A Randomised, Cross-over, Single-blind, Relative Bioavailability Study of Nicotine Delivery From Selected Oral Nicotine Products
Phase: NA
Conditions: Healthy Volunteers
Sponsor: Imperial Brands PLC

 
A Randomised, Cross-Over, Single-Blind, Rela6ve Bioavailability Study of 
Nico6ne Delivery From Selected Oral Nico6ne Products 
 
 
NCT05452278 
 
 
Clinical Study Protocol - FINAL Version 1.0 3 21 Jun 2021 

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
1 (55) 
 
Clinical Study Protocol 
 
Investigational 
Products 
ZoneX #5 slim 14 mg nicotine/pouch, 
ZoneX #5 16 mg nicotine/pouch,  
ZoneX #6 20 mg nicotine/pouch and  
Skruf Slim Fresh #5 16.6 mg nicotine/ 
pouch 
 
Sponsor study code 
IB-OND-ZONEX-11 
 
Protocol version and 
date 
Final version 1.0; 21JUN2021 
 
 
 
A RANDOMISED, CROSS-OVER, SINGLE-BLIND, RELATIVE BIOAVAILABILITY 
STUDY OF NICOTINE DELIVERY FROM SELECTED ORAL  
NICOTINE PRODUCTS  
 
Phase 
I 
Indication 
Healthy volunteers 
Test products and doses 
ZoneX #5 slim 14 mg nicotine/pouch 
ZoneX #5 16 mg nicotine/pouch 
ZoneX #6 20 mg nicotine/pouch 
Comparator product and dose 
Skruf Slim Fresh #5 16.6 mg nicotine/ pouch   
Sponsor signatory 
Principal Investigator 
Clinical study conduct and 
management 
 
 
Imperial
Tobacco
F

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
2 (55) 
1 
STUDY SYNOPSIS 
Study title 
A randomised, cross-over, relative bioavailability study of nicotine delivery from selected oral 
nicotine products  
Study code 
Planned study period 
Q3 2021 to Q1 2022 
Phase of development 
I 
Principal Investigator 
Study design 
This will be a randomised, cross-over, single-blind, confinement study conducted in 27 male or 
female snus or nicotine pouch users. The study will investigate 4 different nicotine containing 
products in a cross-over design, incorporating pharmacokinetic (PK) evaluation, nicotine extraction 
evaluation, subjective questionnaire assessments as well as safety and tolerability evaluation. 
During the study participation, subjects will come for 2 visits to the clinic, including a screening visit 
and a 4-day confinement period. A final follow up end-of-study telephone call will be performed 
within a week of last product use. 
Objectives  
Primary objective 
To evaluate and compare the maximum plasma concentration (Cmax) and the area under the curve at 
the last timepoint measured (AUCt) of nicotine after the use of each product. 
Secondary objectives  
• 
To evaluate other PK parameters of nicotine after the use of each product. 
• 
To evaluate orally extracted dose of nicotine in used products (oral nicotine delivery [OND]). 
• 
To evaluate product perception and preference by use of subjective assessments. 
• 
To evaluate the tolerability and safety of each of the products used. 
Imperial
Tobacco
A

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
3 (55) 
Endpoints 
Primary endpoints 
• 
Cmax and AUCt  
Secondary endpoints 
• 
AUC timepoint 0 to 90 minutes (AUC0-90), AUC timepoint 0 to infinity (AUCinf), time to 
Cmax (Tmax), plasma concentration at last timepoint measured (Clast), and terminal elimination 
half-life (T1/2). 
• 
The orally extracted dose of nicotine from each pouch will be calculated to evaluate the 
correlation between baseline-adjusted AUCinf and orally extracted dose of nicotine. 
• 
Subjective assessment endpoints including: Product evaluation scale (PES), Product 
preference scale (PPS) and the Urge to use questionnaire.  
• 
Frequency, intensity and seriousness of adverse events (AEs). 
• 
Clinically significant changes in laboratory parameters, vital signs and electrocardiogram 
(ECG). 
Number of subjects planned 
Approximately 54 subjects will be screened to achieve a total of 27 randomised subjects. 
Main eligibility criteria 
Male and female snus or nicotine pouch users, aged g19 years, with a body mass index (BMI) of g 
18.0 and f 30.0 kg/m2 will be considered for participation in the study. 
Pregnant or breastfeeding women, or subjects with other conditions believed to either put the subject 
at risk because of participation in the study, or influence the results or the subject’s ability to 
participate in the study, as judged by the Investigator, will be excluded from participation. 
Subjects who intend to change their nicotine-use habits, reduce or stop nicotine use within the next 
3 months will also be excluded. Subjects excluded due to a wish to make a quit attempt will be 
offered advice by the clinical team and provided with contact information for a nicotine cessation 
support service. 
Methodology 
Visit 1 (Screening)  
Visit 1 will take place from Day -28 to Day 1 and will include an eligibility check, review of health 
status and assessment of nicotine user habits.  
Subjects will be advised of the risks of using nicotine and referred to nicotine-use cessation support to 
quit if that is their intention. 
Visit 2 (In-clinic treatment period, Day -1 to Day 4) 
At Visit 2, subjects will be admitted to the clinic on Day -1 and will remain at the clinic until Day 4 
for daily single IP use and PK blood sampling, nicotine extraction, subjective questionnaire 
assessments and safety assessments. 
On Day -1, baseline vital signs, ECG and clinical laboratory profile assessments will be performed. 
Subjects are allowed to use their own snus or nicotine pouch product until 10 pm of Day -1. At 
10 pm, the subjects’ own nicotine containing products will be collected by a member of the clinical 
team. On Day -1, the subjects will also undertake a familiarisation session of the study products and 
questionnaires. The clinical team will explain how the products will be used and the subjects will 
have the opportunity to see the products and the packaging of products. An explanation of how the 
questionnaires will be distributed to the subjects will be given. The familiarisation session does not 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
4 (55) 
include a product trial and the products used in the session will not be used in the clinical study but 
will be retained as demonstration samples for accountability purposes. 
In the morning of Day 1, after pre-use assessments and re-confirmation of eligibility, the subjects will 
be randomised and thereafter administered a single pouch of the IP in the sequence to which they 
have been randomised. The oral nicotine IP will be used for 20 minutes according to standard use 
instructions. PK sampling will be done pre-IP use and at 5, 10, 15, 20, 30, 45, 60, 90 minutes, 2, 4, 6 
and 8 hours post start of IP use. Used pouches will be collected for analysis of nicotine extraction. 
Questionnaires will be administered to the subject at defined intervals throughout the day. Safety will 
be followed throughout the day. Subjects will be allowed to use their own nicotine containing 
products ad lib after the 8-hour timepoint until 10 pm. 
In the morning of Day 2, after pre-IP use assessments, the subjects will be administered a single 
pouch of the IP in the sequence to which they have been randomised. IP will be used for 20 minutes 
according to standard use instructions. PK sampling will be done pre-IP use and at 5, 10, 15, 20, 25, 
30, 45, 60, 90 minutes, 2, 4, 6 and 8 hours post start of IP use. Used pouches will be collected for 
analysis of nicotine extraction. Questionnaires will be distributed to the subject at defined intervals 
throughout the day. Safety will be followed throughout the day. Subjects will be allowed to use their 
own nicotine containing products ad lib after the 8-hour timepoint until 10 pm. 
In the morning of Day 3, after pre-IP use assessments, the subjects will be administered a single 
pouch of the IP in the sequence to which they have been randomised. IP will be used for 20 minutes 
according to standard use instructions. PK sampling will be done pre-IP use and at 5, 10, 15, 20, 25, 
30, 45, 60, 90 minutes, 2, 4, 6 and 8 hours post start of IP use. Used pouches will be collected for 
analysis of nicotine extraction. Questionnaires will be distributed to the subject at defined intervals 
throughout the day. Safety will be followed throughout the day. Subjects will be allowed to use their 
own nicotine containing products ad lib after the 8-hour timepoint until 10 pm. 
In the morning of Day 4, after pre-IP use assessments, the subjects will be administered a single 
pouch of the IP in the sequence to which they have been randomised. IP will be used for 20 minutes 
according to standard use instructions. PK sampling will be done pre-IP use and at 5, 10, 15, 20, 25, 
30, 45, 60, 90 minutes, 2, 4, 6 and 8 hours post start of IP use. Used pouches will be collected for 
analysis of nicotine extraction. Questionnaires will be distributed to the subject at defined intervals 
throughout the day. Safety will be followed throughout the day. Subjects will leave the research clinic 
after completing all 8-hour assessments on Day 4. 
Visit 3 (End-of-Study phone call) 
A follow-up telephone call (Visit 3, end-of-study) will be made on Day 7 (±1) to follow-up on any AEs. 
Investigational Product (IP), dosage and mode of administration 
• 
A: ZoneX #5 slim 14 mg nicotine/pouch 
• 
B: ZoneX #5 16 mg nicotine/pouch 
• 
C: ZoneX #6 20 mg nicotine/pouch 
• 
D: Skruf Slim Fresh #5 16.6 mg nicotine/ pouch   
The ZoneX products are tobacco-free while the comparator (Skruf Slim Fresh #5) contains tobacco. 
Duration of IP use 
Single 20-minute use of each of the 4 oral nicotine products. Subjects will be allowed to use their 
own nicotine containing products ad lib after the 8-hour timepoint until 10 pm each day. 
Duration of each subject’s involvement in the study 
Subjects will participate in the study for up to 35 days, including an up to 28-day screening period. 
Pharmacokinetic (PK) assessments 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
5 (55) 
Blood sampling for nicotine plasma concentration analysis. 
Safety assessments  
• 
AEs 
• 
Clinical laboratory profile 
• 
Vital signs (blood pressure and pulse) 
• 
ECG 
Subjective measures 
PES, PPS and the Urge to use questionnaire 
Statistical methods 
No formal sample size calculation has been performed for this study. The proposed sample size is 
considered sufficient to provide adequate information for the study objectives. 
Continuous data will be presented in terms of evaluable and missing observations, arithmetic mean, 
standard deviation (SD), median, minimum and maximum value. In addition, for the parameters AUC 
and Cmax, the geometric mean and geometric coefficient of variation (CV) will be presented.  
Categorical data will be presented as counts and percentages. When applicable, summary data will be 
presented by treatment, and by assessment time. Individual subject data will be listed by subject 
number, treatment, and, where applicable, by assessment time. 
All descriptive summaries and statistical analyses will be performed using SAS Version 9.4 or later 
(SAS Institute, Inc., Cary, NC). 
The primary objective will be examined by the following statistical comparisons for AUCt and Cmax: 
• 
Product A versus Product B, C and D, respectively 
• 
Product B versus Product C and D, respectively 
• 
Product C versus Product D, respectively 
Log transformed nicotine Cmax and AUCt estimates will be evaluated separately in a linear mixed-
effects analysis of variance model with fixed effects for period, sequence, and product, and a random 
effect for subject. If the assumptions for this model will be inappropriate, the fixed effects period and 
sequence will be removed from the model. The above product differences will be back-transformed to 
present the ratios of geometric least squares (LS) means and 95% confidence intervals (Cis) of each 
test product versus each other from the same model. 
Study reporting 
After completion of the study a clinical study report (CSR) will be prepared.  
 
 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
6 (55) 
2 
TABLE OF CONTENTS 
1 
STUDY SYNOPSIS ............................................................................................... 2 
2 
TABLE OF CONTENTS ...................................................................................... 6 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .................... 10 
4 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR ............................................................................................... 13 
4.1 
Medical emergencies contacts ............................................................................. 13 
5 
INVESTIGATOR AND STUDY ADMINISTRATIVE STRUCTURE ............ 13 
6 
INTRODUCTION ............................................................................................... 15 
6.1 
Background ......................................................................................................... 15 
6.1.1 
Summary of non-clinical data ............................................................................ 15 
6.1.2 
Clinical experience ............................................................................................ 16 
6.2 
Study rationale .................................................................................................... 16 
6.3 
Risk/benefit assessment ....................................................................................... 16 
Risk assessment with regard to the Covid-19 pandemic ........................................................ 17 
7 
STUDY OBJECTIVES AND ENDPOINTS ...................................................... 19 
7.1 
Primary objective and endpoints ........................................................................ 19 
7.2 
Secondary objectives and endpoints ................................................................... 19 
8 
STUDY DESIGN ................................................................................................. 20 
8.1 
Overall study design and schedule of events ...................................................... 20 
8.2 
Rationale for study design .................................................................................. 24 
9 
STUDY POPULATION ...................................................................................... 24 
9.1 
Recruitment ......................................................................................................... 24 
9.2 
Screening and enrolment log .............................................................................. 24 
9.3 
Number of subjects ............................................................................................. 24 
9.4 
Inclusion criteria ................................................................................................. 25 
9.5 
Exclusion criteria ................................................................................................ 25 
9.6 
Restrictions during the study .............................................................................. 26 
9.6.1 
General restrictions............................................................................................ 26 
9.6.2 
Prior and concomitant therapy ........................................................................... 27 
9.7 
Screen failures ..................................................................................................... 27 
9.8 
Subject withdrawal ............................................................................................. 27 
9.8.1 
General withdrawal criteria ............................................................................... 27 
9.8.2 
Procedures for discontinuation of a subject from the study ................................ 28 
9.8.3 
Subject replacement .......................................................................................... 28 
9.9 
Randomisation .................................................................................................... 28 
9.10 
Blinding ............................................................................................................... 29 
10 
TREATMENTS .................................................................................................. 29 
10.1 
Identity of investigational products .................................................................... 29 
10.2 
Identity of non-investigational products ............................................................ 29 
10.3 
Manufacturing, packaging and labelling ........................................................... 29 
10.4 
Conditions for storage ......................................................................................... 29 
10.5 
Preparation and accountability .......................................................................... 29 
10.6 
Treatment administration................................................................................... 30 
Imperial
Tobacco
2
I
6
.......
.
.A
.....

