Conditions: Smoking Cessation
Keywords: smoking cessation in adolescents
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 312
Healthy volunteers: no

Brief summary:
The study is designed to see if varenicline combined with age appropriate (adolescent) smoking cessation counseling will help teens quit smoking.

Detailed description:

Arms:
arm 1: Oral Varenicline 1mg BID, or 1/2 that dose (0.5mg BID) for those subjects that weigh less than or equal to 55kg at baseline, for twelve weeks, follow-up through Week 52 arm 2: Oral Varenicline 0.5mg BID, or 1/2 that dose (0.5 QD) for those subjects that weigh less than or equal to 55kg at baseline, for twelve weeks, follow-up through Week 52 arm 3: Oral placebo for twelve weeks,follow-up through Week 52

Interventions: intervention 1: Varenicline 1mg BID intervention 2: Varenicline 0.5mg BID intervention 3: Placebo
Intervention descriptions: intervention 1: Oral Varenicline 1mg BID, or 1/2 that dose (0.5mg BID) for those subjects that weigh less than or equal to 55kg at baseline, for twelve weeks, follow-up through Week 52 intervention 2: Oral Varenicline 0.5mg BID, or 1/2 that dose (0.5 QD) for those subjects that weigh less than or equal to 55kg at baseline, for twelve weeks, follow-up through Week 52 intervention 3: Oral placebo for twelve weeks,follow-up through Week 52

Protocol document:
Prot_000.pdf: 
CP-526,555
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Final Protocol Amendment 5, 09 July 2012
Page 1
CLINICAL PROTOCOL 
A TWELVE-WEEK, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL-GROUP, DOSE-RANGING STUDY WITH 
FOLLOW-UP EVALUATING THE SAFETY AND EFFICACY OF VARENICLINE 
FOR SMOKING CESSATION IN HEALTHY ADOLESCENT SMOKERS
Compound:
CP-526,555
Compound Name (if applicable):
Varenicline
US IND Number (if applicable):
58,994
Protocol Number:
A3051073
Phase:
4


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Document History
Version
Version Date
Summary of Changes
Amendment 5
09 July 2012
The protocol was amended to comply with Pfizer’s 
revised template and to include administrative 
clarifications.  There are no changes to study design, 
visit schedule, procedures, treatments and data 
collection except as noted below for Section 8.3.
Section 4.1 – Inclusion criteria 7 and 8 revised to 
increase more detailed information regarding women 
of childbearing potential.
Section 5.6 – Medication Errors clarified and added 
as a potentially reportable adverse event.
Section 6.4 – Language revised for clarification on 
the importance of keeping subjects in the study and 
to follow up all unresolved AEs.
Section 8.1 Language revised to comply with Pfizer 
protocol template.
Section 8.3 Drug dependency and drug abuse added 
as examples of reportable AEs and removed from
signs and symptoms resulting from these. 
Medication errors added.
Section 8.6 Language revised to comply with Pfizer 
protocol template.
Section 9.4 Language revised to comply with Pfizer 
protocol template.
Minor administrative clarifications.
Section 15.1 Language revised to clarify disclosure 
of clinical trial results.
Amendment 4
January 20, 2012
Protocol Summary “Safety Assessments” section 
wording has been slightly modified to improve 
quality.
Section 2.2 Addition of an exploratory subgroup 
analysis for each dosing group by weight stratum for 
the primary efficacy endpoint.
Safety assessments language slightly modified to 
improve quality.
Section 5.5 Subject dosing card instructions will be 
supplied to each patient, and subjects will be asked 
to read, initial, and date to demonstrate 
comprehension of sun, moon, and other aspects of 
dosing instructions.
Section 8.10 Language modified to stipulate that if 
female subjects have a positive pregnancy test, they 
will be enrolled in a pregnancy registry if a 
pregnancy registry is ongoing at the time of the 


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Final Protocol Amendment 5, 09 July 2012
Page 3
pregnancy.
Section 9.1 Addition of an exploratory subgroup 
analysis for each dosing group by weight stratum for 
the primary efficacy endpoint.
Amendment 3
23 November 2011
Modify exclusion criteria to indicate that use of 
psychoactive or psychotropic drugs in the 6 months 
prior to screening should be discussed with the 
sponsor, rather than be prohibited (in order to allow 
consideration of ADHD subjects on Ritalin or 
Adderall).
Correction of inadvertent symbol error made in 
Section 5.1 while formatting, which showed 
incorrect dose allocation. 
Remove specification for use of the COT-One 
cotinine testing kit.
Amendment 2
09 August 2011
Modify exclusion criteria to indicate that use of 
psychoactive or psychotropic drugs in the 6 months 
prior to screening should be discussed with the 
sponsor, rather than be prohibited (in order to allow 
consideration of ADHD subjects on Ritalin or 
Adderall).
Correction of inadvertent symbol error made in 
Section 5.1 while formatting, which showed 
incorrect dose allocation.
Amendment 1
11 March 2011
Modification of inconsistency between AE reporting 
period criteria to make timeframe be “informed 
consent through last visit”.
Change of group counseling (Project Ex) to 
individual counseling according to modified Public 
Health Service guidelines.
Addition of 24 week endpoints to make consistent 
with other protocols in program.
Clarification of dosing instructions.
Addition of lower value for range of BMI.
Modification of PK section to modify sample 
processing.
Addition of text to indicate this is a PASS study.
Deletion of “drug delivery by courier” option.
Additional detail in exclusions vis a vis 
psychological disorders.
Addition of mandatory text to include Hy’s Law.
Change to Section 8.2 to correct inconsistency 
between start of AE collection and AE reporting 
periods.


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Version update for HADs and NUI.
Original protocol
15 September 2010


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PROTOCOL SUMMARY
The purpose of this study is to evaluate the efficacy, safety, tolerability, and 
pharmacokinetics of two doses of varenicline in adolescent smokers (12-19 years) in 
conjunction with age appropriate cessation counseling.  The treatment period will be twelve 
weeks and subjects’ smoking status will then be followed for approximately nine months.
Background
Varenicline is a selective nicotinic acetylcholine receptor (nAChR) partial agonist designed 
to have specific and potent binding at the 42 receptor subtype which mediates the behavior 
reinforcing effects of nicotine.  Because of its mixed agonist-antagonist properties, 
varenicline offers the therapeutic benefit of relieving symptoms of nicotine withdrawal and 
cigarette craving during abstinence while blocking the reinforcing effects of chronic nicotine.
Varenicline (Chantix/Champix) was approved as an “aid to smoking cessation treatment” 
in adults by the FDA in May 2006, and by the EMEA in September 2006, and is now 
approved in 98 countries worldwide. The approved dose regimen is 1 mg twice daily (1 mg 
bid) for 12 weeks starting with a 1-week titration.  Post-marketing study commitments 
required under section 2 of the Pediatric Research Equity Act (PREA) include a study to 
determine whether varenicline, as part of an overall smoking cessation program, is effective 
in achieving and maintaining smoking cessation in tobacco-addicted adolescents.  The 
current study is considered to be a post-authorization safety study (PASS) in the adolescent 
population, an age group not included in the current labeling for varenicline.
Phase 2 and Phase 3 clinical trials demonstrated the efficacy and tolerability of varenicline 
1 mg BID in more than 3000 adult cigarette smokers, increasing the odds of quitting 
approximately 4-fold compared with placebo at end of treatment, and nearly 2-fold compared 
with bupropion at end of treatment.  The most frequently reported treatment-emergent 
adverse events associated with varenicline were nausea, sleep disturbance, constipation, 
flatulence and vomiting.1  Nausea was reported by approximately 30% of patients treated 
with varenicline 1 mg BID after an initial week of dose titration compared with 10% in 
patients taking placebo.  In patients taking 0.5 mg BID following initial titration, the 
incidence was 16% compared with 11% for placebo.  Nausea was generally described as 
mild or moderate and often transient.1
Post Marketing Experience
There have been post-marketing reports of neuropsychiatric symptoms, some serious, 
including changes in mood, agitation, psychosis, hallucinations, paranoia, delusions, 
homicidal ideation, hostility, changes in behavior, anxiety, panic, suicidal ideation, suicide 
attempt and completed suicide 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. Smoking cessation with or without treatment is associated with nicotine 
withdrawal symptoms and the exacerbation of underlying psychiatric illness. Not all patients 


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had known pre-existing psychiatric illness and not all had discontinued smoking. The role of 
varenicline in these reports is not known.
Additionally there have been reports of hypersensitivity reactions and serious skin reactions.
The Single Reference Safety Document for varenicline, where complete information is 
available, is the most recent Investigator Brochure (IB).
Rationale for this study
Most adult smokers initiated smoking as adolescents.  According to the CDC’s 2005 Youth 
Risk Behavior Survey,2 23.0% of students in the United States were current cigarette users 
(ie, had smoked cigarettes on more than one of the 30 days preceding the survey) and 
9.4% of students were current frequent cigarette users (ie, had smoked cigarettes on 20 of 
the 30 days preceding the survey).  Among the students who reported current cigarette use,
10.7% had smoked at least 10 cigarettes/day on the days they smoked during the 30 days 
preceding the survey and 54.6% had tried to quit smoking cigarettes during the 12 months 
preceding the survey.  Continued smoking increases lifetime risk for various cancers, 
especially lung cancer, cardiovascular diseases, and respiratory diseases.3  Objective 27-2 of 
the US Department of Health and Human Services Healthy People 2010 initiative is to 
reduce the prevalence of current cigarette use among high school students to 16%.4
The transition from early smoking to nicotine dependence (ND) in adolescents is not fully 
understood, but similar to adults, intensity and frequency of cigarette use is associated with 
ND.5  Past studies of smoking cessation in adolescents defined their target patient population 
by intensity, frequency and in some cases, duration of cigarette smoking, in an attempt to 
identify adolescents who were nicotine dependent. The Fagerström Tolerance Questionnaire 
(FTQ) was modified and validated for use in adolescents age 12-16.6 The validation of the 
FTQ with salivary cotinine in adolescents showed good performance for all questions except 
for “Do you inhale”. As this question did not perform well in either adults or adolescents,
the authors recommended abbreviating the scale to six questions.  These six questions are the 
same as the six items included in the Fagerstrom Test for Nicotine Dependence (FTND) 
(Appendix 2) which will be used in this study as an instrument to identify adolescents likely 
to be nicotine-dependent. 
This study will examine whether varenicline, in conjunction with age-appropriate smoking 
cessation counseling at each clinic visit and telephone contact will be safe and effective in 
helping adolescents who smoke on average 5 cigarettes per day, to stop smoking.  
Primary Objective:

To evaluate the efficacy, safety, and tolerability of varenicline compared with placebo 
in adolescent tobacco smokers (aged 12-19 years).


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Endpoints
Primary efficacy endpoint:

The 4-week continuous quit rate (CQR) from Week 9 through Week 12 of treatment 
for varenicline compared with placebo.
Secondary efficacy endpoints: 

7-day point-prevalence of smoking abstinence at Weeks 12, 24, and 52;

Reduction in number of cigarettes smoked at Weeks 12, 24, and 52;

Continuous abstinence rate from Week 9 through Week 24;

Continuous abstinence rate from Week 9 through Week 52.
Safety Assessments: 

Adverse events spontaneously volunteered or observed, adverse events elicited by the 
Neuropsychiatric Adverse Event Interview (NAEI) (Appendix 4), Columbia Suicide 
Severity Rating Scale (C-SSRS), Hospital Anxiety and Depression Scale (HADS), 
and adverse events associated with safety laboratory tests, or vital signs.
PK Assessments: 

Varenicline exposure at steady-state in adolescent smokers.
Statistical Methods
The primary analysis population will be all subjects who took at least one dose of 
randomized study medication.  All significance tests will be two-sided and will use a 
0.05 significance level.  No adjustments will be made to the nominal p-values for analysis of 
the multiple efficacy endpoints.  Subjects who discontinue the study will be considered 
smokers for the remainder of the study regardless of their last smoking status evaluation.
For the binary endpoints with planned inferential treatment comparisons, a logistic regression 
model will be fitted which will include the main effects of strata, treatment group and center 
as independent variables.  Treatment by center interaction will be investigated by an 
expanded model; however the reported p-values will be based on the main effects model.  
Analysis of the change from baseline in mean number of cigarettes smoked per day will use 
analysis of covariance with baseline value, strata, treatment group and center included in the 
model.  The assumptions of the linear model will be examined and if not satisfied, 
nonparametric methods will be used.  There will be no formal inferential analyses of safety 
assessments.  The standard and additional safety data will be summarized by treatment group 
using descriptive statistics.


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Table 1.
SCHEDULE OF ACTIVITIES
Protocol Activity
SCR
BL
Wk
1
Wk
2
Wk
3
Wk
4
Wk
5
Wk
6
Wk
7
Wk
8
Wk
9
Wk
10
Wk
11
Wk
12
ET
12
Informed consent
X
Medical history
X
Physical examination
X
Body Weight and Height (triplicate)
X
X
X
X
Tobacco use history
X
Nicotine dependence: FTND
X
Randomization
X
Target Quit Date (TQD)
X
Urine Pregnancy testa
X
X
X
X
X
X
X
Urine drug test (dipstick at site)
X
X
X
X
X
X
X
Vital Signs (BP/PR)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Non-drug treatment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology & Chemistry
X
X
X
X
X
Pharmacokinetic samplesb
X
X
X
X
Dispense Medication
X
X
X
X
X
X
X
X
X
X
X
X
Dosing Record
X
X
X
X
X
X
X
X
X
X
X
X
X
SBQ-R
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HADS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Event Monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Neuropsychiatric Adverse Event 
Interview (NAEI)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Nicotine Use Inventory
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review/distribute Smoking Diary 
worksheet 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine cotinine at site 
X
X
X
X
X
X
X


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Protocol Activity
SCR
BL
Wk
1
Wk
2
Wk
3
Wk
4
Wk
5
Wk
6
Wk
7
Wk
8
Wk
9
Wk
10
Wk
11
Wk
12
ET
12
Smoking cessation counseling 
(~10 min)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SCR = screening; BL=baseline; Wk=week; ET=early termination; FTND = Fagerstrom Test for Nicotine Dependence; SBQ-R= Suicidal Behaviors 
Questionnaire-Revised, C-SSRS = Columbia Suicide-Severity Rating Scale; HADS= Hospital and Anxiety Depression Scale; 
a.
Pregnancy tests may also be repeated as per request of IRB/IECs or if required by local regulations; subjects with a positive pregnancy test during the 
treatment period will have study drug discontinued but will be encouraged to remain in the study.  
b.
A pharmacokinetic sample will be collected at a random time during the clinic visit. The times of study drug dosing for the prior 2 doses as well as the time 
of the blood drawing will be recorded at each of these visits on the CRF.


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Non-Treatment Follow-Up Schedule
Protocol Activity
Week 13 
(clinic visit)
Week 14 
(clinic 
visit)
Week 15
(clinic visit)
Week 16
(clinic 
visit)
Week 
20 
(clinic 
visit)
Weeks 24, 
32, 40 and 
48 (phone 
visits)
Weeks 
28,36, and 
44 (clinic 
visits )
Week 
52-ET
(clinic 
visit)
Nicotine use Inventory
X
X
X
X
X
X
X
X
Urine cotinine at site 
X
X
X
X
X
X
X
Review and/or
distribute Smoking 
Diary worksheet
X
X
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
X
HADS
X
X
X
X
X
X
X
Adverse Event
Monitoring
X
X
X
X
X
X
X
Neuropsychiatric 
Adverse Event 
Interview
X
X
X
X
X
X
X
Concomitant 
Medications
X
X
X
X
X
X
X
Non-drug treatments
X
X
X
X
X
X
X
Smoking cessation 
counseling (~10 min)
X
X
X
X
X
X
X
X
Discharge from study
X
ET=early termination.


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TABLE OF CONTENTS
LIST OF TABLES.........................................................................................................................14
LIST OF FIGURES .......................................................................................................................14
1. INTRODUCTION .....................................................................................................................15
1.1. Indication.......................................................................................................................15
1.2. Background and Rationale ............................................................................................15
2. STUDY OBJECTIVES AND ENDPOINTS.............................................................................18
2.1. Primary Objective .........................................................................................................18
2.2. Endpoints.......................................................................................................................18
3. STUDY DESIGN.......................................................................................................................19
4. SUBJECT SELECTION............................................................................................................22
4.1. Inclusion Criteria...........................................................................................................22
4.2. Exclusion Criteria..........................................................................................................23
4.3. Randomization Criteria .................................................................................................25
4.4. Life Style Guidelines.....................................................................................................25
5. STUDY TREATMENTS...........................................................................................................25
5.1. Allocation to Treatment ................................................................................................25
5.2. Breaking the Blind ........................................................................................................26
5.3. Drug Supplies................................................................................................................26
5.4. Formulation and Packaging...........................................................................................26
5.5. Preparation and Dispensing...........................................................................................26
5.6. Administration...............................................................................................................26
5.7. Dosing Compliance.......................................................................................................28
5.8. Drug Storage and Drug Accountability.........................................................................28
5.9. Concomitant Medication(s)...........................................................................................28
6. STUDY PROCEDURES ...........................................................................................................29
6.1. Screening.......................................................................................................................29
6.2. Study Period ..................................................................................................................30
6.2.1. Baseline Visit (Randomization)........................................................................30
6.2.2. Treatment Phase Clinic Visits (Weeks 1 through 12 and ET12).......................31
6.3. Non-Treatment Follow-up Period (Weeks 13-52) ........................................................32
6.3.1. Clinic Visits: Weeks 13-16, 20, 28, 36, 44, and 52/ET....................................32


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6.3.2. Telephone Contacts: Weeks 24, 32, 40, and 48................................................33
6.4. Early Permanent Discontinuation of Study Drug..........................................................33
7. ASSESSMENTS........................................................................................................................35
7.1. Efficacy .........................................................................................................................35
7.1.1. Smoking Status.................................................................................................35
7.1.2. Urine Cotinine Testing .....................................................................................35
7.1.3. Fagerström Test for Nicotine Dependence.......................................................36
7.2. Safety.............................................................................................................................36
7.2.1. Laboratory.........................................................................................................36
7.2.1.1. Blood Volume .................................................................................36
7.2.1.2. Shipment of Laboratory Samples....................................................37
7.2.2. Blood Pressure and Pulse Rate .........................................................................37
7.2.3. Physical Examinations......................................................................................37
7.2.4. SBQ-R...............................................................................................................38
7.2.5. Columbia Suicide Severity Rating Scale (CSSRS) ..........................................38
7.2.6. Actively Solicited Neuropsychiatric Adverse Events (Appendix 4)................38
7.3. Pharmacokinetics (PK)..................................................................................................39
7.3.1. Plasma for Analysis of Varenicline:.................................................................39
7.3.2. Shipment of PK Samples..................................................................................39
8. ADVERSE EVENT REPORTING............................................................................................39
8.1. Adverse Events..............................................................................................................39
8.2. Reporting Period ...........................................................................................................40
8.3. Definition of an Adverse Event.....................................................................................40
8.4. Abnormal Test Findings................................................................................................41
8.5. Serious Adverse Events.................................................................................................41
8.6. Potential Cases of Drug-Induced Liver Injury ..............................................................42
8.7. Hospitalization ..............................................................................................................43
8.8. Severity Assessment......................................................................................................44
8.9. Causality Assessment....................................................................................................44
8.10. Exposure During Pregnancy (Also Referred to as Exposure In Utero) ......................45
8.11. Withdrawal Due to Adverse Events............................................................................46
8.12. Eliciting Adverse Event Information ..........................................................................46


