ranging 
from 0 to 36 (higher scores indicate greater severity of nicotine withdrawal). 
a. [Time frame] The inventory will be administered at baseline, every week from 
weeks 1 – 12, and weeks 16, 20, and 24. 
4. Summed scores on the Questionnaire of Vaping Craving (QVC; Dowd, Motschman, & Tiffany, 
2019), a 10-item inventory with scores ranging from 10 to 70 (higher scores indicate greater 
cravings to vape). 
a. [Time frame] The inventory will be administered at baseline, every week from 
weeks 1 – 12, and weeks 16, 20, and 24. 
5. Summed scores on the General Distress subscale of the Mood and Anxiety Symptoms 
Questionnaire (MASQ-D30; Lin, Yung, Wigman, Killackey, Baksheev, & Wardenaar, 2014). 
a. [Time frame] The inventory will be administered at enrollment, baseline and 
monthly during weeks 4, 8, 12, 16, 20, and 24. 
6. Number of participants who report one or more adverse events as measured by the 
Neuropsychiatric Adverse Events Interview (NAEI; Anthenelli et al., 2016). 


STATISTICAL ANALYSIS PLAN 
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a. [Time frame] The interview will be conducted at enrollment, baseline, and monthly 
during weeks 4, 8, 12, 16, 20, and 24. 
Missing Data 
 
Missing outcome data for the 2 vaping abstinence outcomes and the 3 inventory measures will 
be multiply imputed. 
Biochemically-Verified Vaping Abstinence 
Missing abstinence data for any of the study weeks 9, 10, 11, 12, 16, 20, or 24 will be imputed 
40 times using MICE via the same approach and covariates described for the primary outcome. 
Following each imputation iteration, for continuous abstinence over weeks 9 – 24, the 7 observed 
and/or imputed values per participant across the 7 study visits will be converted into the final binary 
outcome via the rules given above. 
Inventory Measures 
Missing summed scores for the MNWS, QVC, and the MASQ-D30 for any of the study weeks 1 – 
24 will be imputed 40 times using MICE. Summed scores will be imputed using the set of 2 baseline 
covariates described above, as well as a participant’s baseline summed score for the given inventory 
measure. Imputation will be done via fully conditional specification with predictive mean matching using 
linear regression. 
Statistical Models and Tests 
We will conduct 5 secondary analyses total for the 3 vaping abstinence outcomes, 3 secondary 
analyses and 3 exploratory analyses total for the 3 inventory measures, and a secondary analysis for 
adverse events. 
Biochemically-Verified Vaping Abstinence 
We will use a logistic regression model to assess (1) continuous vaping abstinence across study 
weeks 9 – 12, (2) continuous vaping abstinence across study weeks 9 – 24, and (3) 7-day point-
prevalence cotinine-verified self-reported abstinence at week 12. Missing data will be imputed per the 
method specified above. We will then apply our logistic regression model to each set of observed and 
imputed data, and pool the regression estimates according to Rubin’s rule. 
The logistic regression model will include the 2 covariates assessed at baseline (biological sex 
and summed scores for the ECDI). Covariates will be standardized (mean-centered and scaled by the 
standard deviation). The analysis will be intent-to-treat; all subjects randomized at the beginning of the 
study will be included in the analysis, irrespective of whether they receive their assigned behavioral 
treatment or take their assigned medication. 


STATISTICAL ANALYSIS PLAN 
11 
 
 
We will conduct two types of analyses: 
1. We will assess a single dummy-coded contrast comparing the P+BC group (coded as 0) to 
the V+BC group (coded as 1), excluding participants in the EUC group. Statistical significance 
will be determined using a z-test applied to the pooled mean estimate divided by the pooled 
standard error. We will conduct this analysis for our two secondary vaping abstinence 
outcomes. 
2. We will assess a pair of dummy-coded contrasts comparing the EUC group (coded as 0) 
against (1) the V+BC group (coded as 1) and (2) the P+BC group (coded as 1). Statistical 
significance will be determined via an analysis of variance comparing a simpler null model 
(with contrasts for V+BC and P+BC fixed to zero) against the more complex model with both 
contrasts freely estimated. If the Wald test for the model comparison is significant, we will 
conduct post-hoc tests assessing the 3 possible comparisons between groups (EUC vs. P+BC, 
EUC vs. V+BC, and P+BC vs. V+BC). We will conduct this analysis for our primary vaping 
abstinence outcome as well as our two secondary vaping abstinence outcomes. 
Table 1 summarizes all secondary analyses for the vaping abstinence outcomes. Tests will be 
deemed statistically significant for p < 0.05 following a correction using the Benjamini-Hochberg method 
across the 5 analyses. 
 
Table 1: Secondary analyses for vaping abstinence outcomes 
Vaping abstinence outcome 
Contrast 
Continuous abstinence 
 
(over weeks 9 – 12) 
Omnibus test for EUC vs. V+BC, EUC vs. P+BC, and P+BC vs. V+BC 
Continuous abstinence 
Contrast of P+BC vs. V+BC (No EUC) 
(over weeks 9 – 24) 
Omnibus test for EUC vs. V+BC, EUC vs. P+BC, and P+BC vs. V+BC 
Point-prevalence abstinence 
Contrast of P+BC vs. V+BC (No EUC) 
(week 12) 
Omnibus test for EUC vs. V+BC, EUC vs. P+BC, and P+BC vs. V+BC 
 
Inventory Measures 
We will use a linear regression model to assess the post-baseline summed scores collected over 
weeks 1 – 12 (at weekly or monthly intervals) for (1) the MNWS, (2) the QVC, and (3) the MASQ-D30. 
The linear model will be estimated using generalized estimating equations (GEE; Liang & Zeger, 1986), 