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
7 (55) 
10.7 
Treatment compliance ........................................................................................ 30 
10.8 
Return and destruction of investigational products .......................................... 30 
11 
STUDY ASSESSMENTS .................................................................................... 31 
11.1 
Recording of data ................................................................................................ 31 
11.2 
Demographics and other baseline characteristics .............................................. 31 
11.2.1 
Informed consent ............................................................................................... 31 
11.2.2 
Eligibility criteria .............................................................................................. 31 
11.2.3 
Demographic information .................................................................................. 31 
11.2.4 
Physical examination ......................................................................................... 32 
11.2.5 
Weight and height ............................................................................................. 32 
11.2.6 
Medical/surgical history .................................................................................... 32 
11.2.7 
Prior and concomitant medication...................................................................... 32 
11.2.8 
HIV and Hepatitis B/C ...................................................................................... 32 
11.2.9 
Covid-19 rapid test ............................................................................................ 32 
11.2.10 
Pregnancy test ................................................................................................... 33 
11.2.11 
Urine drug screen .............................................................................................. 33 
11.2.12 
Alcohol test ....................................................................................................... 33 
11.2.13 
Baseline symptoms ............................................................................................ 33 
11.2.14 
Assessment of snus or nicotine pouch user habits .............................................. 33 
11.3 
Assessments related to primary endpoints ......................................................... 33 
11.3.1 
Pharmacokinetic sampling and analysis for primary endpoints .......................... 33 
11.4 
Assessments related to secondary endpoints ...................................................... 34 
11.4.1 
Pharmacokinetic sampling and analysis for secondary endpoints ....................... 34 
11.4.2 
Nicotine extraction from pouches ...................................................................... 34 
11.4.3 
Product evaluation scale .................................................................................... 34 
11.4.4 
Product preference scale .................................................................................... 34 
11.4.5 
Urge to use questionnaire .................................................................................. 34 
11.4.6 
Adverse events .................................................................................................. 35 
11.4.7 
Laboratory safety assessments ........................................................................... 39 
11.4.8 
Vital signs ......................................................................................................... 40 
11.4.9 
Electrocardiogram ............................................................................................. 40 
11.5 
Appropriateness of measurements ..................................................................... 40 
12 
PROCEDURES FOR BIOLOGICAL SAMPLES............................................. 40 
12.1 
Sample collection ................................................................................................. 40 
12.2 
Volume of blood .................................................................................................. 40 
12.3 
Handling, storage and destruction of laboratory samples ................................. 41 
12.4 
Chain of custody of biological samples ............................................................... 41 
12.5 
Withdrawal of informed consent for donated biological samples ..................... 41 
13 
QUALITY MANAGEMENT, QUALITY ASSURANCE AND QUALITY 
CONTROL .......................................................................................................... 41 
13.1 
Quality management: critical process, system and data identification ............. 41 
13.2 
Quality assurance and quality control ............................................................... 42 
14 
ETHICAL AND REGULATORY REQUIREMENTS ..................................... 42 
14.1 
Ethical conduct of the study ............................................................................... 42 
14.2 
Ethics and regulatory review .............................................................................. 42 
14.3 
Subject information and consent ........................................................................ 42 
14.4 
Subject data protection ....................................................................................... 43 
Imperial
Tobacco
:
..

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
8 (55) 
14.5 
Changes to the approved clinical study protocol ............................................... 43 
14.6 
Audits and inspections ........................................................................................ 44 
14.7 
Insurance ............................................................................................................. 44 
15 
STUDY MANAGEMENT .................................................................................. 44 
15.1 
Training of study site personnel ......................................................................... 44 
15.2 
Clinical monitoring ............................................................................................. 44 
15.3 
Source data documents ....................................................................................... 45 
15.4 
Study agreements ................................................................................................ 45 
15.5 
Study timetable and end of study ....................................................................... 46 
15.6 
Termination of the study .................................................................................... 46 
15.7 
Reporting and publication .................................................................................. 46 
15.7.1 
Clinical study report .......................................................................................... 46 
15.7.2 
Confidentiality and ownership of study data ...................................................... 46 
15.7.3 
Publication ........................................................................................................ 46 
15.8 
Archiving ............................................................................................................. 46 
16 
DATA MANAGEMENT .................................................................................... 47 
16.1 
The web-based eCRF .......................................................................................... 47 
16.2 
The entering of data into the eCRF .................................................................... 47 
16.3 
The query process ............................................................................................... 48 
16.4 
Audit trail ............................................................................................................ 48 
16.5 
External data ....................................................................................................... 48 
16.6 
Medical coding .................................................................................................... 48 
16.7 
Database lock ...................................................................................................... 48 
17 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE .. 49 
17.1 
General ................................................................................................................ 49 
17.2 
Determination of sample size .............................................................................. 49 
17.3 
Analysis data sets ................................................................................................ 49 
17.3.1 
Full analysis set ................................................................................................. 49 
17.3.2 
Pharmacokinetic analysis set ............................................................................. 49 
17.4 
Description of study population.......................................................................... 50 
17.4.1 
Demographics and baseline characteristics ........................................................ 50 
17.4.2 
Medical/surgical history and prior/concomitant medication ............................... 50 
17.4.3 
Treatment compliance ....................................................................................... 50 
17.5 
Analysis of primary endpoints ............................................................................ 50 
17.5.1 
Analysis of pharmacokinetics ............................................................................ 50 
17.6 
Analysis of secondary endpoints ......................................................................... 51 
17.6.1 
Pharmacokinetics .............................................................................................. 51 
17.6.2 
In vivo extracted amount of nicotine .................................................................. 51 
17.6.3 
Product evaluation scale .................................................................................... 51 
17.6.4 
Product preference scale .................................................................................... 52 
17.6.5 
Urge to use questionnaire .................................................................................. 52 
17.6.6 
Adverse events .................................................................................................. 52 
17.6.7 
Clinical laboratory analyses ............................................................................... 52 
17.6.8 
Vital signs ......................................................................................................... 52 
17.6.9 
12-lead ECG ...................................................................................................... 53 
18 
REFERENCES.................................................................................................... 53 
19 
SIGNATURES .................................................................................................... 54 
Imperial
Tobacco
.......
......
.....
....

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
9 (55) 
19.1 
Principal Investigator statement ........................................................................ 54 
19.2 
Signature page (approval of the clinical study protocol) ................................... 55 
 
List of Tables 
Table 4.1-1 
Medical emergencies contact ......................................................................... 13 
Table 6.3-1 
Covid-19 related risks and mitigating actions ................................................ 17 
Table 7.1-1 
Primary objective and endpoints .................................................................... 19 
Table 7.2-1 
Secondary objectives and endpoints............................................................... 19 
Table 8.1-1 
Overall schedule of events ............................................................................. 22 
Table 8.1-2 
Detailed schedule of events for Day 1, Day 2, Day 3 and Day 4 (Visit 2) ....... 23 
Table 11.4-1 
Safety laboratory parameters...................................................................... 39 
Table 12.2-1 
Estimated blood volumes ........................................................................... 40 
 
List of Figures 
Figure 8.1-1 
Overview of study design .............................................................................. 21 
 
 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
10 (55) 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or term                   Explanation 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical  
AUC 
 
Area under the plasma concentration-time curve 
AUC0-90 
AUC from time 0 to 90 minutes 
AUCinf 
AUC from time 0 to infinity 
AUCt 
AUC from time 0 to the time of the last sampling 
timepoint 
AUEC0-120 
The area under the change from baseline VAS score 
versus time curve from time 0 to 120 minutes, 
calculated using the linear trapezoidal method with 
linear interpolation using actual sample times. 
bpm 
Beats per minute (unit for pulse measurement) 
BMI 
Body mass index 
CC 
Conventional cigarettes 
Clast 
Observed plasma concentration at the last timepoint 
measured 
Cmax 
Maximum observed plasma concentration 
CRO 
Clinical research organisation 
CSP 
Clinical study protocol 
CSR 
Clinical study report 
CTC 
Clinical Trial Consultants AB 
CV 
Coefficient of variation 
DMP 
Data management plan 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EEA 
European Economic Area 
Emax 
The maximum change from baseline VAS score 
(VASpre-use -VASpost-use) 
FAS 
Full analysis set 
GCP 
Good clinical practice 
Imperial
Tobacco
Cast
Cmax 
Emax

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
11 (55) 
GDPR 
General data protection regulation 
Hb 
Haemoglobin 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for 
Human Use  
IEC 
Independent ethics committee 
IME 
Important medical event 
IP 
Investigational product 
ISF 
Investigator site file 
LLOQ 
Lower limit of quantification 
MedDRA 
Medical dictionary for regulatory activities 
mmHg 
Millimetre mercury (unit for blood pressure 
measurements) 
NCA 
Non-compartmental analysis 
NGP 
Next generation products 
OND 
Oral nicotine delivery 
PES 
Product evaluation scale 
PII 
Personally Identifiable Information 
PK 
Pharmacokinetic 
PKAS 
PK analysis set 
PPS 
Product preference scale 
PT 
Preferred term 
QA 
Quality assurance 
QC 
Quality control 
RBC 
Red blood cell 
RBD 
Receptor binding domain 
RBM 
Risk-based monitoring 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SDV 
Source data verification 
SOC 
System organ class 
SOP 
Standard operating procedures 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
12 (55) 
TMF 
Trial master file 
TEmax 
Time of the Emax. 
Tmax 
Time to Cmax 
T½ 
Terminal elimination half-life 
VAS 
Visual analogue scale 
WBC 
White blood cell 
WHO 
World Health Organisation 
WOCBP 
Women of childbearing potential 
Imperial
Tobacco
Tmax
Ty.

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
13 (55) 
4 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR 
4.1 
Medical emergencies contacts 
The Principal Investigator is responsible for ensuring that procedures and expertise are 
available to handle medical emergencies during the study. A medical emergency usually 
constitutes a serious adverse event (SAE) and is to be reported as such. Detailed SAE 
reporting procedures are described in Section 11.4.6.11. 
In the case of a medical emergency, the Investigator may contact the Medical Monitor 
(Table 4.1-1). 
Table 4.1-1 
Medical emergencies contact 
Name 
Function in the study 
Telephone number and e-mail 
Cornelia Lif-Tiberg, MD 
Medical Monitor 
+46 (0)73 978 94 45 
cornelia-lif-tiberg@ctc-ab.se 
5 
INVESTIGATOR AND STUDY ADMINISTRATIVE STRUCTURE  
Sponsor 
Imperial Tobacco Ltd  
121 Winterstoke Road 
Bristol BS3 2LL, United Kingdom 
Sponsor’s Project Manager 
 
Clinical conduct 
CTC Clinical Trial Consultants AB (CTC) 
Dag Hammarskjölds väg 10B 
SE-752 37 Uppsala, Sweden 
Principal Investigator 
 
 
Study management 
CTC  
Dag Hammarskjölds väg 10B 
SE-752 37 Uppsala, Sweden 
Clinical Research Manager  
 
Biostatistician 
 
Medical Writer (CSP author) 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
14 (55) 
 
Medical Monitor 
 
Pharmacokineticist 
Laboratory (Safety) 
 
 
Laboratory  
(Bioanalysis and nicotine extraction) 
 
Investigational Product (IP) 
manufacturing, packaging, labelling 
Electronic data capture (EDC) system 
provider:  
 