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8.13. Reporting Requirements..............................................................................................46
8.13.1. Serious Adverse Event Reporting Requirements ...........................................47
8.13.2. Non-Serious Adverse Event Reporting Requirements ...................................47
8.13.3. Sponsor Reporting Requirements to Regulatory Authorities .........................47
9. DATA ANALYSIS/STATISTICAL METHODS.....................................................................47
9.1. Sample Size Determination...........................................................................................48
9.1.1. Analysis of Primary Endpoint ..........................................................................49
9.1.2. Analysis of Secondary Endpoints.....................................................................49
9.1.2.1. Efficacy Endpoints ..........................................................................49
9.2. Safety Analysis..............................................................................................................50
9.3. Interim Analysis ............................................................................................................51
9.4. Data Monitoring Committee .........................................................................................51
10. QUALITY CONTROL AND QUALITY ASSURANCE.......................................................51
11. DATA HANDLING AND RECORD KEEPING ...................................................................52
11.1. Case Report Forms/Electronic Data Record ...............................................................52
11.2. Record Retention.........................................................................................................52
12. ETHICS....................................................................................................................................53
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..................53
12.2. Ethical Conduct of the Study ......................................................................................53
12.3. Subject Information and Consent................................................................................53
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
Good Clinical Practice (GCP) ....................................................................................54
13. DEFINITION OF END OF TRIAL.........................................................................................54
13.1. End of Trial in all Participating Countries ..................................................................54
14. SPONSOR DISCONTINUATION CRITERIA ......................................................................54
15. PUBLICATION OF STUDY RESULTS................................................................................54
15.1. Communication of Results by Pfizer ..........................................................................54
15.2. Publications by Investigators ......................................................................................55
16. REFERENCES ........................................................................................................................56


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LIST OF TABLES
Table 1.
SCHEDULE OF ACTIVITIES ....................................................................................8
Table 2.
Blood Volume.............................................................................................................37
LIST OF FIGURES
Figure 1.
Clinical Trial Design...................................................................................................21
APPENDICES
Appendix 1. Nicotine Use Inventory .............................................................................................58
Appendix 2. Fagerström Test for Nicotine Dependence ...............................................................59
Appendix 3. Hospital Anxiety and Depression Scale (HADS) .....................................................60
Appendix 4. Neuropsychiatric Adverse Event Interview (NAEI).................................................61


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1. INTRODUCTION
1.1. Indication
Aid to smoking cessation treatment in age 12-19 year-old adolescent tobacco smokers.
1.2. Background and Rationale
Most adult smokers initiated smoking as adolescents.  According to the CDC’s 2005 Youth 
Risk Behavior Survey,2 23.0% of students in the United States were current cigarette users 
(ie, had smoked cigarettes on more than one of the 30 days preceding the survey) and 
9.4% of students were current frequent cigarette users (ie, had smoked cigarettes on 20 of 
the 30 days preceding the survey).  Among the students who reported current cigarette use,
10.7% had smoked at least 10 cigarettes/day on the days they smoked during the 30 days 
preceding the survey and 54.6% had tried to quit smoking cigarettes during the 12 months 
preceding the survey.  Continued smoking increases lifetime risk for various cancers, 
especially lung cancer, cardiovascular diseases, and respiratory diseases.3  Objective 27-2 of 
the US Department of Health and Human Services Healthy People 2010 initiative is to 
reduce the prevalence of current cigarette use among high school students to 16%.4
The transition from early smoking to nicotine dependence (ND) in adolescents is not fully 
understood, but similar to adults, intensity and frequency of cigarette use is associated with
ND.5 Past studies of smoking cessation in adolescents defined their target patient population 
by intensity, frequency and in some cases duration of cigarette smoking in an attempt to 
identify adolescents who were nicotine dependent.  The Fagerström Tolerance Questionnaire 
(FTQ) was modified and validated for use in adolescents.6  The validation of the FTQ with 
salivary cotinine in adolescents showed good performance for all questions except for "Do 
you inhale".  As this question did not perform well in either adults or adolescents the authors 
recommended abbreviating the scale to six questions. These six questions are the same as the 
six items included in the Fagerström Test for Nicotine Dependence (FTND) (Appendix 2) 
which will be used in this study as an instrument to identify adolescents likely to be 
nicotine-dependent. 
Varenicline is a selective nicotinic acetylcholine receptor (nAChR) partial agonist designed 
to have specific and potent binding at the 42 receptor subtype which mediates the behavior 
reinforcing effects of nicotine.  Because of its mixed agonist-antagonist properties, 
varenicline offers the therapeutic benefit of relieving symptoms of nicotine withdrawal and 
cigarette craving during abstinence while blocking the reinforcing effects of chronic nicotine.
Varenicline (as Chantix®) was approved in the United States in May 2006 as an aid to 
smoking cessation treatment in adults. and by the EMEA in September 2006, and is now 
approved in 98 countries worldwide. The approved dose regimen is 1 mg twice daily (1 mg 
bid) for 12 weeks starting with a 1-week titration.  Post-marketing study commitments 
required under section 2 of the Pediatric Research Equity Act (PREA) include a study to 
determine whether varenicline, as part of an overall smoking cessation program, is effective 
in achieving and maintaining smoking cessation in tobacco –addicted adolescents.  


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Postmarketing study commitments required under Section 2 of the Pediatric Research Equity 
Act (PREA) include a study to determine whether varenicline, as part of an overall smoking 
cessation program, is effective in achieving and maintaining smoking cessation in 
tobacco-addicted adolescents. This study is considered to be a PASS study 
(post-authorization safety study), and is a regulatory commitment.
Efficacy, Safety, Tolerability, and Pharmacokinetics of Varenicline in Adults
The approved dosing regimen in adults is 1 mg twice daily (BID) for 12 weeks starting with 
a 1-week titration.  Phase 2 and Phase 3 clinical trials demonstrated the efficacy and 
tolerability of varenicline 1 mg BID in more than 3000 adult cigarette smokers, increasing 
the odds of quitting approximately 4-fold compared with placebo at end of treatment, and 
nearly 2-fold compared with bupropion at end of treatment.  The most frequently reported 
treatment-emergent adverse events associated with varenicline were nausea, sleep 
disturbance, constipation, flatulence and vomiting.  Nausea was reported by approximately 
30% of patients treated with varenicline 1 mg BID after an initial week of dose titration 
compared with 10% in patients taking placebo.  In patients taking 0.5 mg BID following 
initial titration, the incidence was 16% compared with 11% for placebo.  Nausea was 
generally described as mild or moderate and often transient.1
Post Marketing Experience
There have been post-marketing reports of neuropsychiatric symptoms, some serious, 
including changes in mood, agitation, psychosis, hallucinations, paranoia, delusions, 
homicidal ideation, hostility, changes in behavior, anxiety, panic, suicidal ideation, suicide 
attempt and completed suicide 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. Smoking cessation with or without treatment is associated with nicotine 
withdrawal symptoms and the exacerbation of underlying psychiatric 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.
Additionally there have been reports of hypersensitivity reactions and serious skin reactions.
Complete information for this compound may be found in The Single Reference Safety 
Document for varenicline, which for this study, is the most recent Investigator Brochure (IB).
Safety, Tolerability, and Pharmacokinetics of Varenicline in Adolescents
A 2-week multiple-dose study (A3051070) examined pharmacokinetics (PK) and tolerability 
in adolescent smokers, 12-16 years old (see references to report and publication).19, 20  A total 
of 70 subjects were enrolled in two groups (N=35 each group) according to body weight.  In 
the High Body Weight group (>55 kg) subjects were randomized to varenicline 1 mg BID, 
0.5 mg BID or placebo. In the Low Body Weight group (55 kg) subjects were randomized 
to varenicline 0.5 mg BID, 0.5 mg once daily (QD) or placebo.  No subjects discontinued 
treatment or had a dose reduction due to adverse events.  Adverse event incidence was higher 


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in varenicline-treated subjects than in those who received placebo and higher in the Low 
Body Weight group than the High Body Weight group.  The most frequently reported 
treatment-emergent adverse events associated with varenicline were nausea, headache, 
vomiting, and dizziness, with incidences tabulated below.  Psychiatric adverse events that 
were considered possibly treatment-related were reported by 3 subjects.  In the High Body 
Weight group receiving 1 mg BID, one male subject had abnormal dreams rated mild, from 
Days 2-12, and one male subject had anger, rated mild, on Day 10.  In the Low Body Weight 
group receiving 0.5 mg BID, one male subject had abnormal dreams rated mild, on 
Days 4 and 5.  In addition, one female subject in the Low Body Weight group receiving 
0.5 mg QD had mood swings rated moderate on Days 10-14 that were considered not 
treatment-related. 
Low Body Weight (LBW)
High Body Weight (HBW)
Preferred Term
0.5 mg BID 
n=14
0.5 mg QD 
n=15
Placebo
n=8
1 mg BID 
n=14
0.5 mg BID 
n=14
Placebo
n=7
Nausea
5 (36%)
6 (40%)
1 (13%)
2 (14%)
2 (14%)
0
Vomiting
3 (21%)
2 (13%)
0
2 (14%)
1 (7%) 
0
Dizziness
2 (14%)
2 (13%)
1 (13%)
0
1 (7%)
0
Headache
3 (21%) 
2 (13%) 
1 (13%) 
1 (7%) 
3 (21%) 
0
Results from the population pharmacokinetic analysis showed that an open one-compartment 
model with first-order absorption and elimination best described the multiple-dose 
pharmacokinetics of varenicline in adolescent smokers. The final population PK parameter 
estimates (inter-individual variability expressed as %CV) for a typical individual weighing 
70 kg were 10.4 L/hr (30%) for oral clearance (CL/F) and 215 L (18%) for volume of 
distribution (V/F). Body weight was an important predictor of the inter-individual variability 
in V/F.  In adolescents weighing >55, predicted median steady state exposures 
[AUC(0-24)ss] kg were 95.7 ng.h/mL and 197 ng.h/mL for 0.5 mg BID and 1 mg BID, 
respectively. These exposures were consistent with exposure estimates previously reported 
at equivalent daily doses in adult smokers (NDA 21-928, 09 November 2005, Sequence 
# 0000, Module 2.7.221, 22 (see references to pop PK in adults). Adolescents from the Low 
Body Weight group (55 kg) tended to have greater varenicline exposures compared to the 
High Body Weight group. However adjusting the dose to half of that administered to the 
High Body Weight group, adolescents of smaller body size exhibited exposures within the 
range of exposures observed in heavier adolescents and in adults. Consistent with the 
single-dose PK data (Study A305102923), this analysis provided further evidence of 
dose-proportionality in varenicline systemic exposure in adolescents across the dose range of 
0.5 mg to 2 mg daily.
Dose Selection Rationale
Varenicline doses for this study were selected based on the safety, tolerability, 
pharmacokinetics, and efficacy information from the clinical trials in adult smokers and the 
pharmacokinetic and tolerability data from the single-dose (A305102923) and the 
multiple-dose (A305107019, 20) studies conducted in adolescent smokers 12 to 16 years old. 


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In clinical trials in adult smokers, both varenicline 1 mg BID and 0.5 mg BID regimens 
demonstrated efficacy as an aid to smoking cessation, and exposure-response information 
further indicated that higher systemic exposure to varenicline was associated with greater 
probability of 4-week smoking cessation. This study proposes to investigate both 1 mg BID 
and 0.5 mg BID doses compared with placebo in the adolescent population.  
Since Study A3051070 demonstrated that varenicline exposure was adequately adjusted by 
halving the total daily dose of varenicline in subjects at or below the pre-specified weight 
threshold of 55 kg, adolescent subjects 55 kg will have their randomized dose reduced by 
half in this study. Those randomized to 1 mg BID will receive 0.5 mg BID and those 
randomized to 0.5 mg BID will receive 0.5 mg QD.  This dosing scheme should provide an 
adequate range of individual exposures to investigate the exposure-response relationships for 
selected measures of efficacy and tolerability.  All dosing regimens other than 0.5 mg QD 
will begin with a two week titration period followed by 10 weeks at the target dose. 
Smoking Cessation Counseling Program
Smoking cessation attempts are more likely to be successful with counseling and support.  
All subjects will receive brief age-appropriate smoking cessation counseling in accordance 
with the Public Health Service (PHS) guidelines24 at each clinic visit and telephone contact, 
starting with the baseline visit. 
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Primary Objective

To evaluate the efficacy, safety, and tolerability of varenicline compared with placebo 
in adolescent smokers aged 12-19 years.
2.2. Endpoints
Primary efficacy endpoint:

4-week continuous quit rate (CQR) from Week 9 through Week 12 of treatment for 
varenicline compared with placebo. An exploratory subgroup analysis for each dosing 
group by weight stratum will be provided.
Secondary efficacy endpoints: 

7-day point-prevalence of smoking abstinence at Weeks 12, 24, and 52;

Reduction in number of cigarettes smoked at Weeks 12, 24, and 52;

Continuous abstinence rate from Week 9 through Week 24;

Continuous abstinence rate from Week 9 through Week 52.


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Safety Assessments: 

Adverse events spontaneously volunteered or observed, adverse events elicited by the 
Neuropsychiatric Adverse Event Inventory (NAEI), Columbia Suicide Severity 
Rating Scale (CSSRS), Hospital Anxiety and Depression Scale (HADS) and adverse 
events associated with safety laboratory tests, or vital signs.
PK Assessments: 

Varenicline exposure at steady-state in adolescent smokers.
3. STUDY DESIGN
This will be a randomized, double-blind, placebo-controlled, multicenter study to compare 
two doses of varenicline 1 mg BID and 0.5 mg BID with placebo for smoking cessation in 
adolescent smokers aged 12-19 years who are motivated to quit. Since varenicline exposure 
is related to body weight, subjects with a body weight 55 kg will have their varenicline dose 
reduced by half (those randomized to 1 mg BID will receive 0.5 mg BID and those 
randomized to 0.5 mg BID will receive 0.5 mg QD).  
All subjects and their parents/legal guardians will provide informed consent/assent before 
any study activities occur.  Subjects over the age of 18 may sign their own informed consent. 
(Parents, guardians, or caregivers need to be actively involved in the assessment and 
monitoring of these patients). Subject eligibility will be reviewed during a three week 
screening period.
Those subjects deemed eligible will be randomized and enter the 12-week placebo-controlled 
treatment period with weekly clinic visits for efficacy and safety assessments and smoking 
cessation counseling. Varenicline or placebo dosing will begin with two weeks of titration.
(Figure 1). All subjects will set a target quit date (TQD) to coincide with the Week 1 visit. 
The Week 1 visit occurs at the end of the first week of the treatment phase.  A visit window 
of 3 days can be allowed to accommodate unforeseen scheduling issues.  Brief 
age-appropriate smoking cessation counseling, in accordance with Public Health Service 
(PHS) guidelines, up to 10 minutes duration, will be provided by a trained counselor at each 
clinic visit and telephone contact beginning at baseline. The primary efficacy endpoint will 
be complete abstinence from smoking, biochemically verified, during the last 4 weeks of the 
12 week dosing period.  
Follow-up (non-treatment) period: 
The primary purpose of the non-treatment follow-up study phase is to assess the long-term 
smoking abstinence. In addition, during this phase, subjects will be monitored for any 
neuropsychiatric or suicide-related adverse events. 
Subjects will be followed to obtain smoking status for 9 months after the end of the 12-week 
treatment period.  Clinic visits will occur at Weeks 13-16 (inclusive), 20, 28, 36, 44, and 52. 
Telephone contacts are planned for weeks 24, 32, 40, and 48.  To accommodate unforeseen 


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circumstances, a visit window of 3 days can be allowed for week 13 through 20 visits, and a 
visit window of 5 days can be allowed for week 20 to week 52 visits.  
Smoking-cessation counseling up to 10 minutes duration will be provided at each clinic visit 
and telephone contact for the duration of the study. Whenever possible, counseling should be 
conducted by the same counselor throughout, so that the relationship builds and brings 
additional value to the sessions. 
Subjects that stop taking study drug during the treatment phase (wks 1-12) are still eligible to 
remain in the study, provided they continue to comply with remaining visit procedures. All 
efforts should be made to keep the subjects in the study. If an early termination of the study 
occurs, the appropriate ET visit should be completed in accordance with the schedule of 
activities (Table 1).


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Figure 1.
Clinical Trial Design
BL= Baseline
T = Telephone 
f
 
*Varenicline doses are titrated to target dose over the first weeks of 
treatment.  Subjects whose body weight is 55 kg will have their 
randomized dose reduced by half.
Randomization
Randomization
Screening
1
B
6
2
3
4
5
Varenicline 1 mg BID *
Varenicline 0.5 mg BID *
Placebo
7
8
13
9
10
11
12
24
16
20
28
32
36
40
T
44
48
T
Weeks
Treatment
Follow-
52
Screening
Weeks
1
B
6
2
3
4
5
Varenicline 1 mg BID *
Varenicline 0.5 mg BID *
Placebo
7
8
13
9
10
11
12
24
T
16
20
32
T
36
40
T
44
48
T
Weeks
Treatment
up 
titration period 
TQD


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4. SUBJECT SELECTION
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom protocol treatment is considered 
appropriate.  Subject eligibility should be reviewed and documented by an appropriately 
qualified member (ie, PI or sub-I) of the investigator’s study team before subjects are 
included in the study.
All relevant medical and non-medical conditions should be taken into consideration 
when deciding whether this protocol is suitable for a particular subject. If there is 
question on the suitability of a potential subject for this trial, the sponsor should be contacted.
4.1. Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study.
1. Healthy male and female subjects between the ages of 12 and 19 years inclusive 
(at screening), who are motivated to stop smoking.
2. Subjects must be currently smoking at least an average of 5 cigarettes per day during 
the past 30 days, have a total score of 4 or higher on the Fagerström Test for Nicotine 
Dependence, (FTND) (Appendix 2) and must be motivated to stop smoking.
3. Subjects must have had at least one prior failed attempt to quit smoking.
4. Total body weight at screening and randomization 35 kg (77 lbs) and Body Mass 
Index (BMI) of 35 kg/m2 and at the lower end, subject should be no more than 
2 standard deviations or percentiles from normal BMI for age and stature.
5. For each subject, the parent(s)/legal guardian(s) must provide a signed and dated 
written informed consent/assent document indicating that the subject and parent (or a 
legally acceptable representative) have each been informed of all pertinent aspects of 
the trial and that the adolescent agrees to participate.  Parental consent is not required 
for subjects over the age of 18.
6. Subjects, and if required by local/site regulations their parent(s) /legal guardian(s) 
must be willing and able to comply with scheduled visits, treatment plan, laboratory 
tests, and other trial procedures as indicated in the protocol.
7. Male and female subjects of childbearing potential must agree to use a highly 
effective method of contraception throughout the study and for at least 28 days after 
the last dose of assigned treatment. A subject is of childbearing potential if, in the 
opinion of the investigator, he/she is biologically capable of having children and is 
sexually active. 


