Conditions: Safety Issues
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 100
Healthy volunteers: yes

Brief summary:
To study the oral mucosal effects in adult smokers associated with the use of two Nicotine Lozenge formulations.

Detailed description:
To assess the oral mucosal health associated with 3 weeks of use of test product, Nicotine Bitartrate 4 mg mint lozenge, relative to a reference product, Nicorette® \[Nicotine Polacrilex\] 4 mg mint lozenge, in healthy adult smokers motivated to quit smoking.

To evaluate the safety and tolerability of Nicotine Bitartrate 4 mg mint lozenge and Nicorette® \[Nicotine Polacrilex\] 4 mg mint lozenge in this subject population.

Arms:
arm 1: Nicotine Bitartrate Lozenge 4mg. Take 1 lozenge every 1-2 hours, as needed for 21 days arm 2: Nicotine Polacrilex Lozenge 4mg. Take 1 lozenge every 1-2 hours, as needed for 21 days

Interventions: intervention 1: Nicotine Bitartrate Lozenge 4mg intervention 2: Nicotine Polacrilex 4Mg Lozenge
Intervention descriptions: intervention 1: Test Product intervention 2: Active Comparator

Protocol document:
Prot_001.pdf: 
 
PROTOCOL 
 
 
Title of Study: Randomized, Parallel Group, Assessor-Blind Study to Evaluate the 
Oral Mucosal Effects in Healthy Adult Smokers Associated with 3 Weeks of Use of 
Niconovum Nicotine Bitartrate 4 mg Mint Lozenge Relative to the GSK Nicorette® 
Nicotine Polacrilex 4 mg Mint Lozenge. 
 
 
Sponsor Protocol Number: 2016-NBTL-S-005 
 
 
Clinical Research Organization: 
Inflamax Research Limited 
1310 Fewster Drive, 
Mississauga, Ontario, L4W 1A4 CANADA 
 
 
Sponsor:  
Niconovum USA, Inc. 
401 N. Main Street 
Winston-Salem, NC 27101-2990, USA 
 
 
17 FEB 2017 
Final Version 1.0 


Randomized, Parallel Group, Assessor-Blind 
Comparative Study-Oral Mucosal Effects        
Niconovum USA, Inc. 
              Protocol 2016-NBTL-S-005 
 
 
 
 
Page 1 of 10 
 
Title of Study: 
Randomized, Parallel Group, Assessor-Blind Study to Evaluate 
the Oral Mucosal Effects in Healthy Adult Smokers Associated 
with 3 Weeks of Use of Niconovum Nicotine Bitartrate 4 mg Mint 
Lozenge Relative to the GSK Nicorette® Nicotine Polacrilex 4 mg 
Mint Lozenge.  
Study Objectives: 
Primary 
 To assess the oral mucosal health associated with 3 weeks 
of use of test product, Nicotine Bitartrate 4 mg mint 
lozenge (Niconovum), relative to a reference product, 
Nicorette® [Nicotine Polacrilex] 4 mg mint lozenge 
GlaxoSmithKline (GSK), in healthy adult smokers 
motivated to quit smoking.  
Secondary 
 To evaluate the safety and tolerability of Nicotine 
Bitartrate 4 mg mint lozenge and Nicorette® [Nicotine 
Polacrilex] 4 mg mint lozenge in this subject population.  
Design of Study: 
This will be a randomized, parallel group, assessor-blind, 3-week, 
safety study in which 100 healthy adult smokers motivated to quit 
smoking will be instructed to use 9 - 20 lozenges per day over the 
course of the study. Subjects will be randomized on a 1:1 
treatment with Nicotine Bitartrate 4 mg mint lozenge (test) or 
Nicorette® Nicotine Polacrilex 4 mg mint lozenge (reference).  
Randomization 
Subjects will be randomized in a 1:1 ratio to receive either 
nicotine bitartrate 4 mg mint lozenge (Test Product) or Nicorette® 
4 mg mint lozenge (Reference Product). It is expected that 100 
subjects (50 in each group) will be randomized in the study at a 
single study site. Randomization will be stratified by smoking 
status so that in each treatment group a minimum of 10% of the 
subjects will be smokers of ≥ 30 cigarettes/day, and a minimum 
of 40% of the subjects will be smokers of 20 - 29 cigarettes/day.  
Test product  
Nicotine Bitartrate 4 mg mint lozenge 
Reference product 
GSK Nicorette® [Nicotine Polacrilex] 4 mg mint lozenge  
Treatment groups 
Eligible subjects meeting all study criteria will be randomized 
equally to receive one of the following treatments:  
• Niconovum Nicotine Bitartrate 4 mg mint lozenge  


Randomized, Parallel Group, Assessor-Blind 
Comparative Study-Oral Mucosal Effects        
Niconovum USA, Inc. 
              Protocol 2016-NBTL-S-005 
 
 
 
 
Page 2 of 10 
• Nicorette® [Nicotine Polacrilex] 4 mg mint lozenge  
Criteria for 
Inclusion: 
 
 
 
 
 
 
 
 
Potential subjects who meet the following criteria at Screening 
may be included in the study.  
1. Sex and Age: Males and females aged at least 18 years 
and older. 
2. Informed of the nature of the study and have agreed to 
and are able to read, review, and sign the informed 
consent document prior to commencing any study 
specific procedures.  The informed consent document 
will be written in English, therefore the volunteer must 
have the ability to read and communicate in English.  
3. Must have smoked at least 10 cigarettes per day for the 
previous 12 months prior to screening. 
4. Must smoke first cigarette within 30 minutes of waking 
up. 
5. Must be motivated to quit smoking upon enrollment into 
the study.  
6. Contraception: Females of childbearing potential who 
have been, in the opinion of the Investigator, practicing a 
reliable method of contraception for at least two months 
prior to study participation and must agree to remain on an 
acceptable method of contraception while participating in 
the study period using the study medication. Acceptable 
methods of contraception are hormonal birth control, 
intrauterine device, double barrier methods, vasectomized 
partner or abstinence.  
7. Females of childbearing potential will be required to 
undergo a serum (Screening) and urine (Day 0) pregnancy 
test (must be negative).  
8. Females of non-childbearing potential must be surgically 
sterile for at least three months prior to Screening or post-
menopausal for at least two years.  
9. General health: All study participants must have good 
general health and no impairment that would impede or 
affect ability to participate in the study as deemed 
acceptable by the Investigator. 


Randomized, Parallel Group, Assessor-Blind 
Comparative Study-Oral Mucosal Effects        
Niconovum USA, Inc. 
              Protocol 2016-NBTL-S-005 
 
 
 
 
Page 3 of 10 
10. Compliance: All study participants must understand and 
be willing to comply with all study procedures and 
restrictions. 
11. Consent: All study participants must demonstrate 
willingness to participate as evidenced by voluntary 
written informed consent and must have received a signed 
and dated copy of the informed consent form. 
Criteria for 
Exclusion: 
1. Females who have a positive pregnancy test, are pregnant, 
breastfeeding, or intend to become pregnant during the 
course of the study. 
2. Nicotine use: 
a) Is unable/unwilling to stop using forms of tobacco 
(e.g., traditional cigarettes, chewing tobacco, nicotine 
gels, cigars, snuff tobacco, nicotine patch and 
electronic cigarettes) for the duration of the study.  
b) Is unable/unwilling to stop using other nicotine 
replacement therapy products throughout the duration 
of the study.  
3. Disease: Has a medical history, which in the opinion of 
the investigator, would jeopardize the safety of the subject 
or impact the validity of the study results, e.g., known 
history of heart disease, recent myocardial infarction or 
cerebrovascular accident (i.e., within 12 weeks prior to 
enrollment), unstable angina, severe cardiac arrhythmia, 
diabetes or peptic ulcer.  
4. Demonstrates a reactive screen for Hepatitis B surface 
antigens, hepatitis C antibody, or HIV antibody.  
5. Oral condition: 
a) Has history of oral surgery (including extractions) 
within four weeks of screening, operative dental work 
within seven days of screening, or a presence of any 
clinically significant oral pathology (as determined by 
an oral health professional – dentist or dental 
hygienist) including lesions, sores or inflammation of 
the mouth which would interfere with study 
assessments or confound the results.  


Randomized, Parallel Group, Assessor-Blind 
Comparative Study-Oral Mucosal Effects        
Niconovum USA, Inc. 
              Protocol 2016-NBTL-S-005 
 
 
 
 
Page 4 of 10 
b) Has fixed retainers, orthodontic appliances, or either 
maxillary and/or mandibular dentures or other 
appliances which may interfere with the placement of 
the product.  
c) Has current or recurrent disease that could affect the 
site of application, the action, absorption of the study 
treatment, or clinical assessment.  
d) Has severe gingivitis, periodontitis or rampant caries 
(extensive dental decay, i.e., big/deep cavities, in 
many teeth), as diagnosed by an oral health 
professional- dentist or dental hygienist. 
e) Has the presence of oral or peri-oral ulceration 
including herpetic lesions at screening (subjects with 
these lesions may be re-examined at a subsequent 
appointment and may be able to be admitted at a later 
date if the ulceration or herpetic lesion heals) or Study 
Visit Day 0.  
f) Has elective dentistry scheduled during the study 
duration.  
6. Allergy/Intolerance:  
a) Has 
a 
known 
or 
suspected 
intolerance 
or 
hypersensitivity to the study materials (or closely-
related compounds) or any of their stated ingredients.  
b) Has a known genetic deficiency with an inability to 
metabolize aspartame or phenylalanine or has been 
diagnosed with phenylketonuria.  
7. Clinical Study Participation: 
a) Participation in another clinical study or receipt of an 
investigational drug within 30 days of the screening 
visit at the start of the study.  
b)  Previous participation in this study.  
8. Substance abuse:  
a) Current or recent (within two years of screening) 
history of drug or alcohol abuse, misuse, physical or 
psychological dependence.  
b) Demonstrates a positive alcohol breath test.  


Randomized, Parallel Group, Assessor-Blind 
Comparative Study-Oral Mucosal Effects        
Niconovum USA, Inc. 
              Protocol 2016-NBTL-S-005 
 
 
 
 
Page 5 of 10 
c) Demonstrates a positive urine drug screen without 
disclosure of corresponding prescribed concomitant 
medication(s) at Screening and Study Visit Day 0.   
9. Urine glucose:  
a) Positive glucose urine screen.  
10. Personnel: 
a) Is an employee of the Sponsor or the study site. 
b)   Is a member of the same household as another subject 
in this trial.  
11. Use of all over the counter (OTC) and prescription (Rx) 
lozenges after starting the study (Day 0 and onward).  
Investigation Site 
One study center within the United States. One screening center 
in the United States.   
Study Duration: 
Screening period up to 3 weeks; treatment period 3 weeks with 
follow-up visit 3 days after last dose.  
Primary Endpoint 
OMI-20 Total score change from baseline (Day 0) at each study 
visit (Days 3, 7, 14 and 21) in the Modified-Intent-to-Treat 
(mITT) population.  
Secondary 
Endpoints 
In specified subpopulations: 
 OMI-20 Total score change from baseline (Day 0) at each 
study visit (Days 3, 7, 14 and 21).   
 
