An Open-label, Parallel Study to Assess Tobacco-related Biomarkers of Exposure, Biomarkers of Potential Harm, and Nicotine Uptake During a 56-day Switch to Myblu E-cigarettes in Adult Smokers
Phase: NA
Conditions: Healthy Volunteers
Sponsor: Fontem Ventures BV

An Open-Label, Parallel Study to Assess Tobacco-Related Biomarkers of Exposure, 
Biomarkers of Potential Harm, and Nicotine Uptake During a 56-Day Switch to 
mybluTM e-Cigarettes in Adult Smokers 
 
NCT# 04019626 
 
Study Protocol – 24 March 2020 
 
 
 
 

 
Page 1 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
 
 
 
 
 
 
 
 
An Open-Label, Parallel Study to Assess Tobacco-Related Biomarkers of Exposure, 
Biomarkers of Potential Harm, and Nicotine Uptake During a 56-Day Switch to 
myblu™ e-Cigarettes in Adult Smokers 
 
 
 
 
Sponsor Project No.: NER 01/001 
 
 Project No.: CA22747 
 
Final Protocol: 28JAN2019 
Protocol Amendment 1: 23APR2019 
Protocol Amendment 2: 17MAY2019 
Protocol Amendment 3: 24MAR2020 
 
 
 
 
 
 
 
 
 
 
GCP Statement 
This study is to be performed in full compliance with the protocol, Good Clinical Practices 
(GCP), and applicable regulatory requirements. All required study documentation will be 
archived as required by regulatory authorities. 
Confidentiality Statement 
This document is confidential. It contains proprietary information of Nerudia Ltd. Any viewing 
or disclosure of such information that is not authorized in writing by Nerudia Ltd. is strictly 
prohibited. Such information may be used solely for the purpose of reviewing or performing 
this study. 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 7 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
An Open-Label, Parallel Study to Assess Tobacco-Related Biomarkers of Exposure, 
Biomarkers of Potential Harm, and Nicotine Uptake During a 56-Day Switch to 
myblu™ e-Cigarettes in Adult Smokers 
 
 
 
 
 
 
 
 
 
 
Principal 
Investigator: 
 
Printed Name: 
 
Site Name: 
Address: 
 
Tel.: 
Fax: 
E-mail: 
 
 
 
 
 
 
 
 
 
 
 
__________________________________ 
_________ 
 
Signature 
Date 
 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 9 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
SYNOPSIS 
Study Objectives 
Primary: 
1. To assess the change-from-baseline differences in the primary 
tobacco-related biomarkers of exposure (BoE) following a 28-day use 
period of myblu™ electronic cigarettes (e-cigarettes) relative to 
smoking usual brand combustible cigarettes. 
Secondary:  
1. To assess the change-from-baseline differences in the primary 
tobacco-related BoE following a 56-day use period of myblu™ 
e-cigarettes relative to smoking usual brand combustible cigarettes. 
2. To assess the change-from-baseline differences in the secondary 
tobacco-related BoE following 28-day and 56-day use periods of 
myblu™ e-cigarettes relative to smoking usual brand combustible 
cigarettes. 
3. To characterize the change in the primary and secondary BoE and 
BoPH during a 56-day period of use of myblu™ e-cigarettes. 
4. To assess the change-from-baseline differences in the primary and 
secondary tobacco-related BoE between Day 28 and Day 56 in subjects 
using myblu™ e-cigarettes. 
5. To assess change-from-baseline differences in the biomarkers of 
potential harm (BoPH) following 28-day and 56-day use periods of 
myblu™ e-cigarettes relative to smoking usual brand combustible 
cigarettes. 
6. To assess change-from-baseline differences in physiologic endpoints 
following 28-day and 56-day use periods of myblu™ e-cigarettes 
relative to smoking usual brand combustible cigarettes. 
7. To assess elements of abuse liability, subjective effects, and perceptions 
associated with use of myblu™ e-cigarettes. 
8. To characterize use of four myblu™ e-liquids (Tobacco Chill and 
Honeymoon flavor Intense e-liquids, 2.5% and 4.0% nicotine) during a 
56-day use period. 
9. To characterize nicotine uptake from the myblu™ e-cigarettes relative 
to an e-cigarette comparator (JUUL® Virginia Tobacco 5% nicotine) 
and usual brand combustible cigarettes. 
10. To confirm the safety of myblu™ e-cigarettes during a 56-day use 
period. 
Hypothesis 
Switching from usual brand combustible cigarettes to a myblu™ e-cigarette 
will result in a significant decrease from baseline in the primary 
tobacco-related BoE following 28 days of use relative to the change 
associated with continuing to smoke combustible cigarettes. The hypothesis 
will be tested independently for each myblu™ e-liquid cohort. 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 10 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
Study Design 
This will be an open-label, partially-randomized, parallel-arm, multi-site 
study in healthy adult smokers, consisting of two parts – the main study and 
a pharmacokinetics (PK) sub-study.  
The main study will assess BoE, BoPH, physiologic effects, and subjective 
effects with use of myblu™ e-cigarettes relative to continuing to smoke 
combustible cigarettes. Baseline study assessments will be made during use 
of subjects’ usual brand combustible cigarettes during the initial test visit 
from Day -2 through the morning of Day 1 and post-baseline assessments 
will be made during a 56-day use of the assigned study products. Subjects 
randomized to the myblu™ arm will participate in a 3-day in-clinic product 
acclimation period from Day 1 through Day 3 to become familiar with the 
products and to choose a preferred e-liquid. The subset of subjects 
participating in the PK sub-study (described below) will also complete 
selected biomarker assessments on Days 3 and 4 (NNAL, NNN, 3-HPMA, 
CEMA, HMPMA, S-PMA, nicotine equivalents). All subjects in the 
myblu™ and continue-smoking arms will return to the clinic site for 
additional test visits scheduled to occur on Days 14, 28, 42, and 56 for study 
assessments, compliance checks, and product dispensing and return.  
The PK sub-study will characterize nicotine uptake from the myblu™ 
products relative to combustible cigarettes and an e-cigarette comparator 
(JUUL®). A subset of subjects assigned to each of the myblu™ e-liquids and 
the continue-smoking arm, and all subjects in the JUUL® arm, will 
participate in the PK sub-study. PK assessments in subjects assigned to an 
e-cigarette will be completed following an in-clinic period during which the 
subjects will become acclimated to use of the products. PK assessments will 
take place following a 10-hour abstention from all nicotine product use and 
will consist of controlled-use and ad libitum use sessions, with 180 minutes 
of blood sampling during each session. Urge to smoke will also be assessed 
during the ad libitum use sessions. Subjects in the JUUL® arm will only 
participate in the PK sub-study. 
The clinic staff will contact each subject via telephone approximately 
14 days following discharge from the study (scheduled or early terminations) 
for reporting of adverse events (AEs) and use of concomitant medications. 
Study Population 
The study population will be comprised of healthy, adult male and female 
smokers, 21 to 65 years of age. Each subject must self-report smoking an 
average of 5 or more machine-manufactured combustible cigarettes per day 
(CPD) for at least 1 year. Smoking status will be confirmed during Screening 
using urine cotinine and exhaled carbon monoxide (CO) tests. 
Duration of Study 
Conduct 
Screening procedures will be performed within 28 days prior to check-in for 
Test Visit 1. The duration of the study from Screening through the 
Follow-up Period is approximately 14 weeks for subjects in the myblu™ and 
continue-smoking arms and up to 7 weeks for subjects in the JUUL® arm. 
Study Products and 
Administration 
Test Products 
myblu™ system with Tobacco Chill flavor Intense Liquidpod, 2.5% nicotine 
(Product A) 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 11 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
 
myblu™ system with Tobacco Chill flavor Intense Liquidpod, 4.0% nicotine 
(Product B) 
myblu™ system with Honeymoon flavor Intense Liquidpod, 2.5% nicotine 
(Product C) 
myblu™ system with Honeymoon flavor Intense Liquidpod, 4.0% nicotine 
(Product D) 
Control Product 
Subject’s usual brand combustible cigarette (Product E) 
Comparator Product 
JUUL® system with Virginia Tobacco JUULpod, 5.0% nicotine (Product F) 
All subjects in the myblu™ and continue-smoking arms will smoke their 
usual brand combustible cigarettes through the evening of Day -1.  
Subjects randomized to the myblu™ arm will participate in an in-clinic 
product acclimation period from Day 1 through Day 3. The acclimation 
period will afford the subjects the opportunity to try each of the four 
myblu™ e-liquids in order to become accustomed to their use and to 
determine those that they would be willing to use during the study. Initial 
product assignment for each subject will be based on preference to enhance 
compliance. To further improve compliance through Day 56, at the end of 
Test Visit 3, subjects using a myblu™ product may be allowed to choose to 
switch to the alternate nicotine strength of their current flavor, to switch to 
the alternate flavor with the same nicotine strength as their initial choice, or 
to continue using the same e-liquid selected initially. This method for initial 
flavor assignment and the opportunity to re-select after 28 days of use is 
based on natural experimentation that consumers experience when choosing 
an e-cigarette flavor and nicotine strength. 
Subjects randomized to the continue-smoking arm will smoke their usual 
brand cigarette for the duration of the study. 
Subjects in the JUUL® arm will begin using the assigned product after 
check-in for Test Visit 1 and will continue to use the product through 
discharge from the study on Day 1. Subjects in the JUUL® arm will not be 
allowed to use combustible cigarettes from the time of check-in through 
discharge. 
Product use for the PK assessments will consist of two sessions: 1) a fixed 
puffing session in the morning consisting of 10 puffs taken at 30-second 
intervals, with puffs 3 seconds in duration, and 2) an ad libitum use session 
beginning 6 hours after the start of the morning session and consisting of 
unlimited use of the e-cigarette product for 5 minutes or one cigarette, with 
no limits on puff duration or inter-puff interval. 
All product use during confinement will be documented by the clinic staff. 
Subjects in the myblu™ and continue-smoking arms will be required to 
self-report product use from Day 3 through discharge from the study on 
Day 57.  

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 12 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
Number of Subjects 
Planned 
For the main study, a sufficient number of subjects are to be screened and 
randomized to better ensure that at least 29 subjects assigned to each of the 
myblu™ e-liquids and to the continue-smoking arm complete the Day 28 
study assessments. To account for potential attrition, up to 175 subjects are 
planned to be randomized into the myblu™ arm (with approximately 
43 subjects intended to be initially assigned to each myblu™ e-liquid) and up 
to 40 subjects will be randomized into the continue-smoking arm.  
For the PK sub-study, up to 20 subjects assigned to each myblu™ e-liquid, 
20 subjects randomized to the continue-smoking arm, and all 20 subjects in 
the JUUL® arm will be selected to participate. 
In total, up to 235 subjects are intended to be randomized into the study. 
Subject 
Randomization 
Each subject will be assigned to a study arm (myblu™, continue-smoking, or 
JUUL®) according to the randomization plan. The study arms will be 
stratified by sex (male or female) and age class (≤ 40 years of age, 
> 40 years of age). Each sex and age class should not account for more than 
65% of the randomized population in each arm, and Caucasians should not 
comprise more than 80% of the randomized population in each arm. 
Assignment of subjects to a specific myblu™ product will be made based on 
subject product preference. As no consumer preference data is available to 
predict potential product selection among the sex and age categories, every 
effort will be made to assign subjects to a preferred product while attempting 
to reach the stratification limits noted above. An attempt will also be made to 
apply the sex and age class stratification to each product in the PK sub-
study, though the same potential challenges will apply. For logistical and 
operational reasons, the first subject in each sex-age class stratum who 
successfully completes the screening procedures at each site may be 
assigned to the JUUL® arm. 
Study Endpoints 
Primary Study Endpoints 
Biomarkers of Exposure 
Biomarker 
Matrix 
Chemical Constituent 
Carboxyhemoglobin 
(COHb) 
Blood 
Carbon monoxide (CO) 
4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanol (NNAL) 
Urine 
4-(methylnitrosamino)-1-(3-
pyridyl)-1-butanone (NNK) 
3-hydroxypropylmercapturic 
acid (3-HPMA) 
Urine 
Acrolein 
S-phenyl mercapturic acid  
(S-PMA) 
Urine 
Benzene 
 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 13 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
Secondary Study Endpoints 
Biomarkers of Exposure 
Biomarker 
Matrix 
Chemical 
Constituent 
N-nitrosonornicotine (NNN) 
Urine 
NNN 
2-cyanoethyl-mercapturic acid 
(CEMA) 
Urine 
Acrylonitrile 
Hydroxyethyl mercapturic acid 
(HEMA) 
Urine 
Ethylene oxide 
3-hydroxy-1-
methylpropylmercapturic acid 
(HMPMA) 
Urine 
Crotonaldehyde 
Monohydroxybutenylmercapturic 
acid (MHBMA) 
Urine 
1,3-butadiene 
Hydroxypyrene (1-OHP)  
Urine 
Pyrene 
o-toluidine (o-tol) 
Urine 
Toluidine 
3-hydroxybenzo[a]pyrene (3-OH 
B[a]P) 
Urine 
B[a]P 
1-aminonaphthalene (1-AN) 
Urine 
Naphthalene 
2-aminonaphthalene (2-AN) 
Urine 
Naphthalene 
Nicotine equivalents 
Urine 
Nicotine 
Biomarkers of Potential Harm 
Biomarker 
Matrix 
Biological Effect 
Soluble intracellular adhesion 
molecule (sICAM)  
Blood 
Inflammation 
White blood cells (WBCs) 
Blood 
Inflammation 
High density lipoprotein cholesterol 
(HDL-C) 
Blood 
Inflammation 
Monocyte chemoattractant protein 1 
(MCP-1) 
Blood 
Inflammation 
Type III isoprostane (8-epi-
prostaglandin F2α) 
Urine 
Oxidative stress 
11-dehydrothromboxane B2 
Urine 
Platelet activation 
Physiological assessments 
• 
Fractional concentration of exhaled nitric oxide (FeNO) 
• 
Blood pressure 
• 
Heart rate 
Subjective measures 
• 
Penn State [Electronic] Cigarette Dependence Index (PSCDI, PSECDI) 
• 
Cough Questionnaire 
• 
Questionnaire of Smoking Urges-Brief (QSU-Brief) 
• 
Minnesota Tobacco Withdrawal Scale-Revised (MTWS-R) 
• 
Product Evaluation Scale (PES) 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 14 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
• 
Product Liking Questionnaire 
• 
Future Intent to Use Questionnaire 
• 
Product and Health Effect Perceptions Questionnaire 
Product Use 
Daily in-clinic product use documented by the clinic staff: 
• 
Number of cigarettes smoked 
• 
Number of myblu™ and JUUL® pods started 
• 
myblu™ pod weight change (for pods used during the 24 hour urine 
collections) 
• 
Day 3 and Day 29 product preference selection 
Daily product use endpoints documented by subjects (Day 3 through study 
discharge on Day 57): 
• 
Number of cigarettes smoked 
• 
Number of myblu™ pods started 
• 
Number of puffs from the myblu™ product daily (< or ≥ 50 puffs) 
Nicotine Pharmacokinetics Assessment 
Product use during each product use session: 
• 
Number of puffs taken 
• 
myblu™ and JUUL® pod weight change 
PK parameters during each product use session: 
• 
Cmax 
• 
AUC0-t 
• 
Tmax 
Urge to smoke parameters during the ad libitum product use session: 
• 
Maximum reduction from baseline score (Emax_R) 
• 
Time of the Emax_R (TEmax) 
• 
Area under the change from baseline “Urge to Smoke” visual analog 
scale (VAS) score versus time curve (AUEC BL) 
Other Compliance 
Assessments 
Exhaled CO and urine cotinine measurements will be used to confirm 
smoking/nicotine use status prior to Day 1 and to assess subject compliance 
with product assignment requirements thereafter. 
Statistical Analysis 
Comparisons of the Day 28 visit primary BoE change-from-baseline values 
between the continue-smoking arm and each myblu™ e-liquid product 
selected at Day 2 will be made using a linear mixed model analysis of 
variance (ANOVA). The intent-to-treat (ITT) population will be used as the 
primary analysis population and an analysis using the per-protocol (PP) 
population will be used as a supportive analysis.  
An approach similar to that used for the primary endpoints will be used to 
make Day 28 and Day 56 change-from-baseline comparisons for the 
applicable secondary endpoints. For the Day 56 analysis, the initial myblu™ 
e-liquid cohort assignments for each subject will be maintained within the 
statistical model and a separate sensitivity analysis will be performed for 
subjects that do not switch flavors at Day 29. 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 15 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
Comparisons of the primary and secondary BoE change-from-baseline 
values at each time point within and between the four myblu™ e-liquid 
flavor product cohorts will also be made using a linear mixed model 
ANOVA.  
A linear mixed model ANOVA will be performed on the log-transformed 
nicotine AUC and Cmax PK parameters from each product use session. Non-
parametric analysis (Wilcoxon Signed Rank test) will be performed for the 
comparisons of Tmax. Similar models will be used to compare the urge to 
smoke parameters. The comparisons of interest will include each of the 
myblu™ products compared to the usual brand cigarette and JUUL® product. 
Safety Assessments 
Screening safety evaluations will include a physical examination, vital signs, 
electrocardiogram (ECG), clinical laboratory tests (clinical chemistry, 
hematology, urinalysis, and serology), lung function, follicle-stimulating 
hormone (FSH) test (post-menopausal females), and serum and urine 
pregnancy tests (females only).  
On-study evaluations will include a symptom-driven physical examination, 
vital signs, ECG, clinical laboratory tests (clinical chemistry, hematology, 
and urinalysis), lung function, and urine pregnancy tests (females only).  
AEs spontaneously reported by the subjects or observed by the Investigator 
or other study personnel will be documented and monitored from the time of 
first product use after successful completion of the check-in events for Test 
Visit 1 through the end of the Follow-up Period. Any prior and concomitant 
medications taken from 30 days prior to Screening through the Follow-up 
Period will also be recorded. 
 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 16 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
STUDY EVENTS FLOW CHARTS 
Table 1 
Screening Procedures 
EVENTS/ASSESSMENTS 
Screening 1 
Informed Consent 
X 
Review of Inclusion/Exclusion Criteria 
X 
Medical History 
X 
Screening Demographics 
X 
Prior and Concomitant Medication Reporting 
X 
Smoking History and Usual Brand Combustible Cigarette 
Documentation 
X 
Tobacco/Nicotine Use History Questionnaire 
X 
Physical Examination 
X 
Body Weight, Height, and BMI 
X 
Clinical Chemistry, Hematology, Urinalysis 
X 
HIV, HBsAg, and HCV Serology Screen 
X 
Urine Drug Test 
X 
Alcohol Breath Test 
X 
Urine Cotinine Test 
X 
FSH Test (post-menopausal females) 
X 
Serum Pregnancy Test (females) 
X 
Exhaled CO 
X 
Vital Signs 
X 
12-lead ECG 
X 
Spirometry 
X 
Review of Tobacco and Nicotine Restrictions 
X 
Provide Smoking Cessation Information 
X 
 
1 All subjects will complete screening procedures within 28 days of check-in for Test Visit 1. 
 
 
Abbreviations:  BMI = Body mass index, CO = Carbon monoxide, ECG = Electrocardiogram, FSH = follicle 
stimulating hormone, HBsAg = Hepatitis B surface antigen, HCV = Hepatitis C virus, HIV = Human 
immunodeficiency virus. 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 20 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
1 Discharge from Test Visit 1 will be as follows. Day -1: Subjects in the continue-smoking arm who do not participate in the PK. Day 1: Subjects 
in the continue-smoking arm who participate in the PK assessment. Day 3: Subjects in the myblu™ arm who do not participate in the PK 
assessment. Day 5: Subjects in the myblu™ arm participating in the PK assessment. 
2 The clinic staff will make a telephone call within 24 - 48 hours prior to the scheduled visits to remind subjects of the date and time of the 
upcoming Test Visits. 
3 Updated as necessary. 
4 Study discharge/early termination events. 
5 myblu™ arm only. 
6 All subjects will smoke their usual brand combustible cigarettes prior to Day 1 and will use study product according to the randomization from 
Day 1 through discharge from the study. 
7 Pods used during the 24-hour urine collections and PK sessions will be weighed prior to and following use. 
8 Subjects will be trained on use of the ambulatory product use reporting system. 
9 Collections for selected BoE, nicotine equivalents, and questionnaires for myblu™ subjects who participate in the PK sub-study. 
10 Continue-smoking arm on Day 1, myblu™ arm on Day 5.  
11 Two product use sessions: fixed puffing regimen in the morning and an ad libitum regimen in the afternoon. 
12 Blood samples for nicotine concentration measurement will take place approximately 5 minutes prior to and at 3, 5, 7, 10, 12, 15, 20, 30, 60, 120 
and 180 minutes following the start of each product use episode (Day 1 continue-smoking, Day 5 myblu™). 
13 Urge to smoke assessments will take place approximately 10 minutes prior to and within approximately 30 seconds prior to the scheduled blood 
draws at 5, 10, 15, 30, 60, and 120 minutes following the start of the ad libitum product use sessions. 
14 At the discretion of the site, Test Visit 3 and Test Visit 5 may be ambulatory and subjects may complete selected procedures at home 
(e.g., 24-hour urine collection, completion of questionnaires). Subjects will be provided the materials required to complete the selected 
procedures and will be instructed on at-home procedures (e.g., urine collection method, questionnaires). 
 