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8. Female subjects who are not of childbearing potential (ie, meet at least one of the 
following criteria):

Have undergone hysterectomy of bilateral oophorectomy;

Have medically confirmed ovarian failure; or

Are medically confirmed to be post-menopausal (cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; laboratory confirmation may be indicated.
4.2. Exclusion Criteria
Subjects presenting with any of the following will not be included in the study:
1. Female subjects with a positive urine pregnancy test (all female subjects are required 
to have pregnancy testing).
2. Pregnant or nursing female subjects; females of childbearing potential who are 
unwilling or unable to use an acceptable method of contraception from at least 
14 days prior to study medication administration until 30 days after the last dose of 
study medication. Acceptable methods of contraception are: abstinence; any form of 
hormonal contraception such as Depo-Provera, daily oral contraceptive, transdermal 
patch, or Nuva-ring; intra-uterine device, sterilization; or double barrier contraception 
which is a combination of any two of the following methods: condoms, spermicide, 
diaphragm.  (Note, subjects with a positive pregnancy test during the treatment period 
will have study drug discontinued but will be encouraged to remain in the study).
3. Subjects with a prior suicide attempt, subjects hospitalized within the past twelve
months due to suicidal ideation or suicidal behavior, or subjects considered to have 
had serious suicidal ideation or suicidal behavior within the past twelve months.
4. Subjects with active suicidal ideation or behavior identified at the screening or 
baseline visits.
5. Subjects with a score of >7 on the Suicide Behaviors Questionnaire-Revised (SBQ-R) 
at the Screening visit.
6. Subjects with current evidence or history of clinically significant psychiatric disease, 
including, but not limited to Axis 2 disorders; major depression disorder, anxiety 
disorders, panic disorder, hostility or aggression disorder, perceptual/thinking 
disturbances, mania, psychosis, (including schizophrenia), bipolar disorder, 
personality disorder, severe emotional problems (in the past year prior to screening), 
or eating disorder (eg, bulimia or anorexia nervosa). Investigator judgment should be 
used to assess whether a prospective subject is appropriate for participation in the 
study.


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Assessment of any evidence or history of clinically significant psychiatric or neurologic 
disease, and the assessment for suicidality must be done by a Mental Health 
Professional (MHP).  A MHP must be a pediatric/adolescent psychiatrist or a licensed 
PhD level clinical pediatric/adolescent psychologist.
7. Subjects who require use of medications prescribed for mania or psychosis.
8. Subjects with a score 8 for either depression or anxiety on the Hospital Anxiety and 
Depression Rating Scale (HADS) (Appendix 3).
9. Subjects with evidence or history of clinically significant neurological, 
hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, 
or allergic disease (including serious drug allergies).  (Subjects who have seasonal 
allergies, asthma, or acne may be allowed to enroll in the study).
10. Use of prescription or nonprescription drugs within 7 days or 5 half-lives (whichever 
is longer) prior to the first dose of study medication should be discussed with the 
sponsor and recorded on the CRF.  Use of ibuprofen, acetaminophen at doses of 
2 g/day, antihistamines, asthma medications, bronchodilators, migraine medications 
and topical medications is permitted.
11. Use of psychotropic or psychoactive drugs in the 6 months prior to screening should 
be discussed with the sponsor prior to enrolling the subject. Use of Adderal or Ritalin 
may be allowed for treatment of those subjects with ADHD who are otherwise 
deemed appropriate for this study.   
12. Evidence of alcohol and substance abuse/dependence (other than nicotine) within 
3 months prior to screening deemed severe enough to compromise the subject’s 
ability to comply with the study requirements, as determined by the investigator’s 
clinical judgment, OR consecutive positive urine drug screens during screening and 
baseline. If question remains as to the suitability of the subject, contact the sponsor, 
or use DSM IV guidance to assess potential for substance abuse.
13. Treatment with an investigational drug within 30 days or 5 half-lives (whichever is 
longer) preceding the first dose of study medication.
14. History of prior use of or sensitivity to varenicline/Chantix®/Champix®.
15. Subjects who plan to move out of the area in the next year.
16. Subjects who are unwilling or unable to comply with the Life Style Guidelines. 
17. Other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with trial participation or 
investigational product administration or may interfere with the interpretation of trial 
results and, in the judgment of the investigator, would make the subject inappropriate 
for entry into this trial.


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18. Subjects who are investigational site staff members or subjects who are Pfizer 
employees directly involved in the conduct of the trial or family members of such 
employees.
19. Participation in other studies within 30 days before the current study begins and /or 
during study participation.
4.3. Randomization Criteria 
Subjects who meet inclusion and exclusion criteria and have no clinically significant 
abnormalities on laboratory test results or physical examination may be randomized.  A 
computer-generated randomization schedule will be used to assign subjects to treatment.
4.4. Life Style Guidelines 
Participants are expected to abstain from the use of tobacco products such as pipe tobacco, 
cigars, snuff, and chewing tobacco, and the use of marijuana.  If any of these products are 
used, they should be recorded with the concomitant medications section of the CRF. 
Subjects will also be expected to refrain from using any form of nicotine replacement therapy 
during the treatment phase, however, if any of these products are used, they should be listed 
as concomitant drug therapy.
5. STUDY TREATMENTS
5.1. Allocation to Treatment
This is a 52 week, double-blind, parallel group study.  Subjects will be randomized to receive 
12 weeks of varenicline 1 mg BID, varenicline 0.5 mg BID or placebo in a 1:1:1 ratio using a 
block randomization within each site. Within each randomized treatment group, subjects 
who weigh 55 kg at baseline will receive half the assigned dose strength. 
Randomization will be stratified by age group (12-16 vs 17-19). In order to ensure a 
sufficient number of subjects in the 12-16 year old stratum, the 17-19 year old stratum will 
be capped at a maximum of 90 subjects. 
Investigators will obtain subject identification numbers and study drug assignments utilizing 
a web-based or telephone call-in drug management system as directed by the sponsor.  The 
web-based or telephone call-in drug management system will provide identification numbers 
N = 100
N = 100
Varenicline 0.5 mg BID
(Subjects 55 kg
receive 0.5 mg QD)
N = 100
Placebo
N=300 Randomized
N = 100
N = 100
N = 100
Placebo
Varenicline 1 mg BID
(Subjects 55 kg
receive 0.5 mg BID)


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for the subjects at the screening visit. The web-based or telephone call-in drug management 
system will also coordinate drug dispensation to subjects at each clinic visit.
5.2. Breaking the Blind 
The study will be subject, investigator, and sponsor blinded. 
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind.  The method will be either a manual or electronic process.  Blinding codes should only 
be broken in emergency situations for reasons of subject safety.  The investigator should 
contact Pfizer before breaking the blind.  When the blinding code is broken, the reason must 
be fully documented. 
5.3. Drug Supplies
Varenicline doses will consist of one or two 0.5 mg tablets of the clinical image formulation.  
Matching placebo tablets will be provided to maintain the blind.  Study drug will be supplied 
in blister packs. 
5.4. Formulation and Packaging
Varenicline will be supplied as 0.5 mg tablets of the Immediate Release formulation.  Tablets 
(blinded varenicline or placebo) will be supplied in blister packs containing sufficient tablets 
for 10 days.  A new blister pack will be dispensed after each weekly clinic visit to provide 
sufficient study drug until the next scheduled clinic visit. 
5.5. Preparation and Dispensing
Study drug is to be dispensed to subjects by qualified site study staff at (or after) each 
scheduled clinic visit from the Baseline visit to the Week 11 visit (according to the study 
flowchart).  Site personnel should provide instructions for study drug dosing to each subject, 
and request that the subject read for understanding. Once reading is complete, the subject 
will be asked to initial and date the instructions indicating they comprehend the meaning of 
the sun (am) and moon (pm) and other aspects of the dosing card instructions. If the child is 
a minor, the parent should date and sign to indicate their understanding as well. The 
discussion should be documented in source as well. Subjects will receive their first blister 
pack at (or after) the Baseline visit and will receive a new blister pack at (or after) each 
weekly clinic visit through the Week 11 visit.  Upon receipt of each new drug package the 
used package will be returned.  Subjects will be instructed to store the study drug at room 
temperature and out of the reach of small children.
5.6. Administration
To maintain the blind the administration of study medication will use a double-dummy 
strategy so that all subjects will take two morning tablets and two evening tablets throughout 
the 12-week dosing period.  Tablets will be active drug or placebo as outlined below.


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Study drug administration will begin with a two-week titration period.  
Treatment will begin from the Week 1 blister card as soon as possible, the earliest being the
morning after the Baseline visit day.  The blister cards are set up in 2 columns; sun, (am), and 
moon, (pm) to accommodate BID dosing schedule. Each subject will be instructed to take 
two pills from each column each day starting with the top of the blister card (in the direction 
of the arrow printed on the card). It is important that this order is followed. The blister cards 
have been created such that dosing instructions (2 tablets in the morning, 2 tablets in the 
evening) remain the same throughout the study. After the subjects are instructed on proper 
dosing, the subjects should repeat these directions, and initial and date to document 
comprehension of these instructions. If subject is a minor, the parent should initial and date 
as well. 
Dosing should occur with a full glass (240 ml) of water and it is recommended that subjects 
eat prior to dosing.  At least 8 hours is recommended between the morning and evening 
dosing.
Medication errors may result, in this study from the administration or consumption of the 
wrong drug, by the wrong subject, or at a strength of 4 mg/day or higher.  Such medication 
errors occurring to a study participant are to be captured on the adverse event (AE) page of 
the CRF and on the SAE form when appropriate.  In the event of medication dosing error 
(4 mg/day or higher) the sponsor should be notified immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error and, if applicable, any associated adverse event (s) is 
captured on an adverse event (AE) CRF page (refer to Adverse Event Reporting section for 
further details.
The following table shows the dosing scheme for each randomized group with respective 
adjustments for the low bodyweight subjects.


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Treatment Group
Dosing
Titration period
Target Dose
Week 1
Week 2
Weeks 3-12
Varenicline 1 mg BID
subjects >55 kg
0.5 mg QD 
0.5 mg BID
1 mg BID
subjects 55 kg
0.5 mg QD
0.5 mg QD
0.5 mg BID
Varenicline 0.5 mg BID
subjects >55 kg
0.5 mg QD
0.5 mg QD
0.5 mg BID
subjects 55 kg
0.5 mg QD
0.5 mg QD
0.5 mg QD
Placebo
subjects >55 kg
Placebo
Placebo
Placebo
subjects 55 kg
Placebo
Placebo
Placebo
5.7. Dosing Compliance
Subjects will return blister packs at (or after) each visit.  A dosing record and drug 
accountability form will be completed.  Reasons for missed doses should be ascertained and
patterns of missed doses should be discussed in detail.  Subjects may be considered non-
compliant if weekly compliance is less than 80%. 
5.8. Drug Storage and Drug Accountability 
The investigator, or an approved representative (eg, pharmacist), will ensure that all study 
drug is stored in a secured area, under recommended storage conditions and in accordance 
with applicable regulatory requirements.  Varenicline and matching placebo should be stored 
at 15-30C or 59-86F as indicated on the label.
To ensure adequate records, all study drug will be accounted for in the case report form and 
drug accountability inventory forms as instructed by Pfizer.  Unless otherwise authorized by 
Pfizer, at the end of the clinical trial all drug supplies unallocated or unused by the subjects 
must be returned to Pfizer or its designated agent.
5.9. Concomitant Medication(s)
Any use of psychotropic or psychoactive drugs by a potential subject in the past 6 months 
prior to screening should be discussed with the sponsor.  Use of Adderall or Ritalin may be 
allowed for treatment of those subjects with ADHD who are otherwise deemed appropriate 
for this study.  Use of prescription or nonprescription drugs within 7 days or 5 half-lives 
(whichever is longer) prior to the first dose of study medication should be discussed with the 
sponsor, and documented in the CRF. Acetaminophen and ibuprofen may be used 
intermittently throughout the trial, but should not exceed 2 g/day on two consecutive days, 
unless greater quantities are deemed necessary by the investigator.  Antihistamines, asthma 
medications, bronchodilators, migraine medications and topical medications may be 
permitted during the course of the study. If there is any question about whether a 
concomitant medication is appropriate for use in subjects while they are participating in this 
trial, please contact the sponsor.


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All concomitant medication taken during the trial must be recorded with indication and start 
and stop dates of administration.  All subjects will be questioned about concomitant 
medication at each clinic visit through Week 52.
Medications taken within 3 months before the first dose of trial medication will be 
documented as a prior medication.  Medications taken after the first dose of trial medication 
will be documented as concomitant medications.
6. STUDY PROCEDURES 
6.1. Screening
Subjects will be screened within 3 weeks prior to administration of the trial medication to 
allow for the return and evaluation of screening results to confirm that they meet the subject 
inclusion/exclusion criteria for the trial.  Informed consent for the clinical trial must be 
signed prior to the initiation of any study related activities.  In the case of adolescents 
18 years old, informed consent of the parent/legal guardian and subject assent are both
required. 
The following procedures will be obtained:

Obtain informed consent/assent;

Record demography, medical history and assessment of past and present alcohol/drug 
use;

Record concomitant medications as well as prescription medications and non-drug 
treatment/procedures  in the past 3 months;

Subject self administers the Suicidal Behaviors Questionnaire-Revised (SBQ-R) and 
the Hospital and Depression Scale (HADS) (Appendix 3);

Complete Columbia Suicide-Severity Rating Scale (C-SSRS) and record suicide 
related adverse events;

Record tobacco use history, including number of cigarettes per day, number of years 
smoked, number of prior attempts to quit smoking;

Complete and score the Fagerström Test for Nicotine Dependence (FTND)
(Appendix 2);

Physical examination which should include measurement of height and weight, sitting 
blood pressure and orthostatic[BP] and resting sitting, supine and standing pulse rate.

Collect blood specimens for safety laboratory tests in addition to the following:

Urine pregnancy test for all females;


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
Urine drug test (dipstick at site ) for all subjects;

Urine cotinine at site;

Verify trial eligibility by checking Inclusion Criteria/Exclusion Criteria;

To prepare for trial participation, subjects will be instructed on the use of Life Style 
Guidelines and Concomitant Medication(s) and will be provided with a smoking 
diary worksheet;

Subject agrees to a Target Quit date (TQD) which will be planned to coincide with 
the Week 1 visit.  Arrange appointment for the baseline visit (which should be 
~7 days prior to the Week 1 visit/Target Quit date). Baseline visit can be cancelled if 
the inclusion/exclusion criteria, including laboratory results, are not met prior to the 
Baseline visit.
6.2. Study Period
6.2.1. Baseline Visit (Randomization)

Assess baseline symptoms by spontaneous reporting of symptoms and by asking the 
subjects to respond to a non-leading question such as “How do you feel?”  Record 
adverse events;

Record height and weight and orthostatic vital signs (sitting, supine, and standing);

Have Subject self-administer the HADS (Appendix 3);

Conduct Neuropsychiatric Adverse Event Interview (NAEI) (Appendix 4) and record 
solicited adverse events;

Complete the Columbia Suicide-Severity Rating Scale (C-SSRS) and record any 
suicide-related adverse events;

Collect urine for pregnancy test from females;

Perform urine drug test on all subjects;

Urine cotinine at site;

Record concomitant medications; 

Record any non-drug treatments/procedures;

Review previous week’s Smoking Diary Worksheet with subject and distribute the 
following week’s; Complete the Nicotine Use Inventory (NUI) based on subject 
responses (Appendix 1);


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
Provide up to 10 minutes of smoking cessation counseling;

Re-check Inclusion Criteria/Exclusion Criteria;

Randomize to treatment;

Dispense study medication, Week 1 blister pack, for self administration and provide 
dosing instructions.
6.2.2. Treatment Phase Clinic Visits (Weeks 1 through 12 and ET12)
Following the Baseline visit, clinic visits will be conducted weekly for 12 weeks.  All 
subjects should have set a target quit date (TQD) to coincide with the Week 1 visit.  The 
Week 1 visit occurs at the end of the first week of the treatment phase.  Smoking cessation 
counseling up to 10 minutes duration will be provided at each clinic visit beginning at 
Baseline. Whenever possible, counseling should be conducted by the same counselor 
throughout, so that the relationship builds and brings additional value to the sessions. Every 
effort should be made to have the subject return on the same day of the week for the clinic 
visits, thereby keeping visits on time.  To accommodate unforeseen circumstances a visit 
window of 3 days can be allowed as long as proper dosing is maintained.  If an early 
termination occurs before the end of Week 12, an early termination visit (ET12) will be 
conducted.  At each of these visits, the following procedures will be conducted:

Record spontaneously reported adverse events after asking the subjects to respond to 
a non-leading question such as “How do you feel?”

Measure and record sitting and orthostatic blood pressure (BP) and sitting, supine and 
standing pulse rate;

Have Subject self-administer the HADS (Appendix 3);  

Conduct Neuropsychiatric Adverse Event Interview (NAEI) (Appendix 4) and record 
solicited adverse events;

Complete the Columbia Suicide-Severity Rating Scale (C-SSRS) and record any 
suicide-related adverse events;

Record concomitant medications;

Record any non-drug treatments;

Review previous week’s Smoking Diary Worksheet with subject and distribute the 
following week’s; Complete the Nicotine Use Inventory (NUI) based on subject 
responses (Appendix 1);

Provide up to 10 minutes of smoking cessation counseling;


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
Count and document drug returns;  

Dispense next week’s blister pack (except at Week 12 or ET);
The following additional activities will be conducted at Visit Weeks 3, 6, 12, and early 
termination:

Obtain blood samples for safety laboratory tests (week 3, Week 6, and Week 12 or 
ET);

Perform urine pregnancy test for females (also at Week 9);

Perform urine drug test (dipstick at site) (also at Week 9);

Collect blood samples for pharmacokinetic analysis (Week 3, Week 6, and Week 12 
or ET);

Ask subject to recall the times of last 2 doses of trial medications and record this 
information in the dosing log;

At Week 12 or ET12 only, record height and weight;
The following additional activity will be conducted at Visit Weeks 9-12, and at Early 
Termination:

Urine cotinine test at site;
6.3. Non-Treatment Follow-up Period (Weeks 13-52)
Following completion of the week 12 visit, subjects will continue in the non-treatment 
follow-up phase of the protocol. Clinic visits occur weeks 13-16, 20, 28, 36, 44, and 52/ET. 
Subjects will be contacted by phone at weeks 24, 32, 40, and 48. During the non-treatment 
phase, smoking cessation counseling up to 10 minutes duration will be provided at each visit 
and telephone contact. To accommodate unforeseen circumstances, a visit window of 
3 days can be allowed for weeks 13 through 20 visits, and a visit window of +5 days can be 
allowed for week 20 to week 52 visits.  
6.3.1. Clinic Visits: Weeks 13-16, 20, 28, 36, 44, and 52/ET

Record spontaneously reported adverse events by asking the subjects to respond to a 
non-leading question such as “How do you feel?”

Subject self administers the HADS (Appendix 3);  

Conduct Neuropsychiatric Adverse Event Interview (NAEI) (Appendix 4) and record 
solicited adverse events;


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
Complete the Columbia Suicide-Severity Rating Scale (C-SSRS) and record any 
suicide-related adverse events;

Record concomitant medications;

Record any non-drug treatments;

Review previous week’s Smoking Diary Worksheet with subject and distribute the 
following week(s); Complete the Nicotine Use Inventory (NUI) based on subject 
responses (Appendix 1);

Urine cotinine test at site;

Provide up to 10 minutes of smoking cessation counseling.
6.3.2. Telephone Contacts: Weeks 24, 32, 40, and 48 

Review Smoking Diary responses with subject;

Complete the Nicotine Use Inventory (NUI) based on subject responses
(Appendix 1);

Provide up to 10 minutes of smoking cessation counseling.
Discharge from study at Week 52 or early termination only.  If a subject has any clinically 
significant and trial-related abnormalities at the conclusion of a scheduled visit of the trial, 
the Pfizer medical monitor (or designated representative) should be notified and the 
follow-up evaluations will be performed until the abnormalities return to the normal/baseline 
condition.  The investigator should make every effort to arrange follow-up evaluations at
appropriate intervals to document the course of the abnormalities.
6.4. Early Permanent Discontinuation of Study Drug 
Subjects who wish to withdraw from the study will be allowed to do so at any time without 
prejudice, or they may be withdrawn at any time at the discretion of the investigator or 
sponsor for safety or behavioral, or the inability of the subject to comply with the protocol 
required schedule of study visits or procedures at a given study site. Subjects should be 
discontinued if they cannot be contacted for drug monitoring or do not return for subsequent 
scheduled visits. The investigator should inquire about the reason for withdrawal, request the 
subject to return all unused investigational product(s), request the subject return for a final 
visit, if applicable and follow-up with the subject regarding any unresolved adverse events 
(AEs). Diligent attempts will be made by telephone and certified letter to determine the 
circumstances for subjects who are lost to follow-up as this may be related to the study drug.
Early permanent withdrawal of study drug use may occur at any phase of the study.  Possible 
reasons for early permanent withdrawal of study drug use include:


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
Adverse event: The subject develops an adverse event, which in the opinion of the
subject or lead investigator, institutional principal investigator or sub-investigator 
warrants termination of study drug use.

