Clinical trial NCT04602494
Conditions: Vaping Nicotine Dependence
Keywords: Vaping Nicotine Adolescents Cessation Varenicline
Sponsor: Massachusetts General Hospital
Start date: 2020-12-18; Completion date: 2022-06-27
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The Investigators propose a randomized, placebo-controlled trial to test the hypothesis that varenicline added to group behavioral and texting support will be well tolerated and improve vaping cessation rates among nicotine dependent adolescents who vape, do not smoke regularly, and are willing to try treatment to stop vaping compared to placebo added to group behavioral and texting support. The study will consist of a three-arm randomized, placebo-controlled, parallel-group study of (1) varenicline up to 1 mg bid for 12 weeks added to behavioral and texting support compared with (2) behavioral and texting support and placebo and (3) monitoring only. The primary comparison will be of vaping cessation rates in those assigned to varenicline vs placebo.To do this, the investigators propose to enroll 300 adolescents aged 16-25 who meet eligibility criteria.

Detailed description:
Enrollees will include 300 nicotine dependent adolescents aged 16-25, who vape, do not smoke, and want to quit vaping. The study will will consist of a three-arm randomized, placebo-controlled, parallel-group study of (1) varenicline up to 1 mg bid for 12 weeks added to behavioral and texting support for adolescent vaping cessation or (2) behavioral and texting support and placebo or (3) monitoring only. The primary comparison of interest is efficacy of (1) varenicline vs (2) placebo arms on vaping abstinence outcomes. The study consists of one enrollment visit, one baseline visit, twelve weekly individual treatment and assessment sessions, and six monthly visits at weeks 4, 8, 12, 16, 20 and 24 weeks. At the enrollment visit, participants will complete interviews, questionnaires and diagnostic assessments, as well as saliva and urine sample and vitals. At the baseline visit, participants will complete several interviews, questionnaires, provide a saliva sample for cotinine measurement, and be randomized to the varenicline plus behavioral treatment group, the placebo plus behavioral treatment group, or monitoring-only group. Study staff will distribute varenicline or identically appearing placebo with instructions on how to take the study medication at weeks 0, 2, 4 and 8. Participants will be instructed to bring all empty and unused study medication at each in-person study visit through Week 12. At the weekly treatment meetings, participants will participate in cognitive behavioral therapy and complete questionnaires. Monthly visits will consist of interviews, questionnaires and a saliva and urine sample.

Arms: arm 1: Participants will receive varenicline 0.5 mg once daily on days 1-3, 0.5 mg twice daily on days 4-7 and starting on day 8, 1 mg twice daily for a total of 12 weeks added to 12 weeks of group behavioral and texting support specifically designed for teen vaping cessation arm 2: Participants will receive identical placebo 0.5 mg once daily on days 1-3, 0.5 mg twice daily on days 4-7 and starting on day 8, 1 mg twice daily for a total of 12 weeks added to 12 weeks of group behavioral and texting support specifically designed for teen vaping cessation arm 3: Participants will attend weekly and monthly sessions that will only consist of assessments. No study medication, no behavioral or texting support.
Interventions: intervention 1: Varenicline intervention 2: Placebo
Intervention descriptions: intervention 1: varenicline: 0.5 mg once daily on days 1-3, 0.5 mg twice daily on days 4-7 and starting on day 8, 1 mg twice daily for a total of 12 weeks intervention 2: Identical placebo: 0.5 mg once daily on days 1-3, 0.5 mg twice daily on days 4-7 and starting on day 8, 1 mg twice daily for a total of 12 weeks

Protocol documents:
Prot_SAP_000.pdf: 
Varenicline For Nicotine Vaping Cessation In Non Smoker Vaper Adolescents
NCT04602494
Document Date: 09/15/2023


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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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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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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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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 


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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 in consumption of 
alcohol, combusted tobacco, cannabis, and non-medical prescription drugs during the treatment 
and follow-up periods. 
 
Exploratory Hypothesis: 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. 
 
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; 
- 
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; 


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- 
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 
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 


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messages from study staff. Text messages will be sent using Google Voice, and will be used to 
send deidentified study visit reminders to participants.  
  
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 
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: 
 


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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. 
 
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. 
  


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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 
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.  
 
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 


Version 2023.09.15 
10 
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. 
 
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 2023.09.15 
11 
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 2023.09.15 
12 
 
 
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 
- 
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 
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 2023.09.15 
13 
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). 
 
c. Devices to be used: N/A 
 
d. Interventions (for participant randomized to varenicline or placebo arms) 
 


Version 2023.09.15 
14 
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 
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.  


Version 2023.09.15 
15 
 
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 
nicotine, other substance vaping, use of other forms of tobacco, cannabis products, alcohol, non-
medical opioids, and other addictive substances. 
 


Version 2023.09.15 
16 
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. 
 
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, 


Version 2023.09.15 
17 
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 
 
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. 
 
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. 


Version 2023.09.15 
18 
 
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. 
 
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. 
 


Version 2023.09.15 
19 
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. 
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. 


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20 
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. 
 
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 
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. 
 


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21 
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. 
 
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 
 
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 


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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 
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. 
 


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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 
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). 


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24 
 
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%). 
 
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 


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25 
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 
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. 
 
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 


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26 
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  
 
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 


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27 
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. 
 
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 


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28 
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 
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 


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29 
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 
 
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 


Version 2023.09.15 
30 
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  
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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