An Open-Label, Parallel-Group, Controlled Study to Evaluate Changes in Biomarkers of Cigarette Smoke Exposure and Biomarkers of Potential Harm in Adult Smokers Who Completely Switch to Using e-Vapor Products for 24 Weeks
Phase: NA
Conditions: Tobacco Use
Sponsor: Altria Client Services LLC

An Open-Label, Parallel-Group, Controlled Study to Evaluate Changes in Biomarkers of 
Cigarette Smoke Exposure and Biomarkers of Potential Harm in Adult Smokers Who 
Completely Switch to Using e-Vapor Products for 24 Weeks 
NCT04800211 
06JUN2017 

A n Open- Label, Parallel- Group, Controlled Study to Evaluate Changes in Bio markers 
of Cigarette S moke Exposure and Bio markers of Potential Harm  in Adult S mokers 
Wh o Co mpletely S witch to Using e- Vapor Products for 24 Weeks 
Altri a Client Services Study No, AL CS- R A-17-ll-EV 
Final Protocol Date: 22 March, 2017 
Protocol A mend ment 1 Date: 20 April, 2017 
Protocol A mend ment 2 Date: 06 June, 2017 
Sponsor: 
Altri a Client Services LLC 
601 E. Jackson Street 
Rich mond, Virginia 23119 
 
 
 
 
 
( Date) 
Medica l Monitor: 
( Date) 
Th e infor mation contained herein is confidential and the proprietary property of Altria Client Services 
LLC  and any unauthorized use or disclosure of such infor mation without the prior written authorization 
of Altria Client Services L LC  is expressly prohibited. 
Page 1 of 88 
HI G HLY  C O NFI DE NTIAL  
V E RSI O N : A mend ment 2, Date 06 June, 2017 

 
 
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HIGHLY CONFIDENTIAL 
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An Open-Label, Parallel-Group, Controlled Study to Evaluate Changes in Biomarkers 
of Cigarette Smoke Exposure and Biomarkers of Potential Harm in Adult Smokers 
Who Completely Switch to Using e-Vapor Products for 24 Weeks   
Altria Client Services Study No. ALCS-RA-17-11-EV  
 
 
Sponsor’s Contact: 
 
 
 
 
 
 
 
 
 
 

 
 
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HIGHLY CONFIDENTIAL 
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PROTOCOL SIGNATURE PAGE 
Altria Client Services Study No. ALCS-RA-17-11-EV 
An Open-Label, Parallel-Group, Controlled Study to Evaluate Changes in Biomarkers 
of Cigarette Smoke Exposure and Biomarkers of Potential Harm in Adult Smokers 
Who Completely Switch to Using e-Vapor Products for 24 Weeks  
By signing below, the Investigator agrees to adhere to the protocol as outlined and agrees that 
any changes to the protocol must be approved by Altria Client Services LLC (ALCS) prior to 
seeking approval from the Institutional Review Board (IRB). 
This study will be conducted in accordance with Good Clinical Practice (GCP) based on the 
current International Conference on Harmonization (ICH) guidelines for GCP and the 
corresponding sections of the United States (US) Code of Federal Regulations (CFR) 
governing Protection of Human Subjects (Title 21 CFR Part 50), Institutional Review Boards 
(Title 21 CFR Part 56), the Basic Principles of the Declaration of Helsinki, and applicable 
legal and regulatory requirements. 
Principal Investigator: 
 
 
 
 
 
Phone: 
Fax: 
E-mail:  
 
 
 
 
 
(Signature) 
(Date) 
 
 
 
 
 

 
 
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SUMMARY OF AMENDMENT 2 
The primary purpose of Amendment 2 is to modify inclusion criteria #3 and #6 in order to 
allow more subjects from the 12-week ALCS-RA-16-06-EV study to be eligible for the 
current study. 
 
The Study Synopsis (under Inclusion Criteria) and Section 4.1 Inclusion Criteria were 
updated with criteria #3 and #6 modified as follows (new text presented in bold font and 
deleted text presented in strikethrough font): 
 
 
3) have demonstrated consistent daily reporting of product use in the 12-week 
 
 
ALCS-RA-16-06-EV (≥ 80% 75% reporting compliance); 
 
 
6) if randomized to a Test group, have eCO measurements of ≤ 8 ppm at each  
 
the 6-, 9-, and 12-week post Baseline time points in the 12 week ALCS-RA-16-
06-EV study; 
 
 
Footnote “c” under the primary objective (in the Study Synopsis [under Study Objectives] 
and Section 2.1 Primary Objective) was also modified as follows: 
 
“ c Subjects who exclusively use e-vapor products and have eCO measurements 
≤ 8 ppm from Week 3 Week 6 (of the 12-week ALCS-RA-16-06-EV study) through 
Week 24 (EOS) and urine NNN levels from Week 6 (of the 12-week 
ALCS-RA-16-06-EV study) through Week 24 (EOS) consistent with switching to an 
e-vapor product.” 
 
 
In addition, the telephone number for the Medical Monitor was updated in Section 11.1 
Serious Adverse Events. 
 
 

 
 
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SUMMARY OF AMENDMENT 1 
The primary purpose of Amendment 1 is to remove the post-study follow-up contact. Thus, 
all mention of the additional consent for post-study follow-up and post-study follow-up 
phone call was removed in the Study Synopsis (under Study Design), Summary of 
Events/Assessments, and Section 3.1 Design. Section 10.25 Additional Consent for 
Post-Study Follow-up in its entirety was also removed. 
 
In addition, other clarifications and changes were made as noted below. 
 
• Confirmation of usual cigarette brand will be performed only once at the Week 12 
visit, which is Visit 7 in the ALCS-RA-16-06-EV (CA20130) study, the same visit as 
Visit 1 in the current study (ALCS-RA-17-11-EV; CA21021). Thus, to clarify that 
confirmation of usual cigarette brand will only be performed once at Week 12, in the 
Summary of Events/Assessments, the “X” for “Confirm Regular Cigarette Brand” 
under Visit 1, Week 12 (Day 84 +/- 3) was removed. Section 6.6 Confirm Cigarette 
Brand / Photocopy Cigarette Pack was also entirely removed. 
 
• Spirometry results will be captured in the source document and then transferred. 
Thus, in Section 8.3 Spirometry and Section 10.4 Spirometry, the last sentence was 
updated to remove the indication of reporting in the eCRF and now reads as follows 
(deleted text presented in strikethrough font): 
 
“Spirometry results will be captured in the source document and eCRF.” 
 