Personal reason: A subject may withdraw from study drug use at any time.

Pregnancy.
In the event of study treatment discontinuation, subjects should be encouraged to continue to 
attend clinic and telephone visits, and complete study procedures.
The investigator must determine the primary reason for withdrawal of study drug and record 
it on the case report form.  Withdrawal of study drug due to an adverse event should be 
distinguished from withdrawal of study drug due to insufficient response.  A treatment or 
study discontinuation due to a serious adverse event must be reported to Pfizer immediately.  
Return to smoking is not a basis for withdrawing a subject from the study.  Subjects who 
return to smoking should be encouraged to make further quit attempts and to continue their 
participation with the counseling and protocol-specified visits and procedures.
Female subjects who have a positive pregnancy test during the treatment period will 
discontinue study medication but should continue study participation.  Pregnant subjects 
must be followed to the outcome of the pregnancy and an Exposure in Utero Form (EIU) 
must be submitted.  
Any subjects who discontinue treatment for any reason may continue participation in the 
study and should be encouraged to do so.  They will be required to maintain the visit 
schedule and can continue participation through the non-treatment follow-up phase of the 
study.
Subjects should be encouraged to complete the study even if they stop study medication. If 
the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
In post marketing safety surveillance there have been some reports of depressed mood, 
agitation, changes in behavior, psychosis, hallucinations, paranoia, delusions, homicidal 
ideation, hostility, anxiety, panic, and suicidal ideation (suicidal thoughts) and suicide in 
patients attempting to quit smoking while taking 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.  The role of 
varenicline in these reports is not known. A subject who experiences such events should stop 
dosing and immediately report any such symptoms to the study staff. 
Each clinical research site will have an Emergency Response Plan in place to properly 
care for subjects who report events of a serious nature that require immediate or very 


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prompt attention.  This plan will include having a pediatric/adolescent psychiatrist 
available at all times.  
At all clinic visits, the investigator will be proactively monitoring for anxiety, panic, 
hostility, aggression, abnormal thinking, hallucinations, suicidality and depressed mood 
through the use of the C-SSRS, HADS (Appendix 3), and the NAEI (Appendix 4). These 
evaluations should be conducted by an adolescent or pediatric psychiatrist. A subject must be 
discontinued from study medication and referred for appropriate medical or psychiatric 
evaluation and follow-up if there is:  

A positive response to any question on the C-SSRS;

A score 15 for anxiety or >15 for depression on the HADS (Appendix 3);

Moderate or severe adverse event as elicited through the use of the Neuropsychiatric 
Adverse Event Interview.
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, behavioural, 
or administrative reasons.  If a subject does not return for a scheduled visit, every effort 
should be made to contact the subject. In any circumstance, every effort should be made to 
document subject outcome, if possible.  The investigator should inquire about the reason for 
withdrawal, request the subject to return all unused investigational product(s), request the 
subject return for a final visit, if applicable, and follow-up with the subject regarding any 
unresolved adverse events. 
7. ASSESSMENTS
7.1. Efficacy
7.1.1. Smoking Status
Smoking status will be assessed using a standard series of questions referred to as the 
Nicotine Use Inventory (NUI) (Appendix 1).  The subject responds Yes or No to questions 
about cigarette or other nicotine/tobacco use since the last visit or during the past 7 days.
The NUI is completed at each clinic visit and/or phone contact during the treatment period 
and the follow-up period by research staff based on subjects’ responses. 
All subjects will be provided with Smoking Diary Worksheets to use as a tool to record how 
many cigarettes they have smoked each day. The Smoking Diary itself will not be 
data-based.
7.1.2. Urine Cotinine Testing
In order to confirm the self-reported abstinence from smoking urine cotinine testing will be 
done at the site at Weeks 9-12 during the treatment phase and all clinic visits during the 


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follow-up phase.  The test indicates a positive result when the cotinine in the urine exceeds 
200 ng/mL.
7.1.3. Fagerström Test for Nicotine Dependence
The Fagerström Test for Nicotine Dependence provides a short, self-reported measure of 
dependency on nicotine. This test will be completed at screening only. The test’s questions 
and scale are shown in (Appendix 2). This should be scored and reviewed by the PI prior to 
randomization. 
7.2. Safety
7.2.1. Laboratory
The following safety laboratory tests will be performed at protocol-specified time points 
(details in Table 1 Schedule of Activities). Where practical, subjects should be fasted, 
however, if not appropriate designation should be made on the laboratory requisition.
Hematology
Chemistry
Other
Hemoglobin
Hematocrit
RBC count
Platelet count
WBC count
Total neutrophils 
(Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN and Creatinine
Glucose
Ca++
Na+, K+, Cl-
Total CO2
(Bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
Urine Pregnancy 
Test
Urine cotinine
Urine drug test

Results of the screening and baseline urine pregnancy tests must be negative in order 
for a female subject of childbearing potential to receive study medication at baseline.  
Female subjects with a positive pregnancy test during the treatment period must 
discontinue study medications but should be encouraged to remain in the study. 
Pregnancy tests may be repeated for confirmation, as per request of IRB/IECs, or if 
required by local regulations.

Safety laboratory tests from Screening must have no clinically significant findings, as 
judged by the investigator, in order for a subject to be dosed at baseline.
Additional safety measurements may be obtained if deemed necessary by appropriate study 
personnel.
7.2.1.1. Blood Volume
Total blood sampling volume for the individual adolescent subject is approximately 69 mL.


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Table 2.
Blood Volume
Sample Type
Sample 
Volume (mL)
Number of Sampling Times
Total Volume 
(mL)
Screening
Treatment Period
Follow-Up
Safety Labs
15
1
3
0
60
PK
3
0
3
0
9
TOTAL
69
This total volume does not include discarded blood from pre-draws used to remove fluid from flushed 
catheters.  The discarded volume is not expected to exceed 14 mL of blood
7.2.1.2. Shipment of Laboratory Samples
The shipment address and contact information will be provided to the investigator sites prior 
to initiation of the trial.
7.2.2. Blood Pressure and Pulse Rate
Blood pressure and pulse rate will be recorded after subjects have rested in a sitting position 
for approximately 5 minutes.  Sitting blood pressure and pulse rate will be measured with the 
subject’s arm supported at the level of the heart, and recorded to the nearest mm Hg.  The 
same arm (preferably the dominant arm) will be used throughout the trial.  In addition to 
these first measurements, blood pressure and pulse rate will be recorded after subjects have 
been supine for approximately 5 minutes, and then orthostatic blood pressure will 
immediately be recorded when the subject is asked to stand.  The pulse should also be 
recorded at the times that the BP is recorded.
The same size blood pressure cuff, which has been properly sized and calibrated, will be used 
to measure blood pressure each time.  The use of automated devices for measuring blood 
pressure and pulse rate are acceptable, although, when done manually, pulse rate will be 
measured in the brachial/radial artery for at least 30 seconds.  The blood pressure and pulse 
rate should be obtained prior to the blood collection.
Blood pressure and pulse rate will be measured at screening, baseline, and weekly visits 
during the 12-week treatment period.  
7.2.3. Physical Examinations
A physical examination including height and weight will be performed at screening visit by 
trained medical personnel. Height and weight will be collected again at Baseline and at the 
Week 12 end-of-treatment visit or early termination if prior to Week 12. Height and weight 
must be measured at least three times.  Weight should be obtained with a calibrated scale and 
height should be measured with a stadiometer.  
CDC growth charts will be provided to investigators to record height and weight.


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7.2.4. SBQ-R
The Suicidal Behaviors Questionnaire-Revised, a brief self-report measure of past suicidal 
behavior,15 will be completed by subjects at the Screening visit.
7.2.5. Columbia Suicide Severity Rating Scale (CSSRS)
The Columbia suicide Severity Rating Scale (CSSRS)16 is a set of suggested questions 
designed to elicit information about passive and active suicidal ideation, active suicidal 
intent, and self injurious behavior.
The C-SSRS will be completed by a mental health professional (adolescent psychiatrist or 
PhD psychologist), at screening and at each subsequent clinic visit up to and including 
Week 52. 
7.2.6. Actively Solicited Neuropsychiatric Adverse Events (Appendix 4)
The NAEI will be conducted at every clinic visit from baseline through Week 52.  The 
Neuropsychiatric Adverse Event Interview (NAEI) must be conducted by a qualified mental 
health professional, who will actively inquire about the following type of adverse events: 
depression, anxiety, delusions, hallucinations, paranoia, psychosis, mania, panic, agitation, 
dissociative states, feeling abnormal, hostility, aggression and homicidal ideation. If a 
subject has a positive response to any item on the NAEI, a determination will be made by the
investigator as to whether this meets criteria for an adverse event. If it does meet criteria as 
an adverse event it will be recorded on the adverse event pages of the Case Report Form.  
Dosing must be stopped if an adverse event moderate or severe in nature is elicited through 
this interview. 
Hospital Anxiety and Depression Scale (HADS) (Appendix 3).
The Hospital Anxiety and Depression Scale (HADS) measures anxiety and depression in 
hospital and community settings and has also been validated in the adolescent outpatient 
population.17  It is a patient completed questionnaire that establishes the presence and 
severity of both anxiety (7 questions) and depression (7 questions) (Appendix 3).  
The HADS is a self-report scale and contains 14 items rated on 4-point Likert-type scales. 
Two subscales assess depression and anxiety. The HADS will be completed by the subject at 
every clinic visit through Week 52.  Dosing must be stopped if the HADS score for either 
depression or anxiey is 15.
Subjects’ self- report via the HADS is aimed to more fully characterize potential depression 
and anxiety related events. These additional measurements will be collected and evaluated in 
a different manner than the observed or volunteered adverse events.  No attempt will be made 
to resolve any apparent discrepancies between observed or volunteered adverse events and 
the additional data collected from subjects using the HADS self-report.  These additional data 
will be presented in separate tables, separate figures, and separate data listings, and will be 
reviewed in the final study report.


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Adverse event incidence rates will not be calculated from the self- reported HADS data but 
rather from the spontaneously reported information, the NAEI and the CSSRS data described 
above, recorded on the adverse event pages from the Case Report Form (CRF).
7.3. Pharmacokinetics (PK)
7.3.1. Plasma for Analysis of Varenicline:
Blood samples (3 mL) sufficient to provide a minimum of 1 mL of plasma for 
pharmacokinetic analysis will be collected at protocol specified time-points (see Table 1
Schedule of Activities) into appropriately labeled tubes containing sodium heparin. These 
PK samples should not all be collected at the same time after dosing.  A distribution of 
sampling should be encouraged, possibly through randomly scheduling sampling throughout 
the visit day.  The times of study drug dosing for the prior 2 doses as well as the time of the 
blood drawing will be recorded at each of these visits on the source document and data 
collection tool (eg, CRF). 
The samples should be cooled on ice or in a refrigerator at -2-8°C (this procedure is meant to 
minimize hemolysis and mazimize plasma yield from the whole blood), then centrifuged for 
about 10 minutes at 1400-1700 x g. Plasma is to be transferred to appropriately labeled 
screw-capped polypropylene tubes provided by the Central Laboratory. The tubes with 
plasma samples should then be stored at -20°C within one hour of blood collection. Samples 
will be analyzed using a validated analytical method in compliance with Pfizer standard 
operating procedures.
7.3.2. Shipment of PK Samples
The shipment address and contact information will be provided to the investigator site prior 
to initiation of the trial.
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside the control of the investigator that may make it unfeasible to perform 
the test. In these cases the investigator will take all steps necessary to ensure the safety and 
well-being of the subject.  When a protocol required test cannot be performed the 
investigator will document the reason for this and any corrective and preventative actions 
which he/she has taken to ensure that normal processes are adhered to as soon as possible. 
The study team will be informed of these incidents in a timely fashion.
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
The adolescent subjects will be instructed to tell the study doctor immediately if they 
experience any side effects, injury, symptoms or complaints.  They will be provided a 
24 -hour telephone contact number to reach the research site staff. 


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All observed or volunteered adverse events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections.
For all adverse events, the investigator must pursue and obtain information adequate both to 
determine the outcome of the adverse event and to assess whether it meets the criteria for 
classification as a serious adverse event requiring immediate notification to Pfizer or its 
designated representative.  For all adverse events, sufficient information should be obtained 
by the investigator to determine the causality of the adverse event.  The investigator is 
required to assess causality.  Follow-up by the investigator may be required until the event or 
its sequelae resolve or stabilize at a level acceptable to the investigator, and Pfizer concurs 
with that assessment.
As part of ongoing safety review conducted by the Sponsor, any non-serious adverse event 
that is determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  
To assist in the determination of case seriousness further information may be requested from 
the investigator to provide clarity and understanding of the event in the context of the clinical 
trial.
8.2. Reporting Period
For serious adverse events, (SAEs), the active reporting period to Pfizer or its designated 
representative begins from the time that the subject provides informed consent, which is 
obtained prior to the subject’s participation in the study, ie, prior to undergoing any 
study-related procedure and/or receiving investigational product, through the last subject 
visit. Should an investigator be made aware of any serious adverse event occurring any time 
after the active reporting period, it must be promptly reported if a causal relationship to 
investigational product is suspected. 

Adverse events (serious and non-serious) should be recorded on the CRF from the 
time the subject/legal guardian provides informed consent/assent through last subject 
visit.  
8.3. Definition of an Adverse Event
An adverse event is any untoward medical occurrence in a clinical investigation subject 
administered a product or medical device; the event need not necessarily have a causal 
relationship with the treatment or usage.  Examples of adverse events include but are not 
limited to:  

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;


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
Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse;

Drug interactions;

Extravasation;

Exposure during pregnancy (in Utero);

Exposure via breast feeding;

Medication error.
8.4. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an adverse event are as follows: 

Test result is associated with accompanying symptoms, and/or

Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or

Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy, and/or

Test result is considered to be an adverse event by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event.  Any abnormal test result that is determined to be an error does 
not require reporting as an adverse event.
8.5. Serious Adverse Events
A serious adverse event or serious adverse drug reaction is any untoward medical occurrence 
at any dose that:


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
Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect;

Lack of efficacy should be reported as an adverse event when it is associated with a 
serious adverse event.
Medical and scientific judgment should be exercised in determining whether an event is an 
important medical event.  An important medical event may not be immediately 
life-threatening and/or result in death or hospitalization.  However, if it is determined that the 
event may jeopardize the subject and/or may require intervention to prevent one of the other 
adverse event outcomes, the important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.6. Potential Cases of Drug-Induced Liver Injury
Abnormal values in aspartate transaminase (AST) and/or alanine transaminase (ALT) 
concurrent with abnormal elevations in total bilirubin that meet the criteria outlined below in 
the absence of other causes of liver injury are considered potential cases of drug-induced 
liver injury (potential Hy’s Law cases) and should always be considered important medical 
events. 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions. Subjects who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:
a.
Subjects with AST or ALT baseline values within the normal range who subsequently 
present with AST or ALT 3 times the upper limit of normal concurrent with a total 
bilirubin 2 times the upper limit of normal with no evidence of hemolysis and an 
alkaline phosphatase 2 times the upper limit of normal or not available.

For subjects with preexisting ALT OR AST OR total bilirubin values above the upper 
limit of normal, the following threshold values should be used in the definition 
mentioned above:


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
For subjects with pre-existing AST or ALT baseline values above the normal 
range: AST or ALT 2 times the baseline values and 3 X ULN, or 
8 X ULN (whichever is smaller).

Concurrent with: 

For subjects with pre-existing values of total bilirubin above the normal range: 
Total bilirubin increased by one time the upper limit of normal or 3 times the 
upper limit of normal (whichever is smaller).
The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history and physical assessment. In addition to repeating 
AST and ALT, laboratory tests should include albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time/international normalized ratio (INR) and 
alkaline phosphatase.  A detailed history, including relevant information, such as review of 
ethanol, acetaminophen, recreational drug and supplement consumption, family history, 
occupational exposure, sexual history, travel history, history of contact with a jaundiced 
subject, surgery, blood transfusion, history of liver or allergic disease, and work exposure, 
should be collected. Further testing for acute hepatitis A, B, or C infection and liver imaging 
(eg, biliary tract) may be warranted.  All cases confirmed on repeat testing as meeting the 
laboratory criteria defined above with no other cause for LFT abnormalities identified at the 
time should be considered potential Hy’s Law cases irrespective of availability of all the 
results of the investigations performed to determine etiology of the abnormal LFTs. Such 
potential Hy’s Law cases should be reported as serious adverse events.
8.7. Hospitalization
Adverse events reported from studies associated with hospitalization or prolongations of 
hospitalization are considered serious.  Any initial admission (even if less than 24 hours) to a 
healthcare facility meets these criteria.  Admission also includes transfer within the hospital 
to an acute/intensive care unit (eg, from the psychiatric wing to a medical floor, medical floor 
to a coronary care unit, neurological floor to a tuberculosis unit).
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;


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
Routine emergency room admissions;

Same day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
adverse event is not in itself a serious adverse event.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new adverse event or with a worsening of the preexisting condition 
(eg, for work-up of persistent pre-treatment lab abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical exam);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical adverse event (eg, for 
elective cosmetic surgery);

Hospitalization for observation without a medical AE;

Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.
8.8. Severity Assessment
If required on the adverse event case report forms, the investigator will use the adjectives 
MILD, MODERATE, or SEVERE to describe the maximum intensity of the adverse event.  
For purposes of consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an adverse event.  A severe 
event is not necessarily a serious event (SAE).  For example, a headache may be severe 
(interferes significantly with subject's usual function) but would not be classified as serious 
unless it met one of the criteria for serious adverse events, listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all adverse events (serious 
and non-serious); the investigator must record the causal relationship in the CRF, as 
appropriate, and report such an assessment in accordance with the serious adverse reporting 


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requirements if applicable.  An investigator’s causality assessment is the determination of 
whether there exists a reasonable possibility that the investigational product caused or 
contributed to an adverse event; generally the facts (evidence) or arguments to suggest a 
causal relationship should be provided.  If the investigator does not know whether or not the 
investigational product caused the event, then the event will be handled as “related to 
investigational product” for reporting purposes, as defined by the Sponsor (see Section on 
Reporting Requirements).  If the investigator's causality assessment is "unknown but not 
related to investigational product", this should be clearly documented on study records.  
In addition, if the investigator determines a serious adverse event is associated with study 
procedures, the investigator must record this causal relationship in the source documents and 
CRF, as appropriate, and report such an assessment in accordance with the serious adverse 
event reporting requirements, if applicable.
8.10. Exposure During Pregnancy (Also Referred to as Exposure In Utero)
For investigational products and for marketed products, an exposure in-utero (EIU) occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
directly exposed to (eg, environmental exposure) the investigational product, or the 
female becomes, or is found to be, pregnant after discontinuing and/or being directly 
exposed to the investigational product (maternal exposure);
2. A male has been exposed, either due to treatment or environmental, to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy (paternal exposure).
If any study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the investigational product, the investigator must submit this 
information to Pfizer on an Exposure in Utero Form.  In addition, the investigator must 
submit information regarding environmental exposure to a Pfizer product in a pregnant 
woman (eg, a nurse reports that she is pregnant and has been exposed to a cytotoxic product 
by inhalation or spillage) using the Exposure in Utero Form.  This must be done irrespective 
of whether an adverse event has occurred and within 24 hours of awareness of the pregnancy.  
The information submitted should include the anticipated date of delivery (see below for 
information related to induced termination of pregnancy). If at any time a study subject 
becomes or is found to be pregnant and a pregnancy registry is ongoing, the subject will be 
enrolled in the pregnancy registry. 
Follow-up is conducted to obtain pregnancy outcome information on all Exposure in Utero 
reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion or until pregnancy termination (ie, induced abortion) and then notify Pfizer of the 
outcome.  The investigator will provide this information as a follow up to the initial Exposure 
in Utero Form.  The reason(s) for an induced abortion should be specified. An EIU report is 
not created when an ectopic pregnancy report is received since this pregnancy is not usually 
viable.  Rather, a serious adverse event case is created with the event of ectopic pregnancy.


