Clinical trial NCT01509547
Conditions: Nicotine Dependence
Sponsor: Medical University of South Carolina
Start date: 2012-08-01; Completion date: 2018-01-26
Enrollment: 157 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a placebo-controlled smoking cessation treatment study for adolescents ages 14-21. After assessment and inclusion into the study, participants will be randomized to receive a 12-week double blind course of varenicline or placebo.

Detailed description:
The objective of this protocol is to examine the efficacy and safety of varenicline for smoking cessation in adolescents. The guiding design philosophy was to model the adult smoking cessation literature (allowing for indirect comparisons of efficacy in different populations) while fine-tuning some elements specifically geared for adolescents. After assessment and inclusion into the study, participants will be randomized to receive a 12-week double blind course of varenicline or placebo. Participants will provide smoking self-report (cigarettes per day) throughout the study. Biological confirmation with carbon monoxide breathalyzer will occur at all visits, and urine cotinine measurement will occur at key time points (baseline, end of treatment and final post-treatment follow-up). Psychiatric/medical visits will occur weekly throughout active treatment to systematically monitor safety and tolerability. After the 12-week treatment course, participants will return for 3 post-treatment follow-up visits (Week 13, Week 18, and Week 26).

Arms: arm 1: Participants \>55 kg will take varenicline 0.5 mg once daily for 3 days, titrated to 0.5 mg twice daily for 4 days, titrated to 1 mg twice daily for 11 weeks. Participants ≤55 kg will take varenicline 0.5 mg once daily for 7 days, titrated to 0.5 mg twice daily for 11 weeks. arm 2: Participants \>55 kg will take placebo 0.5 mg once daily for 3 days, titrated to 0.5 mg twice daily for 4 days, titrated to 1 mg twice daily for 11 weeks. Participants ≤55 kg will take placebo 0.5 mg once daily for 7 days, titrated to 0.5 mg twice daily for 11 weeks.
Interventions: intervention 1: Varenicline intervention 2: placebo
Intervention descriptions: intervention 1: participants \>55 kg will take varenicline/placebo 0.5 mg once daily for 3 days, titrated to 0.5 mg twice daily for 4 days, titrated to 1 mg twice daily thereafter. Participants ≤55 kg will take varenicline/placebo 0.5 mg once daily for 7 days, titrated to 0.5 mg twice daily thereafter. intervention 2: participants \>55 kg will take varenicline/placebo 0.5 mg once daily for 3 days, titrated to 0.5 mg twice daily for 4 days, titrated to 1 mg twice daily thereafter. Participants ≤55 kg will take varenicline/placebo 0.5 mg once daily for 7 days, titrated to 0.5 mg twice daily thereafter.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
A Randomized Controlled Trial of Varenicline for Adolescent Smoking Cessation 
 
NCT01509547 
 
Study Protocol and Statistical Analysis Plan 
 
Document Date: October 14, 2016 


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A Randomized Controlled Trial of Varenicline for Adolescent Smoking Cessation 
Specific Aims 
Cigarette smoking remains the leading cause of preventable death in the United States and the world.  The 
link between smoking and cancer is clear, and cessation at a young age results in a substantial reduction in 
the risk of cancer.  The overwhelming majority of current smokers began smoking during adolescence.  While 
often motivated to quit, adolescent smokers are less likely than adult smokers to succeed when making a quit 
attempt.  
  Despite  
the  
tremendous  potential  health  
impact  of  smoking  cessation  among  adolescents,  minimal 
effort has been made to develop evidence based cessation treatments for this age group.   
Psychosocial  cessation  approaches  have  generally  yielded  small  effect  sizes  in  adolescents,  and 
pharmacotherapy represents a potential avenue to improve cessation outcomes.  To date, though, medications 
for cessation remain critically understudied and potentially underutilized in this age group.  The few adequately 
powered controlled trials of bupropion SR and nicotine replacement in adolescents suggest potential efficacy 
improvements over psychosocial interventions, but overall rates remain modest, and long-term post-treatment 
effects  are  unclear.    Varenicline,  an α4β2 nicotinic  acetylcholine  receptor  partial  agonist,  has  demonstrated 
superior  cessation  efficacy  compared  to  placebo,  bupropion  SR,  and  transdermal  nicotine  patch  in  adult 
smokers, but no controlled trials have focused on its efficacy in adolescent smokers.  Results from our recent 
adolescent  varenicline  pilot  study,  coupled  with  our established  history  of  adolescent  smoking  cessation 
pharmacotherapy research, support the feasibility and safety of this line of investigation. 
We propose a randomized, controlled, double-blind trial (n=166) of varenicline, versus placebo, to assess 
its  smoking  cessation  efficacy  and  safety  
in  adolescent  smokers,  ages  14-21.    Participants  will receive  12 
weeks  of  
treatment  and  will  
return  
for  
follow-up  at  multiple  post-treatment  
time  points,  
the  
last  at  6 months.  
Medication will be titrated to the goal dose during the first week, and the targeted quit date will be set at the 
end of the first week.  All participants will receive quit smoking brochures and brief cessation counseling.  A 
previously  established  
retention-targeted  contingency  management  
intervention  will  be  employed  within  both 
groups  to  enhance  study  retention.    Our  primary  efficacy  outcome  is  cotinine-confirmed,  7-day  point 
prevalence abstinence at the end of treatment.   
Specific  Aim  1.  To  examine  the  efficacy  of  varenicline,  compared  with  placebo,  for  smoking  cessation  
in 
adolescent smokers. 
Hypothesis  1:  Adolescent  smokers  
treated  with  varenicline,  compared  with  
those  
treated  with  placebo, 
will demonstrate greater 7-day point prevalence abstinence at the end of treatment.   
Abstinence will be measured using participant self-report, biologically confirmed by urine cotinine level ≤50 
ng/mL. 
Specific Aim 2. To examine the safety and tolerability of varenicline, compared with placebo, when used for 
smoking cessation in adolescent smokers. 
Hypothesis  2:  Varenicline  will  demonstrate  adequate  safety  and  
tolerability,  compared  with  placebo,  
in 
the frequency of treatment-emergent adverse events. 
We will rigorously assess safety and tolerability throughout treatment using established protocols.  Weekly 
medical visits, including detailed monitoring of psychiatric and general health parameters and assessment 
of adverse events, will be conducted. 
Despite  
the  public  health  need  
for  aggressive  
tobacco  control  during  adolescence,  
there  are  
few  medication 
trials for smoking cessation within this vulnerable age group.  A controlled test of varenicline, arguably the most 
efficacious  smoking  cessation  pharmacotherapy  
in  adults,  
is  clearly  
indicated.    While  we  acknowledge  that 
post-marketing  anecdotal  reports  of  psychiatric  adverse  events  have  
led  
to  an  FDA  “black  box”  warning  
for 
varenicline,  controlled  studies  in  adults  and  our  pilot  adolescent  data  support  varenicline’s  safety.    In  this 
context, and in light of varenicline’s potential for efficacy in adolescents, we argue that the potential benefits of 
the proposal far outweigh the risks, especially in a study that will incorporate established, rigorous procedures 
to  monitor  safety  and  outcomes.    If  our  study yields  positive  outcomes,  
it  will,  upon  replication,  carry  both 
clinical implications and potential regulatory significance.  If our study yields null outcomes, it will do the same.  
Either  outcome  provides  
important  public  health  value,  and  our  study  
is  well  poised  
to  
fill  a  critical  evidence 
gap in adolescent smoking cessation. 
 
 


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Research Strategy 
A. SIGNIFICANCE 
Tobacco  smoking  remains  the  
leading  cause  of  preventable  death  
in  the  United  States,  killing  440,000 
Americans annually (1).  About half of these deaths are due to lung cancer, an illness with an 80% mortality 
rate (2).  One-fifth of all deaths in the United States result from smoking, a toll greater than those of alcohol, 
illegal drugs, homicide, suicide, car accidents, and AIDS combined (3).   
Nicotine  dependence  almost  universally  begins  in  adolescence.    Nearly  90%  of  adult  smokers  began 
smoking before age 18, and adolescent smoking rates range, in steadily increasing numbers, from 6% of 14-
year-olds to 37% of 21-year-olds (4,5).  Almost all adolescents who smoke regularly will continue smoking well 
into  adulthood,  leading  to  a  life  expectancy  20  years  shorter  than  nonsmokers  (4,6).    Daily  smoking,  a 
particularly  concerning  predictor  of  
long-term  smoking  and  adverse  health  outcomes,  
is  present  
in  3%  of  8
th 
graders,  6%  of  10th graders,  11%  of  12th graders,  and  17%  of  21-year-olds  (5,7).    Nearly  two-thirds  of 
adolescent smokers are interested in quitting, but only 4-6% of unassisted quit attempts are successful (8-10). 
Surprisingly few controlled studies have evaluated adolescent smoking cessation programs, and almost all 
have exclusively focused on psychosocial treatments, yielding generally discouraging results.  For example, a 
meta-analysis of 48 studies showed a mean quit rate of 9.1%, compared with 6.2% among control groups, a 
difference of only 2.9% (odds ratio [OR] 1.5) (11).  In the interest of enhancing these very modest quit rates, 
and in light of clear evidence that adolescent smokers experience nicotine withdrawal and craving (12-14), a 
handful  of  recent  studies  have  explored  the  potential  impact  of  cessation  pharmacotherapy  in  adolescent 
smokers.  Only 6 controlled trials to date have investigated bupropion SR (15-17) and/or nicotine replacement 
therapy (18-20); these are summarized in Table 1.  The table suggests some pharmacotherapies may provide 
better  outcomes  than  psychosocial  treatments  (11)  (though  this  is  an  indirect  comparison),  indicating  that 
medications  should  be  considered  as  a  treatment  option  for  adolescent  smoking  cessation.    Additionally, 
despite  initial  efficacy,  absolute  cessation  rates  remain  modest,  and  are  generally  not  sustained  at  post-
treatment follow-up. 
Table 1. Abstinence outcomes in controlled adolescent smoking cessation pharmacotherapy studies. 
Study 
Total 
n 
Medication 
7-day point prevalence abstinence (% abstinent) 
End of Treatment 
Post-Treatment Follow-Up 
Time 
Point Active Placebo OR Time 
Point Active Placebo OR 
Hanson, 2003 100 
Nicotine Patch 
10 wk* 28% 24% 1.2 
Not reported 
Killen, 2004 211 
Bupropion 150 mg/day+ 10 wk* 23% 28% 0.8 26 wk‡ 8% 
7% 1.2 
Moolchan, 2005 120 
Nicotine Gum (n=46) 
12 wk* 
9% 
5% 
1.8 
26 wk* 
9% 
5% 
1.8 
Nicotine Patch (n=34) 
21% 
4.9 
21% 
4.9 
Muramoto, 2007 312 
Bupropion 150 mg/d (n=105) 
6 wk‡ 
11% 
6% 
1.9 
26 wk* 
3% 
10% 
0.3 
Bupropion 300 mg/d (n=104) 
14% 
2.6 
14% 
1.5 
Rubinstein, 2008 40 
Nicotine Nasal Spray 
8 wk* 0% 12%§ N/A 
Not reported 
Gray, 2011 134 
Bupropion 300 mg/day 
6 wk‡ 18% 10% 2.0 12 wk‡ 8% 
3% 2.6 
Proposed 
166 
Varenicline 
12 wk‡ 
 
26 wk‡ 
 
+all participants (bupropion and placebo) received nicotine patch 
§no placebo provided (control condition only involved psychosocial treatment) 
*carbon monoxide breathalyzer confirmation 
‡cotinine confirmation 
The 2006 introduction of varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, represented an 
enormous  breakthrough  
in  adult  smoking  cessation  pharmacotherapy.  
  
In  addition  
to  
its  superior  efficacy  
in 
comparison with placebo (end-of-treatment ORs 3.9-5.9), varenicline was superior in head-to-head trials with 
the  previously  established  
first-line  pharmacotherapies:  bupropion  SR  
(OR  2.2)  and  nicotine  patch  
(OR  1.7) 
(21-25).    Some  might  argue  that  varenicline  would  never  provide  comparable  outcomes  for  adolescent 
smokers.  However, while overall abstinence rates might be lower among adolescent smokers, the effect size 


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should be comparable, as we have no reason to believe the mechanism by which varenicline works differs by 
age  group  (see  below).    Thus,  given  its  striking  efficacy  in  adults, varenicline  is  a  strong  candidate  for 
evaluation in adolescent smokers.  This critical evidence gap needs to be filled.   
Only  
two  small  pilot  
feasibility  studies  of  varenicline  have  been  conducted  among  adolescents.  
  The  
first 
was  a  2-week  pharmacokinetic  study  (26).    Adolescent  smokers  (ages  12-16, n=72)  were  randomized  to 
receive “high-dose” varenicline (titration to 1 mg twice daily for those >55 kg and to 0.5 mg twice daily for those 
≤55  kg),  
“low-dose”  varenicline  
(titrated  
to  0.5  mg  
twice  daily  
for those  >55  kg  and  
to  0.5  mg  once  daily  
for 
those  ≤55  kg),  or  placebo.  
  Results  
indicated  
that  pharmacokinetics  were  similar  
to  adults  
for  
those  >55  kg, 
and that the body weight exposure effect for those ≤55 kg was adequately offset by the reduced dose. Adverse 
events  occurred  in  more  participants  in  the  varenicline  groups  (64%  “high-dose”,  73%  “low-dose”)  versus 
placebo  (13%),  with  nausea,  headache,  vomiting,  and  dizziness  being  most  common.    Two  participants 
reported  abnormal  dreams  and  one  had  a  brief,  mild  episode  of  anger.    However,  there  were  no  serious 
adverse  events  or  discontinuations  due  to  adverse  events  in  any  group.    Almost  all  adverse  events  were 
considered  mild,  and  none  were  more  frequent  in  the  “high-dose”  versus  “low-dose”  groups.    Though 
participants were not instructed to reduce or quit smoking, there were moderate reductions in smoking over the 
2-week trial (74% cigs/day reduction in “high dose,” 52% in “low dose,” and 40% in placebo participants). 
The second was our recently completed pilot cessation trial, detailed below (Section C1b) (27).  Briefly, we 
demonstrated  1)  varenicline  may  produce  abstinence  rates  superior  to  other  medications,  2)  no  serious 
adverse  events  or  discontinuation  due  to  adverse  events  with  varenicline,  and  3)  feasibility  of  conducting 
varenicline smoking cessation trials in adolescents.   
The  proposed  study  will  have  numerous  clinical  and  policy  
implications.  
  First,  
there  are  
few  options  
for 
smoking cessation among adolescent smokers, despite clear evidence that the trajectory of smoking is most 
malleable during this formative period (28,29).  The existing treatment options produce modest effects at best.  
Many  physicians  are  willing  
to  prescribe  a  medication  off-label  
to  adolescents,  particularly  
if  
that  medication 
has a strong base of support within another population (30,31).  We believe many physicians are either already 
using varenicline in adolescents on their own accord, or wish to do so.  This study will provide the necessary 
data to support or refute this strategy.  Second, we recognize that use of varenicline includes potential added 
risk,  given  recent  anecdotal  reports  of  psychiatric  
instability  (32,33).    Despite  the  FDA’s  strong  reaction  to 
those  anecdotal  reports,  the  vast  majority  of  scientific  evidence  supports  the  safety  of  varenicline.    This 
includes  a  pooled  analysis  of  3091  participants  randomized  to  varenicline  in  controlled  trials,  revealing  no 
significant increase (relative to placebo) in psychiatric symptoms, aside from sleep disturbance (34) (Table 2).  
Additionally, a “real world” primary care cohort study including 10,973 smokers prescribed varenicline revealed 
no  evidence  of  increased  risk  of  self-harm,  compared  with  smokers  prescribed  other  cessation 
pharmacotherapies (35).  Nonetheless, the FDA regulatory constraint, including a “black box” warning, remains.   
We do not suggest that our study alone will provide the necessary information for a change in FDA regulatory 
practice, nor will our study provide sufficient support for a change in indication for varenicline.  It will, however, 
provide valuable evidence regarding varenicline’s potential viability as a treatment for adolescent smokers. 
Table 2. Adverse events (AEs) in pooled analysis of varenicline controlled trials (34) 
 