 
 
 
 
 

 
 
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TABLE OF CONTENTS 
 
1.0 
INTRODUCTION AND STUDY RATIONALE ................................................................ 25 
 
Purpose of this Study .................................................................................................. 25 
1.1
 
Hypothesis .................................................................................................................. 25 
1.2
 
Rationale ..................................................................................................................... 25 
1.3
2.0 
STUDY OBJECTIVES ......................................................................................................... 26 
 
Primary Objective ...................................................................................................... 26 
2.1
 
Secondary Objectives ................................................................................................. 26 
2.2
 
Exploratory Objectives ............................................................................................... 27 
2.3
3.0 
SUMMARY OF STUDY DESIGN ...................................................................................... 27 
 
Design......................................................................................................................... 27 
3.1
 
Study Duration ........................................................................................................... 29 
3.2
 
Clinical Safety Evaluations ........................................................................................ 29 
3.3
4.0 
SUBJECT SELECTION ....................................................................................................... 30 
 
Inclusion Criteria ........................................................................................................ 30 
4.1
 
Exclusion Criteria ....................................................................................................... 31 
4.2
 
Restrictions ................................................................................................................. 32 
4.3
 
Concomitant Medications........................................................................................... 32 
4.4
5.0 
TEST PRODUCTS ................................................................................................................ 32 
 
Test e-Vapor Products ................................................................................................ 32 
5.1
 
Study Material Accountability ................................................................................... 33 
5.2
5.2.1 
Test e-Vapor Products ............................................................................ 33 
 
Study Material Dispensing ......................................................................................... 34 
5.3
5.3.1 
Test e-Vapor Products ............................................................................ 34 
5.3.2 
Conventional Cigarettes .......................................................................... 34 
6.0 
VISIT 1 (WEEK 12 / DAY 84 ±3) ........................................................................................ 34 
 
Informed Consent ....................................................................................................... 35 
6.1
 
Review of Inclusion / Exclusion Criteria ................................................................... 35 
6.2
 
Review of Concomitant Medications ......................................................................... 35 
6.3
 
Review of Tobacco and Nicotine Restrictions ........................................................... 35 
6.4
 
Review of Adverse Events ......................................................................................... 35 
6.5
 
Test e-Vapor Product Dispensation ............................................................................ 35 
6.6

 
 
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Reminder Calls ........................................................................................................... 36 
6.7
 
SMS System Use ........................................................................................................ 36 
6.8
 
Changes in Your Health and Well-Being Questionnaire ........................................... 36 
6.9
7.0 
VISIT 2 (WEEK 15 / DAY 105 ±3) ...................................................................................... 36 
 
Review of Inclusion / Exclusion Criteria ................................................................... 37 
7.1
 
Vital Signs .................................................................................................................. 37 
7.2
 
Review of Concomitant Medications ......................................................................... 37 
7.3
 
Review of Tobacco and Nicotine Restrictions ........................................................... 37 
7.4
 
Physical Examination (Symptom-Driven) ................................................................. 37 
7.5
 
Urine Pregnancy Test ................................................................................................. 37 
7.6
 
Review of Adverse Events ......................................................................................... 37 
7.7
 
Confirm Cigarette Brand / Photocopy Cigarette Pack ............................................... 37 
7.8
 
Test e-Vapor Product Collection ................................................................................ 38 
7.9
 
Test e-Vapor Product Dispensation ............................................................................ 38 
7.10
 
Reminder Calls ........................................................................................................... 38 
7.11
 
Dispense First Urine Void Collection Containers ...................................................... 39 
7.12
 
SMS System Use ........................................................................................................ 39 
7.13
 
Exhaled CO Measurement .......................................................................................... 39 
7.14
8.0 
VISIT 3 (WEEK 18 / DAY 126 ±3) ...................................................................................... 39 
 
Review of Inclusion / Exclusion Criteria ................................................................... 39 
8.1
 
Vital Signs .................................................................................................................. 39 
8.2
 
Spirometry .................................................................................................................. 39 
8.3
 
Review of Concomitant Medications ......................................................................... 40 
8.4
 
Review of Tobacco and Nicotine Restrictions ........................................................... 40 
8.5
 
Physical Examination (Symptom-Driven) ................................................................. 40 
8.6
 
Urine Pregnancy Test ................................................................................................. 40 
8.7
 
Review of Adverse Events ......................................................................................... 40 
8.8
 
QGEN and TQOLIT Questionnaires .......................................................................... 40 
8.9
 
Cough Questionnaire .................................................................................................. 41 
8.10
 
Confirm Cigarette Brand / Photocopy Cigarette Pack ............................................... 41 
8.11
 
Test e-Vapor Product Collection ................................................................................ 41 
8.12
 
Test e-Vapor Product Dispensation ............................................................................ 41 
8.13
 
Reminder Calls ........................................................................................................... 42 
8.14
 
BOE and BOPH Urine Sample Collection ................................................................. 42 
8.15

 
 
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BOPH and COHb Blood Sample Collection .............................................................. 42 
8.16
 
SMS System Use ........................................................................................................ 42 
8.17
 
Exhaled CO Measurement .......................................................................................... 42 
8.18
9.0 
VISIT 4 (WEEK 21 / DAY 147 ±3) ...................................................................................... 43 
 
Review of Inclusion / Exclusion Criteria ................................................................... 43 
9.1
 
Vital Signs .................................................................................................................. 43 
9.2
 
Review of Concomitant Medications ......................................................................... 43 
9.3
 
Review of Tobacco and Nicotine Restrictions ........................................................... 43 
9.4
 
Physical Examination (Symptom-Driven) ................................................................. 43 
9.5
 
Urine Pregnancy Test ................................................................................................. 43 
9.6
 
Review of Adverse Events ......................................................................................... 43 
9.7
 
Confirm Cigarette Brand / Photocopy Cigarette Pack ............................................... 43 
9.8
 
Test e-Vapor Product Collection ................................................................................ 44 
9.9
 
Test e-Vapor Product Dispensation ............................................................................ 44 
9.10
 
Reminder Calls ........................................................................................................... 44 
9.11
 
Dispense First Urine Void Collection Containers ...................................................... 45 
9.12
 
SMS System Use ........................................................................................................ 45 
9.13
 
Exhaled CO Measurement .......................................................................................... 45 
9.14
10.0 
VISIT 5, END OF STUDY (WEEK 24 / DAY 168 ±3) ....................................................... 45 
 
Review of Inclusion / Exclusion Criteria ................................................................... 45 
10.1
 
Vital Signs .................................................................................................................. 45 
10.2
 
Body Weight and Body Mass Index ........................................................................... 46 
10.3
 
Spirometry .................................................................................................................. 46 
10.4
 
Smoking Cessation Information ................................................................................. 46 
10.5
 
Clinical Laboratory Tests ........................................................................................... 46 
10.6
10.6.1 
Clinical Chemistry .................................................................................. 47 
10.6.2 
Hematology ............................................................................................. 47 
10.6.3 
Urinalysis ................................................................................................ 47 
 
Review of Concomitant Medications ......................................................................... 47 
10.7
 
Physical Examination (Symptom-Driven) ................................................................. 47 
10.8
 