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If the outcome of the pregnancy meets the criteria for immediate classification as a serious 
adverse event (ie, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly 
[including that in an aborted fetus, stillbirth or neonatal death]), the investigator should 
follow the procedures for reporting serious adverse events.
In the case of a live birth, the “normality” of the newborn can be assessed at the time of birth 
(ie, no minimum follow-up period of a presumably normal infant is required before an 
Exposure in Utero Form can be completed).  The “normality” of an aborted fetus can be 
assessed by gross visual inspection, unless pre-abortion test findings are suggestive of a 
congenital anomaly.
Additional information about pregnancy outcomes that are classified as serious adverse 
events follows: 

“Spontaneous abortion” includes miscarriage and missed abortion.

All neonatal deaths that occur within 1 month of birth should be reported, without 
regard to causality, as serious adverse events.  In addition, any infant death after 
1 month that the investigator assesses as possibly related to the exposure in utero to 
the investigational medication should be reported.
Additional information regarding the exposure in utero may be requested by the investigator.  
Further follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up 
on preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator must obtain permission from the subject’s partner in order to conduct any 
follow-up or collect any information.
8.11. Withdrawal Due to Adverse Events
Withdrawal due to adverse event should be distinguished from withdrawal due to insufficient 
response, according to the definition of adverse event noted earlier, and recorded on the 
appropriate adverse event CRF page.  
When a subject withdraws due to a serious adverse event, the serious adverse event must be 
reported in accordance with the reporting requirements defined below.
8.12. Eliciting Adverse Event Information
The investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the study subject.  In addition, each study subject will be 
questioned about adverse events.
8.13. Reporting Requirements
Each adverse event is to be assessed to determine if it meets the criteria for serious adverse 
events.  If a serious adverse event occurs, expedited reporting will follow local and 
international regulations, as appropriate.


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8.13.1. Serious Adverse Event Reporting Requirements
If a serious adverse event occurs, Pfizer is to be notified within 24 hours of investigator
awareness of the event by the investigator.  In particular, if the serious adverse event is fatal 
or life-threatening, notification to Pfizer must be made immediately, irrespective of the extent 
of available adverse event information.  This timeframe also applies to additional new 
information (follow-up) on previously forwarded serious adverse event reports as well as to 
the initial and follow-up reporting of Exposure in Utero and exposure via breastfeeding 
cases.  
In the rare event that the investigator does not become aware of the occurrence of a serious 
adverse event immediately (eg, if an outpatient study subject initially seeks treatment 
elsewhere), the investigator is to report the event within 24 hours after learning of it and 
document the time of his/her first awareness of the adverse event.
For all serious adverse events, the investigator is obligated to pursue and provide information 
to Pfizer in accordance with the timeframes for reporting specified above.  In addition, an 
investigator may be requested by Pfizer to obtain specific additional follow-up information in 
an expedited fashion.  This information may be more detailed than that captured on the 
adverse event case report form.  In general, this will include a description of the adverse 
event in sufficient detail to allow for a complete medical assessment of the case and 
independent determination of possible causality.  Information on other possible causes of the 
event, such as concomitant medications and illnesses must be provided.  In the case of a 
subject death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer or its designated representative. 
8.13.2. Non-Serious Adverse Event Reporting Requirements
All adverse events will be reported on the adverse event page(s) of the CRF.  It should be 
noted that the form for collection of serious adverse event information is not the same as the 
adverse event CRF.  Where the same data are collected, the forms must be completed in a 
consistent manner.  For example, the same adverse event term should be used on both forms.  
Adverse events should be reported using concise medical terminology on the CRFs as well as 
on the form for collection of serious adverse event information.
8.13.3. Sponsor Reporting Requirements to Regulatory Authorities
Adverse event reporting, including suspected serious unexpected adverse reactions, will be 
carried out in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this trial 
will be documented in the Statistical Analysis Plan (SAP) and the Statistical Rulebook, 
which will be dated and maintained by the sponsor, before the time of database release.  The 
reasons for any departure from the planned method of analysis will be fully documented.


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9.1. Sample Size Determination
Although analysis for the primary efficacy endpoint will be model based, the sample size 
calculation is based on a two-sided Chi-Square test with a 0.05 significance level and a 
1:1:1 randomization ratio of varenicline 1 mg BID to varenicline 0.5 mg BID to placebo.  
The study is powered at 80% or greater to detect varenicline (1 mg BID or 0.5 mg BID dose) 
vs. placebo differences in the CQR from Weeks 9 through 12. The sample size is based on 
CQR of 9% and 24% for placebo and varenicline respectively, or an odds ratio of 3.2.  
A sample size of 300 subjects randomized to varenicline or placebo in a 1:1:1 (100 to 
varenicline 1 mg BID, 100 to varenicline 0.5 mg BID, 100 to placebo) will provide 
approximately 80% power to detect a difference in the primary endpoint between varenicline 
and placebo groups, assuming a true Week 9-12 CQR of 9% and 24% for placebo and 
varenicline respectively.  
Enrollment will be stratified by age group (12-16 vs. 17-19) and sufficient subjects will be 
enrolled in the 12-16 year old age group to detect a difference in the primary endpoint 
between varenicline and placebo groups, assuming a true Week 9-12 CQR of 9% and 
29% for placebo and varenicline respectively. 
In order to ensure sufficient subjects are enrolled in the 12-16 year old stratum, the 
17-19 year old stratum will be capped at a maximum of 90 subjects, leaving at least 
210 subjects (approximately 70 subjects per treatment group) in the 12-16 year old stratum.
Efficacy Analysis
The primary efficacy inference for the study is a comparison of varenicline to placebo for the 
CQR for Weeks 9 through 12.  This measure will be obtained through reports of cigarette or 
other nicotine use since the last study visit confirmed by urine cotinine. An exploratory 
subgroup analysis for each dosing group by weight stratum for the primary endpoint will be 
provided.
All efficacy analyses will be performed overall as well as on the subgroup of patients who 
are 12-16 years of age.
Secondary efficacy endpoints are listed in Section 2.2.
These efficacy endpoints will be based on subject self-report, with abstinence confirmed by 
cotinine.
To assess the comparability of subjects across treatment groups, demographic, smoking 
history, and baseline nicotine dependence and other baseline characteristics will be 
summarized by treatment group.  In addition, subgroup summaries and analyses may be 
completed, when the number of subjects in the subgroups permits, to evaluate the 
consistency of the efficacy in the primary and key secondary endpoints over demographic 
and other baseline characteristics.  


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Data collected at baseline and other time points will be summarized by treatment group using 
descriptive statistics.  Descriptive statistics, such as the mean, median, standard deviation, 
and range will be used to summarize continuous variables, and counts and percentages for 
categorical variables.  In addition to tabulated descriptive statistics, graphical data displays 
may be used to summarize the data.  
9.1.1. Analysis of Primary Endpoint 
Logistic regression models will be used in the analyses of primary endpoint. The model will 
include strata, treatment, and center as independent variables.  Treatment by center 
interaction will be investigated.  If the treatment by center interaction is significant in the 
model containing treatment, center, and treatment by center interaction, then exploratory 
analyses will be undertaken to explain the nature and source of the interaction.  However, the 
reported p-values will be based on the main effects model.  
Additional analyses may be performed adjusting for baseline covariates as additive terms to 
the primary model, if necessary.  Results from any additional analyses will not be used as a 
substitute for the planned analyses, but may be used as supplemental information for the 
study report. 
Statistical hypotheses for the primary endpoint will be tested in an ordered fashion to 
preserve overall Type I Error.  The 1 mg BID group will be tested against placebo, and if a 
statistically significant difference is observed, the 0.5 mg BID group will be tested against 
placebo. A p-value of 0.05 will be considered statistically significant in both tests. Both 
tests will be presented regardless of the p-value obtained.
The primary efficacy analysis population will be all subjects who took at least 1 dose of 
randomized study medication (Full Analysis set).  Subjects who discontinue the study are 
assumed to be smokers for the time point of discontinuation through the end of the study.  In 
computing responder rates, subjects who discontinue the study will be included in the 
denominator but not in the numerator, regardless of their last smoking status evaluation. 
9.1.2. Analysis of Secondary Endpoints
9.1.2.1. Efficacy Endpoints
There are several secondary smoking abstinence endpoints for this study, as indicated in 
Section 2.2.  Each of these binary secondary endpoints will be analyzed using procedures 
similar to that described above for the primary efficacy endpoint.  All statistical tests will be 
two-sided and at a 0.05 level of significance.  P-values will be reported with no adjustments 
for the analysis of multiple secondary endpoints.  
The number of cigarettes smoked over the past seven days will be collected by completion of 
the NUI at each visit.  The reduction in the number of the cigarettes smoked will be 
calculated at each visit by subtracting the reported number of cigarettes smoked in the past 
7 days at each visit from the number of cigarettes smoked in the past 7 days reported at the 
baseline visit.  Longitudinal repeated measures models including strata, treatment, center, 


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and baseline number of cigarettes smoked will be used to assess the effect of treatment on the 
reduction in the number of cigarettes smoked. 
Pharmacokinetic Endpoints
The plasma concentration-time data collected in this study will be analyzed via nonlinear 
mixed effects (NONMEM software) to describe the population pharmacokinetics (PK) of 
varenicline including an assessment of covariate effects in adolescent smokers. 
Varenicline exposure data derived from the individual Bayesian estimates of the 
pharmacokinetic parameters will be subsequently utilized to characterize the population 
exposure-response relationships for selected measures of efficacy and safety/tolerability of 
varenicline in this pediatric population. Model development may require the use of data 
from previous clinical studies. An analysis plan describing the details of the model building, 
covariate assessment and model validation will be provided separately before the unblinding 
of the data.
9.2. Safety Analysis
All safety analyses will be performed overall as well as on the subgroup of patients who are 
12-16 years of age.  Laboratory and other safety data will be subjected to clinical review and 
summarized, using Pfizer Data Standards, by frequencies of events and mean changes from 
Baseline.  
The following summaries will be used to assess the safety of subjects in this study:

Incidence and type of AEs;

Incidence and type of SAEs;  

Change from baseline in laboratory parameters;  

Incidence of clinically significant laboratory parameters;  

Change from baseline in vital signs;  

Incidence of clinically significant vital sign parameters;  

Frequency and percent of subjects endorsing suicidal ideation or behavior.
All safety analyses will use the population of all subjects who received at least 1 dose of 
study drug.  
In addition to the standard safety summaries for the vital signs data collected at each visit, the 
change from Baseline in BMI at Week 12 will be summarized by treatment group. Change 
from Baseline in BMI and any other safety endpoints of interest may be summarized for 
subgroups of interest if the number of subjects in the subgroup permits.


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9.3. Interim Analysis
Not planned.
9.4. Data Monitoring Committee 
An external Independent Data Monitoring Committee (IDMC) will be established to review 
data during the course of the study for safety monitoring and assessing risk benefit.  Based on 
their review the IDMC will make a recommendation to continue, modify or stop the study.  
The IDMC members will be selected from a pool of experts including one statistician, a 
psychiatrist and an expert in pediatric studies.  The IDMC will meet before study start to 
discuss and finalize the charter.
The frequency of meetings will be dependent upon subject enrollment.  It is suggested that 
the first data review will take place after 30 subjects complete 12 weeks of treatment.  
Subsequently data reviews will take place in increments of 50 subjects completing the 
12 week treatment period, and as subjects complete the 9 month follow-up period; or at a 
minimum of two times a year. Serious adverse event (SAE) reports will be provided to the 
IDMC on a real- time basis. The frequency of meetings will be adjusted by the IDMC chair 
as she/he considers appropriate to fulfill the IDMC's responsibilities.
Details will be outlined in the IDMC charter.
The DMC will be responsible for ongoing monitoring of the efficacy and safety of subjects in 
the study according to the Charter.  The recommendations made by the DMC to alter the 
conduct of the study will be forwarded to Pfizer for final decision.  Pfizer will forward such 
decisions, which may include summaries of aggregate analyses of endpoint events and of 
safety data which are not endpoints, to regulatory authorities, as appropriate.  In this instance, 
such disease-related efficacy endpoints are not reported individually as SAEs. 
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure 
that the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs is accurate.  The 
investigator and institution will allow Pfizer monitors or its agents and appropriate regulatory 
authorities direct access to source documents to perform this verification.
The study site may be subject to review by the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC), and/or to quality assurance audits performed by Pfizer, or 
companies working with or on behalf of Pfizer, and/or to inspection by appropriate 
regulatory authorities.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.


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11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term Case Report Form (CRF) should be understood to refer to 
either a paper form or an electronic data record or both, depending on the data collection 
method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the accuracy, authenticity, and timely 
collection and reporting of all clinical, safety, laboratory data entered on the CRFs and any 
other data collection forms. The CRFs must be signed by the investigator or by an 
authorized staff member to attest that the data contained on the CRFs is true. Any 
corrections to entries made in the CRFs, source documents must be dated, initialed and 
explained (if necessary) and should not obscure the original entry.” 
In most cases, the source documents are the hospital's or the physician's subject chart.  In 
these cases data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigator’s site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent forms, copies of all CRFs, serious adverse event forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports).  The records should be 
retained by the investigator according to ICH, local regulations, or as specified in the Clinical 
Study Agreement, whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent party arranged by Pfizer.  Investigator 
records must be kept for a minimum of 15 years after completion or discontinuation of the 
study or for longer if required by applicable local regulations. The investigator must obtain 
Pfizer's written permission before disposing of any records, even if retention requirements 
have been met.


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12. ETHICS
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent forms, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/IEC.  All correspondence with the 
IRB/IEC should be retained in the Investigator File.  Copies of IRB/IEC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/IEC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for Good Clinical Practice (International Conference on 
Harmonization 1996), and the Declaration of Helsinki (World Medical Association 2008). 
12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
on any sponsor forms, reports, publications, or in any other disclosures, except where 
required by laws. Subject names, address, birth date and other identifiable data will be 
replaced by a numerical code consisting of a numbering system provided by Pfizer in order 
to de-identify the trial subject. In case of data transfer, Pfizer will maintain high standards of 
confidentiality and protection of subject personal data.
The informed consent form must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements.
The informed consent form used in this study, and any changes made during the course of the 
study, must be prospectively approved by both the IRB/IEC and Pfizer before use.
The investigator must ensure that each study subject, or his/her legally acceptable 
representative, is fully informed about the nature and objectives of the study and possible 
risks associated with participation.  The investigator, or a person designated by the 
investigator, will obtain written informed consent from each subject or the subject's legally 
acceptable representative before any study-specific activity is performed.  Direct assent of 
the adolescent subject must also be obtained.  Parental consent is not required for subjects 
over the age of 18.  These subjects must sign their own informed consent document.  The 
investigator will retain the original of each subject's signed consent/ assent form.  


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12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH Good 
Clinical Practice (GCP)
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational product, Pfizer should be informed immediately.  
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in all Participating Countries 
End of Trial in all participating countries is defined as last subject’s last visit.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, drug safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of varenicline at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and 
the hospital pharmacy (if applicable) within 7 days.  As directed by Pfizer, all study materials 
must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS

Publication of study results is discussed in the Clinical Study Agreement.
15.1. Communication of Results by Pfizer
Pfizer fulfils its commitment to publicly disclose the results of studies through posting the 
results of this study on www.clinicaltrials.gov.  Pfizer posts the results of studies that it has 
registered on ClinicalTrials.gov regardless of the reason for registration.  
The results are posted in a tabular format called Basic Results.
For studies involving a Pfizer product, the timing of the posting depends on whether the 
Pfizer product is approved for marketing in any country at the time the study is completed:

For studies involving products applicable under the US FDAAA of 2007, ie, FDA –
approved products, Pfizer posts results within one year of the primary outcome 
completion date (PCD) For studies involving products  approved in any country, but 


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not FDA approved, Pfizer posts results within one year after study completion, 
defined as Last Subject, Last Visit (LSLV).

For studies involving products that are not yet approved in any country, Pfizer posts 
the results of already-completed studies within 30 days of US regulatory approval, or 
one year after the first ex-US regulatory approval of the product (if only submitted for 
approval ex-US).

For studies involving products whose drug development is discontinued before 
approval, Pfizer posts the results within one year after such discontinuation of the 
program (if there are not plans for outlicensing or within two years if outlicensing 
plans have not completed.
15.2. Publications by Investigators
Pfizer has no objection to publication by Investigator of any information collected or 
generated by Investigator, whether or not the results are favorable to the Investigational 
Drug. However, to ensure against inadvertent disclosure of Confidential Information or 
unprotected Inventions, Investigator will provide Pfizer an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed.
Investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to Pfizer 
at least 30 days before they are submitted for publication or otherwise disclosed. If any 
patent action is required to protect intellectual property rights, Investigator agrees to delay 
the disclosure for a period not to exceed an additional 60 days.
Investigator will, on request, remove any previously undisclosed Confidential Information 
(other than the Study results themselves) before disclosure.
If the Study is part of a multi-centre study, Investigator agrees that the first publication is to 
be a joint publication covering all centers. However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the Study at all 
participating sites, Investigator is free to publish separately, subject to the other requirements 
of this Section.
For all publications relating to the Study, Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement.