Abbreviations:  AE = Adverse event, BoE = Biomarker of exposure, BoPH = Biomarker of potential harm, CO = Carbon monoxide, ECG = Electrocardiogram, 
FeNO = Fractional concentration of exhaled nitric oxide, MTWS-R = Minnesota Nicotine Withdrawal Scale-Revised, PES = Product Evaluation Scale, 
PSCDI =  Penn State Cigarette Dependence Index, PSECDI = Penn State Electronic Cigarette Dependence Index, QSU-Brief = Questionnaire of Smoking 
Urges-Brief. 
 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 22 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
4 Or upon early termination. 
5 All subjects will use the assigned study product from completion of check-in events through 
discharge from the study. 
6 Two product use sessions: fixed puffing regimen in the morning and an ad libitum regimen in the 
afternoon. 
7 Pods will be weighed prior to and following use. 
8 Blood samples for nicotine concentration measurement will take place approximately 5 minutes 
prior to and at 3, 5, 7, 10, 12, 15, 20, 30, 60, 120 and 180 minutes following the start of each 
product use episode. 
9 Urge to smoke assessments will take place approximately 10 minutes prior to and within 30 
seconds prior to the scheduled blood draws at 5, 10, 15, 30, 60, and 120 minutes following the start 
of the ad libitum product use sessions. 
 
Abbreviations:  AE = Adverse event, CO = Carbon monoxide, ECG = Electrocardiogram, 
PK = Pharmacokinetic. 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 23 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
ABBREVIATIONS 
PK and other endpoint parameter descriptions are listed in the Sections 7.4.5 and 7.4.6. 
 
1-AN 
1-aminonaphthalene 
1-OHP 
1-hydroxypyrene 
2-AN 
2-aminonaphthalene 
3-HPMA 
3-hydroxypropylmercapturic acid 
3-OH B[a]P 
3-hydroxybenzo[a]pyrene 
AE 
Adverse event 
ANOVA 
Analysis of variance 
AUC 
Area under the curve 
BoE 
Biomarker(s) of exposure 
BoPH 
Biomarker(s) of potential harm 
BMI 
Body mass index 
°C 
Degree Celsius 
CDMS 
Clinical Data Management System 
CEMA 
2-cyanoethyl-mercapturic acid 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CO 
Carbon monoxide 
COHb 
Carboxyhemoglobin 
CPD 
Cigarettes per day 
CYP 
Cytochrome P450 
DMP 
Data Management Plan 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
e-cigarette 
Electronic cigarette 
°F 
Degree Fahrenheit 
FDA 
Food and Drug Administration 
FEF 
Forced expiratory flow 
FeNO 
Fractional concentration of exhaled nitric oxide 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 24 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
FEV1 
Forced expiratory volume in 1 second 
FSH 
Follicle stimulating hormone 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
HbsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HEMA 
Hydroxyethyl mercapturic acid 
HDL-C 
High density lipoprotein - cholesterol 
HIV 
Human immunodeficiency virus 
HMPMA 
3-hydroxy-1-methylpropylmercapturic acid 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
MCP-1 
Monocyte chemoattractant protein 1 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHBMA 
Monohydroxybutenylmercapturic acid 
MTWS-R 
Minnesota Tobacco Withdrawal Scale - Revised 
n 
Sample size 
NNAL 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 
NNK 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone 
NNN 
N-nitrosonornicotine 
o-tol 
o-toluidine 
PES 
Product Evaluation Scale 
PK 
Pharmacokinetic(s) 
PP 
Per-protocol 
PSCDI 
Penn State Cigarette Dependence Index 
PSECDI 
Penn State Electronic Cigarette Dependence Index 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QSU-Brief 
Questionnaire of Smoking Urges – Brief 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 25 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
SD 
Standard deviation 
SEM 
Standard error of the mean 
sICAM 
Soluble intracellular adhesion molecule 
SOP 
Standard operating procedure 
S-PMA 
S-phenyl mercapturic acid 
US 
United States of America 
VAS 
Visual analog scale 
WBC 
White blood cell 
 
 
 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 26 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
DEFINITION OF TERMS 
Concomitant 
medication 
Concomitant medication refers to all medication taken during the 
study conduct period from Screening through the Follow-up 
Period. Medications started prior to Screening but which the 
subject continues to take during the study, are considered to be 
concomitant medications. 
myblu™ Cohorts 
Each of the four myblu™ e-liquid cohorts will be comprised of a 
subset of subjects randomized to the myblu™ arm who are 
assigned to receive one of the four myblu™ e-liquids based on 
subject product preference. 
Product Use Period 1 
The period of time from first use of study product on Day 1 
through the end of Test Visit 3 (myblu™ and continue-smoking 
arms). 
Product Use Period 2 
The period of time from the end of Test Visit 3 through the end of 
Test Visit 5 (myblu™ and continue-smoking arms). 
Randomization 
Assignment of subjects to a product use arm. The randomization 
arms will include: myblu™, continue-smoking, and JUUL®. 
Screening 
Screening is defined as the period during which subjects must 
satisfy criteria for entry into the study (i.e., through completion of 
Test Visit 1 check-in events). 
Screen failure 
Any subject who initiates screening events but does not meet the 
study entry criteria will be considered a screening failure. 
Sponsor 
‘Sponsor’ refers to Nerudia Ltd. 
Study Arms 
Refers to the subjects randomized to receive a myblu™ product, to 
continue smoking their usual brand cigarette, or assigned to the 
JUUL® product 
Subject 
‘Subject’ refers to an individual who participates in the clinical 
study. 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 27 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
TABLE OF CONTENTS 
PROTOCOL REVISION HISTORY ........................................................................................2 
SPONSOR SIGNATURE PAGE ..............................................................................................6 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE .............................................................7 
STUDY CONTACTS ................................................................................................................8 
SYNOPSIS .................................................................................................................................9 
STUDY EVENTS FLOW CHARTS .......................................................................................16 
ABBREVIATIONS .................................................................................................................23 
DEFINITION OF TERMS ......................................................................................................26 
TABLE OF CONTENTS .........................................................................................................27 
1. 
INTRODUCTION AND BACKGROUND ................................................................32 
1.1 
Background ......................................................................................................32 
1.2 
myblu™ Previous Clinical Experience ............................................................32 
1.3 
Rationale for the Study ....................................................................................34 
2. 
STUDY OBJECTIVES AND ENDPOINTS ...............................................................35 
2.1 
Study Objectives ..............................................................................................35 
2.2 
Study Hypothesis .............................................................................................35 
2.3 
Study Endpoints ...............................................................................................36 
2.3.1 
Primary Study Endpoints ..................................................................36 
2.3.2 
Secondary Study Endpoints ..............................................................36 
3. 
SUMMARY OF STUDY DESIGN .............................................................................38 
3.1 
Design and Procedures .....................................................................................38 
3.2 
Justification for Study Design ..........................................................................40 
4. 
STUDY POPULATION ..............................................................................................40 
4.1 
Inclusion Criteria .............................................................................................40 
4.2 
Exclusion Criteria ............................................................................................41 
4.3 
Study Restrictions ............................................................................................44 
4.3.1 
Food, Beverages, and Activity ..........................................................44 
4.3.2 
Medications .......................................................................................44 
4.3.3 
Tobacco Use......................................................................................45 
4.4 
Subject Early Discontinuation or Withdrawal .................................................45 
4.5 
Subject Randomization and Product Assignments ..........................................46 
4.6 
Replacement Subjects ......................................................................................47 
5. 
STUDY PRODUCTS ..................................................................................................47 
5.1 
Description of Study Products .........................................................................47 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 28 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
5.1.1 
Test Product ......................................................................................47 
5.1.2 
Control Product .................................................................................48 
5.1.3 
Comparator Product ..........................................................................48 
5.2 
Study Product Accountability ..........................................................................48 
5.3 
Study Product Storage......................................................................................49 
5.4 
Study Product Dispensing ................................................................................49 
5.4.1 
Confinement Periods .........................................................................49 
5.4.2 
Ambulatory Periods ..........................................................................50 
5.5 
Test Product Failure and Misuse......................................................................50 
5.6 
Test Product Return/Destruction......................................................................50 
6. 
STUDY SCHEDULE AND PROCEDURES ..............................................................51 
6.1 
Study Period Summaries ..................................................................................51 
6.1.1 
Screening Period ...............................................................................51 
6.1.2 
Baseline and Product Use Period 1 ...................................................52 
6.1.3 
Product Use Period 2 ........................................................................59 
6.1.4 
Follow-up Period ..............................................................................61 
6.2 
Study Events ....................................................................................................61 
6.2.1 
Medical History ................................................................................61 
6.2.2 
Demographics ...................................................................................61 
6.2.3 
Prior and Concomitant Medications .................................................62 
6.2.4 
Smoking History and Usual Brand Combustible Cigarette 
Documentation ..................................................................................62 
6.2.5 
Tobacco/Nicotine Product Use History Questionnaire .....................62 
6.2.6 
Physical Examination........................................................................62 
6.2.7 
Body Weight, Height, and BMI ........................................................62 
6.2.8 
Clinical Laboratory Tests ..................................................................63 
6.2.9 
Exhaled Carbon Monoxide ...............................................................63 
6.2.10 
Vital Signs .........................................................................................64 
6.2.11 
Electrocardiogram .............................................................................64 
6.2.12 
Lung Function (Spirometry) .............................................................64 
6.3 
Study Product Use and Reporting ....................................................................65 
6.3.1 
Confinement Periods .........................................................................65 
6.3.2 
Ambulatory Periods ..........................................................................67 
6.3.3 
Product Use Compliance...................................................................67 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 29 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
6.4 
Biomarker Sample Collection ..........................................................................68 
6.4.1 
Blood .................................................................................................68 
6.4.2 
Urine .................................................................................................68 
6.5 
Physiologic Assessments .................................................................................69 
6.5.1 
Fractional Concentration of Exhaled Nitric Oxide ...........................69 
6.5.2 
Blood Pressure and Heart Rate .........................................................69 
6.6 
Subjective Measures ........................................................................................69 
6.7 
Nicotine Pharmacokinetics Assessments .........................................................70 
6.7.1 
Product Use .......................................................................................70 
6.7.2 
Nicotine Pharmacokinetic Blood Sampling ......................................70 
6.7.3 
Urge to Smoke Assessment ..............................................................71 
6.8 
Other Clinical Considerations ..........................................................................71 
6.8.1 
Meals .................................................................................................71 
6.8.2 
Reminder Phone Calls.......................................................................71 
6.9 
Adverse Events ................................................................................................71 
6.9.1 
Monitoring ........................................................................................71 
6.9.2 
Reporting...........................................................................................72 
6.9.3 
Serious Adverse Events ....................................................................72 
6.10 
Pregnancy .........................................................................................................73 
6.11 
Smoking Cessation Information ......................................................................73 
7. 
DATA ANALYSIS ......................................................................................................73 
7.1 
Sample Size Estimation ...................................................................................73 
7.2 
Analysis Populations ........................................................................................74 
7.2.1 
Safety Population ..............................................................................74 
7.2.2 
Intent-to-Treat Population .................................................................74 
7.2.3 
Per-Protocol Population ....................................................................74 
7.2.4 
Pharmacokinetics Population ............................................................75 
7.3 
Calculations......................................................................................................75 
7.3.1 
Urine Nicotine Equivalents ...............................................................75 
7.3.2 
Calculation of Total Mass Excreted ..................................................75 
7.3.3 
Creatinine Adjustments .....................................................................76 
7.4 
Data Summarization.........................................................................................76 
7.4.1 
Product Use and Compliance ............................................................76 
7.4.2 
Biomarkers of Exposure and Potential Harm ...................................76 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 30 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
7.4.3 
Physiologic Assessments ..................................................................77 
7.4.4 
Subjective Measures .........................................................................77 
7.4.5 
Nicotine Pharmacokinetic Analysis ..................................................77 
7.4.6 
Urge to Smoke Parameters................................................................78 
7.5 
Statistical Analysis ...........................................................................................79 
7.5.1 
Primary Endpoints ............................................................................79 
7.5.2 
Secondary Endpoints ........................................................................79 
7.6 
Safety ...............................................................................................................79 
8. 
STUDY ADMINISTRATION.....................................................................................80 
8.1 
Ethics................................................................................................................80 
8.1.1 
Institutional Review Board ...............................................................80 
8.1.2 
Ethical Conduct of the Study ............................................................80 
8.1.3 
Subject Informed Consent.................................................................80 
8.2 
Termination of the Study .................................................................................81 
8.3 
Data Management ............................................................................................81 
8.3.1 
Database Design and Creation ..........................................................81 
8.3.2 
Data Coding ......................................................................................81 
8.3.3 
Data Entry and Verification ..............................................................81 
8.3.4 
Study Results Data Transfer .............................................................81 
8.3.5 
Data Validation .................................................................................82 
8.3.6 
Database Lock ...................................................................................82 
8.4 
Monitoring the Study .......................................................................................82 
8.5 
Reporting for the Study ....................................................................................83 
8.5.1 
Case Report Forms ............................................................................83 
8.5.2 
Study Report .....................................................................................83 
8.6 
Confidentiality .................................................................................................83 
8.7 
Publication Policy ............................................................................................83 
9. 
REFERENCES ............................................................................................................84 
10. 
APPENDICES .............................................................................................................85 
 
 
 
 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 32 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
1. INTRODUCTION AND BACKGROUND 
1.1 
Background 
E-cigarettes have become a popular alternative to cigarette smoking globally and are 
garnering significant attention as potentially reduced exposure products and smoking 
cessation products. E-cigarettes consist of a battery, heating component, and a reservoir 
(often referred to as a pod, cartridge, or tank) containing tobacco-derived nicotine in a 
solution composed of glycerin and/or propylene glycol and flavorings. Upon activation, the 
heating element heats the solution and the consumer inhales the resulting vapor. 
Because e-cigarette use does not involve the combustion of tobacco, it is expected that 
e-cigarette consumers will experience reduced exposure to most biomarkers of tobacco 
exposure compared to combustible cigarettes. Previous studies have shown that switching 
from combustible cigarettes to e-cigarettes with high rates of compliance results in large 
reductions in a number of cigarette smoke toxicants (Cravo et al. 2016, Goniewicz et 
al. 2017, O'Connell et al. 2016, McRobbie et al. 2015, Hecht et al. 2015). This study will 
evaluate a number of urine and blood biomarkers commonly associated with tobacco 
exposure during a 56-day period of use of the myblu™ e-cigarette system. Subjects 
randomized to the myblu™ study arm will be allowed to choose from one of four e-liquids 
(Tobacco Chill or Honeymoon flavor Intense e-liquids, containing either 2.5% or 4.0% 
nicotine) rather than be randomized to a particular flavor that they may not prefer to better 
represent the flavor selection that e-cigarette consumers experience while choosing a product 
in real-life situations. In addition, several BoPH, physiological assessments related to 
cigarette smoking health outcomes, subjective effects, and nicotine uptake will also be 
assessed. 
1.2 
myblu™ Previous Clinical Experience 
One previous clinical study has been conducted with the myblu™ closed system 
(FON-01blu-2018). Fifteen healthy adult smokers enrolled in an open-label, 6-period 
crossover study to characterize nicotine uptake and subjective effects during a 10-puff 
controlled exposure (puffs 3 seconds in duration, taken at approximately 30-second intervals) 
relative to usual brand combustible cigarettes and the blu PRO open system product and to 
determine the potential impact of a nicotine salt e-liquid (with lactic acid). 
Blood samples for plasma nicotine analysis were collected approximately 5 minutes prior to 
and at 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, and 30 minutes following the start of product use. The 
subjective effects questionnaires were completed at approximately 20 minutes following the 
start of each product use and included 6 questions presented on a scale of 1 (not at all) to 7 
(extremely). 
Nicotine AUC0-30 and Cmax increased with increasing nicotine content in the myblu™ 
products (16 – 40 mg nicotine), and was higher in the 25 mg nicotine salt formulation 
compared to the non-salt formulation. The time to reach maximal plasma nicotine 
concentrations (Tmax) ranged from approximately 6.0 – 7.9 minutes following use of myblu™ 
and blu PRO products with nicotine salts and approximately 8.0 minutes following use of 
myblu™ non-salt formulation. AUC0-30 and Cmax to nicotine were lowest following use of blu 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 33 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
PRO compared to all other products tested. Overall exposure over 30 minutes (AUC0-30) and 
peak exposure (Cmax) to nicotine was highest following use of cigarette compared to any 
other product tested. The time to reach peak exposure (Tmax) was shorter following use of the 
five e-cigarette test products compared to the cigarette.  
Arithmetic Mean Baseline Adjusted Plasma Nicotine Concentration-Time Profiles 
Following Fixed Product Use by Product (Linear Scale)
 