 
Signatures are provided in Section 19. 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
15 (55) 
6 
INTRODUCTION 
6.1 
Background 
Smoking is a leading cause of numerous human disorders including lung cancer, chronic 
obstructive pulmonary disease, and atherosclerotic cardiovascular disease. Despite the well 
characterised health risks, smoking rates in adult populations worldwide remain at 15% to 
25%. In addition to methods of helping people quit, investigations are ongoing into the health 
benefits of reducing exposure to toxicants in people who continue to use tobacco. This is 
being done through the development of new tobacco and nicotine products, often referred to 
as next generation products (NGP). 
Tobacco-related health risks are assumed to be due to repeated and sustained exposure to a 
range of smoke toxicants. Smoke from conventional cigarettes (CC) is a complex and 
dynamic mixture of more than 5,600 identified chemical constituents, in both its particulate 
and vapour phases. Some of these chemicals have been identified as potential contributors to 
the harmful effects of cigarette smoke and can be evaluated by measuring the levels of these 
chemicals themselves, or their metabolites, in urine. 
Nicotine is primarily responsible for the addictive properties of cigarette smoking. Nicotine is 
rapidly absorbed into the bloodstream during cigarette smoking, from where it is rapidly 
distributed causing both systemic and central effects. In the central nervous system, nicotine 
acts at neuronal nicotinic receptors and this interaction may underpin its effects on mood and 
relaxation. The pharmacokinetic (PK) profile of nicotine during cigarette smoking is a rapid 
rise and fall in plasma nicotine concentrations. Correspondingly, the delivery of nicotine to 
the brain, and the consequent pleasurable effects experienced by the smoker, are also rapid. 
It is Imperial Brands’ aim to increasingly transition smokers to our NGP portfolio; products 
that are potentially less harmful than CC. Oral Nicotine Delivery (OND) is increasingly 
recognized as having the potential to reduce the risk of smoking. Oral nicotine products also 
offer greater optionality in parts of the world where smoking or vaping is not permitted or 
where smokers prefer oral nicotine. At Imperial Brands we have added to our portfolio of 
NGP the ZoneX Oral Nicotine product, which was launched in European markets in 2019.  
6.1.1 Summary of non-clinical data 
All Imperial Brands snus and OND products (including ZoneX) undergo rigorous risk 
assessment by in-house professional toxicologists and external specialists to determine the 
suitability of ingredients and materials. As a responsible manufacturer we continuously 
review this approach. 
In vitro assays including the Ames test, neutral red uptake (NRU) and micronucleus assays, 
have been performed on smokeless tobacco products to investigate the cytotoxicity and 
genotoxicity of the product category, as described in the literature. The pre-clinical 
assessments have been performed on commercially available Swedish snus brands. 
The peer-reviewed research has demonstrated that extracts of smokeless tobacco products, are 
markedly less mutagenic, clastogenic and cytotoxic than the particulate matter of cigarette 
smoke. It is generally reported that the genotoxicity and cytotoxicity of smokeless tobacco 
products is 10% or less active than cigarette smoke, when assessed in using similar testing 
methodology.  
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
16 (55) 
6.1.2 Clinical experience 
One clinical study evaluating the relative bioavailability of ZoneX #2 (5.8 mg nicotine/pouch) 
and ZoneX#3 (10.1 mg nicotine/pouch) versus 3 comparator products (of which one was a 
conventional cigarette) has been performed (IB-OND-PKZX-01). Plasma exposures (as 
evaluated by maximum plasma concentration [Cmax] the area under the curve from time 0 to 
the time of the last sampling timepoint [AUCt], the AUC from time 0 to 90 minutes [AUC0-90] 
and AUC from time 0 to infinity [AUC0-inf] after a single use of study products were highest 
after use of Swave (tobacco-free nicotine pouch, 10.6 mg nicotine/pouch), comparable 
between ZoneX #3 (10.1 mg nicotine/pouch), Skruf (tobacco-containing snus, 10.9 mg 
nicotine/pouch) and Marlboro (cigarette, 0.8 mg nicotine/cigarette), and the lowest after use 
of ZoneX #2 (5.8 mg nicotine/pouch). Baseline and non-baseline adjusted exposures generally 
showed a similar relative order between the products. 
Evaluation of orally extracted amounts of nicotine from IP pouches were in line with relative 
exposure data and, when evaluating exposures normalised for the amount of nicotine orally 
extracted, no obvious differences were seen between the IPs. 
Subjective product perception and preference assessments after single use of IPs showed few 
general differences between the IPs. Results from the Product evaluation scale (PES) 
subcategory <Satisfaction= and the Product preference scale (PPS) indicated a subjective 
preference for Skruf amongst the study subjects and a majority of the study subjects preferred 
using a pouch product over cigarettes. 
Single use of all products followed by a short ad lib use period was safe and well tolerated in 
a population of healthy dual users of snus and conventional cigarettes as assessed by adverse 
events (AEs), clinical laboratory parameters, vital signs and electrocardiograms (ECGs). 
6.2 
Study rationale 
Ultimately, the intent of Imperial Brands in pursuit of achieving tobacco harm reduction, is to 
develop products that offer the consumer a credible and viable alternative to combustible 
cigarettes and traditional snus. Results from the previous study and those available in the 
limited published literature suggest that the nicotine delivery of these products is affected by a 
number of factors not least the substrate in which the nicotine is held and delivered from to 
the user. As a responsible manufacturer of nicotine containing products, it is our intent to 
achieve further understanding and continue to characterise these higher strength products, 
whilst obtaining valuable and indicative data that the products are safe to use and tolerated by 
the consumer. As such, this randomised, cross-over, single-blind study is designed to 
primarily evaluate the relative bioavailability of nicotine delivery from oral tobacco-free 
nicotine delivery products, in male and female snus or nicotine pouch users and to assess 
safety and tolerability. 
6.3 
Risk/benefit assessment 
It may be considered problematic to expose research subjects to a nicotine delivery product, 
the properties of which are not yet fully known. However, all research subjects are required to 
be daily snus or nicotine pouch users since at least one year (with an average or above snus or 
nicotine pouch use) so the participants are well acquainted with, and used to, the effects of 
nicotine. Hence, the potential adverse effects of the study procedures are likely to be minor 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
17 (55) 
and/or clinically insignificant. Subjects intending to reduce or quit nicotine use are excluded 
from participation. 
As the nicotine delivery profile of a product is likely to be central to its acceptability among 
current tobacco users, it is reasonable to conduct formal clinical studies to assess this feature 
in more detail. All risks related to use of the study product or study procedures will be 
explained in detail to the subjects. Pregnant women are excluded from participation. 
Subjects will remain in the research clinic for at least 8 hours after the last use of either of the 
IP’s and will be closely monitored by medical staff. 
The Principal Investigator at the research clinic will ascertain that adequate facilities and 
procedures are available to handle emergency situations should they occur during the study. 
The medical staff at CTC have extensive experience from Phase I studies and there are 
adequate procedures in place to handle unexpected and expected adverse reactions in the 
study subjects.  
Besides the risks related to the IPs, as described above, there may also be risks related to the 
medical devices used in the study e.g. indwelling venous catheters. However, these are 
devices that are used in routine medical care and the risk associated with their use is 
considered low and ethically justifiable. Study specific evaluations and sampling procedures, 
like blood-pressure measurements using a blood pressure cuff and frequent blood-sampling, 
may cause transient discomfort but the risk is deemed to be low and ethically justifiable. 
Risk assessment with regard to the Covid-19 pandemic 
Current recommendations from the authorities will be considered on a day-to-day basis. 
Assessment sessions with Sponsors, Investigators and clinical research organisation 
(CRO)/vendor representative members to align on local restrictions, impact assessment, 
contingency plans and study-specific risk mitigation strategies will be made to safeguard the 
study conduct and the safety of the subjects included in the study. Risks regarding subject 
safety, study performance and data quality/integrity will hence be assessed on an ongoing 
basis during the study. The risks and mitigating actions will be documented in a risk log as 
part of the Sponsor’s trial master file (TMF). 
EMAs Guidance on the Management of Clinical Trials during the Covid-19 (Coronavirus) 
pandemic as well as local guidelines from the Swedish Medical Products Agency have been 
taken into consideration. Planned prevention and mitigating actions are outlined in 
Table 6.3-1. Risks and mitigating actions will be updated as applicable, and based on the 
development of the pandemic, over the course of the study. 
Table 6.3-1 
Covid-19 related risks and mitigating actions 
Risks identified 
Actions 
Subjects may be exposed to the 
SARS-CoV-2 virus, which may 
lead to subsequent 
development of Covid-19. 
In accordance with recommendations by the Public Health Agency of 
Sweden (Folkhälsomyndigheten), subjects are not allowed to visit the clinic 
if they have any symptoms that may be Covid-19-related, as assessed by the 
Investigator. Subjects will be reminded about the restrictions by a text 
message, that will be sent to the subjects prior to each visit. The absence of 
Covid-19-like symptoms will also be verified in association with site entry.  
Covid-19 Ag rapid tests (Humasis) for detection of the SARS-CoV-2 
nucleocapsid and the SARS-CoV-2 spike receptor binding domain (RBD) 
from nasal swabs may be performed in participating subjects at visits 
associated with overnight stays i.e. Visit 2 (Day -1).  
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
18 (55) 
Risks identified 
Actions 
Rapid testing will not be performed at screening visits or at visits with a 
short duration, including follow-up visits.  
The performance and the result of each test will be documented in the 
subject’s medical records. If a subject tests positive, the subject will be sent 
home and the event will be reported as an AE. 
Rapid testing will be performed as needed based on the prevailing Covid-19 
situation at the time of study conduct as judged by the Investigator. 
Adjustments will be made at the research clinic so that an acceptable 
physical distance can be maintained between the subjects. 
The subjects will be recommended not to use public transport to and from 
the clinic. Subjects will be offered compensation if they use their own car. 
Subjects will be supplied with hand disinfectants to be used during clinic 
visits. 
The site has elevated the level of cleaning to include regular disinfection of 
all surfaces at the clinic and kitchen. 
Subjects may get ill between 
visits and will therefore not be 
able to come to the clinic site 
for study assessments within 
allowed time windows. 
AEs will be followed up by phone calls.  
Subjects with suspected Covid-19 symptoms will be asked to seek SARS-
CoV-2 testing. 
Subjects who test positive for Covid-19 between visits will be referred to 
standard hospital care if needed. 
Subjects may get ill with 
Covid-19-like symptoms 
during a visit.  
There is a clear action plan if a subject becomes ill during the site visit. The 
subject will be isolated and unless unwarranted for safety reasons, the 
subject will sent home, and carefully followed up with phone calls by site 
staff. If the subject cannot be sent home due to safety reasons, the subject 
will be isolated and site staff who are in contact with the subject have to 
wear protective clothing and equipment. The Principal Investigator or 
delegate will contact the nearest infection clinic and decide on further 
actions. 
The hospital laboratory may 
not be able to analyse safety 
samples due to the number of 
COVID-19 samples. 
An accredited lab has been contracted as a back-up lab for analysis of safety 
samples. 
New recommended actions by 
health authorities, such as 
society lock-down if the 
pandemic escalates, which 
will cause a halt in the study.  
This risk does not affect subject safety. 
On-site monitoring is not 
possible to perform in 
accordance with the 
monitoring plan due to the 
Covid-19 outbreak and entry 
restrictions to the site. 
Remote centralised monitoring activities will be increased as will central 
review of data. 
  
Increased number of protocol 
deviations due to the Covid-19 
outbreak. 
All protocol deviations will be documented and handled according to the 
CTU’s standard operating procedures (SOPs).  
 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
19 (55) 
7 
STUDY OBJECTIVES AND ENDPOINTS 
7.1 
Primary objective and endpoints 
Table 7.1-1 
Primary objective and endpoints 
Primary objective 
Primary endpoints 
Assessment 
To evaluate and compare Cmax and AUCt 
of nicotine after the use of each product. 
Cmax and AUCt   
PK sampling and analysis, 
see Section 11.3.1 
7.2 
Secondary objectives and endpoints 
Table 7.2-1 
Secondary objectives and endpoints 
Secondary objectives 
Secondary endpoints 
Assessment(s) 
To evaluate other PK parameters of 
nicotine after the use of each product 
 
• AUC0-90 
• AUCinf 
• time to Cmax (Tmax) 
• plasma concentration at last 
timepoint measured (Clast) 
• terminal elimination half-life (T1/2) 
PK sampling and analysis, 
see Section 11.3.1 
To evaluate orally extracted dose of 
nicotine in used products (OND) 
 
The orally extracted dose of nicotine 
from each pouch will be calculated 
to evaluate the correlation between 
baseline-adjusted AUCinf and orally 
extracted dose of nicotine. 
Collection and analysis of 
pouches, see Section 
11.4.2 
To evaluate product perception and 
preference by use of subjective 
assessments 
 
Subjective assessment endpoints 
including: PES, PPS and the Urge to 
use questionnaire 
PES, see Section 11.4.3 
PPS, see Section 11.4.4 
Urge to use questionnaire, 
see Section 11.4.5 
To evaluate the tolerability and safety 
of each of the products used 
 
Frequency, intensity and seriousness 
of AEs 
 
AE reporting and 
questioning, see Section 
11.4.6 
Clinically significant changes in 
laboratory parameters, vital signs 
and ECG 
Blood sampling for 
clinical chemistry and 
haematology, see Section 
11.4.7 
Blood pressure and pulse, 
see Section 11.4.8 
12-lead ECG, see Section 
11.4.9 
 
 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
20 (55) 
8 
STUDY DESIGN 
8.1 
Overall study design and schedule of events 
This will be a randomised cross-over, single-blind, confinement study conducted in 27 male 
or female snus or nicotine pouch users. The study will investigate 4 different nicotine 
containing products in a cross-over design, incorporating PK evaluation, nicotine extraction 
evaluation, subjective questionnaire assessments as well as safety and tolerability evaluation. 
During the study participation, subjects will come for 2 visits to the clinic, including a 
screening visit and a 4-day confinement period. A final follow up end-of-study telephone call 
will be performed within a week of last product use. 
Visit 1 (Screening)  
Visit 1 will take place from Day -28 to Day -1 and will include an eligibility check, review of 
health status and assessment of snus and nicotine pouch user habits, see Table 8.1-1 for 
details.  
Subjects will be advised of the risks of using nicotine and referred to nicotine-use cessation 
support to quit if that is their intention. 
Visit 2 (In-clinic treatment period, Day -1 to Day 4) 
At Visit 2, subjects will be admitted to the clinic on Day -1 and will remain at the clinic until 
Day 4 for daily single IP use and PK blood sampling, nicotine extraction, subjective 
questionnaire assessments and safety assessments. 
On Day -1, baseline vital signs, ECG and clinical laboratory profile assessments will be 
performed. Subjects are allowed to use their own snus or nicotine pouch product until 10 pm 
of Day -1. On Day -1 the subjects will also undertake a familiarisation session of the study 
products and questionnaires. The clinical team will explain how the products will be used and 
the subjects will have the opportunity to see the product and packaging. An explanation of 
how the questionnaires will be distributed to the subjects will be given. The familiarisation 
session does not include a product trial and the products used in the session will not be used in 
the clinical study but will be retained as demonstration samples for accountability purposes. 
In the morning of Day 1, after pre-use assessments and confirmation of eligibility, the 
subjects will be randomised and then administered a single pouch of the IP in the sequence to 
which they have been randomised. Oral nicotine IP will be used for 20 minutes according to 
standard use instructions. PK sampling will be done pre-IP use and at 5, 10, 15, 20, 25, 30, 45, 
60, 90 minutes, 2, 4, 6 and 8 hours post start of IP use. Used pouches will be collected for 
analysis of nicotine extraction. Questionnaires will be distributed to the subject at defined 
intervals throughout the day. Safety will be followed throughout the day. Subjects will be 
allowed to use their own nicotine containing products ad lib after the 8-hour timepoint until 
10 pm. 
In the morning of Day 2, after pre-IP use assessments, the subjects will be administered a 
single pouch of the IP in the sequence to which they have been randomised. IP will be used 
for 20 minutes according to standard use instructions. PK sampling will be done pre-IP use 
and at 5, 10, 15, 20, 25, 30, 45, 60, 90 minutes, 2, 4, 6 and 8 hours post start of IP use. Used 
pouches will be collected for analysis of nicotine extraction. Questionnaires will be 
distributed to the subject at defined intervals throughout the day. Safety will be followed 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
21 (55) 
throughout the day. Subjects will be allowed to use their own nicotine containing products ad 
lib after the 8-hour timepoint until 10 pm. 
In the morning of Day 3, after pre-IP use assessments, the subjects will be administered a 
single pouch of the IP in the sequence to which they have been randomised. IP will be used 
for 20 minutes according to standard use instructions. PK sampling will be done pre-IP use 
and at 5, 10, 15, 20, 25, 30, 45, 60, 90 minutes, 2, 4, 6 and 8 hours post start of IP use. Used 
pouches will be collected for analysis of nicotine extraction. Questionnaires will be 
distributed to the subject at defined intervals throughout the day. Safety will be followed 
throughout the day. Subjects will be allowed to use their own nicotine containing products ad 
lib after the 8-hour timepoint until 10 pm. 
In the morning of Day 4, after pre-IP use assessments, the subjects will be administered a 
single pouch of the IP in the sequence to which they have been randomised. IP will be used 
for 20 minutes according to standard use instructions. PK sampling will be done pre-IP use 
and at 5, 10, 15, 20, 25, 30, 45, 60, 90 minutes, 2, 4, 6 and 8 hours post start of IP use. Used 
pouches will be collected for analysis of nicotine extraction. Questionnaires will be 
administered to the subject at defined intervals throughout the day. Safety will be followed 
throughout the day. Subjects will leave the research clinic after completing all 8 h-
assessments on Day 4. 
Visit 3 (End-of-Study phone call) 
A follow-up telephone call (Visit 3, end-of-study) will be made on Day 7 (±1) to follow-up on 
any AEs. 
Subjects will participate in the study for up to 35 days, including an up to 28-day screening 
period. 
An overview of the study design is shown in Figure 8.1-1.  
Figure 8.1-1 Overview of study design 
 