CP-526,555
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Page 56
16. REFERENCES
1.
Chantix® USPI, 2008.
2.
Danice K. Eaton DK, Laura Kann L, Steve Kinchen S,  James Ross J, et al. Youth Risk 
Behavior Surveillance --- United States, 2005.  MMWR Surveillance Summaries June 
9, 2006 / 55(SS05);1-108. 
http://www.cdc.gov/mmwr/preview/mmwrhtml/ss5505a1.htm.
3.
CDC. 2004 Surgeon General's Report—The Health Consequences of Smoking.  
Available at http://www.cdc.gov/tobacco/data_statistics/sgr/sgr_2004/index.htm#full.    
4.
US Department of Health and Human Services. Healthy people 2010: understanding 
and improving health. 2nd ed. Washington, DC: US Department of Health and Human 
Services; 2000. Available at 
http://www.healthypeople.gov/document/html/objectives/27-02.htm.   
5.
Wileyto P, O'Loughlin J, lagerlund M, Meshefedjian G, Dugas E, Gervais A.  
Distinguishing risk factors for the onset of cravings, withdrawal symptoms and 
tolerance in novice adolescent smokers.  Tobacco Control 2009;18:387-392.
6.
Prokhorov AV, De Moor C, Pallonen UE, Hudmon KS, Kohely L, Hu S.  Validation of 
the Modified Fagerström Tolerance Questionnaire with Salivary Cotinine Among 
Adolescents.  Addictive Behaviots 200; 25:429-33.
7.
American Lung Association: Not On Tobacco (N-O-T) website 
http://www.lungusa.org/site/c.dvLUK9O0E/b.39865/k.1F9F/Teen_Smoking_Reduced_
Due_To_Not_On_Tobacco_NOT.htm  accessed May 22, 2008.
8.
National Registry of Evidence-based Programs and Practices (NREPP), Substance 
Abuse and Mental Health Services Administration 
(SAMHSA).http://www.nrepp.samhsa.gov/programfulldetails.asp?PROGRAM_ID=189
#ratings accessed August 1, 2008.
9.
Horn K, Dino G, Kalsekar I, Mody R.  The impact of Not on Tobacco on teen smoking 
cessation: end-of-program evaluation results, 1998 to 2003.  Journal of Adolescent 
Research. 2005;20(6):640-661.  
10.
Sussman, Steve, Dent Clyde, Lichtman, Kara. Project EX Outcomes of a teen smoking 
cessation program. Addictive Behaviors 2001; 26:425-438.
11.
Lewis-Esquerre JM, Colby, SM, Tevyaw TO, Eaton CA, et al. Validation of the 
timeline follow-back in the assessment of adolescent smoking. Drug and Alcohol 
Dependence. 2005; 79:33-43.


CP-526,555
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Page 57
12.
Heatherton TF, Kozlowski LT, Frecker RC, Fagerstrőm KO. The Fagerstrom test for 
nicotine dependence: A revision of the Fagerstrom tolerance questionnaire. British 
Journal of Addiction 1991;86:1119-1127.
13.
Nonnemaker JM, Homsi G. Measurement properties of the Fagerstrom Test for nicotine 
dependence adapted for use in an adolescent sample. Addictive Behaviors 
2007;32:181-186.
14.
DiFranza J, Wellman RJ. Hooked on Nicotine Checklist (HONC). 
http://fmchapps.umassmed.edu/honc  Accessed August 1, 2008.
15.
Osman A, Bagge CL, Gutierrez PM, Konich LC, Kopper BA, Barrios FX.  The suicidal 
behaviors questionnaire-revised (SBQ-R): validation with clinical and nonclinical 
samples.  Assessment 2001;8:443-454.
16.
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia classification 
algorithm of suicide assessment (C-CASA): Classification of suicidal events in the 
FDA’s pediatric suicidal risk analysis of antidepressants. Am J Psychiatry 
2007;164:1035-1043.
17.
White D, Leach C, Sims R, Atkinson M, Cottrell D. Validation of the Hospital Anxiety 
and Depression Scale for use with adolescents.  Br. J Psychiatry 1999; 175: 452-454.
18.
Horn K, Dino G, personal communication.
19.
Clinical Study Report A3051070 - Phase 1, Randomized, Sponsor-Open, Investigator-
and Subject-Blind, Parallel-Group, Placebo-Controlled Study to Evaluate the Multiple-
Dose Pharmacokinetics, Safety, and Tolerability of Varenicline in Healthy Adolescent 
Smokers.
20.
Faessel HM, Ravva P, Williams KE. Pharmacokinetics, safety, and tolerability of 
varenicline in healthy adolescent smokers: A multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study. Clin Ther 2009; 31 (1): 177-89.
21.
Report No. 118515 - Population Pharmacokinetic Analysis of Varenicline in Adult 
Smokers. September 2005.
22.
Ravva P, Gastonguay MR, Tensfeldt TG, et al. Population pharmacokinetic analysis of 
varenicline in adult smokers. British J Clin Pharmacol 2009; 68 (5): 669-81.
23.
Clinical Study Report A3051029 - Phase 1, Randomized, Sponsor-Open, Investigator-
and Subject-Blind, Parallel-Group, Placebo-Controlled Study to Evaluate the Single-
Dose Pharmacokinetics, Safety, and Tolerability of Varenicline in Healthy Adolescent 
Smokers.
24.
Treating Tobacco Use and Dependence 2008 Update. Clinical Practice Guideline. 
Rockville, MD. U. S. Department of Health and Human Services. Public Health 
Service. May 2008. Fiore, MC, Jaen CR, Baker, TB et al.


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Appendix 1. Nicotine Use Inventory
Asked at the Week 1 visit through the Week 12 visit

Has the subject smoked any cigarettes (even a puff) since the last study visit?

Has the subject used any other nicotine-containing products (eg, nicotine patch, 
nicotine gum, nicotine nasal spray, nicotine inhaler, nicotine lozenge, pipe, cigars, 
chew, snuff) since the last study visit?

Has the subject smoked any cigarettes (even a puff) in the last 7 days?

If the subject smoked in the last 7 days, has the subject had any days on which no 
cigarettes were smoked, and if so, how many days?

If the subject smoked in the last 7 days, how many cigarettes did the subject smoke 
per day, on average for the days on which smoking occurred?

Has the subject used any other nicotine-containing products (eg, nicotine patch, 
nicotine gum, nicotine nasal spray, nicotine inhaler, nicotine lozenge, pipe, cigars, 
chew, snuff) in the last 7 days?
Asked at the Week 13 visit through the Week 52 visit

Has the subject smoked any cigarettes (even a puff) since the last contact?

Has the subject used any other tobacco products (eg, pipe, cigars, chew, snuff) since 
the last contact?

Has the subject smoked any cigarettes (even a puff) in the last 7 days?

If the subject smoked in the last 7 days, has the subject had any days on which no 
cigarettes were smoked, and if so, how many days?

If the subject smoked in the last 7 days, how many cigarettes did the subject smoke 
per day, on average for the days on which smoking occurred?

Has the subject used any other tobacco products (eg, pipe, cigars, chew, snuff) in the 
last 7 days?
Additionally Asked on the Week 52 visit

Has the subject smoked any cigarettes (even a puff) in the last 4 weeks?

Has the subject used any other tobacco products (eg, pipe, cigars, chew, snuff) in the 
last 4 weeks?

Nicotine replacement therapy and/or other smoking cessation medications should be 
recorded in the concomitant medicine pages in the case report form.


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Appendix 2. Fagerström Test for Nicotine Dependence
Questions
Answers
Points
1. How soon after you wake up do you smoke your 
first cigarette?
Within 5 minutes
6-30 minutes
31-60 minutes
After 60 minutes
3
2
1
0
2. Do you find it difficult to refrain from smoking 
in places where it is forbidden eg, in church, at the 
library, in the cinema, etc.?
Yes
No
1
0
3. Which cigarette would you hate most to give 
up?
The first one in the 
morning
Any other
1
0
4. How many cigarettes/day do you smoke?
10 or less
11-20
21-30
31 or more
0
1
2
3
5. Do you smoke more frequently during the first 
hours after waking than during the rest of the day?
Yes
No
1
0
6. Do you smoke if you are so ill that you are in 
bed most of the day?
Yes
No
1
0


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Appendix 3. Hospital Anxiety and Depression Scale (HADS)
This questionnaire is designed to help your clinician to know how you feel.  Read each item 
below and the reply which comes closest to how you have been feeling in the past week.  
Ignore the numbers printed next to the replies.
Don’t take too long over you replies, your immediate reaction to each item will probably be 
more accurate than a long thought out response.
1. I feel tense or ‘wound up’
□ 3
Most of the time
□ 2
A lot of the time
□ 1
From time to time, occasionally
□ 0 Not at all
8. I feel as if I am slowed down
□ 3
Nearly all the time
□ 2
Very often
□ 1
Sometimes
□ 0
Not at all
2. I still enjoy things I used to enjoy
□ 0
Definitely as much
□ 1
Not quite as much
□ 2
Only a little
□ 3
Hardly at all
9.  I get a sort of frightened feeling like ‘butterflies’ 
in my stomach
□ 0
Not at all
□ 1
Occasionally
□ 2
Quite often
□ 3
Very often
3. I get a sort of frightened feeling as if something 
awful is about to happen
□ 3
Very definitely and quite badly
□ 2
Yes, but not too badly
□ 1
A little, but it doesn’t worry me
□ 0
Not at all
10. I have lost interest in my appearance
□ 3
Definitely
□ 2
I don’t take as much care as I should
□ 1
I may not take quite as much care
□ 0
I take just as much care as ever
4. I can laugh and see the funny side of things
□ 0
As much as I always could
□ 1
Not quite so much now
□ 2
Definitely not so much now
□ 3
Not at all
11. I feel restless as if I have to be on the move
□ 3
Very much indeed
□ 2
Quite a lot
□ 1
Not very much
□ 0
Not at all
5. Worrying thoughts go through my mind
□ 3
A great deal of the time
□ 2
A lot of the time
□ 1
Not too often
□ 0
Very little
12. I look forward with enjoyment to things
□ 0
As much as I ever did
□ 1
Rather less than I used to
□ 2
Definitely less than I used to
□ 3
Hardly at all
6. I feel cheerful
□ 3
Never
□ 2
Not often
□ 1
Sometimes
□ 0
Most of the time
13. I get sudden feelings of panic
□ 3
Very often indeed
□ 2
Quite often
□ 1
Not very often
□ 0
Not at all
7. I can sit at ease and feel relaxed
□ 0
Definitely
□ 1
Usually
□ 2
Not often
□ 3
Not at all
14. I can enjoy a good book or radio or television 
program
□ 0
Often
□ 1
Sometimes
□ 2
Not often
□ 3
Very seldom
HADSS copyright © R.P. Snaith and A.S. Zigmond 1983, 1992, 1994.


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Appendix 4. Neuropsychiatric Adverse Event Interview (NAEI)
Adverse Event
Have you felt depressed (sad, blue, down, empty, as if you didn’t care)?
Do you find that you have lost interest in things or get less pleasure 
from things that you used to enjoy?
Have you cried or felt like crying?
Depression
Have you been worried, or scared?
Have you been nervous or anxious?
Have you felt panicky at all?
Some people have panic attacks when they suddenly feel very 
frightened and have physical symptoms like heart palpitations, (your 
heart is pounding and/or beating rapidly, shortness of breath and chest 
pains.  Have you had this?
Anxiety, Panic
Have you had times when you felt extremely anxious and you had to be 
always moving, even pacing?
Have you had times when you felt extremely agitated?
Agitation
Have you been feeling unusually cheerful, or happy, not just your 
normal self, so that other people noticed?
Have you had much more energy than usual to do things?
Have you needed less sleep than usual to feel rested?
Mania
Have you felt hostile towards others?
Have you been involved in any serious arguments or fights?
Hostility


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Have you had the urge to injure or harm someone?
Have you felt that someone may be after you, or trying to harm you in 
some way?
Paranoia
Has there been anything unusual about the way things look or sound or 
smell?
Have you heard things that other people couldn’t hear, like noises or 
voices of people talking when there was no one around?
Have you seen things that other people couldn’t see?
Hallucinations
Has your mind been playing tricks on you in any way?
Have you had any ideas that other people might not understand or 
might find strange?
Delusions
Have things seemed unreal to you?
Have you felt that you are detached from or have trouble connecting 
with other people?  
Have you been feeling strange or odd in any other way? 
Dissociative 
states
Feeling 
abnormal

SAP_001.pdf: 
Statistical Analysis Plan
FINAL
Page 1 of 39
Protocol A3051073
A TWELVE-WEEK, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL-GROUP, DOSE-RANGING 
STUDY WITH FOLLOW-UP EVALUATING THE SAFETY AND 
EFFICACY OF VARENICLINE FOR SMOKING CESSATION IN 
HEALTHY ADOLESCENT SMOKERS
Statistical Analysis Plan 
(SAP)
Version:
3.0
Author:
(GPD Statistics - Groton)
Date:
19JUL2017
PPD


Protocol A3051073        Statistical Analysis Plan
Statistical Analysis Plan
FINAL
Page 2 of 39
TABLE OF CONTENTS
LIST OF FIGURES ...................................................................................................................3
APPENDICES ...........................................................................................................................4
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................5
1.1. Version 1.1 ................................................................................................................5
1.2. Version 1.2 ................................................................................................................5
1.3. Version 1.3 ................................................................................................................5
1.4. Version 1.4 ................................................................................................................6
1.5. Version 2.0 ................................................................................................................6
1.6. Version 3.0 ................................................................................................................6
2. INTRODUCTION .................................................................................................................7
2.1. Study Design .............................................................................................................7
2.2. Study Objective.......................................................................................................10
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING................................10
4. HYPOTHESES AND DECISION RULES.........................................................................10
4.1. Statistical Hypotheses .............................................................................................10
4.2. Statistical Decision Rules........................................................................................10
5. ANALYSIS SETS ...............................................................................................................11
5.1. Full Analysis Set .....................................................................................................11
5.2. Completer Subjects Analysis Set ............................................................................11
5.3. Safety Analysis Set..................................................................................................11
5.4. Treatment Misallocations........................................................................................11
5.5. Protocol Deviations.................................................................................................11
5.6. Compliance..............................................................................................................12
6. ENDPOINTS AND COVARIATES ...................................................................................12
6.1. Efficacy Endpoint(s) ...............................................................................................12
6.1.1. Primary Efficacy Endpoint .........................................................................12
6.1.2. Secondary Efficacy Endpoints....................................................................12
6.2. Safety Endpoints .....................................................................................................12
6.3. Windowing and Time Point Assignments...............................................................13
6.4. Pooling of Small Sites.............................................................................................14
6.5. Covariates................................................................................................................15
7. HANDLING OF MISSING VALUES ................................................................................15


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8. STATISTICAL METHODOLOGY AND STATISTCAL ANALYSES............................15
8.1. Statistical METHODS.............................................................................................15
8.1.1. Analyses for Categorical Data....................................................................15
8.1.1.1. Descriptive Statistics.................................................................15
8.1.1.2. Efficacy Analysis ......................................................................16
8.1.2. Analyses for Continuous Data....................................................................16
8.1.2.1. Descriptive Statistics.................................................................16
8.1.2.2. Efficacy Analysis ......................................................................16
8.2. Statistical Analyses .................................................................................................16
8.2.1. Baseline Demographics and Other Baseline Characteristics......................17
8.2.2. Compliance.................................................................................................17
8.2.3. Primary Efficacy Analysis..........................................................................17
8.2.4. Secondary Efficacy Analyses .....................................................................19
8.2.4.1. The 7-day Point-prevalence of Smoking Abstinence at 
Weeks 12, 24, and 52 ........................................................................19
8.2.4.2. The Reduction in Number of Cigarettes Smoked at Weeks 
12, 24, and 52 ....................................................................................19
8.2.4.3. The Continuous Abstinence Rate from Week 9 through 
Week 24 and Week 52.......................................................................20
8.2.5. Additional Efficacy Analysis......................................................................21
8.2.6. Safety Analysis ...........................................................................................21
8.2.6.1. Adverse Events..........................................................................21
8.2.6.2. Clinical Laboratory Measures ...................................................22
8.2.6.3. Vital Signs.................................................................................23
8.2.6.4. Height and Weight ....................................................................23
8.2.6.5. Physical Examination................................................................24
8.2.6.6. Suicide Behavior Questionnaire - Revised................................24
8.2.6.7. Hospital Anxiety and Depression Scale....................................24
8.2.6.8. Columbia Suicide Severity Rating Scale (C-SSRS) .................25
LIST OF FIGURES
Figure 1.
Study A3051073 Trial Diagram .............................................................................9


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APPENDICES
Appendix 1. Neuropsychiatric Adverse Events.......................................................................26
Appendix 2. Serious Skin Adverse Events ..............................................................................35
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1. AMENDMENTS FROM PREVIOUS VERSION(S)
1.1. Version 1.1

Updated per protocol amendment.

Added definition of compliance and compliance summary table.

Added summaries of volunteered adverse events.

Added listings of Physical Examination and Suicide Behavior Questionnaire (SBQ-R) 
data from the screening visit.

Updated Section 4.1 to state hypotheses in terms of odds ratios.

Updated Section 6.1 to clarify that some visits are telephone visits and quit rates 
based on these data do not require chemical confirmation.

Updated Section 6.3 to remove upper end to final visit window.

Updated Section 8.2.6.2 to include box plots.
1.2. Version 1.2

Added frequency table for post-treatment non-study smoking cessation aid use by 
treatment group.
1.3. Version 1.3

Revised the alternative hypothesis from H1: OR ≥ 1 to H1: OR ≠ 1 and included 
additional details regarding two sets of hypotheses and the odds ratio - Section 4.1.

Corrected the statement of significance level from “p-value of 0.05 or larger” to
“p-value of 0.05 or smaller” - Section 4.2.

The primary efficacy analysis population will be the Full Analysis Set, defined as all
subjects who were randomized – Section 5.1.

To be consistent with other recent Varenicline studies, the term “continuous 
abstinence” is used instead of “continuous quit” for efficacy endpoints. For the 
primary efficacy endpoint, changed “continuous quit rate (CQR) from Week 9 
through Week 12” to “continuous abstinence (CA) from Week 9 through Week 12 ”.  
See Section 6.1.1.  Note: This term change will not impact the definition of the 
endpoints or the analyses.  The change is only within this SAP, not the protocol.  

Defined visit windows for weeks 14 and 15 - Section 6.3.

Revised the section for “Pooling of Sites” to be consistent with current methods, 
which take into consideration of multiple countries - Section 6.4.


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
Added sensitivity analysis to assess the impact of excluding 16 randomized subjects 
with possibly unreliable data who were randomized at investigational site 
 -
Section 8.1.1.2.

1.4. Version 1.4

Added sensitivity analysis based on imputation.

Added shift tables for HADS subscores.

Removed efficacy analysis by body weight group.
1.5. Version 2.0

Added body weight strata to statistical models.

Added summary tables by strata.

Added efficacy figures.

Added change from baseline summary tables for HADS.

Added clarifying language to definition of treatment emergent responses on the 
C-SSRS.

Removed box plots for laboratory values.

Removed plots for Tier 1 and Tier 2 adverse events.

Added additional terms to Appendix 2.

Removed angioedema specific adverse event summaries.

Removed 

Updated terms in Appendix 4 
1.6. Version 3.0

Corrected body weight strata inequalities.

Updated study design to align with language in the protocol.

