Clinical trial NCT03543137
Conditions: Tobacco Use Disorder
Sponsor: GlaxoSmithKline
Start date: 2018-06-18; Completion date: 2018-11-12
Enrollment: 37 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study will assess the bioequivalence of the test product (Nicotine Prototype Mini lozenge 4 milligrams \[mg\]) to a commercial reference product (nicotine polacrilex mini lozenge 4mg) 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 within 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). This will ensure approximately 29 evaluable participants per treatment arm. Each participant will be treated with a single dose of the two study treatments (test and reference) in a randomized sequence, under fasting conditions. 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 (4mg) by oral/buccal route of administration. arm 2: Participants will receive a single Nicorette Mini lozenge (4 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 4mg 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 4 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: 
Author(s) 
APPROVALS
Name
Reason for Approval
Approval Date CET*(MM/DD/YYYY)
11/28/2018 3:37:17 AM
11/29/2018 9:43:39 AM
11/29/2018 11:04:33 AM
Document Name 
Scope 
Document Type 
Document Subtype 
Document ID 
Version 
Approved Date in CET* 
Pages 
*CET: Central European Time
1.0
66
Protocol Amendment 1
0900c353811b6389
Nov 29,2018  11:04:00 AM
207790-Protocol Amendment-Protocol Amendment 1
Protocol Amendment
Studies
003 Study protocol and Amendment
PPD
PPD
PPD
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Nicotine Polacrilex
207790
Final Clinical Protocol Amendment 1
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
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CLINICAL PROTOCOL 207790
A Single Dose Bioequivalence Study of a 4 mg Prototype 
Mini Nicotine Lozenge vs 4 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:
207790
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 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
 
 
 
 
 
 
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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.........................................................20
4
SUBJECT SELECTION....................................................................................................21
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
5.6
Investigational Product Storage .............................................................................30
 
 
 
 
 
 


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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...................................................................................................31
6.1
Screening................................................................................................................31
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....................................................................................38
7.2.2
Pregnancy Testing .................................................................................39
7.2.3
Physical Examinations...........................................................................40
7.2.4
Height and Weight.................................................................................40
7.2.5
Blood Pressure and Pulse Rate..............................................................40
7.2.6
Respiratory Rate....................................................................................41
7.2.7
Temperature...........................................................................................41
7.2.8
Electrocardiogram .................................................................................41
7.3
Pharmacokinetics (PK) ..........................................................................................41
7.3.1
PK samples and safety laboratory tests .................................................41
7.3.2
Shipment of Pharmacokinetic Samples.................................................42
7.4
Blood Volume........................................................................................................42
7.5
Expired Carbon Monoxide (CO) measurement .....................................................43
8
ADVERSE EVENT...........................................................................................................43
 
 
 
 
 
 


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8.1
Definitions of Adverse Events and Serious Adverse Events.................................43
8.1.1
Adverse Event .......................................................................................43
8.1.2
Serious Adverse Event ..........................................................................44
8.2
Reporting Period ....................................................................................................45
8.2.1
Adverse Event .......................................................................................45
8.2.2
Serious Adverse Event ..........................................................................46
8.3
Reporting Procedures.............................................................................................46
8.3.1
Adverse Event .......................................................................................47
8.3.2
Serious Adverse Event ..........................................................................47
8.3.3
Sponsor’s Reporting Requirements to Regulatory Authorities and 
Ethics Committees.................................................................................48
8.4
Evaluating Adverse Events and Serious Adverse Events......................................48
8.4.1
Severity Assessment..............................................................................48
8.4.2
Causality Assessment............................................................................49
8.5
Withdrawal Due to an Adverse Event and Serious Adverse Events......................49
8.6
Pregnancy...............................................................................................................49
8.6.1
Time Period for Collecting Pregnancy Information..............................49
8.6.2
Action to be Taken if Pregnancy Occurs...............................................49
8.7
Follow-up of Adverse Events and Serious Adverse Events ..................................50
9
DATA MANAGEMENT ..................................................................................................51
9.1
Source Documents/ Data........................................................................................51
9.2
Case Report Form ..................................................................................................51
9.3
Data Handling ........................................................................................................51
9.3.1
Queries...................................................................................................52
9.4
Processing Patient Reported Outcomes .................................................................52
9.5
External Data..........................................................................................................52
10 STATISTICAL CONSIDERATIONS AND DATA ANALYSES...................................53
10.1
Sample Size Determination....................................................................................53
10.2
Statistical Methods and Analytical Plan ................................................................53
10.2.1
Demographic and Baseline Characteristics...........................................53
10.2.2
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)...........................................................................53
10.2.3
Primary Analysis ...................................................................................54
10.2.4
Secondary Analysis ...............................................................................55
10.2.5
Safety Analysis......................................................................................56
 