Varenicline 
(n = 3091) 
Placebo 
(n = 2005) 
RR 95% CI 
Any Psychiatric AE (excluding sleep disturbances) 
10.7% 
9.7% 
1.02 0.86-1.22 
Psychiatric AEs 
occurring in 
≥1% of 
varenicline 
participants 
Sleep Disturbances 
25.1% 
14.5% 
1.70 1.50-1.92 
Anxiety Symptoms 
4.5% 
5.0% 
0.86 0.67-1.12 
Depressed Mood 
2.8% 
1.9% 
1.42 0.96-2.08 
Other Mood Symptoms 
2.4% 
1.5% 
1.21 0.79-1.83 
Other 
psychiatric AEs 
of particular 
concern 
Suicidal and Self Injurious Behaviors 
0.0% 
0.1% 
N/A 
 
Psychiatric Serious AEs 
<0.1% 
0.1% 
N/A 
 
B. INNOVATION 
Despite their tremendous potential public health impact, adolescent smoking cessation treatments remain 
critically  understudied.    Pharmacotherapies,  in  particular,  have  been  the  focus  of  only  six  controlled  trials.  


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While  some  studies  have  
indicated  potential  promise,  many  have  been  beset  by  design  
inconsistencies  and 
methodological  challenges  (see Table  1 above).  
  Trials  have  varied  greatly  
in  several  key  design  
features, 
including  medication  dosing,  length  of  therapy,  span  of  post-treatment  follow-up,  nature  and  intensity  of 
psychosocial treatments, definitions of abstinence, and choice of main outcome variables.  This heterogeneity 
has made it difficult to systematically compare adolescent studies head-to-head, and to contrast findings with 
those of adult studies.  Additionally, significant problems with participant recruitment and retention have led to 
underpowered trials, often yielding null findings and leaving the impression that pharmacotherapy is ineffective.   
Drawing  on  our  research  team’s  collective  experience,  we  intend  to  proactively  address  the  above 
concerns  in  the  present  proposal.    The  proposed  medication  dosing  is  based  on  published  varenicline 
pharmacokinetic  data  in  adolescent  smokers  (26).    Medication  titration  schedule,  length  of  therapy,  and 
intensity of psychosocial treatment are designed to parallel those of large-scale varenicline smoking cessation 
efficacy and safety trials in adults (23,24).  Post-treatment follow-up will be extended to 6 months, consistent 
with  expert  recommendations  (36).    Abstinence  criteria  include  biological  verification  with  urine  cotinine, 
recognized  as  the  current  gold  standard  (36,37).    Recruitment  will  be  bolstered by  several  innovative 
techniques,  
including  
the  continuation  and  expansion  of  a  network  of  smoking  cessation  research  clinics  
in 
area  high  schools.    Retention  will  be  enhanced  using  an  aggressive  retention-targeted  contingency 
management approach, rewarding participants in escalating fashion for study attendance and adherence with 
study  procedures  (38-40).    The  proposed  sample  size  was  chosen  based  upon  consistently  conservative 
estimates from prior relevant research, thereby ensuring sufficient power for hypothesis testing. 
The  proposed  
investigation  of  varenicline  
in  adolescents  
is  
timely  and  supported  by  
the  
research  
team’s 
experience  with  this  medication.    We  have  already  been  granted  Investigational  New  Drug  (IND)  approval 
#104451 from the FDA for adolescent (ages 14-21) smoking cessation research with varenicline.  Aside from 
our  recently  completed  pilot  study,  
there  have  been  no  published  varenicline  adolescent  smoking  cessation 
trials (pilot or otherwise).  Given its superior efficacy compared with placebo, bupropion SR, and transdermal 
nicotine  patch  
in  adults,  and  given  
the  
feasibility  and  safety/tolerability  suggested  by  our  pilot  study  results, 
varenicline is an ideal candidate medication for evaluation in adolescents. 
C. APPROACH 
C1. Preliminary Studies 
Very  few  research  groups  have  conducted  controlled  pharmacotherapy  trials  for  adolescent  smoking 
cessation.  
  We  are  among  
these  
few,  and  argue  
that  our  experience,  also  
inclusive  of  adult  and  adolescent 
cessation trials of varenicline, uniquely positions us to successfully undertake the proposed study. 
C1a. Bupropion SR and Contingency Management for Adolescent Smoking Cessation 
We  conducted  this  large-scale  2x2  controlled  clinical  trial  (n=134)  to  evaluate  bupropion  SR  and 
contingency  management,  each  alone  or  
in  combination,  for  adolescent  smoking  cessation  treatment  (see 
Appendix for manuscript, inclusive of detailed methods and findings) (15).  Briefly, we concluded that combined 
treatment was superior to placebo-only treatment throughout active treatment (cotinine-confirmed 7-day point 
prevalence abstinence odds ratio 3.6 at end of active treatment).  Our completion of this trial demonstrates our 
ability to conduct an adolescent smoking cessation pharmacotherapy trial on the scale of the proposed study. 
C1b. Varenicline versus Bupropion XL for Adolescent Smoking Cessation 
With FDA Investigational New Drug (IND) approval #104451 (varenicline and bupropion XL in adolescents 
age 14-21), we conducted this double blind, randomized pilot trial (n=29) to assess the feasibility and safety of 
evaluating  these  medications  as  adolescent  smoking  cessation  pharmacotherapies  (27).    Participants  were 
randomized to an 8-week trial of either medication, with 1-week titration and 7 weeks at goal dose (1 mg twice 
daily for varenicline participants >55 kg, 0.5 mg twice daily for varenicline participants ≤55 kg, 300 mg daily for 
bupropion  XL  participants),  and  monitored  closely  for  safety,  tolerability,  and  efficacy.    Weekly 
safety/tolerability assessments included vital sign measurement and physician evaluation, inclusive of a) open-
ended  
inquiry  about  health  
issues/complaints,  b)  structured/extensive  review  of  systems  to  augment  open-
ended interview (41), and c) detailed assessment for suicidal ideation or behavior using the Columbia-Suicide 
Severity Rating Scale (C-SSRS) (42).  For efficacy assessment, a participant was considered abstinent on a 
given  week  
if  reporting  zero  cigarettes  smoked  during  
the  week  and  submitting  a  urine  specimen  with  ≤50 
ng/mL  cotinine  (cotinine-confirmed  7-day  point  prevalence  abstinence).    Findings,  summarized  
in Table  2, 
support the feasibility and safety of conducting a controlled trial of varenicline for adolescent smoking cessation.  
Varenicline  efficacy  findings,  including  a  27%  biologically  verified  abstinence  rate,  as  well  as  substantial 


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reduction  in  daily  smoking  among  non-abstainers,  provide  further  support  for  a  larger  efficacy  trial.    Our 
experience with varenicline in adolescents, including IND approval, demonstrates that we are well positioned to 
study this medication further. 
Table 2. Overview of varenicline vs. bupropion XL pilot trial findings (27) 
 
 
Varenicline (n=15) 
Bupropion XL (n=14) 
Safety/ 
Tolerability 
Adverse events in >1 participant 
Insomnia (4), Nausea (3), 
Headache (3) 
Vivid dreams (5), Insomnia 
(2), Nausea (2), Chest 
discomfort (2) 
Discontinuation due to adverse events 
None 
Increased anxiety (1), 
“Feeling too focused” (1) 
Significant vital sign changes 
None 
None 
Suicidal ideation or behavior 
None 
None 
Efficacy 
Participants achieving 7-day cotinine-confirmed 
point prevalence abstinence (primary outcome) 
4 (27%) 
2 (13%) 
Baseline cigs/day (mean±SE) 
8.8 ± 1.2 
12.0 ± 1.9 
End-of-treatment cigs/day (excluding abstainers) 
1.4 ± 0.9 
4.9 ± 1.8 
% Reduction in cigs/day (excluding abstainers) 
84% 
59% 
C1c. Additional Experience with Varenicline 
Our  ongoing  NIDA-funded  P50  component  study  (P50DA16511,  Component  4  “Menstrual  Cycle  and 
Smoking  Cessation  in  Women”,  Co-PIs  Gray/Saladin)  includes  a randomized  trial  of  varenicline  versus 
transdermal  nicotine  patch  
for  smoking  cessation  
in  women.  
  To  date,  135  women  have  been  enrolled  and 
randomized  
in  
the  
trial,  providing  us  with  extensive  experience  
(beyond  
that  gained  
in  
the  above-mentioned 
adolescent study) in safety, tolerability, and efficacy monitoring of varenicline treatment. 
C1d. Broad Experience with Adolescent Smokers 
Our work reflects expertise with and commitment to adolescent smoking research.  In addition to the above 
studies,  we  have  
investigated  nicotine  withdrawal  and  attention-deficit/hyperactivity  (ADHD)  symptoms  (43), 
measures to assess nicotine dependence (44), the trajectory of cigarette smoking during treatment for ADHD 
and substance use disorders (45), and craving (K23DA020482, PI Carpenter) in adolescent smokers. 
C1e. Other Relevant Adolescent Research 
Our  research  on  cannabis  use  in  adolescents,  including  a  controlled  cessation  pharmacotherapy  trial 
(R01DA026777,  PI  Gray),  multiple  
investigations  of  cue  reactivity (46,47),  and  other  
laboratory  and  clinical 
research (48) contributes to our ability to conduct research in the closely related field of adolescent smoking. 
C2. Research Team 
The investigative team, uniquely  experienced  with  adolescent  smoking  cessation  pharmacotherapy 
in  general  and  varenicline  in  particular,  is  ideally  suited  to  undertake  this  study.    Only  6  teams  have 
completed adolescent smoking cessation pharmacotherapy controlled trials, and ours is the only one among 
these  with  additional  adolescent and  adult  varenicline  clinical  
trial  experience.  
  The  
team  
is  
led  by  a  board 
certified  child  and  adolescent  psychiatrist  (Gray),  and  comprised  of  three  clinical  psychologists  (Carpenter, 
Saladin,  Simonian), a  child  and  adolescent  psychiatrist  (Lewis), an  addiction  psychiatrist  (Hartwell), a 
behavioral  psychologist  
(McClure) and  
two  biostatisticians  
(DeSantis,  Baker),  each  with  expertise  vital  
to  
the 
successful completion of the study (see biosketches, budget justification, resources). 
Two  off-site  consultants,  both  with  established  history  of  collaboration  and  consultation  with  
the  
research 
team, will provide input on key areas.  Maxine L. Stitzer, Ph.D., will contribute her expertise in designing and 
conducting  contingency  management  and  smoking  cessation  interventions.    Himanshu  P.  Upadhyaya, 
M.B.B.S., M.S., will provide input on study design and pharmacotherapy safety and efficacy assessments. 
The  study  will  be  conducted  at  a  nationally  recognized  substance  abuse  treatment  research  center, 
assuring  the  ability  to  efficiently  complete  the  project  while  maintaining  the  highest  quality  of  protection  of 
human participants and data integrity. 
C3. Design and Methods of Current Proposal 
C3a. Overview 


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The objective of this proposal is to examine the efficacy and safety of varenicline for smoking cessation in 
adolescents.  The guiding design philosophy was to model the adult smoking cessation literature (allowing for 
indirect  comparisons  of  efficacy  
in  different  populations)  while  
fine-tuning  some  elements  specifically  geared 
for adolescents.  After assessment and inclusion into the study, participants will be randomized to receive a 12-
week  double  blind  course  of  varenicline  or  placebo.    All  participants  will  concurrently  participate  in  a 
contingency  management  (CM) intervention,  specifically  designed  to  reinforce  participant  retention.  
Participants will provide smoking self-report (cigarettes per day) throughout the study.  Biological confirmation 
with  carbon  monoxide  breathalyzer  will  occur  at  all  visits, and  urine cotinine  measurement  will  occur  at  key 
time points (baseline, end of treatment and final post-treatment follow-up).  Psychiatric/medical visits will occur 
weekly  throughout  active  treatment  to  systematically  monitor  safety  and  tolerability.    After  the  12-week 
treatment course, participants will return for 3 post-treatment follow-up visits (Week 13, Week 18, and Week 
26) (see Figure 1).  This approach closely parallels those of the adult varenicline phase III clinical trials (23,24). 
Figure 1. Overview of study design. 
 