Summary of Baseline Adjusted Plasma Nicotine Pharmacokinetics by Study Product 
Parameter 
Product A: 
myblu™ 
25 mg 
Product B: 
myblu™ 25 mg 
(free-base) 
Product C: 
myblu™ 40 mg 
Product D: 
myblu™ 16 mg 
Product E: 
blu PRO 48 mg 
Product F: 
Cigarette 
AUC0-30 
(ng*min/mL) 
125.2 (53.4) 
[n=13] 
98.99 (35.8) 
[n=14] 
190.7 (71.8) 
[n=15] 
118.5 (60.8) 
[n=15] 
84.84 (89.8) 
[n=14] 
324.9 (35.8) 
[n=15] 
Cmax (ng/mL) 
7.576 (80.6) 
[n=13] 
5.048 (49.9) 
[n=14] 
10.27 (83.6) 
[n=15] 
6.510 (76.5) 
[n=15] 
4.845 (108.3) 
[n=14] 
17.81 (49.6) 
[n=15] 
Tmax (min) 
6.033  
(4.58, 16.77) 
[n=13] 
8.034  
(2.28, 15.10) 
[n=14] 
7.900  
(1.97, 15.00) 
[n=15] 
6.967  
(3.98, 15.05) 
[n=15] 
6.908  
(2.35, 15.03) 
[n=14] 
8.050  
(5.00, 15.13) 
[n=15] 
AUC and Cmax are presented as geometric mean and geometric coefficient of variability %, Tmax values are presented as median 
(min, max). 
n: number of observations included in the summary statistics  
 
Product A: myblu™ closed system with CF Cosmic Fog Chilled Tobacco flavor, nicotine salt liquid 25 mg 
Product B: myblu™ closed system with CF Cosmic Fog Chilled Tobacco flavor, non-nicotine salt liquid 25 mg 
Product C: myblu™ closed system with CF Cosmic Fog Chilled Tobacco flavor, nicotine salt liquid 40 mg 
Product D: myblu™ closed system with CF Cosmic Fog Chilled Tobacco flavor, nicotine salt liquid 16 mg 
Product E: blu PRO open system with Purilum Cosmic Fog Chilled Tobacco flavor, nicotine salt liquid 48 mg 
Product F: Subject’s usual brand combustible cigarette 
Mean scores for the subjective effects assessments tended to be highest after combustible 
cigarette use and generally followed by myblu™ 40 mg. With the exception of the questions 
“was it enough nicotine?” and “was it too much nicotine?”, the responses following use of 
the 25 mg salt formulation were comparable to the 25 mg non-salt formulation. 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 34 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
 
Summary of Subjective Effects Score by Study Product (Safety Population) 
Questions 
Study Products 
A 
B 
C 
D 
E 
F 
 n =13 
n =14 
n =15 
n =15 
n =14 
n =15 
Did it make you dizzy? 
2.1 ± 1.32 
1.9 ± 1.73 
2.8 ± 1.78 
1.5 ± 0.74 
1.7 ± 0.99 
3.7 ± 1.80 
Did it make you nauseous?  
1.2 ± 0.44 
1.3 ± 0.83 
1.4 ± 0.91 
1.1 ± 0.26 
1.4 ± 0.84 
1.9 ± 1.44 
Did you enjoy it? 
3.5 ± 1.98 
3.5 ± 1.87 
4.0 ± 1.36 
3.5 ± 1.46 
3.2 ± 1.81 
4.9 ± 1.44 
Did it relieve the urge to smoke? 
3.5 ± 1.98 
3.6 ± 2.10 
4.1 ± 1.79 
3.3 ± 1.91 
3.1 ± 2.11 
5.5 ± 1.60 
Was it enough nicotine? 
3.1 ± 1.93 
4.0 ± 1.96 
4.3 ± 1.79 
3.3 ± 1.99 
3.2 ± 2.08 
5.4 ± 1.55 
Was it too much nicotine? 
1.5 ± 0.97 
2.5 ± 2.21 
2.2 ± 1.66 
1.7 ± 1.11 
1.4 ± 0.63 
2.4 ± 1.55 
Scoring: 1 – Not at all, 2 – Very little, 3 – A little, 4 – Moderately, 5 – A lot, 6 – Quite a lot, 7 – Extremely. 
Scores are presented as mean ± SD. 
n = Number of subjects used in the analysis 
Product A: myblu™ closed system with CF Cosmic Fog Chilled Tobacco flavor, nicotine salt liquid 25 mg 
Product B: myblu™ closed system with CF Cosmic Fog Chilled Tobacco flavor, non-nicotine salt liquid 25 mg 
Product C: myblu™ closed system with CF Cosmic Fog Chilled Tobacco flavor, nicotine salt liquid 40 mg 
Product D: myblu™ closed system with CF Cosmic Fog Chilled Tobacco flavor, nicotine salt liquid 16 mg 
Product E: blu PRO open system with Purilum Cosmic Fog Chilled Tobacco flavor, nicotine salt liquid 48 mg 
Product F: Subject’s usual brand combustible cigarette 
Overall, the study products were well-tolerated under the conditions of use in the study. 
There were no serious adverse events (SAEs) reported in the study, and no subjects were 
discontinued due to AEs. Product use emergent AEs were infrequently reported with four 
subjects reporting a total of 10 AEs. Vessel puncture site pain was the most frequently 
reported AE, experienced by two subjects. All remaining AEs were experienced by one 
subject each. All AEs were mild in severity, with the exception of moderate insomnia (blu 
PRO 48 mg). The PI considered one AE of headache (myblu™ 25 mg [non-salt formulation]) 
to be possibly related to study product and the remaining nine events unlikely or unrelated. 
1.3 
Rationale for the Study 
This study is being conducted to provide information on the myblu™ e-cigarette system with 
Tobacco Chill and Honeymoon flavor Intense e-liquids, and two nicotine strengths (2.5% and 
4.0%). Along with other pre-clinical in vitro studies, clinical, and behavioral and population 
studies, the results of this study are intended to contribute to a body of evidence 
demonstrating the reduced exposure potential of these products. The data may be included in 
future premarket tobacco application submissions to the United States (US) Food and Drug 
Administration (FDA) Center for Tobacco Products. The endpoints to be assessed are based 
on the FDA Electronic Nicotine Delivery Systems Draft Guidance for Industry (May 2016). 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 35 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
The primary objective of this study is: 
1. To assess the change-from-baseline differences in the primary tobacco-related BoE 
following a 28-day use period of myblu™ e-cigarettes relative to smoking usual brand 
combustible cigarettes. 
The secondary objectives of this study are: 
1. To assess the change-from-baseline differences in the primary tobacco-related BoE 
following a 56-day use period of myblu™ e-cigarettes relative to smoking usual brand 
combustible cigarettes. 
2. To assess the change-from-baseline differences in the secondary tobacco-related BoE 
following 28-day and 56-day use periods of myblu™ e-cigarettes relative to smoking 
usual brand combustible cigarettes. 
3. To characterize the change in the primary and secondary BoE and BoPH during a 56-day 
period of use of myblu™ e-cigarettes. 
4. To assess the change-from-baseline differences in the primary and secondary tobacco-
related BoE between Day 28 and Day 56 in subjects using myblu™ e-cigarettes. 
5. To assess change-from-baseline differences in the BoPH following 28-day and 56-day 
use periods of myblu™ e-cigarettes relative to smoking usual brand combustible 
cigarettes. 
6. To assess change-from-baseline differences in physiologic endpoints following 28-day 
and 56-day use periods of myblu™ e-cigarettes relative to smoking usual brand 
combustible cigarettes. 
7. To assess elements of abuse liability, subjective effects, and perceptions associated with 
use of myblu™ e-cigarettes. 
8. To characterize use of four myblu™ e-liquids (Tobacco Chill and Honeymoon flavor 
Intense e-liquids, 2.5% and 4.0% nicotine) during a 56-day use period. 
9. To characterize nicotine uptake from the myblu™ e-cigarettes relative to an e-cigarette 
comparator (JUUL® Virginia Tobacco 5% nicotine) and usual brand combustible 
cigarettes. 
10. To confirm the safety of myblu™ e-cigarettes during a 56-day use period. 
2.2 
Study Hypothesis 
The study hypothesis is that switching from usual brand combustible cigarettes to a myblu™ 
e-cigarette will result in a significantly larger decrease from baseline in the primary 
tobacco-related biomarkers following 28 days of use relative to the change associated with 
continuing to smoke combustible cigarettes. The following hypothesis will be tested 
independently for each myblu™ e-liquid. 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 36 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
H0: Δµtest = Δµcont  
HA: Δµtest > Δµcont 
Where H0 is the null hypothesis, HA is the alternative hypothesis, Δµ = the mean decrease 
from baseline, “test” = myblu™ product, and “cont” = combustible cigarette 
2.3 
Study Endpoints 
2.3.1 Primary Study Endpoints 
Biomarkers of Exposure 
Biomarker 
Matrix 
Chemical Constituent 
COHb 
Blood 
CO 
NNAL 
Urine 
NNK 
3-HPMA 
Urine 
Acrolein 
S-PMA 
Urine 
Benzene 
2.3.2 Secondary Study Endpoints 
Biomarkers of Exposure 
Biomarker 
Matrix 
Chemical Constituent 
NNN 
Urine 
NNN 
CEMA 
Urine 
Acrylonitrile 
HEMA 
Urine 
Ethylene oxide 
HMPMA 
Urine 
Crotonaldehyde 
MHBMA 
Urine 
1,3 butadiene 
1-OHP  
Urine 
Pyrene 
o-tol 
Urine 
Toluidine 
3-OH B[a]P 
Urine 
B[a]P 
1-AN 
Urine 
Naphthalene 
2-AN 
Urine 
Naphthalene 
Nicotine equivalents 
Urine 
Nicotine 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 37 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
Biomarkers of Potential Harm 
Biomarker 
Matrix 
Biological Effect 
sICAM  
Blood 
Inflammation 
WBCs 
Blood 
Inflammation 
HDL-C 
Blood 
Inflammation 
MCP-1 
Blood 
Inflammation 
8-epi-prostaglandin F2α 
Urine 
Oxidative stress 
11-dehydrothromboxane B2 
Urine 
Platelet activation 
Physiological Assessments 
• FeNO 
• Blood pressure 
• Heart rate 
Subjective Measures 
• PSCDI/PSECDI 
• Cough Questionnaire 
• QSU-Brief 
• MTWS-R 
• PES 
• Product Liking Questionnaire 
• Future Intent to Use Questionnaire  
• Product and Health Effect Perceptions Questionnaire 
Product Use 
Daily in-clinic product use documented by the clinic staff: 
• Number of cigarettes smoked 
• Number of myblu™ pods started 
• myblu™ pod weight change (for pods used during the 24 hour urine collections) 
• Day 3 and Day 29 product preference selection 
Daily product use endpoints documented by subjects (Day 3 through study discharge on 
Day 57): 
• Number of cigarettes smoked 
• Number of myblu™ pods started 
• Number of puffs from the myblu™ product daily (< or ≥ 50 puffs) 
Nicotine PK Assessments 
Product use during each product use session: 
• Number of puffs taken 
• myblu™ and JUUL® pod weight change 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 38 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
PK parameters during each product use session: 
• Cmax 
• AUC0-t 
• Tmax 
Urge to smoke parameters during each product use session: 
• Maximum reduction from baseline score (Emax_R) 
• Time of the Emax_R (TEmax) 
• Area under the change from baseline “Urge to Smoke” VAS score versus time curve 
(AUEC_BL) 
Other Compliance Assessments 
• Exhaled CO 
• Urine cotinine  
Safety 
Safety assessments will include physical examinations, vital signs, ECGs, clinical laboratory 
tests, lung function, pregnancy tests, AEs, and use of concomitant medications.  
3. SUMMARY OF STUDY DESIGN 
3.1 
Design and Procedures 
This will be an open-label, partially-randomized, parallel-arm, multi-site study in healthy 
adult smokers, consisting of the main study and a PK sub-study.  
The main study will assess BoE, BoPH, physiologic effects, and subjective effects with use 
of myblu™ e-cigarettes relative to continuing to smoke combustible cigarettes. To account 
for potential attrition, up to 175 subjects are planned to be randomized into the myblu™ arm 
(with approximately 43 subjects intended to be assigned to each myblu™ e-liquid) and up to 
40 subjects will be randomized into the continue-smoking arm. Baseline study assessments 
will be made during use of subjects’ usual brand combustible cigarettes during the initial test 
visit through the morning of Day 1. All subjects in the myblu™ and continue-smoking arms 
will return to the clinic site for test visits scheduled to occur on Days 14, 28, 42, and 56 for 
post-baseline study assessments, compliance checks, and product dispensing and return. The 
subset of subjects participating in the PK sub-study (described below) will also complete 
selected biomarker assessments (NNAL, NNN, 3-HPMA, CEMA, HMPMA, S-PMA, 
nicotine equivalents) on Days 3 and 4. 
Subjects randomized to the myblu™ arm will participate in an in-clinic product acclimation 
period from Days 1 to 3. The acclimation period will afford the subjects the opportunity to 
try each of the four myblu™ e-liquids in order to become accustomed to their use and to 
determine those that they would be willing to use during the study. Initial product assignment 
for each subject will be based on preference as a method to enhance compliance. To further 
improve compliance through Day 56, at the end of Test Visit 3, subjects using a myblu™ 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 39 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
product may be allowed to choose to switch to the alternate nicotine strength of their current 
flavor, to switch to the alternate flavor with the same nicotine strength as their initial choice, 
or to continue using the same e-liquid selected initially. This method for initial flavor 
assignment and the opportunity to re-select after 28 days of use is based on natural 
experimentation that consumers experience when choosing an e-cigarette flavor. 
The PK sub-study will assess nicotine uptake and urge to smoke from the myblu™ products 
relative to combustible cigarettes and an e-cigarette comparator (JUUL®). A subset of up to 
20 subjects assigned to each of the myblu™ e-liquids, 20 subjects from the continue-smoking 
arm, and all 20 subjects in the JUUL® arm will participate. Subjects in the JUUL® arm will 
begin using the product after check-in for Test Visit 1 and will continue to use the product 
through discharge on Day 1 from the study following the PK assessment (subjects in the 
JUUL® arm will only participate in the PK sub-study). PK assessments will be preceded by a 
minimum 10-hour abstention from product use and will take place on Day 1 for the JUUL® 
and continue-smoking arms, and on Day 5 for the myblu™ arm. Product use for the PK 
assessments will consist of two sessions: 1) a fixed puffing session in the morning consisting 
of 10 puffs taken at 30 second intervals, with puffs 3 seconds in duration, and 2) an ad 
libitum use session beginning 6 hours after the start of the morning session and consisting of 
unlimited use of the e-cigarette product for 5 minutes or one cigarette, with no limits on puff 
duration or inter-puff interval. No product use of any kind will be allowed between the 
sessions. E-cigarette pods used for each session will be weighed before and after use to 
measure the amount of e-liquid used. 
All product use during confinement will be documented by the clinic staff. Subjects in the 
myblu™ and continue-smoking arms will be required to self-report product use from Day 3 
through discharge from the study. 
Exhaled CO and urine cotinine measurements will be used to confirm smoking/nicotine use 
status prior to Day 1 and to assess subject compliance with product assignment requirements 
thereafter. 
The clinic staff will contact all subjects via a telephone call approximately 14 days after 
discharge from the study (either as scheduled or after early termination) for reporting of AEs 
and use of concomitant medications. 
Screening safety evaluations will include a physical examination, vital signs, ECG, clinical 
laboratory tests (clinical chemistry, hematology, urinalysis, and serology), lung function, 
urine drug tests, urine cotinine tests, and alcohol breath tests, FSH tests (post-menopausal 
females) and serum and urine pregnancy tests (females only). On-study safety evaluations 
will include a symptom-driven physical examinations, vital signs, ECG, clinical laboratory 
tests (clinical chemistry, hematology, and urinalysis), lung function, and urine pregnancy 
tests (females only). AEs spontaneously reported by the subjects or observed by the 
Investigator or other study personnel will be documented and monitored from the time of 
first product use after successful completion of the check-in events for Test Visit 1 through 
the end of the Follow-up Period. Any prior and concomitant medications taken from 30 days 
prior to Screening through the Follow-up Period will also be recorded. 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 40 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
3.2 
Justification for Study Design 
A parallel study design was chosen due to the length of the exposure period. The 
continue-smoking arm is included as a control group to account for natural variations in 
responses associated with participation in a long-term clinical trial.  
Subjects randomized to receive a myblu™ product will be assigned to an e-liquid flavor 
based upon their preference established during the acclimation period and may be allowed to 
switch flavors after a period of approximately 28 days. This method was chosen to emulate a 
natural condition whereby consumers initially experiment with e-liquid flavors in the market 
before selecting a product for long-term use, and then have the option to switch among other 
flavors and nicotine strengths in the market as their needs change. 
A previous study demonstrated that switching to an early version of the blu product resulted 
in decreases in BoEs in as few as 5 days (O'Connell et al. 2016). The current study will be 
primarily conducted in a less-controlled ambulatory environment over a longer period of time 
to determine whether reductions can be maintained when subjects have access to combustible 
cigarettes. A longer assessment period also provides for a more comprehensive assessment of 
subjective effects and impressions of the study products. 
4. STUDY POPULATION 
Subjects selected for this study will be identified via standard recruitment methods. 
4.1 
Inclusion Criteria 
Subjects must fulfill all of the following inclusion criteria to be eligible for participation in 
the study. 
1. Healthy, adult, male or female smoker, 21 to 65 years of age, inclusive, at Screening. 
2. Reports smoking an average of 5 or more machine-manufactured non-menthol or 
menthol combustible CPD for at least 1 year prior to Screening. Brief periods of 
non-smoking (e.g., up to ~7 consecutive days due to illness, trying to quit, participation 
in a study where smoking was prohibited) during that time will be permitted at the 
discretion of the Investigator. 
3. Has a positive urine cotinine test (approximately 200 ng/mL using NicAlert, Accutest 
Urine Cotinine Test, or other test that provides a similar level of sensitivity, the same 
type of kit will be used at each site) at Screening and check-in for Test Visit 1. 
4. Has an exhaled CO > 10 ppm at Screening and check-in for Test Visit 1. 
5. A female subject of childbearing potential must have been using 1 of the following forms 
of contraception and agree to continue using it through completion of the study: 
• hormonal (e.g., oral, vaginal ring, transdermal patch, implant, or injection) 
consistently for at least 3 months prior to check-in for Test Visit 1; 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 41 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
• double barrier method (e.g., condom with spermicide, diaphragm with spermicide) 
consistently for at least 14 days prior to check-in for Test Visit 1; 
• intrauterine device for at least 3 months prior to check-in for Test Visit 1; 
• a partner who has been vasectomized for at least 6 months prior to check-in for Test 
Visit 1; 
• abstinence for at least 14 days prior to check-in for Test Visit 1 through discharge 
from the study. 
6. A female subject of non-childbearing potential must have undergone one of the following 
sterilization procedures at least 6 months prior to check-in for Test Visit 1: 
• hysteroscopic sterilization; 
• bilateral tubal ligation or bilateral salpingectomy; 
• hysterectomy; 
• bilateral oophorectomy;  
Or be postmenopausal with amenorrhea for at least 1 year prior to check-in for Test Visit 
1 and follicle-stimulating hormone (FSH) level consistent with postmenopausal status. 
7. Is willing to comply with the requirements of the study, including a willingness to use 
alternative tobacco products as required by the protocol. 
8. Has daily access to text messaging capable cellular phone for daily product use reporting. 
9. Provides voluntary consent to participate in this study documented on the signed 
informed consent form (ICF). 
4.2 
Exclusion Criteria 
Subjects may be excluded from the study if there is evidence of any of the following criteria 
during Screening or check-in for Test Visit 1, as applicable. 
1. Has a history or presence of clinically significant gastrointestinal, renal, hepatic, 
neurologic, hematologic, endocrine, oncologic, urologic, pulmonary (especially 
bronchospastic diseases and asthma), immunologic, psychiatric, or cardiovascular 
disease, or any other condition that, in the opinion of the Investigator, would jeopardize 
the safety of the subject or impact the validity of the study results. 
2. Has a clinically significant abnormal finding on the physical examination, medical 
history, vital signs, ECG, or clinical laboratory results, in the opinion of the Investigator. 
3. Has a positive test for human immunodeficiency virus (HIV), hepatitis B surface antigen 
(HBsAg), or hepatitis C virus (HCV). 
4. Has had an acute illness (e.g., upper respiratory infection, viral infection) requiring 
treatment within 14 days prior to Test Visit 1. 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 42 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
5. Has a fever (> 100.5°F) at Screening or check-in for Test Visit 1. 
6. Has a body mass index (BMI) greater than 40.0 kg/m2 or less than 18.0 kg/m2 at 
Screening. 
7. Has a history of drug or alcohol abuse within 24 months of Screening, as determined by 
the Investigator. 
8. Has a systolic blood pressure < 90 mmHg or > 150 mmHg, diastolic blood pressure 
< 40 mmHg or > 95 mmHg, or heart rate < 40 bpm or > 99 bpm at Screening. 
9. Has a post-bronchodilator forced expiratory volume in 1 second to forced vital capacity 
(FEV1:FVC) ratio < 0.7 and FEV1 < 80% of predicted at Screening. 
10. Has a post-bronchodilator FEV1 increase ≥ 12% and > 200 mL from pre- to post-
bronchodilator at Screening. 
11. Is allergic to propylene glycol or glycerin. 
12. Has an estimated creatinine clearance < 70 mL/minute (using the Cockcroft-Gault 
equation) at Screening. 
13. Has a positive urine drug or alcohol breath test at Screening or check-in for Test Visit 1. 
14. If female, the subject is pregnant, lactating, or intends to become pregnant during the 
time period from Screening through the duration of the study.  
15. Has taken medication for depression or asthma within 12 months of check-in for Test 
Visit 1. 
16. Has used prescription anti-diabetic medication and/or insulin therapy within 12 months of 
check-in for Test Visit 1. 
17. Has used medications known to interact with cytochrome P450 (CYP) 2A6 (including, 
but not limited to, amiodarone, desipramine, isoniazid, ketoconazole, miconazole, 
phenobarbital, rifampin, tranylcypromine, methoxsalen) within 3 months prior to check-
in for Test Visit 1.  
18. Has used medications known to impact HDL-C (including, but not limited to, “statins”, 
ezetimibe, fenofibrate, gemfibrozil, niacin) within 3 months prior to check-in for Test 
Visit 1. 
19. Has used inhalers to treat any chronic medical condition within 3 months prior to check-
in for Test Visit 1. 
20. Has used nicotine-containing products other than manufactured cigarettes 
(e.g., e-cigarettes, roll-your-own cigarettes, bidis, snuff, nicotine inhaler, pipe, cigar, 
chewing tobacco, nicotine patch, nicotine spray, nicotine lozenge, or nicotine gum) 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 43 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
within 14 days prior to check-in for Test Visit 1. 
21. Has received any medications or substances (other than tobacco) which interfere with the 
cyclooxygenase pathway (e.g., anti-inflammatory drugs including aspirin and ibuprofen) 
within 7 days prior to check-in for Test Visit 1. 
22. Has used methylene blue within 7 days prior to check-in for Test Visit 1. 
23. Has used any prescription smoking cessation treatments, including, but not limited to, 
varenicline (Chantix®) or buproprion (Zyban®) within 3 months prior to check-in for Test 
Visit 1. 
24. Is a self-reported puffer (i.e., adult smokers who draw smoke from the cigarette into the 
mouth and throat but do not inhale). 
25. Is postponing a planned smoking quit attempt in order to participate in the study. 
26. Has donated plasma within 7 days prior to check-in for Test Visit 1.  
27. Has donated blood or blood products (with the exception of plasma as noted above), had 
significant blood loss, or received whole blood or a blood product transfusion within 
56 days prior to check-in for Test Visit 1. 
28. Has participated in a previous clinical study for an investigational drug, device, biologic, 
or tobacco product within 30 days prior to check-in for Test Visit 1. 
29. Is or has a first-degree relative (e.g., spouse, parent, sibling, child) who is a current or 
former employee of the tobacco or e-cigarette industry or is a named party or class 
representative in litigation with the tobacco or e-cigarette industry. 
30. Is or has a first-degree relative (e.g., spouse, parent, sibling, child) who is a current 
employee of one of the clinic sites.  
31. Is or has a first-degree relative (e.g., spouse, parent, sibling, child) who is a current 
employee of the Sponsor.  
32. Has previously taken part in (from completion of any baseline measurements), has been 
withdrawn from, or has completed this study. 
33. Has previously been diagnosed with any form of cancer, except for basal cell or 
squamous epithelial carcinomas of the skin that have been resected at least 1 year prior to 
Screening 1. 
34. In the opinion of the Investigator, the subject should not participate in this study. 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 44 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
4.3 
Study Restrictions 
4.3.1 Food, Beverages, and Activity 
Subjects will be advised of the following study restrictions. 
• Alcohol should be avoided for 48 hours prior to Screening and Test Visits 1, 3, and 5. 
• Foods containing poppy seeds should be avoided for 48 hours prior to Screening and 
Test Visit 1 to avoid exclusion for a positive urine drug test. 
• Subjects randomized to the myblu™ and continue-smoking arms will be advised to 
avoid eggplant, meats cooked at high temperatures (e.g., barbecued, grilled, or pan-
fried), cured sandwich meats, bacon, salami, and sausages for 2 days prior to Test 
Visits 1, 3, and 5 and during confinement.  
• Strenuous physical activity which could cause muscle aches or injury, including contact 
sports should be avoided for 48 hours prior to Screening and Test Visits 1, 3, and 5 and 
during confinement. 
• Donation of blood or blood products, other than for the purpose of this study, should be 
avoided from Screening through Test Visit 5. 
Subjects will be asked to report violations of this advice. 
Exceptions of the above study restrictions may be permitted at the discretion of the 
Investigator and will be documented. 
4.3.2 Medications 
Medication use will be assessed to satisfy the inclusion and exclusion criteria. All 
medications (and reasons for their use) taken from 30 days prior to Screening through the 
Follow-up Period will be recorded. Except for those medications noted in the exclusion 
criteria, prescription or over-the-counter medications required to treat an 
Investigator-approved disease or condition are permitted at the discretion of the Investigator. 
Hormonal contraceptives (e.g., oral, vaginal ring, transdermal patch, implant, injection) and 
hormonal replacement therapy are permitted. Use of over-the-counter analgesics 
(e.g., acetaminophen), antihistamines, nasal decongestants, and dietary supplements are 
permitted.  
Use of anti-inflammatory medications (e.g., ibuprofen) and methylene blue should be 
avoided for 7 days prior Test Visits 1, 3, and 5 as these medications may interfere with 
biomarkers being assessed. Decisions to use other concomitant medications (including, but 
not limited to, those known to impact HDL-C or to interact with CYP2A6; taken for 
depression, asthma, chronic obstructive pulmonary disease, or diabetes; smoking cessation 
and nicotine replacement therapy products; or inhalers) during the study will be made in the 
best interest of the health of the subject. If other drug therapy is required, a joint decision will 
be made by the Investigator and Sponsor to continue or discontinue the subject. Exceptions 
may be permitted at the discretion of the Investigator in consultation with the Sponsor (or 
Sponsor designee), providing the medication in question would have no impact on the study. 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 45 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
Any exceptions will be documented and required medications that might impact study 
endpoints should be considered during interpretation of the study results. 
4.3.3 Tobacco Use 
Except as required by the study, consumption of other tobacco- or nicotine-containing 
products should be avoided during the entire duration of the study from screening through 
discharge from the study. 
Use of tobacco or nicotine-containing products other than those consistent with the 
randomization will not necessarily lead to discontinuation of the subject, though subjects will 
be encouraged to comply with the randomization requirements. During each Test Visit, the 
clinic staff will stress the importance of compliance with the study requirements and honestly 
reporting product use. Subjects will be reminded that the study procedures will provide an 
indication of compliance with the study requirements (for example, exhaled CO results may 
be provided to the subjects during the compliance discussion).  
Use of any tobacco or nicotine containing products other than combustible cigarettes or the 
test products will be documented as protocol deviations. However, combustible cigarette use 
by subjects in the myblu™ arm during the ambulatory periods will not be documented as 
protocol deviations.  
4.4 
Subject Early Discontinuation or Withdrawal 
Subjects will be advised that they are free to withdraw from the study at any time. In 
addition, subject participation in this study may be discontinued for any of the following 
reasons: 
• AEs 
• Lost to follow-up 
• Non-compliance with study procedures 
• Protocol violations 
• Study terminated by Sponsor, US FDA, or other regulatory authorities 
• Withdrawal of consent 
• Investigator’s discretion, including a severe laboratory abnormality or other medical 
condition that indicates to the Investigator that continued participation is not in the 
best interest of the subject 
Protocol deviations/violations should not lead to subject withdrawal unless they indicate a 
significant risk to the subject’s safety or jeopardize the scientific integrity of the study. 
If premature withdrawal from the study occurs for any reason, the Investigator must 
determine the primary reason and record this information in the electronic case report form 
(eCRF). Additionally, subjects withdrawing after first use of study product according to the 
randomization requirements will undergo all discharge safety procedures as feasible and as 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 46 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
deemed necessary by the Investigator and will be contacted approximately 14 days after early 
termination to determine if any AE has occurred since the last study visit. 
A subject withdrawn from the study due to any AE or clinically significant abnormal 
laboratory test values will be evaluated by the Investigator or other monitoring physician and 
will be treated and/or followed up until the symptoms or values return to normal or 
acceptable levels, or until lost to follow-up, as appropriate in the opinion of the Investigator. 
If a subject becomes lost to follow-up, a reasonable effort will be made to contact the subject 
and perform the end-of-study safety procedures noted in the Study Events tables. A 
reasonable effort is considered, at minimum, two attempts via telephone (at least 1 day apart) 
followed by a certified letter to the subject’s last known address requesting their return to the 
clinic site for a safety evaluation and return of any study products. 
Subjects withdrawing or removed from this study cannot re-enter. 
4.5 
Subject Randomization and Product Assignments 
Each subject will be assigned to a study arm (myblu™, continue-smoking, JUUL®) according 
to the randomization plan. The study arms will be stratified by sex (male or female) and age 
class (≤ 40 years of age, > 40 years of age). Each sex and age class should not account for 
more than 65% of the randomized population in each arm, and the Caucasian race should not 
comprise more than 80% of the randomized population in each arm. For logistical and 
operational reasons, the first subject in each sex-age class stratum who successfully 
completes the screening procedures at each site may be assigned to the JUUL® arm. 
For the main study, a sufficient number of subjects are intended to be randomized to better 
ensure that at least 29 subjects in each of the myblu™ e-liquids and the continue-smoking 
arm complete the Day 28 study assessments. To account for potential attrition, up to 
175 subjects are planned to be randomized into the myblu™ arm (with approximately 
43 subjects intended to be assigned to each myblu™ e-liquid) and up to 40 subjects will be 
randomized into the continue-smoking arm. Assignment of subjects to a specific myblu™ 
product will be based on subject product preference. An attempt will also be made to apply 
the sex and age class stratification to each product in the PK sub-study, though the same 
potential challenges will apply. 
For the PK sub-study, up to 20 subjects assigned to each myblu™ e-liquid, 20 subjects in the 
continue-smoking arm, and all 20 subjects in the JUUL® arm will be selected to participate. 
An attempt will also be made to apply the sex and age class stratification to each product in 
the PK sub-study, though the same potential challenges will apply. 
Subjects randomized to the myblu™ or continue-smoking arms must not be informed of their 
arm assignment until completion of baseline assessments to avoid changes in behavior that 
might impact those assessments. Therefore, subjects should be prepared to stay in the clinic 
through Day 5 with the understanding that they may be discharged from the test visit early 
depending on which arm to which they are randomized. As subjects in the JUUL® arm will 
only participate from Days -2 through 1, these subjects may be informed once the assignment 
is made. 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 47 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
4.6 
Replacement Subjects 
Subjects withdrawn or removed from the study may be replaced at the discretion of the 
Sponsor in order to better ensure that the intended subject completion target is reached. If 
replacement subjects are used, the replacement should be made with subjects matching the 
sex, age class, and race of the subject being replaced, if possible. Replacement subjects will 
be assigned a randomization number 100 higher than the subject being replaced.  
5. STUDY PRODUCTS 
5.1 
Description of Study Products 
The following products will be used during this study: 
Arm 
Product 
Designation Study Product Name 
A 
A 
myblu™ system with Tobacco Chill flavor Intense Liquidpod, 2.5% 
nicotine 
B 
myblu™ system with Tobacco Chill flavor Intense Liquidpod, 4.0% 
nicotine 
C 
myblu™ system with Honeymoon flavor Intense Liquidpod, 2.5% 
nicotine 
D 
myblu™ system with Honeymoon flavor Intense Liquidpod, 4.0% 
nicotine 
B 
E 
Usual brand combustible cigarettes 
C 
F 
JUUL® system with Virginia Tobacco Flavor JUULpod, 5.0% 
nicotine 
5.1.1 Test Product 
myblu™ is a two-piece closed system available in the US market. The myblu™ system is 
comprised of a rechargeable 350 mAh battery and a disposable pod. The pods connect 
directly and contain the mouthpiece, heating element, are pre-filled with e-liquid, and are 
compatible only with myblu™ batteries. During use, a consumer inhales through the 
mouthpiece and a sensor in the battery detects the change in air pressure which activates the 
heating element. The e-liquid heats to an aerosol which the consumer inhales.  
The battery is charged with a micro-USB charger and produces a typical output of 3.7V 
(maximum 3.9V). The pods contain 1.5 mL of e-liquid which lasts approximately 200 puffs, 
depending on individual use behaviors. Each e-liquid contains a mixture of glycerin, 
propylene glycol, nicotine-lactic acid salt, and a proprietary blend of flavors.  

