Randomized, Parallel-Group, Assessor Blind Study To Evaluate Oral Mucosal Effects In Healthy Adult Smokers Associated With 3 Week Use Of Nicotine Bi-tartrate 4mg Mint Lozenges Relative To The Use Of Nicotine Polacrilex 4mg Mint Lozenges
Phase: PHASE1
Conditions: Safety Issues
Sponsor: Niconovum USA

 
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 
 
 
 
 
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• 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 
 
 
 
 
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 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