 
 
 
C3b. Participants and Feasibility of Recruitment and Retention 
Recruitment Strategies 
Adolescents  (n=166)  will  be  recruited  from  the  community,  schools,  and  clinical  settings.    We  have  an 
aggressive plan for recruitment and are confident that our previously established strategies will ensure success.  
Assuming  an  initial  3-month  period  for study  setup,  per-participant  study  duration  of  6  months,  and  a 
concluding 3-month period for data analysis and publication, we anticipate a recruitment window of 48 months.  
To meet the recruitment goal, we must recruit 3.5 participants per month, which is feasible and realistic.   
Our confidence in successful recruitment stems from a complement of strategies developed over years of 
experience.  At the outset of our prior controlled medication (bupropion SR) and behavioral treatment trial in 
adolescent  smokers  (15),  we  only  consented  2.7  and  enrolled  2.1  participants  per  month  using  traditional 
methods,  such  as  newspaper  advertisements  and  flyers.    Recognizing  the  need  for  more  aggressive 
recruitment,  we  developed  an  
innovative  arrangement  with  
the  Charleston  County  School  District.  
  With  
the 
approval  and  support  of  
the  district  and  schools,  we  established  smoking  cessation  
research  clinics  
in  area 
high schools, yielding 4.5 consented and 3.5 enrolled participants per month for the remainder of the trial. 
In our recent varenicline/bupropion XL pilot trial (27), we did not have sufficient travel/recruitment funds to 
utilize the school clinics.  To bolster recruitment within budget, we utilized internet-based recruitment strategies, 
such  as  advertisements  on  Facebook  and  postings  on  Craigslist,  yielding 3.5  enrolled  participants  per 
month.  In this pilot trial and in the prior bupropion SR trial, we recruited at this rate even in light of FDA “black 
box”  warnings  on  all  of  these  medications, reflecting  our  team’s ability  to  recruit  adolescents  
into  smoking 
cessation pharmacotherapy trials at the targeted goal rate even under the tightest regulatory constraints. 
In  our  adolescent  cannabis  cessation  pharmacotherapy  study  (R01DA026777),  we  combined  
the  above 
strategies, and additionally recruited from area pediatric/primary care clinics and nearby College of Charleston.  
We enrolled  7.5  participants  per  month,  demonstrating  impressive  recruitment  success  achieved  by 
combining a number of innovative, aggressive strategies. 
For  the  proposed  study,  we  plan  to  continue  our  established  combined  approach,  utilizing  high  school-
based  clinics  
(see  attached  support  
letters  
from  
the  principals  of  
the  
two  
largest  high  schools  
in  Charleston 
County,  with  combined  enrollment  >5,000 students),  internet/media  advertisements,  pediatric/primary  care 
clinic  
referrals,  and  College  of  Charleston  postings.  
  
In  
the  event  
that  we  encounter  unforeseen  
recruitment 
difficulty,  we  will  broaden  our  school-based  clinic  program  to  additional  high  schools.    We  can  additionally 
utilize  strategies  that  have  been  successful  for  other  MUSC  studies,  
including  (a)  advertising  on  billboards 
along area highways, (b) establishing research clinics in existing suburban/rural MUSC clinics, (c) conducting 
Consent & 
Eligibility 
Assessment 
Wk 1 Weeks 2-12 (weekly visits throughout) Wk 13 
Wk 18 
Wk 26 
Quit Date 
Start Medication 
End of treatment       Post-treatment  
Efficacy assessments 
titration 
goal dose 
post-treatment follow-up 
Randomization 
Varenicline n=83 
Placebo n=83 
Comprehensive safety/tolerability psychiatric & medical assessments at all visits 


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oral  presentations  at  
local  schools and  community  groups  around  
the  Charleston  area, and  (d)  establishing 
additional sites within the South Carolina node of the NIDA Clinical Trials Network. 
Respondent-Driven Sampling (RDS) will be used to enhance recruitment of the sample. The RDS sampling 
methodology  is  based  on  recruiting  the  eligible  friends  and  acquaintances  of  each  participant  so  that  the 
sample “snowballs”. Each eligible participant who is randomized into the study, and agrees to take part in this 
recruitment assistance, will be given coupons to pass on to other potential participants. The coupons will have 
a unique code linked to the person who passes them out. A referral will be instructed to call the study team for 
screening.  
If  
that  person  successfully  completes  a  screening  assessment,  
the  participant  who  
referred  
them 
can redeem the coupon for $10.  If the referral is eligible and returns for the Day 0 study visit (randomization), 
the participant referring them will earn an addition $10 coupon.  Additionally, a correspondence that reminds 
consented participants of the RDS option will be sent.  The brief contact will reinforce that their participation in 
the process is voluntary and does not impact their study participation in this or any future study activity. It is our 
intent  that  the  communication  can  be  sent  either  by  email  or  mail  based  on  the  information  given  by  the 
consented participant at screening. Reminders will be sent to a given participant no more frequently than once 
per  year  
to  
lessen  any  burden/demand  
to  
the  participant.  Participants  are  encouraged  
to  contact  
the  study 
team if they have any questions or concerns about the RDS process or the received mailer in general. 
Following the RDS model, the study will incorporate a Community Recruitment Vendor (CRV) campaign to 
assist in reaching out to the targeted study population.  By identifying persons/businesses in the local area we 
will  establish  an  agreement  whereby  for  a  monthly  retainer,  the  CRV  will  promote  the  study  using  IRB 
approved recruitment materials within their unique network.  The CRV will also be able to receive a bonus if a 
prospective  participant  
identifies  
the  CRV  as  
their  
referral  source and  
is  successfully enrolled  
into  
the  study 
protocol.  
Additionally,  within  the  local  school  environments  we  will  incorporate  the  use  of  a  recruitment  raffle  to 
generate interest at our lunchroom recruitment table.  Students will be asked to complete a submission slip that 
provides for their first name, telephone number, smoking status, and their willingness to be contacted to learn 
more about a research opportunity.  In return for completing the slip, students will be given a raffle ticket.  The 
$50  gift  card  
raffle prize will  be  available  
to  all  students  
in  
the  school  
regardless  of  
their  smoking  history  or 
interest in study participation. Students will only be able to submit once per raffle and raffles will occur at the 
school  once  submission  slip  entries  slow  and  
it  appears  
that  all  students  wanting  
to  participate  have  had  an 
opportunity to do so.  Study personnel will maintain the raffle needs and have a third party/school administrator 
perform the raffle selection to remove possible suspicion of bias.    
   We have also pursued the use of a direct mailing.  Through the approval and cooperation of the CCSD, 
meeting the standards of FERPA and the use of directory information, a postcard/flier will be sent to the homes 
of all students within the protocol’s targeted age range.  
Retention Strategies 
Retention,  like  recruitment,  is  a  considerable  challenge  in  adolescent  smoking  cessation  medication 
studies.  Among the few large-scale randomized trials, only 30-60% of enrolled participants completed the full 
course of treatment (15-19).  Given intent-to-treat analysis (including all randomized participants and assuming 
that  participants  were  smoking  at  each  missed  visit),  poor  retention  may  result  in  an  underestimate  of 
treatment effects.  It also limits participant exposure to treatment, which further attenuates treatment effects. 
Emerging  literature  supports  the  potential  to  address  this  issue  by  implementing  a  contingency 
management  (CM)  strategy  specifically  
targeting  
treatment  adherence  and  retention.  
  CM  
is  an  established 
behavioral  intervention,  based on  instrumental  conditioning  principles,  in  which  target  behaviors  are 
contingently reinforced.  CM has been widely adopted in smoking cessation research, but is typically only used 
to  reinforce  smoking  abstinence  (i.e.,  reinforcement  
is  contingent  upon  biological  verification  of  abstinence) 
(49),  an  approach  we  have  used  in  the  past  with  adolescent  smokers  (15).    Recent  reports  indicate  that 
attendance-based CM may also be successfully used to target treatment adherence and retention (39).  While 
some early findings were mixed (50), it has subsequently become clear that higher magnitude reinforcement is 
associated  with  significantly  
improved  retention (38-40).  
  Additionally,  cash  rewards,  relative  
to  gift  cards  or 
other tokens, are associated with improved session attendance (51).  Adult and adolescent studies reveal that 
contingent rewards are generally not used to purchase cigarettes or other substances of abuse (51,52).  We 
implemented  a  retention-targeted  CM  strategy  (visit-by-visit  escalating  magnitude cash  reward  for  session 
attendance,  with  reset  to  base  reward  after  a  missed session,  based  on  methods  utilized  by  Carroll  and 
colleagues  [38])  in  our  adolescent  cannabis  cessation  pharmacotherapy  study  (R01DA026777)  with  great 


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success.    Of  participants  engaging  
in  the  CM  program  (i.e.,  all  participants  presenting  for  ANY  visits  after 
medication initiation), 84% completed the entire 8-week course of treatment.  Even accounting for all dropouts 
at  all  
time  points  
(including  
initial  enrollees  
that  did  not  
return  after  assessment  or  medication  
initiation), we 
enrolled 4.5  treatment  completers per  month.    While  the  current  proposal’s  intent-to-treat  approach  will 
include all randomized participants, it is important to note that we can feasibly recruit at a completion rate that 
exceeds our goal enrollment rate. 
Based  on  
the  above  
literature  support  and  history  of  success,  we  will provide  compensation contingent 
upon  completing each  visit in  
the  proposed  study,  at  a  
rate  appropriate  
to  
the  
relative participant  burden  
to 
travel to and complete the visit (Table  3).  Of note, we have specifically chosen not to implement abstinence-
targeted CM, as such an approach may compromise our ability to detect medication versus placebo efficacy 
differences.  Participants will be eligible for $40 compensation for completing the Assessment visit and Weeks 
0, 4, and 8 visits; $30 compensation for completing the Weeks 1, 2, 3, 5, 6, 7, 9, 10, 11, 13, and 18 visits; and 
$50 compensation for completing the Weeks 12 and 26 visits. 
 
 
Table 3. Retention-targeted contingency management (CM) compensation schedule 
Visit 
Assessment Wk 
0 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
13 
Wk 
18 
Wk 
26 
Compensation ($) 
$40 
$40 $30 $30 $30 $40 $30 $30 $30 $40 $30 $30 $30 $50 $30 $30 $50 
Maximum Possible Grand Total $590 
Inclusion/Exclusion Criteria 
Inclusion Criteria 
1. Age 14-21 
2. Daily smoker for ≥6 months 
3. Desire  to  quit  smoking,  with  at  least  one  prior  failed  quit  attempt  and  willingness  to  participate  in  a 
treatment study 
4. If  under  age  18,  parent(s)  or  guardian(s)  able  
to  participate  
in  
informed  consent  and  
initial  assessment 
(unless the participant provides evidence of emancipated status) 
5. If female, agreement to use birth control (any form of hormonal contraception such as Depo-Provera, daily 
oral  contraception,  transdermal  patch,  or  Nuva-ring;  intrauterine  device;  sterilization;  or  double  barrier 
contraception,  which  is  a  combination  of  any  two  of  the  following  methods:  condoms,  spermicide, 
diaphragm) to avoid pregnancy 
Exclusion Criteria 
1. Lifetime  history  of  any  DSM-IV-TR  mood  or  psychotic  disorder  (e.g.,  major  depressive  disorder,  bipolar 
disorder, schizophrenia) 
2. Lifetime history of suicidality, homicidality, or clinically significant hostility/aggression 
3. Current substance dependence, other than nicotine 
4. Current unstable major medical disorder 
5. Current pregnancy or breastfeeding 
6. Current use of medications with smoking cessation efficacy 
7. Known hypersensitivity to varenicline 
Age Range 
The  participant  age range  (14-21)  for  the  proposed  study  was  chosen  for  multiple  reasons.    Broad 
agreement exists to support this range.  The Maternal Child Health Bureau defines adolescence as age 11-21, 
and the Center for Disease Control and Prevention defines it as ages 10-24.  NIH defines individuals up to age 
21  as  children.  
  Given  considerable  developmental  variability  
from  age  10-24,  
though,  a  sample  
inclusive  of 
this  range  might  be  overly  heterogeneous.    Additionally,  while  many  adolescents  
initiate  smoking  between 
ages 10-13, very few smoke at the rate necessary for study inclusion (only 3% of 8th graders smoke daily, and 
many  of  those  smoke  <5  cigarettes  per  day)  (7).    Given  the  potential  
identification  of  
individuals  22-24  as 
adults,  we  opted  
to  exclude  
this  age  range  as  well.  
  We  acknowledge  
that  
the  previous  “adult”  varenicline 
clinical  trials  included  participants  as  young  as  age  18,  but  given  the  studies’  mean  age  of  43  ±  SD  11, 
exceedingly few were age 21 or younger, and there have been no published reports on safety, tolerability, and 


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efficacy within these younger participants.  As such, varenicline remains almost completely unstudied among 
adolescents, even by the broadest age definition. 
We  do  recognize  that  the  developmental  context  varies  considerably  even  within  the  narrowed  8-year 
range of 14-21.  To address this, we plan to stratify randomization by age, ensuring that equivalent proportions 
of  those  age  14-17  (“younger  adolescents”)  and  those  age  18-21  (“older  adolescents”)  are  represented  
in 
varenicline and placebo treatment groups.  Given our prior success in recruiting younger adolescents with high 
school-based clinics and other strategies, we anticipate recruiting similar proportions of younger versus older 
adolescents, and will adjust strategies if the proportions become skewed.  This stratified approach will convey 
the added opportunity to compare outcomes (in exploratory fashion) between younger and older adolescents. 
C3c. Intake and Randomization 
All  participants  (and  parents/guardians,  as  appropriate)  will  receive  a  brief  telephone  screening  to 
determine potential study eligibility. They will then be scheduled for an initial assessment session, consisting of 
a variety of self-report forms, semi-structured interviews (including comprehensive psychiatric evaluation), and 
laboratory  tests,  to  determine  study  eligibility.    Parents/guardians  of  participants  under  18  years  old  will 
participate  with  the  adolescent  in  the  screening,  evaluation,  and  informed  consent/assent  procedure.  
Participants  18  years  and older  will  be  able  
to  provide  
their  own  
informed consent.  
 The  
informed  consent 
process  will  
include  a  
thorough  discussion  of  potential  
risks  associated  with  participation,  
including  potential 
adverse  effects  of  study  medication.  
  The  FDA  
“black  box”  warning  
for  varenicline  will  be  
reviewed  
in  detail, 
and  
the  
investigational  nature  of  
this  medication  
in  adolescents  will  be  emphasized.  
 The  complex  
issues  of 
informed consent and assent, and related limitations of confidentiality, as they apply to adolescents and their 
parents/guardians, are understood by the PI and will be communicated clearly during the telephone screening 
and  assessment  visit.  
  