The schedule of events for the study is shown overall in Table 8.1-1 and detailed for Days 1 to 
4 in Table 8.1-2. Study assessments are described in Section 11. 
Imperial
Tobacco
VISIT 3
VISIT 1
VISIT 2
Day -28 Day-1
Day7
Day3 Day 4
:
Day2
to Day -1
IN-CLINIC
SCECEEEEC
ONDSKU1-OND SKU2-ONDSKU3-OND SKU4
ETRDDUTPEY
OND SKU2-OND SKU3-ONDSKU4-OND SKU1
RIIOAIIIIRON
OND SKU3-OND SKU4-OND SKU1-ONDSKU2
OND SKU4-OND SKU1-OND SKU2-OND SKU3
Days 1, 2, 3 and 4:
Health
PK sampling 0-8 hrs post-IP use,
Subjective questionnaire assessments
Telephone
status
Safety assessments
Eligibility
Safety follow up

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
22 (55) 
Table 8.1-1 
Overall schedule of events 
 
Screening 
In-Clinic 
End-of-study 
Visit 
Refer to 
CSP 
section: 
Visit 1 
Visit 2 
Visit 3 
Phone call 
Assessment 
Day -28 to 
Day -1 
Day 
-1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 7 
(+/- 1 day) 
Informed Consent 
14.3 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
9.4, 9.5 
X 
X1 
X1 
 
 
 
 
Demographics 
11.2.3 
X 
 
 
 
 
 
 
Nicotine-use habits 
11.2.14 
X 
 
 
 
 
 
 
Medical/surgical history 
11.2.6 
X 
 
 
 
 
 
 
HIV, hepatitis B and C 
11.2.8 
X 
 
 
 
 
 
 
Alcohol test 
11.2.12 
X 
X 
 
 
 
 
 
Urine Drug Screen  
11.2.11 
X 
X 
 
 
 
 
 
Pregnancy Test (WOCBP only) 
11.2.10 
X2 
X2 
 
 
 
 
 
Weight/height (BMI) 
11.2.5 
X 
 
 
 
 
 
 
Physical Examination 
11.2.4 
X 
 
 
 
 
 
 
Clinical Laboratory Profile 
11.4.7 
X 
X 
 
 
 
X 
 
Vital Signs 
(Blood pressure and pulse) 
11.4.8 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
11.4.9 
X 
X 
 
X 
 
PES 
11.4.3 
 
 
X 
X 
X 
X 
 
PPS 
11.4.4 
 
 
 
 
 
X 
 
Urge to use questionnaire 
11.4.5 
  
  
X 
X 
X 
X 
 
Randomisation 
9.9 
 
 
X 
 
 
 
 
IP use 
10.6 
 
 
X 
X 
X 
X 
 
PK blood sampling 
11.3.1 
 
 
X 
X 
X 
X 
 
Nicotine pouch collection 
11.4.2 
 
 
X 
X 
X 
X 
 
Meals3 
9.6.1 
 
X 
X 
X 
X 
X 
 
Baseline symptoms4 
11.2.13 
X 
X 
X 
 
 
 
 
Adverse events5 
11.4.6 
 
 
--------------------- X ------------------- 
Prior and concomitant 
medications 
11.2.7 
------------------------------ X ---------------------------- 
BMI = Body mass index, CSP=clinical study protocol, WOCBP = women of childbearing potential, HIV = human immunodeficiency 
virus 
1. 
Confirmation of eligibility criteria on Day-1 or Day 1 
2. 
WOCBP only. Urine dipstick. 
3. 
Meals (breakfast, lunch, snack, dinner and evening snack) will be served at the research clinic during Visit 2. On Days 1 to 4, 
lunch, snack, dinner and evening snack will be served approximately 4, 7, 9 and 11 hours, respectively, after start of each IP use. 
Breakfast will be served approximately 1 hour before start of each IP use. 
4. 
Baseline symptoms will be recorded up until start of first use of IP on Day 1. 
5. 
Adverse events will be recorded from start of first use of IP on Day 1 
 
Imperial
Tobacco
0
N
X
X2
x
x
x
x
x
--

 
                                                                                              Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
23 (55) 
Table 8.1-2 
Detailed schedule of events for Day 1, Day 2, Day 3 and Day 4 (Visit 2) 
 
Day 1, Day 2, Day 3 and Day 4 
Assessment 
/time-point 
Pre- 
IP use 
00:00 
00:05 
00:10 
00:15 
00:20 
00:25 
00:30 
00:45 
01:00 
01:30 
02:00 
04:00 
06:00 
08:00 
Inclusion/exclusion criteria 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (Blood pressure 
and pulse) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
12-lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
Clinical laboratory profile 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
PES questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
PPS questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X2 
Urge to use questionnaire 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomisation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IP use 
 
------------------------X---------------------- 
 
 
 
 
 
 
 
 
Ad lib use until 
10 pm3 
PK blood sampling4 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Nicotine pouch collection 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Meals5 
---------------------------------------------------X------------------------------------------------- 
Baseline symptoms6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events7 
 
------------------------------------------------------X---------------------------------------------------- 
Prior and concomitant 
medications 
------------------------------------------------------X---------------------------------------------------- 
1. 
Confirmation of eligibility criteria on Day-1 or Day 1. 
2. 
Day 4 only (i.e. not on Days 1 to 3).  
3. 
Subjects will be allowed to use their own nicotine products after the 8 hour PK sample until 10 pm each day. 
4. 
PK sampling for 8 hours post-IP use on Days 1 to 4. Pre-use sample to be taken within 5 minutes of start of IP-use. PK sampling time windows, refer to Section 11.3.1. 
5. 
Meals (breakfast, lunch, snack, dinner and evening snack) will be served at the research clinic during Visit 2. Lunch, snack, dinner and evening snack will be served approximately 4, 7, 9 and 11 hours, 
respectively, after start of each IP use. Breakfast will be served approximately 1 hour before start of each IP use. 
6. 
Baseline symptoms will be recorded up until start of first use of IP on Day 1. 
7. 
Adverse events will be recorded from start of first use of IP on Day 1. 
Imperial
Tobacco
x
x
X2
X2
X?
x
x
x
x-
x
x
x
x
x
x
x
x
x
5
*

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
24 (55) 
8.2 
Rationale for study design 
The study will provide important PK, safety and tolerability data to support the design of 
further studies. The time points for PK blood sampling were selected based on data obtained 
from previous non-clinical and clinical studies. 
A crossover design was chosen to yield a more efficient comparison of treatments than a 
parallel study design, i.e., fewer subjects are required since each subject will serve as its own 
control. 
Randomisation will be used to minimise bias in the assignment of subjects to a treatment 
sequence. 
The study will be single-blind, i.e. the subjects will not know the identity, and most 
importantly, not the strength/nicotine content of each IP. A single-blind approach will reduce 
potential bias during data collection, in particular during the collection of questionnaire data, 
and evaluation of endpoints. 
9 
STUDY POPULATION  
Prospective approval of protocol deviations to eligibility criteria, also known as protocol 
waivers or exemptions, is not permitted. 
9.1 
Recruitment 
The subjects will be recruited from CTC’s database of healthy volunteers and from 
advertising in media (including social media). 
9.2 
Screening and enrolment log 
Investigators must keep a record of all screened subjects even if they were not subsequently 
included in the study. This information is necessary to verify that subjects were selected 
without bias. The reason for screen failure should be stated for all subjects screened but not 
included. The reason for withdrawal should be stated for all subjects included but not 
completed. 
A screening number will be allocated to each subject in connection to the informed consent 
process at the Screening visit. The screening number is generated automatically in the 
electronic case report Form (eCRF). The screening number will allow identification of 
subjects irrespective of their possible eligibility for the study. 
Subjects included and randomised will be assigned a randomisation number (101, 102 etc.). 
If a subject cannot perform the first planned use of IP within 28 days after screening (i.e., the 
time interval between signing informed consent until first IP use) the subject should be 
rescreened before proceeding in the study. 
9.3 
Number of subjects 
Approximately 54 subjects will be screened to achieve a total of 27 randomised subjects. 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
25 (55) 
For replacements of subjects who discontinue from the study, see Section 9.8. 
9.4 
Inclusion criteria 
For inclusion in the study, subjects must fulfil the following criteria:  
1. Willing and able to give written informed consent for participation in the study.  
2. Male or female subject aged g19 years at the time of screening. 
3. BMI g 18.0 and f 30.0 kg/m2. 
4. Clinically normal medical history, physical findings, vital signs, ECG and laboratory 
values at the time of screening, as judged by the Investigator. 
5. User of snus or nicotine pouches for g1 year, with a minimum weekly use of 2 or more 
snus or nicotine pouch cans and who is willing and considered able to use brands with 
nicotine content in the range of 14 to 20 mg nicotine/pouch.  
9.5 
Exclusion criteria 
Subjects must not enter the study if any of the following exclusion criteria are fulfilled: 
1. History of any clinically significant disease or disorder which, in the opinion of the 
Investigator, may either put the subject at risk because of participation in the study, or 
influence the results or the subject’s ability to participate in the study. 
2. Any clinically significant illness, medical/surgical procedure or trauma within 4 weeks 
of the first use of IP. 
3. Any planned major surgery within the duration of the study. 
4. Any positive result on screening for serum hepatitis B surface antigen, hepatitis C 
antibody and HIV. 
5. After 10 minutes supine rest at the time of screening, any vital signs values outside the 
following ranges: 
• Systolic blood pressure <90 or >140 mmHg, or 
• Diastolic blood pressure <50 or >90 mmHg, or  
• Pulse <40 or >90 bpm 
6. Female subjects who are pregnant, who are currently breast feeding or who has the 
intent to become pregnant. 
7. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged 
by the Investigator, or history of hypersensitivity to drugs with a similar chemical 
structure or class to nicotine. 
8. Planned treatment or treatment with another IP within 1 month or investigational drug 
within 3 months prior to Day -1. Subjects consented and screened but not dosed in 
previous phase I studies are not excluded. 
9. Positive screen for drugs of abuse or alcohol at screening or on admission to the 
research unit prior to use of the IP. 
10. History of alcohol abuse or excessive intake of alcohol, as judged by the Investigator. 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
26 (55) 
11. Presence or history of drug abuse, as judged by the Investigator. 
12. History of, or current use of, anabolic steroids, as judged by the Investigator.  
13. Excessive caffeine consumption defined by a daily intake of >5 cups of caffeine 
containing beverages. 
14. Plasma donation within one month of screening or blood donation (or corresponding 
blood loss) during the three months prior to screening. 
15. Subjects who intend to change their nicotine-use habit or make a quit attempt within the 
next 3 months from the screening visit. 
16. Investigator considers the subject unlikely to comply with study procedures, restrictions 
and requirements. 
9.6 
Restrictions during the study 
The subjects must be willing to comply to the following restrictions during the entire study 
duration i.e., from screening to the end-of-study visit. 
9.6.1 General restrictions 
• Subjects shall abstain from snus and all other nicotine containing products from 10 pm 
the evening prior to the anticipated start of each IP use on Days 1 to 4.  
• Use of other nicotine-containing products, than defined by this study protocol, is not 
allowed during the study from 10 pm Day-1 until the end of Visit 2.  
• Subjects are not allowed to eat or drink or conduct any other mouth related procedure 
(e.g. tooth brushing) 30 minutes before IP use, during IP use and 30 minutes after the 
IP has been taken out. 
• Meals and Dietary Restrictions:  
Meals will be served while the study subjects are in the research clinic. Breakfast will 
be served approximately 1 hour prior to IP use. Lunch will be served 4 hours after start 
of each IP use. Snack, dinner and evening snack will be served approximately 7, 9 and 
11 hours post-IP use, respectively. Water is allowed ad lib at the clinic except 
30 minutes before IP use until 30 minutes after IP use on Days 1 to 4. 
• Alcohol: Consumption of alcohol is not allowed within 48 hours prior to the screening 
visit or Visit 2. Consumption of alcohol is not allowed during the subject’s stay at the 
clinic during Visit 2.  
• Drugs of abuse: Use of drugs of abuse is not allowed during the study. In addition to the 
urine drug testing described in Table 8.1-1, additional random testing can be performed 
at the clinic visits. 
• Coffee: Not more than 5 cups of coffee per day will be allowed from admission to the 
clinic on Day -1 until the end of Visit 2.  
• Xanthine or taurine containing products/beverages: Energy drinks (e.g. Red bull) are not 
allowed from admission to the clinic on Day -1 until the end of Visit 2. 
• Exercise: The subjects must refrain from strenuous exercise (defined as greater than 
70% of the maximal pulse rate for one hour or more) during Visit 2.  
Imperial
Tobacco
0