In all populations: 
 OMI-20 Erythema subscore change from baseline at each 
study visit (Days 3, 7, 14 and 21) 
 OMI-20 Ulcer subscore change from baseline at each 
study visit (Days 3, 7, 14 and 21).  
 
Safety Endpoints:  
Other safety endpoints measured at study visits (Days 3, 7, 14 and 
21 as applicable): 
 Clinical laboratory assessments (clinical chemistry; 
hematology; serology; urinalysis) 
 Vital signs 
 12-lead Electrocardiogram (ECG) 
 Analysis of biopsied materials (if any) and adverse events 
(AE) assessment.  


Randomized, Parallel Group, Assessor-Blind 
Comparative Study-Oral Mucosal Effects        
Niconovum USA, Inc. 
              Protocol 2016-NBTL-S-005 
 
 
 
 
Page 6 of 10 
 
Recovery Assessments:  
 OMI-20 Total score Day 24 versus Day 21 
 OMI-20 Erythema score Day 24 versus Day 21 
 OMI-20 Ulcer score Day 24 versus Day 21 
 Safety endpoints Day 24 versus Day 21 
Statistical Methods 
Modified Intent-to-Treat (mITT) Population: 
The mITT population will include all subjects who were 
randomized and used at least 1 lozenge. This will be the main 
population for analysis.  
 
Per-Protocol (PP) Subpopulation: 
The per-protocol population will be a subset of the mITT 
population and will consist of subjects who complete the study 
without any major protocol deviations, as determined by clinical 
review. Examples of major protocol deviations:  
 CO levels exceeding 10 ppm at one or more study visits  
 Used < 9 or > 20 lozenges/day on more than 2 study days  
 
Heavy Lozenge Use Subpopulation: 
The heavy lozenge use population will be a subset of the mITT 
population and will consist of subjects who use an average of 15 
or more lozenges per day (irrespective of completion of the 
study).  
 
Concomitant Smoker Subpopulation: 
The concomitant smoker population will be a subset of the mITT 
population and will consist of subjects who either admit smoking 
during the study or who have a CO > 10 ppm at any study day 
excluding Day 0 or Day 24 that cannot otherwise be explained. 
 
Oral Mucosal Safety Assessment:  
OMI-20 assessments are based on change from baseline values. 
At each time point, the OMI-20 will be evaluated for each group 
using group mean and SD of all test product subject scores. The 
assessments will be conducted by a dental hygienist.  
 OMI-20 Total (Range 0-60)  
 OMI-20 Erythema (Range 0-27)  


Randomized, Parallel Group, Assessor-Blind 
Comparative Study-Oral Mucosal Effects        
Niconovum USA, Inc. 
              Protocol 2016-NBTL-S-005 
 
 
 
 
Page 7 of 10 
 OMI-20 Ulcer (Range 0-27)  
 
Statistics - This data will be presented for Days 0, 3, 7, 14, 21 and 
24 by treatment group as continuous data (mean, median, standard 
deviation, minimum, maximum). A high score would indicate 
worse oral health. Data will be presented according to the number 
of subjects remaining in the study at each visit. Data will not be 
imputed.  
 
Primary Endpoint Analyses:  
The primary endpoint change from baseline (Day 0) compared to 
each study visit day (Days 3, 7, 14 and 21) in OMI-20 total score 
will be summarized using descriptive statistics (mean, standard 
deviation, minimum, maximum, median) and presented by 
treatment group using mITT populations.  
No formal comparisons between groups will be conducted.  
 
Secondary Endpoint Analyses 
The change from baseline in erythema and ulcer subscores will be 
summarized using descriptive statistics (mean, standard 
deviation, minimum, maximum, median) and presented by 
treatment group using the mITT population.  
 
The change from baseline (Day 0) compared to each study visit 
day (Days 3, 7, 14 and 21) in OMI-20 total score, erythema 
subscore, and ulcer subscore will be summarized using 
descriptive statistics (mean, standard deviation, minimum, 
maximum, median) and presented by treatment group for the 
following subpopulations: 
 Per protocol population 
 Heavy lozenge use subpopulation 
 Concomitant smoker subpopulation 
No formal statistical comparisons between treatment groups will 
be conducted.  
 
For other parameters, continuous data will be summarized using 
descriptive statistics (mean, standard deviation, minimum, 
maximum, median) to aid the data interpretation at each study 
visit: 


Randomized, Parallel Group, Assessor-Blind 
Comparative Study-Oral Mucosal Effects        
Niconovum USA, Inc. 
              Protocol 2016-NBTL-S-005 
 
 
 
 
Page 8 of 10 
 
 
 
 
 
Adverse events and other categorical variables will be tabulated 
by the number and % of subjects experiencing the event by 
treatment group. Other indicators will include severity, 
seriousness and relationship to study drug by treatment group.  
No formal statistical comparisons between treatment groups will 
be conducted.  
 
Recovery will be assessed by comparing OMI-20 total score, 
erythema subscore, ulcer subscore and all safety endpoints on Day 
24 versus Day 21.   
 
Compliance  
 Breath carbon monoxide levels will be presented by 
subject for each visit and will be used to identify 
concurrent smokers (CO > 10 ppm) and to stratify results 
of compliant and noncompliant subjects. 
 Average number of lozenges used per day will be 
tabulated. Reasons for lozenge use of < 9 or > 20 lozenges 
per day will be collected at each visit and presented by 
treatment group and by visit. 


Randomized, Parallel Group, Assessor-Blind 
Comparative Study-Oral Mucosal Effects        
Niconovum USA, Inc. 
              Protocol 2016-NBTL-S-005 
 
 
 
 
Page 9 of 10 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations 
Term or Definition 
C 
Celsius 
F   
Fahrenheit  
ACTH 
Adrenocorticotropic hormone 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
BP 
Blood Pressure  
CFB 
Change from baseline 
CFR 
Code of Federal Regulations 
cm 
Centimeters  
CO 
Carbon Monoxide 
CTCAE  
Common Terminology Criteria for Adverse Events 
DBP 
Diastolic Blood Pressure  
ECG 
Electrocardiogram 
EOT 
End of Treatment  
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ePDAT® 
Electronic Patient Data Acquisition Tablet  
GCP 
Good Clinical Practice 
GSK 
GlaxoSmithKline 
IB 
Investigators Brochure 
ICF 
Informed Consent Form  
ICH 
International Conference on Harmonization  
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
kg 
Kilograms 
L 
Liters 
mg 
Milligrams 
mITT 
Modified-intent-to-treat  
NCI 
National Cancer Institute  
NRT 
Nicotine Replacement Therapy  
OMI 
Oral Mucositis Index  


Randomized, Parallel Group, Assessor-Blind 
Comparative Study-Oral Mucosal Effects        
Niconovum USA, Inc. 
              Protocol 2016-NBTL-S-005 
 
 
 
 
Page 10 of 10 
 
 
 
 
 
 
 
 
 
 
 
 
OTC 
Over the counter 
pH 
A measure of the acidity or alkalinity of a solution 
PI 
Principal Investigator 
PP 
Per protocol  
ppm 
Parts-per-million 
RAISC 
RAI Services Company  
RAI 
Reynolds American Inc. 
RBC 
Red blood cell count  
Rx 
Prescription 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure  

SAP_000.pdf: 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Randomized, Parallel Group, Assessor-Blind Study to Evaluate the Oral Mucosal 
Effects in Healthy Adult Smokers Associated with 3 Weeks of Use of Niconovum 
Nicotine Bitartrate 4 mg Mint Lozenge Relative to the GSK Nicorette® Nicotine 
Polacrilex 4 mg Mint Lozenge. 
 
Sponsor Protocol Number: 2016-NBTL-S-005 
Final V1.0, 17 FEB 2017  
 
Clinical Research Organization: 
Inflamax Research Limited 
    1310 Fewster Drive, 
    Mississauga, Ontario, L4W 1A4  CANADA 
 
 
Sponsor: 
Niconovum USA, Inc.  
401 N. Main Street 
Winston-Salem, NC 27101-2990, USA 
 
 
 
 
     17 MAY 2017 
 Final Version 1.0 
 
 
 
 
 


 
 
Statistical Analysis Plan 
 
 
 
Sponsor: Niconovum USA, Inc. 
Sponsor Protocol No. 2016-NBTL-S-005 
 
17-May-2017 Final Version 1.0    
 
Page 2 of 53 
Abbreviations 
 
Abbreviations 
Term or Definition 
AE 
Adverse Event 
BMI 
Body Mass Index 
°C 
Centigrade 
CS 
Concomitant Smoker 
DBP 
Diastolic Blood Pressure 
eCRF  
Electronic Case Report Form 
CO 
Carbon Monoxide  
ECG 
Electrocardiogram 
EOS 
End of Study 
ePDAT 
Electronic Patient Data Acquisition Tablet 
ET 
Early Termination 
GSK 
GlaxoSmithKline 
mITT 
Modified Intent-to-Treat 
HIV 
Human Immunodeficiency Virus 
HLU 
Heavy Lozenge Use 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
mmol 
Millimole 
L 
Liter 
kg 
Kilograms 
mm 
Millimeter 
mmHg 
Millimeters of Mercury 
MedDRA 
Medical Dictionary for Regulatory Activities 
OMI 
Oral Mucositis Index 
PP 
Per protocol 
PT 
Preferred Term 
SAP 
Statistical Analysis Plan  
SAE 
Serious Adverse Event 
SAS 
Statistical Analysis System 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SOC 
System Organ Class 


 
 
Statistical Analysis Plan 
 
 
 