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 48 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
The Tobacco Chill and Honeymoon Intense e-liquids are available in the US market. 
5.1.2 Control Product 
Usual brand combustible cigarettes will serve as the control product. Subjects will supply 
their own usual brand combustible cigarettes for use during the study. There will be no 
limitation on brand, brand style, or cigarette size; however, they must be machine-
manufactured and commercially available in the US market. Each subject’s usual brand 
combustible cigarette will be documented at Screening and will be updated at subsequent 
visits as necessary. 
5.1.3 Comparator Product 
The JUUL® Virginia Tobacco product was chosen as a similar, pod-based, closed-system in 
the e-cigarette category currently in the US market. According to the company website 
(www.juul.com), JUUL® e-liquids contain propylene glycol, glycerin, benzoic acid, nicotine, 
and natural and artificial flavor ingredients. 
5.2 
Study Product Accountability 
The staff at each site will coordinate shipping of the myblu™ products from the Sponsor (or a 
distribution vendor). JUUL® products will be obtained from commercial sources. The clinic 
staff will document the date products were received and recorded in the inventory records, 
the content of all shipments received, the total number of products dispensed during the 
study, and the total number of products remaining at the end of clinical conduct. 
Appropriate documentation of the receipt and return of products supplied by subjects must 
also be kept. Subjects will be required to provide enough unopened packs of their usual brand 
cigarettes for use during the test visits (calculated as cigarettes smoked per day times the 
number of days in confinement, rounded up to the next pack, plus two packs). Cigarette 
packages that have been opened prior to check-in for the test visit are not to be accepted for 
use in the clinic and subjects will be reminded of this requirement during the reminder phone 
call. If a subject presents to a test visit with only opened packages, presents to the clinic with 
an insufficient supply based on reported CPD, or if the subject runs out of cigarettes during 
the confinement period, the subject or site should purchase a sufficient number of packages 
for use and this information will be documented appropriately. Unused cigarettes will be 
returned to the subjects in the continue-smoking arm at discharge for each confinement test 
visit and to the myblu™ and JUUL® arms at discharge from the study.  
For each subject, dispensing records for in-clinic use must include the date and time study 
products were dispensed and returned, or in the case of the PK sessions, the start and stop 
time of the session. If a subject mistakenly disposes of a product, a reasonable effort should 
be made to retrieve the product. If retrieval is not possible, the approximate time that use of 
the product was finished and a description of the occurrence should be noted in the source 
documents. The subject will be advised that further disposal may result in dismissal from the 
study. Reconciliation of the dispensed and returned products should be completed to ensure 
adequate accountability of the products. If a daily allotment of products is transferred to the 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 49 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
clinic from a central storage location (e.g., site pharmacy or product storage room), the 
number of products transferred from and back to the central storage location must be 
documented. Only one product at a time may be dispensed to a subject. 
For each subject, dispensing records for at-home use of the myblu™ products will include the 
date and time of dispensing, the number of products dispensed, the number of unused 
products returned, and where appropriate, the number of and reason for missing or lost 
products. Subjects will be asked to return used pods, but the number returned will not be used 
for accountability purposes. Used pods may be disposed of by the site. 
5.3 
Study Product Storage 
All products will be stored in a locked, limited-access area in the clinic site (e.g., pharmacy 
or other storage area) and kept at controlled room temperature (defined as 20 - 25°C 
[68 - 77°F], with excursions permitted to 15 - 30°C [59 - 86°F]), until dispensed to the clinic 
for daily subject use or to the subjects for ambulatory use. Subjects will be advised to store 
the products at room temperature during ambulatory periods, to avoid prolonged exposure at 
temperature extremes, and to keep the products out of the reach of children during the 
ambulatory periods. 
During each day of the confinement periods, a sufficient supply for each subject may be 
transferred and kept in a secure area in the clinic (e.g., locked drawer or cupboard) as 
necessary.  
5.4 
Study Product Dispensing 
Study products (including the myblu™ batteries, pods, and USB chargers, usual brand 
cigarettes, and JUUL® products) will be dispensed for use during the confinement and 
ambulatory periods by the Investigator or an appropriate designee in accordance with the 
protocol, the site’s usual dispensing process, and any required local regulations. Individual 
study product dispensing records for confinement and ambulatory periods will be maintained 
by the clinic site for each subject as appropriate. 
Care should be taken when repackaging the study products to avoid exposure to air and 
moisture to the extent possible. Appropriate protection (e.g., gloves) should be considered 
when handling the products. 
Female subjects should not be provided study products at any test visit until a negative 
pregnancy result has been obtained.  
5.4.1 Confinement Periods 
Instructions on the proper use of the myblu™ and JUUL® products will be provided prior to 
use, and subjects will demonstrate an understanding of the instructions. All myblu™ and 
JUUL® products will be provided assembled, charged, and ready for use during confinement. 
On Days 1 through 3, myblu™ pods should be used until the contents are fully consumed at 
which time a new pod will be provided. On Days -2 and -1, JUUL® pods should be used until 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 50 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
the contents are fully consumed. Fresh myblu™ and JUUL® pods will be provided for use 
during each PK session. Any product failures will be reported to the clinic staff and 
documented, and the product will be immediately replaced. 
Except for use during the PK sessions, study products will be dispensed by the clinic staff 
upon subject request and subjects will be instructed to return the study products (e-cigarettes 
or cigarette butts) when they are finished using them. Only one combustible cigarette may be 
dispensed at each request. Use during the PK sessions will be under a controlled regimen or 
ad libitum as described in Section 6.7.1. 
5.4.2 Ambulatory Periods 
Only myblu™ products will be dispensed by the staff for use during the ambulatory periods. 
All myblu™ products for use during ambulatory periods will be packaged and labeled with, 
at minimum, the product identifier, the subject number, protocol number, date of dispensing, 
statements of “For investigational use only” and “Keep out of reach of children”, and any 
other information as required by local law. 
Prior to discharge from Test Visit 1, subjects in the myblu™ arm will be dispensed two 
batteries (batteries used during the confinement period may be re-dispensed), an initial 
supply of 22 pods of the assigned e-liquid, and necessary accessories for use through Day 14. 
The number of pods dispensed at subsequent visits will be based on the subject’s prior daily 
use. All used and unused pods will be returned to the clinic site at each subsequent Test Visit. 
Unused pods may be re-dispensed provided any applicable expiration date will not be 
exceeded. 
Subjects will be reminded to keep the study products out of the reach of children and to not 
share the study products with anyone. Subjects will also be reminded at each dispensing that 
they are expected to exclusively use the test products without dual use of combustible 
cigarettes. Subjects will be instructed to contact the clinic site if they believe that they will 
run out of pods or if the products fail to work properly, and will make arrangements to obtain 
additional supplies. The clinic staff will be required to document as deviations any days 
during which subjects report being without sufficient working study supplies. 
5.5 
Test Product Failure and Misuse 
Any occurrence of test product failure or misuse by subjects will be documented. 
5.6 
Test Product Return/Destruction 
All unused myblu™ and JUUL® products and components remaining at the end of the study 
will be returned or destroyed according to the Test Product Manual. All returns or destruction 
of products will be documented with shipping receipts or certificates of destruction which 
will be included in the site study file. 
Unused myblu™ and JUUL® products can only be destroyed after being inspected and 
reconciled by the study monitor or other Sponsor designee. 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 51 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
6. STUDY SCHEDULE AND PROCEDURES 
6.1 
Study Period Summaries 
6.1.1 Screening Period 
Potential subjects will undergo screening procedures within 28 days prior to check-in for 
Test Visit 1 to ensure that they meet the requirements for inclusion in the study. Pre-
screening of potential subjects according to a site’s usual processes may be completed to 
assess basic inclusion and exclusion requirements (e.g., demographics, smoking history, etc.) 
prior to the subject presenting to the clinic site for Screening. Screening visits will typically 
be scheduled in the morning, but may be scheduled according to the sites’ preference as long 
as all pre-study visit requirements (e.g., arriving having fasted) are followed. Re-checks of 
applicable screening events will be at the Investigators discretion and may occur at additional 
visits if necessary. A subject who begins screening procedures but fails to successfully satisfy 
the entry requirements of the study will be considered a “screen failure”. Subjects who fail 
screening may not re-screen. Subjects who initially pass screening procedures but who do not 
check-in within the allowed window may rescreen at the discretion of the Investigator and in 
consultation with the Sponsor.  
Subjects will be instructed to maintain their usual smoking behaviors prior to Screening and 
through check-in for Test Visit 1. 
All screening assessments must be performed after written informed consent is obtained. 
Unless indicated, the assessments may be performed without regard to specific timing 
relative to the other assessments. 
Table 4 
Screening Visit Schedule 
Time 
Procedures 
Comments 
 