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
27 (55) 
• Blood donation: The subjects must not donate blood or plasma during the study until 
3 months after the end of Visit 2. 
• Participation in other clinical studies: Study subjects are not allowed to participate in 
any other interventional clinical study during the study period. 
• Visits to the clinic: Subjects are not allowed to leave the research clinic during study 
visits, unless authorised by the study personnel. 
9.6.2 Prior and concomitant therapy 
Medications (prescribed or non-prescribed medication including antacids, analgesics, herbal 
remedies, vitamin supplements and minerals) considered necessary for the subject’s safety 
and wellbeing may be given at the discretion of the Investigator during the residential period. 
Following consultation with the Sponsor, the Investigator will determine whether or not the 
subject should continue in the study.  
9.7 
Screen failures 
Screen failures are defined as subjects who consent to participate in the clinical study but do 
not fulfil all eligibility criteria and are not subsequently randomised in the study. A minimal 
set of screen failure information is required to ensure transparent reporting of screen failure 
subjects. Minimal information includes documentation of signed and dated informed consent 
form (ICF) and reason(s) for screening failure. 
Subjects who do not meet the criteria for participation in this study may be rescreened.  
Re-screening can be performed if any of the following were reasons for screening failure or 
non-randomisation (as judged by the Investigator): 
• Practical reasons.  
• Non-significant medical conditions (e.g. influenza, nasopharyngitis).  
• Reserve subject in a previous group 
• Plasma or blood donation outside allowed time windows. 
For subjects who are re-screened, a new screening number will be assigned and a new, signed 
ICF will be collected. 
9.8 
Subject withdrawal 
9.8.1 General withdrawal criteria  
Subjects are free to discontinue their participation in the study at any time and for whatever 
reason without affecting their right to an appropriate follow-up investigation or their future 
care. If possible, the reason for withdrawal of consent should be documented. 
Subjects may be discontinued from the study at any time at the discretion of the Investigator. 
Reasons for discontinuation include:  
• Subject decision 
• Severe non-compliance to study protocol procedures, as judged by the Investigator 
and/or Sponsor 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
28 (55) 
• Subject is lost to follow-up.  
• Significant AEs posing a risk for the subject, as judged by the Investigator and/or 
Sponsor 
• Withdrawal of informed consent to the use of biological samples  
• Pregnancy 
• Death 
• Meeting of an exclusion criterion during the study, which, in the opinion of the 
Investigator, may pose a risk for the subject  
9.8.2 Procedures for discontinuation of a subject from the study 
A subject who prematurely discontinues participation in the study will always be asked about 
the reason(s) for discontinuation and the presence of any AEs. If a subject withdraws consent, 
the Investigator must ask the subject if he/she is willing, as soon as possible, to be assessed 
according to the procedures scheduled for the end-of-study visit. Any ongoing AEs will be 
followed as described in Section 11.4.6.12.  
The primary reason for discontinuation/early withdrawal must be specified in the eCRF and 
final product accountability must be performed. 
9.8.3 Subject replacement 
Subjects who are prematurely withdrawn from the study for any reason may be replaced 
during the course of the study. 
9.9 
Randomisation 
On Day 1, subjects will be randomised to one of 4 treatment sequences. The 4 different 
products are: 
• A: ZoneX #5 slim 14 mg nicotine/pouch 
• B: ZoneX #5 16 mg nicotine/pouch 
• C: ZoneX #6 20 mg nicotine/pouch 
• D: Skruf Slim Fresh #5 16.6 mg nicotine/ pouch   
The 4 randomisation sequences are: 
• Sequence 1: A:B:C:D 
• Sequence 2: B:C:D:A 
• Sequence 3: C:D:A:B 
• Sequence 4: D:A:B:C 
A computer-generated randomisation list will be created by CTC using SAS Proc Plan, SAS 
Version 9.4 (or later). The randomisation list will contain subject number, sequence and 
treatment and will be kept by the randomiser until database lock. A copy of the randomisation 
list will be provided to the research clinic. 
Imperial
Tobacco
.

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
29 (55) 
9.10 Blinding 
This is a single-blind study, i.e. the Investigator and study staff, but not the subjects, will 
know the identity of each IP. 
The IP:s differ somewhat in size but are otherwise identical in appearance. The subjects will 
not know the strength/nicotine content of each IP.  
10 TREATMENTS  
The IPs will be supplied by Imperial Tobacco. 
10.1 Identity of investigational products  
The 4 IPs to be used in the study are:  
• A: ZoneX #5 slim 14 mg nicotine/pouch 
• B: ZoneX #5 16 mg nicotine/pouch 
• C: ZoneX #6 20 mg nicotine/pouch 
• D: Skruf Slim Fresh #5 16.6 mg nicotine/ pouch 
The ZoneX products are tobacco-free while the comparator (Skruf Slim Fresh #5) contains 
tobacco.  
10.2 Identity of non-investigational products 
Not applicable. 
10.3 Manufacturing, packaging and labelling 
The IPs will be manufactured by Imperial Tobacco. 
The IPs will be sent to the research clinic (CTC) from the manufacturing plant. The products 
will arrive in labelled cans.  
The comparator (Skruf Slim Fresh #5) is also an Imperial Brands product, commercially 
available and will be provided directly to the research clinic from the manufacturing plant.  
10.4 Conditions for storage 
The oral nicotine products will be stored in an access-controlled storage area at CTC, at 
refrigerated temperature (4 to 8°C).  
The temperature is recorded continuously by an automatic temperature control system. 
10.5 Preparation and accountability 
IP preparation for each individual subject and day will be done by trained personnel, i.e. a site 
pharmacist or a registered nurse, in a dedicated room at CTC according to the randomisation 
Imperial
Tobacco
.
.

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
30 (55) 
list. Each individual nicotine pouch will be weighed (in grams, with 2 decimals) before 
administration to the study subjects. The weight of each pouch will be recorded in the eCRF. 
CTC and the Investigator will maintain a Storage and Accountability Log as well as an IP 
Dispensing Log detailing the dates and quantities of study product received, prepared for and 
used by each subject and IP returned or destroyed at the end of the study. No IP will be 
destroyed until full accountability is completed by the monitor and the sponsor approves its 
destruction. Any discrepancies between prepared and returned IP must be explained and 
documented. Products deliberately and/or accidentally destroyed by the site or the subject 
must be accounted for. 
10.6 Treatment administration 
In the morning of Days 1 to 4, subjects will be administered a single pouch as randomised.  
Following completion of the single use session and after the 8-hour PK sample, the subjects 
will be allowed to use their own nicotine containing products ad lib after the 8-hour timepoint 
until 10 pm each day. 
All IPs will be used in the same way as follows: 
• A pouch of IP will be placed between the upper lip and gum and will be kept still there 
for 20 minutes. 
• The IPs, being oral nicotine pouches, should not be chewed during use.  
• The IPs should not be swallowed (swallowing saliva during IP use is allowed).  
10.7 Treatment compliance 
All IPs will be administered at the research clinic under medical supervision to ensure 
compliance. 
10.8 Return and destruction of investigational products 
Any unused study product and all empty containers will be returned to the Sponsor or 
destroyed at the site upon confirmation from the Sponsor. The Monitor will perform final IP 
accountability reconciliation at the study end to verify that all unused IP is adequately 
returned/destroyed and documented. 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
31 (55) 
11 STUDY ASSESSMENTS 
The study assessments are described in the sections below and the timing of these assessments 
are described in overview and in detail in the schedule of events (Table 8.1-1 and 
Table 8.1-2). 
11.1 Recording of data 
The Principal Investigator will provide the Sponsor with all data produced during the study 
from the scheduled study assessments. He/she ensures the accuracy, completeness, legibility, 
and timeliness of the data reported to Sponsor in the eCRF and in all required reports. 
It is important that PK blood sampling occurs as close as possible to scheduled time. In order 
to achieve this, the timing priority order at a particular time point is: 
1. IP pouch collection 
2. Blood samples for PK 
3. Questionnaires  
4. Vital signs 
5. Standard 12-lead ECG 
6. Safety laboratory samples 
Time points for PK blood sampling, clinical laboratory samples, ECGs, vital signs and 
questionnaires are outlined in the schedule of events (Table 8.1-1 and Table 8.1-2). 
For information on time windows for PK sampling, se Section 11.3.1. 
11.2 Demographics and other baseline characteristics 
11.2.1 Informed consent 
Signed informed consent must be obtained before any screening procedures are initiated. The 
informed consent procedure is further described in Section 14.3. 
11.2.2 Eligibility criteria 
Eligibility criteria should be checked during screening and verified before first IP use. The 
criteria are specified in Sections 9.4 and 9.5. 
11.2.3 Demographic information 
The following demographic data will be recorded: gender, age, ethnicity and race. 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
32 (55) 
11.2.4 Physical examination 
A physical examination will include general appearance including skin, auscultation of lungs 
and heart, abdomen (liver and spleen palpation). Any abnormalities will be specified and 
documented as clinically significant or not clinically significant.  
11.2.5 Weight and height 
Weight and height will be measured without shoes. BMI will be calculated, with one decimal, 
from the height and weight recorded. 
11.2.6 Medical/surgical history  
Medical/surgical history will be obtained by subject interview in order to verify that the 
eligibility criteria are met. 
The medical/surgical history should include all relevant diseases and operations within 
2 weeks prior to screening as judged by the Investigator.  
11.2.7 Prior and concomitant medication 
Prior medications taken within 2 weeks will be obtained by subject interview in order to 
verify that the eligibility criteria are met (see also Section 9.6.2). 
Medications are classified as prior if the stop date was before or on the day of the first IP use 
(pre-IP use) and as concomitant if ongoing on the day of the first IP use, stopped after the first 
IP use or started after the first IP use. To distinguish between prior and concomitant 
medications on Day 1 (i.e. the first IP use day), the start time of any newly introduced 
medication or the stop time of any previously ongoing medication must be recorded in the 
eCRF.  
Any use of concomitant medication from screening until the end-of-study visit must be 
documented appropriately in the subject’s eCRF. Relevant information (i.e. name of 
medication, dose, dose form, unit, route, frequency, start and stop dates, reason for use) must 
be recorded. All changes in medication should be noted in the eCRF. 
11.2.8 HIV and Hepatitis B/C 
Subjects will be tested for HIV-1 and HIV-2 antibodies and HIV-1 p24 antigen, hepatitis B 
virus surface antigen and hepatitis C virus antibodies prior to inclusion into the study. Any 
positive result will exclude the subject from participating in the study. 
11.2.9 Covid-19 rapid test 
Due to the prevailing Covid-19 pandemic, and to reduce the risk for Covid-19 spread via 
subjects participating in the study, Covid-19 Ag rapid testing (Humasis or equivalent) for 
detection of the SARS-CoV-2 nucleocapsid and the SARS-CoV-2 spike RBD from nasal 
swabs will be performed in all participating subjects at visits associated with overnight stays 
at the clinic. Rapid testing will not be performed at screening visits or at visits with a short 
duration, including follow-up visits.  
The performance and the result of each test will be documented in the subject’s medical 
records. If a subject tests positive, the subject will be sent home and the event will be reported 
as an AE. 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
33 (55) 
Covid-19 AG rapid testing will only be performed if judged as necessary by the Investigator 
based on the Covid-19 situation at the time of study conduct.  
11.2.10Pregnancy test 
All WOCBP will do a pregnancy test (urine dipstick) at visits outlined in the schedule of 
events (Table 8.1-1). 
11.2.11 Urine drug screen 
Urine will be screened for drugs of abuse at time points outlined in the schedule of events 
(Table 8.1-1) using the AlereTM Drug Screen Test Panel. Additional random tests can be 
performed during the study period. 
11.2.12 Alcohol test 
An alcohol test will be performed at visits outlined in the schedule of events (Table 8.1-1). 
Additional random tests can be performed during the study period. 
11.2.13 Baseline symptoms  
A baseline symptom is defined as an event that occurs between the subject’s signing of the ICF 
until the start of the first IP use (i.e. an event that occurs during the screening period). Such 
events are not AEs and will be recorded as baseline symptoms in the Medical History Log in 
the eCRF. 
11.2.14 Assessment of snus or nicotine pouch user habits 
At the screening visit, subject will be asked about their nicotine-use habits;  
<Which snus or nicotine pouch product is your usual choice?=  
<Which strength does the product have?= (in mg/g) 
<How many portions do you use per day?= 
Answers will be collected in the eCRF.  
11.3 Assessments related to primary endpoints 
11.3.1 Pharmacokinetic sampling and analysis for primary endpoints 
Venous blood samples (approximately 4 mL/sample) for the determination of plasma 
concentrations of nicotine after use of the IP, will be collected through an indwelling venous 
catheter at pre-specified time-points (Table 8.1-2). 
Pre-IP use sampling may be performed within 5 minutes prior to IP use on Days 1 to 4, 
respectively. 
The following time windows will apply for the PK sampling post-IP use: 
± 1 minute for time-points up to 30 minutes after start of IP use. 
± 2 minutes for time-points up to 90 minutes after start of IP use. 
± 5 minutes for time-points up to 8 hours after start of IP use. 
The actual time of collection of each sample will be recorded in the eCRF. 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
34 (55) 
The blood samples will be collected in pre-labelled tubes. All the collected blood samples will 
be centrifuged to separate plasma. The separated plasma from each blood sample will be 
divided into 2 aliquots in pre-labelled cryotubes and frozen at -70°C. 
Plasma samples for determination of plasma concentrations of nicotine will be analysed by 
Lablytica Life Science AB by means of a validated using LC-MS/MS method.  
11.4 Assessments related to secondary endpoints 
11.4.1 Pharmacokinetic sampling and analysis for secondary endpoints 
Refer to Section 11.3.1. 
11.4.2 Nicotine extraction from pouches 
The individual nicotine pouch given in the morning will be weighed (in grams, with 
2 decimals) before administration to the study subjects. The weight of the pouch will be 
recorded in the eCRF. 
Used pouches will be collected after 20 minutes (+/- 1 minute) of use for the determination of 
residual nicotine in the IPs (morning puch). After the 20-minute exposure period, each pouch 
will be collected into a labelled poly bag, sealed and immediately frozen at -20°C. The label 
should include study number, day number, subject ID and product ID. 
11.4.3 Product evaluation scale 
The subject will self-assess their experience of product effect using the PES [1] approximately 
8 hours (after PK sampling) after the start of use of each IP, see Table 8.1-1. Each question 
will be answered using a Likert scale ranging from 1 to 7, where 1 corresponds to <not at all= 
and 7 to <extremely=. The answers, provided using a paper questionnaire, will be entered in 
the eCRF by the study personnel. 
11.4.4 Product preference scale 
The subject will self-assess their product preference using the PPS approximately 8 hours 
(after PK sampling) after start of use of the last IP on Day 4, see Table 8.1-1. 
Using a paper questionnaire, the subject will rank the products in relation to each other, where 
1 will correspond to the product that the subject preferred the most and 4 to the product that 
was least preferred by the subject. The answers will be entered in the eCRF by the study 
personnel. 
11.4.5 Urge to use questionnaire 
The subject will self-assess their urge to use a nicotine pouch pre IP-use and at each PK 
sampling time point (after PK sampling).   
Using a 100 mm visual analogue scale (VAS), with the anchor points 0 mm (= not at all/no 
urge) and 100 mm (= extremely/extreme urge), the subjects will answer the question: How 
strong is your urge to use a nicotine pouch right now? 
The self-assessment for each question at each time point (in mm’s) will be entered in the 
eCRF by the study personnel. 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
35 (55) 
11.4.6 Adverse events 
In this study, the IP is a nicotine product and not an investigational medicinal product. 
However, the procedures for monitoring, collecting and reporting of AEs will be the same as 
for an investigational medicinal product, as far as possible. The Principal Investigator is 
responsible for ensuring that all medical staff involved in the study are familiar with the 
content of this section and the content of CTCs SOPs regarding emergencies and Phase I 
studies. 
11.4.6.1 Definition of adverse event  
An AE is defined as any untoward medical occurrence in a subject administered an IP and 
which does not necessarily have a causal relationship with this IP. An AE can therefore be 
any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of an IP, whether or not considered related to 
the IP. 
11.4.6.2 Definition of serious adverse event  
An SAE is any AE which: 
• results in death 
• is life-threatening (this refers to a reaction in which the subject was at risk of death 
at the time of the reaction; it does not refer to a reaction that hypothetically might 
had led to death if the reaction was more severe) 
• requires in-patient hospitalisation or prolongation of existing hospitalisation 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 
• is an important medical event (IME) (this refers to a reaction that may not be 
immediately life-threatening or result in death or hospitalisation, but may jeopardise 
the subject or may require intervention to prevent any of the other outcomes defined 
above) 
Examples of IMEs are intensive treatment in an emergency room for allergic bronchospasm 
or blood dyscrasias, convulsions that do not result in hospitalisation, development of drug 
dependency, and drug abuse. 
Planned hospitalisations or surgical interventions for a condition that existed before the 
subject signed the ICF and that did not change in intensity are not SAEs. 
If there is any doubt as to whether an AE meets the definition of an SAE, a conservative 
viewpoint must be taken, and the AE must be reported as an SAE. 
11.4.6.3 Definition of adverse reaction 
The term adverse reaction is to be used whenever either the Investigator or Sponsor or 
designee assessed the AE as at least possibly related to the IP. 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
36 (55) 
11.4.6.4 Time period and frequency for collecting adverse events 
All AEs (including SAEs) will be collected from the start of IP use until the end-of-study 
visit. 
Any AE with start date on the day of the first IP use must be recorded with start time. 
At the end-of-study visit, information on new AEs or SAEs, if any, and stop dates for ongoing 
events must be recorded as applicable. 
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator must 
promptly notify the Sponsor. 
11.4.6.5 Assessment of intensity 
The intensity of each AE is to be graded by the Investigator. The intensity grades are defined 
as follows:  
Mild 
The event is usually transient and requires minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of 
daily living. 
Moderate 
The event is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant of permanent risk or harm to the subject. 
Severe 
The event interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.  
11.4.6.6  
Assessment of causal relationship 
The Investigator must assess the causal relationship between an AE and the IP using the 
definitions below and record it the AE Log of the eCRF: 
Probable 
The event has a strong temporal relationship to the IP or recurs on re-
challenge, and another aetiology is unlikely or significantly less likely. 
Possible 
The event has a suggestive temporal relationship to the IP, and an alternative 
aetiology is equally or less likely. 
Unlikely 
The event has no temporal relationship to the IP or is due to 
underlying/concurrent illness or effect of another drug (that is, there is no 
causal relationship between the IP and the event). 
 