Sponsor: Niconovum USA, Inc. 
Sponsor Protocol No. 2016-NBTL-S-005 
 
17-May-2017 Final Version 1.0    
 
Page 3 of 53 
Table of Contents 
 
1 
INTRODUCTION TO THE STATISTICAL ANALYSIS PLAN ......................................... 7 
2 
INTRODUCTION TO THE STUDY ........................................................................................... 8 
2.1 
Overview of Study ................................................................................................................................. 8 
2.2 
Study Objectives ................................................................................................................................... 8 
2.2.1 
Primary ................................................................................................................................................... 8 
2.2.2 
Secondary .............................................................................................................................................. 8 
2.3 
Subject Selection .................................................................................................................................. 8 
2.4 
Study procedures.................................................................................................................................. 8 
3 
RANDOMIZATION AND BLINDING ...................................................................................... 11 
3.1 
Randomization ..................................................................................................................................... 11 
3.2 
Blinding ................................................................................................................................................. 11 
3.3 
Sample Size Calculation .................................................................................................................... 11 
4 
DEFINITION OF ANALYSIS POPULATIONS .................................................................... 11 
4.1 
Randomized Population ..................................................................................................................... 11 
4.2 
Modified Intent-to-Treat (mITT) Population .................................................................................... 11 
4.3 
Per-Protocol (PP) Population ............................................................................................................ 12 
4.4 
Heavy Lozenge Use (HLU) Population ............................................................................................ 12 
4.5 
Concomitant Smoker (CS) Population ............................................................................................ 12 
5 
ASSESSMENT AND STUDY ENDPOINTS ........................................................................ 12 


 
 
Statistical Analysis Plan 
 
 
 
Sponsor: Niconovum USA, Inc. 
Sponsor Protocol No. 2016-NBTL-S-005 
 
17-May-2017 Final Version 1.0    
 
Page 4 of 53 
5.1 
Oral Safety Assessment .................................................................................................................... 12 
5.2 
Primary Endpoint ................................................................................................................................ 12 
5.3 
Secondary Endpoints ......................................................................................................................... 13 
5.4 
Safety Endpoints ................................................................................................................................. 13 
5.5 
Other Safety Endpoints ...................................................................................................................... 13 
6 
STATISTICAL METHODOLOGY ........................................................................................... 13 
6.1 
Summary Statistics ............................................................................................................................. 13 
6.2 
Reporting Precision ............................................................................................................................ 14 
6.3 
Commonly Used Algorithms ............................................................................................................. 14 
6.3.1 
Duration of Adverse Events ............................................................................................................... 14 
6.4 
Data Handling Rules ........................................................................................................................... 14 
6.4.1 
Derived Variables ................................................................................................................................ 14 
6.4.2 
Missing Data ........................................................................................................................................ 14 
6.5 
Level of Significance .......................................................................................................................... 15 
6.6 
Interim Analysis .................................................................................................................................. 15 
7 
STATISTICAL ANALYSES ...................................................................................................... 15 
7.1 
Subject Disposition and Withdrawals ............................................................................................. 15 
7.2 
Baseline Characteristics .................................................................................................................... 16 
7.3 
Concomitant Medication .................................................................................................................... 16 
7.4 
Medication Administration and Treatment Compliance .............................................................. 16 
7.5 
Primary Analyses ................................................................................................................................ 17 
7.6 
Secondary Analyses ........................................................................................................................... 18 
7.7 
Safety Analyses ................................................................................................................................... 18 


 
 
Statistical Analysis Plan 
 
 
 
Sponsor: Niconovum USA, Inc. 
Sponsor Protocol No. 2016-NBTL-S-005 
 
17-May-2017 Final Version 1.0    
 
Page 5 of 53 
7.7.1 
Adverse Events ................................................................................................................................... 18 
7.7.2 
Physical Examination ......................................................................................................................... 19 
7.7.3 
Vital Signs ............................................................................................................................................ 19 
7.7.4 
12-Lead Electrocardiogram ............................................................................................................... 19 
7.7.5 
Clinical Laboratory .............................................................................................................................. 19 
7.7.6 
Recovery .............................................................................................................................................. 20 
7.8 
Analysis Prior to Study Completion ................................................................................................ 20 
8 
TABLES, LISTINGS AND GRAPHS (TLGS) SHELLS ................................................... 21 
Table 14.1.1 Disposition of Subjects and Analysis Sets ................................................................................. 22 
Table 14.1.2 Demographics and Baseline Characteristics ............................................................................ 23 
Table 14.1.3 Summary of Tobacco Use History .............................................................................................. 24 
Table 14.2.2.1 Summary of Change from Baseline in OMI-20 Total Score ................................................ 25 
Table 14.2.2.2 Summary of Change from Baseline in OMI-20 Total Score ................................................ 26 
Table 14.2.2.3 Summary of Change from Baseline in OMI-20 Total Score ................................................ 26 
Table 14.2.2.4 Summary of Change from Baseline in OMI-20 Total Score ................................................ 26 
Table 14.2.3.1 Summary of Change from Baseline in OMI Erythema Score .............................................. 26 
Table 14.2.3.2 Summary of Change from Baseline in OMI Erythema Score .............................................. 26 
Table 14.2.3.3 Summary of Change from Baseline in OMI Erythema Score .............................................. 26 
Table 14.2.3.4 Summary of Change from Baseline in OMI Erythema Score .............................................. 26 
Table 14.2.4.1 Summary of Change from Baseline in OMI Ulcer Score ...................................................... 26 
Table 14.2.4.2 Summary of Change from Baseline in OMI Ulcer Score ...................................................... 26 
Table 14.2.4.3 Summary of Change from Baseline in OMI Ulcer Score ...................................................... 26 
Table 14.2.4.4 Summary of Change from Baseline in OMI Ulcer Score ...................................................... 26 
Table 14.3.1.1 Overall Summary of Treatment Emergent Adverse Events (TEAEs) ................................. 27 
Table 14.3.1.2 Summary of Treatment Emergent Adverse Events by System Organ Class and 
Preferred Term ...................................................................................................................................................... 28 
Table 14.3.1.3 Treatment-Emergent Adverse Events by System Organ Class, Preferred Term and 
Maximum Relationship (Modified Intent-to-Treat Population) ........................................................................ 29 
Table 14.3.4 Summary of Vital Signs ................................................................................................................ 30 
Table 14.3.5.1 Summary of Overall ECG Interpretation ................................................................................. 31 
Table 14.3.5.2 Summary of ECG Continuous Data Safety Population ........................................................ 32 
Table 14.3.6.1 Summary of Breath carbon monoxide (CO) levels (mITT Population) ............................... 33 
Table 14.3.6.2 Summary of Study Drug Administration.................................................................................. 34 
Table 14.3.6.3 Summary of Medication Compliance (mITT Population) ..................................................... 35 
Table 14.3.7.1 Summary of difference in OMI-20 Total Score Between Day 21 and Day 24 ................... 36 
Table 14.3.7.2 Summary of difference in OMI Erythema Score Between Day 21 and Day 24 ................ 37 
Table 14.3.7.3 Summary of difference in OMI Ulcer Score Between Day 21 and Day 24 ........................ 37 
Listing 16.1.7 Randomization Scheme .............................................................................................................. 38 


 
 
Statistical Analysis Plan 
 
 
 
Sponsor: Niconovum USA, Inc. 
Sponsor Protocol No. 2016-NBTL-S-005 
 
17-May-2017 Final Version 1.0    
 
Page 6 of 53 
Listing 16.2.1 Subject Disposition and Completion/Early Termination ......................................................... 39 
Listing 16.2.2 Protocol Deviations ...................................................................................................................... 40 
Listing 16.2.4.1 Demographic Data ................................................................................................................... 41 
Listing 16.2.4.2 Urine Drug Screen and Alcohol Breath Test ........................................................................ 42 
Listing 16.2.4.3 Medical History ......................................................................................................................... 43 
Listing 16.2.4.4 Concomitant Medications ........................................................................................................ 44 
Listing 16.2.4.5 Serology Screen ....................................................................................................................... 45 
Listing 16.2.4.6 Pregnancy Tests ....................................................................................................................... 46 
Listing 16.2.4.7 Tobacco Product Use History ................................................................................................. 47 
Listing 16.2.5.1 Study Drug Administration ...................................................................................................... 48 
Listing 16.2.5.2 Carbon Monoxide Breath Test ................................................................................................ 49 
Listing 16.2.6.1 Oral Mucositis Index (OMI-20) ................................................................................................ 50 
Listing 16.2.7.1 Adverse Events ......................................................................................................................... 51 
Listing 16.2.8.X Laboratory Measurements: <Laboratory Panel> ................................................................. 52 
Listing 16.2.9 Vital Signs ..................................................................................................................................... 53 
 
 


 
 
Statistical Analysis Plan 
 
 
 
Sponsor: Niconovum USA, Inc. 
Sponsor Protocol No. 2016-NBTL-S-005 
 
17-May-2017 Final Version 1.0    
 
Page 7 of 53 
1 INTRODUCTION TO THE STATISTICAL ANALYSIS PLAN 
This Statistical Analysis Plan (SAP) provides a thorough description of statistical analysis 
methods and presentation of the study data from the clinical trial described in Study Protocol 
2016-NBTL-S-005: 
 
 “Randomized, Parallel Group, Assessor-Blind Study to Evaluate the Oral Mucosal Effects 
in Healthy Adult Smokers Associated with 3 Weeks of Use of Niconovum Nicotine 
Bitartrate 4 mg Mint Lozenge Relative to the GSK Nicorette® Nicotine Polacrilex 4 mg 
Mint Lozenge”.  
 
This SAP is based on the final protocol dated 27 February 2017 (Final 1.0).  
 
The SAP includes details of data handling procedures and statistical methodology.  
No interim analysis is planned for this study. 
 
The final statistical analysis will proceed according to the SAP approved by Niconovum USA, 
Inc. as well as by Inflamax Research. There are no deviations of analysis methods from the 
protocol. Any deviations in final analysis from this SAP will be documented in the final Study 
Summary Report. 
 
Tables and Listings are numbered following the International Conference on Harmonization 
(ICH) structure E3 “Structure and Content of Clinical Study Report”. All summary tables and 
listings will be generated using SAS® Version 9.2 or higher. Tables, listings and graphs will be 
delivered to the Sponsor as .rtf files. 
 