12-Lead ECG .............................................................................................................. 47 
10.9
 Urine Pregnancy Test ................................................................................................. 47 
10.10
 Review of Adverse Events ......................................................................................... 47 
10.11
 QGEN and TQOLIT Questionnaires .......................................................................... 47 
10.12

 
 
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 Cough Questionnaire .................................................................................................. 48 
10.13
 mCEQ Questionnaire ................................................................................................. 48 
10.14
 Reasons of Use/Not-Use Test Product Questionnaire (Test group only) ................... 48 
10.15
 Confirm Cigarette Brand / Photocopy Cigarette Pack ............................................... 48 
10.16
 Test e-Vapor Product Collection ................................................................................ 48 
10.17
 Reminder Calls ........................................................................................................... 48 
10.18
 BOE and BOPH Urine Sample Collection ................................................................. 48 
10.19
 BOPH and COHb Blood Sample Collection .............................................................. 49 
10.20
 SMS System Use ........................................................................................................ 49 
10.21
 Exhaled CO Measurement .......................................................................................... 49 
10.22
 Changes in Your Health and Well-Being Questionnaire ........................................... 49 
10.23
 End of Study Questionnaire ....................................................................................... 49 
10.24
11.0 
ADVERSE EVENTS ............................................................................................................. 49 
 
Serious Adverse Events .............................................................................................. 51 
11.1
 
Adverse Events / Serious Adverse Events Follow Up ............................................... 53 
11.2
 
Pregnancy ................................................................................................................... 53 
11.3
12.0 
SUBJECT EARLY TERMINATION.................................................................................. 53 
13.0 
SUBJECT DISCONTINUATION ....................................................................................... 54 
14.0 
CLINICAL LABORATORY SAMPLES ............................................................................ 55 
15.0 
BIOANALYTICAL LABORATORY ................................................................................. 55 
 
BOEs Urine (1st void of the day): ............................................................................... 57 
15.1
 
BOE Blood (after overnight fasting, at least 8 hours): ............................................... 57 
15.2
 
BOPHs Urine (1st void of the day): ............................................................................ 57 
15.3
 
BOPHs Blood (after overnight fasting, at least 8 hours): ........................................... 57 
15.4
 
Urine Creatinine (1st void of the day) ......................................................................... 57 
15.5
16.0 
STATISTICAL METHODS ................................................................................................. 57 
 
Statistical Analysis Plan ............................................................................................. 57 
16.1
 
Sample Size Estimation .............................................................................................. 58 
16.2
 
Criteria for Evaluation ................................................................................................ 58 
16.3
16.3.1 
Primary Endpoints .................................................................................. 58 
16.3.2 
Secondary Endpoints .............................................................................. 58 
16.3.3 
Exploratory Endpoints ............................................................................ 59 
16.3.4 
Clinical Safety Endpoints ....................................................................... 59 

 
 
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Analyses Data Set ....................................................................................................... 60 
16.4
16.4.1 
Demographics and Baseline Characteristics ........................................... 60 
16.4.2 
Endpoint Analyses .................................................................................. 60 
 
Dealing with Missing Data ......................................................................................... 62 
16.5
 
Subgroup Analysis ..................................................................................................... 62 
16.6
17.0 
DATA MANAGEMENT ...................................................................................................... 62 
 
Database Design and Creation ................................................................................... 63 
17.1
 
Data Coding ................................................................................................................ 63 
17.2
 
Data Entry and Verification ....................................................................................... 63 
17.3
 
Study Results Data Transfer ....................................................................................... 63 
17.4
 
Data Validation .......................................................................................................... 63 
17.5
 
Database Lock ............................................................................................................ 63 
17.6
18.0 
MONITORING THE STUDY ............................................................................................. 64 
19.0 
REPORTING FOR THE STUDY ....................................................................................... 64 
 
Case Report Forms ..................................................................................................... 64 
19.1
 
Study Report ............................................................................................................... 64 
19.2
20.0 
GENERAL ............................................................................................................................. 64 
 
Confidentiality ............................................................................................................ 64 
20.1
 
Responsibility of the Investigator ............................................................................... 65 
20.2
 
Procedure for Amendments to Protocol ..................................................................... 65 
20.3
 
Institutional Review Board ......................................................................................... 65 
20.4
 
Termination of Study.................................................................................................. 66 
20.5
 
Study Records Retention ............................................................................................ 66 
20.6
21.0 
REFERENCES ...................................................................................................................... 67 
APPENDICES .................................................................................................................................... 68 
 
 
 
 

 
 
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STUDY SYNOPSIS 
ALCS Protocol Number:  
ALCS-RA-17-11-EV 
Abbreviated Protocol Title:  
e-Vapor SWITCHing Study to Assess Health Risks in Adult Smokers- Extension 
(e-SWITCH-EXT) 
Long Protocol Title:  
An Open-Label, Parallel-Group, Controlled Study to Evaluate Changes in Biomarkers of 
Cigarette Smoke Exposure and Biomarkers of Potential Harm in Adult Smokers Who 
Completely Switch to Using e-Vapor Products for 24 Weeks 
Study Products: 
Test e-vapor products (supplied by Altria Client Services LLC): 
• 
Product XLCB = Test EVP (currently marketed by Nu Mark LLC as MarkTen® XL 
Bold Classic [4.0% NBW]) [CVR2.6.8] Formula: 10381-44-B; Name: “Rosetta”; 
Label: B44 
• 
Product XLMB = Test EVP (currently marketed by Nu Mark LLC as MarkTen® XL 
Bold Menthol [4.0% NBW]) [CVR2.6.8] Formula: 10381-40-E; Name: “Spencer”; 
Label: 40E  
Reference product (supplied by subject at their own cost): 
• 
Subject’s own brand1 commercially available conventional cigarettes 
1 own brand: subject’s choice, no restriction on brand at any time during the study 
Study Duration: 
The study participants in this extension study will continue to use the Test and Control 
Products, in the groups assigned, for an additional 12 weeks after completing the 12-week 
ALCS-RA-16-06-EV [CA20130] study, for a total of 24 weeks. The expected study 
duration from Screening (of the 12-week ALCS-RA-16-06-EV study) to End of Study for 
each individual subject is approximately 28 weeks. 
Estimated Study Sites:  
6-10 study sites 
Study Objectives: 
The Primary Objective is to:  
Compare absolute changes in selected biomarkersa from Baselineb to Week 24 (EOS) 
between adult smokers who continue to smoke conventional cigarettes (Control group) ad 
libitum and adult smokers who have completelyc switched to ad libitum use of the test 
e-vapor products (Test groups) for 24 weeks.  