STATISTICAL ANALYSIS PLAN 
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providing estimates and standard errors robust to violations of distributional assumptions (e.g., 
normality) and heteroscedasticity.  
The linear regression model will include covariates for (a) biological sex and baseline summed 
scores for the ECDI (see above), (b) a participant’s baseline score on the given inventory measure, and 
(c) linear and quadratic time trend terms using number of days since the baseline visit. Covariates will be 
standardized (mean-centered and scaled by the standard deviation). The analysis will be intent-to-treat; 
all subjects randomized at the beginning of the study will be included in the analysis, irrespective of 
whether they receive their assigned behavioral treatment or take their assigned medication. 
We will conduct two types of analyses: 
3. We will assess a single dummy-coded contrast comparing the P+BC group (coded as 0) to 
the V+BC group (coded as 1), excluding participants in the EUC group. Statistical significance 
will be determined using a z-test applied to the pooled mean estimate divided by the pooled 
standard error. This will be a secondary analysis. 
4. We will assess a pair of dummy-coded contrasts comparing the EUC group (coded as 0) 
against (1) the V+BC group (coded as 1) and (2) the P+BC group (coded as 1). Statistical 
significance will be determined via an analysis of variance comparing a simpler null model 
(with contrasts for V+BC and P+BC fixed to zero) against the more complex model with both 
contrasts freely estimated. If the Wald test for the model comparison is significant, we will 
conduct post-hoc tests assessing the 3 possible comparisons between groups (EUC vs. P+BC, 
EUC vs. V+BC, and P+BC vs. V+BC). This will be an exploratory analysis. 
Table 2 summarizes all secondary and exploratory analyses for the inventory measures. Tests 
will be deemed statistically significant for p < 0.05 following a correction using the Benjamini-Hochberg 
method across the 3 secondary analyses and 3 exploratory analyses, respectively. 
 
 
 


STATISTICAL ANALYSIS PLAN 
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Table 2: Secondary and exploratory analyses for inventory measures 
Inventory measure 
Contrast 
Exploratory 
MNWS 
Contrast of P+BC vs. V+BC (No EUC) 
 
 
Omnibus test for EUC vs. V+BC, EUC vs. P+BC, and P+BC vs. V+BC 
Yes 
QVC 
Contrast of P+BC vs. V+BC (No EUC) 
 
 
Omnibus test for EUC vs. V+BC, EUC vs. P+BC, and P+BC vs. V+BC 
Yes 
MASQ-D30 
Contrast of P+BC vs. V+BC (No EUC) 
 
 
Omnibus test for EUC vs. V+BC, EUC vs. P+BC, and P+BC vs. V+BC 
Yes 
 
Adverse events 
We will tally the number participants who report one or more adverse events during the NAEI 
interview across weeks 4, 8, and 12, looking specifically at the 2 x 2 contingency tables for (a) the P+BC 
group versus V+BC group, and (b) the EUC group versus the V+BC group. We will then assess whether 
the number of participants reporting one or more adverse events differs between the two groups using 
Fisher’s exact test. Differences between groups will be deemed statistically significant for p < 0.025. 
 
 


STATISTICAL ANALYSIS PLAN 
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Sensitivity Analyses 
Across our primary and secondary analyses, at a minimum we will conduct the following 
sensitivity analyses: 
1. We will test whether our conclusion on efficacy is robust to the inclusion/exclusion of the 
two covariates (biological sex and nicotine dependence severity). We will rerun analyses 
excluding these covariates and see if conclusions change. 
2. We will test whether our conclusion on efficacy is robust to the approach for imputation of 
missing data. We will (a) rerun the adjusted (i.e., with covariates) models on the observed 
data only and (b) rerun the adjusted models on a dataset with the observed data and all 
missing outcome data imputed as non-abstinent. 
3. We will conduct a per protocol analysis by evaluating results among participants who use 
varenicline on most days in the trial (e.g., > 50 or 75%). 
 
 


STATISTICAL ANALYSIS PLAN 
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Power 
Sample size was determined based on the assumption that use of varenicline for vaping 
cessation in adolescents would require an effect that at least doubled cessation rates over placebo to be 
worth the risks inherent in use of pharmacotherapy. Abstinence rates of 24% have been reported with 
TIQ alone in adolescents who vaped and were not necessarily dependent (Graham, Jacobs, & Amato, 
2020; Graham, Amato, Cha, Jacobs, Bottcher, & Papandonatos, 2021). In this trial, requiring nicotine 
dependence to enroll, we postulate that addition of varenicline to behavioral counseling and TIQ will 
double abstinence rates. A sample size of 100 per arm, with 80 analyzable per arm, would yield power of 
0.88 with a two-sided alpha of 0.05 with abstinence rates of 25% in the P+BC arm and 50% in the V+BC 
arm. 
 
 


STATISTICAL ANALYSIS PLAN 
16 
 
Software and Data Management 
All analyses will be done using the statistical software R (version 4.1.1; R Core Team, 2021) and 
integrated development environment RStudio (version 2020.9.0.351; RStudio Team, 2021). Data will be 
prepared using the R packages ‘dplyr’ (version 1.0.7; Wickham, François, Henry, & Müller, 2021) and 
‘tidyr’ (version 1.1.4; Wickham, 2021). Models will be fit using the R package ‘geepack’ (version 1.3-2; 
Højsgaard, Halekoh, & Yan, 2006). Missing data will be imputed using the R package ‘mice’ (version 
3.13.0; Van Buuren & Groothuis-Oudshoorn, 2011). Reproducible code and de-identified data will be 
organized using the R package ‘targets’ (version 0.8.1; Landau, 2021). 
 
 
 


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