Informed consent 
Must be obtained prior to completing 
the remaining assessments 
 
Screening demographics 
documentation/confirmation 
Any information collected during pre-
screening must be confirmed 
 
Urine collection for urinalysis, drug and 
cotinine tests 
Alcohol breath test  
Exhaled CO measurement 
Subjects must have negative drug and 
alcohol tests, and have acceptable urine 
cotinine and exhaled CO results prior to 
completing the remaining assessments. 
Exhaled CO should be measured within 
2 hours of check-in. 
 
Review of inclusion / exclusion criteria 
 
 
Medical history 
 
 
Prior and concomitant medication reporting 
 
 
Tobacco use history/usual brand cigarette 
documentation 
 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 52 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
Time 
Procedures 
Comments 
 
Physical examination 
 
 
Body weight/height/BMI 
 
 
12-lead ECG 
Subjects must be supine for at least 
5 minutes prior to measurement, must 
be collected at least 15 minutes after the 
last cigarette smoked. 
 
Vital signs 
Subjects must be seated for at least 
5 minutes prior to measurement, must 
be collected at least 15 minutes after the 
last cigarette smoked. 
 
Blood collection for clinical chemistry, 
hematology, serology, FSH (post-
menopausal females) and serum pregnancy 
test (females) 
Blood collection must be preceded by 
an 8-hour fast. 
 
Spirometry 
To be performed after completion of the 
assessments listed above, and must be 
preceded by a minimum 60-minute 
abstention from cigarette smoking. 
 
Review of tobacco and nicotine restrictions 
 
 
Smoking cessation information provided 
 
 
6.1.2 Baseline and Product Use Period 1 
Upon successful completion of Screening, subjects who continue to meet study requirements 
will be scheduled to check in to the clinic for Test Visit 1 on Day -2 at a time designated by 
the clinic staff (check-in for JUUL® arm should be as early in the day as possible to 
maximize the time to use the product) and will remain in the clinic until completion of all 
study events as required by their randomization arm. Reminder telephone calls will be made 
to the subjects 24 to 48 hours prior to the test visit. Subjects who fail the check-in 
requirements will be considered a “screen failure” and will be excluded from participation. 
For the myblu™ and continue-smoking arms, the Baseline Period will consist of the time 
between check-in and first product use on Day 1. The following table provides the general 
clinic schedule for Test Visit 1. The procedures listed should be performed for subjects as 
appropriate for the randomization arm. 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 61 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
Time* 
Procedures 
Comments 
After urine 
collection 
FeNO 
Must be preceded by a 
minimum 1 hour food and 
water restriction and a 30 
minute abstention from study 
product use. 
After FeNO 
Spirometry 
Must be preceded by a 
minimum 60 minute 
abstention from study product 
use. 
~18:00 
Discharge subjects  
Symptom-driven physical 
Vital signs 
12-lead ECG 
Provide smoking cessation information 
Subject cigarettes returned 
Discharge events may be 
completed prior to 18:00. 
Subjects must be seated for at 
least 5 minutes prior to vital 
signs measurement and supine 
for at least 5 minutes prior to 
ECG measurement, and both 
must be collected at least 
15 minutes after the last study 
product used.  
* For any procedures to be performed at home, subjects will be instructed to perform these 
procedures as close to the scheduled times as possible. Subjects will also record the exact 
clock time of performing the procedures. 
6.1.4 Follow-up Period 
All subjects will be contacted by telephone 14 days (± 2 days) following discharge from the 
study on Day 57 (or following early termination if deemed necessary in the opinion of the 
Investigator) to document the occurrence of AEs and the need for concomitant medications 
since the last clinic visit. The Investigator will determine whether additional follow-up will 
be necessary based on the outcome of this call. 
6.2 
Study Events 
6.2.1 Medical History 
Medical history is defined as any condition that started prior to Day -2. Relevant medical 
history, as determined by the Investigator or a qualified designee, will be documented at 
Screening and updated at Test Visit 1 as necessary.  
6.2.2 Demographics 
Basic demographic data and subject identification information, including sex, age (each 
subject must show proof of age with government-issued identification (ID) [e.g., driver’s 
license]), race, and ethnicity will be recorded for each subject at Screening.  

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 62 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
Additional demographic data, including income level, educational level, marital status, and 
gender choice (if self-determined to be different from sex), will be obtained during Test 
Visit 1.  
The demographics questionnaires are located in Appendix 1. 
6.2.3 Prior and Concomitant Medications 
Any prior and concomitant medications (with the exception of albuterol used during 
spirometry measurements) taken from 30 days prior to Screening through the Follow-up 
Period will be recorded. Subjects will be advised to report regular use of medications to the 
clinic staff as the need arises during the ambulatory periods. Occasional use of medications 
during the ambulatory periods may be reported at the next Test Visit. Details to be recorded 
include the drug name (generic and trade name if applicable), route of administration, total 
dose/unit, indication, start date, and stop date. Prior and concomitant medications will be 
coded using the World Health Organization (WHO) Drug Dictionary. 
6.2.4 Smoking History and Usual Brand Combustible Cigarette Documentation 
Smoking history will include the number of years the subject has smoked and the average 
number of cigarettes (single value, not a range) smoked per day during the past year.  
In addition, a color photocopy of each subject’s usual brand cigarette package will be 
obtained initially at the Screening. An updated photocopy will be taken and product 
characteristics documented if the subject’s usual brand changes during the study. The 
following characteristics of the usual brand product will be documented: brand, brand style, 
flavor, and cigarette length. A data collection form will be provided to the site.  
6.2.5 Tobacco/Nicotine Product Use History Questionnaire 
Subjects will be required to report previous tobacco-product and nicotine-product use 
histories during Screening and updated at Check-in for Test Visit 1 (if necessary) to satisfy 
the study inclusion and exclusion criteria. 
The Tobacco/Nicotine Product Use History Questionnaire is provided in Appendix 12. 
6.2.6 Physical Examination 
A standard physical examination assessing the general physical well-being will be performed 
at Screening. A symptom-driven physical examination will be conducted at other times to 
evaluate AEs. If no symptoms are present, an examination will not be required. 
6.2.7 Body Weight, Height, and BMI 
Body weight will be measured in light indoor clothing during Screening and Test Visits 1, 3 
and 5. Height and BMI will be documented during Screening. Measurements will be reported 
in metric units. BMI will be recorded as kg/m2. 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 63 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
6.2.8 Clinical Laboratory Tests 
All clinical laboratory tests will be conducted by a central laboratory facility accredited by 
the Centers for Medicare and Medicaid Services (Clinical Laboratory Improvement 
Amendments of 1988 [CLIA-88]) or at the clinic site. For inclusion into the study, values for 
the clinical laboratory parameters are to be within the laboratory normal ranges or deemed 
not clinically significant in the opinion of the Investigator.  
Clinical Chemistry 1 
Urinalysis 2  
Additional Tests 
• 
Albumin 
• 
Alkaline phosphatase 
• 
Alanine aminotransferase 
• 
Aspartate 
aminotransferase 
• 
Bicarbonate 
• 
Bilirubin 
• 
Blood urea nitrogen 
• 
Creatinine 
• 
Glucose 
• 
Potassium 
• 
Sodium 
• 
Total protein 
• 
Uric acid  
 
Hematology 
• 
Hematocrit 
• 
Hemoglobin 
• 
Platelet count 
• 
Red blood cell count 
• 
White blood cell count 
with differential 
 