In  
the  case  of  adolescents  
in  South  Carolina  Department  of  Social  Services  custody, 
state guidelines regarding consent for clinical research participation will be followed.   
If volunteers complete the informed consent/assent process and are eligible for participation, they will be 
randomized to double blind varenicline or placebo and will proceed with treatment. In order to avoid accidental 
bias, we will utilize a stratified urn randomization procedure.  We will stratify by the prognostic covariates age 
(14-17 versus 18-21) and baseline smoking level (<12 versus 12 or more cigarettes per day, based on median 
baseline  smoking  in  our  prior  randomized  adolescent  smoking  cessation trial).    The  age  stratification  will 
ensure  
that  both  younger  and  older  adolescents  will  be  equally  represented  
in  
the  varenicline  and  placebo 
groups.    The  smoking  level  stratification  will  help  avoid  significantly  discrepant  baseline  smoking  between 
treatment  groups.    We  considered  additional  stratification  variables  (e.g.,  gender,  severity  of  nicotine 
dependence,  presence  of  other  smokers  
in  household,  history  of  attention-deficit/hyperactivity  disorder),  but, 
amid  concern  over  excessive  division  of  participants  among  multiple  cells,  judged  that  these  could  be 
adequately explored as covariates during efficacy analyses (see Section C3f). 
C3d. Treatment 
Pharmacological Intervention 
The MUSC Investigational Drug Service (IDS) will obtain varenicline 0.5 mg and 1 mg tablets and matched 
placebo tablets. All tablets will be packaged in blister packs, with individual labels for time/date of each dose 
(e.g.,  Tuesday  morning  October  5
th).    This  date- and  time-labeled  blister  pack  method  has  demonstrated 
superior  participant  adherence,  compared  to  traditional  packaging,  and  offers  the  additional  advantage  of 
tracking  the  exact  timing  of  any  missed  doses  (53-55).    The  IDS  successfully  used  identical  methods  for 
medication/placebo dispensing in our adolescent varenicline pilot study. 
If  assessment  procedures  reveal  that  a  participant  meets  inclusion  criteria,  the  IDS  will  randomize  the 
participant to varenicline or placebo in double-blind fashion.  He/she will be given a 7-day supply of medication 
to take home.  Participants will be given an additional 7-day supply “replacement pack” of medication for use in 
the event that they cannot make it back for a visit within the 7-day window between visits. 
In keeping with recommendations from an adolescent varenicline pharmacokinetic study (26), participants 
>55  kg  will  
take  varenicline/placebo  0.5  mg  once  daily  
for  3  days,  
titrated  
to  0.5  mg  
twice  daily  
for  4  days, 
titrated to 1 mg twice daily thereafter.  Participants ≤55 kg will take varenicline/placebo 0.5 mg once daily for 7 
days, titrated to 0.5 mg twice daily thereafter.  In our previous experience with varenicline within adolescents, 
most participants (80%) weighed enough to receive the 2 mg per day dosage.   
During  weekly  visits,  study  personnel  will  review  medication  
logs,  
inspect  blister  packs,  and  perform  pill 
counts  to  monitor  medication  adherence.    Participant  compensation  at  medication  visits  will  be,  in  part, 
contingent  upon  bringing  in  blister  packs  and  completing  medication logs.   The  study medical  clinician 


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(physician  or  physician  assistant) will  systematically  assess  medication  tolerability  and  effects, including 
neuropsychiatric  effects (see  Section  C3e  below).  
  Medication  supply  will  be  
refreshed  
for  ongoing  use  over 
the  
following  week.  
  Participants will  be  encouraged  
to  contact the  study medical  clinician between  visits  
to 
address any immediate concerns regarding adverse effects.  The study medical clinician will be available “on 
call”  at  all  
times  
for  evaluation  and  management  of  adverse  events.  
  
If  a participant  experiences  
intolerable 
medication-related  adverse  effects  at  any  point  during  
the  study,  a  dose  
reduction  may  be  undertaken.  
  
If  a 
participant is unable to tolerate the reduced dose, medication will be discontinued, and the participant will be 
encouraged to remain in the study for monitoring and non-medication study procedures. 
Psychosocial Intervention 
During  
the  assessment  visit,  participants  will  be  given  adolescent-targeted  smoking  cessation  brochures 
and briefly counseled on cessation strategies.  Participants will be instructed to set a quit date that will occur 
one  week  after  medication  
initiation.    At  weekly  visits,  participants  will  be  provided  with  brief  (<10  minute) 
individual  skills-based  cessation  counseling  (i.e.,  enhancing  motivation,  enlisting  social  support,  recognizing 
smoking  triggers,  managing  craving/withdrawal/stress),  paralleling  psychosocial  interventions  in  similarly 
structured  adolescent  (17)  and  adult  (23-25)  cessation  pharmacotherapy  studies.    We  considered 
implementing  a  more  
intensive/formal  counseling  approach,  but  opted  against  
it  
for  multiple  
reasons:  1)  
the 
main test is a pure comparison of varenicline versus placebo, 2) the absence of intensive behavioral treatment 
is consistent with “real world” clinical practice (physician provision of pharmacotherapy without intensive/formal 
counseling),  and  3)  utilizing  psychosocial  methods  
that  closely  parallel  prior  
research  
improves  our  ability  
to 
compare outcomes with the existing adolescent (17) and adult (23-25) cessation literature. 
C3e. Instruments/Measures/Materials 
Baseline Screening, Diagnostic, and Motivation/Self-Efficacy/Psychosocial Assessments 
1. Demographic and Smoking  History Questionnaire:  Basic  demographics,  
including  age,  gender,  
race, 
social history, and a detailed smoking history will be collected. 
2. Locator  Form:   Contact  information  including  address,  phone,  email,  etc.  will  be  collected.    Contact 
information will be reviewed and updated as necessary throughout the study.  The research team will have 
a Facebook page. Privacy settings will be such that only the research team will be able to see the list of 
“friends” associated with the account, no one can post on the “wall”, and the research team will not post on 
the  walls  of  any  “friends”  associated  with  
the account.  The  research  
team  will  use  private  messages  
to 
contact participants through Facebook.  
3. History and Physical Examination: This will be used to assess for any significant medical conditions that 
would  preclude  study  participation.  The  physical  examination  will  
include  all  major  systems  
that  may  be 
examined non-intrusively (i.e., excluding breast and genitourinary examination). 
4. Mini  International  Neuropsychiatric  Interview (MINI)  (56, 57):  The  MINI  is  a  structured  interview 
designed to ascertain a current, past, or lifetime history of the major Axis I psychiatric disorders in DSM-IV 
and ICD-10.  Based on the original MINI, an expanded version (MINI Plus) and a pediatric version (MINI 
Kid) have been developed and validated.  The appropriate instrument (MINI Plus for participants ≥18 years 
and  MINI  Kid  for  participants  <18  years)  will  be  administered  by  trained  staff  and  used  to  evaluate  for 
potentially exclusionary co-morbid psychiatric and substance use disorders. 
5. Structured Clinical Interview for DSM-IV (SCID-I/P) (89): The SCID-P is a structured diagnostic interview 
that  assesses  each  of  
the  criteria  
for  DSM-IV  diagnoses.  The substance use  disorder  modules from  
the 
SCID are used as an alternative for these modules in the MINI.  The SCID has proven to have excellent 
inter-rater and test-retest reliability. 
6. Adolescent  Smoking  Consequences  Questionnaire (ASCQ)  (59):  The  ASCQ  
is  a  validated  30-item 
instrument used to assess outcome expectancies of cigarette smoking among adolescents. 
7. Adolescent  Reasons  for  Quitting  Smoking (ARQS)  (60):  The  ARQS  is  a  validated  measure  of 
adolescent motives for smoking cessation. 
8. Modified  Fagerström  Tolerance  Questionnaire (mFTQ)  (61):  The  mFTQ  
is  a modified  version  of  
the 
Fagerström  Test  for  Nicotine  Dependence  self-rating  questionnaire  for  nicotine  dependence  developed 
specifically for adolescents.  It will be used to determine nicotine dependence status. 
9. Autonomy Over Tobacco Scale (AUTOS) (62): The AUTOS is an adolescent-validated questionnaire that 
assesses severity of nicotine dependence via determination of loss of autonomy over tobacco use. 
10. Readiness to Quit and Confidence in Ability to Quit: These will be assessed on 10-point scales. 


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11. Satisfaction With Life Scale (SWLS) (63): This 5-item instrument measures global cognitive judgments of 
satisfaction with one’s life. 
12. Generalized  Self-Efficacy  Scale (GSES)  
(64):  This  10-item  self-report  measure  will  be  used  
to  assess 
participant general self-efficacy. 
13. Smoking  Abstinence  Self-Efficacy (65):  We  will  use  Velicer’s  9-item  scale  of  the  ability  to  resist 
temptations to smoke in various contexts.  We will additionally use a single item (0-10 visual analog scale) 
measure of smoking abstinence self-efficacy (66). 
14. Multidimensional Scale of Perceived Social Support (MSPSS) (67, 68): The MSPSS is an adolescent-
validated 12-item instrument that assesses perceived support from family, friends, and a significant other. 
15. Barratt  Impulsiveness  Scale (BIS-11)  (69):  The  BIS-11  
is  an  adolescent-validated  30-item  self-report 
questionnaire of impulsive personality traits. 
16. Toronto Alexithymia Scale (TAS-20) (87): The TAS is a scale which measures alexithymia, a condition in 
which people have trouble identifying and describing feelings.  Items are rated using a 5-point Likert scale 
whereby  1  =  strongly  disagree  and  5  =  strongly  agree.  Both  
the  original,  1985  version  and  
the  revised, 
1992 version will be administered at the assessment visit. 
17. Wisconsin  Predicting  Patient’s  Relapse  
(WI-PREPARE) (88): The WI-PREPARE is a 7-item scale that 
predicts relapse to smoking through assessment of nicotine physical dependence, environmental factors, 
and individual difference characteristics.  
18. Technology  Acceptability Questionnaire: This  54-item,  locally  developed  questionnaire  will  be 
administered to participants once during the course of the study to gain information on their technology use 
and acceptability.  
Psychiatric Symptom Assessments (to be administered at all visits) 
1. Psychiatric  
Interview: The study medical clinician (directly supervised by the PI, a board certified child & 
adolescent  psychiatrist) will  conduct  an  interview  inquiring  about  symptoms  of  depression, 
mania/hypomania,  pathological  anxiety, psychosis,  substance  abuse,  sleep  disturbance,  and  suicidality 
since  
the  
last  visit.  
  The  screening  
items  
from  
the  MINI  (56,57)  will  be modified  
for  use as  a  prompt  
to 
evaluate all major components of psychiatric symptomatology. 
2. ADHD Rating Scale-IV (ADHD-RS) (70): This validated measure will assess ADHD symptom severity. 
3. Hospital  Anxiety  and  Depression  Scale  (HADS)  (71-73):  This  self-report  instrument,  validated  in 
adolescents and adults, will be used to monitor anxiety and depression symptoms. 
4. Columbia-Suicide  Severity  Rating  Scale (C-SSRS)  (42): The  C-SSRS  is  a  brief,  low-burden  suicide 
assessment  scale  administered  by  a  clinician,  which  provides  a  validated  measure  of  variables  such  as 
impulsivity,  poor  frustration  tolerance,  sadness,  and  hopelessness.    We  have  successfully  used  this 
instrument, regarded as the gold standard suicidality assessment instrument in pediatric and adult clinical 
trials, in our prior adolescent varenicline pilot study and in our ongoing adult varenicline trial. 
Cigarette and Other Substance Use Assessments 
1. Timeline  Follow-Back (TLFB)  (74):  The  TLFB  is  a  calendar-based  instrument  that  measures  daily 
amounts  of  drug  consumption  
for  a  specified  period  of  
time  by  patient  self-report.  
  Study  personnel  will 
administer this instrument.  A 30-day calendar will be used at baseline for cigarettes and other substances 
to  gather  information  related  to  amount  of  use  for  each  day.    TLFB  will  again  be  utilized  at  the  post-
treatment  
follow-up  visits  
to  assess  cigarette  smoking  and  other  substance  use.  
  We  have  successfully 
used TLFB in our prior adolescent smoking studies. 
2. Cigarette  and  Other  Substance  Use  Diary: Participants will maintain a daily diary of cigarette and other 
substance use during active medication treatment and will return the diary for review at each weekly visit.  
We have successfully utilized this method in our prior adolescent smoking studies. 
3. Cotinine: Nicotine is metabolized to cotinine by the liver.  Cotinine has a longer half-life than nicotine, and 
thus serves  as  a  more  
reliable  biomarker  of  cigarette  smoking  
(75).  Urine  samples  will  be  collected  and 
delivered  to  the  MUSC  Clinical  Neurobiology  Lab for  determination  of  cotinine  level  at  three  key  time 
points:  baseline,  end  of  
treatment  (week  12)  and  
final 6-month  
follow-up  (week  26).  
  Expert consensus 
guidelines  support  urine  cotinine  testing  to  biologically  confirm  7-day  abstinence,  with  a  recommended 
“cutoff” of 50 ng/mL (37).  Cotinine may also be measured through saliva samples provided by participants 
at these three time points. 
4. Carbon  Monoxide  Breathalyzer (Bedfont):  This  method,  less  intrusive  and  costly  than  urine  cotinine 
measurement, will be used during all study visits to detect residual levels of carbon monoxide from recent 