 
 
 
 
 


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10.2.6
Other Analysis.......................................................................................56
10.2.7
Definition of Analysis Populations .......................................................56
10.2.8
Exclusion of Data from Analysis ..........................................................57
10.2.9
Handling of Dropouts and Missing Data...............................................57
10.2.10
Interim Analysis ....................................................................................57
11 STUDY GOVERNANCE CONSIDERATIONS..............................................................58
11.1
Quality Control ......................................................................................................58
11.2
Quality Assurance..................................................................................................58
11.3
Regulatory and Ethical Considerations..................................................................59
11.3.1
Institutional Review Board/ Ethics Committee.....................................59
11.3.2
Ethical Conduct of the Study.................................................................59
11.3.3
Subject Information and Consent..........................................................59
11.3.4
Subject Recruitment ..............................................................................60
11.3.5
Reporting of Safety Issues and Serious Breaches of the Protocol or 
ICH GCP ...............................................................................................60
11.4
Posting of Information on Publicly Available Clinical Trial Registers.................60
11.5
Provision of Study Results to Investigators...........................................................60
11.6
Records Retention..................................................................................................61
11.7
Conditions for Terminating the Study ...................................................................62
11.8
Definition of Study End/ End of Study..................................................................62
12 REFERENCES ..................................................................................................................62
13 APPENDIX........................................................................................................................63
13.1
ABBREVIATION..................................................................................................63
 
 
 
 
 
 


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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....................................................................................38
Table 7-2
Blood Volume .......................................................................................42
Table 13-1
Abbreviation..........................................................................................63
 
 
 
 
 
 


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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 4 mg nicotine prototype mini lozenge to the 4 
mg mini mint lozenge.
Objectives and Endpoints
Primary objectives:

To assess the bioequivalence of the nicotine 4 mg prototype mini lozenge with the 4 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 4 mg prototype mini lozenge to the 4 mg nicotine polacrilex 
mini mint lozenge (Nicorette) in terms of tmax, t½, and Kel 

To evaluate the safety of the nicotine 4 mg protype mini lozenge
Secondary endpoints

tmax, the time of the maximum plasma concentration

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
 
 
 
 
 
 


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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 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 thirty-seven (37) healthy adult 
smokers, to ensure that twenty-nine (29) complete the entire study assuming a 20% dropout and 
non-evaluable rate. The highest intra-subject CV observed in previous studies was 22%. The 
protocols that were used to select the highest CV for the sample size calculation are: 
 
 
 
 and S6491365 (4mg nicotine 
polacrilex mini cherry lozenge v.s 4mg nicotine polacrilex mini mint lozenge: Cmax =13.7%; 
AUC0-t =10%). A total of twenty-nine (29) 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. 
 
 
 
 
 
 
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Product Information
Test Product
Reference Product
Product Name
Nicotine Prototype Mini lozenge 4 mg
Nicorette Mini Lozenge 4 mg
Product 
Formulation Code 
(MFC)
Commercially Available
Dose
4 mg
4 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 4mg (Test) is less than 80% or greater than 125% of that of Nicorette Mini Lozenge 
4mg (Reference).
H1: The (geometric) mean AUC0-t (likewise AUC0-inf and Cmax) of nicotine prototype mini 
lozenge 4mg (Test) is between 80% and 125% of that of Nicorette Mini Lozenge 4mg 
(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 will be calculated and a 90% confidence interval (CI) for the treatment difference will 
 
 
 
 
 
 
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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 
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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)
Meals
X
X
X
X
X
X
X
X
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.


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gUrinalysis Dipstick measurements for pH, specific gravity, protein, glucose, blood, ketones, nitrates, leukocyte esterases, urobilinogen, 
urine bilirubin.
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 4 mg prototype mini 
lozenge with the 4 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 4 mg 
prototype mini lozenge to the 4 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 
4 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.
 
 
 
 
 
 


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3
STUDY DESIGN AND SUBJECT POPULATION

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.  

Enough healthy adult smokers will be screened to randomize at least 37 subjects to 
ensure 29 evaluable subjects complete the entire study. This will ensure approximately 
29 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.
 
 
 
 
 
 


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4
SUBJECT SELECTION
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom 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.  
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 27 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 and to routinely smoking his or her first cigarette within 30 minutes upon 
awakening. 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.
 
 
 
 
 
 


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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 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 
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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 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 
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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 
at screening. 
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. 
 