The following documents were reviewed in preparation of the SAP: 
• 
Electronic Case Report Form (eCRF) Final Version 1.0 dated on 20MAR2017 
• 
Data Management Plan Final Version 1.0 dated on 03APR2017 
• 
eCRF Completion Guidelines Final Version 1.0 dated on 20MAR2017 
• 
Codelist Details Final Version dated on 30MAR2017 
 
 


 
 
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2 INTRODUCTION TO THE STUDY 
2.1 Overview of Study  
This will be a single-center, ambulatory, randomized, parallel group, assessor-blind, 3-week, 
safety study in healthy adults motivated to quit smoking. Subjects will be instructed to quit 
smoking (starting Day 1) and use 9 - 20 lozenges per day for 3 weeks.  Subjects will be 
randomized 1:1 to treatment with Nicotine Bitartrate 4 mg mint lozenge (test product) or 
Nicorette® [Nicotine Polacrilex] 4 mg mint lozenge (reference product).  In each treatment group 
a minimum of 10% of the study population will be smokers of ≥ 30 cigarettes/day, and a 
minimum of 40% of the study population will be smokers of 20 - 29 cigarettes/day.  
Randomization will be stratified by smoking status so that the treatment assignment is balanced 
within smoking status.    
2.2 Study Objectives 
2.2.1 Primary 
• 
To assess the oral mucosal health associated with 3 weeks of use of test product, Nicotine 
Bitartrate 4 mg mint lozenge (Niconovum), relative to a reference product, Nicorette® 
[Nicotine Polacrilex] 4 mg mint lozenge (GSK), in healthy adult smokers motivated to quit 
smoking. 
2.2.2 Secondary 
• 
To evaluate the safety and tolerability of Nicotine Bitartrate 4 mg mint lozenge and 
Nicorette® [Nicotine Polacrilex] 4 mg mint lozenge in this subject population.   
 
2.3 Subject Selection  
A total of 100 healthy males or females at the age of 18 years or up who have signed written 
informed consent and satisfy the study inclusion/exclusion criteria per protocol will be selected 
to participate in this study. The Day 0 visit reconfirms their eligibility.  
 
2.4 Study procedures 
There will be at least seven study visits, including the Screening Visit, as summarized in Table 1 
‘Schedule of Study Events’. At the Screening Visit, safety assessments, evaluation of oral health 
by a dental hygienist, carbon monoxide assessment and other procedures will be performed to 
determine eligibility of potential subjects to enroll in the study, and informed consent forms will 
be obtained prior to any screening procedures.  
 
At the Test Visit Day 0 (baseline), eligibility will be reconfirmed and subjects will be enrolled. 
Evaluation of oral health will be conducted by a dental hygienist, and recorded as baseline 


 
 
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score. Subjects will receive a Study Kit consisting of individual Daily Packs each containing 20 
lozenges on Day 0 and subsequent lozenge dispensing will occur on Days 7 and 14. Subjects 
will be informed that daily use is permitted to vary between 9 - 20 lozenges per day, and be 
instructed to use lozenges from only one Daily Pack per day. At baseline (Day 0), subjects will 
each receive Inflamax’s ePDAT® (Electronic Patient Data Acquisition Tablet) system for the 
daily (at least once daily) recording of their daily lozenge usage. In addition, subjects will also be 
instructed to indicate on the ePDAT® system (once daily) if they have experienced any change 
in health and/or if any concomitant medication was taken or how many (if any) cigarettes were 
smoked. Furthermore, subjects will also be given a take-home journal on Day 0 of the study and 
will be instructed to record/describe, at their own discretion, further detail of any changes in 
health experienced and concomitant smoking/medication.  
 
On all other visits (Days 3, 7, 14, 21 and Day 24 post-dosing), oral examinations by a blinded 
dental assessor (dental hygienist, dentist or dental surgeon) will be conducted using the Oral 
Mucositis Index (OMI-20) scale. In addition, the blinded assessor will identify any new areas of 
leukoplakia, erythroplakia or ulceration over 1 cm in diameter, or other oral lesions that cannot 
be diagnosed by clinical observation alone for potential biopsy. Vital signs, adverse events, and 
concomitant medications will be collected at each visit by the study staff to assess systemic 
health effects in addition to those on the oral mucosa. Clinical laboratory evaluations and 
electrocardiograms will be conducted at selected visits.  
 
Subjects will be discharged from the study following completion of study procedures and all 
appropriate safety assessments, at the Investigator’s discretion.  
 
 
 


 
 
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Table 1: Schedule of Study Events 
 
1 Changes in health (adverse events), any concomitant medication used and smoking history will be monitored through the ePDAT® system as per subject entries and take-home journals 
throughout the study duration.  
2 A dentist or dental hygienist will evaluate the oral health of the subjects for exclusion criteria.  
3 Serum pregnancy test at Screening; urine pregnancy test at Check-in of Day 0 Test Visit. 
4 Vital sign measurements include systolic blood pressure, diastolic blood pressure, and heart rate.  
5 ECG will be obtained after the subject has rested in the supine position for at least 5 minutes and either before obtaining blood samples or at least 30 minutes after venipuncture. ECG will be 
recorded for Day 24 if needed for safety follow-up of previously documented abnormalities.  
6 Abnormal clinical lab results will be followed up if needed on subsequent visit days and post-study completion, if necessary.  
7 Carbon monoxide measured by breath CO monitoring machine.  
8 Subjects will be instructed to take their first lozenge the next morning (i.e., Quit day = Day 1). 
9 Assessment of lozenge use will be collected through the ePDAT® system (once daily) and take-home journals.  
10 Biopsy will only be performed in the case of suspicious lesions as determined by oral examinations through a second opinion by a dentist or dental surgeon. Each lesion will be biopsied once.  
11 Clinically significant abnormalities at Study Day 21 will be re-evaluated at Day 24 for recovery. 
 
 
Assessment 
Screening 
Visit 
Baseline 
Treatment 
Follow-up 
Day -21 to 
Day -1 
Day 0  
Day 3 
Day 7 
Day 14 
Day 21 
Day 24 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
X 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
Height, weight and determine 
BMI 
X 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
Smoking History1 
X 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
Oral Health Assessment2 
X 
X 
 
 
 
 
 
ePDAT® Instruction  
 
X 
 
 
 
 
 
Pregnancy test(females)3 
X 
X 
 
 
 
 
 
Urine drug screen and alcohol 
breathalyzer test  
X 
X 
 
 
 
 
 
Urinalysis  
X 
X 
 
X 
 
X 
 
Vital signs4 
X 
X 
X 
X 
X 
X 
X11 
Electrocardiogram5 
X 
 
 
X 
 
X 
X5 
Clinical 
laboratory 
evaluations6 
X 
X 
 
X 
 
X 
X11 
Concomitant medication1 
X 
X 
X 
X 
X 
X 
X 
Carbon 
monoxide 
assessment7 
 
X 
X 
X 
X 
X 
 
Oral assessment (OMI-20) 
 
X 
X 
X 
X 
X 
X 
Study drug dispensing 
 
X8 
 
X 
X 
 
 
Recording  of lozenge use9 
 
 
X 
X 
X 
X 
 
Adverse event monitoring1 
 
X 
X 
X 
X 
X 
X 
Biopsy10 
 
 
X 
X 
X 
X 
X 


                             
                                                                                           
 
 
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3 Randomization and Blinding 
3.1 Randomization  
Subjects will be randomized in a 1:1 ratio to receive either Nicotine Bitartrate 4 mg mint lozenge 
(Test Product) or Nicorette® 4 mg mint lozenge (Reference Product). A total of 100 subjects (50 
in each group) will be randomized in the study at a single study site. Randomization will be 
stratified by smoking status so that in each treatment group a minimum of 10% of the subjects 
will be smokers of ≥ 30 cigarettes/day, and a minimum of 40% of the subjects will be smokers of 
20 - 29 cigarettes/day. 
3.2 Blinding 
The study staff conducting the oral assessment (dentist or dental hygienist) shall be blinded to 
the subject’s treatment arm. These staff will not be present during distribution or use of 
lozenges. Subjects will be instructed not to show their investigational product to the oral 
assessors. In addition, subjects and blinded assessor will be instructed to not discuss the 
lozenge type (study arm) that the subject is using, and a separate study team member will 
manage all distribution and collection of study medication to assure assessor blinding is 
maintained. Furthermore, the blinded assessor will input OMI-20 scores using a separate eCRF 
which will not include subject lozenge use or type. 
 
3.3 Sample Size Calculation  
The primary purpose of this study is to assess the oral mucosal health associated with use of 
test product Nicotine Bitartrate 4 mg mint lozenge (Niconovum), relative to a reference product, 
Nicorette® [Nicotine Polacrilex] 4 mg mint lozenge (GSK). A total of 100 subjects, 50 in each 
test or reference treatment group, are considered reasonable for this purpose and no formal 
statistical analysis was performed in determining sample size.    
 
4 DEFINITION OF ANALYSIS POPULATIONS  
4.1 Randomized Population 
The Randomized Population will consist of all subjects who are randomized to the Treatment. 
4.2 Modified Intent-to-Treat (mITT) Population 
The mITT population will include all subjects who were randomized and used at least 1 lozenge. 
This will be the main population for analysis. 


                             
                                                                                           
 
 
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4.3 Per-Protocol (PP) Population 
The per-protocol population will be a subset of the mITT population and will consist of subjects 
who complete the study without any major protocol deviations, as determined by clinical review. 
Major protocol deviations include: 
• 
CO levels exceeding 10 ppm at one or more study day visit (CO is expected to be > 10 
ppm on Day 0) 
• 
Use of < 9 or > 20 lozenges/day on more than 2 study days 
 
4.4 Heavy Lozenge Use (HLU) Population 
The heavy lozenge use population will be a subset of the mITT population and will consist of 
subjects who use on average 15 or more lozenges per day (irrespective of completion of the 
study). 
4.5 Concomitant Smoker (CS) Population 
The concomitant smoker population will be a subset of the mITT population and will consist of 
subjects who either admit smoking during the study or who have a CO > 10 ppm at any study 
day excluding Day 0 or Day 24 that cannot otherwise be explained. 
5 ASSESSMENT AND STUDY ENDPOINTS  
5.1 Oral Safety Assessment 
Oral examinations will be conducted using a 20 Item Oral Mucositis Index (OMI-20), a validated 
scale developed to measure several indications of oral mucositis. Assessors will be licensed 
dental professionals (dental hygienists or dentists). These selected dental professionals will be 
trained in the assessment protocol and the OMI-20 by a board-certified oral medicine 
professional. Prior to initiation of study visits, the selected dental professionals will be trained 
onsite in the assessment protocol and the OMI-20 test. An assessment will be conducted to 
ensure consistent evaluation among the dental professionals that will partake in the study. All 
assessors will be blinded to the study treatment the subject has been randomized to receive. 
OMI-20 will be assessed on Days 0, 3, 7, 14, 21 and Day 24 (post dose) visits. 
5.2 Primary Endpoint 
OMI-20 Total score change from baseline (Day 0) at each study visit (Days 3, 7, 14 and 21) in 
the Modified-Intent-to-Treat (mITT) population.  
 