 
 
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a Seleted biomarkers include: 
o White Blood Cell Count (WBC) 
o High Density Lipoprotein Cholesterol (HDL-C)  
o Urinary 8-epi-prostaglandin F2α 
o Urinary 11-dehydrothromboxane B2 
o Blood Soluble Intercellular Adhesion Molecule-1 (sICAM-1)  
o Urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total 
NNAL)  
o Carboxyhemoglobin (COHb)  
b Baseline of the 12-week ALCS-RA-16-06-EV study (CA20130), Week 1, will be used. 
c Subjects who exclusively use e-vapor products and have exhaled carbon monoxide (eCO) 
measurements ≤ 8 ppm from Week 6 (of the 12-week ALCS-RA-16-06-EV study) through 
Week 24 (EOS) and urine N-nitrosonornicotine (NNN) levels from Week 6 (of the 12-week 
ALCS-RA-16-06-EV study) through Week 24 (EOS) consistent with switching to an 
e-vapor product. 
The Secondary Objectives are to:  
• Assess changes in forced expiratory volume in the first second (FEV1), forced vital 
capacity (FVC) and FEV1/FVC ratios from Screening/Visit 2 of the 12-week 
ALCS-RA-16-06-EV study (CA20130) to Week 18 and to Week 24 (EOS) between 
the Test and Control groups 
• Compare changes in selected biomarkers (same as those in the primary objective) 
from Baseline to Week 18 between Test and Control groups  
• Determine the number of cigarettes smoked (Test and Control groups) from Baseline 
through Week 24 (EOS) 
• Assess changes in the amount of test e-vapor product use (Test groups only) from 
Baseline through Week 24 (EOS) 
• Assess adherence to protocol by comparing changes from Baseline through Week 24 
(EOS) within the Test groups for eCO and urinary NNN  
The Exploratory Objectives are to: 
• Assess changes in biomarkers of potential harm (BOPHs) and biomarkers of 
exposure (BOEs) (same as in the primary objective) from Baseline through Week 24 
(EOS) between the subgroups that used different flavored Test e-vapor products  
• Assess changes in urine nicotine equivalents (NE) from Baseline through Week 24 
(EOS) within and between Test and Control groups 

 
 
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• Assess changes in the QGEN and TQOLIT questionnaires and the Cough 
Questionnaire responses from Baseline through Week 24 (EOS) between the Test 
and Control groups 
• Assess reasons for test product use/not-use at EOS and modified Cigarette 
Evaluation Questionnaire (mCEQ) questionnaires from Baseline to Week 24 (EOS) 
for the Test groups 
• Collect blood and urine samples for future assessment of BOE and or BOPH 
Study Design:  
This research study will utilize a parallel-group, open-label, controlled design and will be 
conducted at multiple study sites. Up to 250 adult male and female (neither gender should 
account for more than 60% of the population) smokers (30 to 65 years of age, inclusive, 
determined at Screening [Visit 1] of the 12-week ALCS-RA-16-06-EV study) who 
completed the 12-week ALCS-RA-16-06-EV study (CA20130), were compliant with the 
requirements of the 12-week study, and continue to satisfy all inclusion/exclusion criteria of 
that study, will be invited to enroll into this study and remain in the group into which they 
were randomized in the 12-week ALCS-RA-16-06-EV study. 
Enrolled subjects in Test Product groups will be provided a 3-week supply of the Test 
Product to which they were randomized in the 12-week ALCS-RA-16-06-EV study and will 
be given a return date for Visit 2 (Week 15). 
At Visits 2 and 4 (Week 15 and Week 21, respectively), subjects will return to the study site 
with all of their used and unused cartridges, which will be counted. Vital signs will be taken 
and medical history and symptom-driven physical examination will be performed. 
Compliance with daily tobacco use reporting will be discussed and eCO will be measured; 
use of non-Test Product and/or eCO measurements > 5 ppm will prompt counceling by 
clinic staff on the Tobacco and Nicotine Restrictions and, for measurements > 8 ppm, 
potential for removal from the study. Test Product for the following 3 weeks and a urine 
collection container will be dispensed. Subjects will receive reminder calls regarding their 
following clinic visits and need to collect the first void urine prior to returning to the study 
site (Visits 3 and 5). 
At Visit 3 (Week 18), procedures will be as described for Visits 2 and 4 (Weeks 15 and 21, 
respectively), with the addition of spirometry, questionnaires, and collection of urine and 
blood for Week 18 biomarkers and future biomarker assessments. A urine collection 
container will not be dispensed at Visit 3. 
At Visit 5 (Week 24), subjects will return to the study site with all of their used and unused 
cartridges (which will be counted), blood and urine samples will be collected for Week 24 
biomarker assessments, questionnaires will be completed, and subjects will undergo EOS 
procedures and be discharged from the study. 

 
 
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All subjects will report their cigarettes per day (CPD) (Control and Test groups) and Test 
product use (Test groups only) daily using a Short Message Service (SMS), i.e., text 
message, based system (Med-Quest). The self-reported CPD, use of other tobacco products, 
and measurements of eCO and NNN taken during the in-clinic visits will be used to monitor 
subject compliance with exclusive use of the Test products. All subjects will return to the 
study sites for four visits at Weeks 15, 18, 21, and 24. 
Throughout this protocol, Screening refers to Visit 1 and/or Visit 2 of the 12-week 
ALCS-RA-16-06-EV study (CA20130), and study weeks are relative to Week 1 (Visit 3) of 
the 12-week ALCS-RA-16-06-EV study. Baseline values reported on Day 1 (Week 1) or at 
Screening (for spirometry only) of the 12-week ALCS-RA-16-06-EV study (CA20130) will 
be used. 
Study Diagram: 
 
Study Visits: 
• Visit 1: (Week 12, Day 84 +/- 3 days) same visit as Visit 7 of the 
ALCS-RA-16-06-EV (CA20130) study 
• Visit 2: (Week 15, Day 105 +/- 3 days) 
• Visit 3: (Week 18, Day 126 +/- 3 days) 
• Visit 4: (Week 21 Day 147 +/- 3 days) 
• Visit 5: (Week 24, Day 168 +/- 3 days, EOS [or Early Termination])  

 
 