 
 
 
 
 


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
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. 
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 
 
 
 
 
 
 


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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.
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 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.
 
 
 
 
 
 


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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 
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 4 mg
Nicorette Mini Lozenge 4 mg
Dose
4 mg (1 lozenge)
4 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 completed 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 completed 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.
 
 
 
 
 
 
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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.  
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.
® Smokerlyzer is a registered trademark of Bedfont Scientific Ltd..
 
 
 
 
 
 


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The primary package study labels will include, but not limited to the following information: the 
protocol number, product name, contents and batch number.
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. Upon 
receipt, all study treatments should be stored according to the instructions specified on the 
 
 
 
 
 
 


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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.
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.  
 
 
 
 
 
 


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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

Adverse events
To prepare for study participation, subjects will be instructed on the use of the Lifestyle 
Guidelines and Concomitant Treatment(s) sections of the protocol.
 
 
 
 
 
 


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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.

Subjects will begin fasting at least 10 hours prior to dosing on Day 0.
 
 
 
 
 
 


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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?” 

Meals as required.  Time and consumption of meals will be recorded on CRF.
 
 
 
 
 
 


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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.

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.
 
 
 
 
 
 


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
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 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.

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 
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 
 
 
 
 
 
 


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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:

Vomiting shortly (within 30 minutes) after study drug administration

Swallowing the lozenge during the administration period

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)

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 
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:
 
 
 
 
 
 


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
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.  
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
BUN/urea and Creatinine
Glucose (fasting) 
pH
Glucose (qual) 
Urine drug screenb
Serologyc
 
 
 
 
 
 


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Hematology
Chemistry
Urinalysis
Other
Hematocrit RBC 
count 
MCV
MCH
MCHC
Platelet count 
MPV
WBC count
Total neutrophils 
(Abs)
Eosinophils (Abs)
Monocytes (Abs) 
Basophils (Abs) 
Lymphocytes 
(Abs)
Calcium 
Magnesium 
Sodium 
Potassium 
Chloride
Total CO2(Bicarbonate)
 AST, ALT
Direct Bilirubin
Indirect Bilirubin
Total Bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
Protein (qual) 
Blood (qual) 
Ketones 
Nitrites
Leukocyte esterase 
Urobilinogen
Urine Bilirubin
Specific gravity
Microscopya
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
d Female subjects will be tested for serum human chorionic gonadotropin (hCG) at the Screening 
and start of each period (Days -1 and 5-7).
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 
 
 
 
 
 
 


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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. 
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 
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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 
consumption.  
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.  
 
 
 
 
 
 


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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.
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.  
 
 
 
 
 
 


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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.
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.
® Smokerlyzer is a registered trademark of Bedfont Scientific Ltd..
 
 
 
 
 
 


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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: 

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 
 
 
 
 
 
 


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
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 
normal life functions.

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 
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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 
product. 
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, 
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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 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

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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.
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. 
 
 
 
 
 
 
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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 
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 
 
 
 
 
 
 


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within 24 hours of learning of the subject becoming pregnant. The subject will be 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 
assessment of data quality and study performance. 
 
 
 
 
 
 


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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 thirty-seven (37) healthy adult 
smokers, to ensure that twenty-nine (29) complete the entire study assuming a 20% dropout and 
non-evaluable rate. The highest intra-subject CV observed in previous studies was 22%. The 
protocols that were used to select the highest CV for the sample size calculation are: 
 
 
 
 and S6491365 (4mg nicotine 
polacrilex mini cherry lozenge v.s 4mg nicotine polacrilex mini mint lozenge: Cmax =13.7%; 
AUC0-t =10%). A total of twenty-nine (29) 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
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.
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 4 mg prototype mini lozenge (Test) versus the 4 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 for each time 
point.
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 
 
 
 
 
 
 


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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.  
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 
This adjustment will only be applied in cases where the pre-dose value is greater than zero.
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
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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.
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 
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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.
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 “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.
 
 
 
 
 
 


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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.
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.
 
 
 
 
 
 


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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). 
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.
 
 
 
 
 
 


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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. 
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.
 
 
 
 
 
 


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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.
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.
 
 
 
 
 
 


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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 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
 
 
 
 
 
 
CCI
CCI
CCI


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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
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
 
 
 
 
 
 


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Abbreviation
Term
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
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
ICF
informed consent form
ICH
International Conference on Harmonisation
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
 
 
 
 
 
 


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Abbreviation
Term
PD
pharmacodynamics
PG 
pharmacogenomics
PI
principal investigator
PII
personally identifiable information
PK
pharmacokinetics
PKAS1
PK analysis set 1
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
 
 
 
 
 
 

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