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cigarette use.  Per expert consensus guidelines, a “cutoff” of 8 parts per million will be used as a biological 
abstinence confirmation measure (37). 
5. Urine  Drug  Screen (UDS) (iScreen,  US  Screening  Source):  The  UDS  will  be  used  
to  assess  
for  
recent 
non-nicotine substance use, including marijuana, cocaine, opioids, and amphetamines. 
6. Penn Alcohol Craving Scale (PACS) (86) consists of five items that assess the frequency, intensity, and 
duration  of  alcohol  craving.  
Individuals  rate  
their  responses  on  a  scale  of  0–6,  with  a  range  of  possible 
scores falling between 0–30. The PACS will be administered at all study visits. 
Medication Monitoring and Safety/Tolerability Assessments 
1. Medication Log: Participants will be asked to maintain a log to report adherence with medication.  This log 
will be reviewed at each medication-monitoring visit. 
2. Concurrent Medications Form: The use of other medications will be monitored and documented at each 
clinic visit for safety purposes. 
3. Vital  Signs:  Blood  pressure,  pulse,  height,  and  weight  will  be  monitored  
to  assess  medical  stability  and 
monitor for any changes during study participation. 
4. Urine  Pregnancy  Test:  This  will  be  monitored  among  
female  participants.  All  pregnancy  
testing  will  be 
done prior to conducting the urine drug screens.  If a participant tests positive for pregnancy at the initial 
assessment, the participant will be ineligible to participate in the study and no further study procedures will 
be  conducted.  At  subsequent  study  visits,  urine  pregnancy  testing  will  be  done  prior  to  urine  drug 
testing.  If  a  pregnancy  
test  
is  positive,  study  medication  will  be  discontinued  
immediately  and  no  
further 
urine  drug  
testing  will  be  performed.  We  will  encourage  any  participant  
testing  positive  
for  pregnancy  
to 
continue  participating  
in  all  non-medication  and  non-drug  
testing  components  of  
the  study,  and will,  with 
participant consent, follow the participant through the course and outcome of pregnancy. 
5. Adverse  Events: During  psychiatric  and  medical  evaluation  at  each  visit,  adverse  events  will  be 
documented and rated as mild, moderate, or severe.  The study medical clinician will additionally assess 
relatedness of adverse events to study interventions (i.e., not at all, unlikely, uncertain, possible, probable, 
definite).  
  The  Data  and  Safety  Monitoring  Board  
(See  Human  Subjects  Section  4)  will  evaluate  adverse 
event information (e.g., frequency, severity, number leading to discontinuation) by treatment group during 
closed sessions of yearly meetings.  Established procedures will be used in the event of a serious adverse 
event (SAE; see Human Subjects Section 4.6). 
6. Review  of  Systems: A  detailed,  structured  psychiatric  and  medical  review  of  systems  (41)  will  be 
conducted during weekly medication monitoring visits to augment open-ended adverse event questioning.  
We have utilized this method with success in prior adolescent smoking cessation pharmacotherapy studies.  
This exhaustive, systematic method reduces the likelihood of underreported adverse events. 
7. Penetration  of  Blind  Assessment: At  key  
time-points  during  
the  study,  participants will  be  asked  by  a 
study  clinician  
if  
they  
think  
they  are  
receiving  active  study  medication  or  placebo.  The  study  clinician  will 
also document whether they think the participant is receiving active medication or placebo. 
Self-Report Craving, Withdrawal, and Satisfaction Forms 
1. Questionnaire  on  Smoking  Urges—Brief (QSU-B)  (76): Participants  will  complete  this  brief  form 
detailing  symptoms  of  nicotine  craving.  
  Participants  will  additionally  complete  ratings  of  current  
level  of 
craving  and  maximum  &  average  levels  of  craving  over  the  last  week.  Similar  measures  of  current, 
maximum, and average ratings of ability to resist temptation to smoke will be collected. 
2. Minnesota  Nicotine  Withdrawal  Scale (MNWS)  (77):  The  MNWS, a  DSM  IV-based  instrument  that 
assesses symptoms of nicotine withdrawal, will be used to track participants’ nicotine withdrawal symptoms. 
3. Modified  Cigarette  Evaluation  Questionnaire (mCEQ)  (78,79):  The  12-item  mCEQ  assesses  the 
reinforcing  effects  of  smoking  and  contains  5  subscales  (smoking  satisfaction,  psychological  reward, 
enjoyment of respiratory tract sensations, craving relief, aversion). 
4. Craving and Temptation to Smoke:  These will be assessed on 10-point scales at every visit. 
C3f. Statistical Methods 
Outcome Measures 
The primary efficacy outcome is cotinine-verified 7-day point prevalence abstinence at the end of treatment 
(Week 12).  The primary safety outcome is frequency of treatment-emergent adverse events. 
Sample Size and Power 


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The proposed study is powered on the primary efficacy hypothesis that varenicline will increase abstinence 
(cotinine verified 7-day  point  prevalence  abstinence),  
relative  
to  placebo,  at the end of treatment (Week 12).  
While 30-day point prevalence abstinence or continuous abstinence outcomes are ideal, we do not believe an 
adequately  powered  study  for  either  approach  is  feasible  within  the  proposed  funding  period.    There  is 
considerable precedent for using 7-day point prevalence as primary outcome in adolescent smoking cessation 
pharmacotherapy  trials  (see Table  1).    We  have  recently  published  a  conversion  method  to  estimate 
continuous abstinence from point prevalence outcomes with a fair degree of confidence (80), and we will track 
other abstinence outcomes as secondary measures. 
The  first  step  towards  a  sample  size  analysis  is  estimating  cotinine-confirmed  7-day  point  prevalence 
abstinence  at  end  of  placebo  
treatment.  
  We  estimate  
this  
to  be  6.25%,  based  on  
the  placebo-only  end  of 
treatment group abstinence rate in our prior bupropion SR/contingency management smoking cessation study, 
which  was  conducted  
in  a  nearly  
identical  population  to  that  of  the  proposed  study  (15).    This  estimate  
is 
consistent  with  placebo  group  end  of  
treatment  outcomes  
in  other  adolescent  smoking  cessation  
trials  
(e.g., 
5% in Moolchan et al., 2005; 5.6% in Muramoto et al., 2007) (17,19).  The slightly higher rate in our trial will 
result in a conservative estimate of the expected effect size (active – placebo), thereby increasing sample size 
and ensuring sufficient power for hypothesis testing. 
The second step towards a sample size analysis is to estimate the effect of varenicline within adolescent 
smokers.  The only existing adolescent varenicline abstinence data come from our recent pilot trial, in which 
26.7% of participants achieved cotinine-confirmed 7-day point prevalence abstinence (27).  This results in an 
anticipated  effect  size  
(odds  
ratio)  of  5.5.  
  We  
recognize  
that  
this  estimate  
is  based  on  a  small  sample  size 
(n=15  
in  
the  pilot  
trial  varenicline  group).  
  However,  we  do  not  believe  
the  absolute  end  of  
treatment  7-day 
point  prevalence  abstinence  rates  from  adult  varenicline  studies  (ranging  from  50  to  60%) would  be 
appropriate for sample size estimation in this case, as absolute adolescent abstinence rates (see Table 1) are 
consistently lower than those in adult studies (23,24,81).  We do, however, believe that varenicline effect sizes 
may  be  comparable  across  adult  and  adolescent  trials.    By  this  measure,  our  estimates  converge.    For 
example, end of treatment abstinence odds ratios in adults were as follows: 3.8 (23), 4.1 (24), and 9.1 (82). 
Thus, the sample size estimation is based on anticipated abstinence rates of 6.25% (placebo) and 26.7% 
(varenicline), for an odds ratio of 5.5.  With a type 1 error rate of 5% (α = 0.05) and power (1- β) of 80%, this 
would require 51 participants per group using a two-sided Pearson’s Chi Square test statistic.  However, we 
still wish to aim even more conservatively, recognizing that (a) this effect size may be an overestimate since 
the varenicline abstinence rate came from a small sample pilot study, and (b) we must account for attrition for 
the intent-to-treat analysis.  In light of the range of odds ratios in prior adult varenicline studies, we have 
conservatively targeted detection of an odds ratio of 4.0 for power analysis.  Original plans were that we will 
enroll and randomize 83 participants per group, for a total sample size of 166.  This will allow us to detect 
an odds ratio of 4.0 over the anticipated placebo rate of 6.25%, which would correspond to a varenicline 
abstinence rate of 21.1%.  Due to the higher than expected retention losses within our target population of 
adolescents and following the current ratio of successfully consented to randomized participants, we estimate 
that 240 participants will need to be enrolled (consented) to meet our sample size needs.  
 
Efficacy: Primary Analysis 
Categorical clinical and demographic variables will be assessed by chi-square tests of independence, while 
continuous  variables  will  be  assessed  using  Student’s t-test.    The  effect  of  varenicline  versus  placebo  on 
abstinence  at  end  of  treatment  will  be  examined  using  
logistic  regression.    Models  will  be  computed  both 
unadjusted  and  adjusted  for  significant  covariates  found  in  the  descriptive  analysis.    For  these  efficacy 
analyses, 7-day point prevalence abstinence will be defined as having no cigarettes (or other tobacco/nicotine 
products) for 7 days, confirmed by urine cotinine level ≤50 ng/mL.  All randomized participants will be included 
in the analyses (intent-to-treat approach), and participants will be considered non-abstinent at any missed visit. 
Safety: Primary Analysis 
Similar to adult varenicline phase III studies (23,24), we define any treatment-emergent adverse event any 
adverse  event  occurring  between  treatment  initiation  and  one  week  following  treatment  conclusion.    Non-
inferiority analysis will be utilized to compare adverse event rates between varenicline and placebo groups (84).  
With a type 1 error rate of 5% (α = 0.05) and power (1- β) of 80%, the proposed total sample size of 166 and 
an  estimated  placebo  rate  of  treatment-emergent  adverse  events  of  75%  (23)  will  afford  a  non-inferiority 
margin (NIM) of 16.7% for the varenicline adverse event rate.  We considered incorporating a larger sample 


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size  that  would  afford  a  smaller  NIM.    However,  even  to  detect  a  12.5%  NIM,  a  total  sample  size  of  376 
participants would be necessary.  That sample size would not be feasible within the proposed funding period. 
Smoking-Related Outcomes: Secondary Analysis 
Secondary outcomes include the following:  a) 7-day biologically confirmed point prevalence abstinence at 
6 months, b) continuous abstinence, c) time to lapse (first puff), d) time to relapse (first of 3 consecutive days 
smoking ≥ 1 cigarette), and e) longitudinal efficacy of varenicline.  These will be tested via logistic regression to 
examine a) point  prevalence  at  6  months and b) continuous  abstinence from  
targeted  quit  date  
(Week  1)  
to 
both treatment conclusion (Week 12) and final follow-up visit (Week 26), Cox Proportional hazard models (83) 
to examine c) time to first lapse (first puff, first cigarette), d) time to relapse (first of 3 consecutive days smoking 
≥1 cigarette), and e) Generalized Estimating Equation (repeated measures) to examine the entire study time 
course.  
 Repeated  measures  analysis  of  variance  will  be  used  
to  assess  
treatment  effects  of  varenicline  on 
craving (QSU-B), withdrawal (MNWS), and smoking reinforcement (mCEQ) throughout the study.  All efficacy 
analyses (primary and secondary) will be repeated among participants with ≥80% medication adherence, per 
protocol analysis, and completers analysis.  Medication adherence (pill counts), nicotine dependence (mFTQ, 
AUTOS),  motivation/readiness to  quit  (baseline  rating),  self-efficacy  (GSES),  perceived  social  support 
(MSPSS), and impulsivity (BIS-11) will be explored as possible moderators influencing the effect of varenicline 
on abstinence. 
Safety: Secondary Analysis 
Of  particular  
interest  will  be  adverse  events  
leading  
to  medication  discontinuation  and  
the  occurrence  of 
treatment-related  serious  adverse  events  (SAEs)  (see  Human  Subjects  Section  4.6).    We  will  specifically 
compare  neuropsychiatric  adverse  events  (Psychiatric  Interview) using  non-inferiority  testing, as  well  as 
depression/anxiety (HADS) and suicidality (C-SSRS) ratings using one-sided 2-sample t-tests.  Based on adult 
literature (34,35), we anticipate no serious adverse events, and appropriate stopping plans are in place (see 
section C3g) for added precaution. 
Participant Retention Analysis 
Total  number  of  
treatment  visits  attended  will  be  compared  using a  Student’s t-test,  while  
the  number  of 
days retained will be assessed using Cox Proportional Hazards regression models. 
C3g. Clinical Management Issues 
Study Termination 
Study  
termination  may  be  
initiated  by  a  study  participant  
(or parent/guardian,  as  applicable)  
for  personal 
reasons, or by the PI or members of the Data Safety and Monitoring Board for reasons of participant safety or 
the additional requirement for more intensive or a different form of therapy for addiction, medical, or psychiatric 
disorders.  Another cause for termination would be any participant behavior that is felt to present a threat or 
harm to staff, including sexual or verbal harassment.  Other terminations may be due to a participant becoming 
lost to follow up and/or moving from the geographic area.  Frequency counts for reasons for termination will be 
analyzed for both treatment groups using chi square analytic procedures.  If a participant is terminated for any 
reason,  attempts  will  be  made  to  continue  collecting  adverse  event  and  smoking  data  over  the  12-week 
treatment trial and follow-up period so that data can be entered for the intent-to-treat analysis. 
Clinical Deterioration “Rescue Plan” 
A  clinical  deterioration  “rescue”  plan  will  be  in  place  for  participants  that  experience  psychiatric  or 
substance  use  deterioration  during  the  study.    Symptoms  will  be  monitored  closely  throughout  the  trial  to 
assess  
for  deterioration.  
  Any  participant  demonstrating  gross  clinical  deterioration  will  be  discontinued  
from 
the trial and appropriate intervention will be arranged.  The rescue measures will include withdrawal from the 
study,  immediate  assessment  by  the  PI  or  physician  Co-I  for  a  comprehensive  psychiatric  and  substance 
abuse evaluation and determination of appropriate intervention, as well as emergency therapy sessions if the 
participant does not meet criteria for withdrawal from the study.  In the case that the participant is aged 14-17, 
the PI will contact the parent/guardian to discuss the clinical deterioration and enlist involvement with proposed 
intervention.  The  intervention  may  include  outpatient,  day  treatment,  partial  hospitalization,  or  inpatient 
treatment  in  the  Medical  University  of  South  Carolina  Institute  of  Psychiatry.  These  programs  have  highly 
trained  clinicians  competent  
in  
treating  all  psychiatric  and  substance  use  disorders.  
  The  PI  holds  admitting 
privileges for all of these clinical programs, allowing for efficient referral and management. 
Referral for Participants Needing Continuing Treatment 
At the end of the study, if a participant (or parent/guardian, as applicable) requires or requests continuing 


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treatment  for  nicotine  dependence,  we  will  make  a  treatment  referral  to  an  appropriate  smoking  cessation 
clinical program or the state Quitline. 
C3h. Operational Plan and Research Timetable 
Funding  
for  
five  years  
is  
requested.  The  
first  
three  months  will  be  used  
for  hiring  and  
training  personnel, 
submitting  regulatory  documents,  and  preparing  for  study  initiation.  Fifty-four  months  will  be  needed  for 
participant recruitment (48 months) and data collection (additional 6 months for last enrolled participants). The 
final three months will be used for data analysis and manuscript preparation. At a targeted recruitment rate of 
3.5 participants per month, an adequate sample will be obtained within the time allotted. 
C4. Conclusion 
Despite  
the  
tremendous  potential  health  
impact  of  smoking  cessation  among  adolescents,  minimal  effort 
has  focused  on  developing  evidence  based  cessation  treatments  for  this  age  group.    Given  varenicline’s 
superior efficacy in adults, and the limited efficacy of other treatments previously investigated in adolescents, a 
controlled  
trial  of  varenicline  
in  adolescents  
is  warranted.  
  The  research  
team,  experienced  with  adolescent 
smoking  cessation  clinical  
trials  
in  general  and  varenicline  
in  particular,  
is  
ideally  suited  
to  conduct  
this  
trial.  
Specific strengths of the trial design include: a) methods that parallel those of adult smoking cessation studies 
(allowing for indirect adolescent versus adult comparisons), b) comprehensive safety/tolerability assessments 
(addressing  potential  medication  safety  concerns),  c)  outcome  measures  informed  by  expert  guidelines 
(allowing for the most stringent evaluation of efficacy), and d) established methods to address the considerable 
challenges of recruitment and retention of adolescent smokers in pharmacotherapy trials.  We believe that this 
study has the potential to substantially advance adolescent smoking cessation treatment. 
 