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Number of Subjects and Groups: 
Up to 250 adult smokers who completed and were compliant with the requirements of the 
12-week ALCS-RA-16-06-EV study (CA20130) will be enrolled as follows: 
• Test 1 group (n=100): Exclusive ad libitum use of test e-vapor Product XLCB, 
without use of any other type of tobacco/nicotine containing product, for the entire 
additional 12 weeks 
• Test 2 group (n=100): Exclusive ad libitum use of test e-vapor Product XLMB, 
without use of any other type of tobacco/nicotine containing product, for the entire 
additional 12 weeks 
• Control group (n=50):  Continue smoking under ad libitum use of subjects’ own 
brand of conventional lit-end cigarettes, without use of any other type of 
tobacco/nicotine containing product, for the entire additional 12 weeks 
Study Population:  
The study population will consist of up to 250 adult (30 – 65 years of age as determined at 
Screening [Visit 1] of the 12-week ALCS-RA-16-06-EV study) cigarette smokers who were 
compliant with the requirements and continue to satisfy all inclusion/exclusion criteria of 
the 12-week ALCS-RA-16-06-EV study (CA20130). In addition, subjects must satisfy the 
following inclusion/exclusion criteria. 
Inclusion criteria: 
Subjects must satisfy the following criteria before being enrolled into the study. Subjects 
must: 
1) have participated in and completed the 12-week ALCS-RA-16-06-EV study and 
have Baseline biomarker samples collected; 
2) demonstrate willingness to participate by signing an IRB-approved informed 
consent form (ICF) for the study; 
3) have demonstrated consistent daily reporting of product use in the 12-week 
ALCS-RA-16-06-EV study (≥ 75% reporting compliance); 
4) if randomized to a Test group, have reported an average of no more than 10% of 
Baseline cigarette smoking per day through Week 11 of the 12-week 
ALCS-RA-16-06-EV study; 
5) if randomized to a Test group, have reported use of at least two Test product 
cartridges per week in the 12-week ALCS-RA-16-06-EV study; 
6) if randomized to a Test group, have eCO measurements of ≤ 8 ppm at the 6-, 9-, 
and 12-week post-Baseline time points in the 12-week ALCS-RA-16-06-EV study; 

 
 
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7) have daily access to text messaging capable cellular phone for daily product use 
reporting; 
8) if female (all females), have a negative urine pregnancy test at Week 12 (Visit 1) 
through Week 24 (Visit 5), inclusive; 
9) if female, heterosexually active, and of childbearing potential (i.e., not surgically 
sterile or 2 years naturally postmenopausal), must have used a medically accepted 
method of contraception (listed below in a) and b)) prior to Screening, Visit 1 of the 
12-week ALCS-RA-16-06-EV study and must agree to continue to use such 
method(s) through Week 24 (EOS); 
a) Surgically sterile includes bilateral tubal ligation, Essure, hysterectomy, or 
bilateral oophorectomy at least 6 months prior to Screening, Visit 1 of the 
12-week ALCS-RA-16-06-EV study. Naturally postmenopausal is defined as 
women having 2 years without menses. 
b) Acceptable methods of contraception are: hormonal (i.e., oral, transdermal patch, 
implant, or injection) consistently for at least 3 months prior to Screening, 
Visit 1 of the 12-week ALCS-RA-16-06-EV study; double barrier (i.e., condom 
with spermicide or diaphragm with spermicide) consistently for at least 4 weeks 
prior to Screening, Visit 1 of the 12-week ALCS-RA-16-06-EV study; and 
intrauterine device for at least 3 months prior to Screening, Visit 1 of the 
12-week ALCS-RA-16-06-EV study; or only have a partner who has been 
vasectomized for at least 6 months prior to Screening, Visit 1 of the 12-week 
ALCS-RA-16-06-EV study. 
10) Be willing and able to comply with the requirements of the study. 
Exclusion criteria: 
Subjects may be excluded from the study if there is evidence of any of the following 
criteria. Exceptions may be permitted at the discretion of the Investigator and in 
consultation with the Sponsor or designee provided there would be no additional risk to the 
subject. Any exceptions will be documented.  
1) Have clinically significant abnormal findings on the physical examination, vital 
signs, or electrocardiogram (ECG) at the EOS visit (Visit 7) of the 12-week 
ALCS-RA-16-06-EV study that would jeopardize the safety of the subject, in the 
opinion of the Investigator;  
2) Female subjects who are pregnant (as determined at the EOS visit [Visit 7] of the 
12-week study), lactating, or intend to become pregnant from Visit 1 (Week 12) 
through Week 24 (EOS); 
3) Use of any medication for depression, asthma, or diabetes at any time during the 
study; 

 
 
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4) Use of HDL-C raising medication / supplements (e.g., niacin, gemfibrozil, 
fenofibrate, etc.) at any time during the study; 
5) Subject or a first-degree relative (i.e., parent, spouse, sibling, or child) is a current 
or former employee of the tobacco industry or a named party or class representative 
in litigation with any tobacco company;  
6) Subject or a first-degree relative (i.e., parent, spouse, sibling, or child) is a current 
or former employee of Celerion or any of the clinical study sites. 
Statistics:  
Sample size estimation  
The 12-week ALCS-RA-16-06-EV study (CA20130) was designed to detect a statistically 
significant difference in change from Baseline to the end of the study in 5 out of the 
7 primary biomarkers between the Test and the Control groups. Total NNAL, COHb, 
11-dehydrothromboxane B2, 8-epi-prostaglandin F2α, WBC, and HDL values from a 
previous PMUSA longitudinal study (Study #: EHCJLI/02/02) for the Electronic Heating 
Cigarette Smoking System and sICAM values from another source22 were used for the 
sample size calculation. A total of 450 subjects (300 in the Test groups and 150 in the 
Control group) were randomized. 
In the current study, a total of up to 250 subjects (up to 100 in each of the Test groups and 
50 in the Control group) who were compliant with the requirements of the 12-week 
ALCS-RA-16-06-EV study and continue to satisfy all inclusion/exclusion criteria of that 
study will be enrolled. The number of subjects is based on the anticipated number of 
protocol-compliant subjects in the Test groups rather than the power required to 
discriminate between Test and Control groups. 
Primary Endpoints  
The primary endpoints are changes from Baseline to Week 24 (EOS) in the following 
biomarkers measured at Week 24: 
• WBC in whole blood (103 µg/L) 
• HDL-C in serum (mg/dL) 
• 8-epi-prostaglandin F2α in urine with creatinine adjusted (ng/g Cr) 
• 11-dehydrothromboxane B2 in urine with creatinine adjusted (ng/g Cr) 
• Soluble Intercellular Adhesion Molecule – 1 (sICAM-1) in serum (ng/mL) 
• Total NNAL in urine with creatinine adjusted (ng/g Cr) 
• COHb in whole blood (% sat) 

 
 