Indicated pooling of small centers will be based on the 12-16 year old, ≤55 kg
stratum.
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
Corrected ‘including’ to ‘excluding’ in Section 8.1.1.2  referencing a sensitivity 
analysis of site 
.
2. INTRODUCTION
Note: in this document any text taken directly from the protocol is italicised. 
Most adult smokers initiated smoking as adolescents.  According to the CDC’s 2005 Youth 
Risk Behavior Survey, 23.0% of students in the United States were current cigarette users 
(i.e. had smoked cigarettes on more than one of the 30 days preceding the survey) and 9.4% 
of students were current frequent cigarette users (i.e. had smoked cigarettes on 20 of the 
30 days preceding the survey).  Among the students who reported current cigarette use,
10.7% had smoked at least 10 cigarettes/day on the days they smoked during the 30 days 
preceding the survey and 54.6% had tried to quit smoking cigarettes during the 12 months 
preceding the survey.  Continued smoking increases lifetime risk for various cancers, 
especially lung cancer, cardiovascular diseases, and respiratory diseases.  Objective 27-2 of 
the US Department of Health and Human Services Healthy People 2010 initiative is to 
reduce the prevalence of current cigarette use among high school students to 16%. 
Varenicline is a selective nicotinic acetylcholine receptor (nAChR) partial agonist designed
to have specific and potent binding at the 42 receptor subtype which mediates the behavior 
reinforcing effects of nicotine.  Because of its mixed agonist-antagonist properties, 
varenicline offers the therapeutic benefit of relieving symptoms of nicotine withdrawal and 
cigarette craving during abstinence while blocking the reinforcing effects of chronic nicotine.
Varenicline (as Chantix®) was approved in the United States in May 2006 as an aid to 
smoking cessation treatment in adults.  Postmarketing study commitments required under 
section 2 of the Pediatric Research Equity Act (PREA) include a study to determine whether 
varenicline, as part of an overall smoking cessation program, is effective in achieving and 
maintaining smoking cessation in tobacco-addicted adolescents. 
The purpose of this statistical analysis plan is to outline the proposed statistical analysis 
methods.  This analysis plan provides additional details concerning the statistical analyses 
that were originally outlined in the study protocol A3051073.
2.1. Study Design
This will be a randomized, double-blind, placebo-controlled, multicenter study to compare 
two doses of varenicline 1 mg BID and 0.5 mg BID with placebo for smoking cessation in 
adolescent smokers aged 12-19 years who are motivated to quit. Since varenicline exposure 
is related to body weight, subjects with a body weight 55 kg will have their varenicline dose 
reduced by half (those randomized to 1 mg BID will receive 0.5 mg BID and those 
randomized to 0.5 mg BID will receive 0.5 mg QD).  
Randomization will be stratified by age group (12-16 vs 17-19) and body weight.  In order to 
ensure a sufficient number of subjects in the 12-16 year old stratum, the 17-19 year old 
stratum will be capped at a maximum of 90 subjects.
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Those subjects deemed eligible will be randomized and enter the 12-week placebo-controlled 
treatment period with weekly clinic visits for efficacy and safety assessments and smoking 
cessation counseling. Varenicline or placebo dosing will begin with two weeks of 
titration. (Figure 1). All subjects will set a target quit date (TQD) to coincide with the 
Week 1 visit. The Week 1 visit occurs at the end of the first week of the treatment phase. The 
primary efficacy endpoint will be complete abstinence from smoking, biochemically verified, 
during the last 4 weeks of the 12 week dosing period.
Follow-up period: Subjects will be followed to obtain smoking status for 9 months after the 
end of the 12-week treatment period.  Clinic visits will occur at Weeks 13-16 (inclusive), 20, 
28, 36, 44, and 52.  Telephone visits are planned for Weeks 24, 32, 40, and 48.  
The clinical trial is illustrated in Figure 1.


Protocol A3051073        Statistical Analysis Plan
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Page 9 of 39
Figure 1.
Study A3051073 Trial Diagram
BL = Baseline; T = Telephone contact
f
Screening
Weeks
Randomization
1
B
6
2
3
4
5
Varenicline 1 mg BID *
Varenicline 0.5 mg BID *
Placebo
7
8
13
9
10
11
12
24
16
20
28
32
36
40
T
44
48
T
Weeks
Treatment
Follow-up
52
BL = Baseline;
 
Screening
Weeks
Randomization
1
B
6
2
3
4
5
Varenicline 1 mg BID *
Varenicline 0.5 mg BID *
Placebo
7
8
13
9
10
11
12
24
T
16
20
32
T
36
40
T
44
48
T
Weeks
Treatment
Follow-up
*Varenicline doses are titrated to target dose over the first 2 weeks of treatment.  Subjects 
whose body weight is 55 kg will have their randomized dose reduced by half.


Protocol A3051073        Statistical Analysis Plan
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Page 10 of 39
2.2. Study Objective
To evaluate the efficacy, safety, and tolerability of varenicline compared with placebo in 
adolescent smokers aged 12-19 years.
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING 
No interim analyses are planned for this study.  The final analysis will be first performed at 
database release.
A Data Monitoring Committee will be used to monitor unblinded safety data in an ongoing 
manner.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
The primary hypotheses of interest are designed to assess the efficacy objective of this study, 
and are as follows;
1 mg BID group vs. placebo
1
:
1
:
1
0


OR
H
OR
H
0.5 mg BID group vs. placebo
1
:
1
:
1
0


OR
H
OR
H
where OR is the odds ratio (relative to placebo) of continuous abstinence from Week 9 to 
Week 12 (the last 4 weeks of treatment). The OR will be evaluated using a logistic 
regression model based on the predicted Week 9-12 continuous abstinence rate (CAR).
4.2. Statistical Decision Rules
Statistical hypotheses for the primary endpoint will be tested in an ordered fashion to 
preserve overall Type I Error. The 1 mg BID group will be tested against placebo, and if a 
statistically significant difference is observed, the 0.5 mg BID group will be tested against 
placebo. A p-value of 0.05 or smaller will be considered statistically significant in both 
tests. Both tests will be presented regardless of the p-value obtained.  
P-values will be reported with no adjustments for the analysis of multiple secondary 
endpoints or analyses by strata.  


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5. ANALYSIS SETS
In each of the following efficacy populations, subjects who discontinue the study are 
assumed to be smokers from the time point of discontinuation through the end of the study.  
In computing responder rates, subjects who discontinue the study will be included in the 
denominator but not in the numerator, regardless of their last smoking status evaluation.  
5.1. Full Analysis Set
The primary efficacy analysis population will be the Full Analysis Set, defined as all subjects 
who were randomized.  
5.2. Completer Subjects Analysis Set
The Completer Subjects population is defined as the subset of the Full Analysis Set who have 
at least 80% treatment compliance, as measured by having any dose of study medication for 
80% of the planned number of days in the trial treatment period. 
5.3. Safety Analysis Set
The Safety Analysis population will be all subjects who took at least 1 dose of randomized 
study medication, including partial doses.
5.4. Treatment Misallocations 
Errors in treatment allocation will be handled in the following way:
If a subject was:

Randomized but not treated, are excluded from all safety analyses as actual treatment 
is missing but will be included in the Full Analysis Set for the primary efficacy 
analysis.

Treated but not randomized, will be excluded from the efficacy analyses since 
randomized treatment is missing, but will be reported under the treatment they 
actually received for all safety analyses.

Randomized but took incorrect treatment, will be reported under their randomized 
treatment group for all efficacy analyses, but will be reported under the treatment they 
actually received for all safety analyses.
5.5. Protocol Deviations
The definitions of the Full Analysis Set and Completer populations are based only on patient 
treatment compliance as described in Sections 5.1 through 5.2.  Violations of the protocol 
inclusion or exclusion criteria or other protocol violations or deviations will not exclude 
subjects from the defined analysis populations.
A summary by treatment group as well as a list of all clinically important protocol deviations 
will be included in the study report.


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5.6. Compliance
The definition of compliance for the purpose of assessing the extent to which patients are 
complying with the prescribed dosing for the entire trial treatment period is as follows:
Compliance = 
taken
be
to
tablets
of
number
Expected
taken
tablets
of
number
Actual
, where
Actual number of tablets taken is as per the dosing log in the CRF and expected number of 
tablets taken is the number of tablets prescribed.  
Note that this is not the definition of compliance as used for the Completers Population, 
which requires only that patients take any amount of study drug for 80% of the planned 
number of days in the trial treatment period.
6. ENDPOINTS AND COVARIATES
6.1. Efficacy Endpoint(s)
Efficacy assessments will include measurement of smoking cessation and reduction obtained 
from the Nicotine Use Inventory (NUI) and urine cotinine measurements. The Week 24, 32, 
40, and 48 visits are telephone visits, and therefore do not include collection of urine 
cotinine.  Abstinence rates based on or including these visits do not require chemical 
confirmation.  Urine cotinine is collected at all in-person clinic visits, and all abstinence rates 
based on in-clinic visits utilize urine cotinine to confirm abstinence.  The reduction in the 
number of cigarettes smoked is based solely on the reported number of cigarettes on the NUI
at baseline and the post-baseline visit of interest.  The endpoints derived from these include: 
6.1.1. Primary Efficacy Endpoint

4-week continuous abstinence rate (CA) from Week 9 through Week 12 of treatment for 
varenicline compared with placebo.
6.1.2. Secondary Efficacy Endpoints

7-day point-prevalence of smoking abstinence at Weeks 12, 24, and 52;

Reduction in number of cigarettes smoked at Weeks 12, 24, and 52;

Continuous abstinence rate from Week 9 through Week 24;

Continuous abstinence rate from Week 9 through Week 52.
6.2. Safety Endpoints

Adverse events spontaneously volunteered or elicited by the Neuropsychiatric Adverse 
Event Inventory (NAEI), Columbia Suicide Severity Rating Scale (C-SSRS), Hospital 
Anxiety and Depression Scale (HADS), safety laboratory tests, and vital signs.


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6.3. Windowing and Time Point Assignments
No windows will be used to determine planned weeks and days for this study.  All analyses 
will be based on nominal day and week as recorded on the CRF.  The exception will be the 
early termination visit.  This visit will be assigned a nominal week according to the following 
windowing algorithm. (Note: The count of days starts from the first day of dosing and all 
intervals below are inclusive of the end days):
Week 1: day 2 through 10
Week 2: day 11 through 17
Week 3: day 18 through 24
Week 4: day 25 through 31
Week 5: day 32 through 38
Week 6: day 39 through 45
Week 7: day 46 through 52
Week 8: day 53 through 59
Week 9: day 60 through 66
Week 10: day 67 through 73
Week 11: day 74 through 80
Week 12: day 81 through 87
Week 13: day 88 through 94
Week 14: day 95 through 101
Week 15: day 102 through 108
Week 16: day 109 through 126
Week 20: day 127 through 147
Week 22: day 148 through 161
Week 24: day 162 through 182
Week 28: day 190 through 210
Week 32: day 218 through 238
Week 36: day 246 through 266
Week 40: day 274 through 294
Week 44: day 302 through 322
Week 48: day 330 through 350
Week 52: day 358 on
In the event of ties, the non “early termination” visit (i.e. the earlier visit) will be selected as 
the representative visit.
Day will be computed by subtracting the date of the first dose of study medication from the 
date of the evaluation.  In order that the first day of dosing be defined as Day 1, one day will 
be added to this difference.
Baseline will be defined as the latest evaluation performed prior to the first dose of study 
medication.


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6.4. Pooling of Small Sites
Pooling of sites will be performed only once prior to any efficacy statistical analysis.
Any investigator center having less than 2 subjects in any given treatment group or efficacy 
outcome category within each age group strata will be defined as a ‘small’ center.  The 
pooling of small centers will be based on the total number of subjects randomized at each 
center.  Small centers will be pooled to large centers within the same country.  When there 
are only small centers within a given country, small centers will be pooled to large centers 
within the same region.  
Small centers will be pooled with other similar small centers using the following process:
Part A: Pool centers based on frequency in binary efficacy endpoints in the 12-16 year old 
stratum and the ≤55 kg stratum.
1. For the completer subjects population, create a center by CAR 9-52 frequency table 
(say Table 1).
2. Identify small centers from Table 1 (small center defined as a center with a 0 count in 
any column of Table 1).
3. Identify the country for each small center.
4. Within each country, independently order the small centers and the non-small centers
(those with non-zero cells) based on the total number of subjects in the center.   
5. Within each country, pool the smallest small (zero-cell) center to the largest nonsmall
(non-zero cell). Then pool the next smallest small center to the next largest non-small 
center, and so on, until all small centers have being pooled with a nonsmall center. At 
this point the center by CAR 9-52 frequency table should not have any cell with zero 
frequency.
6. Renumber the pooled centers after the last two centers are pooled.
7. Repeat Steps 1 to 6 for each of the other efficacy endpoints to ensure there are no 
zero frequency cells in the frequency table of pooled center by any binary endpoint.
Part B: Pool centers based on frequency in each treatment group. Repeat ‘Part A’ by
replacing the binary endpoint with treatment group data.
After applying 'Part A' and 'Part B', check the convergence of the CAR 9-52 model that
includes treatment groups and centers (pooled centers) on the Completers population:

If model converges, check the convergence of all other logistic models specified in
this SAP.


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
If model does not converge (unlikely) apply ‘Part C’ described below.
Part C:
Repeat ‘Part A’ and ‘Part B’ with small center defined as a center with a count of 1 in any
column of Table 1.
Notes:
a.
If two centers have same frequency, select the one with the smallest center number.
b. If for a given country, there is only one center, replace country by region in Steps 3 to 
6 above (only for the given country, for other countries do as specified above).
The final pooled centers will be used in the analysis for the rest of the efficacy endpoints.
6.5. Covariates 
Age Strata, body weight strata, and center will be included in statistical models as fixed 
effects.  The additional effects of treatment by center interaction, treatment by age, and 
treatment by body weight may be included in exploratory models.
7. HANDLING OF MISSING VALUES
Subjects who discontinue the study will be considered smokers for the remainder of the study 
regardless of their last smoking status evaluation. This implies that subjects who discontinue 
will continue to be represented in the denominator but not in the numerator regardless of 
smoking status at the time of discontinuation. This can be considered a worst case carried 
forward analysis and represents a conservative approach to imputation of missing data. 
For the HADS-A and HADS-D, if more than one question within a domain (anxiety or 
depression) is missing, the score will be set to missing.  If only one question is missing, the 
missing response will be imputed with the domain-specific mean based on the remaining 
questions.
8. STATISTICAL METHODOLOGY AND STATISTCAL ANALYSES
8.1. Statistical METHODS 
All PK/PD analyses will be performed by the Pfizer Pharmacometrics/Clin Pharm groups. 
An analysis plan providing details of these analyses will be provided separately.
No adjustment for multiple comparisons will be made.  
8.1.1. Analyses for Categorical Data 
8.1.1.1. Descriptive Statistics
Categorical data will be summarized by presenting the counts and percentages with the 
denominator being the number of subjects in the analysis set in the particular treatment group
with non-missing data.  


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8.1.1.2. Efficacy Analysis
Logistic regression models will be used in the analyses of primary endpoint, as well as 
several secondary endpoints.  The model will include strata, and pooled center as 
independent variables.  Treatment by center, treatment by age stratum, and treatment by 
body weight stratum interaction will be investigated.  If interactions are significant, then 
exploratory analyses will be undertaken to explain the nature and source of the interaction.  
However, the reported p-values will be based on the main effects model.  
Additional analyses may be performed adjusting for baseline covariates as additive terms to 
the primary model, if necessary.  Results from any additional analyses will not be used as a 
substitute for the planned analyses, but may be used as supplemental information for the 
study report.
In addition, a sensitivity analysis excluding 16 subjects from investigative site 
will be 
performed on the primary endpoint – Continuous Abstinence Rate from Week 9 through 12 –
using the primary analysis model. 
This sensitivity analysis will be performed for the following groups:

Overall study.

12-16 year old age stratum.
8.1.2. Analyses for Continuous Data
8.1.2.1. Descriptive Statistics
Continuous variables for baseline demographic and smoking history data will be summarized 
(n, mean, standard deviation, median, minimum and maximum) by treatment group.  
8.1.2.2. Efficacy Analysis
Analysis of the continuous endpoints will be performed by using longitudinal repeated
measures models including treatment, visit, age strata, body weight strata, pooled study 
center, and baseline measure.
SAS PROC MIXED will be used, with an unstructured covariance structure.  If the 
unstructured covariance does not converge, compound symmetric variance structure will be 
used. 
8.2. Statistical Analyses
All efficacy analyses will be based on the Full Analysis Set as described in Section 5.1.  
Efficacy analyses will also be performed on the Completer Set as described in Section 5.2.  
Missing values will be handled as explained in Section 7. 
All analyses will be performed overall as well as on the age stratum of patients who are 
12-16 years of age (with corresponding removal of age strata terms from analysis models).
PPD


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Subjects in this adolescent study will be considered smokers, regardless of the self reported 
smoking status, if the urine cotinine test is positive.
8.2.1. Baseline Demographics and Other Baseline Characteristics
Height, weight, BMI, and age at screening will be summarized as continuous measures as 
described in Section 8.1.1.1. Age group and race will be summarized as categorical 
measures as described in Section 8.1.2.1.  Smoking history information and the Fagerstrom 
Test for Nicotine Dependence will be summarized as described in Sections 8.1.1.1 and 
8.1.2.1.
These will be summarized for the following groups:

Overall study.

12-16 year old age stratum.

12-16 year old age stratum, ≤55 kg weight stratum.

12-16 year old age stratum, >55 kg weight stratum.

17-19 year old age stratum.
8.2.2. Compliance
Compliance will be calculated overall as well as by visit as described in Section 5.6.  
Compliance will be summarized by visit as well as overall.  Early termination visits will be 
windowed as indicated in Section 6.3.
These will be summarized for the following groups:

Overall study.

12-16 year old age stratum.

12-16 year old age stratum, ≤55 kg weight stratum.

12-16 year old age stratum, >55 kg weight stratum.

17-19 year old age stratum.
8.2.3. Primary Efficacy Analysis
The primary efficacy analysis will be analysis of the 4-week continuous abstinence rate 
(CAR) from Week 9 through Week 12 of treatment for each varenicline treatment group
compared with placebo.
The 4-week CAR will be summarized by treatment group using descriptive statistics and bar 
charts.  


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This will be summarized for the following groups:

Overall study.

12-16 year old age stratum.

12-16 year old age stratum, ≤55 kg weight stratum.

12-16 year old age stratum, >55 kg weight stratum.

17-19 year old age stratum.
The 4-week CAR will be analyzed using a logistic regression model as described in
Section 8.1.1.2.  Odds ratios and 95% confidence intervals will be shown in plots.
These will be analysed for the following groups:

Overall study.

12-16 year old age stratum (without age strata covariate).

12-16 year old age stratum, ≤55 kg weight stratum (without age strata or body weight 
strata covariates).

12-16 year old age stratum, >55 kg weight stratum (without age strata or body weight 
strata covariates).
While the analysis will be performed for sets listed above, the primary analysis of the 
primary efficacy endpoint is the overall study.
Statistical hypotheses for the primary endpoint will be tested in an ordered fashion to 
preserve overall Type I Error. The 1 mg BID group will be tested against placebo, and if a 
statistically significant difference is observed, the 0.5 mg BID group will be tested against 
placebo. A p-value of 0.05 will be considered statistically significant in both tests. Both tests 
will be presented regardless of the p-value obtained.
A sensitivity analysis excluding site 
 will be performed based on the primary analysis of 
the primary endpoint. This site was terminated based on concerns regarding GCP non-
compliance. 
As a sensitivity analysis of the primary endpoint, multiple imputation methods will be used 
to evaluate the impact of missing data.  Subjects who discontinue the study due to 
insufficient clinical response, adverse event, or death will be imputed based upon the 
observed placebo distribution, regardless of randomized treatment assignment.  Imputation 
will be based on age stratum, body weight stratum, pooled study center, and baseline number 
of cigarettes smoked.  Subjects who discontinue the study for other reasons, or who complete 
the study but have a missing Week 9-12 CAR, will be imputed based on observed subjects in 
the same treatment group.  Imputation will be based on treatment, age stratum, body weight 
stratum, pooled study center, and baseline number of cigarettes smoked.
PPD


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A final sensitivity analysis will be performed based on discontinuation from treatment, 
regardless of study completion status.  
8.2.4. Secondary Efficacy Analyses
8.2.4.1. The 7-day Point-prevalence of Smoking Abstinence at Weeks 12, 24, and 52
The 7-day point prevalence of abstinence will be summarized by treatment group and visit
from Week 3 through Week 52 using descriptive statistics and bar charts.
These will be summarized for the following groups:

Overall study.

12-16 year old age stratum.

12-16 year old age stratum, ≤55 kg weight stratum.

12-16 year old age stratum, >55 kg weight stratum.

17-19 year old age stratum.
The 7-day point prevalence of abstinence at Weeks 12, 24, and 52 will be analyzed using 
separate logistic regression models as described in Section 8.1.1.2. Odds ratios and 95% 
confidence intervals will be shown in plots.
These will be analysed for the following groups:

Overall study.

12-16 year old age stratum (without age strata covariate).

12-16 year old age stratum, ≤55 kg weight stratum (without age strata or body weight 
strata covariates).

12-16 year old age stratum, >55 kg weight stratum (without age strata or body weight 
strata covariates).
8.2.4.2. The Reduction in Number of Cigarettes Smoked at Weeks 12, 24, and 52
The reduction in the number of the cigarettes smoked will be calculated at each visit by 
subtracting the reported average number of cigarettes smoked per day in the past 7 days at 
each visit from the average number of cigarettes smoked per day in the past 7 days reported 
at the baseline visit.  
The reduction in the mean number of cigarettes smoked per day over the past 7 days will be 
summarized by treatment group and visit using descriptive statistics.  


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These will be summarized for the following groups:

Overall study.

12-16 year old age stratum.

12-16 year old age stratum, ≤55 kg weight stratum.

12-16 year old age stratum, >55 kg weight stratum.

17-19 year old age stratum.
The reduction in the mean number of cigarettes smoked per day will be analyzed using 
longitudinal repeated measures models as described in Section 8.1.2.2.  In addition to 
treatment and visit, baseline number of cigarettes smoked, pooled study center, age strata, 
and body weight strata will be included as covariates.  A treatment by visit interaction will be 
included for estimation purposes. Least square means and 95% confidence intervals will be 
shown in plots.
These will be analysed for the following groups:

Overall study.

12-16 year old age stratum (without age strata covariate).

12-16 year old age stratum, ≤55 kg weight stratum (without age strata or body weight 
strata covariates).

12-16 year old age stratum, >55 kg weight stratum (without age strata or body weight 
strata covariates).
8.2.4.3. The Continuous Abstinence Rate from Week 9 through Week 24 and Week 52
The continuous abstinence rate at a given time point will be defined as the proportion of 
subjects who remained abstinent from Week 9 through the time point being summarized.
The continuous abstinence rates from Week 9 through Week 24 and Week 9 through
Week 52 will be summarized by treatment group using descriptive statistics and bar charts.
These will be summarized for the following groups:

Overall study.

12-16 year old age stratum.

12-16 year old age stratum, ≤55 kg weight stratum.

12-16 year old age stratum, >55 kg weight stratum.


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
17-19 year old age stratum.
The continuous abstinence from Week 9 through Week 24 and from Week 9 through 
Week 52 endpoints will be analyzed using separate logistic regression models as described in
Section 8.1.1.2.  Odds ratios and 95% confidence intervals will be shown in plots.
These will be analysed for the following groups:

Overall study.

12-16 year old age stratum (without age strata covariate).

12-16 year old age stratum, ≤55 kg weight stratum (without age strata or body weight 
strata covariates).

12-16 year old age stratum, >55 kg weight stratum (without age strata or body weight 
strata covariates).
8.2.5. Additional Efficacy Analysis 
Subjects who reported using any non-study smoking cessation aids during the non-treatment 
follow-up period will be displayed in a table described in Section 8.1.1.1.  Additionally, this 
subset of concomitant medication use will be listed in a separate listing.
8.2.6. Safety Analysis
All subjects who received at least one dose of study medication will be included in the safety 
analyses and presentations. All safety data as described in Section 6.2 will be subjected to 
clinical review and summarized descriptively by treatment group as frequencies of events 
and mean changes from Baseline, as appropriate. 
These will be summarized for the following groups:

Overall study.

12-16 year old age stratum.

12-16 year old age stratum, ≤55 kg weight stratum.

12-16 year old age stratum, >55 kg weight stratum.

17-19 year old age stratum.
8.2.6.1. Adverse Events
The Neuropsychiatric Adverse Event Interview (NAEI) will actively inquire about the 
following type of adverse events: depression, anxiety, delusions, hallucinations, paranoia, 
psychosis, mania, panic, agitation, dissociative states, feeling abnormal, hostility, aggression 
and homicidal ideation.  If a subject has a positive response to any item on the NAEI, a 


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determination will be made by the investigator as to whether this meets criteria for an 
adverse event.  If it does meet criteria as an adverse event it will be recorded on the adverse 
event pages of the Case Report Form.  
All adverse events will be reported using the MedDRA dictionary. The incidence of 
treatment emergent AEs will be summarized by treatment group and system organ class, 
higher level group term, and preferred term.  Additionally, the incidence of treatment 
emergent Neuropsychiatric AEs (Appendix 1) and serious skin adverse events (Appendix 2), 
will be summarized by treatment group in separate tables.  
Adverse events will be reported according to Pfizer Data Standards (PDS) without 
consideration of reporting status (volunteered or solicited via the NAEI). Additionally, 
adverse events will be summarized including only volunteered events.  The lag period for 
this study will be set at 30 days.  
It should be recognized that most studies are not designed to reliably demonstrate a causal 
relationship between the use of a pharmaceutical product and an adverse event or a group of 
adverse events. Except for select events in unique situations, studies do not employ formal 
adjudication procedures for the purpose of event classification.
 
 
  
All adverse event summaries will be produced for the following groups:

Overall study 

12-16 year old age stratum

12-16 year old age stratum, ≤55 kg weight stratum

12-16 year old age stratum, >55 kg weight stratum

17-19 year old age stratum
8.2.6.2. Clinical Laboratory Measures
Laboratory abnormalities will be summarized by treatment group according to the following 
three baseline statuses: Normal Baseline, Abnormal Baseline, and Without Regard to 
Baseline.  Median change from baseline to final observed laboratory data will also be 
summarized by treatment group.  Shift tables from baseline to each assessment will be 
provided by treatment group.  
CCI
CCI
CCI


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These will be summarized for the following groups:

Overall study 

12-16 year old age stratum

12-16 year old age stratum, ≤55 kg weight stratum

12-16 year old age stratum, >55 kg weight stratum

17-19 year old age stratum
8.2.6.3. Vital Signs
Descriptive statistics will be presented by treatment group for pulse, systolic blood pressure, 
and diastolic blood pressure at baseline and each available visit. Multiple measurements 
repeated at a given visit will be summarized by the mean of the repeated values.  Median 
changes from baseline in blood pressure and pulse rate will also be presented.  Shift tables 
from baseline to each assessment will be provided by treatment group.  
These will be summarized for the following groups:

Overall study 

12-16 year old age stratum

12-16 year old age stratum, ≤55 kg weight stratum

12-16 year old age stratum, >55 kg weight stratum

17-19 year old age stratum
8.2.6.4. Height and Weight
As this is a study of adolescents who may still be growing, height will be measured at 
baseline and Week 12 (or end of treatment) in addition to weight.  Descriptive statistics will 
be presented by treatment group and for height, weight, and body mass index (BMI) at 
baseline and Week 12.  In addition, summary statistics for change from baseline to Week 12 
will be displayed for each measure.  Multiple measurements repeated at a given visit will be 
summarized by the mean of the repeated values.  
These will be summarized for the following groups:

Overall study 

12-16 year old age stratum

12-16 year old age stratum, ≤55 kg weight stratum


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
12-16 year old age stratum, >55 kg weight stratum

17-19 year old age stratum
8.2.6.5. Physical Examination
A physical examination including height and weight will be performed at screening visit by 
trained medical personnel.  Physical examination data will be included in a listing.
8.2.6.6. Suicide Behavior Questionnaire - Revised
The Suicidal Behaviors Questionnaire-Revised (SBQ-R), a brief self-report measure of past 
suicidal behavior, will be completed by subjects at the Screening visit.  SBQ-R data will be 
included in a listing.
8.2.6.7. Hospital Anxiety and Depression Scale
The Hospital Anxiety and Depression Scale (HADS) measures anxiety and depression in 
hospital and community settings and has also been validated in the adolescent outpatient 
population.  It is a patient completed questionnaire that establishes the presence and severity 
of both anxiety (7 questions) and depression (7 questions).
The baseline anxiety total score and depression total score as well as change from baseline at 
each visit will be summarized by treatment group as described in Section 8.1.2.1.  In addition 
the maximum increase in the anxiety total score and depression total score per subject while 
on treatment will be summarized by treatment group.  
Shift tables for HADs Depression subscore and HADS Anxiety Subscore will be produced 
by treatment and stratum, as well as overall. The shift will be from baseline to the worst 
score post-baseline. Both baseline and post-baseline will be categorized to 0-7, 8-10, and 
11+. The number and percent of patients who increased to a higher category will be 
tabulated as well.
If more than one question within a domain (anxiety or depression) is missing, the score will 
be set to missing.  If only one question is missing, the missing response will be imputed with 
the domain-specific mean based on the remaining questions.
These will be summarized for the following groups:

Overall study 

12-16 year old age stratum

12-16 year old age stratum, ≤55 kg weight stratum

12-16 year old age stratum, >55 kg weight stratum

17-19 year old age stratum


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8.2.6.8. Columbia Suicide Severity Rating Scale (C-SSRS)
The Columbia Suicide Severity Rating Scale (CSSR-S) is a set of suggested questions 
designed to elicit information about passive or active suicidal ideation, active suicidal intent, 
and self-injurious behavior.  
Frequency counts and percents for the C-CASA categories will be displayed in figures as 
well as tables for screening (Lifetime), baseline, treatment emergent, and follow up findings 
by treatment group.   Treatment emergent responses are those between the date of first dose 
of study medication and the date of last dose plus 30 days.  If last dose plus 30 days falls 
within the look back period for the ‘since the last visit’ administration of the C-SSRS, the 
responses are considered treatment emergent.  Follow Up is all responses more than 30 days 
after the date of last dose.  Listings will include both C-SSRS observed data as well as C-
CASA categories.
These will be summarized for the following groups:

Overall study 

12-16 year old age stratum

12-16 year old age stratum, ≤55 kg weight stratum

12-16 year old age stratum, >55 kg weight stratum

17-19 year old age stratum


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Appendix 1. Neuropsychiatric Adverse Events
Neuropsychiatric adverse events will be the MedDRA preferred terms included below. 
Anxiety:
HLT Name
PT Name
Adjustment disorders
Adjustment disorder with anxiety
Anxiety disorders NEC
Anxiety disorder
Anxiety disorder due to a general medical 
condition
Generalised anxiety disorder
Neurosis
Anxiety symptoms
Activation syndrome
Anticipatory anxiety
Anxiety
Nervousness
Stress
Tension
Fear symptoms and phobic disorders (incl 
social phobia)
Autophobia
Impulse control disorders
Impulse-control disorder
Impulsive behaviour
Pyromania
Trichotillomania
Obsessive-compulsive disorders and 
symptoms
Compulsions
Obsessive thoughts
Obsessive-compulsive disorder
Panic attacks and disorders
Limited symptom panic attack
Stress disorders
Acute stress disorder
Burnout syndrome
Post-traumatic stress disorder
Behaviour and socialisation disturbances
Impatience
Anxiety symptoms
Somatoform disorder cardiovascular
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Anxiety: 
HLT Name
PT Name
Fear symptoms and phobic disorders (incl 
social phobia)
Acrophobia
Agoraphobia
Animal phobia
Arachnophobia
Claustrophobia
Dysmorphophobia
Fear
Fear of animals
Fear of closed spaces
Fear of crowded places
Fear of death
Fear of disease
Fear of eating
Fear of falling
Fear of injection
Fear of open spaces
Fear of pregnancy
Fear of weight gain
Haphephobia
Hydrophobia
Noctiphobia
Nocturnal fear
Nosophobia
Ochlophobia
Osmophobia
Paruresis
Performance fear
Phagophobia
Phobia
Phobia of driving
Phobia of exams
Phobia of flying
Phobic avoidance
Phonophobia
Photaugiaphobia
Social fear
Social phobia
Thanatophobia


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Depression: 
HLT Name
PT Name
Adjustment disorders
Adjustment disorder with depressed mood
Adjustment disorder with mixed anxiety 
and depressed mood
Behaviour and socialisation disturbances
Asocial behaviour
Social avoidant behaviour
Depressive disorders
Agitated depression
Depression
Dysthymic disorder
Major depression
Menopausal depression
Postpartum depression
Mood alterations with depressive 
symptoms
Anhedonia
Decreased interest
Depressed mood
Depressive symptom
Feeling guilty
Feeling of despair
Feelings of worthlessness
Morose
Negative thoughts
Psychomotor retardation
Tearfulness
Mood disorders NEC
Apathy
Boredom
Laziness
Mood disorder due to a general medical 
condition
Seasonal affective disorder
Personality disorders NEC
Self esteem decreased
Abnormal behaviour NEC
Regressive behaviour
General signs and symptoms NEC
Crying


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Feeling Abnormal: 
HLT Name
PT Name
Abnormal behaviour NEC
Abnormal behavior
Mental disorders NEC
Mental disorder
Mental status changes
Dyslogia
Confusion and disorientation
Confusional state
Disorientation
Emotional and mood disturbances NEC
Emotional disorder
Emotional distress
Behaviour and socialisation disturbances
Personality change
Mental impairment (excl dementia and 
memory loss)
Mental impairment
Psychiatric symptoms NEC
Psychiatric symptom
Trance
Nervous system disorders NEC
Nervous system disorder
Feelings and sensations NEC
Feeling drunk
Feeling abnormal
Disability issues
Activities of daily living impaired
Impaired driving ability
Impaired work ability
Bedridden
Disability
General signs and symptoms NEC
Performance status decreased
Impaired self-care
Decreased physical activity levels
Catatonia
Dementia NEC
Pseudodementia
Dissociative states
Depersonalisation
Dissociation
Dissociative amnesia
Dissociative disorder
Dissociative fugue
Dissociative identity disorder
Perception disturbances
Derealisation
Parasomnias
Confusional arousal
Disturbances in consciousness NEC
Altered state of consciousness
Consciousness fluctuating
Emotional and mood disturbances NEC
Mood altered
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Feeling Abnormal: 
HLT Name
PT Name
Partial complex seizures
Dreamy state
Thinking disturbances
Bradyphrenia
Circumstantiality
Confabulation
Derailment
Ideas of reference
Illogical thinking
Impaired reasoning
Loose associations
Magical thinking
Morbid thoughts
Obsessive rumination
Perseveration
Poverty of thought content
Tachyphrenia
Tangentiality
Thinking abnormal
Thought blocking
Hostility:
HLT Name
PT Name
Behaviour and socialisation disturbances
Antisocial behaviour
Belligerence
Hostility
Impulse control disorders
Intermittent explosive disorder
Personality disorders with dramatic 
behaviour (Cluster B)
Psychopathic personality
Agitation:
HLT Name
PT Name
Anxiety symptoms
Agitation
Increased physical activity levels
Restlessness
Mental impairment (excl dementia and 
memory loss)
Disturbance in attention
Dyskinesias and movement disorders 
NEC
Hyperkinesia


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Aggression: 
HLT Name
PT Name
Criminal activity
Homicide
Incest
Physical abuse
Physical assault
Sexual abuse
Spousal abuse
Verbal abuse
Behaviour and socialisation disturbances
Aggression
Violence-related symptom
Personality disorders with dramatic 
behaviour (Cluster B)
Antisocial personality disorder
Emotional and mood disturbances NEC
Anger
Dysphoria
Delusions: 
HLT Name
PT Name
Delusional symptoms
Cotard's syndrome
Delusion
Delusion of grandeur
Delusion of reference
Delusion of replacement
Delusions, mixed
Depressive delusion
Erotomanic delusion
Jealous delusion
Persecutory delusion
Somatic delusion
Thought broadcasting
Thought insertion
Thought withdrawal
Delusional disorders
Alice in wonderland syndrome
Delusional disorder, erotomanic type
Delusional disorder, grandiose type
Delusional disorder, jealous type
Delusional disorder, mixed type
Delusional disorder, persecutory type
Delusional disorder, somatic type
Delusional disorder, unspecified type
Perception disturbances
Deja vu
Delusional perception
Jamais vu
Behaviour and socialisation disturbances
Grandiosity


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Hallucination: 
HLT Name
PT Name
Perception disturbances
Hallucination
Hallucination, auditory
Hallucination, gustatory
Hallucination, olfactory
Hallucination, synaesthetic
Hallucination, tactile
Hallucination, visual
Hallucinations, mixed
Illusion
Somatic hallucination
Narcolepsy and associated conditions
Hypnagogic hallucination
Hypnopompic hallucination
Mania: 
HLT Name
PT Name
Thinking disturbances
Flight of ideas
Mood alterations with manic symptoms
Hypomania
Mania
Emotional and mood disturbances NEC
Elevated mood
Euphoric mood
Personality disorders NEC
Self esteem inflated
Bipolar disorders
Bipolar disorder
Bipolar I disorder
Bipolar II disorder
Cyclothymic disorder
Affect alterations NEC
Affect lability
Behaviour and socialisation disturbances
Disinhibition
Fluctuating mood symptoms
Mood swings
Panic: 
HLT Name
PT Name
Panic attacks and disorders
Panic attack
Panic disorder
Panic disorder with agoraphobia
Panic disorder without agoraphobia
Panic reaction
Abnormal behaviour NEC
Breath holding


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Paranoia: 
HLT Name
PT Name
Behaviour and socialisation disturbances
Paranoia
Suspiciousness
Personality disorders with eccentric 
behaviour (Cluster A)
Paranoid personality disorder
Psychiatric symptoms NEC
Hypervigilance
Psychosis: 
HLT Name
PT Name
Affect alterations NEC
Flat affect
Inappropriate affect
Brief psychotic disorder
Brief psychotic disorder with marked 
stressors
Brief psychotic disorder without marked 
stressors
Transient psychosis
Psychotic disorder NEC
Acute psychosis
Hysterical psychosis
Psychotic behaviour
Psychotic disorder
Psychotic disorder due to a general 
medical condition
Reactive psychosis
Shared psychotic disorder
Schizoaffective and schizophreniform 
disorders
Schizoaffective disorder
Schizoaffective disorder bipolar type
Schizoaffective disorder depressive type
Schizophreniform disorder
Schizophrenia NEC
Schizophrenia
Schizophrenia simple
Schizophrenia, catatonic type
Schizophrenia, disorganised type
Schizophrenia, paranoid type
Schizophrenia, residual type
Schizophrenia, undifferentiated type
Personality disorders with eccentric 
behaviour (Cluster A)
Schizotypal personality disorder
Behaviour and socialisation disturbances
Negativism


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Homicidal Ideation: 
HLT Name
PT Name
Behaviour and socialisation disturbances
Homicidal ideation
Suicidal Behavior:
HLT Name
PT Name
Suicidal and self-injurious behaviour
Intentional self-injury
Self injurious behaviour
Suicidal behaviour
Suicide attempt
Suicidal Ideation:
HLT Name
PT Name
Suicidal and self-injurious behaviour
Self-injurious ideation
Suicidal ideation
Suicide:
HLT Name
PT Name
Suicidal and self-injurious behaviour
Completed suicide
Depressive disorders
Depression suicidal


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Appendix 2. Serious Skin Adverse Events
Serious skin adverse events will be the MedDRA preferred terms included below. 
Acute generalised exanthematous pustulosis 
Cutaneous vasculitis 
Dermatitis bullous 
Dermatitis exfoliative 
Dermatitis exfoliative generalised 
Drug reaction with eosinophilia and systemic symptoms
Epidermal necrosis 
Erythema multiforme 
Exfoliative rash 
Oculomucocutaneous syndrome
Skin necrosis 
Stevens-Johnson syndrome 
Toxic epidermal necrolysis 
Toxic skin eruption


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