 


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Human Subjects Research 
1.  
 
Risks to Human Subjects 
1.1 
 
Human Subjects Involvement and Characteristics  
The  PI  and  Co-Is  have  all  completed  the  University  of  Miami  computer-based  CITI  Human  Subjects 
Research Education Course.  A total of 240 male and female adolescent smokers, between 14 and 21 years 
old,  will  be  
recruited  over  48  months.  
  The  sample  size  was  determined  based  on  statistical  power  analysis 
(Section  C3f).    Participants  will  be  recruited  from  clinical  sites,  schools,  and  the  general  community.  
Advertisement will be used for study recruiting.  The inclusion/exclusion criteria are as follows: 
Inclusion Criteria 
a) Age 14-21 
b) Daily smoker for ≥6 months 
c) Desire  
to  quit  smoking,  with  at  
least  one  prior  
failed  quit  attempt  and  willingness  
to  participate  
in  a 
treatment study 
d) If under age 18, parent(s) or guardian(s) able to participate in informed consent and initial assessment 
(unless the participant provides evidence of emancipated status) 
e) If female, agreement to use birth control (any form of hormonal contraception such as Depo-Provera, 
daily  oral  contraception,  transdermal  patch,  or  Nuva-ring;  
intrauterine  device;  sterilization;  or  double 
barrier contraception, which is a combination of any two of the following methods: condoms, spermicide, 
diaphragm) to avoid pregnancy 
Exclusion Criteria 
a) Lifetime history of any DSM-IV-TR mood or psychotic disorder (e.g., major depressive disorder, bipolar 
disorder, schizophrenia) 
b) Lifetime history of suicidality, homicidality, or clinically significant hostility/aggression  
c) Current substance dependence, other than nicotine 
d) Current unstable major medical disorder 
e) Current pregnancy or breastfeeding 
f) Current  use  of  medications  with  smoking  cessation  efficacy  (e.g.,  bupropion,  nicotine  replacement, 
clonidine, nortriptyline) 
g) Known hypersensitivity to varenicline 
Demographics 
The 2007 South Carolina Youth Tobacco Survey reveals that, among South Carolina high school students, 
6.6%  of  males,  4.2%  of  
females,  6.6%  of  whites,  and  3.0%  of  African  Americans  are  “heavy”  smokers  (≥6 
cigarettes  per  day)  (http://www.scdhec.gov/health/chcdp/tobacco/docs/ytsbook2007.pdf).    The  rates  among 
other  minority  groups  are  not  
reported.  
  United  States  Census  data  
from  2009  
reveal  
that  
the  population  
in 
South Carolina is 68.9% white (64.9% white, not Hispanic origin), 28.2% African American, and 4.5% Hispanic 
(http://quickfacts.census.gov/qfd/states/45000.html).  Other minority groups collectively comprise only 2.4% of 
the population.  Given these data, we anticipate enrolling a sample that is a) 60% male and 40% female, and 
b) 82% white, 15% African American, and 3% Hispanic.  These numbers are generally consistent with those in 
our prior large-scale controlled pharmacotherapy trial in adolescent smokers (15). 
1.2 
 
Sources of Materials  
Research  materials  obtained  from  participants  include  responses  to  questionnaires,  psychiatric  and 
physical  examination  
results,  urine  
tests  
(cotinine,  drug  metabolites,  and  pregnancy),  and  expired  air  carbon 
monoxide breathalyzer tests.  Materials will be obtained specifically for research purposes.  There will be no 
use of existing specimens, records, or data.  Every effort will be made to maintain participant confidentiality, in 
accordance with HIPAA. 
1.3 
 
Potential Risks 
Questionnaires  and  interviews  are  all  non-invasive  and,  as  such,  involve  minimal  physical  risk  to 
participants.  Potential risks incurred by participants include: 
1. Adverse events related to study medication 
2. Loss of confidentiality 


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1.3.1   
Adverse events related to study medication   
The  varenicline  package  insert  (http://www.pfizer.com/files/products/uspi_chantix.pdf)  details  adverse 
events associated with the medication.  Specifically, it reports that “the most common adverse reactions (>5% 
and twice the rate seen in placebo-treated patients) were nausea, abnormal (e.g., vivid, unusual, or strange) 
dreams, constipation, flatulence, and vomiting.” 
Meta-analyses of the four main adverse events in varenicline versus placebo groups in adult trials yielded 
relative risks (RRs) of 3.21 (95% CI 2.71, 3.80) for nausea, 1.50 (95% CI 1.26, 1.79) for insomnia, 2.79 (95% 
CI 2.09, 3.72) for abnormal dreams, and 1.20 (95% CI 1.00, 1.45) for headache (85).  Similarly, adverse events 
in  our  adolescent  pilot  cessation  trial  
included  
insomnia  (4/15  participants)  nausea  (3/15  participants),  and 
headache  (3/15  participants)  (27).    No  other  adverse  events  were  reported  by  more  than  one  participant 
(including abnormal dreams – 1/15 participants).  In a 2-week adolescent varenicline pharmacokinetic study, 
the most common adverse events were nausea, headache, vomiting, and dizziness (26). 
While  post-marketing  anecdotal  reports  of  psychiatric  adverse  events  
(32,33)  
led  
to  an  FDA  “black  box” 
warning  
for  varenicline,  a  meta-analysis  of  controlled  varenicline  
trials  
in  adults  
(total n=3091  
randomized  
to 
varenicline)  yielded  no  significant  
increase,  
relative  
to  placebo,  
in  any  psychiatric  adverse  events  aside  
from 
sleep  disturbance  (see Table  2 in  Section  A)  (34).   Additionally,  a  “real  world”  primary  care  cohort  study 
including  10,973  smokers  prescribed  varenicline  revealed  no  evidence  of  increased  risk  of  self-harm, 
compared  with  smokers  prescribed  other  cessation  pharmacotherapies  (35).  The  2-week  adolescent 
pharmacokinetic study by Faessel and colleagues (26) revealed 2 participants with sleep disturbances and 1 
with  a  brief,  mild  episode  of  anger/irritability  
(out  of  57  participants  
taking varenicline).  
  Our  adolescent  pilot 
data  similarly  did  not  reveal  psychiatric  adverse  events  with  any  notable  frequency.    We  are  nonetheless, 
especially in light of regulatory and public caution surrounding varenicline, committed to excluding potentially 
vulnerable  individuals  (i.e.,  those  with  any  lifetime  history  of  mood  or  psychotic  disorders,  suicidality,  or 
clinically  significant  hostility/aggression)  and  providing  detailed,  rigorous  monitoring  and  management  of 
potential psychiatric adverse events enrolled participants. 
1.3.2   
Loss of confidentiality 
Any communication of personal information carries the potential risk of breach of confidentiality.  
2. 
 
Adequacy of Protection Against Risks 
2.1 
 
Recruitment and Informed Consent 
Recruitment of the participants will be from clinics, schools, and the community. The Medical University of 
South Carolina (MUSC) Institutional Review Board (IRB) approved Informed Consent (IC) will be obtained prior 
to the initial assessment.  The consent will be explained orally and in the written form, and will be documented 
by the signature of the participant on the IC.  For participants under 18 years old, a parent/legal guardian will 
provide consent and the participant will provide assent.  The consent document will contain a thorough review 
of  potential  risks  associated  with  trial  participation,  including  potential  medication-related  risks  (i.e., 
neuropsychiatric  adverse  events).    Details  of  varenicline’s  “black  box”  warning  status  will  be  provided  to 
participants and parents/legal guardians, and will be discussed at length.   
For re-consenting purposes for those participants under 18 years of age whose parent/legal guardian 
is not available to attend a study visit, we would conduct the re-consent process over the phone. We 
understand the importance of parental/guardian presence in the initial consenting procedures of study 
participation due to the seriousness of study medication (i.e. black box warnings).  The issue that may 
arise,  however,  
is  
that it  may  become  
intrusive  and  demanding  
for  
them  
to  
return  
for  a  
re-consent 
need  when  
in  most  cases  
the  
IC  
revisions  are  very  minor  and  more  editorial  and  administrative  
in 
nature.    We  would  not  want  their  child’s  study  participation  to  potentially  negatively  impact  the 
parent/guardian’s  employment, nor  do  we  want  such  a  need  to  be  a  barrier  in  the  child’s  study 
participation.   
The process that study personnel would follow includes:  Discussion with the parent/guardian by 
trained/approved  study  personnel  would  be  completed  prior  
to  
the  next  scheduled  visit  where  a  
re-
consent  is  to  take  place.    When  possible,  study  personnel  will  have  forwarded  the  new  ICF 
(electronically or hard copy) to the parent so he/she they could have the document in front of him/her 


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during  the  re-consent  discussion.    Study  personnel  would  clearly  document  the  conversation  and 
detailing the changes in the ICF.  If the parent/legal guardian expresses understanding of the study 
changes and approves the child’s continued participation and the ICF is available to the parent/legal 
guardian, he/she will sign and date the ICF accordingly, returning it for the minor’s assent and study 
personnel’s signature at the subsequent visit. If the parent/legal guardian does not have access to the 
ICF at the time, then the document will be sent home with the minor after their next completed study 
visit where the assent and staff’s signature was obtained.  The parent will sign the form accordingly 
and  it  will  be  returned  to  the  study  site  at  the  following  study  visit.    A  copy  of  the  fully  signed 
document would be provided to the parent/legal guardian either by hardcopy (postal mail or minor’s 
delivery)  or  electronically  (email  or  fax)  per  the  parent/legal  guardian’s  preferred  method.    If  the 
parent/legal  guardian  does  not  
feel  comfortable  with  
the  changes,  requesting  
to  have  additional  
in 
person  discussion  with  study  personnel,  
then  
the  minor’s  next  visit  would  be  cancelled/rescheduled 
for a date when the parent/legal guardian is able to attend the visit.  At that time, routine in person 
consenting procedures would occur.   
Absence of Coercion: Participation in the study is voluntary. Participants will be compensated $40 for the 
initial assessment.  The informed consent agreement that will be read to each volunteer (and parent/guardian 
as applicable) prior to enrollment in the study explains the following: 
a) Compensation is supplied at each study visit. 
b) Participants may discontinue participation in the study at any point. 
c) Withdrawing from the study will not result in any adverse consequences to the participants. 
2.2 
 
Protection Against Risk 
2.2.1   
Adverse events related to study medication   
The informed consent process will be used to thoroughly educate participants and parents/guardians about 
potential  medication-related  risks  (including  neuropsychiatric  adverse  events).    This  discussion  will  include 
thorough review of the FDA “black box” warning for varenicline, and clear communication that varenicline’s use 
in adolescents is investigational.  Rigorous screening procedures and strict exclusion criteria are designed to 
exclude  potential  participants  at  elevated  risk  
for  adverse  events.  
  This  
includes  comprehensive  psychiatric 
assessment and evaluation to exclude individuals with any lifetime history of mood disorder, psychotic disorder, 
suicidality,  homicidality,  or  clinically  significant  hostility/aggression.  
  The  study medical  clinician (physician  or 
physician assistant, directly supervised by the PI, a board certified child & adolescent psychiatrist) will conduct 
serial  psychiatric  and  medical  evaluations  weekly  throughout  treatment,  providing  comprehensive,  detailed 
adverse  event  monitoring  (see  Section  C3e).    Additionally,  vital  signs  and  validated  ratings  of  depression, 
anxiety,  and  suicidality  symptoms  (in  light  of  caution  around  potential  psychiatric  adverse  events)  will  be 
collected and reviewed at each visit.  Participants and parents/guardians will have access to the study medical 
clinician 24 hours, 7 days a week for emergencies.  Participants experiencing intolerable adverse events will 
have  the  opportunity  to  reduce  dose  or  discontinue  medication  altogether,  while  remaining  
in  the  study  for 
ongoing  monitoring.    The  PI  has  admitting  privileges  for  a  full  spectrum  of  psychiatric  treatment services, 
including outpatient, day treatment, partial hospitalization, and inpatient programs, in the event that symptom 
acuity warrants intensive intervention.  Urine pregnancy tests will be conducted weekly throughout treatment 
for female participants. 
2.2.3   
Loss of confidentiality  
The research team has established procedures in place to minimize the risk of any confidentiality breach.  
Participant  records  are  stored  
in  
locked  
files  within  
locked  offices  
in  areas  
that  are  
locked  during  holidays, 
weekends,  and  non-working  hours.  Information  contained  in  computer  databases  is  password  protected, 
maintained  by  participant  number  only,  and  devoid  of  specific  
identifiers.  No  specific  or  general  participant 
information will be left in public access areas, and no oral communication regarding participants with identifiers 
will be made in any public areas. Research staff members have been given extensive training in maintaining 
confidentiality as well as HIPAA regulations. 