An AE is considered causally related to the use of the IP when the causality 
assessment is probable or possible. 
11.4.6.7 Assessment of outcome 
The Investigator must assess the outcome of an AE using the definitions below and record 
it on the AE Log of the eCRF: 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
37 (55) 
Recovered/resolved 
The subject has recovered completely, and no symptoms remain. 
Recovering/resolving  The subject’s condition is improving, but symptoms still remain. 
Recovered/resolved 
with sequelae 
The subject has recovered, but some symptoms remain (for 
example, the subject had a stroke and is functioning normally but 
has some motor impairment). 
Not recovered/not 
resolved 
The subject’s condition has not improved and the symptoms are 
unchanged (for example, an atrial fibrillation has become chronic). 
Fatal 
 
Unknown 
 
11.4.6.8 Reporting of action taken with study treatment 
The Investigator must report the action taken with study product using the definitions below 
and record it on the AE Log of the eCRF: 
Dose increased   
Dose not changed 
Dose rate reduced 
Dose reduced 
Drug interrupted 
Drug withdrawn 
Not applicable 
Unknown 
11.4.6.9 Collecting adverse events 
AEs identified using any of the following methods will be recorded: 
• AEs spontaneously reported by the subject 
• AEs observed by the Investigator or medical personnel 
• AEs elicited based on non-leading questions from the Investigator or medical 
personnel 
11.4.6.10 Recording adverse events 
AEs must be recorded in the AE Log of the eCRF. The Investigator must provide 
information on the AE, preferably with a diagnosis or at least with signs and symptoms; 
start and stop dates, start and stop time; intensity; causal relationship to IP; action taken, 
and outcome. 
If the AE is serious, this must be indicated in the eCRF.  
AEs, including out-of-range clinically significant clinical safety laboratory values, must be 
recorded individually, except when considered manifestations of the same medical condition 
or disease state; in such cases, they must be recorded under a single diagnosis. 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
38 (55) 
11.4.6.11  Reporting of serious adverse events  
SAE reporting should be performed by the Investigator within 24 hours of awareness via the 
eCRF. All available information regarding the SAE should be entered in the eCRF SAE form 
(i.e. term, intensity, causality, outcome, SAE criteria, action taken, narrative including rational 
for causality assessment) for the specific subject. By saving the event as <serious= in the 
eCRF and once the Investigator has signed-off of the event, an e-mail alert is automatically 
sent to predefined recipients to highlight that an SAE has been registered. The same 
information is automatically sent to sae@ctc-ab.se. 
If the SAE report in the eCRF is updated and signed by the Investigator, a new e-mail alert 
will be sent. 
In case the eCRF cannot be accessed, the SAE should be reported by manual completion of 
the paper SAE Form, provided in the Investigator Site File (ISF). The completed, signed and 
dated paper SAE Form should, within 24 hours, be scanned and e-mailed to:  
Cornelia Lif-Tiberg, MD, Medical Monitor 
Phone: +46 (0)73 978 94 45 
E-mail: cornelia-lif-tiberg@ctc-ab.se  
A copy of the paper SAE form must also be e-mailed to CTC at: sae@ctc-ab.se. 
The study site should notify the site Monitor via phone or e-mail about the submission of 
the SAE report. As soon as the site personnel have access to the eCRF, the SAE should be 
reported electronically as well. 
11.4.6.12 Treatment and follow-up of adverse events 
Subjects with AEs that occur during the study must be treated according to daily clinical 
practice at the discretion of the Investigator. 
AEs must be followed up until resolution or to the end-of-study visit, whichever comes first. 
At the end-of-study visit, information on new AEs, if any, and stop dates for previously 
reported AEs must be recorded (if known). AEs assessed as stable by the Investigator at the 
end-of-study visit will not have to be followed up until resolution. 
It is the responsibility of the Investigator to follow up on all SAEs until the subject has 
recovered, stabilised, or recovered with sequelae, and to report to the Sponsor all relevant new 
information using the same procedures and timelines as those for the initial report. Relevant 
information includes discharge summaries, autopsy reports, and medical consultation. 
11.4.6.13 Procedures in case of pregnancy 
In case of pregnancy or suspicion of possible pregnancy of any female subjects, the use of IP 
must be stopped immediately, and the subject discontinued from participation in the study. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP may have 
interfered with the effectiveness of the contraceptive medication. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, normal birth or congenital 
abnormality) must be followed up and documented even after the subject was discontinued 
from the study. 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
39 (55) 
All events of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages 
should also be reported and handled as AEs. All outcomes of pregnancy must be reported to 
the Sponsor and the Principal Investigator on the pregnancy outcomes report form. 
11.4.6.14 Treatment of overdose 
An overdose is a dose in excess of the dose specified in this CSP. 
Over-dosing is not likely to occur in this study since all IP will be administered by site 
personnel under medical surveillance. In cases of accidental overdose, standard supportive 
measures should be adopted as required. 
An overdose should be documented as follows:  
• An overdose with associated AE is recorded as the AE diagnosis/symptoms in the AE 
Log of the eCRF.  
• 
An overdose without associated symptoms is only reported in the subject’s medical 
records. 
No known antidote is available. 
11.4.7 Laboratory safety assessments 
Blood samples for analysis of clinical chemistry and haematology will be collected through 
venepuncture or an indwelling venous catheter and sent to the certified clinical chemistry 
laboratory at Uppsala University Hospital and analysed by routine analytical methods.  
Urine analysis will be performed at the research clinic using dip sticks. 
The safety laboratory parameters are defined in Table 11.4-1 and will be assessed at visits 
detailed in Table 8.1-1. 
Any lab values outside the normal ranges will be judged as not clinically significant  or 
clinically significant. The assessment will be recorded in the eCRF. Abnormal values assessed 
by the Investigator as clinically significant will be reported as AEs. If an abnormal value is 
associated with corresponding clinical signs or symptoms, the sign/symptom should be 
reported as the AE. 
Table 11.4-1 Safety laboratory parameters 
Category 
Parameter 
Clinical chemistry 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Creatinine  
Glucose (non-fasting) 
Haematology 
Haematocrit 
Haemoglobin (Hb) 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) count 
Pregnancy test (WOCBP 
only) 
Urine pregnancy test (dipstick) 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
40 (55) 
11.4.8 Vital signs 
Systolic and diastolic blood pressure and pulse will be measured in supine position after 
10 minutes of rest. 
Any vital signs outside the normal ranges will be judged as not clinically significant or 
clinically significant. The assessment will be recorded in the eCRF. Abnormal post-IP use 
vital signs judged as clinically significant by the Investigator will be reported as AEs. 
11.4.9 Electrocardiogram 
Single 12-lead ECG will be recorded in supine position after 10 minutes of rest using an ECG 
machine. HR and PR, QRS, QT and QTcF intervals will be recorded.  
Safety ECGs will be reviewed and interpreted on-site by the Investigator. 
Any abnormalities will be specified and documented as clinically significant or not clinically 
significant. Abnormal post-IP use findings assessed by the Investigator as clinically 
significant will be reported as AEs. 
11.5 Appropriateness of measurements 
All methods used for safety assessments are commonly used in standard medical care and in 
Phase I clinical studies. Non-compartmental analysis of PK parameters is standard for Phase I 
clinical studies. 
12 PROCEDURES FOR BIOLOGICAL SAMPLES 
12.1 Sample collection  
The sample collection procedure for PK analysis is described in Section 11.3.1. 
Safety laboratory samples are collected according to standard procedures. 
12.2 Volume of blood 
The anticipated volume of blood samples collected during the study from each subject will 
not exceed 450 mL (i.e., less than the volume drawn during a regular blood donation). 
Estimated blood volumes to be collected are presented in Table 12.2-1. 
Table 12.2-1 Estimated blood volumes 
Category 
Estimated number 
of sampling 
occasions 
Estimated 
volume per 
occasion 
Estimated 
total 
volume 
Clinical chemistry, haematology 
3 
8 mL 
24 mL 
HIV, Hepatitis B/C 
1 
4 mL 
4 mL 
PK sampling 
56 
4 mL 
224 mL 
Total: 
 