• 
Bilirubin 
• 
Blood 
• 
Glucose 
• 
Ketones 
• 
Leukocyte esterase 
• 
Nitrite 
• 
pH 
• 
Protein 
• 
Specific gravity 
• 
Urobilinogen 
• 
Serology 
o HIV 
o HbsAg 
o HCV 
• 
FSH 
• 
Serum/urine pregnancy 3  
• 
Urine cotinine 4 
• 
Urine drug test 
o Amphetamines 
o Cannabinoids 
o Cocaine 
o Methamphetamine 
o Opiates 
• 
Alcohol breath test 
 1 Clinical chemistry tests will be performed after a minimum 8-hour fast; however, in case of 
dropouts or rechecks, subjects may not have fasted for 8 hours prior to the serum chemistry sample 
is taken and test results will be interpreted appropriately. 
2  A microscopic examination for red blood cells, white blood cells, bacteria, and casts will be 
performed if an abnormality is noted in leukocyte esterase, protein, blood, or nitrite. 
3  Human chorionic gonadotropin (females only). 
4  NicAlert, Accutest Urine Cotinine Test, or other screening kit providing real-time results with a 
similar level of sensitivity. The same type of kit will be used at each site. 
6.2.9 Exhaled Carbon Monoxide 
Exhaled CO levels will be measured using a Bedfont Micro+ Smokerlyzer, or similar device, 
within 2 hours of presentation to the study site at the Screening Visit and within 1 hour of 
presentation to the site at other Test Visits where noted. Measurements will be used to 
confirm eligibility prior to randomization and will be used as a measure of compliance 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 64 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
thereafter. Subjects may be provided their results during compliance discussions to 
demonstrate compliance/noncompliance. 
6.2.10 Vital Signs 
Vital signs (respiratory rate, heart rate, blood pressure, and oral temperature) will be 
measured at Screening, check-in and discharge for Test Visits 1, 3, and 5. Measurements will 
be taken after the subject has been in a seated position for at least 5 minutes and at least 
15 minutes after the last cigarette smoked or study product used. 
6.2.11 Electrocardiogram 
12-lead ECGs will be taken following resting in the supine position for at least 5 minutes and 
at least 15 minutes after the last cigarette smoked or study product used during Screening and 
at discharge from the study. ECGs will be interpreted, signed, and dated by the Investigator 
or a qualified designee. Clinic site reference ranges will be applied to all ECG parameters. 
The ECG machine will compute the PR and QT intervals, QT interval corrected for heart rate 
using Bazett’s (QTcB) formula, QRS duration, and heart rate and this information will be 
documented in the subject file. The ECGs will be interpreted as normal, having a clinically 
insignificant abnormality, or having a clinically significant abnormality. The overall 
interpretation will be noted in the eCRF. 
6.2.12 Lung Function (Spirometry) 
Subjects will undergo lung function testing at Screening to affirm eligibility (FEV1, 
FEV1:FVC ratio) and as a safety endpoint (FEV1, FVC, FEV1:FVC ratio, and forced 
expiratory flow (FEF)25-75%).  
Spirometry measurements will be conducted in accordance with the 2005 American Thoracic 
Society / European Respiratory Society Joint Task Force on the standardization of spirometry 
(Miller et al., 2005). The spirometry predicted values will be standardized by the Third 
National Health and Nutrition Examination Survey predicted set. Personnel performing 
spirometry tests must receive appropriate training and the spirometer must be kept calibrated 
as recommended by the manufacturer. 
The spirometry tests should be performed in a sitting position following at least 15 minutes 
of rest and at least 1 hour from the last cigarette smoked or last myblu™ product use. 
Spirometry must be performed after exhaled CO and FeNO measurements when these events 
are to be performed on the same day. Multiple measurements may be attempted, but no more 
than 8 test maneuvers should be performed during a test session. If a subject shows signs of 
fatigue during repeated testing, testing will be halted and further attempts will only be 
allowed at the Investigator’s discretion. 
The subjects will be instructed on how to correctly perform spirometry tests by appropriately 
trained personnel prior to the measurements being recorded. Spirometry measurements will 
be performed before and after administration of a short-acting bronchodilator (albuterol). 
Following acceptable pre-bronchodilator measurements, subjects will be administered 4 puffs 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 65 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
from an albuterol metered-dose inhaler at approximately 30 second intervals (~360 µg total 
dose assuming 90 µg per puff) using a spacer and a 5-second breath hold after each puff. 
Post-bronchodilator measurements will be made approximately 10 - 15 minutes following the 
last albuterol puff.  
Each clinic site will be responsible for procuring sufficient supplies to perform the 
spirometry measurements, including quantities of albuterol and any additional materials for 
its administration, and for keeping accurate documentation of accountability, 
dispensing/administration, and disposal of these items as appropriate.  
6.3 
Study Product Use and Reporting 
Subjects will never be forced to smoke or use any study product. 
All subjects will smoke their usual brand cigarette according to their usual smoking 
behaviors through check-in of Test Visit 1 and will be instructed to follow their 
randomization arm assignments through discharge from the study. However, subjects will be 
instructed to report use of any other tobacco- or nicotine-containing products.  
Each day from Day 3 through discharge from the study on Day 57, subjects randomized to 
the myblu™ arm will report the number of pods started, whether they took more than 
50 puffs from the myblu™ product, and the number of cigarettes smoked. Subjects 
randomized to the continue-smoking arm will report the number of cigarettes smoked each 
day from Day 3 through discharge from the study. Subject self-report will be via a text-
message system.  
Subjects will be instructed to report product failures to the clinic staff (to be documented by 
the clinic staff) and to temporarily stop use if they experience any signs of nicotine toxicity 
(such occurrences will be reported to the clinic staff and documented as AEs). 
6.3.1 Confinement Periods 
Areas dedicated to product use (within the clinic or outdoors) during the confinement periods 
must be in accordance with applicable state and local regulations governing the facility. All 
applicable regulations regarding indoor and outdoor smoking/study product use must be 
understood and followed by the Investigator. 
Dedicated space for use by product type (e-cigarette or combustible cigarette) during product 
use will be identified to minimize the potential for cross-contamination and illicit study 
product use. The subjects using an e-cigarette product should not have access to areas where 
smoking is allowed, and should not share confined sleeping quarters. If necessary, the clinic 
may schedule the study arms to be confined on separate days to alleviate these concerns. 
The clinic staff will provide a demonstration and training of the proper use and care of the 
myblu™ and JUUL® products before use by subjects in those respective arms, and subjects 
will demonstrate an understanding of the instructions. During the product training on the 
myblu™ product, subjects may sample each e-liquid if they choose to do so. 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 66 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
Generally, study product use will be ad libitum upon request to the staff following check-in 
through 23:00, except during certain events or as otherwise noted. All product use during the 
confinement periods will be documented by the clinic staff (i.e., each product check-out and 
return).  
Use of products during the PK product use sessions are described in Section 6.7.1. 
myblu™ Product Use 
Subjects randomized to the myblu™ arm will turn over all cigarettes to the clinic staff upon 
check-in on Day -2 and will smoke their usual brand cigarettes through 23:00 on Day -1. On 
the morning of Day 1, they will begin participation in a 3-day in-clinic product acclimation 
period through the evening of Day 3. The acclimation period will afford the subjects the 
opportunity to try each of the four myblu™ e-liquids in order to become accustomed to their 
use and to determine those that they would be willing to use during the study. Following 
product training on Day 1, subjects will use each of the four products individually for 
approximately 2 hours each, with the order of use selected by the subject. However, only one 
e-liquid may be used during each 2-hour period to ensure that subjects have an adequate time 
to try each. Following the last 2-hour period, subjects may choose any of the e-liquids freely 
through 23:00 on Day 2.  
At 20:00 on Day 2, subjects will complete the myblu™ Product Preference Questionnaire 
(Appendix 2). Subjects will rank in the order of preference those products that they would be 
willing to use through the end of the study. It should be emphasized that they should only 
rank those products that they would be willing to use. Initial product assignment for each 
subject will be made by the clinic staff based on preference. Beginning on the morning of 
Day 3, subjects will use the assigned e-liquid through Day 28. 
Subjects participating in the PK sub-study will continue to use the assigned product through 
the evening of Day 4. New pods will be issued for use during the 24-hour urine collection 
from the afternoon of Day 3 to Day 4. All pods used during the 24-hour urine collections will 
be weighed within 24 hours before and after use, with the weights documented. A new pod 
will be provided after completion of the urine collection. 
Upon presentation to the clinic for Test Visits 3 and 5, subjects will turn over to the clinic 
staff the myblu™ device. Prior to the start of the urine collection, subjects may use the same 
pod as was being used prior to presenting to the clinic and new pods will be issued for use 
during the 24-hour urine collection. All pods used during the 24-hour urine collections will 
be weighed within 24 hours before and after use, with the weights documented. A new pod 
may be used after completion of the urine collection if time allows for product use prior to 
discharge from the test visit. 
To further improve compliance through Day 56, during the Day 28 visit subjects using a 
myblu™ product may be allowed to choose to switch to the alternate nicotine strength of 
their current flavor, to switch to the alternate flavor with the same nicotine strength as their 
initial choice, or to continue using the same e-liquid selected initially. Subjects will be 
allowed a brief trial with the alternate products if desired. The site staff will document this 
use, but subjects will not need to report these as a part of their product use reporting. 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 67 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
Usual Brand Cigarette Use 
Subjects randomized to the continue-smoking arm will smoke their usual brand cigarettes 
throughout each confinement visit. Subjects will turn-over all cigarettes upon check-in to 
each test visit. 
JUUL® Product Use 
Subjects in the JUUL® arm will begin using the product following the demonstration and 
training on Day -2 and will continue to use the product through 23:00 on Day -1. Subjects in 
the JUUL® arm will not be allowed to smoke at any time from the time of check-in on Day -2 
through discharge on Day 1. 
6.3.2 Ambulatory Periods 
Study product use according to the randomization will be ad libitum during the ambulatory 
periods according to the subject’s usual smoking or e-cigarette use behaviors. Subjects are to 
follow the product use requirements of their respective randomization arm. 
6.3.3 Product Use Compliance 
Subject compliance with study product use and reporting is a critical component of this 
study, though 100% compliance from all subjects is an unrealistic expectation. Subjects in 
the myblu™ arm will be reminded at each dispensing for ambulatory use that they are 
expected to exclusively use the test products without dual use of combustible cigarettes, but 
that they should be honest about smoking combustible cigarettes as the laboratory 
assessments will detect use of these products.  
Subject self-reported product use will be used as a measure of compliance. The clinic staff 
will monitor the frequency with which subjects complete the daily product use entries 
leading up to each Test Visits 2 through 5 and will discuss with subjects any concerns about 
the entries (e.g., missed reporting, significantly abnormal product use entries). Subjects who 
complete the daily product use entries on less than 70% of the study days prior to a test visit 
will be reminded of the importance of documenting product use. Subjects who continue to 
regularly fail to complete the daily product use entries may be identified by the Investigator 
as individuals whose noncompliance may jeopardize the integrity of the study data. 
Disqualification for noncompliance with these product use requirements may only occur in 
consultation with the Sponsor. 
As solely relying on self-reported product use may lead to a conclusion of a higher rate of 
compliance than actually occurred, biochemical verification of compliance will also be used. 
While it is recognized that there are many other potential sources of CO and nicotine 
exposure, exhaled CO and urine cotinine will be used as methods of verifying compliance in 
real-time. Subjects with values inconsistent with their randomization arm (i.e., subjects in the 
myblu™ arm with exhaled CO values > 8 ppm or negative urine cotinine tests, subjects in the 
continue-smoking arm with exhaled CO values < 10 ppm or negative urine cotinine tests) 
will be questioned regarding their recent product use and any information provided will be 
documented in the subject file. Subjects will be reminded of the importance of compliance 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 68 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
with study instructions, including accurate reporting of other nicotine and tobacco products 
used.  
NNAL is a tobacco-specific nitrosamine with a longer half-life than CO, thus may provide an 
estimate of compliance over a long period of time by comparison of the post-baseline values 
to the baseline values. As this will be measured in a bioanalytical assay, real-time monitoring 
will not be possible and the verification will be completed at the end of the study. 
6.4 
Biomarker Sample Collection 
6.4.1 Blood 
Blood samples for COHb in whole blood (2 x 4 mL), sICAM in plasma (1 x 4 mL), WBCs in 
whole blood (measured in hematology sample), HDL-C in serum (1 x 3.5 mL), MCP-1 in 
serum (1 x 3.5 mL), and serum for bio-banking (up to 17 mL) will be collected during Test 
Visits 1, 3, and 5. Samples for COHb will be collected in the afternoon and samples for the 
other biomarkers and bio-banking will be collected following an overnight fast of at least 
8 hours.  
Up to approximately 118 mL of blood will be required for the planned assessments during 
the entire study. 
Detailed instructions for collection, processing, and shipping of blood samples will be 
provided separately. 
6.4.2 Urine 
24-hour urine collections for biomarker measurements will take place during Test Visits 1, 3, 
and 5. Each 24-hour urine collection will begin at a time following check-in and will end at 
the same time ± 30 minutes the following day. 
Subjects will be instructed as to urine collection methods. Subjects will be instructed to 
attempt to void prior to the beginning and at the end of each interval. All urine must be 
collected during the entire 24-hour interval. The start and stop time of each 24-hour interval 
and the total weight of the collection will be documented. The weight of the 24-hour urine 
collection containers will be documented prior to the collection (tare weight) and following 
completion of the collection. 
Urine will be refrigerated during the collection interval. Collections for each subject will be 
pooled periodically into one labeled container throughout the interval and the total weight (g) 
will be measured and recorded at the end of the 24-hour interval. Any missed voids will be 
documented, including the reason for missing. Aliquots will be prepared as noted in the 
following chart. 
At the discretion of the site, 24-hour urine collection during Test Visits 3 and/or 5 may be 
completed by subjects at home. Subjects will be provided the materials required and will be 
instructed on the at-home urine collection method. 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 69 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
Biomarker 
Number of Aliquots/ 
Volume Required 
Container 
Type 
Nicotine equivalents 
1-OHP  
8-epi- PGF2α  
11-DHTXB2   
Creatinine (for adjustment) 
2 aliquots of 5 mL each 
polypropylene  
NNAL / NNN   
MHBMA   
3-HPMA / CEMA / HMPMA   
S-PMA  
HEMA 
1-AN / 2-AN  
o-tol 
3-OH-B[a]P 
2 aliquots of 10 mL each 
UV shielded 
polypropylene 
Bio-banking 
2 aliquots of 300 mL each 
polypropylene 
 
All aliquots will be prepared within 120 minutes from end of the collection and will be stored 
at -20 ± 10°C until shipped for analysis. 
Detailed instructions for collection, processing, and shipping of urine samples will be 
provided separately. 
6.5 
Physiologic Assessments 
6.5.1 Fractional Concentration of Exhaled Nitric Oxide 
FeNO will be measured using a Niox Vero (or similar device) during Test Visits 1, 3, and 5. 
FeNO measurements will be preceded by a 30-minute (minimum) abstention from study 
product use. Water and food intake should be restricted for 1 hour prior to measurement. 
Subjects will be requested to rinse their mouths with water prior to the procedure. 
6.5.2 Blood Pressure and Heart Rate 
Blood pressure (systolic and diastolic) and heart rate measurements for physiologic 
assessment purposes will be taken from the Test Visit 1, 3, and 5 check-in vital signs 
measurements. 
6.6 
Subjective Measures 
The PSCDI/PSECDI, Cough Questionnaire, QSU-Brief, MTWS-R, PES, Product Liking 
Questionnaire, Future Intent to Use Questionnaire, and Product and Health Effect 
Perceptions Questionnaire will be completed during Test Visits 1, 3, and 5, as applicable, 
using an electronic device.  
All relevant software and staff training specific to the electronic questionnaires will be 
provided.  
All subjective measures questionnaires are provided in the Appendices 3 - 10. 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 70 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
At the discretion of the site, some or all questionnaires during Test Visits 3 and/or 5 may be 
completed by subjects at home. Subjects will be provided the materials required and will be 
instructed on the at-home questionnaire completion. 
6.7 
Nicotine Pharmacokinetics Assessments 
6.7.1 Product Use 
Product use for the PK assessments will consist of two sessions of use of the assigned study 
product (Day 1 for the continue-smoking and JUUL® arms, Day 5 for the myblu™ arm). The 
first session will be performed in the morning following an abstention from product use of at 
least 10 hours and will consist of a fixed puffing regimen of 10 puffs taken at 30-second 
intervals. Puff duration will be 3 seconds for the e-cigarette products and as desired for the 
combustible cigarette. The clinic staff will indicate to the subjects when to start and stop each 
puff. The second session will begin 6 hours following the start of the first session and will 
consist of ad libitum use of the e-cigarette product for 5 minutes or use of one cigarette, with 
no limits on the duration or inter-puff interval for any product. No product use of any kind 
will be allowed between the sessions. 
The clinic staff will document the start and stop time of each session, the number of puffs 
taken, and reasons for missed puffs during the fixed puffing session. Subjects assigned to an 
e-cigarette arm will be provided a fully charged battery with a fresh pod for each product use. 
Pods will be weighed within 24 hours before and after use with the weights documented in 
grams to 4 decimal places. Products that stop functioning should be replaced as soon as 
possible, with the failure documented.  
6.7.2 Nicotine Pharmacokinetic Blood Sampling 
A 4 mL blood sample for plasma nicotine analysis will be drawn into a plastic K2-EDTA 
(lavender top) vacutainer tube approximately 5 minutes prior to and at 3, 5, 7, 10, 12, 15, 20, 
30, 60, 120 and 180 minutes following the start of each product use episode, with allowable 
deviation windows of ± 30 seconds for the samples collected from 3 to 15 minutes, 
± 1 minute for the samples collected from 20 to 60 minutes, and ± 3 minutes for all other 
samples. 
Approximately 96 mL of blood will be required for the planned PK assessments. Additional 
blood (typically up to approximately 1 mL) may need to be collected during each time point 
for the purpose of clearing a blood collection device or line as necessary. 
The samples may be kept at room temperature prior to centrifugation, and within 60 minutes 
from collection will be centrifuged at approximately 1000 to 1300 RCF at ~5°C for 
approximately 10 minutes. After centrifugation, the plasma will be transferred to two 3.5 mL 
methanol prewashed polypropylene screw cap tubes, properly labeled, and then stored 
at -20°C (± 10°C) or below (within 120 minutes from collection) until shipped for analysis. 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 71 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
6.7.3 Urge to Smoke Assessment 
Urge to smoke will be assessed using a 100 mm VAS (Appendix 11) approximately 
10 minutes prior to and within approximately 30 seconds prior to the scheduled blood draws 
at 5, 10, 15, 30, 60, and 120 minutes following the start of the ad libitum product use 
sessions. 
6.8 
Other Clinical Considerations 
6.8.1 Meals 
Meals and snacks will be served at appropriate times during confinement as determined by 
the clinic, taking into account fasting requirements for endpoint assessments. In addition, 
subjects will fast for at least 1 hour prior to and 1 hour after the start of each PK product use 
session. Low-mutagen meals (e.g., no meats cooked at high temperatures [barbecued, grilled, 
or pan-fried], cured sandwich meats, smoked meats, bacon, salami, and sausages) should be 
served on days with urine collections for biomarkers. Eggplant is also not to be served during 
the confinement periods. Subjects will not be allowed to use study products during meals. 
Water will be provided as desired during the study, and subjects will be encouraged to 
maintain their usual hydration habits. Up to one caffeinated beverage per meal may be 
served. 
6.8.2 Reminder Phone Calls 
Reminder telephone calls should be made within 24 to 48 hours prior to each test visit to 
remind them of the date and time of the visits. Subjects should be reminded to maintain their 
usual smoking/vaping behavior prior to arrival at the clinic. Subjects required to bring their 
cigarettes to the clinic will also be reminded to bring only unopened packs to check-in for 
Test Visits 1, 3, and 5. 
6.9 
Adverse Events 
An AE is any untoward medical occurrence associated with the use of a study product, 
whether or not considered study product-related. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a study product, whether or not related to the study 
product. 
Details of the monitoring and reporting of AEs will be provided in the Safety Management 
Plan. 
6.9.1 Monitoring 
The subjects will be instructed to inform the study physician or staff of any AEs and 
intercurrent illnesses experienced during the trial. Additionally, a specific inquiry regarding 
AEs will be conducted at each scheduled clinic visit and during follow-up telephone calls. 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 72 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
The inquiry will be posed in a non-specific manner using open-ended questions so as not to 
bias the response (e.g., How are you feeling today?). 
A subject who has any clinically significant AE or clinically significant abnormal laboratory 
test value will be evaluated by the Investigator or other monitoring physician and will be 
treated and/or followed up until the symptoms or values return to normal or acceptable levels 
(as appropriate in the opinion of the Investigator), or until the subject is lost to follow-up. 
Where appropriate, medical tests and examinations will be performed to document resolution 
of the event(s). 
6.9.2 Reporting 
Events reported prior to use of study products on Day -2 will be documented as baseline 
signs and symptoms in the medical history. All events occurring after use of study products 
on Day -2 must be recorded on the eCRF as AEs. Documentation will include the date and 
time of onset, action taken, outcome (resolved, improved, unchanged, worse, fatal, or 
unknown/lost to follow-up), duration, relationship to product administration, and severity for 
each event. AEs will be coded using most current version of the Medical Dictionary for 
Regulatory Activities (MedDRA)® available at 
 
The Investigator will review each event and assess its relationship to product administration 
as unrelated, unlikely, possibly, probably, or likely. 
In addition, each sign or symptom reported will be graded on a 3-point severity scale using 
mild, moderate, or severe. 
6.9.3 Serious Adverse Events 
A SAE is any AE that in the view of either the Investigator (or designee) or Sponsor, results 
in any of the following outcomes: death, a life threatening AE, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions, or a congenital anomaly/birth 
defect. Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in the above definition. 
Life threatening is defined as an AE that in the view of the Investigator (or designee) or 
Sponsor, its occurrence places the subject at immediate risk of death. It does not include an 
AE that, had it occurred in a more severe form, might have caused death. 
Unexpected is defined as an AE that is not consistent with the known risk information 
associated with the study product. 
All SAEs, whether or not considered study-related, must be reported by telephone and by fax 
or e-mail to the Sponsor within 24 hours of the site’s learning of the SAE or, at the latest, on 
the following workday. The Sponsor’s representative to contact about this study is provided 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 73 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
in the list of study contacts. The Investigator must also inform the IRB, in compliance with 
GCP reporting guidelines, and the site monitor of any SAE. 
6.10 Pregnancy 
A positive pregnancy test prior to use of study products on Day -2 will result in the subject 
failing screening. A positive pregnancy test thereafter will be documented by the Investigator 
on the pregnancy form and will be documented as a protocol deviation. The Investigator or 
designee will discontinue the pregnant subject from the study and will advise her to seek 
prenatal care and counseling from her primary care provider. Pregnancy itself is not an AE.  
The clinic staff will request the pregnant subject to notify the site of the outcome of the 
pregnancy (i.e., birth, loss, or termination). To help ensure this, the clinic staff will follow up 
with the subject until the end of pregnancy, if in compliance with the site’s standard 
operating procedures (SOPs) and with the subject’s consent. This request and the subject’s 
response will be documented in the subject’s source document. 
6.11 Smoking Cessation Information 
At screening and prior to discharge from the study (or upon early termination) all subjects 
will be advised that to reduce the health effects of smoking, the best thing to do is to quit. 
Subjects will be referred to the Center for Disease Control and Prevention website for quit 
strategies (https://www.cdc.gov/tobacco/campaign/tips/quit-smoking) and will be encouraged 
to contact a qualified medical professional for additional advice on smoking cessation. 
7. DATA ANALYSIS 
Data will be handled and processed according to 
 SOPs, which are written based on 
the principles of GCP. A brief description of the statistical analysis is included below, 
detailed methodology for all summary and statistical analyses of the data collected in this 
trial will be documented in a statistical analysis plan (SAP) prepared by 
 and agreed 
upon by the Sponsor. The SAP may modify the plans outlined in the protocol; however, any 
major modifications of the primary endpoints and/or their analysis will also be reflected in a 
protocol amendment. If deemed appropriate, additional statistical analyses other than those 
described in this section may be performed and included in the plan. 
7.1 
Sample Size Estimation 
This study is prospectively powered to find significant decreases in the primary BoE in 
subjects who switch to myblu™ e-cigarettes for 28 days. 
Exclusive use of blu products during a 5-day in-clinic period was previously shown to reduce 
the primary BoE to be assessed in this study by ~60% to ~95% (O’Connell et al., 2016). In 
the same study, reducing cigarette consumption by ~30% of that during the baseline period 
resulted in ~13% to ~27% reductions. However, no published data are available for the 
current test products, or similar e-cigarette products, over a longer use period from which a 
sample size may be estimated for this study. Therefore, the sample size estimation was made 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 74 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
using Day 30 data from FDA Center of Tobacco Products Docket # FDA-2017-D-3001 
(study ZRHM-REXA-08-US) where the applicant assessed similar BoE in subjects who 
switched to a tobacco heating product or continued to smoke combustible cigarettes during 
an out-of-clinic product use period. 
Based on this previous data, a minimum of 29 subjects per cohort is estimated to be needed 
to find differences in the Day 28 S-PMA change-from-baseline value equivalent to a 50% 
reduction in biomarker value compared to the continue-smoking arm using one-sided 
significance level of 0.0125 (alpha of 0.05 adjusted for multiple comparisons using the 
Bonferroni method) with a power of at least 80%. Approximately 43 subjects are planned to 
be randomized into each myblu™ e-liquid cohort and 40 subjects into the continue-smoking 
arm to better ensure that the minimum number complete the Day 28 assessments. The 
following table provides the power estimate for each of the primary endpoint biomarkers 
assuming 29 subjects in the ITT population complete the study. 
Biomarker 
Test group 
baseline 
value 
Test group  
change-from-baseline 
SD 
Control group  
change-from-baseline 
SD 
Power 
COHb (% sat) 
6.95 
2.28 
1.73 
>0.9999 
NNAL (ng) 
340 
178 
133 
0.9623 
3-HPMA (µg) 
1325 
494 
500 
0.9968 
S-PMA (ng) 
3348 
2370 
1512 
0.8106 
The baseline and change-from-baseline SD values in this table were derived from study ZRHM-REXA-08-US 
in US FDA Center of Tobacco Products Docket # FDA-2017-D-3001 who had reported Baseline and Day 30 
measurements for the listed biomarkers. 
 