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3. 
 
Potential Benefits of the Proposed Research to the Participants and Others / Importance 
of the Knowledge to be Gained 
Despite  considerable  public  health  
implications,  minimal  
research  has  
focused  on  developing  efficacious 
adolescent smoking cessation treatments, particularly pharmacotherapies.  As the most efficacious cessation 
pharmacotherapy  
in  adults,  varenicline  
is  a  strong  candidate  
for  evaluation  
in  adolescents.  
  Results  of  
this 
study will fill a critical evidence gap, providing key information to guide clinical practice. 
Participants in the study, regardless of randomization to varenicline or placebo, will benefit by receiving a) 
comprehensive  medical  and  psychiatric  evaluation,  and  b)  weekly  smoking  cessation  counseling  
throughout 
active treatment. 
4. 
 
Data and Safety Monitoring Plan 
This  section  
is  based  on  
the  recommendations  
in  NIDA’s  “Guidelines  
for  Developing  a  Data  and  Safety 
Monitoring Plan” (http://www.nida.nih.gov/funding/dsmbsop.html). 
4.1 
 
Summary of the Protocol  
 
This application proposes a randomized, placebo-controlled trial (n = 166) of varenicline, testing its efficacy 
and  safety  for  adolescent  smoking  cessation.    Treatment-seeking  adolescent  smokers  will  be  recruited  via 
schools, clinics, and the community.  The primary efficacy outcome of interest is cotinine-confirmed 7-day point 
prevalence  abstinence  at  the  end  of  treatment  in  varenicline-randomized  participants,  relative  to  those 
randomized  
to  placebo.  
  The  primary  safety  outcome  
is frequency  of  
treatment-emergent  adverse  events  
in 
varenicline-randomized  participants,  
relative  
to  
those  
randomized  
to  placebo.  
  
Inclusion/exclusion  criteria  are 
outlined above.  Power and sample size calculations are in Section C3f. 
4.2 
 
Trial Management  
All aspects of the study will be run through the MUSC Department of Psychiatry and Behavioral Sciences, 
where the PI holds his faculty appointment. The target population is described in Section C3b, Human Subjects 
Section 1.1, and the adjoining Targeted/Planned Enrollment Table. The timetable is as follows: 
 
 


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Year 1 
(months) 
Year 2 
(months) 
Year 3 
(months) 
Year 4 
(months) 
Year 5 
(months) 
Refine all procedures 
1-3 
 
 
 
 
Procure supplies 
1-3 
 
 
 
 
Refine recruitment methods 
1-3 
 
 
 
 
Train Personnel 
1-3 
 
 
 
 
Study Enrollment 
 
 
 
 
 
   Cumulative N to enroll* 
(30) 
(72) 
(114) 
(156) 
(166) 
   First Participant Enrolls 
 4 
 
 
 
 
   First Participant Completes 
10 
 
 
 
 
   Last Participant Enrolls 
 
 
 
 
51 
   Last Participant Completes 
 
 
 
 
57 
Data Analysis 
 
 
 
 
58-60 
Manuscript Preparation 
 
 
 
 
58-60 
All numbers reflect months within total study duration (*with the exception of cumulative N)  
4.3 
 
Data Management and Analysis  
Data will be collected by the appropriate individual (research assistant, PI, Co-I) using standardized paper 
forms or will be directly entered using iPads.  Data will only be identified with the study’s ID of the participant. 
The codes linking the name of the participant to the study ID will be kept confidential in a secured cabinet by 
the PI.  All data will be transferred to and managed in the REDCap system.  REDCap provides: 1) an intuitive 
interface  for  data  entry  (with  data  validation);  2)  audit  trails for  tracking  data  manipulation  and  export 
procedures;  3)  automated  export  procedures  
for  seamless  data  downloads  
to  common  statistical  packages 
(SPSS,  SAS,  Stata,  R);  4)  procedures  
for  
importing  data  
from  external  sources;  and  5)  advanced  
features, 
such as branching logic and calculated fields. These procedures are effective in minimizing data entry errors 
(e.g., missing or errant data). The data analysis plan is outlined in Section C3f.  
4.4 
 
Quality Assurance  
Accuracy  and  completeness  of  the  data  collected  will  be  ensured  by  weekly  review.    A  10%  random 
sample  of  the  primary  source  document  will  be  crosschecked  with  the  database  on  a  quarterly  basis.    If 
inaccuracies exceed 4%, then a second 10% will be randomly chosen for audit.  The REDCap system does not 
accept outliers, illogical response patterns, etc. The PI will have weekly meetings with the research assistants 
to discuss qualitative comments received during data collection and any problems in data collection or entry. 
The  statistician  will  periodically  examine  the  database  to  look  for  irregularities.  Initial  data  analyses  will 
examine distributions of variable scores and comparability of baseline characteristics across conditions in case 
analyses need to be adjusted for these. Confidentiality protections are outlined above. 
4.5 
 
Regulatory Issues 
Prior  to  the  start  of  the  study,  the  protocol  will  be  registered  on  the  clinical  trials  registry 
(www.clinicaltrials.gov).  All  serious  adverse  events  will  be  reported  
to  
the  MUSC  
Institutional  Review  Board 
(IRB)  within  24  hrs.  Follow-up  of  all  serious  adverse  events  will  be  
reported  as  well.  All  adverse  events  are 
reviewed weekly by the PI and yearly by both the DSMB and the IRB. Any significant actions taken by the local 
IRB, including significant protocol changes, will be relayed to NIDA. We anticipate the serious adverse event 
rate to be extremely low. If monitoring indicates otherwise, we will convene a special meeting of the DSMB.  
4.6 
 
Trial Safety 
The  potential  
risks  and  benefits  and  methods  
to  minimize  
these  
risks  are  outlined  
in  Sections  1.3  and  2.   
Guidelines  have  been  developed  for  managing  and  reporting  of  adverse  events  (AEs),  including  serious 
adverse  events  
(SAE;  defined  as  any  untoward  medical  occurrence  
that  
results  
in  death,  
is  
life-threatening, 
requires  or  prolongs  hospitalization,  causes  persistent  or  significant  disability/incapacity,  
results  
in  congenital 
anomalies/birth defects, or in the opinion of the investigators represents other significant hazards or potentially 
serious  harm  
to  research  subjects  or  others).  
  Dr.  Gray  will  serve  as  
the  Program  Manager  
for  AEs.    The 


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Adverse Event Log will be used to document all AEs in tabular form.  If an AE is non-serious (self-limited with 
no  
intervention  needed),  no  
further  action  will  be  necessary.  
  However,  
in  
the  case  of  a  serious,  unresolved 
event, an AE follow-up log will be completed. The clinician will then call Dr. Gray with initial reports within 24 
hours of the start of the SAE.  The clinician will record the information on SAE Notification Form.  He/she will 
forward hard copies of the complete report (SAE Notification Form, Concomitant Medication Log, and AE Log) 
to  Dr.  Gray,  who  will,  in  turn  notify  the IRB,  DSMB,  and  NIH  about  the  SAE.    Additionally,  Dr.  Gray  will 
communicate  summary  reports  of  DSMB  discussion  of  the  SAE,  or  any  deliberations  of  IRB  regarding  the 
review of the SAE or the trial itself, to NIH.  If the event is “Serious, Unexpected and Associated” (an SAE is 
considered unexpected if  
it  
is  not  described  
in  
the  Package  
Insert),  Dr.  Gray  will  complete  Food  and  Drug 
Administration  
(FDA)  Form  3500A  and  will  
forward  
it  
to  
the  FDA.  
  Dr.  Gray  also  will  
inform  
the  
IRB  and  
the 
study participants (and parents/guardians, as appropriate) about the SAE. In all of these reviews and reports, 
strict patient confidentiality will be maintained. 
AEs will be coded on a weekly basis using Medical Dictionary for Regulatory Activities (MedDRA) rules and 
entered into a database. For each weekly study meeting, the research assistants will prepare a summary of all 
AEs,  listed  by frequency  of  each  type  of  event  by  various  demographic  characteristics  such  as  gender, 
ethnicity,  age,  as  well  as  by  severity  and  
relatedness to  
the  study  
intervention. The  PI  will  
review  
this  at  
the 
weekly study meeting (or before if more urgent). 
Study  procedures  will  follow  as  much  as  possible  the  FDA’s Good  Clinical  Practice  Guidelines 
(www.fda.gov/oc/gcp).  
  We  will  encourage  participants  
(and  parents/guardians  as  appropriate)  
to  notify  
their 
physicians  that  a)  they  are  in  a  research  study  evaluating  varenicline,  compared  to  placebo,  for  smoking 
cessation in adolescents, and b) the physician should contact the PI directly if he/she has any questions. 
The research assistants will be instructed not to reveal whether a person is a participant in the study and 
will report to the PI any outside requests for information about a participant or any breaches in confidentiality. 
All requests by participants’ physicians and other medical providers will be referred directly to the PI.  
4.7 
 
Trial Efficacy 
The Data and Safety Monitoring Board (see 4.9) may request a blinded interim efficacy report (blinded to 
the  PI  and  
research  
team)  
for  
review  while  
the  
trial  
is  ongoing.  
  Final  
(fully  unblinded)  efficacy  analysis  will 
occur after all participants have completed all visits. 
4.8   
DSM Plan Administration  
Monitoring  for  this  trial  will  be  provided  by  the  DSMB  through  NIDA  and  will  review  safety  data  on  a 
quarterly  basis.  The  statistician  will  examine  
the  outcomes  database  quarterly  
for  missing  data,  unexpected 
distributions or responses, and outliers. The PI will weekly check the adverse event database prepared by the 
research  assistants  
immediately  prior  
to  
the  
lab  meeting  
to  a)  see  
if  any  particular  MedDRA  categories  are 
being endorsed more frequently than anticipated, and b) determine if any side-effect symptom checklist scores 
are higher than expected. A DSM report will be filed with the IRB and NIDA on a yearly basis, unless greater 
than  expected  problems  occur.  The  
report  will  
include  participant  characteristics,  
retention  and  disposition  of 
study  participants,  quality  assurance  
issues  and  reports  of  adverse  events,  significant/unexpected  adverse 
events and serious adverse events. We will report efficacy at the end of the trial. 
4.9 
 
DSM Board  
Safety and if requested, efficacy data will be reviewed by a Data and Safety Monitoring Board (DSMB) that 
will meet approximately once every 3 months.  The board will be blinded to participants’ actual treatment 
assignments, but may break the blind if safety concerns arise from the blinded data. 
The DSMB will meet quarterly (more frequently as needed for emergent situations) to review any AEs 
related to the study, as well as review any data management related errors. The board may be called at any 
point if needed for serious adverse events, etc. Modification will be made in the procedures and/or the protocol 
if necessary based on the findings of the board. 
The investigator and/or study physician is responsible for defining, in his/her best judgment, the 
relationship of the AE/SAE to the study drug/placebo, and their severity.  The investigators in this study have 
the responsibility of promptly reporting all SAEs to the NIDA DSM, IRB, and FDA. Events will be reported when 


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they are serious, unexpected (i.e. not in the medication insert information), and at least possibly related to the 
study medication.  
Any SAEs due to any cause, that occur during the course of this investigation, whether or not related to the 
investigational agent, must be reported within 24 hours by telephone or entered into the Serious Adverse Event 
Tracking and Reporting System (SAETRS) to the Study Medical Monitor and the NIDA Medical Monitor. 
The IND sponsor is required to report SAEs to the FDA: 1) in 7 days if the SAE is unexpected (or, if 
expected, unusually serious or rarely seen), life-threatening or lethal, and at least possibly related to the 
investigational product, with a follow-up written report in 8 days; 2) in 15 days if the SAE is unexpected (or, if 
expected, unusually serious or rarely seen), at least possibly related to the investigational product, but not 
immediately life-threatening; and 3) in an annual report in all other cases. 
 
 
 
 
 
 


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ICF_001.pdf: 
 
 
 
 
 
 
 
A Randomized Controlled Trial of Varenicline for Adolescent Smoking Cessation 
 
NCT01509547 
 
Informed Consent Form 
 
Document Date: June 21, 2016 


 
IRB Number: «ID» 
Date Approved «ApprovalDate» 
Page 1 of 8  
 
 
 
 
 
 
 
Version 21JUN2016 
College of Charleston IRB approval: GNHN-06-14-2016 
 
Medical University of South Carolina 
CONSENT TO BE A RESEARCH SUBJECT 
A Randomized Controlled Trial of Varenicline for Adolescent Smoking Cessation 
If participants include those under 18 years of age: 1) The subject’s parent or legal guardian will be 
present when the informed consent form is provided. 2) The subject will be able to participate only if 
the parent or legal guardian provides permission and the adolescent (age 12-17) provides his/her 
assent. 3) In statements below, the word “you” refers to your child or adolescent who is being asked 
to participate in the study. 
A. 
PURPOSE AND BACKGROUND: 
You are being asked to volunteer for a research study. This research is sponsored by the 
National Institute on Drug Abuse. The purpose of this study is to examine the effectiveness of 
varenicline, compared with placebo (a pill with no active medication), for smoking cessation 
(quitting smoking) in adolescent smokers and to examine the safety and tolerability of 
varenicline, compared with placebo, when used for smoking cessation in adolescent smokers. 
 
You are being asked to participate in this study because you are a smoker aged 14-21. The 
investigator in charge of this study is Dr. Kevin M. Gray. This study is being done at the 
Medical University of South Carolina and will involve approximately 240 volunteers. 
 
B. 
PROCEDURES: 
If you agree to be in this study, the following will happen: 
 
1. Initial assessment: You will be asked to complete a variety of self-report forms about smoking 
and how you are feeling.  A psychiatric evaluation will be completed, and urine will be collected for 
laboratory tests (urine drug screen, urine pregnancy test for females, and urine cotinine) to 
determine if you are able to participate in the study.  For females, the urine pregnancy test will be 
done before any other testing, including the urine drug screen.  If the pregnancy test is positive you 
will not be eligible to participate in the study and no further study procedures will be conducted.  You 
may also be asked to provide a saliva sample to be measured for cotinine.  A study medical 
clinician (either a study doctor or a physician assistant) will also do a brief physical exam to make 
sure you are healthy.  This will include checking your vital signs, like your blood pressure, heart 
rate, height, and weight.  We will also do a breathalyzer test, where you will blow into a machine, to 
determine your recent smoking status.  Parents/guardians of participants under 18 years old will 
participate in the screening, evaluation, and informed consent/assent procedure.   
 