 
252 mL 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
41 (55) 
12.3 Handling, storage and destruction of laboratory samples 
All biological samples will be registered in a biobank at CTC (893).  
Any remains from the safety laboratory samples will be disposed of after analyses.  
The samples for analyses of PK parameters will be stored at <-70°C until analysed. The 
samples will be disposed of after finalisation of the clinical study report (CSR). 
12.4 Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle.  
CTC keeps full traceability of collected biological samples from the subjects while in storage 
at the research clinic until shipment and keeps documentation of receipt of arrival.  
The sample receiver (the analytical laboratory) keeps full traceability of the samples while in 
their storage and during use until used or disposed of.  
The Sponsor keeps oversight of the entire life cycle through internal procedures, monitoring 
of study sites and auditing of external laboratory providers.  
12.5 Withdrawal of informed consent for donated biological samples 
If a subject withdraws consent to the use of biological samples donated, the samples will be 
disposed of /destroyed, if not already analysed and documented.  
The Principal Investigator will ensure that:  
• Subject withdrawal of informed consent is notified immediately to Sponsor.  
• Biological samples from the subject, if stored at the research clinic, are immediately 
identified, disposed of/destroyed and the action is documented.  
The Sponsor has to ensure that the laboratory(ies) holding the samples is/are informed about 
the withdrawn consent immediately and that samples are disposed of/destroyed or returned to 
the research clinic and the action is documented. 
13 QUALITY MANAGEMENT, QUALITY ASSURANCE AND QUALITY 
CONTROL 
13.1 Quality management: critical process, system and data identification 
During CSP development, the Sponsor will identify those processes, systems (facilities, 
computerised systems) and data that are critical to ensure human subject protection and the 
reliability of trial results according to applicable SOPs and International Council for 
Harmonisation (ICH) E6 R2. 
Identified risks, including risks associated with the Covid-19 (Coronavirus) pandemic, will be 
categorised separately from the CSP. 
Sponsor oversight responsibilities, such as monitoring, adverse event reporting, 
safety  monitoring, changes in investigators and key study team staff and quality assurance 
(QA) activities may need to be reassessed in relation to the Covid-19 pandemic and 
temporary, alternative proportionate mechanisms of oversight may be required. 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
42 (55) 
13.2 Quality assurance and quality control 
The Sponsor is responsible for implementing and maintaining QA and quality control (QC) 
systems with written SOPs with regards to management of identified risks, CSP compliance, 
good clinical practice (GCP) compliance and applicable regulatory requirements.  
The Sponsor is responsible for securing agreements with involved subcontractors and to 
perform regular subcontractor oversight to ensure CSP compliance, GCP compliance and 
compliance with applicable regulatory requirements.  
The Sponsor is responsible for implementing a risk-based validated electronic data capture 
system and maintain SOPs for the whole life cycle of the system. 
QC should be applied to each stage of data handling to ensure that all data are reliable and 
have been processed correctly. 
The Sponsor has delegated the responsibilities outlined above to CTC whilst maintaining 
overall study oversight. 
14 ETHICAL AND REGULATORY REQUIREMENTS  
14.1 Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki [2] and are consistent with ICH/GCP E6 (R2), EU Clinical Trials 
Directive, and applicable local regulatory requirements. 
14.2 Ethics and regulatory review 
The Principal Investigator is responsible for submission of the CSP, the subject information 
and ICF, any other written information to be provided to the subjects and any advertisements 
used for recruitment of subjects to applicable independent ethics committee (IEC) for 
approval.  
Approval must be obtained in writing from the IEC before the first subject can be recruited. 
The Sponsor will provide the IEC and Principal Investigators with relevant safety information 
during the course of the study in accordance with local regulations and requirements. 
14.3 Subject information and consent 
It is the responsibility of the Investigator or an authorised associate to give each potential 
study subject adequate verbal and written information before any study specific assessments 
are performed. 
The information will include the objectives and the procedures of the study as well as any 
risks or inconvenience involved. It will be emphasised that participation in the study is 
voluntary and that the subject may withdraw from participation at any time and for any 
reason, without any prejudice. All subjects will be given the opportunity to ask questions 
about the study and will be given sufficient time to consider participation before signing the 
ICF. 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
43 (55) 
Before performing any study-related procedures the ICF must be signed and personally dated 
by the subject and by the Investigator. A copy of the subject information including the signed 
ICF will be provided to the subject. 
Documentation of the discussion and the date of informed consent must be recorded in the 
source documentation and in the eCRF. The subject information sheet and the signed ICF 
should be filed by the Investigator for possible future audits and/or inspections.  
The final approved version of the subject information and ICF must not be changed without 
approval from the Sponsor and the applicable IEC.  
14.4 Subject data protection 
The ICF includes information that data will be recorded, collected and processed and may be 
transferred to European Economic Area (EEA) or non-EEA countries. In accordance with the 
General Data protection Regulation (GDPR) (EU) 2016/679, the data will not identify any 
persons taking part in the study.  
The potential study subject should be informed that by signing the ICF he/she approves that 
authorised representatives from Sponsor and CTC, the concerned IEC and CA have direct 
access to his/her medical records for verification of clinical study procedures. For further 
details on the subject information and ICF process, refer to Section 14.3. 
The subject has the right to request access to his/her personal data and the right to request 
rectification of any data that is not correct and/or complete in accordance with the European 
Union Data Protection Directive (95/46/EC) and the request will be raised to the Principal 
Investigator.  
The Investigator must file a Subject Identification List which includes sufficient information 
to link records, i.e. the eCRF and clinical records. This list should be preserved for possible 
future inspections/audits but must not be made available to the Sponsor except for monitoring 
or auditing purposes. 
Personal data that are collected in the study such as health information and ethnicity are 
considered as sensitive personal data. This data will be pseudoanonymised, i.e. personally 
identifiable information (PII) will be removed and replaced by a unique subject ID and will be 
processed by the Sponsor and other involved parties during the study.  
For this study, the Sponsor is the data controller of all data processed during the study (e.g. 
TMF, study reports) and CTC AB is the data processor. Any subcontractors used in the study, 
are also data processors.  
For data that are processed at the clinic(s) (e.g. medical records and ISF), CTC AB is the data 
controller.  
14.5 Changes to the approved clinical study protocol  
Any proposed change to the approved final CSP (including appendices) will be documented 
in a written and numbered clinical protocol amendment. All substantial amendments to the 
protocol must be approved by the appropriate IEC before implementation according to 
applicable regulations. 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
44 (55) 
14.6 Audits and inspections 
Authorised representatives of Sponsor, or an IEC may perform audits or inspections at the 
research clinic, including source data verification (SDV). The purpose of an audit or 
inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the protocol, ICH-GCP guidelines and any 
applicable regulatory requirements. The Investigator will contact the Sponsor immediately if 
contacted about an inspection at the site. 
14.7 Insurance 
Subjects will be covered under the Sponsor’s liability insurance policy. The certificate of 
insurance and an information leaflet containing essential information about the insurance 
coverage can be provided upon request. The participating subjects are also protected in 
accordance with national regulations, as applicable. CTC has a company insurance covering 
services performed by CTC. 
15 STUDY MANAGEMENT 
15.1 Training of study site personnel 
Before enrolment of the first study subject a Sponsor representative or delegate will perform a 
study initiation visit at the research site. The requirements of the CSP and related documents 
will be reviewed and discussed and the investigational staff will be trained in any study 
specific procedures and system(s) utilised. 
It is the responsibility of the Investigator to ensure that all personnel involved in the study are 
fully informed of all relevant aspects of the study and have a detailed knowledge of and 
training in the procedures that are to be executed by them. Any new information of relevance 
to the performance of this study must be forwarded to the staff involved in a timely manner. 
The Investigator will keep a list of all personnel involved in the study together with their 
function and study related duties delegated. A Curriculum Vitae will be available for all staff 
to whom study-specific duties are delegated. 
15.2 Clinical monitoring  
The Sponsor is responsible for securing agreement from all involved parties to ensure direct 
access to all study related sites, source data/documents, and reports for the purpose of 
monitoring and auditing by the Sponsor, and inspection by domestic and foreign regulatory 
authorities.  
As defined in the risk-based monitoring (RBM) plan, approved by the Sponsor and provided 
separately, the responsible Monitor will periodically visit the study site at times agreed upon 
by the Investigator and the Monitor. Adaptations related to the on-site monitoring plan, when 
it is impossible or inappropriate to follow due to the Covid-19 pandemic, may be required 
such as supplementation with (additional/increased) centralised monitoring and central review 
of data if considered possible and meaningful. Results of adjusted monitoring/review 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
45 (55) 
measures should be reported to the Sponsor in monitoring reports and in the CSR. At the time 
of each monitoring visit, the role of the Monitor is (but not limited to) to: 
• provide information and support to the investigational team. 
• confirm that facilities and resources remain acceptable. 
• confirm that the investigational team is adhering to the CSP, applicable SOPs, 
guidelines, manuals and regulatory requirements.  
• verify that data are being accurately and timely recorded in the eCRFs and that IP 
accountability checks are being performed. 
• verify that data in the eCRF are consistent with the clinical records (SDV) in 
accordance with the RBM plan.  
• verify that the correct informed consent procedure has been adhered to for participating 
subjects.  
• ensure that withdrawal of informed consent to the use of the subject’s biological 
samples will be reported and biological samples are identified and disposed 
of/destructed accordingly, and that this action is documented and reported to the 
subject. 
• verify that AEs are recorded and reported in a timely manner and according to the CSP. 
• raise and escalate any serious quality issues, serious GCP breach and any data privacy 
breach to the Sponsor.  
Centralised monitoring will also be performed continuously by study team members at CTC 
in accordance with the RBM plan.  
When the study has been completed and all queries have been resolved and the database has 
been locked, the Monitor will perform a close-out visit. 
15.3 Source data documents 
A separate Origin of Source Data List will be generated for each site before start of 
enrolment, specifying the location of the source of derived information appearing in the 
eCRF. This document must be signed by the Principal Investigator and the Monitor to confirm 
agreement before start of recruitment. 
Source documents are all documents used by the Investigator or hospital that relate to the 
subject’s medical history, that verifies the existence of the subject, the inclusion and exclusion 
criteria, and all records covering the subject’s participation in the trial. They include 
laboratory notes, memoranda, material dispensing records, subject files, etc. The eCRF may 
constitute source data if clearly defined in the Origin of Source Data List.  
The Investigator should guarantee access to source documents to the Monitor and the IEC if 
required. 
15.4 Study agreements 
The Principal Investigator must comply with all the terms, conditions, and obligations of the 
Clinical Study Agreement for this study. 
Imperial
Tobacco
F