Abbreviations: 3-HPMA = 3-hydroxypropylmercapturic acid, COHb = carboxyhemoglobin, NNAL = 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, SD = standard deviation, S-PMA = S-phenyl mercapturic acid. 
 
7.2 
Analysis Populations 
7.2.1 Safety Population 
The safety population will include all subjects with at least one reported product use from 
Day -1. 
7.2.2 Intent-to-Treat Population 
The ITT population will consist of randomized subjects with at least one documented 
product-use experience from Day 1, irrespective of their compliance of the product-use to 
which they were randomized. 
7.2.3 Per-Protocol Population 
The PP population is a subset of the ITT population who meet the requirements below. 
Separate populations for Product Use Periods 1 and 2 will be established based on data 
collected during each of those periods.  

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 75 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
myblu™ and continue-smoking arms 
• Have no protocol deviations significantly impacting the integrity of the analysis or 
interpretation of the individual endpoint under consideration (e.g., compromised urine 
samples, use of prohibited medications impacting the endpoint) 
• Have a daily product use response rate of at least 70% during the product use period 
• Have a positive urine cotinine test at each scheduled assessment 
myblu™ arm 
• Self-report reducing cigarette consumption by at least 90% of that reported at baseline 
• Have exhaled CO values ≤ 8 ppm at each scheduled post-baseline assessment 
• Have post-baseline urine NNAL values reduced by ≥ 75% from baseline 
7.2.4 Pharmacokinetics Population 
The PK population for each product use session will include subjects who used a product and 
have evaluable PK profiles. 
7.3 
Calculations 
7.3.1 Urine Nicotine Equivalents 
Nicotine equivalents will be calculated as the molar sum of nicotine and 5 major nicotine 
metabolites. Values of individual components reported as below the limit of quantitation 
(BLQ) will be set to one-half of the limit of quantitation prior use in the calculation below. 
Missing urine data will not be imputed. 
Nicotine equivalents (µg/mL) = (nicotine [ng/mL]/162.23 [mg/mmol] + nicotine-gluc 
(ng/mL)/338.36 [mg/mmol] + cotinine [ng/mL]/176.22 
[mg/mmol] + cotinine-gluc [ng/mL]/352.34 [mg/mmol] 
+ trans-3'-hydroxycotinine [ng/mL]/192.22 [mg/mmol] 
+ trans-3'-hydroxycotinine-gluc [ng/mL]/368.34 
[mg/mmol]) x 162.23 (mg/mmol) x 1 µg/1000 ng 
7.3.2 Calculation of Total Mass Excreted 
Urine biomarker concentrations will be converted into biomarker quantities excreted in 
24 hours by multiplying the measured concentration by the total weight (i.e., 1 kilogram = 
1 liter) of urine produced by the subject during the 24-hour period. 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 76 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
7.3.3 Creatinine Adjustments 
Urine creatinine will be measured and used to adjust the values of the primary and secondary 
urine BoPH and BoE as follows. 
      Biomarker            = Biomarker (units) x 100 
(unit/g creatinine) 
      creatinine (mg/dL) 
7.4 
Data Summarization 
Data summarizations and statistical analyses will be performed using SAS procedures. In 
general, all data will be listed by subject, product, and period (and time point as necessary) 
and summarized by product and period (and time point as necessary). Absolute and percent 
change-from-baseline values, and absolute and percent differences between Test Visits 3 
and 5, will also be listed and summarized where indicated. Descriptive statistics (number of 
observations, mean, median, standard deviation, minimum, and maximum) will be used for 
continuous data variables and frequency counts (number of observations and percentage) for 
categorical data variables. Figures will be used to display the data graphically. All data 
summarizations and figures will be generated using the ITT and PP populations. 
Additional information specific to certain study endpoints are discussed in the sections that 
follow. 
7.4.1 Product Use and Compliance 
Product use (including the PK product use sessions) and compliance variables will be 
summarized descriptively by time point, period, and product use session as appropriate. No 
inferential statistical analysis will be performed. 
7.4.2 Biomarkers of Exposure and Potential Harm 
Biomarker concentrations reported as below the limit of quantitation will be reported as 
“BLQ” in the listings and set to one-half of the limit of quantitation for summarization and 
statistical analysis.  
The following variables will be determined and summarized for each urine biomarker. 
• Measured concentration  
• Total biomarker mass excreted per 24 hours 
• Creatinine-adjusted excretion level 
Absolute and percent change-from-baseline will be determined for the mass excreted and 
creatinine-adjusted values. The total urine biomarker mass excreted per 24 hours change-
from-baseline value will be used as the primary variable in the statistical analysis.  

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 77 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
7.4.3 Physiologic Assessments 
Test Visit 1, 3, and 5 check-in blood pressure (systolic and diastolic) and heart rate 
measurements will be assessed for physiologic assessment purposes. 
7.4.4 Subjective Measures 
Each item on each of the subjective measures questionnaires will be summarized. In addition, 
the following total scores, factor scores, and subscales will also be calculated and 
summarized. 
• PSCDI/PSECDI total score 
• MTWS-R total score  
• QSU-brief factor scores:  
o Factor 1 (anticipation of pleasure from smoking) - average of items 1, 3, 6, 7, 
and 10 
o Factor 2 (relief of nicotine withdrawal) - average of items 2, 4, 5, 8, and 9 
• PES subscales: 
o Satisfaction - average of items 1, 2, 3, and 12 
o Psychological reward - average of items 4 through 8 
o Aversion - average of items 9, 10, 16, and 18 
o Relief - average of items 11, 13, 14, 15, and reversed for item 20 
o Items 17, 19, 21 will be summarized as individual item scores 
7.4.5 Nicotine Pharmacokinetic Analysis 
Nicotine PK parameters will be determined from the individual plasma concentrations 
applying a noncompartmental approach using appropriate validated PK software 
(e.g., Phoenix® WinNonlin® version 7.0 or higher).  
For each study product and product use session, the following PK parameters will be 
calculated from the nicotine concentration-time data: 
AUC0-t 
Area under the nicotine concentration-time curve from time zero (defined as 
the start of product use) to the last quantifiable concentration during the 
interval as calculated by the linear trapezoidal with linear interpolation 
method. 
Cmax 
Maximum measured plasma concentration over the duration of the 
measurement interval. 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 78 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
Tmax 
Time to reach the maximum measured plasma concentration over the duration 
of the measurement interval. If the maximum value occurs at more than one 
time point, Tmax is defined as the first time point with this value. 
For the calculation of the PK parameters, plasma concentrations below the limit of 
quantitation (BLQ) will be set to one-half of the LLOQ for the calculation of descriptive 
statistics of unadjusted plasma nicotine concentrations. 
Adjustments for existing pre-product use nicotine concentrations will be performed for 
calculation of PK parameters. The values used for all pre-product use adjustments is the 
plasma nicotine concentration value obtained before the first product use of each session and 
the adjustment will be subject-specific.  
*Baseline-adjustment method: For each PK profile, the pre-product administration nicotine 
concentration value for each subject will be subtracted from each nicotine concentration 
obtained after test product administration in that period/day using the following equation: 
Ct  = Ct uncorrected – [C0 · e-Kel· t1] 
Where: 
Ct = Corrected concentration. 
Ct uncorrected = the uncorrected concentration.  
C0 = the pre-product administration concentration. 
Kel£ = 
ln (2)
t1/2 
t1/2 is 2.0 hours for all subjects (estimated nicotine half-life) 
t = actual sampling time since product administration. 
t1 = actual sampling time since pre-product administration sampling. 
After correction for pre-product administration values, some concentrations may be below 
the lower limit of quantitation and some may be negative values. Negative values will be 
assigned a value of zero in the analyses and all other values obtained will be reported as is 
even if these values are BLQ. 
7.4.6 Urge to Smoke Parameters 
The following parameters will be calculated for the urge to smoke assessments performed 
during the PK assessments. 
Emax_R 
The maximum reduction from baseline VAS score (VASpre-use – VASpost-
use). If there is no reduction, a value of zero will be reported. 
 
TEmax 
Time of the Emax_R. If the maximum value occurred at more than one time 
point, TEmax will be defined as the first time point with this value. 
 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 79 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
AUEC_0-120 
The area under the change from baseline “Urge to Smoke” VAS score versus 
time curve from 0 to 120 minutes, calculated using the linear trapezoidal 
method with linear interpolation using actual sample times. 
7.5 
Statistical Analysis 
7.5.1 Primary Endpoints 
Comparisons of the Day 28 visit primary BoE change-from-baseline values between the 
continue-smoking arm and each myblu™ e-liquid product selected at Day 1 will be made 
using a linear mixed model ANOVA. The ITT population will be used as the primary 
analysis population and an analysis using the PP population will be used as a supportive 
analysis. 
7.5.2 Secondary Endpoints 
An approach similar to that used for the primary endpoints will be used to make Day 28 and 
Day 56 change-from-baseline comparisons between the myblu™ products and the 
continue-smoking arm for the applicable secondary BoE, BoPH, physiologic endpoints, and 
subjective measure endpoints as described in the SAP. For the Day 56 analysis, the initial 
myblu™ flavor cohort assignments for each subject will be maintained within the statistical 
model and a separate sensitivity analysis will be performed for subjects that do not switch 
flavors at Day 29.  
Comparisons of the primary and secondary BoE change-from-baseline values at each time 
point within and between the myblu™ product cohorts will also be made using a linear mixed 
model ANOVA. 
A linear mixed model ANOVA will be performed on the log-transformed nicotine PK 
parameters AUC and Cmax from each product use session. Non-parametric analysis 
(Wilcoxon Signed Rank test) will be performed for the comparisons of Tmax. Similar 
methods will be used to compare the urge to smoke parameters. The comparisons of interest 
will include each of the myblu™ products compared to the usual brand cigarette and JUUL® 
product. 
7.6 
Safety 
All clinical safety data will be listed by subject and time point and summarized as described 
in the SAP. 
All reported events captured in the database will be listed in by-subject data listings. 
However, only study product use-emergent AEs. A study product use-emergent AE is 
defined as an AE that is starting or worsening at the time of or after the first study product 
use on Day -2. 
Frequencies of subjects with study product use-emergent AEs, regardless of relationship to 
study product will be summarized and sorted by system organ class. Frequencies of subjects 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 80 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
with study product use-emergent SAEs will be likewise summarized. Frequencies of study 
product use-emergent AEs will be summarized by severity and relationship to study product. 
Changes in physical examinations (if any) will be described in the text of the final report. 
All prior and concomitant medications recorded during the study will be listed by subject. 
The following pre- and post-bronchodilator lung function variables will be summarized.  
• Measured and percent of predicted FEV1 
• Measured and percent of predicted FVC 
• Measured and percent of predicted FEV1:FVC ratio 
• Measured and percent of predicted FEF25-75% 
8. STUDY ADMINISTRATION 
8.1 
Ethics 
8.1.1 Institutional Review Board 
This protocol will be reviewed by an institutional review board (IRB) and the study will not 
start until the IRB has approved the protocol or a modification thereof. The IRB is 
constituted and operates in accordance with the principles and requirements described in the 
US Code of Federal Regulations (21 CFR Part 56). The IRB is compliant with the 
International Council for Harmonisation (ICH). 
8.1.2 Ethical Conduct of the Study 
This research will be carried out in accordance with the protocol, US Code of Federal 
Regulations, 21 CFR Parts 50, 56, and 312, the ethical principles set forth in the Declaration 
of Helsinki, GCP, and the ICH harmonized tripartite guideline regarding GCP (E6 R2 
Consolidated Guidance, November 2006). 
8.1.3 Subject Informed Consent 
All prospective subjects will have the study explained by the Investigator or his/her designee 
in non-technical terms and will be required to read, sign, and date an IRB-approved ICF prior 
to completion of screening or other study procedures.  
The consent form will provide the subjects with the purpose of the study, procedures to be 
carried out, and potential hazards, and subjects will be allowed sufficient time to review and 
ask questions about the study. The subjects will be assured that they may withdraw from the 
study at any time without jeopardizing medical care related to or required as a result of study 
participation. The subject will be informed that any samples collected prior to withdrawal 
and awaiting analysis will be analyzed unless he/she provides written instruction to have 
such samples destroyed. 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 81 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
The ICF will be signed and dated by the subject and by a member of the clinical staff 
qualified to conduct the informed consent discussion. The fully signed ICF will be filed in 
the source documents and a copy will be given to the subject. 
8.2 
Termination of the Study 
The Sponsor reserves the right to discontinue this study and the Investigator reserves the 
right to terminate the study for safety reasons at any time.  
8.3 
Data Management 
Data management activities will be detailed in the Data Management Plan (DMP). Each 
vendor involved with this study will adhere to Good Documentation Practices and their 
standard operating procedures covering their respective activities relevant to participation in 
this study. The Investigator will ensure that all data related to the conduct of this study at 
his/her site is attributable, legible, contemporaneous, original, accurate, enduring, and readily 
accessible.  
8.3.1 Database Design and Creation 
An appropriate database will be designed and created within a validated Clinical Data 
Management System (CDMS). Electronic data capture will be used for this study and eCRFs 
will be developed according to the study protocol specifications. Certain clinical and 
analytical laboratory data will be collected external to CDMS as external data files. 
8.3.2 Data Coding 
AEs and medical history coding will be undertaken using most current version of MedDRA. 
Concomitant medications will be coded using the WHO Drug Dictionary. Each dictionary 
version will remain the same throughout the trial. Coding will be completed by qualified 
members of the 
 staff. 
8.3.3 Data Entry and Verification 
Data will be transcribed from original sources by the Investigator or Investigator’s staff into 
the eCRF. Data received from external sources (e.g., questionnaire or clinical laboratory 
results) will be integrated into the Clinical Data Interchange Standards Consortium study data 
tabulation model datasets. 
8.3.4 Study Results Data Transfer 
Study data transfers will be sent to the Sponsor or their designee, electronically on a schedule 
and in a format mutually agreed upon by the Sponsor or their designee, and 
 for the 
analysis of these study data. No personally identifiable information will be transferred to the 
Sponsor at any point in the study. 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 82 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
8.3.5 Data Validation 
After the data have been entered and source data verified by the monitor, various edit checks 
(including manual review of listings) will be performed to ensure the accuracy, integrity and 
validation of the database against the eCRF as described in the DMP. 
Inconsistencies that arise from these edit checks will be resolved with the Investigator or 
designee. 
8.3.6 Database Lock 
On study completion, after data entry is complete, the data has been pronounced clean, and 
the Investigators have reviewed and provided approval via signature, the database will be 
locked and final write access will be removed. 
The Sponsor will be required to provide database lock approval. 
Any changes to the data following database lock will be documented and approved by the 
Sponsor prior to unlocking the database to make changes to the data. 
The final transfer of all study data (without subject personally identifying information) to the 
Sponsor will be in SAS format with supporting SAS documentation according to the 
specifications of the Sponsor. Subject initials, date of birth (except year), and other personal 
identifiers will be removed from this data transfer file; any such information removed will be 
documented at the time of transfer. 
8.4 
Monitoring the Study 
The responsible study monitor will contact and visit the Investigator as necessary, and he/she 
will be allowed, upon request, to inspect and verify all records of the study (e.g., source 
document, ICFs, eCRFs, regulatory documents) in a manner consistent with GCP and all 
other applicable state and federal law. 
It will be the study monitor’s responsibility to inspect the source documents to verify the 
adherence to the protocol and the completeness, consistency, and accuracy of the data being 
entered in the eCRF. The monitor will verify that each subject has consented in writing prior 
to any study procedures being performed. Where the terms of the informed consent, GCP, 
and all other applicable state and federal law permit, the monitor should have access to 
laboratory test reports and other subject records needed to verify the entries on the eCRF. 
The Investigator (or his/her designee) agrees to cooperate with the monitor to ensure that any 
issues detected in the course of these monitoring visits are resolved. 
In addition, the Sponsor’s internal auditors (or designee) and government inspectors may 
evaluate the study and must be allowed access to eCRFs, source documents, and other study 
files. 
The Investigator must notify the Sponsor (or designee) promptly of any inspections of the 
study or activities related to the study scheduled by regulatory authorities, allow the Sponsor 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 83 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
(or designee) to be present, and promptly forward copies of inspection reports to the Sponsor 
(or designee).  
8.5 
Reporting for the Study 
8.5.1 Case Report Forms 
Electronic CRFs will be completed for each screened subject whether or not he/she has 
completed the study. The Investigator will assure complete and accurate entries on the forms. 
All eCRFs will be reviewed and signed by the Investigator. 
8.5.2 Study Report 
Two study reports are intended to be produced for this study: one describing the main study 
results and a one describing the PK sub-study. The reports will include appropriate 
descriptions of the clinical conduct of the study, safety evaluation, analytical methods and 
results, and the statistical analysis described in the statistical methodology section of the 
protocol and the SAP.  
At the time the draft study reports are completed, 
 Quality Assurance (QA) unit 
will audit the reports against the SAS data and the raw data. At the completion of the audit, a 
QA report will be issued internally allowing any findings to be addressed before report 
finalization. 
8.6 
Confidentiality 
All clinic sites and vendors will have signed confidentiality agreements with 
 
 will regard all information provided to the Investigator dealing with the study and 
information obtained during the course of the study as confidential. 
Neither the clinic site nor 
 will supply to the Sponsor any subject names, initials, 
date of birth (except year), or other personal identifiers (HIPAA 2007). All such information 
appearing on any study document must be redacted before a copy of the document is 
supplied to the Sponsor. The photocopied government-issued ID to verify subject age will be 
kept separate from other source documentation and not provided to the Sponsor. Study 
findings stored on a computer will be stored in accordance with local data protection laws. 
The subjects will be informed during the consenting process that representatives of the 
Sponsor, IRB, or regulatory authorities may inspect their medical records to verify the 
information collected, and that all personal information made available for inspection will be 
handled in the strictest confidence and in accordance with local data protection laws. 
8.7 
Publication Policy 
All unpublished information given to 
 by the Sponsor shall not be published or 
disclosed to a third party without the prior written consent of the Sponsor. 
The data generated by this study are considered confidential information and the property of 
the Sponsor. This confidential information may be published only in collaboration with 
participating personnel from the Sponsor or upon Sponsor’s written consent to publish the 
information. 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 84 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
9. REFERENCES 
Cox LS et al., 2001. Evaluation of the brief questionnaire of smoking urges (QSU-brief) in 
laboratory and clinical settings. Nicotine Tob Res. 3:7-16 
Cravo AS et al., 2016. A randomized, parallel group study to evaluate the safety profile of an 
electronic vapour product over 12 weeks. Regul Toxicol Pharmacol. 81:S1-S14. 
Food and Drug Administration, Center for Tobacco Products. Premarket Tobacco Product 
Applications for Electronic Nicotine Delivery Systems, Draft Guidance for Industry. 2016. 
https://www.fda.gov/downloads/TobaccoProducts/Labeling/RulesRegulationsGuidance/UC
M499352.pdf  
Fould J et al., 2015. Development of a questionnaire for assessing dependence on electronic 
cigarettes among a large sample of ex-smoking e-cigarette users. Nicotine Tob Res. 17:186-
192. 
Goniewicz ML et al., 2017. Exposure to nicotine and selected toxicants in cigarette smokers 
who switched to electronic cigarettes: a longitudinal within-subjects observational study. 
Nicotine Tob Res. 19:160-167. 
Hatsukami DK et al., 2013. Subjective responses to oral tobacco products: scale validation. 
Nicotine Tob Res. 15:1259-1264. 
Hecht SS et al., 2015. Evaluation of toxicant and carcinogen metabolites in the urine of 
e-cigarette users versus cigarette smokers. Nicotine Tob Res. 17:704-709. 
HIPAA Privacy Rule. Information for Researchers. De-identifying Protected Health 
Information Under the Privacy Rule. U.S. Department of Health and Human Services. NIH 
(Feb 2007). http://privacyruleandresearch.nih.gov/pr_08.asp#8a. Last accessed 21-Dec-2018. 
McRobbie H et al., 2015. Effects of switching to electronic cigarettes with and without 
concurrent smoking on exposure to nicotine, carbon monoxide, and acrolein. Cancer Prev 
Res (Phila). 8:873-878. 
Miller MR et al., 2005. Standardisation of spirometry. Eur Respir J 26:319-338. 
O’Connell G et al., 2016. Reductions in biomarkers of exposure (BoE) to harmful or 
potentially harmful constituents (HPHCs) following partial or complete substitution of 
cigarettes with electronic cigarettes in adult smokers. Toxicol Mech Methods. 26:443-454.  
Pellegrino R et al., 2005. Interpretative strategies for lung function. Eur Respir J. 26:948-968. 
 