                             
                                                                                           
 
 
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5.3 Secondary Endpoints 
• 
OMI-20 Total score change from baseline (Day 0) at each study visit (Days 3, 7, 14 and 
21) in PP population, heavy lozenge use population and concomitant smoker population. 
• 
OMI-20 Erythema subscore change from baseline at each study visit (Days 3, 7, 14 and 
21) in all populations. 
• 
OMI-20 Ulcer subscore change from baseline at each study visit (Days 3, 7, 14 and 21) 
in all populations. 
5.4 Safety Endpoints 
• 
Clinical laboratory assessments (clinical chemistry; hematology; serology; urinalysis) 
• 
Vital signs 
• 
12-lead Electrocardiogram (ECG) 
• 
Analysis of biopsied materials (if any) and adverse events 
5.5 Other Safety Endpoints 
• 
OMI-20 Total score Day 24 versus Day 21 
• 
OMI-20 Erythema score Day 24 versus Day 21 
• 
OMI-20 Ulcer score Day 24 versus Day 21 
• 
Safety endpoints Day 24 versus Day 21  
6 STATISTICAL METHODOLOGY 
6.1 Summary Statistics 
Subject disposition will be summarized for all the randomized subjects. The primary endpoints 
will be summarized for mITT population. The secondary endpoints will be summarized for mITT 
population, PP population, HLU population and CS population. The safety endpoints and 
baseline characteristics will be summarized only for the mITT population.  
The standard summary statistics that will be calculated for quantitative and qualitative variables 
are: 
Quantitative: 
number of subjects, mean, median, standard deviation (SD), minimum 
and maximum of the raw data 
Qualitative: 
number of subjects, number of missing data (if not zero), absolute and 
relative frequencies per class   
 


                             
                                                                                           
 
 
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6.2 Reporting Precision 
Summary statistics will be presented to the following degree of precision: 
Statistics 
Degree of Precision 
Mean (of all kinds), Median,  
 
One more decimal place than the raw data 
Standard deviation  
Two more decimal places than the raw data 
 
Minimum, Maximum 
The same number of decimal places as the raw 
data 
 
Percent 
One decimal place 
 
 
6.3 Commonly Used Algorithms 
6.3.1 Duration of Adverse Events 
When adverse events (AEs) have incomplete start dates and times, no imputation will be 
performed. Duration will be calculated for AEs that resolve as the difference between the 
resolution date and time and onset date and time and will be expressed in days, hours and 
minutes. If either time is missing, duration will be expressed in days. Duration will only be 
calculated when both dates are complete. 
6.4 Data Handling Rules  
The following section describes the rules for handling data, including the definitions of derived 
variables and handling missing data. 
6.4.1 Derived Variables 
• 
Age is calculated in years after rounding down as follows: 
Year of age = (Date [in days format] informed consent signed - Date [in days format] of 
birth) / 365.25  
 
6.4.2 Missing Data 
Any missing values for the study endpoints will not be replaced and the observed data will be 
used for the endpoint analysis. No data interpolation or extrapolation will be carried out if there 
is missing data.  


                             
                                                                                           
 
 
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6.5 Level of Significance 
No formal comparisons between groups will be conducted. No inferential statistics will be 
output. Therefore, no level of significance will be assigned. 
6.6 Interim Analysis 
No interim analysis is planned for this study. 
 
7 STATISTICAL ANALYSES 
7.1  Subject Disposition and Withdrawals 
The following frequencies (number and percent) will be displayed by treatment group and 
overall for all the randomized subjects: 
• 
Subjects in the Randomized Population (number only) 
• 
Subjects in the Modified Intent-to-Treat Population (number only) 
• 
Subjects in the Per-Protocol Population (number only) 
• 
Subjects in the Heavy Lozenge Use Population (number only) 
• 
Subjects in the Concomitant Smoker Population (number only) 
• 
Subjects who completed the study (number and percent) 
• 
Subjects who discontinued early, as well as reasons for subject discontinuation (number 
and percent) 
The denominators for the percent calculations will be the number of subjects in the Randomized 
population per treatment or overall. 
Subjects’ completion/discontinuation status will be listed by treatment group and will include 
subject identifier, date of enrollment, date of completion/early discontinuation, date of last 
contact and, for those who discontinued early, the specific reason for discontinuation. 
All deviations related to study inclusion or exclusion criteria, conduct of the trial, subject 
compliance or subject concomitant smoking will be listed. The justification of major/minor on 
protocol deviations may be determined among the Principal Investigator and Biostatistician from 
Inflamax Research, and the Sponsor. 
 


                             
                                                                                           
 
 
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7.2 Baseline Characteristics 
Demographics (age, sex, race, ethnicity, weight, height and BMI) will be summarized using 
descriptive statistics (number of subjects, mean, standard deviation, minimum, median and 
maximum for quantitative variables, and number of subjects and percent of subjects for 
qualitative variables) by treatment group and overall for the mITT population. No formal 
statistical comparison between treatment groups will be performed. Together with the informed 
consent date, the above information will be listed by treatment groups for the randomized 
subjects. 
Other baseline characteristics will be listed by treatment group for all subjects: 
• 
Medical/medication history 
• 
History of Tobacco/nicotine product use/consumption and smoking/vaping habits 
• 
Pregnancies (female only) 
• 
Urine drug screen and alcohol breathalyzer test 
The history of tobacco/nicotine production use/consumption and smoking/vaping habits will be 
listed as treatment, subject, substance name, start date of use, end date of use, ongoing use, 
frequency of use, amount used (amount/unit/frequency).. A summary table will be produced by 
treatment for the duration of substance use and average amount. The summary statistics will 
also report the number of subjects who reported using the product at each frequency level (less 
than 20 cigarettes per day, 20 – 29 per day, and more than 30 per day) within treatment group 
and overall. 
7.3 Concomitant Medication 
The use of concomitant medications will be requested in the ePDAT® system, and subjects will 
be able to indicate whether any concomitant medication was used during the study. The full 
description of the concomitant medication usage will be recorded in the take-home journals 
provided to the subjects, indicating the following information (as possible): Name of drug, 
Reason for use, Frequency of use, Route of administration, Dose, and Start date and Stop date 
(where applicable). The above information will listed by treatment. No summary table will be 
output.  
7.4 Medication Administration and Treatment Compliance 
Subjects will be instructed to self-administer 9-20 lozenges per day and record lozenge use 
through Inflamax’s ePDAT take-home tablet once daily. Number of used lozenges since last 
visit will be calculated as deduction of the dispensed lozenge number of last visit from the 


                             
                                                                                           
 
 
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returned lozenge number of this visit. Average number of lozenges used per day will be also 
calculated as dividing total number of used lozenges by total number of treatment days.  
Treatment compliance will be determined by Breath Carbon Monoxide (CO) and average 
number of lozenges.  
Breath carbon monoxide (CO) levels will be presented by subject for each visit and will be used 
to identify concurrent smokers. Based on level of CO, subjects will be divided as compliant 
subjects (CO<=10 ppm at all study day visits) and non-compliant subjects (CO>10 ppm at any 
study day visit). Breath carbon monoxide (CO) levels will be listed by treatment, together with 
visit and date. In the listing, non-compliance will be flagged. For those who comply with the 
requirements, CO level will be summarized with descriptive statistics (number, mean, SD, 
minimum, median and maximum) by treatment and visit. The number of subjects and 
percentage will be calculated based on whether the CO level is higher or lower than 10 ppm. 
Number of lozenges will also be used to determine compliance. Lozenge use of less than 9 or 
more than 20 for more than 2 study days will be treated as a major violation of compliance and 
qualifies subjects as non-compliant.  
The average number of used lozenges will be summarized with descriptive statistics (n, mean, 
SD, minimum, median and maximum) by treatment for the mITT population and subpopulations. 
The number of subjects and percentage will also be calculated based on compliance.  
Compliance or non-compliance will be tabulated by treatment with frequency and percentage 
using the mITT population.  
Medication administration will be listed by treatment, including subject number, visit, visit date, 
the number of dispensed lozenges, the number of returned lozenges, the number of used 
lozenges and average number of lozenges used per day. Non-compliance on specific day(s) will 
be flagged, and total number of non-compliant days will be listed. 
 
7.5 Primary Analyses 
The primary endpoint, change from baseline (Day 0) compared to each treatment study visit day 
(Days 3, 7, 14 and 21) in OMI-total score, will be summarized using descriptive statistics 
(number, mean, standard deviation, minimum, maximum, median) and presented by treatment 
group using mITT populations. No inferential statistical comparisons between groups will be 
conducted. 


                             
                                                                                           
 
 
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7.6 Secondary Analyses 
The primary endpoint change from baseline (Day 0) compared to each treatment study visit day 
(Days 3, 7, 14 and 21) in OMI-total score will be summarized using descriptive statistics 
(number, mean, standard deviation, minimum, maximum, median) and presented by treatment 
group using the PP population, HLU population, and CS population.  
The change from baseline in erythema and ulcer subscores for each treatment study visit day 
(Days 3, 7, 14 and 21) will be summarized using descriptive statistics (number, mean, standard 
deviation, minimum, maximum and median) and presented by treatment group using the mITT 
population, PP population, HLU population, and CS population. 
No inferential statistical comparisons between groups will be conducted. 
 
7.7 Safety Analyses 
Safety data in this study are comprised of adverse events, physical examination, vital signs and 
clinical laboratory assessment. All safety data will be analyzed using the mITT Population.  
 
The continuous type safety endpoints will be summarized by treatment using descriptive 
statistics (n, mean, SD, median, minimum, maximum) for mITT population. The categorical type 
safety endpoints will be summarized by treatment using frequency and percentage for mITT 
population. No formal inferential tests will be performed on safety data. 
7.7.1 Adverse Events  
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Coding Dictionary version 19.1. All subjects in the mITT population will be included 
in the adverse event analysis. All adverse events will be listed chronologically by treatment, 
subject and AE start date/time. This listing will include all data collected in the eCRF, along with 
the derived variable duration of AE and the coded variables system organ class (SOC) and 
preferred term (PT). 
 
Displays of AEs will include: 
• 
Overall Summary of AEs 
This table will include the number of events, number and percent of subjects who 
experienced AEs, serious AEs, severe AEs, related AEs and AEs leading to study 
discontinuation, summarized by treatment. 


                             
                                                                                           
 
 
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• 
Summary of AEs by SOC, PT and Treatment 
A summary of the number of events, number and percent of subjects who experienced 
at least one AE, as well as the number of events, number and percent of subjects who 
experienced each specific SOC, and PT will be presented by treatment. If a subject has 
more than one occurrence of the same PT then the PT will be counted only once for that 
subject under the SOC at which it was experienced. 
7.7.2 Physical Examination 
Subjects will take a complete physical examination including a review of all body systems at the 
Screening Visit.  On Day 0 visit, an assessment of general oral health by a dental professional 
will be conducted to assure compliance with relevant inclusion and exclusion criteria. Any 
abnormal findings at baseline will be recorded as medical history, and findings after baseline will 
be recorded as adverse events. No separate listing will be produced. 
 