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
46 (55) 
Agreements between Sponsor and CTC must be in place before any study-related procedures 
can take place, or subjects be enrolled. 
15.5 Study timetable and end of study 
The study is expected to start in Q3 2021 and to be completed by Q1 2022. 
A subject is considered to have completed the study if he/she has completed all visits in the 
study including the last visit. The end of the study is defined as the date of the last visit of the 
last subject in the study. 
15.6 Termination of the study 
The Sponsor reserves the right to discontinue the study at any time but intends only to 
exercise this right for valid scientific or administrative reasons. 
After such a decision, the PI must inform all participating subjects and perform relevant 
assessments, preferably according to the scheme for the final assessments. All delivered and 
unused IP and other study materials must be returned and all eCRFs completed as far as 
possible. 
15.7 Reporting and publication 
15.7.1 Clinical study report  
After completion of the trial, a final study report will be written following the guidance in 
ICH Topic E3. A CSR, describing the conduct of the study, any statistical analyses performed 
and the results obtained, will be prepared by CTC. The report will be reviewed and approved 
by, as a minimum, the Principal Investigator, the Statistician and the Sponsor. 
15.7.2 Confidentiality and ownership of study data 
Any confidential information relating to the IP or the study, including any data and results 
from the study, will be the exclusive property of the Sponsor. The Investigator and any other 
persons involved in the study are responsible for protecting the confidentiality of this 
proprietary information belonging to the Sponsor. 
15.7.3 Publication 
The results from this study may be submitted for publication at the discretion of the Sponsor.  
15.8 Archiving  
The Principal Investigator is responsible for maintaining essential documents, (as defined in 
ICH E6 GCP, Section 8) for 10 years after finalisation of the CSR. This includes any original 
source documents related to the study, the Subject Identification List (providing the sole link 
between named subject source records and anonymous eCRF data), the original signed ICFs 
and detailed records of disposition of IP. 
It is the responsibility of the Sponsor to inform the Investigator/institution as to when these 
documents no longer need to be retained. 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
47 (55) 
The Sponsor will archive the TMF in accordance with ICH E6 GCP, Section 8 and applicable 
regulatory requirements. 
The data from the eCRFs will be sent to the Sponsor and a copy will be sent to the clinic and 
filed in the Investigator Study File for archiving for 10 years after finalisation of the CSR. 
The completed eCRFs are the sole property of the Sponsor and should not be made available 
in any form to third parties, except for authorised representatives of appropriate 
Health/Regulatory Authorities, without written permission from the Sponsor. 
16 DATA MANAGEMENT 
The data management routines include procedures for handling of the eCRF, database set-up 
and management, data entry and verification, data validation, QC of the database, and 
documentation of the performed activities including information of discrepancies in the 
process. The database, data entry screens, and program will be designed in accordance with 
the CSP. 
Data validation/data cleaning procedures are designed to assure validity and accuracy of 
clinical data. These procedures consist of computerised online edit checks identifying e.g. 
data values that are outside the allowed range and SAS-programmed batch checks on data 
exports. All study-specific and standard data validation programming will be tested prior to 
being used on final data.. 
Detailed information on data management will be described in a study-specific Data 
Management Plan (DMP). 
16.1 The web-based eCRF 
Clinical data will be entered into a 21 CFR Part 11-compliant eCRF (Viedoc™) provided by 
Viedoc Technologies AB. The eCRF includes password protection and internal quality 
checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, 
or inaccurate. Clinical data will be entered directly from the source documents or at bedside 
(if the eCRF data constitutes source data). Source data are to be defined at the site before 
inclusion of the first subject (Section 15.3). 
Authorised site personnel designated by the Investigator will complete data collection. 
Appropriate training and security measures will be completed with the Investigator and all 
authorised trial site personnel prior to the trial being initiated and any data being entered into 
the system for any study subject. 
16.2 The entering of data into the eCRF 
All entries, corrections, and alterations are to be made by the Investigator or designee. Neither 
the Monitor nor any other study team member besides site staff can enter data in the eCRF. 
All data should be entered in English. The eCRFs should be completed as soon as possible 
during or after the subject’s visit. To avoid inter-observer variability, every effort should be 
made to ensure that preferably the same individual who made the initial baseline 
determinations completes all corresponding follow-up evaluations. The Investigator must 
verify that all data entries in the eCRFs are accurate and correct. If some assessments are not 
done, or if certain information is not available, not applicable or unknown, the Investigator or 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
48 (55) 
assigned clinical staff should record such information in the eCRF. The Investigator will be 
required to electronically sign off the clinical data. This will be performed by means of the 
Investigator’s unique User ID and password; date and time stamps will be added 
automatically at time of electronic signature. 
16.3 The query process 
The Monitor will review the eCRFs and evaluate them for completeness and consistency. 
Data in the eCRF will be compared with the respective source documents to ensure that there 
are no discrepancies for critical data as described in the RBM plan. All entries, corrections, 
and alterations are to be made by the Investigator or designee. Neither the Monitor nor any 
other study team member besides site staff can enter data in the eCRF.  
If corrections are needed, queries will be raised within the eCRF, either as a result of built-in 
edit checks or manually raised by the monitor. An appropriate member of the site staff will 
answer the queries in the eCRF either by correcting the data or by entering a response to the 
query. The monitor will either approve the answer/correction or re-issue the query. 
16.4 Audit trail 
All entries in the eCRF will be fully recorded in a protected audit trail. Once clinical data 
have been saved, corrections to the data fields will be audit trailed, meaning that the reason 
for change, the name of the person who made the change, together with time and date will be 
logged. 
16.5 External data 
External data consists of data that are not recorded in the eCRF. Data may be received in 
electronic format or as a paper printout. Key variables are defined in order to uniquely 
identify each sample record. File and data formats are agreed with the external data provider.  
16.6 Medical coding 
Medical coding will be performed by trained personnel at CTC. AEs and medical/surgical 
history verbatim terms will be coded using the Medical Dictionary of Regulatory Activities 
(MedDRA; latest version available at eCRF set-up). Prior and concomitant medications will 
be coded according to the World Health Organisation (WHO) Anatomic Therapeutic 
Chemical (ATC) classification system. All coding will be approved by Sponsor prior to 
database lock. 
16.7 Database lock 
When all data have been entered and discrepancies solved, clean file will be declared, the 
database will be locked and the data will be analysed. 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
49 (55) 
17 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE  
The principal features of the statistical analysis to be performed are described in this section. 
A more technical and detailed elaboration of the principal features will be presented in a 
separate Statistical Analysis Plan (SAP), which will be signed and approved prior to database 
lock. 
All data analyses will be performed by CTC. 
17.1 General 
Continuous data will be presented in terms of evaluable and missing observations, arithmetic 
mean, standard deviations (SD), median, minimum and maximum value. In addition, for the 
parameters AUC and Cmax the geometric mean and coefficient of variation (CV) will be 
presented.  
Categorical data will be presented as counts and percentages. When applicable, summary data 
will be presented by treatment, and by assessment time. Individual subject data will be listed 
by subject number, treatment, and, where applicable, by assessment time. 
All descriptive summaries and statistical analyses will be performed using SAS Version 9.4 or 
later (SAS Institute, Inc., Cary, NC). 
Baseline will be defined as the visit with last data collection point prior to the first use of IP. 
No imputation of missing data will be performed.  
For subject questionnaires measured at each PK time point, the Bonferroni-Holm p-value 
adjustment will be applied. 
17.2 Determination of sample size 
No formal sample size calculation has been performed for this study. The proposed sample 
size is considered sufficient to provide adequate information for the study objectives. 
Approximately 54 subjects will be screened to achieve 27 randomised subjects. 
17.3 Analysis data sets 
17.3.1 Full analysis set 
The Full Analysis Set (FAS) will consist of all subjects who have been randomised and used 
at last one of the IPs and who has at least one post-baseline assessment of data.  
17.3.2 Pharmacokinetic analysis set 
The Pharmacokinetic analysis set (PKAS) will consist of all subjects who used at last one of 
the IPs and provided an evaluable plasma concentration profile and who have no AEs or 
protocol deviations judged to affect the PK analysis. Individual PK values may be excluded 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
50 (55) 
from the analysis as specified in the SAP. The PKAS will be used as the per protocol analysis 
set. 
17.4 Description of study population 
17.4.1 Demographics and baseline characteristics 
Descriptive statistics for demographics, physical examinations, weight and height will be 
presented by sequence. All data will be listed by subject. 
17.4.2 Medical/surgical history and prior/concomitant medication 
Medical/surgical history will be presented by system-organ-class (SOC) and preferred term 
(PT). Prior/concomitant medications will be presented by ATC level 3 and 5. 
Medical/surgical history and prior medications will be presented overall by descriptive 
statistics and listings. Concomitant medications will be presented by sequence.  
All data will be listed by subject. 
17.4.3 Treatment compliance 
The number of subjects treated in sequence and their individual IP use will be listed. 
17.5 Analysis of primary endpoints 
17.5.1 Analysis of pharmacokinetics  
The PK analysis will be based on the PK analysis set and performed by CTC. The PK 
parameters will be calculated by non-compartmental analysis (NCA) using the software 
Phoenix WinNonlin® version 8.1 or later (Certara, U.S.A.).  
The following non-compartmental PK parameters will be determined for each IP use: 
• AUCinf (baseline adjusted [when possible] and non-baseline adjusted) 
• AUCt (baseline adjusted [when possible] and non-baseline adjusted) 
• 
AUC0-90 (baseline adjusted [when possible] and non-baseline adjusted) 
• Cmax (baseline adjusted [when possible] and non-baseline adjusted) 
• Clast (baseline adjusted [when possible] and non-baseline adjusted) 
• Tmax (baseline adjusted [when possible] and non-baseline adjusted) 
• T½ (baseline adjusted [when possible] and non-baseline adjusted) 
The elimination rate constant, Lambdaz (with acceptance criteria; R2, extrapolated AUC) will 
be calculated to support baseline adjustment of above PK parameters. 
Cmax and Tmax will be derived from the observed plasma concentration data. The AUC will be 
calculated using log-linear trapezoidal interpolation (linear - up, log – down). Calculations 
will be based on the actual sampling times recorded during the study. Concentrations below 
Lower limit of quantification (LLOQ) occurring before Cmax will be treated as zero. 
Concentrations below LLOQ occurring after Cmax will be omitted from the analysis. AUCt, 
and Cmax will be corrected for and calculated with and without nicotine baseline corrections. 
Where plasma nicotine concentrations are above the lower limit of quantification immediately 
Imperial
Tobacco
0

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
51 (55) 
prior to product use (-5 minutes), PK parameters will be calculated from baseline adjusted 
concentrations using subjects' elimination rate constant. 
Summary statistics for the PK parameters will be presented by product with number of 
measurements, arithmetic mean, SD, CV, median, minimum, maximum, geometric mean, 
geometric CV%. All data will be listed by subject. 
The primary objective will be examined by the following statistical comparisons for AUCt 
and Cmax: 
• Product A versus Product B, C and D, respectively 
• Product B versus Product C and D, respectively 
• Product C versus Product D  
Log transformed nicotine Cmax and AUCt estimates will be evaluated separately in a linear 
mixed-effects analysis of variance model with fixed effects for period, sequence, and product, 
and a random effect for subject. If the assumptions for this model will be inappropriate will 
the fixed effects period and sequence be removed from the model. The above product 
differences will be back-transformed to present the ratios of geometric least squares (LS) 
means and 95% CIs of each test product versus each other from the same model. 
17.6 Analysis of secondary endpoints 
17.6.1 Pharmacokinetics 
Refer to section 17.5.1. 
17.6.2 In vivo extracted amount of nicotine 
The data needed for the analysis of in vivo extracted amount of nicotine are the individual 
data of amount of nicotine for unused reference pouches and the amount of nicotine left in the 
study pouches. The mean nicotine concentration of the reference pouch and weight of each 
individual study pouch and residual nicotine amount will be used to calculate the extracted 
amount. The mean of extracted amount (mg/unit) and extraction fraction (%) of nicotine for 
each IP pouch, will be calculated. The orally extracted dose of nicotine will be analysed using 
the signed Wilcoxon rank sum test for within subject difference (i.e. between IPs). Amount of 
nicotine in reference pouches and in used pouches will be presented through descriptive 
statistics. All data will be listed by subject. 
17.6.3 Product evaluation scale 
Each question of the PES will be answered using a 7-point Likert scale. Responses will be 
presented as the following factor scores: 1 = not at all, 2 = very little, 3 = a little, 4 
= moderately, 5 = a lot, 6 = quite a lot, 7 = extremely 
Four multi-item subscales will be derived from "Satisfaction" (items 1, 2, 3, and 12); 
"Psychological Reward" (items 4 through 8); "Aversion" (items 9, 10, 16, and 18); and 
"Relief" (items 11, 13, 14, 15, and reversed for item 20) and single items 17, 19, and 21 will 
be summarized. 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
52 (55) 
The total score of PES and the sub-scales will be calculated for each product and 
intraindividual difference for each timepoint assessed will be analysed using a Wilcoxon 
Signed Rank Sum test. 
Data will be presented using descriptive statistics. Subscales will be tabulated by study 
product and overall at applicable timepoints.  
All data will be listed by subject. 
17.6.4 Product preference scale 
The PPS will be presented using a frequency table with number of observations and all 
combinations of the subject’s preference. 
All data will be listed by subject. 
17.6.5 Urge to use questionnaire 
The following parameters will be calculated for the urge to use assessments: 
Emax 
The maximum change from baseline VAS score (VASpre-use - VASpost-use). 
TEmax 
Time of the Emax. If the maximum value occurs at more than one time point, 
TEmax will be defined as the first time point with this value. 
AUEC0-120 
The area under the change from baseline VAS score versus time curve from 
time 0 to 120 minutes, calculated using the linear trapezoidal method with 
linear interpolation using actual sample times. 
Responses and derived parameters will be summarized by IP and overall using descriptive 
statistics. 
An appropriate statistical method, similar to the PK analysis detailed in Section 17.5.1 will be 
used to compare Urge to Smoke parameters (no data transformation). 
All data will be listed by subject. 
17.6.6 Adverse events  
An overview of all AEs, including SAEs, intensity, relationship to IP, and deaths will be 
presented. Incidence of AEs and SAEs will be summarised by SOC and PT by IP and overall.   
All AE data will be listed by subject and include the verbatim term entered by the 
Investigator. 
17.6.7 Clinical laboratory analyses 
Clinical laboratory data will be summarised by IP with absolute and percent change from 
baseline. 
All data will be listed by subject. 
17.6.8 Vital signs 
Vital signs (systolic/diastolic blood pressure and pulse) will be summarised by IP. Data will 
be presented with absolute and percent change from baseline. 
All data will be listed by subject. 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
53 (55) 
17.6.9 12-lead ECG 
All ECGs will be categorised as =normal=, =abnormal, not clinically significant=, or 
=abnormal, clinically significant= (as judged by the Investigator) and summarised by IP using 
frequency tables.  
All data will be listed by subject. 
18 REFERENCES 
1. Hatsukami DK, Zhang Y, O’Connor RJ, Severson HH. Subjective responses to oral 
tobacco products: scale validation. Nicotine Tob Res. 2013;15(7):1259-64. 
2. World Medical Association, WMA Declaration of Helsinki – Ethical principles for 
medical research involving human subjects [website], https://www.wma.net/policies-
post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-
human-subjects/, (accessed 10JUN2020) 
 
Imperial
Tobacco

 
 
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1.0 
CONFIDENTIAL                                         
    
 
54 (55) 
19 SIGNATURES 
19.1 Principal Investigator statement 
I have read and understood this CSP and agree to conduct the study accordingly and to 
comply with the Investigator obligations stated in this CSP, GCP and applicable regulatory 
requirements.  
 
Principal Investigator 
 
Imperial
Tobacco

Imperial
Tobacco
Clinical Study Protocol IB-OND-ZONEX-11, Final version 1. 0
19.2 Signature page (approval of the clinical study protocol)
Sponsor signatories
DocuSigned by:
Simon MeDermott
Signer Name: Simon McDermott
Signing Reason:
I approve this document
Signing Time: 21-Jun-2021
| 12:10 CEST
8C84342FAEB94392B83F319302F7DD1F
Simon McDermott, Sr CRM
CONFIDENTIAL
55 (55)