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Secondary Endpoints 
The secondary endpoints are: 
1) FEV1 (% predicted), FCV, and FEV1/FVC measured at Screening (Visit 2 of the 
12-week ALCS-RA-16-06-EV study), Week 18, and Week 24 (EOS) 
2) Levels of selected biomarkers (same as the primary endpoints) and the following 
additional biomarkers measured at Baseline, Week 18, and Week 24 (EOS): 
a) Creatinine-adjusted NNN in urine (ng/g Cr) and eCO 
3) The average daily cigarettes smoked and Test Product use reported by subjects from 
Baseline through Week 24 (EOS) 
a) Test Products used per day, as determined by the number of new cartridges used 
and the average number of puffs taken (1 – 20 or >20), to be documented 
through text message 
b) The number of cigarettes smoked per day will be documented by the subjects 
through text message 
Exploratory Endpoints 
The exploratory endpoints are: 
1) Assess changes in BOPHs and BOEs (same as in the primary objective) measured at 
Baseline, Week 18, and Week 24 (EOS) between the subgroups that used different 
flavored Test e-vapor products 
2) NE (nicotine, cotinine, trans-3'-hydroxycotinine, trans-3'-hydroxycotinine-O-
glucuronide, nicotine-N-glucuronide, and cotinine-N-glucuronide) in urine with 
creatinine adjustment (mg/g Cr) measured at Baseline, Week 18, and Week 24 
(EOS) 
3) Responses (Score) to the QGEN and TQOLIT questionnaires and the Cough 
Questionnaire recorded at Baseline, Week 18, and Week 24 (EOS) 
4) Reponses to Reasons for Use and Not-use of Test Product (Week 24 [EOS]) and 
mCEQ questionnaires (Baseline and Week 24) (Test group only) 
Statistical Analysis Method: 
Subject Demographics and Baseline Characteristics: 
Demographics and baseline characteristics will be summarized by study group with 
descriptive statistics (the number of non-missing values, mean, median, standard deviation 
[SD], median, minimum, maximum, coefficient of variation [CV], and 95% confidence 
interval, as appropriate) for continuous variables (e.g., BMI) and frequency counts for 
categorical variables (e.g., gender). 

 
 
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Primary and Secondary Variables  
Primary Variable Analysis 
A linear mixed model for repeated measures (MMRM) analysis will be used for comparing 
each Test group to the Control group in the mean absolute change from Baseline to 
Week 24 (EOS) for each primary endpoint. In the model, study group, visit, and study group 
by visit interaction, gender, age class, race, and BMI class are the fixed effect factors. The 
baseline value of the response biomarker is the covariate and subject is the random effect 
factor. The unstructured covariance structure will be used for modeling covariance. The 
least-squares mean difference, 95% confidence interval, and p-value will be provided for 
the group difference. The analysis will be conducted on the modified intent to treat (MITT) 
population. 
To assess the robustness of the primary MMRM analysis to the possible violation of the 
missing at random (MAR) assumption, the pattern mixture model based on the non-future 
dependent missing value restriction will be applied. In addition, a supportive analysis based 
on the per-protocol (PP) population will also be conducted.  
Descriptive statistics (the number of subjects with non-missing data, number of subjects 
with missing data, mean, standard deviation, median, minimum, and maximum) will be 
used to summarize the raw values (creatinine-adjusted raw values for urine variables) and 
absolute change from baseline values. 
Secondary Variable Analyses  
• Changes in FEV1, FVC, and FEV1/FVC ratios from Baseline to Week 18 and to 
Week 24 (EOS) in the Test and Control groups. 
• The MMRM as used for the primary endpoints will be used to test the differences in 
the mean absolute change from Baseline to Week 18 for the selected biomarkers 
(WBCs, HDL-C, COHb, total NNAL, 8-epi-prostaglandin F2α, 
11-dehydrothromboxane B2, and sICAM-1) between each Test group and the 
Control group. 
• Descriptive statistics (the number of subjects with non-missing data, number of 
subjects with missing data, mean, standard deviation, median, minimum, and 
maximum) will be used to summarize the average cigarettes per day and the average 
number of e-vapor cartridge used per day by group from Week 12 through Week 18 
and from Week 19 through Week 24 (EOS). Frequency tables will also be used to 
summarize the number and percent of subjects with a reduction, no change, or 
increase in cigarette or e-vapor cartridge use from Baseline to Week 24 (EOS) for 
each study group.  
• A frequency table (n and %) will be used to summarize use of other tobacco 
products, eCO and NNN for assessment of compliance and noncompliance for each 
study group. 

 
 
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Exploratory Endpoints/Variable Analyses 
The MMRM approach will be used to provide the estimates for: 
• changes in BOPHs and BOEs from Baseline to Week 24 (EOS) between the 
subgroups that used different flavored Test e-vapor products  
• changes in urine NE from Baseline to Week 18 and Week 24 (EOS) within each test 
group and between the Test and Control groups 
• changes in the QGEN and TQOLIT questionnaires and the Cough Questionnaire 
from Baseline to Week 24 (EOS) in the Test and Control groups 
Subgroup Analysis 
Subgroup analyses will be conducted for the Week 24 (EOS) change from Baseline in the 
primary biomarkers for covariates including gender, age class, race, and BMI that prove to 
be statistically significant in the MMRM model. 
Clinical Safety 
Adverse events (AEs) will be coded with the Medical Dictionary for Regulatory Activities 
(MedDRA®). 
AEs will be listed in by-subject data listings. Frequency counts of AEs will be provided by 
system organ class and preferred terms, and study group. Frequency counts of AEs will also 
be listed and summarized by severity and relationship to product.  
Clinical safety analyses will include summaries of clinical safety measures (blood pressure, 
ECG, vital signs, clinical chemistry, and hematology). 
More details about the data analysis will be described in the Statistical Analysis Plan (SAP). 
All statistical analyses will be performed with SAS® software. 
 
 
 

 
 
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SUMMARY OF EVENTS/ASSESSMENTS 
EVENTS/ASSESSMENTS 
Visit 1 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Week 12 
Day 84 
(+/- 3) 
Week 15 
Day 105 
(+/- 3) 
Week 18 
Day 126 
(+/- 3) 
Week 21 
Day 147 
(+/- 3) 
Week 24 
Day 168 (+/- 3) 
End of Study / 
Early Term 
Informed Consent 
X 
 
 
 
 
Review of Inclusion / Exclusion Criteria 
X 
X 
X 
X 
X 
Vital Signs 2 
 
X 
X 
X 
X 
Body Weight 
 
 
 
 
X 
Body Mass Index 
 
 
 
 
X 
Spirometry 3 
 
 
X 
 
X 
Smoking Cessation Information 
 
 
 
 
X 
Clinical Chemistry (8 hr fasting) 
 
 
 
 
X 
Hematology (8 hr fasting) 
 
 
 
 
X 
Urinalysis 
 
 
 
 
X 
Review of Concomitant Medications 
X 
X 
X 
X 
X 
Review of Tobacco and Nicotine 
Restrictions 
X 
X 
X 
X 
 
Physical Examination 
 
X 4 
X 4 
X 4 
X 4 
12-Lead ECG 5 
 
 
 
 
X 
Urine Pregnancy Test 
 
X 
X 
X 
X 
Review of AEs 
X 
X 
X 
X 
X 
QGEN and TQOLIT 6 questionnaires 
 
 
X 
 
X 
Cough Questionnaire 
 
 
X 
 
X 
mCEQ Questionnaire 
 
 
 
 
X 
Reasons of Use/Not-Use Test Product 
Questionnaire 7 
 
 
 
 
X 
Confirm Regular Cigarette Brand 
 
X 8 
X 8 
X 8 
X 8 
Test e-Vapor Product Dispensation 
X 
X 
X 
X 
 
Test e-Vapor Product Collection 
 
X 
X 
X 
X 
Reminder Phone Calls 
X 
X 
X 
X 
X 
Distribute 1st Morning Void Containers 
 
X 
 
X 
 
Urine (1st Void of Day) for BOEs and 
BOPHs 9, 10 
 
 
X 
 
X 
Blood Collection for BOPHs 11 
 
 
X 
 
X 
Blood Collection for COHb 11 
 
 
X 
 
X 
Bio-Banking 
 
 
X 
 
X 
Product Use Reporting 12 
X 
X 
X 
X 
X 

 
 
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EVENTS/ASSESSMENTS 
Visit 1 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Week 12 
Day 84 
(+/- 3) 
Week 15 
Day 105 
(+/- 3) 
Week 18 
Day 126 
(+/- 3) 
Week 21 
Day 147 
(+/- 3) 
Week 24 
Day 168 (+/- 3) 
End of Study / 
Early Term 
Exhaled CO Measurement 
 
X 
X 
X 
X 
Changes in Your Health and Well-Being 
Questionnaire 
X 
 
 
 
X 
End of Study Questionnaire 
 
 
 
 
X 
 
 
AE = adverse event; BOE = biomarker of exposure; BOPH = biomarker of potential harm; CO = carbon 
monoxide; COHb = carboxyhemoglobin; CPD = cigarettes per day; ECG = electrocardiogram; FEV1 = forced 
expiratory volume in 1 second; FVC = forced vital capacity; HDL-C = high-density lipoprotein cholesterol; 
hr = hour(s); ID = identification; IVRS = interactive voice response system; NE = nicotine equivalents; 
NNAL = 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol; 
sICAM-1 
= 
Soluble 
intercellular 
adhesion 
molecule-1; SMS = Short Message Service; WBC = white blood cell. 
 
1 
Visit 1 of the current study is the same visit as Visit 7 of the 12-week ALCS-RA-16-06-EV (CA20130) 
study. Study procedures scheduled at this visit should be performed only once (with the exception of 
rechecks). 
2 
Vital signs (respiratory rate, pulse rate, blood pressure, and oral temperature) in the sitting position after at 
least 5 minutes of rest and at least 15 minutes after the last conventional cigarette smoked or test e-vapor 
product used. 
3 
Spirometry includes FEV1, FVC, and FEV1/FVC ratio measurements. 
4 
Physical examination (symptom-driven). 
5 
After at least 5 minutes resting in supine position. 
6 
All Groups will be given the same QGEN questionnaire but different TQOLIT questionnaires: 
Appendix 1A for the Control Group, Appendix 1B for the Test Groups 
7 
Questionnaire given to Test group only. 
8 
Control group only, photocopy the pack if there has been a change from Screening of the 12-week 
ALCS-RA-16-06-EV (CA20130) study. 
9 
Urinary creatinine will be measured in all urine samples to allow for adjustment of all urine biomarkers. 
10 Spot urine (first void of the day, after at least 4 hours since prior void) collections will be used for the 
analysis of BOEs (total NNAL, NE, NNN) and BOPHs (11-dehydrothromboxane B2, 8-epi-prostaglandin 
F2α).  
11 Blood will be collected after overnight fasting (at least 8 hours) and will be used for the analysis of COHb 
and BOPHs (WBC, sICAM-1, HDL-C). 
12 Daily product use (conventional cigarettes or test e-vapor product) will be reported daily (Day 84/Week 12 
through Day 168/Week 24) by subjects using a SMS, i.e., text message, based system (Med-Quest) to 
assess product use and compliance during the study. 
 
 

 
 
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ABBREVIATIONS AND DEFINITIONS 
AE 
Adverse event 
ALCS 
Altria Client Services LLC 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
BOE 
Biomarker of exposure 
BOPH 
Biomarker of potential harm 
BUN 
Blood urea nitrogen  
°C 
Degrees Celsius 
CDMS 
Clinical Data Management System 
CFR 
Code of Federal Regulations 
CLIA-88 
Clinical Laboratory Improvement Amendments of 1988 
CO 
Carbon monoxide 
COHb 
Carboxyhemoglobin 
CPD 
Cigarettes per day 
CRO 
Clinical Research Organization 
CSP 
Clinical safety population 
CV 
Coefficient of variation 
DMP 
Data management plan 
ECG 
Electrocardiogram 
eCO 
Exhaled carbon monoxide 
eCRF 
Electronic case report form 
EOS 
End of study 
°F 
Degrees Fahrenheit 
FDA 
Food and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
HDL-C 
High-density lipoprotein cholesterol 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
ID 
Identification 
LLC 
Limited Liability Company 
IRB 
Institutional Review Board 
ITT 
Intent to treat 
IVRS 
Interactive Voice Response System 
Kg 
Kilogram(s) 
LED 
Light-emitting diode 
M 
Meter(s) 
MAR 
Missing at random 
mCEQ 
Modified Cigarette Evaluation Questionnaire 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram(s) 
MITT 
Modified intent to treat 
mL 
Milliliter(s) 

 
 
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MMRM 
Mixed model for repeated measures 
N 
Number, sample size 
NBW 
Nicotine by weight 
NE 
Nicotine equivalents 
ng 
Nanograms 
NNAL 
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol 
NNN 
N-nitrosonornicotine 
PFT 
Pulmonary function test 
pg 
Picogram 
PK 
Pharmacokinetic 
PP 
Per-protocol 
ppm 
Parts per million 
QA 
Quality assurance 
QGEN 
Generic Quality of Life 
RBC 
Red blood cell  
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
sICAM-1 
Soluble intercellular adhesion molecule-1 
SD 
Standard deviation 
SMS 
Short Message Service 
SOP(s) 
Standard operating procedure(s) 
TQOLIT 
Tobacco Quality of Life Impact Tool 
US 
United States 
USP 
United States Pharmacopoeia 
WBC 
White blood cell  
WHO-DD 
World Health Organization Drug Dictionary 
 
 
 

 
 
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1.0 
INTRODUCTION AND STUDY RATIONALE 
 
Purpose of this Study 
1.1
In section VI (H) (2) of the FDA draft guidance for industry, Premarket Tobacco 
Product Applications for Electronic Nicotine Delivery Systems, it states: “To evaluate 
the acute and chronic health effects associated with the product, FDA recommends 
including studies, other scientific evidence, or both, that identify biomarkers of 
exposure, biomarkers of harm, and health outcome measurements or endpoints.” The 
current study is an extension of the 12-week ALCS-RA-16-06-EV (CA20130) study 
and its purpose is to evaluate changes in BOPHs and BOEs in adult cigarette smokers 
who completely switch to the test e-vapor products (Product XLCB or 
Product XLMB) for 24 weeks. Changes will be evaluated compared to Baseline 
values reported on Day 1 (Week 1) of the 12-week ALCS-RA-16-06-EV (CA20130) 
study. 
 