 
 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 85 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
10. APPENDICES 
Appendix 1: Demographics Questionnaires 
Screening Demographics Questionnaire  
 
1. What is your date of birth? 
 
 _____________________ 
 
2. What is your sex? 
 
 Male 
 Female 
 
3. Which one of these groups would you say best describes your race? 
 
 White/Caucasian 
 Black/African American 
 Asian 
 Native Hawaiian or other Pacific Islander 
 American Indian or Alaska Native 
 Other (SPECIFY): _________________________________   
 
4. Are you Hispanic or Latino? 
 
 Yes 
 No 
 
 
 
 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 86 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
Additional Demographics Questionnaire  
 
1. What was your annual household income from all sources over the past year? 
 
 Under $20,000 
 $20,000 - $29,999 
 $30,000 - $39,999 
 $40,000 - $49,999 
 $50,000 - $59,999 
 $60,000 - $74,999 
 $75,000 - $99,999 
 $100,000 - $149,999 
 $150,000 and over  
 I do not wish to answer 
 
2. What was the highest grade or year of school you completed? 
 
 Never attended school or only attended kindergarten 
 Grades 1 through 8 (elementary) 
 Grades 9 through 11 (some high school) 
 Grade 12 or GED (high school graduate) 
 College 1 year to 3 years (some college or technical school) 
 College 4 years or more (college graduate) 
 Postgraduate/masters/doctorate/law/MD 
 Other 
 I do not wish to answer 
 
3. What is your marital status? 
 
 Single 
 Married/living with significant other 
 Separated/divorced/widowed 
 I do not wish to answer 
 
4. Which of the following options do you identify with? 
 
 Heterosexual or straight 
 Lesbian or gay 
 Bisexual 
 Transgender 
 Something else 
 Don’t know/not sure 
 I do not wish to answer 
 
 
 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 87 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
Appendix 2: myblu™ Product Preference Questionnaire 
For the rest of the study you will be expected to replace all of your usual brand cigarettes 
with the e-cigarette product.  
 
Please rank each product that you will be willing to use to replace all of your cigarettes for 
the rest of the study, with 1 being the most preferred. Do not use a number more than once 
(there are no “ties”).   
 
You will be assigned one of the products that you rank. 
Do not rank a flavor that you will not be willing to use instead of your cigarettes. 
 
 
____  Tobacco Chill - low nicotine 
 
____  Tobacco Chill - high nicotine 
 
____ Honeymoon - low nicotine 
 
____  Honeymoon - high nicotine 
 
 
 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 88 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
Appendix 3: Penn State [Electronic] Cigarette Dependence Index (PSCDI/PSECDI) 
(Foulds et al., 2015) 
The following questionnaire will be administered to subjects in the myblu™ and continue-
smoking arms at Test Visits 1 (Day -2), 3, and 5. 
 
Note: For the Electronic Cigarette Dependence Index, substitute the underlined word with 
the words in square brackets. 
1. How many cigarettes [times] per day do you usually smoke [use your electronic 
cigarette]? ([assume that one “time” consists of around 15 puffs or lasts around 10 
minutes]) 
(Scoring: 0–4 times/day = 0, 5–9 = 1, 10–14 = 2, 15–19 = 3, 20–29 = 4, 30+ = 5) 
2. On days that you can smoke [use your electronic cigarette] freely, how soon after you 
wake up do you smoke your first cigarette of the day [first use your electronic cigarette]? 
(Scoring: 0–5 mins = 5, 6–15 = 4, 16–30 = 3, 31–60 = 2, 61–120 = 1, 121+ = 0) 
3. Do you sometimes awaken at night to have a cigarette [use your electronic cigarette]? 
(Scoring: Yes = 1, No = 0) 
4. If yes, how many nights per week do you typically awaken to smoke [use your electronic 
cigarette]? 
(Scoring: 0–1 nights = 0, 2–3 nights = 1, 4+ nights = 2) 
5. Do you smoke [use an electronic cigarette] now because it is really hard to quit? 
(Scoring: Yes = 1, No = 0) 
6. Do you ever have strong cravings to smoke [use an electronic cigarette]? 
(Scoring: Yes = 1, No = 0) 
7. Over the past week, how strong have the urges to smoke [use an electronic cigarette] 
been? 
(Scoring: None/Slight = 0, Moderate/Strong= 1, Very Strong/Extremely Strong = 2) 
8. Is it hard to keep from smoking [using an electronic cigarette] in places where you are not 
supposed to? 
(Scoring: Yes = 1, No = 0) 
When you haven’t used tobacco [an electronic cigarette] for a while or when you tried to 
stop smoking [using]… 
9. Did you feel more irritable because you couldn’t smoke [use an electronic cigarette]? 
(Scoring: Yes = 1, No = 0) 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 89 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
10. Did you feel nervous, restless, or anxious because you couldn’t smoke [use an electronic 
cigarette]? 
(Scoring: Yes = 1, No = 0) 
Total scoring: 0 - 3 = not dependent, 4 - 8 = low dependence, 9 - 12 = medium dependence, 
13+ = high dependence. 
 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 90 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
Appendix 4: Cough Questionnaire 
The following questionnaire will be administered to subjects in the myblu™ and continue-
smoking arms at Test Visits 1 (Day -2), 3, and 5. 
 
1. Did you have a cough during the last 5 days?  
1. Yes – PROCEED TO QUESTIONS 2 TO 5. 
2. No – STOP. DO NOT ANSWER THE REST OF THE QUESTIONS. 
 
2. How would you rate the intensity of your cough during the last 5 days?  
1. Very mild 
2. Somewhat mild 
3. Mild 
4. Somewhat moderate 
5. Moderate 
6. Severe 
7. Very severe 
 
3. How often did you cough up phlegm during the last 5 days?  
1. Every time 
2. Most times 
3. Several times 
4. Some times 
5. Occasionally 
6. Rarely 
7. Never 
 
4. How often did your cough disturb your sleep during the last 5 days?  
1. All of the time 
2. Most of the time  
3. A good bit of the time 
4. Some of the time 
5. A little bit of the time 
6. Hardly any of the time 
7. None of the time 
 
5. How often did you have coughing bouts during the day, during the last 5 days?  
1. All of the time (continuously) 
2. Most of the time 
3. A good bit of the time 
4. Some of the time 
5. A little bit of the time 
6. Hardly any of the time 
7. None of the time 
 
 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 91 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
Appendix 5: Questionnaire of Smoking Urges-Brief (QSU-Brief) (Cox et al., 2001) 
The following questionnaire will be administered to subjects in the myblu™ and continue-
smoking arms at Test Visits 1 (Day -2), 3, and 5, and also to the subjects in the myblu™ arm 
on Test Visit 1, Day 3. 
 
 
 
Factor 1 (anticipation of pleasure from smoking): average of items 1, 3, 6, 7, and 10. 
Factor 2 (relief of nicotine withdrawal): average of items 2, 4, 5, 8, and 9. 
 
 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 92 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
Appendix 6: Minnesota Tobacco Withdrawal Scale-Revised (MTWS-R) 
The following questionnaire will be administered to subjects in the myblu™ and continue-
smoking arms at Test Visits 1 (Day -2), 3, and 5, and also to the subjects in the myblu™ arm 
on Test Visit 1, Day 3. 
 
Note:  The DSM-5 and craving items from the MTWS have been included here. Please see 
http://www.med.uvm.edu/behaviorandhealth/research/minnesota-tobacco-withdrawal-scale.  
 
Please rate yourself for the period of the last 24 hours. 
 
1. Angry, irritable, frustrated  
0   1   2   3   4 
2. Anxious, nervous  
0   1   2   3   4 
3. Depressed mood, sad  
0   1   2   3   4 
4. Difficulty concentrating  
0   1   2   3   4 
5. Increased appetite, hungry, weight gain  
0   1   2   3   4 
6. Insomnia, sleep problems, awakening at night  
0   1   2   3   4 
7. Restless  
0   1   2   3   4 
8. Desire or craving to smoke  
0   1   2   3   4 
---------------------------------------------------------------- 
Scale: 0 = none, 1 = slight, 2 = mild, 3 = moderate, 4 = severe 
 
 
 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 93 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
Appendix 7: Product Liking Questionnaire  
Note:  Each of these questions will be paired with a VAS. The VAS will be anchored with 
“Not at All” on the left and “Extremely” on the right.  
 
The following question will be administered to subjects in the myblu™ and continue-smoking 
arms at Test Visit 1 (Day -2), and to the subjects in the continue-smoking arm at Test Visits 3 
and 5. 
Please respond to each phrase with how you feel about the study product you are using by 
drawing a vertical mark anywhere along the horizontal line. 
 
How much do you like your usual brand cigarette? 
 
The following question will be administered to the myblu™ subjects at Test Visits 1 (Day 3), 
3 and 5. 
Please respond to each phrase with how you feel about the study product you are using by 
drawing a vertical mark anywhere along the horizontal line. 
 
How much do you like the test e-cigarette you are using? 
 
 
 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 94 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
Appendix 8: Product Evaluation Scale (PES) (Hatsukami et al., 2013) 
The following questionnaire will be administered to subjects in the myblu™ and continue-
smoking arms at Test Visits 1 (Day -2), 3, and 5, and also to the subjects in the myblu™ arm 
on Test Visit 1, Day 3. 
Please mark the number that best represents how using the product made you feel. 
 
1. Was it satisfying? 
2. Did it taste good? 
3. Did you enjoy the sensations in your mouth? 
4. Did it calm you down? 
5. Did it make you feel more awake? 
6. Did it make you feel less irritable? 
7. Did it help you concentrate? 
8. Did it reduce your hunger for food? 
9. Did it make you dizzy? 
10. Did it make you nauseous? 
11. Did it immediately relieve your craving for a cigarette? 
12. Did you enjoy it? 
13. Did it relieve withdrawal symptoms? 
14. Did it relieve the urge to smoke? 
15. Was it enough nicotine? 
16. Was it too much nicotine? 
17. Was it easy to use? 
18. Were there bothersome side effects? 
19. Were you comfortable using the product in public? 
20. Did you still have a craving for a cigarette after using the product? 
21. Are you concerned that you would become dependent on this product? 
---------------------------------------------------------------- 
Scale: 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. 
 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 95 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
Appendix 9: Future Intent to Use Questionnaire 
Note:  Each of these questions will be paired with a VAS. The VAS will be anchored with 
“Not at All” on the left and “Extremely” on the right. 
 
The following question will be administered to subjects in the myblu™ and continue-smoking 
arms at Test Visit 1 (Day -2), and to the subjects in the continue-smoking arm during Test 
Visits 3 and 5. 
Please respond to each phrase by drawing a vertical mark anywhere along the horizontal line. 
1. How likely are you to continue to smoke after you complete this study? 
2. Except as required for this study, how likely are you to use an e-cigarette product in the 
future? 
 
The following questions will be administered to the myblu™ arm at Test Visits 3 and 5.  
Please respond to each phrase by drawing a vertical mark anywhere along the horizontal line. 
1. How likely are you to continue to smoke after you complete this study? 
2. If available, how likely are you to buy your assigned study product in the future? 
3. How likely are you to buy an e-cigarette other than your assigned product in the future? 
 
 
 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 96 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
Appendix 10: Product and Health Effect Perceptions Questionnaire 
Note:  Each of these questions will be paired with a VAS. The VAS will be anchored with 
“Definitely Would Not” on the left and “Definitely Would” on the right, and “Don’t Know” 
in the center. 
 
The following items will be administered to subjects in the myblu™ and continue-smoking 
arms at Test Visit 1 and to the subjects in the continue-smoking arm during Test Visits 3 and 
5. 
Please respond to each phrase by drawing a vertical mark anywhere along the horizontal line. 
1. E-cigarettes would help me to reduce the number of cigarettes that I smoke each day. 
2. E-cigarettes would help me to completely quit smoking cigarettes.  
3. Using e-cigarettes instead of some of my cigarettes would be healthier for me. 
4. Using e-cigarettes instead of all of my cigarettes would be healthier for me. 
 
The following items will be administered to the myblu™ arm at Test Visits 3 and 5. 
Please respond to each phrase by drawing a vertical mark anywhere along the horizontal line. 
1. The study product would help me to reduce the number of cigarettes that I smoke each 
day. 
2. The study product would help me to completely quit smoking cigarettes. 
3. Using the study product instead of some of my cigarettes would be healthier for me. 
4. Using the study product instead of all of my cigarettes would be healthier for me. 
 
 
 
 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 97 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
Appendix 11: Urge to Smoke Questionnaire 
Note:  The following question will be paired with a VAS. The VAS will be anchored with 
“Not at All” on the left and “Extreme” on the right. 
 
Please respond to the question by drawing a vertical mark anywhere along the horizontal 
line. 
 
How strong is your urge to smoke right now? 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 98 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
Appendix 12: Tobacco/Nicotine Product Use History Questionnaire 
Please read each product description and then indicate the tobacco products that (1) you have ever used the product (even once) 
and (2) used in the past 14 days. If you have used in the past 14 days, indicate the approximate number of days. 
 
Tobacco Product or Nicotine Containing Product 
Have you ever used 
this product, even 
once? 
Have you used the product 
in the past 14 days? 
If “yes” indicate the 
number of days 
ELECTRONIC CIGARETTES or E-VAPOR products: 
An e-cigarette is a battery-powered device that is puffed 
like a cigarette 
□ Yes 
☐ No 
□ Yes 
☐ No 
______ days 
BIDIS OR KRETEKS: 
Popular in other parts of the world. Bidis are small hand-
rolled cigarettes. Kreteks are clove- flavored cigarettes. 
An example of a kretek brand is DJARUM BLACK 
□ Yes 
☐ No 
□ Yes 
☐ No 
______ days 
PREMIUM CIGARS: 
Come in different sizes and shapes. Some examples of 
premium cigar brands are MACANUDO, ARTURO 
FUENTE AND ROMEO Y JULIETA. 
□ Yes 
☐ No 
□ Yes 
☐ No 
______ days 
LARGE CIGARS: 
Not premium cigars; generally wider and longer than 
cigarillos. PHILLIES BLUNT cigars is an example of a 
large cigar brand 
□ Yes 
☐ No 
□ Yes 
☐ No 
______ days 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 99 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
Tobacco Product or Nicotine Containing Product 
Have you ever used 
this product, even 
once? 
Have you used the product 
in the past 14 days? 
If “yes” indicate the 
number of days 
CIGARILLOS: 
Generally narrower and shorter than premium cigars; they 
may come with plastic or wooden tips. BLACK & MILD 
is an example of a cigarillo brand. Other examples include 
SWISHER SWEETS and DUTCH MASTERS 
□ Yes 
☐ No 
□ Yes 
☐ No 
______ days 
LITTLE CIGARS: 
Look similar to cigarettes, except they are brown and 
have a filter like a cigarette. Some examples of little 
filtered cigar brands are WINCHESTER, CAPTAIN 
BLACK and WRANGLER 
□ Yes 
☐ No 
□ Yes 
☐ No 
______ days 
CHEWING TOBACCO: 
Coarsely shredded and sold in pocket-sized packs of loose 
tobacco leaves or in a “plug” or “twist” form. Brands 
include RED MAN, LEVI GARRETT and BEECH-NUT 
□ Yes 
☐ No 
□ Yes 
☐ No 
______ days 
SNUFF (DIP): 
Finely ground form of tobacco that is usually sold in a tin. 
It can be fine cut, long cut, pouched or pre-portioned. 
Brands include GRIZZLY, COPENHAGEN and SKOAL 
□ Yes 
☐ No 
□ Yes 
☐ No 
______ days 
SNUS: 
Spitless tobacco product that comes in small pouches and 
is usually sold in a tin. CAMEL SNUS is an example of a 
snus brand 
□ Yes 
☐ No 
□ Yes 
☐ No 
______ days 

myblu Safety/Tolerability Study 
Nerudia Ltd. 
 Project No.: CA22747 
 
Page 100 
CA22747_PROTOCOL AMENDMENT 3_24MAR2020 
Tobacco Product or Nicotine Containing Product 
Have you ever used 
this product, even 
once? 
Have you used the product 
in the past 14 days? 
If “yes” indicate the 
number of days 
OTHER NEW ORAL TOBACCO OR 
TOBACCO- DERIVED NICOTINE 
PRODUCTS: 
Meant to be chewed or dissolved in the mouth. 
Examples include CAMEL ORBS, STRIPS, or 
STICKS; ARIVA or STONEWALL and VERVE 
DISCS 
□ Yes 
☐ No 
□ Yes 
☐ No 
______ days 
HOOKAH: 
Or “narghile” pipe, is a type of water pipe used to smoke 
tobacco 
□ Yes 
☐ No 
□ Yes 
☐ No 
______ days 
PIPE: 
A regular smoking pipe has a bowl for tobacco, stem 
and mouthpiece 
□ Yes 
☐ No 
□ Yes 
☐ No 
______ days 
NICOTINE REPLACEMENT THERAPY: 
Patch, gum, inhaler, nasal spray or lozenge 
□ Yes 
☐ No 
□ Yes 
☐ No 
______ days