7.7.3 Vital Signs 
Systolic (SBP), diastolic (DBP) blood pressure and heart rate will be measured, for all 
scheduled study visit days (Days 0, 3, 7, 14, 21 and 24), including Screening, in a seated 
position after at least 5 minutes of rest. Subjects with a systolic blood pressure ≥ 150 mmHg or 
a diastolic blood pressure ≥ 95 mmHg on Day 0 may be excluded from the study, as judged by 
the Investigator. The vital signs will be summarized by treatment and visit using the standard 
summary statistics (n, mean, SD, minimum, median and maximum) for mITT population. All 
data will also be listed by treatment, subject, visit and vital sign parameters. 
7.7.4 12-Lead Electrocardiogram 
During the Screening Visit, a standard12-lead Electrocardiogram (ECG) will be obtained after 
the subject has rested in the supine position for at least 5 minutes. This assessment can be 
performed any time before blood sampling or at least 30 minutes after blood sampling, if 
applicable. Additionally, ECG will be measured on Day 7, Day 21 and Day 24 (if follow-up is 
required). ECG will be summarized by treatment and visit using the standard summary statistics 
(n, mean, SD, minimum, median and maximum) for the mITT population. All data will also be 
listed by treatment, subject, visit and ECG parameters. Overall assessment will be summarized 
using frequencies and percentage. 
7.7.5 Clinical Laboratory 
Serum chemistry, hematology and urinalysis will be measured in all subjects at Screening, Day 
0 (baseline), Day 7 and Day 21. A drug screen will be conducted at Screening and Day 0. All 
clinical laboratory samples and urine samples for urinalysis will be analyzed at a central 
laboratory. The urine pregnancy test will be analyzed in the clinic. The Investigator will evaluate 


                             
                                                                                           
 
 
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the clinical significance of each laboratory value outside of the reference range. 
Each abnormal test will be evaluated as clinically significant or not clinically significant. All 
clinically significant abnormal laboratory values that represent an unexpected change from 
Baseline will be assessed as adverse events (AEs), and an AE eCRF must be completed.  
Data in each of the three categories of hematology, chemistry and urinalysis will be listed by 
treatment, subject and parameter.   
7.7.6 Recovery  
Recovery will be assessed by comparing OMI-20 total score, erythema subscore, and ulcer 
subscore at Day 24 with those at Day 21. Other safety endpoints with clinically significant 
abnormal values at Day 21 will be re-evaluated on Day 24 to assess recovery from Day 21. 
Difference between Day 21 and Day 24 in OMI-total score, erythema subscore and ulcer 
subscore will be summarized using descriptive statistics (mean, standard deviation, minimum, 
maximum, and median) and presented by treatment group using the mITT population and 
subpopulations. No inferential statistical comparisons between groups will be conducted. 
 
7.8 Analysis Prior to Study Completion 
An early statistical analysis of data of administrative type is planned for this study following 
completion of the 60th randomized subject and prior to the completion of full study with 100 
randomized subjects and hard lock of the clinical database.  This statistical analysis provides 
with only descriptive summaries and without any confirmatory type of analysis using statistical 
significance.  This will provide an initial evaluation of selected study results and an assessment 
of adequacy of the result outputs for the final study report. 
 
The study is blinded only to the extent that the dental hygienist evaluating the oral health of 
subjects does not know to which treatment group the subjects have been assigned.  Otherwise 
the study could be considered an open label study as the subjects, investigators, and study staff 
are not blinded to the treatment. The individual dental hygienist evaluating the oral health of 
subjects will not be informed of the results of this pre-planned analysis prior to the completion of 
the full study analysis.  The study will continue to recruit and randomize beyond 60 subjects until 
the protocol specified 100 randomized subjects are evaluated. Also, the results of the completed 
study will be presented in the final report, only descriptively.   
 


                             
                                                                                           
 
 
Statistical Analysis Plan 
 
 
 
Sponsor: Niconovum USA, Inc. 
Sponsor Protocol No. 2016-NBTL-S-005 
 
17-May-2017 Final Version 1.0    
 
Page 21 of 53 
8 TABLES, LISTINGS AND GRAPHS (TLGs) SHELLS  
The following TL shells are provided as a framework for the display of data from this study. The 
shells may change due to unforeseen circumstances. These shells may not be reflective of 
every aspect of this study but are intended to show the general layout of the Tables and Listings 
that will be included in the final report. Table headers, variables names and footnotes will be 
modified as needed following data analyses.  


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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        Page 22 of 53 
Table 14.1.1 Disposition of Subjects and Analysis Sets 
 
 
Nicotine Polacrilex 
n (%) 
Nicotine Bitartrate  
n (%) 
Overall 
n (%) 
Number of Subjects in Randomized Population 
xx 
xx 
xx 
Number of Subjects in Modified Intent-to-Treat Population 
xx 
xx 
xx 
Number of Subjects in Per Protocol Population 
xx 
xx 
xx 
Number of Subjects in Heavy Lozenge Use Population 
xx 
xx 
xx 
Number of Subjects in Concomitant Smoker Population 
xx 
xx 
xx 
Number (%) of Subjects who Completed the Study 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Number (%) of Subjects who Discontinued Early 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Reasons for Early Discontinuation 
 
 
 
Adverse Event 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Physician Decision 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Protocol Deviation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Sponsor’s Decision 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Subject Non-compliance 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Withdrawal by Subject 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Note: Percentages are calculated based on the number of subjects in the Randomized Population per treatment and overall. 
Data Source: Listing 16.2.1 
 
 
 
 
 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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        Page 23 of 53 
Table 14.1.2 Demographics and Baseline Characteristics 
Modified Intent-to-Treat Population 
 
Nicotine Polacrilex 
(N=xx) 
Nicotine Bitartrate 
(N=xx) 
Overall 
(N=xx) 
Age (years)* 
 
 
 
n 
xx 
xx 
xx 
Mean 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
Minimum 
xx 
xx 
xx 
Median 
xx 
xx 
xx 
Maximum 
xx 
xx 
xx 
 
 
 
 
Sex, n (%) 
 
 
 
n 
xx 
xx 
xx 
Male 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Female 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
… 
 
 
 
 
Note: *Age at Informed Consent 
          Percentages are calculated based on the number of subjects in the ITT Population per treatment and overall. 
Data Source: Listing 16.2.4.1, Listing 16.2.4.2 
Programming Note: Table will also include race, ethnicity, height (cm), weight (kg), BMI (kg/m2) 
 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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        Page 24 of 53 
 
Table 14.1.3 Summary of Tobacco Use History 
Modified Intent-to-Treat Population 
Product 
Categories 
Nicotine Polacrilex 
(N=xx) 
Nicotine Bitartrate 
(N=xx) 
Overall 
(N=xx) 
Cigarettes 
Duration (Years) 
 
 
 
 
n 
xx 
xx 
xx 
 
Mean 
xx.xxx 
xx.xxx 
xx.xxx 
 
SD 
xx.xxxx 
xx.xxxx 
xx.xxxx 
 
Minimum 
xx.xx 
xx.xx 
xx.xx 
 
Median 
xx.xxx 
xx.xxx 
xx.xxx 
 
Maximum 
xx.xx 
xx.xx 
xx.xx 
 
Cigarettes (Per Day) 
 
 
 
 
n 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
 
SD 
xx.xx 
xx.xx 
xx.xx 
 
Minimum 
xx 
xx 
xx 
 
Median 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
xx 
 
Frequency 
 
 
 
 
≥ 30 cigarettes/day 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
20 - 29 cigarettes/day 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
< 20 cigarettes/day 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
Data Source: Listing 16.2.4.9 
 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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        Page 25 of 53 
Table 14.2.2.1 Summary of Change from Baseline in OMI-20 Total Score  
Modified Intent-to-Treat Population 
 
 
 
Treatment 
 
 
 
Statistics 
Nicotine Polacrilex 
Nicotine Bitartrate 
Baseline  
n 
xx 
xx 
Mean  ±  SD 
xx.x ± x.xx 
xx.x ± x.xx 
Median 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
Day 3  
n 
xx 
xx 
Mean  ±  SD 
xx.x ± x.xx 
xx.x ± x.xx 
Median 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
Change from baseline  to Day 3 
n 
xx 
xx 
Mean  ±  SD 
xx.x ± x.xx 
xx.x ± x.xx 
Median 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
Day 7  
n 
xx 
xx 
Mean  ±  SD 
xx.x ± x.xx 
xx.x ± x.xx 
Median 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
 
 
 
Change from baseline  to Day 7 
n 
xx 
xx 
Mean  ±  SD 
xx.x ± x.xx 
xx.x ± x.xx 
Median 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
Note: OMI – Oral Mucositis Index 
Data Source: Listing 16.2.6.1 
<Programming Note: continue for Day 14 and Day 21.> 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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        Page 26 of 53 
Similar tables as 14.2.2.1 will be generated for:  
Table 14.2.2.2 Summary of Change from Baseline in OMI-20 Total Score 
Per-Protocol Population 
Table 14.2.2.3 Summary of Change from Baseline in OMI-20 Total Score 
Heavy Lozenge Use Population 
Table 14.2.2.4 Summary of Change from Baseline in OMI-20 Total Score 
Concomitant Smoker Population 
Table 14.2.3.1 Summary of Change from Baseline in OMI Erythema Score 
Modified Intent-to-Treat Population 
Table 14.2.3.2 Summary of Change from Baseline in OMI Erythema Score 
Per-Protocol Population 
Table 14.2.3.3 Summary of Change from Baseline in OMI Erythema Score 
Heavy Lozenge Use Population 
Table 14.2.3.4 Summary of Change from Baseline in OMI Erythema Score 
Concomitant Smoker Population 
Table 14.2.4.1 Summary of Change from Baseline in OMI Ulcer Score 
Modified Intent-to-Treat Population 
Table 14.2.4.2 Summary of Change from Baseline in OMI Ulcer Score 
Per-Protocol Population 
Table 14.2.4.3 Summary of Change from Baseline in OMI Ulcer Score 
Heavy Lozenge Use Population 
Table 14.2.4.4 Summary of Change from Baseline in OMI Ulcer Score 
Concomitant Smoker Population 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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        Page 27 of 53 
 
 
 
Table 14.3.1.1 Overall Summary of Treatment Emergent Adverse Events (TEAEs) 
Modified Intent-to-Treat Population 
 