During this visit, you will be given smoking cessation brochures and briefly counseled on strategies 
to help you quit smoking.  You will be instructed to set a quit date that will occur one week after you 
start taking the study medication. 
 
The research team will use several methods of contact to keep in touch with you. We will ask you to 
provide us with phone numbers, e-mail addresses, current home and work addresses, and contact 


 
IRB Number: «ID» 
Date Approved «ApprovalDate» 
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College of Charleston IRB approval: GNHN-06-14-2016 
 
information of family and friends who may know how best to reach you.  We will also have a 
Facebook account that we may use to contact you. The research team will only use private 
messages to contact you through Facebook. 
 
2. Randomization (week 0):  Once you complete the initial assessment and we determine that you 
are eligible for participation, you will be randomized to double blind varenicline or placebo and will 
proceed with treatment. There will be two treatment groups.  One group will receive varenicline, the 
active medication and the other group will receive a placebo, a pill with no active medication.  
Volunteers will be randomly assigned to one of the two groups, which means that you have a 50/50 
chance (like flipping a coin) of being assigned to either treatment group.  Neither the researchers 
nor you will make the choice of which group to which you are assigned.  Also, neither the 
researchers nor you will know which group you have been assigned.   
 
3. Treatment (weeks 1 – 12): Once you are randomized to one of the two treatment groups you will 
receive either study medication or placebo (depending on your treatment group) in a blister pack 
that will include instructions on how and when to take the pills.  You will be given a 7-day supply of 
medication to take home and an additional 7-day supply, which is a replacement pack of medication 
for use in the event that you cannot make your next scheduled appointment. 
During treatment with the study medication you will be scheduled for weekly visits to see the study 
medical clinician, who will ask you questions about how you are feeling, including any side effects 
you may be experiencing. 
 
You will be asked to keep study logs to keep track of the amount of medication you are taking each 
day.  You will also be asked to keep a record of the amount of cigarettes you are smoking each day 
and if you are drinking any alcohol or using any drugs.   
 
During the weekly visits, study personnel will review medication logs, inspect blister packs, and 
perform pill counts to monitor the amount of medication you are taking.  You will also complete 
questionnaires about cravings, withdrawal, and satisfaction.  Over the course of the 12 weeks you 
will also have periodic visits that will include additional medication safety and tolerability 
assessments.   
 
At the weekly visits, you will be provided with brief (less than 10 minutes) individual counseling to 
help you quit smoking.  
 
4.  Post-Treatment Follow-Up (weeks 13 – 26): You will be asked to come in for 3 follow-up visits 
once you’ve completed taking the study medication.  One visit will be scheduled one week after you 
have stopped taking the study medication, the second visit will be scheduled 6 weeks after you stop 
the study medication and the final visit will be scheduled 14 weeks after stopping the study 
medication.  During these visits the study doctor will ask you about any side effects you may have.  
You will also complete several self-report forms, similar to the ones you completed at other study 
visits.  We will collect a urine sample at the final study visit for a urine drug screen and a urine 
cotinine test.  Female participants will have a urine pregnancy test at the week 13 follow-up visit 


 
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prior to the urine drug screen.  If the pregnancy test is positive, the urine drug screen will not be 
performed.  You may also be asked to provide a saliva sample to be measured for cotinine.   
 
You may be withdrawn from the study without your consent if the researchers believe it is in your 
best interest or if you fail to follow study procedures. 
C. 
DURATION: 
Participation in the study will take about 28 weeks with a total of 17 visits.  The first should last 
about 2 hours and remaining visits should last about 30 minutes – 1 hour. 
 
D. 
RISKS/DISCOMFORTS:  
1. Varenicline: If you are in the group that receives varenicline, the following side effects are 
possible: The most common adverse reactions were nausea (upset stomach), abnormal 
(e.g., vivid, unusual, or strange) dreams, constipation, flatulence, vomiting, and headache.  
In a 2-week adolescent varenicline pharmacokinetic study, the most common adverse 
events were nausea, headache, vomiting, and dizziness.   
 
There are no published reports on the safety and efficacy of varenicline in adolescents. 
More than 15 million adults have taken varenicline since it was made available as a 
prescription drug.  Since this time, there have been post-marketing reports of 
neuropsychiatric symptoms, some serious.  In other words, after varenicline was 
approved by the FDA, symptoms related to mental health and nervous system 
functioning were reported by those who used it.  These symptoms include:  
- Changes in mood  
- Agitation (irritation) 
- Psychosis (mental disorder impairing thoughts/beliefs)   
- Hallucinations (seeing or hearing things not real)  
- Paranoia (feelings of suspicion)  
- Delusions (false notions/beliefs)  
- Homicidal ideation (thoughts of harming others)  
- Hostility (aggression)  
- Changes in behavior  
- Anxiety (worry)  
- Panic (fear)  
- Suicidal ideation (thoughts of killing self)  
- Suicide attempt (attempting to kill self)  
- Completed suicide (suicide resulting in death)  
 
The above neuropsychiatric symptoms occurred in patients attempting to quit smoking with 
varenicline. Because these events are reported voluntarily from a population of uncertain size, 
it is not always possible to reliably estimate their frequency or establish causal relationship to 
drug exposure.   


 
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If you have cardiovascular disease (heart or blood vessel problems), taking varenicline may 
 
increase your risk of certain cardiovascular adverse events.  Contact the study doctor if you 
 
experience new or worsening symptoms of cardiovascular disease while taking varenicline, for 
 
example:  
- 
Shortness of breath or trouble breathing  
- 
New or worsening chest pain  
- 
New or worsening pain in legs when walking  
Smoking cessation with or without treatment is associated with nicotine withdrawal symptoms 
and the exacerbation of underlying psychiatric illness (i.e., worsening of existing illness).  Not 
all patients had known pre-existing psychiatric illness and not all had discontinued smoking.  
The role of varenicline in these reports is not known.  
 
You should stop taking study medication and immediately report any such symptoms to 
the study staff, and be sure to make known any history of psychiatric illness prior to 
beginning treatment.  
2. Randomization: You will be assigned to a treatment program by chance. The treatment you 
receive may prove to be less effective or to have more side effects than the other study 
treatment(s) or other available treatments. 
3. Placebo: If you are in the group that receives placebo, your condition will go without active 
treatment for 12 weeks. 
4. If you are or become pregnant and test positive for illegal drugs, it is a law that the South 
Carolina Department of Social Services (DSS) must be notified. You and your family will be 
evaluated by the agency. You could be ordered to mandatory drug treatment, lose custody 
of your children, or possibly be jailed.  
5. Unknown Risks: The experimental treatments may have unknown side effects. The 
researchers will let you know if they learn anything that might make you change your mind 
about participating in the study. 
6. Loss of confidentiality:  Any communication of personal information carries the potential risk 
of loss of confidentiality.  
E. 
BENEFITS:  
The potential benefit to you is that the treatment you receive may prove to be more effective 
than the other study treatment or than other available treatments, although this cannot be 
guaranteed. 
 
If you are in the group that receives varenicline and it proves to treat your condition with fewer 
side effects than the current standard therapy, you may benefit from participating in the study; 
however, this cannot be guaranteed. 
 


 
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F. 
COSTS: 
You will not be charged for any of the study treatments or procedures. The costs of the study 
medication, all tests associated with this study, and all office visits will be covered by the study. 
 
F.   
PAYMENT TO PARTICIPANTS: 
You will receive compensation upon completion of each visit, according to the schedule in the 
table below.   
 
Compensation schedule 
Visit 
Assessment Wk 
0 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Wk 
13 
Wk 
18 
Wk 
26 
Compensation ($) 
$40 
$40 $30 $30 $30 $40 $30 $30 $30 $40 $30 $30 $30 $50 $30 $30 $50 
Maximum Possible Grand Total $590 
If you receive $600 or more from MUSC (including cash, checks, gift cards or other gifts) 
during the calendar year, you will receive a tax Form 1099 and the IRS will be notified of the 
amount you received.  
You are also invited to participate in the recruitment of other participants for this study. If you 
choose to participate, we will provide you with coupons that you may give to other people (e.g., 
peers, acquaintances) who you think would be eligible and interested in this study. You may 
choose to tell people to whom you give these coupons to call the study team if they are 
interested in participating in the study. These individuals will not be identified unless they 
contact the study office themselves. If any of your coupons result in successful scheduling and 
completion of a screening visit, you will receive $10 for each one. If that person is enrolled in 
the study (i.e. is eligible for the study and returns for the Week 0 visit), you will earn an 
additional $10.  Participation in this process is completely voluntary, and if you elect not to 
participate your participation in this study will not be affected in any way. 
G.   
ALTERNATIVES: 
If you choose not to participate in this study, you could receive other treatments for your 
condition. Other treatments are available to help adolescents quit smoking include smoking 
cessation counseling. Your study doctor will discuss with you the major risks and benefits of 
the standard of care and alternative treatment option(s). 
 
H.   
NEW INFORMATION: If there are significant new findings during the course of the study, you 
will be notified. 
 
I.   
STUDENT PARAGRAPH: Your participation or discontinuance will not constitute an element 
of your academic performance nor will it be a part of your academic record at this Institution.  
The Charleston County School District nor any school that is a part of this district is neither 
sponsoring nor conducting this research.  There is no penalty for not participating.  Participants 


 
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may withdraw from the study at any time without penalty. 
 
J.   
EMPLOYEE PARTICIPATION: Your participation or discontinuance will not constitute an 
element of your job performance or evaluation nor will it be a part of your personnel record at 
this Institution. 
 
K.     CONFIDENTIALITY CERTIFICATE:  
A Certificate of Confidentiality has been obtained from the Federal Government for 
this study to help insure your privacy. This certificate means that researchers 
cannot be forced to tell people who are not connected with the study, including 
courts, about your participation, without your written consent. If we see 
something that would immediately endanger you, your child, or others, we may 
discuss it with you, if possible, or seek help. 
 
 
 
L.   
DISCLOSURE OF PREGNANCY TESTING RESULTS OF FEMALES AGED 17 YEARS AND 
YOUNGER:  
 
During your participation in this study, you will be given a pregnancy test. If you are under 16 
years of age, the results will be shared with your parents and/or legal guardian. 
 
If you are 16 years or older, you have the right to direct that such test results not be shared 
with your parents or legal guardian. Please initial in the space below to indicate your choice. 
Your choice will not affect your ability to participate in this research project: 
 
___ Yes, you may share my pregnancy test results with my parents or legal guardian. 
___ No, you may not share my pregnancy test results with my parents or legal guardian.  
 
M. INVITATION TO PARTICIPATE IN FUTURE STUDIES 
 
From time to time we have other research studies for which you might be eligible. 
We are inviting you to allow us to contact you by phone, mail, or both to see if 
you would be interested in participating in any future studies. By checking the 
“yes” box below, you are indicating that you would like to give us your phone 
number, any alternate phone numbers, and address so that we may contact you if 
another study becomes available. To maintain your confidentiality, we will not 
leave identifiable messages or any identifiable information on letters or envelopes 
that are mailed to you.  By checking the “no” box below, you are indicating that 
you do not want study personnel to contact you for any future studies. You may 


 
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still participate in the current study if you check “no” and you will not suffer any 
adverse consequences in doing so.  
 
 Yes! I would like to be re-contacted for future studies. I give permission for study 
personnel to contact me by phone or by mail to inform me of other available studies I 
may be eligible for. Please initial here_________. 
      
  No. I do not wish to be re-contacted for any future studies. Please initial 
here_______. 
 
 
Results of this research will be used for the purposes described in this study. This information may be 
published, but you will not be identified. Information that is obtained concerning this research that can 
be identified with you will remain confidential to the extent possible within State and Federal law. The 
sponsor and the Food and Drug Administration (FDA) will receive copies of the research records. The 
investigators associated with this study, employees of the sponsor, the FDA, and the MUSC 
Institutional Review Board for Human Research will have access to identifying information. All records 
in South Carolina are subject to subpoena by a court of law.  
 
In the event of a study related injury, you should immediately go to the emergency room of the 
Medical University Hospital, or in case of an emergency go to the nearest hospital, and tell the 
physician on call that you are in a research study. They will call your study doctor who will make 
arrangements for your treatment. If the study sponsor does not pay for your treatment, the Medical 
University Hospital and the physicians who render treatment to you will bill your insurance company. 
If your insurance company denies coverage or insurance is not available, you will be responsible for 
payment for all services rendered to you.  
 
Your participation in this study is voluntary. You may refuse to take part in or stop taking part in this 
study at any time. You should call the investigator in charge of this study if you decide to do this. Your 
decision not to take part in the study will not affect your current or future medical care or any benefits 
to which you are entitled.  
 
The investigators and/or the sponsor may stop your participation in this study at any time if they 
decide it is in your best interest. They may also do this if you do not follow the investigator’s 
instructions.  
 
Volunteers Statement 
I have been given a chance to ask questions about this research study. These questions have been 
answered to my satisfaction. If I have any more questions about my participation in this study or study 
related injury, I may contact Dr. Kevin Gray at 843-792-2123.   I may contact the Medical University of 
SC Hospital Medical Director (843) 792-9537 concerning medical treatment.  
 


 
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If I have any questions, problems, or concerns, desire further information or wish to offer input, I may 
contact the Medical University of SC Institutional Review Board for Human Research IRB Manager or 
the Office of Research Integrity Director at (843) 792-4148. This includes any questions about my 
rights as a research subject in this study.  
 
 
 
I agree to participate in this study. I have been given a copy of this form for my own records.  
If you wish to participate, you should sign below. 
 
                                                                            
                                                                                      
  
Signature of Person Obtaining Consent              Date       
*Name of Participant                                     Date 
 
                                                                            
  
Signature of Adult Participant 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Parent/Legal Guardian               
Date                                                                              
*12-17 years of age:  
“My participation has been explained to me, and all of my questions have been answered.  I am 
willing to participate.” 
 
Signature:                                                            
 
Age:                             Date of Birth: