Clinical trial NCT03541044
Conditions: Tobacco Use Disorder
Sponsor: GlaxoSmithKline
Start date: 2018-06-18; Completion date: 2019-03-24
Enrollment: 46 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study will assess the bioequivalence of the test product (Nicotine Prototype Mini lozenge 2 milligrams \[mg\]) to a commercial reference product (nicotine polacrilex mini lozenge 2 mg) in healthy smokers under fasting conditions.

Detailed description:
This study will be a single center, randomized, open label, single dose, two-way crossover in healthy smokers that smoke their first cigarette more than 30 minutes of waking. This study will consist of following Visits: Visit 1 (Screening), Visit 2 (Study Period 1), followed by a Washout period and Visit 3 (Study Period 2). Each participant will be treated with a single dose of the two study treatments (test and reference) in a randomized sequence. Participants will be confined in the study facility for approximately 60 hours during each study session (for 36 hours pre-dosing and for 24 hours post dosing) during which pharmacokinetic (PK) blood samples will be obtained. Participants are to abstain from smoking during the confinement periods and be subject to random measurements of expired carbon monoxide (CO) to confirm abstinence. The CO levels must be ≤10 parts per million (ppm) throughout the study session. There will be at least 5-day and not more than 7-day clinical furlough period between treatment periods. For each treatment period, the clinical confinement period with restriction of smoking is at least 36 hours prior to dosing.

Arms: arm 1: Participants will receive a single Nicotine Prototype Mini lozenge (2mg) by oral/buccal route of administration. arm 2: Participants will receive a single Nicorette Mini lozenge (2 mg) by oral/buccal route of administration.
Interventions: intervention 1: Nicotine Prototype Mini lozenge intervention 2: Nicorette Mini Lozenge
Intervention descriptions: intervention 1: A single dose of a prototype nicotine 2mg lozenge will be placed in participants mouth, occasionally moving it side to side. Allowing it to slowly dissolve and try to minimize swallowing. Participants will be instructed not to chew lozenge. The lozenge should be completely dissolved. intervention 2: A single dose of a 2 mg nicotine polacrilex mini lozenge (Nicorette Minis) will be placed in participants mouth, occasionally moving it side to side. Allowing it to slowly dissolve and try to minimize swallowing. Participants will be instructed not to chew lozenge. The lozenge should be completely dissolved.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
Clinical Protocol  
207791 
 
 
A Single Dose Bioequivalence Study of a 2 mg Prototype 
Mini Nicotine Lozenge vs 2 mg Nicotine Mini Lozenge 
(Nicorette Minis) in Healthy Smokers Under Fasting 
Conditions 
 
 
 
GlaxoSmithKline Consumer Healthcare  
GlaxoSmithKline Research & Development 
Limited 980 Great West Road Brentford 
Middlesex, TW8 9GS UK 
 
 
1. Protocol approval date: 16-May-2018 
2. Final Amendment to Protocol approval date: 10-Jan-2019 
 
 
 
 
Copyright: GlaxoSmithKline. This document contains confidentiality statements 
that are not relevant for this publicly available version 


Author(s) 
APPROVALS
Name
Reason for Approval
Approval Date CET*(MM/DD/YYYY)
1/8/2019 9:23:29 PM
1/9/2019 8:04:30 AM
1/10/2019 11:56:44 AM
Document Name 
Scope 
Document Type 
Document Subtype 
Document ID 
Version 
Approved Date in CET* 
Pages 
*CET: Central European Time
1.0
68
Protocol Amendment 2
0900c35381215f5c
Jan 10,2019  11:57:00 AM
207791-Protocol Amendment-Protocol Amendment 2
Protocol Amendment
Studies
003 Study protocol and Amendment
PPD
PPD
PPD
PPD


Nicotine Polacrilex
207791
Final Clinical Protocol Amendment #2
This document contains confidentiality statements
that are not relevant for this publicly available version.
Property of GSK Consumer Healthcare
Confidential
May not be used, divulged, published or otherwise disclosed 
without the consent of GSK
Template Version Effective: 22-Jun-2017
Page 1 of 67
Clinical Protocol 207791
A Single Dose Bioequivalence Study of a 2 mg Prototype Mini 
Nicotine Lozenge vs 2 mg Nicotine Mini Lozenge (Nicorette Minis) 
in Healthy Smokers under Fasting Conditions
Compound Name:  
Nicotine Polacrilex
United States (US) Investigational New 
Drug (IND) Number:
56,295
European Clinical Trials Database 
(EudraCT) Number:
N/A
Other Regulatory Agency Identified 
Number:
N/A
Protocol Number:
207791
Phase:
I


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Sponsor information
Sponsor Legal Registered Address
GlaxoSmithKline Research & Development 
Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Sponsor Contact Address
GlaxoSmithKline Consumer Healthcare (GSK CH)
184 Liberty Corner Rd, Warren NJ 07059
The contact information for the sponsor for the study 
is documented in the study contact list located in the 
supporting study documentation.


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Document History
Document
Version Date
Summary of Changes 
Protocol amendment 2
13-Dec-2018
- Changing Inclusion Criteria
increased upper range of BMI 
from 27 to 28 (criteria #5)
removed criteria of subjects 
smoking more than 30 minutes 
of waking (criteria #7)
Protocol amendment 1
26-Nov-2018
– Change in Principal Investigator
– Incorporate protocol 
administrative change letters 
(PACL) into protocol:
Use of samples for future 
research (PACL #1)
Clarification on the schedule of 
activities and study procedures 
(PACL #2)
Original protocol
16-May-2018
Not applicable (N/A)


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PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE

I confirm agreement to conduct the study in compliance with the protocol and any 
amendments and according to the current ICH GCP guidelines.

I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.

I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure site staff 
receives all appropriate information throughout the study.

I agree to conduct this study in full conformance with the laws and regulations of the 
country in which the research is conducted and the Declaration of Helsinki.
Investigator Name:
Robert Schwab
Investigator Qualifications:
M.D.
Investigator Signature:
Date of Signature/ Agreement:
DD/MMM/YYYY
PPD
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Table of contents
Sponsor information ............................................................................................................2
Document History................................................................................................................3
PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE ...............................4
Table of contents..................................................................................................................5
List of tables.........................................................................................................................9
PROTOCOL SUMMARY.................................................................................................10
SCHEDULE OF ACTIVITIES .........................................................................................14
1
INTRODUCTION .............................................................................................................18
1.1
Mechanism of Action/Indication ...........................................................................18
1.2
Background and Rationale.....................................................................................18
2
STUDY OBJECTIVES AND ENDPOINTS.....................................................................19
3
STUDY DESIGN AND SUBJECT POPULATION.........................................................19
4
SUBJECT SELECTION....................................................................................................20
4.1
Inclusion Criteria....................................................................................................21
4.2
Exclusion Criteria ..................................................................................................21
4.3
Randomization Criteria..........................................................................................24
4.4
Lifestyle Guidelines...............................................................................................24
4.4.1
Meals and Dietary Restrictions .............................................................24
4.4.2
Alcohol, Caffeine and Tobacco.............................................................25
4.4.3
Activity..................................................................................................25
4.4.4
Contraception ........................................................................................25
4.5
Screen Failures.......................................................................................................26
4.6
Sponsor’s Qualified Medical Personnel.................................................................26
5
STUDY TREATMENTS...................................................................................................27
5.1
Blinding and Allocation to Treatment/Randomization..........................................27
5.2
Breaking the Blind .................................................................................................28
5.3
Subject Compliance ...............................................................................................28
5.4
Investigational Product Supplies............................................................................28
5.4.1
Dosage Form and Packaging.................................................................28
5.4.2
Preparation and Dispensing...................................................................29
5.5
Administration .......................................................................................................29
5.5.1
Medication Errors..................................................................................29


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5.6
Investigational Product Storage .............................................................................30
5.7
Investigational Product Accountability..................................................................30
5.7.1
Destruction of Investigational Product Supplies...................................31
5.8
Concomitant Treatment(s) .....................................................................................31
5.9
Rescue Medication.................................................................................................31
6
STUDY PROCEDURES...................................................................................................32
6.1
Screening................................................................................................................32
6.2
Study Period...........................................................................................................33
6.2.1
Visit 2 (Day -2)......................................................................................33
6.2.2
Visit 2 (Day -1)......................................................................................33
6.2.3
Visit 2 (Day 0).......................................................................................34
6.2.4
Visit 2 (Day 1).......................................................................................34
6.2.5
Washout period......................................................................................35
6.2.6
Visit 3 (Day 3 to 5)................................................................................35
6.2.7
Visit 3 (Day 4 to 6)................................................................................35
6.2.8
Visit 3 (Day 5 to 7)................................................................................35
6.2.9
Visit 3 (Day 6 to 8)................................................................................36
6.3
Subject Withdrawal................................................................................................37
7
ASSESSMENTS................................................................................................................38
7.1
Efficacy..................................................................................................................38
7.2
Safety .....................................................................................................................38
7.2.1
Laboratory Tests....................................................................................39
7.2.2
Pregnancy Testing .................................................................................40
7.2.3
Physical Examinations...........................................................................40
7.2.4
Height and Weight.................................................................................40
7.2.5
Blood Pressure and Pulse Rate..............................................................41
7.2.6
Respiratory Rate....................................................................................41
7.2.7
Temperature...........................................................................................41
7.2.8
Electrocardiogram .................................................................................41
7.3
Pharmacokinetics (PK) ..........................................................................................42
7.3.1
PK samples and safety laboratory tests .................................................42
7.3.2
Shipment of Pharmacokinetic Samples.................................................43
7.4
Blood Volume........................................................................................................43
7.5
Expired Carbon Monoxide (CO) measurement .....................................................43
8
ADVERSE EVENT...........................................................................................................44


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8.1
Definitions of Adverse Events and Serious Adverse Events.................................44
8.1.1
Adverse Event .......................................................................................44
8.1.2
Serious Adverse Event ..........................................................................45
8.2
Reporting Period ....................................................................................................46
8.2.1
Adverse Event .......................................................................................46
8.2.2
Serious Adverse Event ..........................................................................46
8.3
Reporting Procedures.............................................................................................47
8.3.1
Adverse Event .......................................................................................47
8.3.2
Serious Adverse Event ..........................................................................48
8.3.3
Sponsor’s Reporting Requirements to Regulatory Authorities and 
Ethics Committees.................................................................................49
8.4
Evaluating Adverse Events and Serious Adverse Events......................................49
8.4.1
Severity Assessment..............................................................................49
8.4.2
Causality Assessment............................................................................49
8.5
Withdrawal Due to an Adverse Event and Serious Adverse Events......................50
8.6
Pregnancy...............................................................................................................50
8.6.1
Time Period for Collecting Pregnancy Information..............................50
8.6.2
Action to be Taken if Pregnancy Occurs...............................................50
8.7
Follow-up of Adverse Events and Serious Adverse Events ..................................51
9
DATA MANAGEMENT ..................................................................................................52
9.1
Source Documents/ Data........................................................................................52
9.2
Case Report Form ..................................................................................................52
9.3
Data Handling ........................................................................................................52
9.3.1
Queries...................................................................................................53
9.4
Processing Patient Reported Outcomes .................................................................53
9.5
External Data..........................................................................................................53
10 STATISTICAL CONSIDERATIONS AND DATA ANALYSES...................................54
10.1
Sample Size Determination....................................................................................54
10.2
Statistical Methods and Analytical Plan ................................................................54
10.2.1
Demographic and Baseline Characteristics...........................................54
10.2.2
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)...........................................................................54
10.2.3
Primary Analysis ...................................................................................55
10.2.4
Secondary Analysis ...............................................................................57
10.2.5
Safety Analysis......................................................................................57


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10.2.6
Other Analysis.......................................................................................58
10.2.7
Definition of Analysis Populations .......................................................58
10.2.8
Exclusion of Data from Analysis ..........................................................58
10.2.9
Handling of Dropouts and Missing Data...............................................58
10.2.10
Interim Analysis ....................................................................................59
11 STUDY GOVERNANCE CONSIDERATIONS..............................................................59
11.1
Quality Control ......................................................................................................59
11.2
Quality Assurance..................................................................................................60
11.3
Regulatory and Ethical Considerations..................................................................60
11.3.1
Institutional Review Board/ Ethics Committee.....................................60
11.3.2
Ethical Conduct of the Study.................................................................60
11.3.3
Subject Information and Consent..........................................................61
11.3.4
Subject Recruitment ..............................................................................61
11.3.5
Reporting of Safety Issues and Serious Breaches of the Protocol or 
ICH GCP ...............................................................................................62
11.4
Posting of Information on Publicly Available Clinical Trial Registers.................62
11.5
Provision of Study Results to Investigators...........................................................62
11.6
Records Retention..................................................................................................62
11.7
Conditions for Terminating the Study ...................................................................63
11.8
Definition of Study End/ End of Study..................................................................64
12 REFERENCES ..................................................................................................................64
13 APPENDIX........................................................................................................................64
13.1
ABBREVIATION..................................................................................................64


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List of tables
Table 1-1
Schedule of Activities............................................................................14
Table 2-1
Study Objectives and Endpoints............................................................19
Table 7-1
Laboratory Tests....................................................................................39
Table 13-1
Abbreviation..........................................................................................64


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PROTOCOL SUMMARY 
Background and Rationale:
Nicotine replacement therapy (NRT) has proven to be an effective aid to smoking cessation 
by reducing nicotine withdrawal symptoms associated with smoking cessation.  There are 
several oral NRT options available, in a range of formats and flavors to address customer 
preferences.
GlaxoSmithKline Consumer Healthcare (GSKCH) markets a nicotine mini lozenge (Nicorette 
Minis), which is a therapeutic equivalent to the larger lozenge (Nicorette), with the added 
benefit of quicker dissolution.  The current mini lozenge has a mint flavor. In order to offer 
the consumer with a mini lozenge with better tasting aesthetics, a new nicotine prototype  
mini lozenge has been developed.  To confirm that the new prototype mini lozenge delivers 
the same nicotine blood profile, a bioequivalence study will need to be performed comparing 
this new prototype mini lozenge to the currently marketed mini mint lozenge (Nicorette 
Minis), which have been identified as the appropriate Reference Standard (RLD).  This 
investigation will be conducted to confirm the bioequivalence of the 2 mg nicotine prototype 
mini lozenge to the 2 mg mini mint lozenge (Nicorette Minis).
Objectives and Endpoints
Primary objectives:

To assess the bioequivalence of the nicotine 2 mg prototype mini lozenge with the 
2 mg nicotine polacrilex mini lozenge (Nicorette), in terms of nicotine AUC0-t, AUC0-
inf and Cmax
Primary endpoints

AUC0-t --Area under the plasma concentration versus time curve from time zero to 
time t, where t is the time of the last measurable plasma concentration of nicotine, 
estimated.

AUC0-inf --Area under the plasma concentration versus time curve from time zero 
extrapolated to infinity.

Cmax --The highest observed plasma nicotine concentration.
Secondary objectives

To compare the nicotine 2 mg prototype mini lozenge to the 2 mg nicotine polacrilex 
mini mint lozenge (Nicorette Minis) in terms of tmax, t½, and Kel 

To evaluate the safety of the nicotine 2 mg prototype mini lozenge
Secondary endpoints

tmax, the time of the maximum plasma concentration


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
t1/2, the plasma half life

Kel, the elimination rate constant

Safety assessments consists of monitoring and recording adverse events (AEs) and 
clinical safety laboratory test
Study Design

This study will be a single center, randomized, open label, single dose, two-way 
crossover in healthy smokers.  

Each subject will be treated with a single dose of the two study treatments in a 
randomized sequence.

Subjects will be confined in the study facility for approximately 60 hours during each 
study session (for 36 hours pre dosing and for 24 hours post dosing) during which 
pharmacokinetic (PK) blood samples will be obtained.

Subjects are to abstain from smoking during the confinement periods and be subject to 
random measurements of expired carbon monoxide (CO) to confirm abstinence.  The 
CO levels must be  10 ppm throughout the study session.

There will be at least 5-day and not more than 7-day clinical furlough period between 
treatment periods. For each treatment period, the clinical confinement period with 
restriction of smoking is at least 36 hours prior to dosing. The reported plasma t1/2 for 
nicotine is approximately 1 to 4 hours from previous pharmacokinetics studies 
. The 36 hour smoking restriction period prior to dosing will therefore 
minimize the residual nicotine amount from smoking during previous furlough.
Type and Planned Number of Subjects
Enough healthy adult smokers will be screened to randomize forty (40) healthy adult smokers, 
to ensure that thirty-two (32) complete the entire study assuming a 20% dropout and non-
evaluable rate. The highest intra-subject CV observed in previous studies was 23%. The 
protocols that were used to select the highest CV for the sample size calculation are: 
 
 
 
 
and S6491365 (2mg nicotine polacrilex mini cherry lozenge v.s 
2mg nicotine polacrilex mini mint lozenge: Cmax =13.7%; AUC0-t =10%). A total of thirty-two 
(32) evaluable subjects will achieve a 90% power at 5% significance level. The true ratio that 
was used in the sample size calculation was 1.05. 
CCI
CCI


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Product Information
Test Product
Reference Product
Product Name
Nicotine Prototype Mini lozenge 2 mg
Nicorette Mini Lozenge 2 mg
Product 
Formulation Code 
(MFC)
Commercially Available
Dose
2 mg
2 mg
Route of 
Administration
Oral/Buccal
Oral/Buccal
Dosing Instructions
Place one lozenge in mouth, 
occasionally moving it side to side. 
Allow it to slowly dissolve and try to 
minimize swallowing.  Do not chew 
lozenge.  The lozenge should be 
completely dissolved.
Place one lozenge in mouth, 
occasionally moving it side to side. 
Allow it to slowly dissolve and try 
to minimize swallowing.  Do not 
chew lozenge. The lozenge should 
be completely dissolved
Statistical Methods
The PK analysis set, PKAS1 will be used for the PK evaluations. PKAS1 is defined as all 
randomized subjects who completed both periods, and who had no major protocol deviations 
concerning pharmacokinetics. Subjects with baseline nicotine concentration >5% of the 
individual Cmax for either period will be excluded from the PK population.
The PK parameters that will be used in the primary analyses are AUC0-t, AUC0-inf and Cmax.
The null and alternative hypotheses to be tested in the primary analyses are:
H0: The (geometric) mean AUC0-t (likewise AUC0-inf  and Cmax) of nicotine prototype mini 
lozenge 2mg (Test) is less than 80% or greater than 125% of that of Nicorette Mini Lozenge 
2mg (Reference).
H1: The (geometric) mean AUC0-t (likewise AUC0-inf and Cmax) of nicotine prototype mini 
lozenge 2mg (Test) is between 80% and 125% of that of Nicorette Mini Lozenge 2mg 
(Reference).
A linear mixed effects model will be fit to the log-transformed PK variables (AUC0-t, AUC0-inf 
,and Cmax), as the dependent variable, and treatment, and period as fixed effects. Subject 
nested within sequence will be a random effect. Least squares estimates of treatment effects 
CCI
CCI


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will be calculated and a 90% confidence interval (CI) for the treatment difference will be 
computed. The treatment difference and its CI will be exponentiated to obtain the ratio of the 
geometric means between the test and reference products and its CI.
Bioequivalence between the test and reference treatments will be concluded if the 90% 
confidence interval for the ratio of the means for each of the PK parameters AUC0-t, AUC0-inf, 
and Cmax of the nicotine profiles lie entirely within the interval 0.8 to 1.25.


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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to conduct 
evaluations or assessments required to protect the well-being of the subject.
Table 1-1
Schedule of Activities
Screening
Study Period 1
Washout
Study Period 2
Procedure/
Assessment
Visit 1
Days -21 to 
-2
Visit 2
Checkin
(Day -2)
Visit 2
Baseline
(Day -1)
Visit 2
Treatment 
Phase 
(Day 0)
Visit 2 
Treatment 
Phase
(Day 1)
Washout 
Periodb
Visit 3
Checkin
(Day 3 to 
5)
Visit 3
Baseline 
(Day 4 
to 6)
Visit 3
Treatment 
Phase 
(Day 5 to 
7)
Visit 3 
Treatment 
Phase (Day 
6 to 8)
Informed consent
X
Inclusion/Exclusion 
criteriac
X
X
X
Medical history 
X
X
X
Demographics 
X
Physical examination – 
full
X
Xd
Physical examination - 
brief
X
Xj
Xj
X
Xj
Xj


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Screening
Study Period 1
Washout
Study Period 2
Procedure/
Assessment
Visit 1
Days -21 to 
-2
Visit 2
Checkin
(Day -2)
Visit 2
Baseline
(Day -1)
Visit 2
Treatment 
Phase 
(Day 0)
Visit 2 
Treatment 
Phase
(Day 1)
Washout 
Periodb
Visit 3
Checkin
(Day 3 to 
5)
Visit 3
Baseline 
(Day 4 
to 6)
Visit 3
Treatment 
Phase 
(Day 5 to 
7)
Visit 3 
Treatment 
Phase (Day 
6 to 8)
Fagerstrom Test for 
nicotine dependence
X
Smoking history
X
Clinical laboratory tests
X
Xd
Urine drug testf
X
X
X
Urine alcohol testf
X
X
X
Urinalysisg
X
Xd
Serum pregnancy teste
X
X
X
Contraception reviewe
X
X
X
ECG (12-lead)
X
Vital signs 
BP, respiratory rate, PR, 
oral body temperature
X
X
X
X
X
Subject check-in for 
baseline & treatment
X
X
Expired CO 
measurements
Xh
Xh
Xh
Xh
Xh
Xh
Random expired CO 
measurements
4x 
randomly
4x 
randomly
Meals
X
X
X
X
X
X
X
X


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Screening
Study Period 1
Washout
Study Period 2
Procedure/
Assessment
Visit 1
Days -21 to 
-2
Visit 2
Checkin
(Day -2)
Visit 2
Baseline
(Day -1)
Visit 2
Treatment 
Phase 
(Day 0)
Visit 2 
Treatment 
Phase
(Day 1)
Washout 
Periodb
Visit 3
Checkin
(Day 3 to 
5)
Visit 3
Baseline 
(Day 4 
to 6)
Visit 3
Treatment 
Phase 
(Day 5 to 
7)
Visit 3 
Treatment 
Phase (Day 
6 to 8)
Randomization
X
PK blood drawi
X
X
X
X
Study treatment 
administration
X
X
Concomitant 
Treatments
X
→
→
→
→
→
→
→
→
Adverse Eventsa
X
→
→
→
→
→
→
→
→
Study conclusion
X
Abbreviations:  → = ongoing/continuous event; ECG = electrocardiogram; BP = blood pressure; PR = pulse rate.
a Any serious and non serious adverse event assessed as related to study participation that occurs subsequent to the signing of informed 
consent will be recorded.
bWashout period must be at least 5 days to a maximum of 7 days, after first dose. Subjects will be allowed to smoke ad libitum during 
this period.
cConfirm subject meets inclusion/exclusion criteria at screening and at baseline visits.
dAfter final blood sample is taken
eSerum pregnancy test and contraception review at each visit.
fUrine drug and alcohol screens at baseline: results will be available prior to dosing.
gUrinalysis Dipstick measurements for pH, specific gravity, protein, glucose, blood, ketones, nitrates, leukocyte esterases, urobilinogen, 
urine bilirubin.


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hBreath CO measurement taken at Baseline, immediately prior to randomization in Period 1 and immediately prior to dosing in Period 2 
and immediately after the last PK sample in each period.
iPK blood samples will be collected at -45, -30, -15 (pre-dose), and at 5, 10, 20, 30, 40, 50, 60, 75 and 90 minutes and 2, 3, 4, 6, 8 10, 14, 
16, 20 and 24 hours (post-dose).
jBrief physical examination will focused on subject reported symptoms of adverse events, if reported


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1
INTRODUCTION
1.1
Mechanism of Action/Indication
Nicotine lozenges are indicated as an aid to smoking cessation, of tobacco dependence 
through the relief of nicotine withdrawal symptoms, including nicotine cravings in smokers.
1.2
Background and Rationale
Nicotine replacement therapy (NRT) has proven to be an effective aid to smoking cessation 
by reducing nicotine withdrawal symptoms associated with smoking cessation.  Various 
dosage forms of NRT are available, including nicotine gum, nicotine transdermal system, 
nicotine inhaler, nicotine nasal spray, nicotine sublingual tablet and nicotine lozenge.  
Variable patterns, quantities and rates of nicotine are delivered by these formulations.  One of 
the most widely used presentations is the oral administration of nicotine polacrilex, either in 
the form of a chewing gum or lozenge.  
Although effective and well tolerated the standard nicotine lozenge (Nicorette Lozenge) is 
considered by some users to be rather large and to have some unpleasant organoleptic 
properties.
The prototype mini lozenge has been developed which is smaller in size and thus more 
discrete to use as well as having improved organoleptic properties.  Nicotine is released upon 
dissolution of the lozenge in the oral cavity.  
The purpose of this study is to assess the bioequivalence of the prototype mini lozenge to the 
reference product nicotine polacrilex mini lozenge (Nicorette Minis). 
Complete information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the IB. 
The SRSD for the comparative agent is the Drug Facts Label.


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2
STUDY OBJECTIVES AND ENDPOINTS
Table 2-1
Study Objectives and Endpoints
Objectives
Endpoints
Primary

To assess the bioequivalence of the 
nicotine 2 mg prototype mini lozenge 
with the 2 mg nicotine polacrilex mini 
lozenge (Nicorette Minis), in terms of 
nicotine AUC0-t, AUC0-inf , and Cmax.
AUC0-t – Area under the plasma 
concentration versus time curve from 
time zero to time t, where t is the time of 
the last measurable plasma concentration 
of nicotine, estimated.
AUC0-inf – Area under the plasma 
concentration versus time curve from 
time zero extrapolated to infinity
Cmax – The highest observed plasma 
nicotine concentration
Secondary
PK

To compare the nicotine 2 mg 
prototype mini lozenge to the 2 mg 
nicotine polacrilex mini lozenge 
(Nicorette Minis) in terms of tmax, t½, 
and Kel
tmax – time to maximum plasma 
concentration (Cmax)
t1/2 – plasma half-life
Kel – apparent elimination rate constant 
for plasma nicotine
Safety

To evaluate the safety of the nicotine 
2 mg prototype mini lozenge.
Safety assessments consists of 
monitoring and recording adverse events 
(AEs) and clinical safety laboratory test
This study will be considered successful if bioequivalence between the test and reference 
treatments conclude that the 90% confidence intervals for the ratio of the means of the 
primary pharmacokinetic parameters AUC0-t and AUC0-inf and Cmax of the nicotine profiles lie 
completely within the range 0.8-1.25.
3
STUDY DESIGN AND SUBJECT POPULATION

This study will be a single center, randomized, open label, single dose, two-way 
crossover in healthy smokers.  


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
Enough healthy adult smokers will be screened to randomize at least 40 subjects to 
ensure 32 evaluable subjects complete the entire study. This will ensure approximately 
32 evaluable subjects per treatment arm.

Each subject will be treated with a single dose of the two study treatments in a 
randomized sequence, under fasting conditions.

Subjects will be confined in the study facility for approximately 60 hours during each 
study session (for 36 hours pre dosing and for 24 hours post dosing) during which 
pharmacokinetic (PK) blood samples will be obtained.

Subjects are to abstain from smoking during the confinement periods and be subject to 
random measurements of expired carbon monoxide (CO) to confirm abstinence.  The 
CO levels must be  10 ppm throughout the study session.

There will be at least 5-day and not more than 7-day clinical furlough period between 
treatment periods. For each treatment period, the clinical confinement period with 
restriction of smoking is at least 36 hours prior to dosing. The reported plasma t1/2 for 
nicotine is approximately 1 to 4 hours in a heterogeneous population such as the US. 
The 36 hour smoking restriction period prior to dosing will therefore minimize the 
residual nicotine amount from smoking during previous furlough.

Rationale for study design:  This will be an open label study.  Blinding is not 
considered essential as study measurements (blood nicotine concentrations) are 
biological.  A crossover design, using the same subjects to test each product, will be 
used to reduce variability.  

The blood sampling times have been chosen based on the information available 
particularly on nicotine absorption, as well as its elimination.

Smokers have been chosen as the population for this study as they are the population 
that the investigational product would target, if marketed.

Dose justification: This is a study to assess the bioequivalence of the test product to a 
commercial reference product.
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 participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.  


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4.1
Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study.
Subject must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Evidence of a personally signed and dated informed consent document indicating that the 
subject has been informed of all pertinent aspects of the study before any assessment is 
performed.
2. Male and female subjects who, at the time of screening, are between the ages of 19 and 
55 years, inclusive.
3. Subjects who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
4. Healthy subjects which is defined as in general good physical health, as judged by the 
investigator and no clinically relevant abnormalities identified by a detailed medical 
history, full physical examination, including blood pressure, respiratory rate, oral body 
temperature and pulse rate measurement, 12-lead ECG or clinical laboratory tests. 
5. Body Mass Index (BMI) of 19 to 28 kg/m2, inclusive; and a total body weight >50 kg 
(110 lbs).
6. Female subjects of childbearing potential and at risk for pregnancy must agree to use a 
highly effective method of contraception throughout the study and for at least 5 days after 
the last dose of assigned treatment.  Female subjects who are not of childbearing potential 
must meet requirements in Section 4.4.4.
7. Subject admits to having smoked commercially-available cigarettes daily for the 
preceding 12 months. Brief periods of non-smoking (e.g., due to illness, trying to quit, 
participation in a study where smoking was prohibited) during that time will be permitted 
at the discretion of the PI.
4.2
Exclusion Criteria
Subject with any of the following characteristics/conditions will not be included in the study:
1. Subjects who are investigational site staff members directly involved in the conduct of the 
study and their family members, site staff members otherwise supervised by the 
investigator, or subjects who are GSK employees directly involved in the conduct of the 
study.
2. Participation in other studies involving investigational drug(s) within 30 days prior to first 
dose and during study participation.
3. Acute or chronic medical or psychiatric condition or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 


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judgment of the investigator, would make the subject inappropriate for entry into this 
study.
4. Pregnant female subjects.
5. Breastfeeding female subjects.
6. Known or suspected intolerance or hypersensitivity to the study materials (or closely 
related compounds) or any of their stated ingredients.
7. Unwilling or unable to comply with the Lifestyle guidelines described in this protocol. 
8. Subject has used any nicotine replacement therapy within 21 days prior to the first study 
session.
9. Subject has used chewing tobacco, tobacco products or electronic cigarettes other than 
cigarettes within 21 days of Visit 1.
10. Use of prescription or non-prescription drugs and dietary supplements within two weeks 
or 5 half-lives, whichever is longer, prior to the first dose of investigational product until 
the end of the study. 
Allowed treatments are:

systemic contraceptives and hormone replacement therapy, as long as female 
subject is on stable treatment for at least 3 months and continues treatment 
throughout the study.
11. Evidence or history of clinically significant laboratory abnormality, hematological, renal, 
endocrine, pulmonary, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease 
within the last 5 years that may increase the risk associated with study participation.
12. History of regular alcohol consumption exceeding 14 drinks/week (1 drink = 5 ounces 
(150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor) 
within 6 months of Screening.
13. A positive urine drug screen for THC, amphetamine, cocaine, 3,4-methylenedioxy-N-
methylamphetamine (MDMA)/ecstasy, methamphetamine, or opiates; and urine alcohol 
testing during screening or baseline testing.
14. Subject is unwilling to abstain from tobacco or nicotine-containing product use during 
each study session (from start of baseline to the completion of the last PK blood 
sampling).  CO measurement immediately prior to randomization (first treatment session) 
and dosing (second treatment session) should be ≤ 10 parts per million (ppm) for the 
subject to be dosed.
15. Subject ingests more than 5 cups of coffee or tea a day (or equivalent xanthine 
consumption using other products).
16. Treatment with an investigational drug within 30 days (or as determined by the local 
requirement) or 5 half-lives preceding the first dose of investigational product (whichever 
is longer). 
17. A medical history that, in the opinion of the investigator, might jeopardize the safety of 
the subject, e.g., recent myocardial infarction or cerebrovascular accident (i.e., within 


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12 weeks prior to the first study session), severe cardiac arrhythmia, history of seizures, 
orthostatic hypotension, cardiovascular disease, stroke, or TIA.
18. A medical history, which, in the opinion of the investigator, might impact the validity of 
the study results, may require treatment, or make the subject unlikely to finish the study.
19. Oral surgery within 4 weeks of dosing, dental work or extractions within 2 weeks of 
dosing, or presence of any clinically significant (as determined by the principal 
investigator or designee) oral pathology including lesions, sores or inflammation.
20. Diagnosis of long QT syndrome or QTc > 460 msec for males and > 470 msec for females 
at screening.
21. Any surgical or medical condition which may significantly alter the absorption, 
distribution, metabolism or excretion of any drug substance including, but not limited to, 
any of the following:
i)
Presence of active oesophagitis, oral or pharyngeal ulceration, inflammation, 
gastritis, gastric ulcer or peptic ulcer or other diseases;
ii)
Presence of gum disease, xerostomia, dentures or any dental work that could 
affect the conduct of the study as determined by the investigator or designee;
iii)
Renal disease or impaired renal function at screening as indicated by abnormal 
levels of serum creatinine or urea or the presence of clinically significant 
abnormal urinary constituents (e.g. albuminuria).  Minor deviations of 
laboratory values from the normal range are permitted, if judged by the 
investigator to have no clinical relevance;
iv)
Ongoing hepatic disease or impaired hepatic function at screening. A candidate 
will be excluded if more than one of the following lab value deviations are 
found and are clinically relevant: AST/SGOT, ALT/SGPT, γGGT, alkaline 
phosphatase, bilirubin or CK.  Minor deviations of laboratory values from the 
normal range are permitted, if judged by the investigator to have no clinical 
relevance;
v)
History or clinical evidence at screening of pancreatic injury or pancreatitis;
vi)
Evidence of urinary obstruction or difficulty in voiding at screening; 
vii)
History of malignancy or neoplastic disease of any organ system (except for 
localized basal cell skin carcinoma), treated or untreated, within the past 5 years 
prior to screening, regardless of whether there is evidence of local recurrence or 
metastases.
viii) Clinically relevant chronic or acute infectious illnesses or febrile infections 
within 2 weeks prior to start of the study (enrollment).
ix)
Other clinically significant laboratory findings in the opinion of the Investigator 
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22. A positive serum Hepatitis B surface antigen, Hepatitis C antibodies, or human 
immunodeficiency virus (HIV) test result.
23. Blood
i)
Has donated or experienced significant blood loss (470 mL) within 56 days of 
Visit 1.
ii) Hemoglobin value < 12.0 g/dL. 
24. Subjects who have previously been enrolled in this study. 
4.3
Randomization Criteria
Subjects will be randomized into the study provided they have satisfied all subject selection 
criteria. 
4.4
Lifestyle Guidelines
4.4.1
Meals and Dietary Restrictions

Subjects must abstain from all food and drink (except water) at least 4 hours prior 
to any safety laboratory evaluations and 10 hours prior to the collection of the 
pre-dose pharmacokinetic sample.  Water is permitted until 1 hour prior to 
investigational product administration.  

Non-carbonated water may be consumed without restriction beginning 1 hour after 
dosing.  Non-caffeinated drinks (except grapefruit or grapefruit-related citrus fruit 
juices – see below) may be consumed with meals and the evening snack.

Lunch will be provided approximately 4 hours after dosing.

Dinner will be provided approximately 12 hours after dosing.

An evening snack may be permitted approximately 2 hours after evening meal.

Subjects will not be allowed to eat or drink grapefruit or grapefruit-related citrus 
fruits (e.g., Seville oranges, pomelos, papaw, dragon fruit, kiwi fruit, mango, 
passion fruit, pomegranate, rambutan, star fruit or products that contain these fruits) 
from 14 days prior to the first dose of investigational product until collection of the 
final pharmacokinetic blood sample. 

Boiled sweets will be allowed during the study as needed up to 4 hours prior to 
investigational product administration. This will not be included in the total daily 
caloric intake for the subjects.

While confined, the total daily nutritional composition should be approximately 
55% carbohydrate, 30% fat and 15% protein.  The daily caloric intake per subject 
should not exceed approximately 3200 kcal. 


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4.4.2
Alcohol, Caffeine and Tobacco 

Subjects will abstain from alcohol for 24 hours prior to admission to the clinical site 
and continue abstaining from alcohol until collection of the final pharmacokinetic 
sample of each study period.  Subjects may undergo a urine alcohol test or blood 
alcohol test at the discretion of the investigator.

Subjects will abstain from caffeine-containing products for 36 hours prior to the start 
of dosing until collection of the final pharmacokinetic sample of each study period. 

Subjects will abstain from the use of tobacco- or nicotine-containing products for 
36 hours prior to dosing and during confinement at the clinical site. 
4.4.3
Activity

Subjects will abstain from strenuous exercise (e.g., heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests and throughout the entire study.  Walking at a normal pace will be 
permitted.
4.4.4
Contraception
All female subjects who are of childbearing potential and are sexually active and at risk for 
pregnancy must agree to use a highly effective method of contraception consistently and 
correctly for the duration of the active study period and for at least 5 days after the last dose of 
investigational product.  The investigator or his or her designee, in consultation with the 
subject, will confirm that the subject has selected an appropriate method of contraception for 
the individual subject from the permitted list of contraception methods (see below) and 
instruct the subject in its consistent and correct use.  Subjects need to affirm that they meet the 
criteria for the correct use of at least 1 of the selected methods of contraception.  The 
investigator or his or her designee will discuss with the subject the need to use highly 
effective contraception consistently and correctly according to the schedule of activities and 
document such conversation in the subject’s chart.  In addition, the investigator or his or her 
designee will instruct the subject to call immediately if the selected contraception method is 
discontinued.
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (i.e., perfect use) 
and include the following:
1. Established use of oral, inserted, injected, transdermal, or implanted hormonal methods of 
contraception is allowed provided the subject plans to remain on the same treatment 
throughout the entire study and has been using that hormonal contraceptive for an 
adequate period of time to ensure effectiveness as deemed appropriate by the investigator.
2. Copper-containing intrauterine device (IUD). 
3. Male condom or female condom used WITH a spermicide (i.e., foam, gel, film, cream, or 
suppository).  For countries where spermicide is not available or condom plus spermicide 
is not accepted as highly effective contraception, this option is not appropriate.


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4. Male sterilization with absence of sperm in the post-vasectomy ejaculate.
5. Bilateral tubal ligation / bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
6. Female who meets the criteria for non-childbearing potential as described below.  
Female subjects of non-childbearing potential must meet at least one of the following 
criteria:
a.
Achieved postmenopausal status, defined as follows: cessation of regular 
menses for at least 12 consecutive months with no alternative pathological or 
physiological cause; and have a serum follicle-stimulating hormone (FSH) 
level confirming the post-menopausal state;  
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy.
All other female subjects (including females with tubal ligations) will be considered to be of 
childbearing potential.
4.5
Screen Failures
Screen failures are defined as subjects who consent to participate in the clinical study but are 
not subsequently randomized. In order to ensure transparent reporting of screen failure 
subjects, a minimal set of screen failure information will include demography, screen failure 
details (e.g., withdrawal of consent), eligibility criteria, and any serious adverse events. 
Individuals who do not meet the criteria for participation in this study (screen failure) may not 
be re-screened.
4.6
Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical/dental personnel for 
the study is documented in the study contact list located in the supporting study 
documentation.
The contact number can be used by investigational staff if they are seeking advice on 
medical/dental questions or problems; however, it should be used only in the event that the 
established communication pathways between the investigational site and the study team are 
not available.  It is therefore intended to augment, but not replace, the established 
communication pathways between the investigational site and the study team for advice on 
medical/dental questions or problems that may arise during the study.  The contact number is 
not intended for use by the subject directly, and if a subject calls that number, he or she will 
be directed back to the investigational site.
To facilitate access to appropriately qualified medical/dental personnel on study-related 
medical/dental questions or problems, subjects are provided with a contact card.  The contact 
card contains, at a minimum, protocol identifiers, subject study numbers, contact information 
for the investigational site, and contact details in the event that the investigational site staff 


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cannot be reached to provide advice on a medical question or problem identified from the 
subject’s healthcare professional other than the investigator.  
5
STUDY TREATMENTS
This is a study to assess the bioequivalence of the test product to a commercially available 
reference product. The details are as follows:
Test Product 1
Reference Product 1
Product Name 
Nicotine Prototype Mini 
lozenge 2 mg
Nicorette Mini Lozenge 2 mg
Dose
2 mg (1 lozenge)
2 mg (1 lozenge)
Product 
Formulation 
Code (MFC)
Commercially Available
Route of 
Administration
Oral/Buccal
Oral/Buccal
Dosing 
Instructions
Place one lozenge in mouth, 
occasionally moving it side 
to side. Allow it to slowly 
dissolve and try to minimize 
swallowing.  Do not chew 
lozenge. The lozenge should 
be completely dissolved
Place one lozenge in mouth, 
occasionally moving it side to 
side. Allow it to slowly 
dissolve and try to minimize 
swallowing.  Do not chew 
lozenge. The lozenge should 
be completely dissolved
For the purposes of this study, and per International Conference on Harmonization (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active ingredient 
or placebo being tested or used as a reference in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use (ICH E6 1.33).
5.1
Blinding and Allocation to Treatment/Randomization
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular subject or affect the order in which subjects are enrolled.
Celerion will provide a randomization schedule to the investigator and, in accordance with the 
randomization numbers, the subject will receive the study treatment regimen assigned to the 
corresponding randomization number.  
CCI
CCI


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Treatments will be provided in an open-label manner. However, the analytical laboratory will 
remain blinded to treatment during the analysis of the plasma samples.
5.2
Breaking the Blind
Not applicable given the open label study design.
5.3
Subject Compliance
Subject will not smoke or use any tobacco or nicotine containing products 36 hours prior to 
dosing and for the duration of the confinement period. Compliance will be monitored with 
expired carbon monoxide (CO) measurements.
Using a calibrated Bedfont Smokerlyzer®, the investigator or designee will perform three (3) 
scheduled CO measurements, one upon check-in at Baseline, one immediately before 
randomization (first treatment session) or dose administration (second treatment session), and 
another immediately after the last PK sample has been collected at each study session.  
Additionally, the investigator or designee will conduct at least four (4) random CO 
measurements during each treatment session to verify smoking abstinence.  The timing of the 
random CO measurements will be decided by the investigator or designee. See Section 7.5 
Expired Carbon Monoxide (CO) measurement for assessment of subject’s CO values. All 
values, including time of measurement will be recorded in the CRF.
Study treatment will be administered under the supervision of investigator site personnel.
5.4
Investigational Product Supplies
5.4.1
Dosage Form and Packaging
Study lozenges described as test and reference study product will be provided to the study site 
in specific quantity primary packed vials placed into secondary packaging. The secondary 
packaging will be tamper proof sealed. Each secondary package will contain a common count 
of primary packaged units. The site will randomly select the required secondary packages to 
run the study with and retain the remaining secondary units as retains per FDA guidelines.
Each primary and secondary package of study medication tablets will contain a study label. 
The study label will be in accordance with all applicable regulatory requirements and will be 
the responsibility of the GSKCH Clinical Supplies Department.
The primary package study labels will include, but not limited to the following information: 
the protocol number, product name, contents and batch number.
® Smokerlyzer is a registered trademark of Bedfont Scientific Ltd..


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The Secondary package labels will include, but not limited to the following information: the 
protocol number, product name, contents, storage/handling conditions and the appropriate 
regulatory precautionary information, study site name and phone # and the sponsor name.
Packaging and labeling of all study products will be carried out according to cGMP guidelines 
and will be the responsibility of the Clinical Supply Department, GSKCH, Lincoln, NE, USA.
Care should be taken with the supplied products and their labels so that they are maintained in 
good condition.  It is important that all labels remain intact and legible for the duration of the 
study. The study labels are not to be removed or defaced.
5.4.2
Preparation and Dispensing 
The study products will be prepared and/or dispensed by qualified unblinded site personnel 
according to the dosage and administration instruction. 
5.5
Administration
Following an overnight fast of least 10 hours, subjects will receive investigational product at 
approximately 0800 hours (plus or minus 2 hours). 
Subjects will keep the lozenge in their mouth, occasionally moving it side to side, allowing it 
to slowly dissolve completely, and try to minimize swallowing.
Subject will not chew the lozenge.
In order to standardize the conditions on pharmacokinetic sampling days, all subjects will be 
required to refrain from lying down (except when required for blood pressure, pulse rate, and 
ECG measurements), eating, and drinking beverages, with the exception of water, for the first 
4 hours after dosing. Water may be given after one hour post-dosing. 
5.5.1
Medication Errors
Medication errors may result, in this study, from the administration or consumption of: 

the wrong product,

by the wrong subject, 

at the wrong time, 

or at the wrong dosage strength (other examples of concern may be added based on 
the investigational product administration, such as inadvertent exposure).  
Such medication errors occurring to a study participant are to be captured in the CRF.  In the 
event of medication dosing error, the sponsor should be notified immediately.


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Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving subject exposure to the investigational product;

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 a 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.
5.6
Investigational Product Storage 
The investigator, or an approved representative, e.g., pharmacist, will ensure that all 
investigational products, including the comparator are stored in a secured area with controlled 
access under required storage conditions and in accordance with applicable regulatory 
requirements and product label.  
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should be 
captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure that ensures active daily evaluation for 
excursions should be available.  The operation of the temperature-monitoring device and 
storage unit (for example, refrigerator), as applicable, should be regularly inspected to ensure 
it is maintained in working order. 
Any excursions from the product-label storage conditions should be reported upon discovery.  
The site should actively pursue options for returning the product to the storage conditions as 
described in the labeling, as soon as possible.  Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the Sponsor.  
Once an excursion is identified, the investigational product must be quarantined and not used 
until the Sponsor provides documentation of permission to use the investigational product.  It 
will not be considered a protocol deviation if the sponsor approves the use of the 
investigational product after the temperature excursion.  Use of the investigational product 
prior to sponsor approval will be considered a protocol deviation.  Specific details regarding 
information the site should report for each excursion will be provided to the site. 
5.7
Investigational Product Accountability
All products supplied are for use only in this clinical study and should not be used for any 
other purpose.
Study treatments must be received by a designated person at the study sites, handled and 
stored safely and properly, and kept in a secured location to which only the staff have access. 


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Upon receipt, all study treatments should be stored according to the instructions specified on 
the treatment labels. The provided environmental data logger graph and signed instruction 
sheet must be returned to the GSKCH Clinical Supplies Department as listed on the data 
logger instructions. Clinical supplies are to be dispensed only in accordance with the protocol.
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All study drugs will be accounted 
for using a drug accountability form/record. 
The inventory must be available for inspection by the study monitor during the study. 
Monitoring of treatments accountability will be performed by the field monitor during site 
visits and at the completion of the study.
5.7.1
Destruction of Investigational Product Supplies 
All investigational study treatments shipped for this clinical trial will be returned to the 
Sponsor or designated vendor at the termination of the study.  At the conclusion of the study, 
the Principal Investigator or an appropriate designee, and a representative of Celerion will 
inventory all used and unused investigational study treatment.  The study treatment inventory 
record for returned study treatment will then be completed. All investigational product for this 
clinical study (empty containers), as well as all unused study products, except retentions will 
be returned to the GSK CH Clinical Supplies Department or designated vendor using the 
return instructions provided. 
5.8
Concomitant Treatment(s)
Subjects will abstain from all concomitant treatments, except for contraceptives, and those 
treatments that needs to be used for the treatment of adverse events unless they jeopardize the 
integrity of the study.  The study Sponsor should be immediately informed.
All concomitant treatments taken during the study must be recorded with indication, unit dose, 
daily dose, and start and stop dates of administration.  All subjects will be questioned about 
concomitant treatment at each clinic visit.
Treatments taken within 90 days before the first dose of study investigational product will be 
documented as a prior treatment.  Treatments taken after the first dose of study investigational 
product will be documented as concomitant treatments.
5.9
Rescue Medication 
No rescue therapy is appropriate for this study.


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6
STUDY PROCEDURES
6.1
Screening
Subjects will be screened within 21 days prior to administration of the investigational product 
to confirm that they meet the subject selection criteria for the study.  
The following procedures will be completed:

Obtain written informed consent and record in the CRF.

Review Inclusion and Exclusion criteria and record in the CRF.

Collect demography, including year of birth, gender, ethnicity and race and record in 
the CRF.

Collect height and weight. The results for each measurement will be recorded in the 
CRF.

Obtain medical history as related to the inclusion/exclusion criteria, including any 
relevant medical or surgical history, allergies or drug sensitivity, history of illegal 
drug and alcohol use. Significant findings that are present before consent must be 
included in the CRF.

Collect smoking habits, including number of cigarettes smoked per day, time to first 
cigarettes and Fagerstrom score (from Fagerstrom test for nicotine dependence) and 
record in the CRF.

Obtain complete medication history of all prescription or nonprescription drugs, and 
dietary and herbal supplements taken within 90 days prior to consent, and record in 
the CRF.

Obtain supine blood pressure (BP), pulse rate (PR) and oral body temperature. The 
results for each measurement will be recorded in the CRF.

Conduct full physical examination. Any clinically relevant findings will be noted in 
the AE CRF page and enrollment will be based upon investigator judgement.

Contraceptive review

Collect single 12-lead electrocardiogram (ECG). Results or any clinically significant 
abnormalities found will be recorded on the CRF.

Following at least a 4-hour fast, collect blood and urine specimens for the following, 
and recorded on the CRF:

Safety laboratory tests;

Urine drug screening;

Alcohol screening; Serum FSH concentration for any female who has been 
amenorrheic for at least 12 consecutive months;  

Serum β-hCG for all females

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To prepare for study participation, subjects will be instructed on the use of the Lifestyle 
Guidelines and Concomitant Treatment(s) sections of the protocol.
6.2
Study Period
For the study period described below, when multiple procedures are scheduled at the same 
time point(s) relative to dosing, the following chronology of events should be adhered to, 
where possible.

Blood pressure/pulse rate: obtain as close as possible to scheduled time, but prior to 
blood specimen collection;

Pharmacokinetic blood specimens: obtain at scheduled time;

Other procedures, including expired CO measurements: obtain all other procedures as 
close as possible to the scheduled time, but may be obtained before or after blood 
specimen collection.
6.2.1
Visit 2 (Day -2)
Subjects will be admitted to the clinical site at least 36 hours prior to Day 0 dosing.
The following procedures will be completed following admission to the clinical site:

Review Inclusion and Exclusion criteria and record in the CRF.

Brief physical examination including evaluation of general appearance, heart, lung and 
physical measures (weight only). The results will be recorded in the CRF.

Collect urine for drug screening. The results will be recorded in the CRF.

Collect serum pregnancy test for all females. The results will be recorded in the CRF.

Confirm proper contraception is being used and the results will be recorded on the 
CRF. 

Collect urine for urine alcohol test. Result will be recorded on the CRF.

Review changes in the subject’s medical history. Any changes will be recorded on the 
CRF.

Meals as required.  Time and consumption of meals will be recorded on CRF.

Adverse events

Review concomitant treatment.
6.2.2
Visit 2 (Day -1)
The following procedures will be completed:
Collect expired CO measurement. Result will be recorded on the CRF.
Review concomitant treatment.
Adverse events
Meals as required.  Time and consumption of meals will be recorded on CRF.


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
Subjects will begin fasting at least 10 hours prior to dosing on Day 0.
6.2.3
Visit 2 (Day 0)
Prior to dosing, the following procedures will be completed and recorded on the CRF:

Expired CO measurements to be collected prior to I/C final check.

Collect supine blood pressure and pulse rate.

Collect respiratory rate, oral body temperature and record in the CRF.

Randomization

Collect a blood sample for pharmacokinetic analysis at the following time points prior 
to dosing -45, -30, -15 minutes. A deviation of ±3 minutes will be accepted for the 
blood samples. Time of blood sampling will be recorded in the CRF.

After all pre-dose procedures have been completed, administer the investigational 
product (see Study Treatments and Administration Sections). 
After dosing, the following procedures will be completed and recorded in the CRF:

Collect blood samples for pharmacokinetic analysis at the following time points 
following dosing on Day 0: 5, 10, 20, 30, 40, 50, 60, 75 and 90 minutes and at 2, 3, 4, 
6, 8, 10, 14, 16, 20 hours. A deviation of ±3 minutes will be accepted for the blood 
samples. Time of blood sampling will be recorded in the CRF.

Collect 4x random CO measurements (see section 7.5 Expired Carbon Monoxide 
(CO) measurement), and record in the CRF.

Record changes in concomitant medication or non-drug treatments/procedures.

Meals as required.  Time and consumption of meals will be recorded on CRF.

Assess symptoms of spontaneous reporting of adverse events by brief physical 
examination and by asking the subjects to respond to a non-leading question such as 
“How do you feel?”
6.2.4
Visit 2 (Day 1)
The following procedures will be completed and recorded in the CRF:

Collect blood samples for pharmacokinetic analysis at 24 (±3 minutes) hours. Time of 
blood sampling will be recorded in the CRF.  

Assess supine blood pressure and pulse rate 24 hours after dosing on Day 0.

Collect respiratory rate, oral body temperature and record in the CRF.

Record changes in concomitant medication or non-drug treatments/procedures. 

Assess symptoms of spontaneous reporting of adverse events by brief physical 
examination and by asking the subjects to respond to a non-leading question such as 
“How do you feel?” 


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
Meals as required.  Time and consumption of meals will be recorded on CRF.
6.2.5
Washout period
Washout period of at least 5 days to a maximum of 7 days after first dose, where subjects will 
be allowed to smoke ad libitum.
6.2.6
Visit 3 (Day 3 to 5)
Subjects will be admitted to the clinical site at least 36 hours prior to Day 5 to 7 dosing.
The following procedures will be completed following admission to the clinical site:

Review Inclusion and Exclusion criteria and record in the CRF.

Brief physical examination including evaluation of general appearance, heart, lung 
and physical measures (weight only). The results will be recorded in the CRF.

Collect urine for drug screening. The results will be recorded in the CRF.

Collect serum pregnancy test for all females. The results will be recorded in the CRF.

Confirm proper contraception is being used. 

Collect urine for urine alcohol test, Result will be recorded on the CRF.

Review changes in the subject’s medical history. Any changes will be recorded on the 
CRF.

Review any concomitant treatments and record in the CRF.

Adverse events

Meals as required.  Time and consumption of meals will be recorded on CRF.
6.2.7
Visit 3 (Day 4 to 6)
The following procedures will be completed:

Collect expired CO measurement. Result will be recorded on the CRF.

Review any concomitant treatments and record in the CRF.

Adverse events

Meals as required.  Time and consumption of meals will be recorded on CRF.

Subjects will begin fasting at least 10 hours prior to dosing on Day 5 to 7.
6.2.8
Visit 3 (Day 5 to 7)
Prior to dosing, the following procedures will be completed and recorded in the CRF:

Collect supine blood pressure and pulse rate.


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
Collect respiratory rate, oral body temperature and record in the CRF.

Expired CO measurements to be immediately collected prior to dosing.

Collect a blood sample for pharmacokinetic analysis at the following time points prior 
to dosing -45, -30, -15 minutes. A deviation of ±3 minutes will be accepted for the 
blood samples. Time of blood sampling will be recorded in the CRF.

After all pre-dose procedures have been completed, administer the investigational 
product (see Study Treatments and Administration Sections). 
After dosing, the following procedures will be completed:

Collect blood samples for pharmacokinetic analysis at the following time points 
following dosing on Day 6-8: 5, 10, 20, 30, 40, 50, 60, 75 and 90 minutes and at 2, 3, 
4, 6, 8, 10, 14, 16, 20 hours. A deviation of ±3 minutes will be accepted for the blood 
samples. Time of blood sampling will be recorded in the CRF.

Collect 4x random CO measurements (see section 7.5 Expired Carbon Monoxide 
(CO) measurement), and record in the CRF.

Record changes in concomitant medication or non-drug treatments/procedures.

Assess symptoms of spontaneous reporting of adverse events by brief physical 
examination and by asking the subjects to respond to a non-leading question such as 
“How do you feel?”

Meals as required.  Time and consumption of meals will be recorded on CRF.
6.2.9
Visit 3 (Day 6 to 8)
The following procedures will be completed and recorded in the CRF:

Collect blood samples for pharmacokinetic analysis at 24 (±3 minutes) hours. Time of 
blood sampling will be recorded in the CRF.  

Obtain blood and urine samples for safety laboratory tests.

Assess supine blood pressure, respiratory rate, oral body temperature and pulse rate 
24 hours after dosing on Day 5-7.

Conduct full physical examination.

Record changes in concomitant medication or non-drug treatments/procedures. 

Assess symptoms by spontaneous reporting of adverse events and by asking the 
subjects to respond to a non-leading question such as “How do you feel?” 

Meals as required.  Time and consumption of meals will be recorded on CRF.

Discharge from clinical site.  
If a subject has any clinically significant, study-related abnormalities at the conclusion of a 
scheduled inpatient portion of the study, the GSK CH medical monitor (or designated 


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representative) should be notified and depending on the abnormality, the subject may be asked 
to remain at the clinical site until such abnormalities are deemed not clinically significant, or 
it is safe for outpatient follow-up.  If the subject is unable or unwilling to remain at the clinical 
site and/or when outpatient follow-up is deemed appropriate, the GSK CH medical monitor 
(or designated representative) should be so notified, and the investigator should make every 
effort to arrange follow-up evaluations at appropriate intervals to document the course of the 
abnormalities.
6.3
Subject Withdrawal
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 or, behavioral 
reasons, or the inability of the subject to comply with the protocol-required schedule of study 
visits or procedures at a given study site.  
The following circumstances require discontinuation of study treatment and/or premature 
subject withdrawal:

Protocol violation that may impact the outcome of the subject’s safety

Protocol violation that may interfere with the drug’s PK, including:
o
Vomiting shortly (within 30 minutes) after study drug administration
o
Swallowing the lozenge during the administration period
o
Any reported or suspected noncompliance of the smoking restriction during 
post dose PK observation period, e.g. CO > 10 ppm at any time during the 24 
post dose period (see Section 7.5 Expired Carbon Monoxide (CO) 
measurement for subject assessment)
o

Withdrawal of informed consent

Subject lost to follow-up 

Pregnancy

Death
If a subject is discontinued or prematurely withdraws from the study, reasons for 
discontinuation or withdrawal and associated date must be documented in the relevant 
section(s) of the CRF. 
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  The Investigator or site staff should attempt to contact the subject twice.  After two 
attempts, clinical site staff must send a registered letter.  If no response is received from the 


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subject, the subject will be considered lost to follow up.  All attempts to contact the subject 
and information received during contact attempts must be documented in the CRF.  In any 
circumstance, every effort should be made to document subject outcome, if possible.  The 
investigator should inquire about the reason for withdrawal, request that the subject return for 
a final visit, if applicable, and follow-up with the subject regarding any unresolved adverse 
events (AEs).
It may be appropriate for the subject to return to the clinical site for final safety assessments. 
Subjects should be questioned regarding their reason for withdrawal.  Assessments, at the 
investigator’s discretion, will include the following:

Brief physical examination;

Supine blood pressure respiratory rate, oral body temperature and pulse rate 
measurements.
Lack of completion of all or any of the early termination procedures will not be viewed as 
protocol deviations so long as the subject’s safety was preserved.
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.
7
ASSESSMENTS
Every effort should be made to ensure that 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 must 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 the missed test as a protocol deviation and any corrective and 
preventative actions that he or she has taken to ensure that required processes are adhered to, 
as soon as possible.  The study team must be informed of these incidents in a timely manner.
7.1
Efficacy
Not applicable as there are no efficacy assessments.
7.2
Safety
The following safety assessments will be performed at times defined in the Study Procedures 
section of this protocol.  


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7.2.1
Laboratory Tests 
Additional laboratory results may be reported on these samples as a result of the method of 
analysis or the type of analyzer used by the clinical laboratory; or as derived from calculated 
values.  These additional tests would not require additional collection of blood.  Unscheduled 
clinical labs may be obtained at any time during the study to assess any perceived safety 
concerns.
Table 7-1
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit RBC 
count 
MCV
MCH
MCHC
Platelet count 
MPV
WBC count
Total neutrophils 
(Abs)
Eosinophils (Abs)
Monocytes (Abs) 
Basophils (Abs) 
Lymphocytes 
(Abs)
BUN/urea and Creatinine
Glucose (fasting) 
Calcium 
Magnesium 
Sodium 
Potassium 
Chloride
Total CO2(Bicarbonate)
 AST, ALT
Direct Bilirubin
Indirect Bilirubin
Total Bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
pH
Glucose (qual) 
Protein (qual) 
Blood (qual) 
Ketones 
Nitrites
Leukocyte esterase 
Urobilinogen
Urine Bilirubin
Specific gravity
Microscopya
Urine drug screenb
Serologyc
Serum pregnancy test 
(WCBP)d
Alcohol urine test
GGT
CK
FSH
Definitions:  RBC= Red blood cell; MCV= Mean corpuscular volume; MCH= Mean 
corpusuclar hemoglobin; MCHC= Mean copusuclar hemoglobin concentration; MPV= Mean 
platelet volume; WBC= White blood cells; BUN=Blood urea nitrogen; AST= aspartate 
aminotransferase; ALT= alanine aminotransferase; GGT= Gamma-glutamyl transpeptidase; 
CK=creatine kinase; FSH= follicle stimulating hormone.
a Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
b Minimum requirement for drug testing includes: cocaine, THC, opiates/opioids, 3,4-
methylenedioxy-N-methylamphetamine 
(MDMA)/ecstasy, 
methamphetamine 
and 
amphetamines; to be done Visit 1, Visit 2 (Day -1) and Visit 3 (Days 5-7)
c HIV (human immunodeficiency virus); Hepatitis B surface antigen, Hepatitis C antibodies
dFemale subjects will be tested for serum human chorionic gonadotropin (hCG) at the 
Screening and start of each period (Days -1 and 5-7).


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Any remaining serum/plasma from samples collected for clinical safety labs at baseline and at 
all times post-dosing must be retained and stored for the duration of the study. 
7.2.2
Pregnancy Testing
For all female subjects, a serum pregnancy test, will be performed by the investigator or 
designee at Screening and Days -1 and 5-7.  Results will be obtained prior to dosing during 
each period.  
A negative pregnancy result is required before the subject may receive the investigational 
product.  Pregnancy tests will also be done whenever one menstrual cycle is missed during the 
active study period (or when potential pregnancy is otherwise suspected). Pregnancy tests may 
also be repeated as per request of IRBs/ECs or if required by local regulations.
In the case of a positive confirmed pregnancy, the subject will be withdrawn from 
administration of investigational product and from the study.
7.2.3
Physical Examinations 
Physical examinations may be conducted by a physician, trained physician's assistant, or nurse 
practitioner as acceptable according to local regulation.  A full physical examination will 
include head, ears, eyes, nose, mouth, throat skin and lung examinations, lymph nodes, 
gastrointestinal, musculoskeletal, cardiovascular and neurological systems.  
The brief physical examination will be focused on general appearance, the respiratory and 
cardiovascular systems, as well as towards subject reported symptoms of adverse events if 
reported.
Any untoward findings identified on physical exams conducted after informed consent will be 
captured as an adverse event, if those findings meet the definition of an adverse event.
7.2.4
Height and Weight 
Height in centimeters (cm) and body weight in kilograms (kg) to the nearest 0.1 kilogram will 
be measured.
For measuring weight, a scale with appropriate range and resolution is used and must be 
placed on a stable, flat surface.  Subjects must remove shoes, bulky layers of clothing, and 
jackets so that only light clothing remains.  They must also remove the contents of their 
pockets and remain still during measurement of weight. 


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7.2.5
Blood Pressure and Pulse Rate 
Additional collection times, or changes to collection times of blood pressure and pulse rate 
will be permitted, as necessary at the discretion of the investigator, to ensure appropriate 
collection of safety data.
Supine blood pressure will be measured with the subject’s arm supported at the level of the 
heart and recorded to the nearest mm Hg after approximately 5 minutes of rest.  The same arm 
(preferably the dominant arm) will be used throughout the study.  
The same properly sized and calibrated blood pressure cuff will be used to measure blood 
pressure each time. The use of an automated device for measuring BP and pulse rate is 
acceptable, although, when done manually, pulse rate will be measured in the brachial/radial 
artery for at least 30 seconds.  When the timing of these measurements coincides with a blood 
collection, blood pressure and pulse rate should be obtained prior to the nominal time of the 
blood collection.
7.2.6
Respiratory Rate
Respiratory rate will be measured after approximately 5 minutes rest in supine position by 
observing and counting the respirations of the subject for 30 seconds and multiplied by 2.  
When blood pressure is to be taken at the same time, respiration measurement will be done 
during the 5 minutes of rest and before blood pressure measurement.
7.2.7
Temperature
Temperature will be measured orally, and results recorded in the CRF.
No eating, drinking or smoking is allowed for 15 minutes prior to the measurement.
7.2.8
Electrocardiogram
A standard 12 lead ECG will be performed at Visit 1. Interpretation of the tracing must be 
made by a qualified physician or designee and documented on the ECG section of the CRF. 
Each ECG tracing should be labeled with the study number, subject initials, subject number, 
date, and kept in the source documents at the study site. Results or any clinically significant 
abnormalities should be reported in the CRF. Clinically significant abnormalities should also 
be recorded on the Adverse Event CRF. Clinically significant findings must be discussed with 
the GSK Clinical Project Lead (CPL) prior to enrolling the subject in the study.
Subjects should be in a quiet environment and not speak during the resting period or 
measurement.  Generally, ECGs should not be collected within 3 hours after food or beverage 
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7.3
Pharmacokinetics (PK)
Twenty-two (22) blood samples will be collected for pharmacokinetic analysis:  at baseline 
(-45 minutes, -30 minutes and -15 minutes prior to dosing), and at 5, 10, 20, 30, 40, 50, 60, 75 
and 90 minutes and at 2, 3, 4, 6, 8 10, 14, 16, 20 and 24 hours following study drug 
administration. A blood volume of 6 mL per time point, will be collected via direct 
venipuncture. If the blood volume is unable to be collected by venipuncture, due to failure or 
inability draw blood, then catheter will be used for collection. Study drug administration is 
defined as the placement of the nicotine lozenge in the mouth of the subject.
A total of approximately 296 mL blood will be taken during the trial, including 264 mL for 
PK samples and 32 mL for safety laboratory tests.
7.3.1
PK samples and safety laboratory tests
During all study periods, blood volumes (6 mL) to provide a minimum of 1.5 mL plasma for 
pharmacokinetic analysis will be collected into appropriately labeled lavender top tubes 
containing K2EDTA at times specified in the Study Procedures section of the protocol.  The 
plasma will be split into 2 transfer tubes.
The actual times may change but the number of samples will remain the same.  All efforts will 
be made to obtain the pharmacokinetic samples at the exact nominal time relative to dosing.  
However, samples obtained within 3 minutes will not be captured as a protocol deviation, as 
long as the exact time of the sample collection is noted on the source document and data 
collection tool (e.g., CRF).
Samples will be analyzed using a validated analytical method in compliance with applicable 
Celerion standard operating procedures.
The PK samples must be processed and shipped as indicated to maintain sample integrity.  
Any deviations from the PK processing steps, including any actions taken, must be 
documented and reported to the sponsor.  On a case-by-case basis, the sponsor may make a 
determination as to whether sample integrity has been compromised.  Any sample deemed 
outside of established stability, or of questionable integrity, will be considered a protocol 
deviation.
Samples will be stored for a period of up to 5 years, until regulatory submissions are 
completed, or upon the request of GSK, at which all samples will be destroyed.   The 
individual subject samples may also be destroyed upon request of the subject. The samples 
will be stored according to Celerion’s standard operating procedures.  There will be no use of 
these samples for further research.


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7.3.2
Shipment of Pharmacokinetic Samples
The shipment address and assay lab contact information will be provided to the investigator 
site prior to initiation of the study.
7.4
Blood Volume
The total blood sampling volume for each subject in this study is approximately 296 mL.  The 
table below reflects approximate sample volumes needed for each measured endpoint.  The 
actual collection times of blood sampling may change, but the total blood volume collected 
will not increase.  Additional blood samples may be taken for safety assessments at the 
discretion of the investigator or GSK CH.
Table 7-2
Blood Volume
Number of Sampling Times
Sample Type
Sample 
Volume 
(mL)
Screening
Study Period
Follow-Up
Total Volume 
(mL)
Safety Labs
16
1
1
32
Retained Sample 
(optional)
PK
6
22 x 2
264
TOTAL
296
This total volume does not include discarded blood from pre-draws used to remove fluid from flushed 
catheters, if applicable.  
7.5
Expired Carbon Monoxide (CO) measurement
Using a calibrated Bedfont Smokerlyzer®, the investigator or designee will perform six (6) 
scheduled CO measurements, one upon check-in at Baseline, one immediately before 
randomization in Period 1, one immediately prior to dose administration in Period 2, and 
another immediately after the last PK sample has been collected at each study session.  
Additionally, the investigator or designee will conduct at least four (4) random CO 
measurements during each study period to verify smoking abstinence.  The timing of the 
random CO measurements will be decided by the investigator or designee.  For each CO 
measurement, subjects will be instructed to inhale deeply, hold their breath for 15 seconds and 
produce a non-forced, steady 15 second exhalation through the disposable mouthpiece of the 
inflow valve of the CO monitor.
Prior to randomization: If the CO value is not within limits just prior to randomization, an 
additional CO measurement can be repeated after 2 hours if the value is ≤15ppm. If CO value 
remains out of limit, then subject will not be randomized.
® Smokerlyzer is a registered trademark of Bedfont Scientific Ltd..


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During study: If a CO value is not within limits during the study, an additional CO 
measurement may be taken to confirm the results. 

If second value is still not within the limits, subject will be discontinued from study

If second value is within limits, state reason for repeated measure (e.g. incorrect use of 
CO monitor). Repeat measurement again in 30 minutes to confirm. If the third 
measurement is within limits, subject may continue with study. If third measurement is 
not within limits, then subject will be discontinued from study.
All values, including time of measurement and reason for re-measurement will be recorded in 
the CRF.
8
ADVERSE EVENT 
8.1
Definitions of Adverse Events and Serious Adverse Events
8.1.1
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of an investigational or washout product or medical device, whether or 
not considered related to the investigational or washout product or medical device.
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of a study treatment.
Events Meeting the AE Definition:  

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae.
Events NOT meeting the AE definition: 


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
Any clinically significant abnormal laboratory findings (if applicable) or other 
abnormal safety assessments which are associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the subject’s condition. 

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition. 

Medical or surgical procedure (e.g., endoscopy, appendectomy) is not the AE. The 
condition that leads to the procedure is an AE (e.g., appendicitis).

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
8.1.2
Serious Adverse Event
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death

Is life-threatening 

The term 'life-threatening' in the definition of 'serious' refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe;

Requires inpatient hospitalization or prolongation of existing hospitalization 

In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AE. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE.

Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
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
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption

Results in congenital anomaly/birth defect

Other situations

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious.

Examples of such events include invasive or malignant cancers, 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.
8.2
Reporting Period
8.2.1
Adverse Event
AEs (serious and nonserious) will be collected from the signing of the ICF and until 5 days 
following last administration of the investigational product. For studies that have a run-in 
period or washout period, adverse events will be collected from the time the run-in or washout 
period begins. 
Medical occurrences that begin before obtaining informed consent will be recorded on the 
Medical History/Current Medical Conditions section of the case report form (CRF).
8.2.2
Serious Adverse Event
SAEs assessed as related to study participation (e.g., investigational product, protocol 
mandated procedures, invasive tests, or change in existing therapy) or related to a GSK 
concomitant medication will be recorded from the time a subject provides informed consent, 
which is obtained prior to the subject’s participation in the study, i.e., prior to undergoing any 
study-related procedure and/or receiving investigational product and until 5 days following 
last administration of the investigational product.
SAEs assessed as not related to study participation (e.g., investigational product, protocol 
mandated procedures, invasive tests, or change in existing therapy) or not related to a GSK 
concomitant medication will be recorded from the time the subject has taken at least 1 dose of 
investigational product and until 5 days following last administration of the investigational 
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8.3
Reporting Procedures
The investigator and any designees are responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up on 
AEs that are serious, considered related to the study treatment or the study, or that caused the 
participant to discontinue the study. 
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject. In addition, each study subject will be questioned about AEs. 
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to the 
event.
The investigator or site staff will then record all relevant information regarding an AE/SAE in 
the CRF.
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to GSK in lieu of completion of the GSK /AE/SAE CRF page.
There may be instances when copies of medical records for certain cases are requested by 
GSK.  In this instance, all subject identifiers, with the exception of the subject number, will be 
blinded on the copies of the medical records prior to submission to GSK.
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information.  In such cases, the diagnosis will be documented as the 
AE/SAE and not the individual signs/symptoms. Clinical AEs will be described by diagnosis 
and not by symptoms when possible (e.g., upper respiratory tract infection, seasonal allergy, 
etc. instead of runny nose).
Medical conditions reported prior to the time period for reporting AEs/SAEs should be 
recorded as part of the subject’s medical history.
AEs elicited by the investigator in a standard manner at the study visits should also be 
recorded in the AE section of the CRF. Care will be taken not to introduce bias when 
detecting AE and/or SAE. Open-ended and non-leading verbal questioning of the participant 
is the preferred method to inquire about AE occurrence.
8.3.1
Adverse Event
All AEs will be reported on the AE page(s) of the CRF by the investigator or site staff.  It 
should be noted that the form for collection of SAE information is not the same as the AE 


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CRF.  Where the same data are collected, the forms must be completed in a consistent 
manner.  For example, the same AE term should be used on both forms.  AE should be 
reported using concise medical terminology on the CRF as well as on the form for collection 
of SAE information.
8.3.2
Serious Adverse Event
A paper copy of the SAE form provided in the investigator study master file should be 
completed as fully as possible. 
It is essential to enter the following information: 

Protocol and subject identifiers

Subject’s demography

Description of events, with diagnosis if available

Investigator opinion of relationship to study product 

Criterion for seriousness.
The following are desirable and are of particular relevance for investigator and GSK CH 
assessment of the SAE report:

Date of onset of AE 

Date AE stopped, if relevant

Study product start date

Study product end date if relevant

Action taken on study product

Outcome if known
Celerion will email the SAE form to the Case Management Group, Global Clinical Safety and 
Pharmacovigilance at GSK (
), with copy to the appropriate GSK CH 
Study Manager as soon as possible, but not later than 1 business day after study site 
personnel learn of the event. The GSK CH Study Manager will be responsible for forwarding 
the SAE form to other GSK CH personnel as appropriate.
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8.3.3
Sponsor’s Reporting Requirements to Regulatory Authorities and 
Ethics Committees
GSK has a legal responsibility to notify, as appropriate, the local regulatory authority and 
other regulatory authorities about the safety of a product under clinical investigation.  Prompt 
notification of SAEs by the investigator to GSK is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects are met.
GSK will comply with country specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/EC and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information eg, summary or listing of SAE, from the sponsor will review and then file 
it along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according 
to local requirements.
8.4
Evaluating Adverse Events and Serious Adverse Events
8.4.1
Severity Assessment
The investigator or designee will make an assessment of severity for each AE and SAE 
reported during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort and 
not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. 
Note: An AE that is assessed as severe will not be confused with an SAE. Severity is a 
category utilized for rating the intensity of an event; and both AEs and SAEs can be assessed 
as severe. For example, a headache may be severe (interferes significantly with the subject's 
usual function) but would not be classified as serious unless it met one of the criteria for 
SAEs, listed above. 
8.4.2
Causality Assessment
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. For each AE/SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality. The 


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investigator’s assessment of causality must be provided for all AEs (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 SAE reporting requirements if applicable.  
A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
Generally, the facts (evidence) or arguments to suggest a causal relationship should be 
provided.
The investigator will use clinical judgment to determine the relationship and will also consult 
the Investigator Brochure (IB), Safety Statement and/or Product Information, for marketed 
products, in the determination of his/her assessment.  Alternative causes, such as underlying 
disease(s), concomitant therapy, other risk factors, and the temporal relationship of the event 
to the study product will be considered and investigated.
There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important that the 
investigator always make an assessment of causality for every event prior to the initial 
transmission of the SAE data to GSK. The investigator may change his/her opinion of 
causality in light of follow-up information and send an SAE follow-up report with the updated 
causality assessment. 
8.5
Withdrawal Due to an Adverse Event and Serious Adverse 
Events
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF page. 
When a subject withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.6
Pregnancy
8.6.1
Time Period for Collecting Pregnancy Information
Pregnancy information will be collected on all pregnancies reported following administration 
of any investigational product or washout product and until 48 hours after the last dose.
8.6.2
Action to be Taken if Pregnancy Occurs
The investigator will collect pregnancy information on any subject who becomes pregnant 
while participating in the study after administration of the investigational product. The 
investigator will record pregnancy information on the appropriate form and submit it to the 
Case Management Group, Global Clinical Safety and Pharmacovigilance group mailbox at 
GSK within 24 hours of learning of the subject becoming pregnant. The subject will be 


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followed to determine the outcome of the pregnancy. Information on the status of the mother 
and infant / neonate (including concomitant medications taken by the mother during the 
pregnancy) will be forwarded to the Case Management Group, Global Clinical Safety and 
Pharmacovigilance group mailbox at GSK. Generally, follow-up will be no longer than 6 to 8 
weeks following the estimated delivery date. Any termination of the pregnancy will be 
reported. 
While pregnancy itself is not considered to be an AE, abnormal pregnancy outcomes (eg, 
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are 
considered to be and should be recorded as an SAE.
Any female participant who becomes pregnant while participating will discontinue study 
treatment or be withdrawn from the study. 
Like with SAE and Incident Forms, Celerion will email the pregnancy form to the Case 
Management Group, Global Clinical Safety and Pharmacovigilance group mailbox at GSK 
(
) with copy to the appropriate GSK CH Study Manager. 
8.7
Follow-up of Adverse Events and Serious Adverse Events
After the initial report, the investigator is required to proactively follow up with each subject 
and provide further information on the subject’s condition.
All AEs/SAEs will be followed until resolution, until the condition stabilizes, until the event 
is otherwise explained, or until the subject is lost to follow-up.  
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to elucidate as 
fully as possible the nature and/or causality of the AE or SAE. This may include additional 
laboratory tests or investigations, histopathological examinations, or consultation with other 
health care professionals.
New or updated information will be recorded in the originally completed CRF.
The investigator will submit any updated SAE data to GSK within 24 hours of receipt of the 
information.
Investigators are not obliged to actively seek AEs or SAEs in former subjects.  However, if 
the investigator learns of any SAE, including the death, at any time after a subject has been 
discharged from the study, and considers the event reasonably related to the investigational 
product or study participation, the investigator will promptly notify GSK by emailing the 
information to the GSK CH Clinical Operations Safety Reporting email box (
). The GSK CH Study Manager or designee will be responsible for 
forwarding the information to the Case Management Group, Global Clinical Safety and 
Pharmacovigilance group mailbox at GSK (
).
The investigator will submit any updated SAE data to GSK within the designated reporting 
time frames.
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9
DATA MANAGEMENT
As used in this protocol, the term 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. 
For this study subject data will be entered into a Contract Research Organization (CRO) 
electronic CRF, using a validated data system.
9.1
Source Documents/ Data
The source documents (e.g., hospital records, clinical and office charts, laboratory notes, 
memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded 
data from automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, x-rays, subject files and records kept at the pharmacy, at the laboratory and at the 
medico-technical departments involved in the clinical study) which contain the source of data 
recorded in the CRF should be specified in Section 6 .  The CRF can be used as a source 
document at the discretion of data management.
Each subject will be assigned and identified by a unique Number. Any reference made to an 
individual subject within the study must be done using the unique Screening Number.
9.2
Case Report Form
A CRF is a printed, optical, or electronic document designed to record all of the protocol 
required information to be reported to the sponsor on each trial subject.
For each subject who has given informed consent/assent and has been screened, CRF must be 
completed and signed by the Principal Investigator (or authorized designee) to certify that the 
data are complete and correct.  
Management of clinical data will be performed in accordance with applicable GSK CH 
standards and data cleaning procedures to ensure the integrity of the data e.g. removing errors 
and inconsistencies in the data. 
In order to protect the privacy of subjects, no Personally Identifiable Information (PII) 
(including the subject's name or initials or full birth date) is to be recorded in the CRF or as 
part of the query text.
All CRF pages should be completed during a subject assessment when the CRF has been 
designated as the source.  Data that is sourced elsewhere should be entered into the CRF in an 
agreed upon timeframe between the Investigator and Sponsor.  
GSK CH will obtain and retain all CRFs and associated study data at the completion of the 
study. 
9.3
Data Handling
Documentation of all data management activities should allow step-by-step retrospective 
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Any changes or corrections to data will be performed in the Electronic Data Capture (EDC) 
System, and it will include rationale for changes. The EDC system has an audit trail, which 
will provide a complete record of the changes and corrections endorsed by the Investigator.
Adverse events will be coded using MedDRA (Medical Dictionary for Regulatory Activities) 
and concomitant medications terms using an internal validated medication dictionary, 
GSKDrug.  
9.3.1
Queries
Programmed edit checks will be generated automatically, as the data is being entered into the 
system. Data Management will also run reports and listings on the CRF data, in addition to the 
queries already programmed and generated by the system, to raise manual queries as needed 
for site clarification or correction. The Clinical Dictionary Development and Management 
Group will raise queries as needed on safety data to code the terms (Adverse Events and 
Drugs) appropriately. 
The study monitor at the study site will review the CRFs in accordance with the monitoring 
plan, and any queries will be generated in the EDC System to the Investigator or designee, 
enabling the errors to be addressed in parallel with Data Management review. The study 
monitor can also run reports and listings on the CRFs, to raise manual queries as needed for 
site clarification or correction.
9.4
Processing Patient Reported Outcomes
There will be no Patient reported outcome (PRO) data for this study.  
9.5
External Data 
External Data are subject data obtained externally to the CRF. These data are generated from 
laboratory instruments, computers or other sources and then transcribed into a file and format 
agreed upon by GSK CH to identify the subject and time point referenced in the CRF and/or 
protocol. 
An agreed upon quality control process is performed against the transcribed data to the source 
to ensure the accuracy of the transcription. The transcribed data is transmitted in an agreed 
upon format to GSK CH. 
Reconciliation will be performed between the transcribed data and the clinical database to 
ensure subject and time point referenced in the Clinical Database match before Clinical 
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10
STATISTICAL CONSIDERATIONS AND DATA ANALYSES
10.1
Sample Size Determination
Enough healthy adult smokers will be screened to randomize forty (40) healthy adult smokers, 
to ensure that thirty-two (32) complete the entire study assuming a 20% dropout and non-
evaluable rate. The highest intra-subject CV observed in previous studies was 23%. The 
protocols that were used to select the highest CV for the sample size calculation are: 
 
 
 
 and S6491365 (2mg nicotine polacrilex mini cherry 
lozenge v.s 2mg nicotine polacrilex mini mint lozenge: Cmax =13.7%; AUC0-t =10%). A total 
of thirty-two (32) evaluable subjects will achieve a 90% power at 5% significance level. The 
true ratio that was used in the sample size calculation was 1.05.
10.2
Statistical Methods and Analytical Plan
Additional details of the proposed statistical analysis will be documented in the statistical 
analysis plan (SAP), which will be written following finalization of the protocol and prior to 
the database lock and analysis. SAP creation and statistical analysis will be performed by 
Celerion.
Pharmacokinetic variables will be calculated by Celerion.
All concentration and PK data will be listed. This includes any data for subjects who are not 
included in the analysis.
10.2.1
Demographic and Baseline Characteristics
Baseline data, relevant screening data, and demographic characteristics will be summarized 
for all randomized subjects.
10.2.2
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)
The number of subjects exposed to each treatment will be tabulated for the safety population. 
Treatment deviations for individual subjects will be listed and summarized. Cases of partial 
exposure, including swallowing or premature expulsion of the treatment and subjects with 
baseline > 5% of the Cmax will also be summarized. For predose-adjusted data, baseline 
nicotine concentration is defined as the time zero concentration estimated by the log-linear 
regression according to a mono-compartmental deconvolution of the three pre-dose time 
points, i.e. – 45 minutes, - 30 minutes and -15 minutes prior to dosing. Other medications and 
other concomitant non-drug therapies will be listed for the safety population.
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10.2.3
Primary Analysis
10.2.3.1
Criteria for assessing bioequivalency
The bioequivalence between the test and reference treatments will be concluded if the 90% 
confidence intervals for the ratio of the means of the primary pharmacokinetic parameters 
AUC0-t and AUC0-inf and Cmax of the nicotine profiles lie completely within the range 0.8-1.25.
10.2.3.2
Pharmacokinetics Analysis
Variables:
For each study product, the following pharmacokinetic parameters will be estimated: 
AUC0-t: Area under the plasma concentration versus time curve from time zero to time t, 
where t is the time of the last measurable plasma concentration of nicotine, 
estimated.
AUC0-inf: Area under the plasma concentration versus time curve calculated from time zero to 
infinity.
Cmax: The highest observed plasma nicotine concentration.
PK evaluation:
The primary objective will be evaluated based on the following comparison: 
The nicotine 2 mg prototype mini lozenge (Test) versus the 2 mg nicotine polacrilex mini 
lozenge (Nicorette Mini, Reference), in terms of nicotine AUC0-t, AUC0-inf and Cmax.
The primary statistical analyses will be done based on PK analysis set, PKAS1 (see section 
10.2.7 for definition). An additional analysis (for pre-dose adjusted data only) will be 
performed on PK analysis set, PKAS2. Safety population will be used for individual plasma 
concentration listings and figures.  
Individual plasma concentrations will be listed and summarized descriptively at each time 
point; the concentration vs. time profile will be graphed by formulation for individual 
subjects and for the mean on both original and logarithmic scales with Safety population.
All PK parameters (except Kel, t½ and tmax) will be summarized for each treatment by 
descriptive statistics (N, arithmetic mean, standard deviation, geometric mean, coefficient of 
variation, median, minimum, and maximum). A listing containing individual and summary 
statistics for each PK parameter will be provided.  A similar listing will be provided for log 
and linear blood concentrations over time containing individual values and summary statistics 
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BE of the test product with reference will be assessed by pairwise comparison of the PK 
parameters (Cmax, AUC0-t, and AUC0-inf) for the nicotine concentration profiles based on the 
PK analysis set, PKAS1. 
A linear mixed effects model will be fit to the log-transformed PK variables (AUC0-t, AUC0-inf 
and Cmax), as the dependent variable, and treatment, and period as fixed effects. Subject nested 
within sequence will be a random effect. For each pairwise comparison, only the data from 
the two, corresponding treatments will be included in the model. The presence of a 
statistically significant sequence effect will be noted and its implications will be discussed. 
Least squares estimates of treatment effects will be calculated and a 90% confidence interval 
(CI) for the treatment difference will be computed. The treatment difference and its CI will be 
exponentiated to obtain the ratio of the geometric means between the test and reference 
products and its CI. Bioequivalence will be determined if the 90% confidence interval for the 
treatment geometric mean ratio lies completely within the range 0.80 – 1.25.  
10.2.3.3
Correction for non-zero baseline for an additional analysis.
The pre-dose nicotine concentration will be estimated based on a log-linear regression 
according to a mono-compartmental deconvolution of the three pre-dose time points, i.e. -45 
minutes, -30 minutes and -15 minutes prior to dosing. Subsequent plasma concentrations will 
be corrected by subtracting an estimate of the residual baseline plasma nicotine concentration 
computed with log-linear regression according to a mono-compartmental deconvolution as 
follows:
RCt,ij = Cpre-dose,ij *exp (-Kelij*t)
where
RCt = estimated residual concentration (nicotine in plasma) at time t,
Cpre-dose = plasma nicotine concentration before dosing,
Kel = slope calculated by log-linear regression using the elimination portion of the PK profile 
for the associated treatment.
t = time (h) between the considered blood sampling and the time of pre-dose sampling.
i = treatment (Test or Reference)
j = patient
The plasma concentration at time t, observed after dosing and corrected for baseline, will be 
equivalent to the following:
Ct,ij(R)=Ct(O)-RCt
Where:
Ct(R) = baseline corrected nicotine concentration Ct(O) = observed nicotine concentration 
detected in patient plasma 
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10.2.4
Secondary Analysis
The PK analysis set, PKAS1 will be used for the secondary analysis. 
For each study product, the following pharmacokinetic parameters will be estimated: 
tmax
time to maximum plasma nicotine concentration;
t1/2
apparent elimination half-life;
Kel
apparent elimination rate constant for plasma nicotine.
The parameters Kel and t½ and tmax be summarized (mean, median, Q1, Q3, minimum, 
maximum, standard deviation, and coefficient of variation) for each study treatment. A 
nonparametric analysis will be performed to compare study treatments using the Wilcoxon 
Signed Rank Test. Median difference, 95% confidence interval and p-value will also be 
presented.
Additional PK parameters or statistical analyses may be performed as appropriate.
10.2.5
Safety Analysis
Safety variables will be summarized for the safety population.
Adverse Event:
Treatment Emergent adverse events, i.e. AEs that are emergent or that worsen after the first 
mini lozenge administration, will be summarized by presenting, for each treatment, the 
number and percentage of subjects having any AE, any AE in each MedDRA System Organ 
Class (SOC) and having each individual AE. The subset of AEs suspected of a relationship to 
study drug will be presented similarly. All treatment-emergent AEs will also be tabulated by 
severity. Any other information collected (e.g. action taken, duration, outcome) will be listed. 
Each AE will be attributed to the treatment taken most recently before the onset of the AE.
Vital signs:
Vital signs including temperature will be summarized by time-point and treatment.  Summary 
statistics will include mean, standard deviation, minimum, median, and maximum. No 
inferential statistics will be presented. Data will be listed with abnormal values flagged.
Physical examination
Physical Examination data will be listed with abnormal values flagged.
Safety Laboratory:
Safety Laboratory data will be listed with abnormal values flagged.


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10.2.5.1
Criteria for assessing safety
Vital signs, clinical safety laboratory tests and monitoring of adverse events will be used to 
assess the safety and tolerability of the study products
10.2.6
Other Analysis
Data for the following variables will be listed for the safety population: 

CO monitoring
10.2.7
Definition of Analysis Populations
The safety population is defined as all randomized subjects who receive at least one dose of 
study medication.
The PK population is defined as all randomized subjects who completed both periods, and 
who had no major protocol deviations concerning pharmacokinetics. 
The following 2 PK analysis sets are defined to address the PK objectives and further PK 
considerations within this study:

PKAS1 includes all subjects of the PK population. Subjects with baseline nicotine 
concentration > 5% of the individual Cmax for either period will be excluded. This analysis 
set will be used in PK summaries, the primary analysis, and the secondary analysis..

PKAS2 includes all subjects of the PK population, for which the relevant predose-adjusted 
PK parameters (at least one AUC or Cmax) can be derived. This analysis set will be used 
in PK summaries and an additional analysis. 
10.2.8
Exclusion of Data from Analysis 
Subjects who deviate from the protocol will be identified and excluded from the 
pharmacokinetic analyses as agreed by the biostatistician and medical director or designee. 
For the primary analysis of PK parameters, subjects with baseline concentrations > 5% of Cmax 
will be excluded (from PKAS1).
Exclusion of any data from the analyses will be determined during a Blind Data Review 
Meeting prior to database lock. Any reasons for exclusion from an analysis population will be 
listed, if applicable.
10.2.9
Handling of Dropouts and Missing Data 
All existing data for subjects who are dropouts from the study will be included in the 
pharmacokinetic statistical analysis.


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If any concentration data is missing or deviates from the planned time of collection, then the 
pharmacokineticist may calculate the PK parameters using the available data. 
Missing values of Kel can be estimated from the subject’s mean Kel value from the other 
treatments. If a Kel value cannot be calculated from the other treatments, then the Kel will be 
obtained from the treatment mean value for subjects with non-missing values of Kel in the 
period in which it is not available. This estimated Kel can be used to calculate other Kel 
dependent variables. This Kel value derivation is only applied for pre-dose concentration 
adjustments.
For nicotine concentration:

BLOQ values obtained before Cmax will be imputed as zero.

BLOQ values obtained after Cmax will be imputed as “Not detectable” (ND), which 
will be shown as missing (explanations will be specified in the footnote of TFLs).
10.2.10
Interim Analysis 
No interim analysis is planned for this study
11
STUDY GOVERNANCE CONSIDERATIONS
11.1
Quality Control 
In accordance with applicable regulations including GCP, and GSK procedures, GSK or 
designee (i.e. third party vendor) monitors will contact the site prior to the start of the study to 
review with the site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.
When reviewing data collection procedures, the discussion will include identification, 
agreement and documentation of data items for which the CRF will serve as the source 
document.
GSK or designee will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.
The extent and nature of monitoring will be described in a written monitoring plan on file at 
GSK CH. The investigator (or designee) agrees to allow the monitor direct access to all 
relevant documents and agrees to co-operate with the monitor to ensure that any problems 
detected in the course of these monitoring visits are resolved.


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11.2
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
agencies may conduct a regulatory inspection at any time during or after completion of the 
study. 
In the event of an assessment, audit or inspection, the investigator (and institution) must agree 
to grant the advisor(s), auditor(s) and inspector(s) direct access to all relevant documents and 
to allocate their time and the time of their staff to discuss the conduct of the study, any 
findings/relevant issues and to implement any corrective and/or preventative actions to 
address any findings/issues identified.
The investigator(s) will notify GSK CH or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with GSK 
CH or its agents to prepare the study site for the inspection and will allow GSK CH or its 
agent, whenever feasible, to be present during the inspection. The investigator will promptly 
apply copies of the inspection finding to GSK CH or its agent. Before response submission to 
the regulatory authority, the investigator will provide GSK CH or its agents with an 
opportunity to review and comment on responses to any such findings. 
The sponsor will be available to help investigators prepare for an inspection.
11.3
Regulatory and Ethical Considerations
11.3.1
Institutional Review Board/ Ethics Committee 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, investigator brochure/safety statement 
(including any updates) and other relevant documents, e.g., recruitment advertisements, if 
applicable, from the IRB/EC.  All correspondence with the IRB/EC should be retained in the 
investigator file.  Copies of IRB/EC approvals should be forwarded to GSK CH prior to the 
initiation of the study, and also when subsequent amendments to the protocol are made.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In that 
event, the investigator must notify the IRB/EC and GSK CH in writing immediately after the 
implementation.
11.3.2
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 GCP (ICH 1996 and revision 2), and the Declaration of 
Helsinki (World Medical Association 2013). 


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In addition, the study will be conducted in accordance with the protocol, the ICH guideline on 
GCP, and applicable local regulatory requirements and laws.
11.3.3
Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by laws. 
When study data are compiled for transfer to GSK CH and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by GSK CH in order to de-identify study subjects. The use of 
initials should be avoided.  
The study site will maintain a confidential list of subjects who participated in the study, 
linking each subject’s numerical code to his or her actual identity.  In case of data transfer, 
GSK CH will maintain high standards of confidentiality and protection of subjects’ personal 
data consistent with applicable privacy laws.
The informed consent documents must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws.
The informed consent documents used during the informed consent process must be reviewed 
and approved by the sponsor, approved by the IRB/EC before use, and available for 
inspection.
The investigator must ensure that each study subject 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 before any study-specific activity is performed.  The investigator 
will retain the original of each subject's signed informed consent document.
11.3.4
Subject Recruitment 
Advertisements approved by IRBs/ECs and investigator databases may be used as recruitment 
procedures.  Use of ethics committee approved, generic, prescreening questionnaire to assess 
basic subject characteristics to determine general eligibility for this study is allowed.  This 
generic questionnaire may be used by sites as a phone script and/or to review internal 
databases to identify subjects.  
GSK CH will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study subjects before such materials are used. 


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11.3.5
Reporting of Safety Issues and Serious Breaches of the Protocol or 
ICH GCP 
Within a GSK CH a serious breach is defined as a breach likely to affect to a significant 
degree the safety and rights of a subject or the reliability and robustness of the data generated 
in GSK CH- sponsored human subject research studies. 
In the event of any prohibition or restriction imposed (i.e., clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, GSK CH should be informed immediately. 
In addition, the investigator will inform GSK CH 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.
11.4
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins in accordance with applicable GSK processes.
11.5
Provision of Study Results to Investigators
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-agreeable 
location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
The procedures and timing for public disclosure of the results summary and for development 
of a manuscript for publication will be in accordance with GSK Policy.
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge.
11.6
Records Retention
Following closure of the study, the investigator must maintain all site study records (except 
for those required by local regulations to be maintained elsewhere), in a safe and secure 
location.


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The records (study/ site master file) must be maintained to allow easy and timely retrieval, 
when needed (e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of these records 
can be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); 
however, caution needs to be exercised before such action is taken. 
The investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original and meet accessibility and retrieval standards, including re-generating a 
hard copy, if required.  Furthermore, the investigator must ensure there is an acceptable back-
up of these reproductions and that an acceptable quality control process exists for making 
these reproductions.
The investigator must assure that the subject’s anonymity will be maintained.  On CRFs or 
other documents submitted to GSK CH, subjects should not be identified by their names or 
initials, but by an identification code. The investigator should keep a separate log of subjects’ 
codes, names and addresses.  Documents not for submission to GSK CH, e.g. subjects’ 
written consent forms, should be maintained by the investigator in strict confidence.
Records and documents, including signed ICF, pertaining to the conduct of this study must be 
retained by the investigator for 25 years from the issue of the final Clinical Study Report 
(CSR)/ equivalent summary unless local regulations or institutional policies require a longer 
retention period. The minimum retention time will meet the strictest standard applicable to 
that site for the study, as dictated by any institutional requirements or local laws or 
regulations, GSK standards/procedures, and/or institutional requirements.  
No study document should be destroyed without a prior written agreement between GSK CH 
and the investigator. The investigator must notify GSK of any changes in the archival 
arrangements, including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the investigator is no longer associated with the site.
11.7
Conditions for Terminating the Study 
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of GSK CH.  In addition, GSK CH retains the right to discontinue development of 
nicotine prototype mini lozenge at any time. 
If a study is prematurely terminated, GSK CH will promptly notify the investigator.  After 
notification, the investigator must promptly contact all participating subjects and should 
assure appropriate therapy/ follow-up for the subjects.  As directed by GSK CH, all study 
materials must be collected and all CRFs completed to the greatest extent possible. Where 
required by the applicable regulatory requirements, GSK CH should inform the regulatory 


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authority(ies) and the investigator should promptly inform the IRB/EC and provide the 
IRB/EC a detailed written explanation of the termination or suspension. 
If the IRB/EC terminates or suspends its approval/favorable opinion of a trial, the investigator 
should promptly notify the GSK CH and provide GSK CH with a detailed written explanation 
of the termination or suspension.
Upon completion or premature discontinuation of the study, the GSK CH monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in accordance 
with applicable regulations including GCP, and GSK CH Standard Operating Procedures.
11.8
Definition of Study End/ End of Study 
Study End (SE) date is defined as the date of the last subject visit of the last subject to 
complete the study (LSLV). 
The End of Study (EOS) is the date of the last event/testing/reading related to the primary and 
secondary endpoints, to be achieve no later than 8 months after SE.
12
REFERENCES
1.
 
2.
 
3.
 
4. S6491365 (2011) A Single Dose Bioequivalence Study of 2 mg and 4 mg Mini Cherry 
Nicotine Lozenges. GSK Study
13
APPENDIX
13.1
ABBREVIATION
The following is a list of abbreviations that may be used in the protocol.
Table 13-1
Abbreviation
Abbreviation
Term
AE
adverse event
Abs
absolute
CCI
CCI
CCI


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Abbreviation
Term
ALT
alanine aminotransferase
ANOVA
analysis of variance
AST
aspartate aminotransferase
AUC
area under the curve
AUC0-t
area under the concentration‑time curve from time 0 to 24 hours
AUC0-inf
area under the concentration-time curve from time 0 to infinity
AUClast
area under the concentration-time curve from time 0 to the time of the last 
quantifiable concentration
BA
bioavailability
BE
bioequivalence
BLOQ
below level of quatification
BMI
body mass index
BP
blood pressure
BPM
beats per minute
BUN
blood urea nitrogen
Cav
average concentration
CDS
core data sheet
Ceff
efficacious concentration
CI
confidence interval
CL/F
apparent oral clearance
CLr
renal clearance
Cmax
peak or maximum observed concentration
CK
Creatine kinase
CO2
carbon dioxide (bicarbonate)
CPL
clinical project lead
CRF
case report form
CRO
contract research organization
CSA
clinical study agreement
CSF
cerebrospinal fluid
CTA
clinical trial application
CV
coefficient of variation
DCT
data collection tool
DNA
deoxyribonucleic acid
EC
ethics committee
ECG
electrocardiogram
EDC
electronic data capture
EDTA
edetic acid (ethylenediaminetetraacetic acid)
EOS
end of study


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Abbreviation
Term
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (United States)
FDAAA
Food and Drug Administration Amendments Act (United States)
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transpeptidase
hCG
human chorionic gonadotropin
HDL-C
high density lipoprotein cholesterol
HIV
human immunodeficiency virus
IB
investigator’s brochure
ICH
International Conference on Harmonisation
ICF
informed consent form
ID
identification
IND
investigational new drug application
INR
international normalized ratio
IRB
institutional review board
IRC
internal review committee
IUD
intrauterine device
IUS
Intrauterine system
K2EDTA
dipotassium ethylene diamine tetraacetic acid
LDL-C
low density lipoprotein-cholesterol
LFT
liver function test
LSLV
last subject last visit 
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
medical Dictionary for Regulatory Activities
MTD
maximum tolerated dose
N/A
not applicable
ND
not done
NOAEL
no observed adverse effect level
NOEL
no observed effect level
PD
pharmacodynamics
PG 
pharmacogenomics
PI
principal investigator
PII
personally identifiable information
PK
pharmacokinetics
PKAS1
PK analysis set 1


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Abbreviation
Term
PKAS2
PK analysis set 2
PR
pulse rate
PT
prothrombin time
QC
quality control
QTc
corrected QT
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SCr
serum creatinine
SE
study end
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SOC
system organ class
SOP
standard operating procedure
SmPC
summary of product characteristics
SRSD
single reference study document
SS
safety statement
SUSAR
suspected unexpected serious adverse reactions
t1/2
terminal half-life
Tmax
time to reach maximum concentration
TFL
tables, figures and listings
THC
tetrahydrocannabinol
ULN
upper limit of normal
US
United States
USPI
United States package insert
Vz/F
apparent oral volume of distribution
WBC
white blood cell
Trade marks are owned by or licensed to the GSK group of companies

SAP_001.pdf: 
 
 
 
 
Statistical Analysis Plan for 
Protocol 
207791 
 
 
A Single Dose Bioequivalence Study of a 2 mg Prototype 
Mini Nicotine Lozenge vs 2 mg Nicotine Mini Lozenge 
(Nicorette Minis) in Healthy Smokers Under Fasting 
Conditions 
 
 
GlaxoSmithKline Consumer Healthcare 
GlaxoSmithKline Research & Development 
Limited 980 Great West Road Brentford 
Middlesex, TW8 9GS UK 
 
1. Statistical Analysis Plan approval date: 28-May-2019 
 
 
 
 
 
Copyright: GlaxoSmithKline. This document contains confidentiality statements 
that are not relevant for this publicly available version 


Nicotine Polacrilex 
Study 207791 
Final Statistical Reporting and Analysis Plan, 23-MAY-2019 
This document contains confidentiality statements
that are not relevant for this publicly available version
Property of GSK Consumer Healthcare 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of GSK 
Page 1 of 28 
STATISTICAL REPORTING AND ANALYSIS PLAN  
A Single Dose Bioequivalence Study of a 2 mg Prototype 
Mini Nicotine Lozenge vs 2 mg Nicotine Mini Lozenge 
(Nicorette Minis) in Healthy Smokers Under Fasting 
Conditions
Protocol Number: 207791 
Celerion Number: 
Phase: 
CA22714 
1 


Nicotine Polacrilex 
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Final Statistical Reporting and Analysis plan, 23-MAY-2019 
 
 
 
GlaxoSmithKline Consumer Healthcare Confidential 
Page 2 of 28 
Document History 
 
Document 
Version Date 
Summary of Changes (New analysis or Change 
in planned analysis) 
Final Analysis Plan 
23-MAY-2019 
Not applicable (N/A) 
 
 
 
 


Nicotine Polacrilex 
Study 207791 
Finni Statistical Reporting and Analysis plnn. 23-MA Y-2019 
Statistical Reporting and Analysis Plan Signature Page 
Compound Name: Prototype Mini Nicotine Lozenge 
Protocol: 207791 
Study Title: A Single Dose Bioequivalence Study of a 2 mg Prototype Mini Nicotine Lozenge 
vs 2 mg Nicotine Mini Lozenge (Nicorette Minis) in Healthy Smokers Under Fasting 
Conditions 
Issue Date: 23 May 2019 
Signarurc: 
, 
S 
Bfostatisticinn, Data Management and Biometrics 
Celerion, Lincoln, Nebraska, USA 
Date: 
Pharmacokinetic Scientist, Clinical Pharmacology and Pharmacometrics, 
Data Management and Biometrics 
Celerion, Montreal, Quebec, Canada 
sig
..
 
, MS 
Principal Statistician 
Biostatistics and Data Management (US) 
GSK Consumer Healthcare, Warren, New Jersey, USA 
GlaxoSmithKline Consumer Healthcare Confidential 
Page 3 of28 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Final Statistical Reporting and Analysis plan, 23-MAY-2019 
 
 
 
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Table of contents 
Document History ............................................................................................................... 2 
Table of contents ................................................................................................................. 4 
List of Abbreviations .................................................................................................................. 7 
1 
Summary of Key Protocol Information ............................................................................... 8 
1.1 
Study Design ............................................................................................................ 8 
1.2 
Study Objectives ...................................................................................................... 9 
1.3 
Treatments ............................................................................................................... 9 
1.4 
Sample Size Calculation ........................................................................................ 10 
2 
Planned Analyses ............................................................................................................... 10 
2.1 
Interim Analysis ..................................................................................................... 10 
2.2 
Final Analyses ....................................................................................................... 10 
3 
Considerations for data analyses and Data Handling Conventions ................................... 11 
3.1 
Baseline Definition ................................................................................................ 11 
3.2 
Subgroups/Stratifications ....................................................................................... 12 
3.3 
Centers Pools ......................................................................................................... 12 
3.4 
Timepoints and Visit Windows ............................................................................. 12 
4 
Data Analysis ..................................................................................................................... 12 
4.1 
Populations for Analysis ........................................................................................ 12 
4.1.1 
Subject Disposition and Eligibility for Analysis Populations ............... 12 
4.1.2 
Protocol Deviations ............................................................................... 13 
4.1.3 
Analysis Populations ............................................................................. 14 
4.2 
Subject Demographics and Other Baseline Characteristics ................................... 15 
4.2.1 
Demographic Characteristics ................................................................ 15 
4.2.2 
General Medical History ....................................................................... 15 
4.2.3 
Substance Use and Fagerstrom Test Of Nicotine Dependence ............. 15 
4.3 
Treatments (Study Products, Other Concomitant Therapies, Compliance) .......... 15 
4.3.1 
Study Product Compliance and Exposure ............................................. 15 
4.3.2 
Non-Smoking Compliance and CO Monitoring Results ...................... 16 
4.3.3 
Prior and Concomitant Medication ....................................................... 16 
4.4 
Analysis of Pharmacokinetics ................................................................................ 16 
4.4.1 
Primary Pharmacokinetic Endpoint ...................................................... 16 
4.4.2 
Handling of Missing Values/Censoring/Discontinuations .................... 20 
4.5 
Analysis of Secondary Objectives ......................................................................... 21 


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4.5.1 
Pharmacokinetic (Secondary) ............................................................... 21 
4.6 
Analysis of Safety .................................................................................................. 23 
4.6.1 
Adverse Events and Serious Adverse Events ........................................ 23 
4.6.2 
Laboratory Tests .................................................................................... 24 
4.6.3 
Vital Signs ............................................................................................. 24 
4.6.4 
Findings on Physical Examination ........................................................ 24 
4.6.5 
Other Safety Variables .......................................................................... 25 
4.6.6 
Handling of missing values/censoring/discontinuations ....................... 25 
4.7 
Analysis of Other Variables ................................................................................... 25 
5 
Changes to the Protocol Defined Statistical Analysis Plan ............................................... 26 
6 
Reference List .................................................................................................................... 27 
Attachment 1: List of Data Displays ........................................................................................ 28 
 


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The purpose of this Statistical Reporting and Analysis Plan is to describe the planned analyses 
and outputs to be included in the Clinical Study Report (CSR) for Protocol 207791. 
This statistical reporting and analysis plan (RAP) is intended to describe the bioequivalence 
analyses required for the study.  
 
 
 


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List of Abbreviations 
 
AE 
Adverse event 
ATC 
Anatomical therapeutic chemical 
AUC0-inf 
Area under the plasma concentration versus time curve calculated from time zero to infinity 
AUC0-t 
Area under the plasma concentration versus time curve from administration to last observed 
concentration t 
BDRM 
Blinded Data Review Meeting  
BE 
Bioequivalence 
BLOQ 
Below lower limit of quantitation 
BMI 
Body mass index  
CI 
Confidence interval  
Cmax 
The highest observed plasma nicotine concentration 
CO 
Carbon monoxide  
CSR 
Clinical study report  
CV% 
Coefficient of variation 
DBP 
Diastolic blood pressure 
ECG 
Electrocardiogram 
GMR 
Geometric mean ratio 
GSKDrug 
GSK Drug Dictionary 
ICH 
International Council for Harmonisation 
Kel 
Apparent elimination rate constant for plasma nicotine 
LLOQ 
Lower limit of quantification  
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
Pharmacokinetic  
PKAS 
Pharmacokinetic analysis set 
Q1 
1st quantile 
Q3 
3rd quantile 
RCt 
Estimated residual concentration (nicotine in plasma) at time t 
SAE 
Serious adverse event  
SBP 
Systolic blood pressure 
SEM 
SD 
Standard error of the mean 
Standard deviation 
SOC 
System organ class 
RAP 
Statistical reporting and analysis plan 
t1/2 
Apparent elimination half life 
TEAE 
Treatment emergent adverse event 
TFLs 
Tables, figures, and listings 
Tmax 
Time to maximum plasma nicotine concentration 


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1 
Summary of Key Protocol Information 
The purpose of this study is to assess the bioequivalence of the prototype mini lozenge to the 
reference product nicotine polacrilex mini lozenge (Nicorette Minis). 
The study will follow a randomized, open label, single dose, single center crossover design 
with 2 treatments. However, the analytical laboratory, pharmacokinetic scientist, programmer 
responsible for programming PK TFLs, and sponsor personnel, with the exception of the 
sponsor’s biostatistician, will remain blinded to treatment during the analysis of the plasma 
samples. After a 21-day screening period, subjects will check into the clinic on Day -2 and 
will be randomized to a sequence prior to dosing. Subjects will be randomized by sequence to 
receive 2 mg prototype mini lozenges in Period 1 followed by 2 mg nicotine mini lozenges 
(Nicorette Minis) in Period 2 or 2 mg nicotine mini lozenges (Nicorette Minis) in Period 1 
followed by 2 mg prototype mini lozenges in Period 2 according to a randomization scheme.  
1.1 
Study Design 
This study will be a single center, randomized, open label, single dose, two-way crossover in 
healthy smokers that smoke their first cigarette within 30 minutes of waking. Each subject 
will be treated with a single dose of the two study treatments in a randomized sequence. 
Subjects will be confined in the study facility for approximately 60 hours during each study 
session (for 36 hours pre dosing and for 24 hours post dosing) during which pharmacokinetic 
(PK) blood samples will be obtained. Subjects are to abstain from smoking during the 
confinement periods and be subject to random measurements of expired carbon monoxide 
(CO) to confirm abstinence. The CO levels must be ≤ 10 ppm throughout the study session. 
There will be at least a 5-day and not more than a 7-day clinical furlough period between 
treatment periods. For each treatment period, the clinical confinement period with restriction 
of smoking is at least 36 hours prior to dosing. The reported plasma half-life (t1/2) for 
nicotine is approximately 1 to 4 hours from previous pharmacokinetics studies (GSK study 
S3010466). The 36 hour smoking restriction prior to dosing will therefore minimize the 
residual nicotine amount from smoking during previous furlough.  
Treatment sequences are presented in Table 1-1: Treatment Sequences 
Table 1-1: Treatment sequences 
Sequence 
Period 1 
Period 2 
1 
A 
B 
2 
B 
A 
Treatment A: 2 mg Prototype Mini Nicotine Lozenge 
Treatment B: 2 mg Nicorette Mini Lozenge 
 
 


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1.2 
Study Objectives 
 
Objectives 
Endpoints 
Primary Objective 
Primary Endpoint 
• 
To assess the bioequivalence of the 
nicotine 2 mg prototype mini lozenge with 
the 2 mg nicotine polacrilex mini lozenge 
(Nicorette Minis), in terms of nicotine 
AUC0-t, AUC0-inf and Cmax 
• 
AUC0-t – Area under the plasma 
concentration versus time curve from time 
zero to time t, where t is the time of the last 
measurable plasma concentration of nicotine, 
estimated. 
• 
AUC0-inf – Area under the plasma 
concentration versus time curve from time 
zero extrapolated to infinity. 
• 
Cmax – The highest observed plasma 
nicotine concentration.  
Secondary Objectives 
Secondary Endpoints 
• 
To compare the nicotine 2 mg prototype 
mini lozenge to the 2 mg nicotine 
polacrilex mini lozenge (Nicorette Minis) 
in terms of tmax, t1/2, and Kel 
• 
Tmax – The time of the maximum plasma 
concentration 
• 
t1/2 – The plasma half life  
• 
Kel – The elimination rate constant 
• 
To evaluate the safety of the nicotine 2 
mg prototype mini lozenge 
• 
Safety assessments consists of monitoring 
and recording adverse events (AEs) and 
clinical safety laboratory tests 
 
1.3 
Treatments 
In each treatment period, each subject will receive one single dose of the respective study 
drug according to the treatment sequence they would be randomized to (See Table 1-1: 
Treatment Sequences).  
Following an overnight fast of least 10 hours, subjects will receive investigational product at 
approximately 8:00 AM (plus or minus 2 hours). Subjects will keep the lozenge in their 
mouth, occasionally moving it side to side, allowing it to slowly dissolve completely, and try 
to minimize swallowing. Subjects will not chew the lozenge. In order to standardize the 
conditions on pharmacokinetic sampling days, all subjects will be required to refrain from 
lying down (except when required for blood pressure and pulse rate), eating, and drinking 
beverages, with the exception of water, for the first 4 hours after dosing. Water may be given 
after one hour postdose.  
The nicotine prototype mini lozenge (test) and the Nicorette Mini lozenges (reference) will be 
supplied as 2 mg lozenges. 
For PK and safety analyses, treatments will be described as follows: 
 


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Table 1-2: Treatment Descriptions 
Treatment 
Short Description (text, tables headers, 
figures, listings, SAS output) 
Long Description  
A 
Prototype 2 mg Lozenge 
2 mg Prototype Mini Nicotine Lozenge 
B 
Nicorette 2 mg Lozenge 
2 mg Nicorette Mini Lozenge 
 
1.4 
Sample Size Calculation 
Enough healthy adult smokers will be screened to randomize at least forty (40) healthy adult 
smokers, to ensure that thirty-two (32) complete the entire study assuming a 20% dropout and 
non-evaluable rate. The highest intra-subject coefficient of variation (CV) observed in 
previous studies was 23%. The protocols that were used to select the highest CV for the 
sample size calculation are: 
 
 
 
 
 and GSK study S6491365 (2mg nicotine polacrilex mini cherry lozenge vs 2mg 
nicotine polacrilex mini mint lozenge: Cmax =13.7%; AUC0-t =10%). A total of thirty-two 
(32) evaluable subjects will achieve a 90% power at 5% significance level. The true ratio that 
was used in the sample size calculation was 1.05. 
2 
Planned Analyses 
2.1 
Interim Analysis 
No interim analysis is planned; however, there will be 2 Blinded Data Review Meetings 
(BDRMs) where blinded data (Safety and PK) will be reviewed. 
2.2 
Final Analyses 
The final planned primary analyses will be performed after the completion of the following 
sequential steps: 
1. All subjects have completed the study as defined in the protocol. 
2. All required database cleaning activities have been completed and database has been 
locked. 
3. All criteria for unblinding the randomization codes have been met and the randomization 
codes have been distributed. 
 
CCI


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3 
Considerations for data analyses and Data Handling 
Conventions 
3.1 
Baseline Definition 
For PK endpoint analyses: 
The predose nicotine concentration will be estimated based on a log-linear regression 
according to a mono-compartmental deconvolution of the three predose time points, i.e. -45 
minutes, -30 minutes, and -15 minutes prior to dosing. Blood samples for calculation of 
predose nicotine concentrations will be collected during both study periods. If mono-
compartmental deconvolution cannot be computed due to high variability between the -45 
minutes, -30 minutes, and -15 minutes time points, then the -15 minutes time point will be 
used as predose. If the -15 minutes time point is missing, then the -30 minutes time point will 
be used. Likewise, if the -30 minutes time point is missing, then the -45 minutes time point 
will be used. 
The individual residual baseline nicotine concentration at time t (RCt,ij) will be estimated 
using log-linear regression according to a mono-compartmental deconvolution as follows: 
Ct,ij(R) = Ct,ij(O) – [Cpredose,ij * exp (-Kelij*t)] 
Where:  
Ct,ij(R) = baselineadjusted nicotine concentration at time t,  
Ct,ij(O) = observed nicotine concentration detected in subject plasma at time t, 
Cpredose = plasma nicotine concentration before dosing (estimated by mono-compartmental 
deconvolution of the three predose time points (-45 minutes, -30 minutes, and -15 minutes)), 
Kel = slope calculated by log-linear regression using the elimination portion of the PK profile 
for the associated treatment, 
t = time (h) between the considered blood sampling and the time of predose sampling, 
i = treatment (Test or Reference), and  
j = Subject 
For baseline-adjustment, if Kel cannot be calculated for an associated treatment, the Kel for 
the same subject from the other period will be used. Where Kel is not calculable for both 
periods, no baseline-adjustment will be performed for that subject. 
Unless otherwise stated, if baseline data is missing, no derivation will be performed and the 
predose value will be set to one-half of the lower limit of quantitation (LLOQ). After 
correction for baseline adjustment values, some concentrations may be below the lower limit 
of quantitation and some may be negative values. Negative values will be assigned a value of 
zero in the analyses and all other values obtained will be reported as is even if these values are 
BLQ.  


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For safety endpoint analyses: 
• Subject level baseline is defined as the latest assessment with a non-missing value 
before the first dosing (e.g. clinical laboratory tests and vital signs). 
• Treatment level baseline is defined as the latest assessment with a non-missing value 
before the Treatment dosing (e.g. expired CO measurements).  
3.2 
Subgroups/Stratifications 
Not applicable 
 
3.3 
Centers Pools 
This will be a single center study. 
 
3.4 
Timepoints and Visit Windows 
Not Applicable 
4 
Data Analysis 
Data analysis will be performed by Celerion Data Management and Biometrics. The statistical 
analysis software used will be SAS version 9.3 or higher in a WINDOWS environment using 
SAS Enterprise Guide.   
Prior to database closure, 2 BDRMs will be conducted in which various aspects of the trial 
will be discussed and study populations will be agreed upon.  
Except as described below, all listings will be produced for all randomized subjects.   
4.1 
Populations for Analysis 
Tables described in this section will be produced for all randomized subjects. Subject 
disposition (Table 14.1-1) will include all screened subjects. All screening failure subject data 
will be listed. 
4.1.1 
Subject Disposition and Eligibility for Analysis Populations 
Subject disposition for all screened subjects will be summarized as the number of subjects 
screened, number of subjects enrolled (subjects are considered enrolled when they check in 
and have at least one assessment on Day -2 of Period 1), number of subjects not randomized 
with discontinuation reason, number and percentage of subjects who received test product, 
completed the study, and who discontinued with discontinuation reason within each period by 


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sequence and overall (Table 14.1-1).  All randomized subject disposition data will be 
presented in Listing 16.2.1-1. 
Data from screening failures and any non-randomized subjects (screening number, date of 
screening, date of informed consent, year of birth, sex, race, ethnicity, occurrence of SAE 
during the screening period and before randomization, if applicable, primary reason for 
screening failure and criteria number met/not met) will be presented in Listing 16.2.1-2. The 
Inclusion/ Exclusion criteria will be presented by number in Listing 16.2.1-3, with subject 
eligibility for study presented in Listing 16.2.5-1. Subject check-in and return responses will 
be presented in Listing 16.2.5-2. A complete listing of subjects with screening and 
randomization numbers is presented in Listing 16.2.1-4.  
The number and percentage of subjects eligible for each of the subject analysis populations, 
and the number of subjects excluded from each population broken down by the reason for 
exclusion will be presented (Table 14.1-3.1 and Table 14.1-3.2). Subjects will be listed with 
their inclusion status to each analysis population, and the reason for exclusion if applicable 
(Listing 16.2.3-1and Listing 16.2.3-2). 
4.1.2 Protocol Deviations 
Protocol deviations will be collected and stored in the Celerion SharePoint system. All 
deviations collected in SharePoint will be categorized and subcategorized according to the 
Protocol Deviation Management Plan by the Celerion clinical study manager and provided as 
a Microsoft Excel file and read into SDTM to generate the data listing. 
Prior to database lock, any protocol deviation reported will be classified as major or minor. 
Major protocol deviations are those that may affect the integrity of the study data or may 
impact the eligibility or validity of subjects or data points for the analysis. 
The number and percentage of subjects with any major protocol deviation will be presented 
by treatment (Table 14.1-2). All major and minor protocol deviations will be listed (Listing 
16.2.2-1). 
Important 
protocol 
deviations 
(including 
deviations 
related 
to 
study 
inclusion/exclusion criteria, conduct of the trial, subject management or subject assessment) 
will be summarized and listed. 
Protocol deviations will be tracked by the study team throughout the conduct of the study. 
Data will be reviewed prior to unblinding and closure of the database to ensure all important 
deviations are captured and categorized.  
 
 
 


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4.1.3 Analysis Populations 
Three analysis populations are defined. 
  Population 
Definition / Criteria 
Analyses Evaluated 
Randomized 
The randomized population is defined as all 
subjects who were randomized. Any subject 
who received a randomization number will be 
considered to have been randomized. 
• Safety and PK 
Safety 
The safety population is defined as all 
randomized subjects who receive at least one 
dose of study medication. 
• Safety 
 
Pharmacokinetic 
The PK population is defined as all 
randomized subjects who completed both 
periods, and who had no major protocol 
deviations concerning pharmacokinetics.  
• PK 
NOTES :  
• Please refer to Attachment 1: List of Data Displays which details the population to be 
used for each displays being generated. 
The number of subjects included in each of the analysis populations, and the number excluded 
from each population broken down by the reason for exclusion will be presented (Table 
14.1.3-1 and Table 14.1.3-2).  Subjects eligible for analysis populations will be listed (Listing 
16.2.3-1).  Subjects excluded from any of the analysis populations will be listed in Listing 
16.2.3-2, with the reason for exclusion.   
The primary analysis will be to assess bioequivalence of both test products. The secondary 
analysis will be to assess similarities of Tmax and t1/2 of both test products. Pharmacokinetic 
analysis set 1 (PKAS1) will be used to draw conclusions for the primary and secondary 
analyses using baseline-adjusted data. 
The following 2 PK analysis sets (PKAS) are defined to address the PK objectives and further 
PK considerations within this study: 
• PKAS1 includes all subjects of the PK population. Subjects with baseline nicotine 
concentration > 5% of the individual Cmax for either period will be excluded. This 
analysis set will be used in PK summaries of observed and baseline-adjusted data, the 
primary analysis, and the secondary analysis. Both observed concentrations and 
baseline-adjusted concentrations are subsets of PKAS1. Subjects for whom there are 
insufficient data to calculate the PK parameters will be included in the concentration 
tables only and excluded from the PKAS1. 
• PKAS2 (for baseline-adjusted data only) includes all subjects of the PK population, 
for which the relevant baseline-adjusted PK parameters (at least one AUC or Cmax) 
can be derived, including those with baseline nicotine concentrations > 5% of the 


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individual Cmax for either period. This analysis set will be used in PK summaries and 
an additional analysis.  
4.2 
Subject Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics summaries will be produced for the Safety 
Population, PKAS1, and PKAS2 if different from PKAS1. 
4.2.1 Demographic Characteristics 
Categorical demographic variables sex, race, and ethnicity will be summarized by frequency 
tables. Continuous variables age, weight, height, and body mass index (BMI) will be 
summarized using descriptive statistics (mean, standard deviation, minimum, median, and 
maximum, Table 14.1-4). All demographic information will be listed in Listing 16.2.4-1. Age, 
while not included in the CRF, will be extracted from the clinical database and included in the 
demographic source data. 
4.2.2 General Medical History 
Medical conditions will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 21.0 according to the primary system organ class (SOC) and preferred 
term (PT). Medical diagnoses/surgeries, with start date and end date or ongoing at the start of 
study drug, will be listed in Listing 16.2.4-2.  
4.2.3 
Substance Use and Fagerstrom Test Of Nicotine Dependence 
Subject substance use and Fagerstrom test of nicotine dependence will be listed in Listing 
16.2.4-3 and Listing 16.2.4-4 respectively. 
4.3 
Treatments (Study Products, Other Concomitant Therapies, 
Compliance) 
Exposure to study products and other medications, as well as carbon monoxide (CO) 
monitoring results will be summarized on the Safety Population. 
4.3.1 Study Product Compliance and Exposure 
Study product exposure and compliance to the treatment will be summarized as follows by 
treatment (Table 14.3-1.1): 
• number (%) of subjects exposed to study drug; 
• number (%) of subjects fully compliant to dosing requirements (without any deviation); 
• number (%) of subjects with deviation from dosing requirements: 
- any deviation (total) 
- partial exposure (e.g. swallowing or premature expulsion of the lozenge) 
• number (%) of subjects with baseline nicotine concentration > 5% of the Cmax post-dose. 


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Study drug administration will be listed in Listing 16.2.5-3. 
4.3.2 Non-Smoking Compliance and CO Monitoring Results 
CO monitoring results will be listed in Listing 16.2.5-5.  
Number (%) of subjects with elevated maximum CO results (elevated CO threshold is 
> 10 ppm) will be summarized by treatment in Table 14.3-1.2. 
4.3.3 Prior and Concomitant Medication 
Prior and concomitant medications will be coded using Anatomical Therapeutic Chemical 
(ATC) classification and GSK Drug Dictionary (GSKDrug 1.4). 
The number (%) of subjects with concomitant medication during the study (ongoing or started 
after randomization) and the number (%) of subjects with concomitant medication during each 
treatment period (i.e. by treatment) will be summarized in a frequency table (Table 14.3-2). 
Frequncy counts of the number (%) of subjects in each ATC class will also be summarized by 
overall and treatment in the same table. 
All prior and concomitant medications will be listed (Listing 16.2.5-6); the listing will include 
the ATC 1st and 2nd levels, ATC code, GSKDrug preferred term , indication, dose, frequency, 
route, start date/time, and end date/time (or ongoing at final visit, as appropriate).  
Listing 16.2.5-6 will include all screened subjects while Table 14.3-2 will summarize only the 
safety population. 
4.4 
Analysis of Pharmacokinetics  
4.4.1 Primary Pharmacokinetic Endpoint 
4.4.1.1 
Primary Pharmacokinetic Endpoint Definition 
PK blood samples will be collected at predose (-45, -30, and -15 minutes), and 5, 10, 20, 30, 
40, 50, 60, 75, and 90 minutes and 2, 3, 4, 6, 8, 10, 14, 16, 20, and 24 hours postdose. 
Plasma concentrations of nicotine will be determined using liquid chromatography-tandem 
mass spectrometry (LC-MS/MS) methods validated with respect to accuracy, precision, 
linearity, sensitivity, and specificity at Celerion, Lincoln, Nebraska. The LLOQ for nicotine is 
expected to be 0.2 ng/mL. 
The primary objective will be evaluated based on the following comparison: 
The nicotine 2 mg prototype mini lozenge (Test) versus the 2 mg nicotine polacrilex mini 
lozenge (Nicorette Mini) Reference, in terms of nicotine AUC0-t, AUC0-inf and Cmax. 
The primary statistical analyses will be done based on baseline-adjusted data from the PK 
analysis set PKAS1 (see Section 4.1.3 for definition). An additional analysis (for 
baseline-adjusted data only) will be performed on PK analysis set, PKAS2. Safety population 


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will be used for individual plasma concentration listings and figures. The PKAS1 and PKAS2 
will be used for mean concentration-time figures.  
The PK evaluation will be done for the following two nicotine plasma concentration variables 
(details on correction are given in Section 4.4.1.4):  
• Observed concentration for PKAS1 
• Baseline-adjusted concentration (adjusted for non-zero baseline, as described in 
Section 4.4.1.4) for PKAS1 and PKAS2  
4.4.1.2 
Calculation of Primary Pharmacokinetic Parameters 
The appropriate noncompartmental PK parameters will be calculated from the plasma nicotine 
concentration-time for observed and baseline adjusted data using Phoenix® WinNonlin® 
Version 7.0 or higher or SAS Version 9.3 or higher, as appropriate. Baseline-adjustment on 
concentration data will be completed prior to PK parameter generation by the Data Analyst at 
Celerion. Actual sample times will be used in the calculations of PK parameters. The 
calculation of the actual time for nicotine will be in respect to the start of dose administration 
time of prototype mini nicotine lozenges (test) and nicotine mini lozenges (Nicorette Minis) 
Reference on Day 1. All PK parameters included in the protocol are listed in Table 4-1 below, 
and are defined as appropriate for study design. 
Table 4-1: Noncompartmental PK Parameters to be Calculated 
 
 
Parameter 
Label to be 
Used in the 
Text, Tables 
and Figures 
Definition 
Method of 
Determination 
AUC0-t 
AUC0-t 
Area under the plasma concentration 
versus time curve from time zero to 
time t, where t is the time of the last 
measurable plasma concentration of 
nicotine  
Calculated using the 
Linear Trapezoidal with 
Linear Interpolation 
Method  
AUC0-inf 
AUC0-inf 
Area under the plasma concentration 
versus time curve calculated from 
time zero to infinity 
AUC0-∞ = AUC0-t + 
(Clast/kel) 
where Clast is the last 
observed/measured 
concentration  
Cmax 
Cmax 
The highest observed plasma nicotine 
concentration 
Taken directly from 
bioanalytical data 
Pharmacokinetic parameters will not be calculated for subjects with less than 3 consecutive 
postdose time points with quantifiable concentrations. Subjects for whom there are 
insufficient data to calculate the PK parameters will be included in the concentration tables 
only and excluded from the statistical analysis (summary and inferential statistics). If a subject 


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is missing AUC0-inf in a given period, they will be included in the ANOVA model for the 
period in which they have calculable AUC0-inf parameter, as appropriate.   
The Kel will be determined using linear regressions composed of least 3 data points. The Kel 
will not be assigned if 1) the terminal elimination phase is not apparent, 2) if Tmax is one of 
the 3 last data points, or 3) if the R2 value is less than 0.70. In cases where the Kel interval is 
not assigned, the values of AUC0-inf are considered not calculable and will not be reported. 
Wherever the resulting t1/2 is more than half as long as the sampling interval, the Kel values 
and associated parameters AUC0-inf may not be presented as judged appropriate and in 
accordance with Celerion SOPs.  
4.4.1.3 
Statistical Hypothesis, Model, and Method of Analysis 
The PK analysis set, PKAS1 will be used for the PK evaluations on observed and baseline-
adjusted data. Subjects with baseline nicotine concentration > 5% (as observed at the -15 
minute time point) of the individual Cmax for either period, as well as subjects with less than 
3 consecutive postdose time points with quantifiable concentrations, will be excluded from 
the PKAS1 population. 
The PK parameters that will be used in the primary analyses are AUC0-t, AUC0-inf, and 
Cmax on baseline-adjusted concentration data. The AUC0-t, AUC0-inf, and Cmax on 
observed concentration data will also be presented for information purposes only.   
The null and alternative hypotheses to be tested in the primary analyses are: 
H0: The (geometric) mean AUC0-t (likewise AUC0-inf and Cmax) of nicotine prototype mini 
lozenge 2mg (Test) is less than 80.0% or greater than 125.0% of that of Nicorette Mini 
Lozenge 2mg (Reference). 
H1: The (geometric) mean AUC0-t (likewise AUC0-inf and Cmax) of nicotine prototype mini 
lozenge 2mg (Test) is between 80.0% and 125.0% of that of Nicorette Mini Lozenge 2mg 
(Reference). 
Individual plasma concentrations will be listed and summarized descriptively by treatment at 
each time point (n, arithmetic mean, standard deviation [SD], standard error of the mean 
[SEM], coefficient of variation [CV%], median, minimum, and maximum). The concentration 
vs. time profile will be graphed by formulation for individual subjects and for the mean on 
both original and logarithmic scales with PK Population (PKAS1).  
Observed and baseline-adjusted PK parameters will be summarized for each treatment by 
descriptive statistics (n, arithmetic mean, SD, SEM, geometric mean, CV%, geometric CV%, 
median, minimum, and maximum). A listing containing individual PK parameter values will 
be provided. A similar listing will be provided for observed and baseline-adjusted linear/raw   
plasma concentrations over time containing individual values and summary statistics for each 
time point. 
The level of precision for each concentration and PK parameter statistic will be presented as 
follows:  


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• Minimum/maximum in same precision as in bioanalytical data or parameter output,  
• Geometric mean/arithmetic mean/median in one more level of precision than 
minimum/maximum,  
• SD in one more level of precision than geometric mean/arithmetic mean/median,  
• n will be presented as an integer, and  
• Geometric CV%/CV% will be presented to the nearest tenth. 
BE of the test product with reference will be assessed by pairwise comparison of the PK 
parameters (Cmax, AUC0-t, and AUC0-inf) for the baseline-adjusted nicotine concentration 
profiles based on the PK analysis set PKAS1. 
A linear mixed effects model will be fit to the natural log-transformed PK variables (AUC0-t, 
AUC0-inf and Cmax), as the dependent variable, and treatment, period, and sequence as fixed 
effects. Subject nested within sequence will be a random effect. The presence of a statistically 
significant sequence effect at 5% significance level will be noted and its implications will be 
discussed in text, when applicable. 
Least squares estimates of treatment effects will be calculated and a 90% confidence interval 
(CI) for the treatment difference will be computed. The treatment difference and its CI will be 
exponentiated to obtain the ratio of the geometric means between the test and reference 
products and its CI. Bioequivalence will be determined if the 90% confidence interval for the 
treatment geometric mean ratio lies completely within the range 80.0 – 125.0%. 
Example SAS code: 
PROC MIXED DATA=XXX; 
CLASS TREATMENT SUBJECT PERIOD SEQUENCE; 
MODEL LOG_PK = TREATMENT PERIOD SEQUENCE / OUTPRED=RESIDS DDFM=KR; 
RANDOM SUBJECT(SEQUENCE); 
ESTIMATE “TEST A VS REFERENCE B” TREATMENT 1 -1 / CL ALPHA=0.1 E; 
LSMEANS TREATMENT / PDIFF ALPHA=0.1; 
ODS OUTPUT LSMEANS=LSM; 
ODS OUTPUT DIFFS=DIFF; 
RUN; 
4.4.1.4 
Correction for non-zero baseline for an additional analysis 
The predose nicotine concentration will be estimated based on a log-linear regression 
according to a mono-compartmental deconvolution of the three predose time points, i.e. -45 
minutes, -30 minutes and -15 minutes prior to dosing. Subsequent plasma concentrations will 
be adjusted by subtracting an estimate of the residual baseline plasma nicotine concentration 
computed with log-linear regression according to a mono-compartmental deconvolution as 
follows: 


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Ct,ij(R) = Ct,ij(O) – [Cpredose,ij * exp (-Kelij*t)] 
Where:  
Ct,ij(R) = baseline-adjusted nicotine concentration at time t,  
Ct,ij(O) = observed nicotine concentration detected in subject plasma at time t, 
Cpredose = plasma nicotine concentration before dosing (estimated by mono-compartmental 
deconvolution of the three predose time points (-45 minutes, -30 minutes, and -15 minutes)), 
Kel = slope calculated by log-linear regression using the elimination portion of the PK profile 
for the associated treatment, 
t = time (h) between the considered blood sampling and the time of predose sampling, 
i = treatment (Test or Reference), and  
j = Subject 
This adjustment will only be applied in cases where the predose value is greater than zero. 
If mono-compartmental deconvolution cannot be computed due to high variability between 
the -45 minutes, -30 minutes, and -15 minutes time points, then the -15 minutes time point 
will be used as predose. For further details, see Section 5 (Changes to the Protocol and 
Defined Statistical Analysis Plan).  
4.4.2 
Handling of Missing Values/Censoring/Discontinuations 
Subjects who deviate from the protocol will be identified and excluded from the PK analyses 
as agreed by the biostatistician and medical director or designee. For the primary analysis of 
PK parameters, subjects with baseline concentrations greater than 5% Cmax will be excluded 
from PKAS1.  
Exclusion of any data from the analyses will be determined during a Blinded Data Review 
Meeting prior to database lock. Any reasons for exclusion from an analysis population will be 
listed, if applicable. Formal documentation of these exclusion will be provided to Celerion 
from GSK prior to postlock analysis commencing.  
For nicotine concentration: 
• Below lower limit of quantitation (BLOQ) values obtained before Cmax will be 
imputed as zero. 
• BLOQ values obtained after Cmax will be imputed as “Not detectable” (ND), which 
will be treated as missing (explanations will be specified in the footnote of the tables, 
figures, and listings [TFLs]). 
If any concentration data is missing or deviates from the planned time of collection (i.e., if 
there are overlapping blood draw collection time points with subsequent blood draws), then 


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the pharmacokineticist may calculate the PK parameters using the available data, except if 
subjects have less than 3 consecutive postdose time points with quantifiable concentrations. 
Missing values of Kel can be estimated from the subject’s Kel value from the other treatment. 
If a Kel value cannot be calculated from the other treatment, then the Kel will be obtained 
from the treatment mean value for subjects with non-missing values of Kel in the treatment in 
which it is not available. This estimated Kel may be used to calculate other Kel dependent 
variables and may also be applied for predose concentration adjustments.  
All existing data for subjects  who do not complete the 2 periods from the study will be 
excluded from the PK statistical analysis (PKAS1 and PKAS2).  
4.5 
Analysis of Secondary Objectives 
4.5.1 
Pharmacokinetic (Secondary) 
4.5.1.1 
Secondary Pharmacokinetic Endpoint Definition 
The PK analysis sets PKAS1 and PKAS2 will be used for the secondary analysis. 
The PK evaluation will be done for the following two nicotine plasma concentration variables 
(details on correction are given in Section 4.4.1.4): 
• Observed concentration 
• Baseline-adjusted concentration (observed and adjusted for non-zero baseline, as 
described in Section 4.4.1.4) 
4.5.1.2 
Calculation of Secondary Pharmacokinetic Parameters 
The appropriate noncompartmental PK parameters will be calculated from the plasma nicotine  
concentration-time for baseline and baseline adjusted data using Phoenix® WinNonlin® 
Version 7.0 or higher or SAS Version 9.3 or higher, as appropriate. Actual sample times will 
be used in the calculations of the PK parameters. The calculation of the actual time for 
nicotine will be in respect to the start of dose administration time of prototype mini nicotine 
lozenges (test) and nicotine mini lozenges (Nicorette Minis, reference) on Day 1. All PK 
parameters included in the protocol are listed in Table 4-2 below, and are defined as 
appropriate for study design. 
Table 4-2: Noncompartmental PK Parameters to be Calculated 


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Parameter 
Label to be 
Used in the 
Text, Tables 
and Figures 
Definition 
Method of 
Determination 
tmax 
Tmax 
Time to maximum plasma nicotine 
concentration. If the maximum value 
occurs at more than one time point, 
Tmax is defined as the first time point 
with this value. 
Taken from clinical 
database as the 
difference in the time of 
administration and the 
time of the blood draw 
which is associated with 
the Cmax. 
t1/2 
t1/2  
Apparent elimination half-life. 
Calculated as 
t1/2 = ln(2) / Kel 
 
Kel 
Kel 
Apparent elimination rate constant for 
plasma nicotine 
The negative of the slope 
of a linear regression of 
the log(concentration)-
time for all 
concentrations > LLOQ 
Pharmacokinetic parameters will not be calculated for subjects with less than 3 consecutive 
postdose time points with quantifiable concentrations. Subjects for whom there are 
insufficient data to calculate the PK parameters will be included in the concentration tables 
only and excluded from the statistical analysis (summary and inferential statistics). 
The Kel will be determined using linear regressions composed of least 3 data points. The Kel 
will not be assigned if 1) the terminal elimination phase is not apparent, 2) if Tmax is one of 
the 3 last data points, or 3) if the R2 value is less than 0.7. In cases where the Kel interval is 
not assigned, the values of t1/2 are considered not calculable and will not be reported. 
Wherever the resulting t1/2 is more than half as long as the sampling interval, the Kel values 
and associated parameters (t1/2) may not be presented as judged appropriate and in 
accordance with Celerion SOPs. 
4.5.1.3 
Statistical Hypothesis, Model, and Method of Analysis 
The parameters Kel, t1/2 and tmax will be summarized (n, mean, median, first quantile [Q1], 
third quantile [Q3], minimum, maximum, SD, SEM) for each study treatment. A 
nonparametric analysis for Tmax will be performed to compare treatment differences using 
the Wilcoxon Signed Rank test. Median difference (Test-Reference), the Hodges-Lehmann 
estimator, and estimated confidence interval will be used to examing the location shift in 
Tmax (Hollander and Wolf (1999)). Tmax will not be ln-transformed. 
 The following methodology will be used for the nonparametric analysis for Tmax; 
• 
The treatment differences (Di, i=1, …, n) within each subject were calculated.   
• The M = [n(n+1)/2] Walsh averages were calculated using the following definition: 
Wij = (Di + Dj)/2, for i<=j,  i=1, …, n and j=1, …, n 


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• The M Walsh averages were ordered in sequential ascending order (denoted as       
W (1)<=W (2)<= …<=W (M)). 
• The median of the M Walsh averages was calculated. 
• The following was defined (using a normal approximation): 
Cα* = [n(n + 1)/4] – Zα/2 [(n*(n + 1)*(2n +1))/24]1/2, 
where Zα/2 is the upper α/2 percentile of the standard normal distribution. 
• The 1-α CI (ΔL, ΔU) are given by: 
∆L = W (Cα + 1),    ∆U = W (M - Cα) , 
where Cα is the largest integer less than or equal to Cα*. 
For the purposes of analysis, α was 0.05 in order to provide a 95% CI. 
Additional PK parameters may be calculated or statistical analyses performed, as appropriate.  
Pharmacokinetic parameters will be reported to 3 significant figures for individual parameters, 
with the exception of Tmax, which will be presented with 2 decimal places. The level of 
precision for each PK parameter statistic will be presented as follows:  
• Minimum/maximum/Q1/Q3 in same precision as in parameter output,  
• Mean/median in one more level of precision than minimum/maximum/Q1/Q3,  
• SD and SEM in one more level of precision than mean/median, and 
• n will be presented as an integer 
4.6 
Analysis of Safety 
4.6.1 
Adverse Events and Serious Adverse Events 
All treatment-emergent adverse events (TEAEs) will be summarized by primary system organ 
class and preferred term.  All TEAEs will be coded using MedDRA Version 21.0. 
TEAEs will be summarized with an overview (Table 14.3.1-1) and then by the number and 
percentage of subjects having any adverse event, an adverse event in each System Organ 
Class, and each individual adverse event (preferred term) (Table 14.3.1-2).  TEAEs suspected 
of a relationship to study medication will be presented in a similar manner (Table 14.3.1-3).  
All TEAEs will also be tabulated by maximum severity (Table 14.3.1-4).   
Additionally, all adverse events and serious adverse events will be listed (Listing 16.2.7-1 and 
Listing 16.2.7-2). Also, any adverse events that occur in screening failure subjects will be 
listed (Listing 16.2.7-3). 
Deaths occurring during treatment (if any) will be listed by treatment, including the date and 
study day of death, and the principal cause of death (Listing 14.3.2-1).  Non-fatal serious 
adverse events and adverse events causing study treatment discontinuation will be listed 
(Listing 14.3.2-2 and Listing 14.3.2-3).   


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4.6.2 
Laboratory Tests 
Laboratory normal ranges will be listed in Listing 16.2.8-1.1. Listings of all clinical 
laboratory evaluations (hematology, clinical chemistry, urinalysis) will be provided with the 
abnormal values flagged (Listing 16.2.8-1.2, Listing 16.2.8-1.3, and Listing 16.2.8-1.4). Urine 
illicit drug screen will be listed in Listing 16.2.8-2. 
Out-of-normal range flags will be recorded and presented as follows: high (H) and low (L) for 
numerical results and did-not-match (*) for categorical results. If a value fails the reference 
range, it will automatically be compared to a computer clinically significant (CS) range. If the 
value falls within the computer CS range, it will be noted as “N” for not clinically significant. 
If the value fails (i.e., fall outside of the CS range) the computer CS range, it will be flagged 
with a “Y” which prompts the PI to determine how the out-of-range value should be followed 
using 4 Investigator flags: "N", not clinically significant, "R", requesting a recheck, "^", 
checking at the next scheduled visit, or "Y", clinically significant. To distinguish the PI flag 
from the computer CS range flags, the PI flags of “N” and “Y” will be presented as “-“ and 
“+”, respectively, in the data listing. Additionally, a derived flag based on a search of the PI 
comments for a comment of “CS” or “Clinically Significant” will be used. The derived flag 
will be populated with “+” if the positive clinically significant determination is found in the 
comments for cases when the PI flag is populated with a “^” or an “R”. 
4.6.3 
Vital Signs 
Vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse rate, 
respiration, and body temperature) will be summarized with descriptive statistics (mean, 
standard deviation, minimum, median, and maximum) for the observed values by time point 
and treatment (Table 14.3-3). A listing of vital signs results, including body weight, will be 
provided with the abnormal values flagged (Listing 16.2.9-1).  
Normal vital signs are as follows: oral body temperature between 35.0 and 37.5 ºC; SBP 
between 90 and 140 mmHg; DBP between 55 and 90 mmHg; pulse rate between 50 and 
100 bpm. Low/high (L/H) values based upon normal ranges, the repeated measurement (R), 
and the scheduled measurement not done (*) will be flagged. 
 
4.6.4 
Findings on Physical Examination 
Any abnormal findings judged to be clinically significant which occurred before signing the 
informed consent form were to be documented as medical history and those occurring after 
signing the informed consent form were to be recorded as an AE. Any physical examination 
findings documented as AEs will be included in the summary of AEs. 
Findings from physical examination will be listed in Listing 16.2.9-4.  Any abnormal findings 
judged to be clinically significant which occurred before signing the informed consent form 
will be documented as medical history and those occurring after signing the informed consent 
form will be recorded as an AE. 


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4.6.5 
Other Safety Variables 
Data for the following variables will be listed only: 
• ECG (Listing 16.2.9-2) 
• Confirm Contraception (Listing 16.2.9-3)  
4.6.6 
Handling of missing values/censoring/discontinuations 
• No imputation of missing values is foreseen for any safety data. Incomplete dates recorded 
on the CRF will not be imputed. 
4.7 
Analysis of Other Variables 
Meal records will be listed in Listing 16.2.9-5. Phone call records will be listed in Listing 
16.2.9-6. Comments from all domains will be listed in Listing 16.2.9-7.  
 
 


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5 
Changes to the Protocol Defined Statistical Analysis Plan 
As per the Amended protocol (Amendment 2 dated 13 December 2018), the concentrations 
and PK parameters were to be presented on linear and log scales. However, after further 
discussion with GSK Consumer Healthcare, it was decided to present both the concentrations 
and PK parameters on linear scale only.   
As per the Amended protocol (Amendment 2 Dated 13 December 2018), the predose nicotine 
concentrations would be estimated bsed on a log-linear regression according to a mono-
compartmental deconvolution of the three predose time points (-45 minutes, -30 minutes, and 
-15 minutes). However, due to the high degree of variability of nicotine concentrations at the 
three predose time points, the log-linear regression according to a mono-compartmental 
deconvolution to zero time was not possible in a large proportion of subjects. Therefore, the 
baseline (time zero) concentation for all analyses was taken as being equivalent to the closest 
time prior to product administration (15 minutes). 
 
 
 
 
 


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6 
Reference List 
Hollander and Wolf. (1999). Nonparametric Statistical Methods, 2nd Edition, Wiley. 
 
 
 


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Attachment 1: List of Data Displays 
 
 
 
 
  
Study 207791 List of 
Outputs.xlsx