All Adverse Events 
 
Nicotine Polacrilex  
(N=xx) 
Nicotine Bitartrate  
(N=xx) 
Number (%) of Subjects with TEAE 
xx (xx.x%) [xx] 
xx (xx.x%) [xx] 
Number (%) of Subjects with Serious TEAE 
xx (xx.x%) [xx] 
xx (xx.x%) [xx] 
Number (%) of Subjects with Severe TEAE 
xx (xx.x%) [xx] 
xx (xx.x%) [xx] 
Number (%) of Subjects with Related TEAE 
xx (xx.x%) [xx] 
xx (xx.x%) [xx] 
Number (%) of Subjects with Study Discontinued Due to TEAE 
xx (xx.x%) [xx] 
xx (xx.x%) [xx] 
 
Note: An AE is considered to be related if it is possibly or probably related to study processes. 
          Summaries are presented as: number of subjects, (percentage of subjects), and [number of events]. 
Data Source: Listing 16.2.7 
 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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        Page 28 of 53 
 
Table 14.3.1.2 Summary of Treatment Emergent Adverse Events by System Organ Class and Preferred Term 
Modified Intent-to-Treat Population 
 
 
All Adverse Events 
System Organ Class/ 
      Preferred Term 
Nicotine Polacrilex  
(N=xx) 
Nicotine Bitartrate  
(N=xx) 
 
Any System Organ Class 
 
 
 
      Any Event 
xx (xx.x%) [xx] 
xx (xx.x%) [xx] 
 
Cardiac Disorders 
xx (xx.x%) [xx] 
xx (xx.x%) [xx] 
 
      Any Event 
xx (xx.x%) [xx] 
xx (xx.x%) [xx] 
 
      Bradycardia 
xx (xx.x%) [xx] 
xx (xx.x%) [xx] 
 
… 
 
 
 
 
Note:  All adverse events recorded throughout the study are summarized by treatment and MedDRA System Organ Class and Preferred Term. 
          Summaries are presented as: number of subjects, (percentage of subjects), and [number of events]. If multiple events occur in a category, it 
will be counted only once for calculation of frequencies at subject level. 
Data Source: Listing 16.2.7 
 
 
 
 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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        Page 29 of 53 
 
Table 14.3.1.3 Treatment-Emergent Adverse Events by System Organ Class, Preferred Term and Maximum 
Relationship (Modified Intent-to-Treat Population) 
 
 
 
All Adverse Events 
System Organ Class/ 
      Preferred Term 
Maximum  
Relationship 
Nicotine Polacrilex  
(N=xx) 
Nicotine Bitartrate  
(N=xx) 
 
Any System Organ Class 
 
 
 
 
      Any Event 
Unlikely 
xx (xx.x%) [xx] 
xx (xx.x%) [xx] 
 
 
Possible 
xx (xx.x%) [xx] 
xx (xx.x%) [xx] 
 
 
Probably 
xx (xx.x%) [xx] 
xx (xx.x%) [xx] 
 
 
 
 
 
 
Cardiac Disorders 
 
 
 
 
      Any Event 
Unlikely 
xx (xx.x%) [xx] 
xx (xx.x%) [xx] 
 
 
Possible 
xx (xx.x%) [xx] 
xx (xx.x%) [xx] 
 
 
Probably 
xx (xx.x%) [xx] 
xx (xx.x%) [xx] 
 
 
 
 
 
 
 
Note:  All adverse events recorded throughout the study are summarized by treatment and MedDRA System Organ Class and Preferred Term. 
          Summaries are presented as: number of subjects, (percentage of subjects), and [number of events]. If multiple events occur in a category, it 
will be counted only once for calculation of frequencies at subject level. 
Data Source: Listing 16.2.7 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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        Page 30 of 53 
Table 14.3.4 Summary of Vital Signs 
Modified Intent-to-Treat Population 
Parameter (Unit) 
Visit 
 
Statistic 
Nicotine Polacrilex 
(N=xx) 
Nicotine Bitartrate 
(N=xx) 
Systolic Blood Pressure (mmHg) 
Screening 
 
 
 
 
 
n 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
 
 
SD 
xx.xx 
xx.xx 
 
 
Minimum 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
 
Day 0 Baseline 
… 
 
 
 
Day 3  
… 
 
 
….. 
 
 
 
 
 
Note: EOS=End of Study, ET=Early Termination 
Data Source: Listing 16.2.9 
Programming Note: Parameter also includes Diastolic Blood Pressure (mmHg), Pulse Rate (bpm), Programming will continue for Day 7, 14, 21 
and EOS. 
 
 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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        Page 31 of 53 
 
 
Table 14.3.5.1 Summary of Overall ECG Interpretation  
Modified Intent-to-Treat Population 
 
Visit  
 
Nicotine Polacrilex 
(N=xx) 
Nicotine Bitartrate 
(N=xx) 
Baseline 
 
 
 
 
n 
xx 
xx 
 
Normal, n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
Abnormal, Not Clinically Significant, n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
Abnormal, Clinically Significant, n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
… 
 
 
Day 7 
 
 
 
 
n 
xx 
xx 
 
Normal, n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
Abnormal, Not Clinically Significant, n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
Abnormal, Clinically Significant, n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Note: EOS=End of Study 
 
Data Source: Listing 16.2.10 
Programming Note: Programming will continue for Day 14, 21 and EOS/ET. 
 
 
 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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Table 14.3.5.2 Summary of ECG Continuous Data 
Safety Population 
ECG Parameters 
(unit) 
 
Visit 
 
Statistics 
Nicotine Polacrilex 
(N=xx) 
Nicotine Bitartrate 
(N=xx) 
Ventricular Rate (bpm) 
Baseline* 
 
 
 
 
 
n 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
 
 
SD 
xx.xx 
xx.xx 
 
 
Minimum 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
 
Day 7 
 
 
 
 
 
n 
xx 
xx 
 
 
mean 
xx.x 
xx.x 
 
 
.. 
xx.x 
xx.x 
 
 
xx 
xx 
xx 
 
… 
 
 
 
 
Note: *Baseline is defined as the last observation prior to the dose. 
<ECG Parameter (unit)> = Ventricular Rate (bpm), PR Interval (msec), QRS Duration (msec), QT Interval (msec), QTcB Interval (msec) 
Programming Note: Table also includes Day 14, 21 and EOS/ET. 
 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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Table 14.3.6.1 Summary of Breath carbon monoxide (CO) levels (mITT Population) 
 
 
 
 
Treatment 
 
 
Visit 
 
Statistics 
Nicotine Polacrilex 
Nicotine Bitartrate 
Day 3 
Average CO level (Compliant) 
n 
xx 
xx 
Mean  ±  SD 
xx.x ± x.xx 
xx.x ± x.xx 
Median 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
 
 
 
 
 
 
CO level <=10pmm or not?  
n (%) 
 
 
 
Yes 
 
xx (xx.x%) 
xx (xx.x%) 
 
No 
 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Day 7 
 
 
 
 
Day 14 
 
 
 
 
 
 
Day 21 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data Source: Listing 16.2.5.1 
 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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        Page 34 of 53 
Table 14.3.6.2 Summary of Study Drug Administration  
 
 
 
 
Treatment 
 
 
Population  
 
Statistics 
Nicotine Polacrilex 
Nicotine Bitartrate 
mITT 
mITT Average number of 
used lozenges per day 
n 
xx 
xx 
Mean  ±  SD 
xx.x ± x.xx 
xx.x ± x.xx 
Median 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
 
 
 
 
 
 
Number of non-compliance 
days>2 or not 
n (%) 
 
 
 
Yes 
 
xx (xx.x%) 
xx (xx.x%) 
 
No 
 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
PP 
 
 
 
 
HLU 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data Source: Listing 16.2.5.2 
 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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        Page 35 of 53 
Table 14.3.6.3 Summary of Medication Compliance (mITT Population) 
 
 
 
Treatment 
 
Compliance 
Nicotine Polacrilex n (%) 
Nicotine Bitartrate n (%) 
 
 
 
 
 
 
Yes 
xx (xx.x%) 
xx (xx.x%) 
No 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
Data Source: Listing 16.2.5.1 & Listing 16.2.5.2 
 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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Table 14.3.7.1 Summary of difference in OMI-20 Total Score Between Day 21 and Day 24 
 
 
 
 
Treatment 
 
 
Population 
 
Statistics 
Nicotine Polacrilex 
Nicotine Bitartrate 
mITT 
Day 21  
n 
xx 
xx 
Mean  ±  SD 
xx.x ± x.xx 
xx.x ± x.xx 
Median 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
 
Day 24  
n 
xx 
xx 
Mean  ±  SD 
xx.x ± x.xx 
xx.x ± x.xx 
Median 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
 
Difference between Day 21 
n 
xx 
xx 
Mean  ±  SD 
xx.x ± x.xx 
xx.x ± x.xx 
Median 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
 
 
 
PP
 
 
 
 
 
 
HLU 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: OMI – Oral Mucositis Index 
Data Source: Listing 16.2.6.1 
 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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Similar tables as 14.3.7.1 will be generated for:  
 
Table 14.3.7.2 Summary of difference in OMI Erythema Score Between Day 21 and Day 24 
Modified Intent-to-Treat Population 
Table 14.3.7.3 Summary of difference in OMI Ulcer Score Between Day 21 and Day 24 
Modified Intent-to-Treat Population 
 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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        Page 38 of 53 
 
Listing 16.1.7 Randomization Scheme 
 
Subject 
Treatment 
Age* 
(years) 
Gender 
Date of Informed Consent 
Date of Enrollment 
Smoking category 
xxxxx 
Nicotine 
Polacrilex 
xx 
Male 
DDMONYYYY 
DDMONYYYY 
Type 1 
…… 
 
 
 
 
 
 
 
Note: *Age at informed consent.  
          Type 1: # of smoked cigarette per day < 20; Type 2: 20-29; Type 3: >=30. 
 
 
 
 
 
 
 
 
 
 
 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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Listing 16.2.1 Subject Disposition and Completion/Early Termination 
 
Treatment 
Subject 
Date of Study Completion 
or Early Discontinuation 
Date of Last 
Contact 
Completed Study 
Reason for Study 
Discontinuation* 
Nicotine 
Polacrilex 
xxxx 
DDMONYYYY 
DDMONYYYY 
No 
xxxxxxxxxxx 
 
…… 
 
 
 
 
…… 
 
 
 
 
 
 
Note: *A corresponding AE number will be displayed if Reason for Discontinuation or Reason for Study Discontinuation is “Adverse Event”. 
 
 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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Listing 16.2.2 Protocol Deviations 
 
Treatment 
Subject 
Deviation Start 
Date 
Visit 
Protocol Deviation 
Type 
Description of Protocol Deviation 
Nicotine 
Polacrilex 
xxxx 
DDMONYYYY 
xxxx 
Xxxxx 
Xxxxxxx 
 
…… 
 
 
 
 
…. 
 
 
 
 
 
 
 
 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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Listing 16.2.4.1 Demographic Data 
 
Treatment 
Subject 
Informed 
Consent Date 
Gender 
Date of Birth 
Age* 
(years) 
Race 
Ethnicity 
Height 
(cm) 
Weight 
(kg) 
BMI 
(kg/m2) 
Nicotine 
Polacrilex 
xxxx 
DDMONYYYY 
x 
DDMONYY
YY 
xx 
xxxxx 
xxxxx 
xxx 
xx 
xx 
 
…… 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
Note: *Age at Informed Consent. 
 
 
 
 
 
 
 
 
 
 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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Listing 16.2.4.2 Urine Drug Screen and Alcohol Breath Test 
 
 
Treatment 
 
Subject 
 
Visit 
Collection 
Date 
Ampheta 
-mines 
Barbitur 
-ates 
Benzodia 
-zepines 
Canna 
-binoids 
 
Cocaine 
 
Opiates 
 
Alcohol 
Nicotine 
Polacrilex 
xxxx 
Screen 
DDMONYYYY   
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
Negative 
 
 
Day 0  
…. 
 
 
 
 
 
 
 
 
    ….. 
 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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Listing 16.2.4.3 Medical History 
 
Treatment 
Subject 
MH # 
Medical History Category 
Medical History Term 
Start Date and Time 
End Date and Time 
Nicotine 
Polacrilex 
xxxx 
x 
 
Xxxxxx 
DDMONYYYY 
DDMONYYYY 
 
 
x 
 
Xxxxxx 
DDMONYYYY 
Ongoing 
 
…… 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
Note: MH=Medical History (including relevant medical [within last 5 years]). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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Listing 16.2.4.4 Concomitant Medications 
 
Treatment 
Subject 
MH # 
Medication Name 
Dose/Unit/Frequency 
/Route 
Start Date/Stop Date 
Indication/ 
Administered for 
AE or MH? 
Nicotine 
Polacrilex 
xxxx 
x 
xxxxxxxxx 
20/ mg/ Once/ Oral 
DDMONYYYY HH:MM / 
 DDMONYYYY HH:MM 
Headache/  
Yes (AE # 4) 
 
 
x 
xxxxxxxxx 
xxx/ xxx/ xxxx/xxxx 
DDMONYYYY HH:MM / 
Ongoing 
xxxxx/  
No 
 
…… 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
 
 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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Listing 16.2.4.5 Serology Screen 
 
Treatment 
Subject 
Collection Date and Time 
Hepatitis B Surface Antigen 
Hepatitis C Virus Antibody 
HIV Antibody 
Nicotine 
Polacrilex 
xxxx 
DDMONYYYY HH:MM 
Negative 
Negative 
Non-Reactive 
 
…… 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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Listing 16.2.4.6 Pregnancy Tests 
Treatment 
Subject 
Visit 
Collection Date and Time 
Results 
Nicotine 
Polacrilex 
xxxx 
Screening 
DDMONYYYY   HH:MM 
Negative 
 
 
Day 0 
DDMONYYYY  HH:MM 
Negative 
 
 
 
 
 
 
…… 
 
 
 
 
…… 
 
 
 
 
 
 
Note: Serum pregnancy test at Screening; urine pregnancy test at Check-in of Day 0 Test Visit. 
 
 
 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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Listing 16.2.4.7 Tobacco Product Use History  
 
Treatment 
Subject 
Substance 
Start Date of 
Substance Used 
End Date of 
Substance Used 
Substance 
Use 
Ongoing? 
Frequency 
of Use 
Amount/ 
Unit/ 
Frequency 
Typically 
Used Brand 
Style 
Nicotine 
Polacrilex 
xxxx 
Cigarettes 
20JAN1990 
 
Yes 
Daily 
10/Cigarette/Per Day 
xxxx 
 
…… 
 
 
 
 
 
 
 
 
xxxx 
Cigarettes 
01JUL2005 
01AUG2015 
No 
Daily 
15/Cigarette/Per Day 
xxxx 
 
 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
 
 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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Listing 16.2.5.1 Study Drug Administration 
 
Treatment 
Subject 
Visit 
Dispense/ 
Administration 
Date 
Number of 
Dispensed 
Number of 
Returned 
Number of 
Daily Use 
Compliance  
Flag* 
Number of  
Non-Compliance 
Days 
Nicotine 
Polacrilex 
xxxx 
Day 0 
DDMONYYYY  
xx 
 
 
 
 
 
 
Day 1 
DDMONYYYY 
 
 
xx 
Yes 
 
 
 
Day 7 
DDMONYYYY 
xx 
xx 
xx 
No 
 
 
 
…. 
 
 
 
 
 
 
 
 
Day 21 
DDMONYYYY 
 
 
xx 
Yes 
 
 
 
Day 24 
DDMONYYYY 
 
xx 
 
 
xx 
 
xxxx 
Day 0 
 
 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Drug dispense happens on Day 0, 7 and 14; Drug return happens on Day 7, 14 and 24. 
          *Compliance will be flagged ‘No’ for daily lozenge use fewer than 9 or more than 20.  
 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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        Page 49 of 53 
Listing 16.2.5.2 Carbon Monoxide Breath Test 
 
Treatment 
Subject 
Visit 
 
Collection Date 
CO Level (ppm) 
Compliance Flag 
Total Number of  
Non-Compliance 
Days 
Nicotine 
Polacrilex 
xxxx 
Day 0 
 
DDMONYYYY   
xxx 
 
 
 
 
Day 3  
 
 
 
 
 
 
…… 
Day 7 
 
 
 
…… 
 
Day 21 
 
 
xx 
 
 
 
 
 
 
 
Note: CO = Carbon Monoxide; CO levels exceeding 10 ppm during treatment will be flagged as ‘No’;  
          CO level should be higher than 10 ppm on Day 0. CO level will be measured on Day 0, 3, 7, 14 and 21. 
 
 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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        Page 50 of 53 
 
Listing 16.2.6.1 Oral Mucositis Index (OMI-20) 
 
Treatment 
Subject 
Visit 
Collection Date  
Organ 
Location  
Atrophy 
Erythema 
Edema 
Ulcer 
/Pseudomembrane 
Nicotine 
Polacrilex 
xxxx 
 
DDMONYYYY  
Labial Mucosa 
Lower 
 
xx 
 
xx 
 
 
 
 
 
Upper 
 
xx 
 
xx 
 
xxxx 
 
DDMONYYYY  
Buccal Mucosa 
Right 
 
xx 
 
xx 
 
 
 
 
 
Left 
 
xx 
 
xx 
 
…… 
 
 
Tongue 
Dorsal 
xx 
xx 
 
xx 
 
 
 
 
 
Lateral 
 
xx 
xx 
xx 
 
 
 
 
 
Ventral 
 
xx 
 
xx 
 
 
 
 
Mouth Floor 
 
 
xx 
 
xx 
 
 
 
 
Soft Palate 
 
 
xx 
 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
 
 
 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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        Page 51 of 53 
Listing 16.2.7.1 Adverse Events 
 
Treat 
-ment 
Subje
ct 
Visit 
AE # 
Treatment 
Emergent? 
System Organ Class/ 
Preferred Term/ 
Verbatim Term 
Start Date and Time/ 
Stop Date and Time/ 
Duration 
(DD:HH:M
M)* 
Severity/ 
Serious/  
Relationship to 
study 
Outcome 
Action 
Taken/ 
Other 
Action 
Caused 
Study 
Discontin 
-uation 
Nicotin
e 
Polacril
ex 
xxxx 
Day 1 
x 
Yes 
Nervous system 
disorders/ Headache/ 
Headache 
DDMONYYYY 
HH:MM/ / Ongoing 
 
 
Mild/ Yes 
(Death)/ 
Unrelated/  
Recovered/
Resolved 
None/None 
No 
 
 
 
x 
Yes 
Gastrointestinal 
disorders/ Vomiting/ 
Vomiting 
DDMONYYYY 
HH:MM/ 
DDMONYYYY 
HH:MM 
DD:HH:MM 
Moderate/ No/ 
Related /  
Recovered/
Resolved 
None/None 
No 
 
…… 
 
 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  *DD: HH: MM = Days: Hours: Minutes. 
 
Programming Note: 1) if the status of the adverse event is ongoing at the end of the study (i.e. AEONGO=”Y” and AEENDTC is missing), the “Stop 
Date and Time” will be presented as “Ongoing”; 2) if any serious adverse event (SAE) occurs, a similar listing will be produced for SAEs 
separately.  
 
 
 
 
 
 
 
 
 
 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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        Page 52 of 53 
 
Listing 16.2.8.X Laboratory Measurements: <Laboratory Panel> 
Full Analysis Set Population 
 
Treatment 
Subject 
Test 
Performed? 
Date of Sample 
Collection 
Lab Test (Unit) 
Value 
Reference 
Range 
Indicator 
Normal 
Range 
Clinically 
Significant? 
 
xxxx 
Yes 
DDMONYYYY 
xxxxxx(xxxx) 
xx 
High 
xx - xxx 
No 
 
 
 
 
xxxxx (xxxx) 
xx 
Abnormal 
Negative 
 
 
 
 
 
…… 
 
 
 
 
 
xxxx 
No 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
 
 
Programming Note: < Laboratory Panel> = Hematology, Chemistry, Urinalysis. X will be assigned as 1, 2, and 3 for each laboratory panel, and 
each listing will continue for all parameters (unit) in that panel. 
 
 
 
 
 
 
 
 
 
 
 
 


Niconovum USA, Inc./ 2016-NBTL-S-005                                                                                                                                                   Page 1 of X 
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        Page 53 of 53 
Listing 16.2.9 Vital Signs 
Full Analysis Set Population 
 
Treatment 
Subject 
Visit 
Collection Date 
and Time 
Position 
SBP 
(mmHg) 
DBP 
(mmHg) 
HR 
(bpm) 
 
xxxx 
Screening 
DDMONYYYY 
HH::MM 
Sitting 
xxx 
xx 
xx 
 
 
Day 0 
DDMONYYYY  
 
xxx 
xx 
xx 
 
 
 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
…… 
 
 
 
 
 
 
 
 
Note: SBP=Systolic Blood Pressure, DBP=Diastolic Blood Pressure, HR=Heart Rate. 
         EOS = End of Study, ET = Early Termination. 
 
Programming Note: The table will continue on Day 3, 7, 14, 21 and EOS.