Hypothesis 
1.2
If adult smokers completely switch to exclusive use of an e-vapor test product for 
24 weeks, all selected biomarkers will change in a favorable direction, with at least 5 
out of 7 biomarkers demonstrating a statistically significant change from baseline 
compared to cigarette smoking.  
 
Rationale 
1.3
Cigarette smoking produces the predominance of the morbidity and mortality from 
the use of tobacco products. Cigarette smoking is the leading preventable cause of 
death in the United States, primarily due to cancers, respiratory, and cardiovascular 
disease1. More than 4,800 different chemical constituents have been identified in 
cigarette smoke2, many of these chemicals are present either in the particulate or 
gas/vapor phase of the smoke aerosol. The test e-vapor products do not produce the 
vast majority of these compounds, therefore switching from cigarettes to the test 
e-vapor products should result in large reductions in exposure to many of the 
chemicals present in cigarette smoke. However, there is currently no evidence of the 
impact of switching from cigarettes to the test e-vapor products. This study is 
designed to measure changes in biomarkers of exposure and biomarkers of potential 
harm when adult smokers switch to the test e-vapor products for 24 weeks. The 
results from this study will provide supportive evidence to the overall assessment of 
the reduced risk potential of test e-vapor products. 

 
 
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2.0 
STUDY OBJECTIVES 
 
Primary Objective 
2.1
The primary objective of this study is to compare absolute changes in selected 
biomarkersa from Baselineb to Week 24 (EOS) between adult smokers who continue 
to smoke conventional cigarettes (Control group) ad libitum and adult smokers who 
have completelyc switched to ad libitum use of the test e-vapor products (Test groups) 
for 24 weeks.  
a Seleted biomarkers include: 
• WBC 
• HDL-C 
• Urinary 8-epi-prostaglandin F2α 
• Urinary 11-dehydrothromboxane B2 
• Blood sICAM-1 
• Urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides 
(total NNAL)  
• COHb 
b Baseline of the 12-week ALCS-RA-16-06-EV study (CA20130), Week 1, will be 
used. 
c Subjects who exclusively use e-vapor products and have eCO measurements 
≤ 8 ppm from Week 6 (of the 12-week ALCS-RA-16-06-EV study) through Week 24 
(EOS) and urine NNN levels from Week 6 (of the 12-week ALCS-RA-16-06-EV 
study) through Week 24 (EOS) consistent with switching to an e-vapor product. 
 
Secondary Objectives 
2.2
The secondary objectives are to: 
• Assess changes in FEV1, FVC and FEV1/FVC ratios from Screening/Visit 2 of the 
12-week ALCS-RA-16-06-EV study (CA20130) to Week 18 and to Week 24 
(EOS) between the Test and Control groups 
• Compare changes in selected biomarkers (same as those in the primary objective) 
from Baseline to Week 18 between Test and Control groups 
• Determine the number of cigarettes smoked (Test and Control groups) from 
Baseline through Week 24 (EOS) 
• Assess changes in the amount of test e-vapor product use (Test groups only) from 
Baseline through Week 24 (EOS) 
• Assess adherence to protocol by comparing changes from Baseline through 
Week 24 (EOS) within the Test groups for eCO and urinary NNN 

 
 
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Exploratory Objectives 
2.3
The exploratory objectives are to: 
• Assess changes in BOPHs and BOEs (same as in the primary objective) from 
Baseline through Week 24 (EOS) between the subgroups that used different 
flavored Test e-vapor products 
• Assess changes in urine NE from Baseline through Week 24 (EOS) within and 
between Test and Control groups 
• Assess changes in the QGEN and TQOLIT questionnaires and the Cough 
Questionnaire responses from Baseline through Week 24 (EOS) between the Test 
and Control groups 
• Assess reasons for test product use/not-use at EOS and mCEQ questionnaires 
from Baseline to Week 24 (EOS) for the Test groups 
• Collect blood and urine samples for future assessment of BOE and or BOPH 
3.0 
SUMMARY OF STUDY DESIGN 
 
Design 
3.1
This research study will utilize a parallel-group, open-label, controlled design and 
will be conducted at multiple study sites. Up to 250 adult male and female (neither 
gender should account for more than 60% of the population) smokers (30 to 65 years 
of age, inclusive, determined at Screening [Visit 1] of the 12-week ALCS-RA-16-06-
EV study) who completed the 12-week ALCS-RA-16-06-EV study (CA20130), were 
compliant with the requirements of the 12-week study, and continue to satisfy all 
inclusion/exclusion criteria of that study, will be invited to enroll into this study and 
remain in the group into which they were randomized in the 12-week 
ALCS-RA-16-06-EV study. 
• Control Group (n=50): Continue smoking under ad libitum use of subjects’ 
own brand of conventional lit-end cigarettes, without use of any other type of 
tobacco/nicotine containing product, for the entire additional 12 weeks 
• Test 1 Group (n=100): Continue ad libitum use of test e-vapor products 
(Product XLCB), without use of any other type of tobacco/nicotine containing 
product, for the entire additional 12  weeks 
• Test 2 Group (n=100): Continue ad libitum use of test e-vapor products 
(Product XLMB), without use of any other type of tobacco/nicotine 
containing product, for the entire additional 12 weeks 

 
 
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Enrolled subjects in Test Product groups will be provided a 3-week supply of the Test 
Product to which they were randomized in the 12-week ALCS-RA-16-06-EV study 
and will be given a return date for Visit 2 (Week 15). 
At Visits 2 and 4 (Week 15 and Week 21, respectively), subjects will return to the 
study site with all of their used and unused cartridges, which will be counted. Vital 
signs will be taken and medical history and symptom-driven physical examination 
will be performed. Compliance with daily tobacco use reporting will be discussed and 
eCO will be measured; use of non-Test Product and/or eCO measurements > 5 ppm 
will prompt counceling by clinic staff on the Tobacco and Nicotine Restrictions and, 
for measurements > 8 ppm, potential for removal from the study. Test Product for the 
following 3 weeks and a urine collection container will be dispensed. Subjects will 
receive reminder calls regarding their following clinic visits and need to collect the 
first void urine prior to returning to the study site (Visits 3 and 5). 
At Visit 3 (Week 18), procedures will be as described for Visits 2 and 4 (Weeks 15 
and 21, respectively), with the addition of spirometry, questionnaires, and collection 
of urine and blood for Week 18 biomarkers and future biomarker assessments. A 
urine collection container will not be dispensed at Visit 3. 
At Visit 5 (Week 24), subjects will return to the study site with all of their used and 
unused cartridges (which will be counted), blood and urine samples will be collected 
for Week 24 biomarker assessments, questionnaires will be completed, and subjects 
will undergo EOS procedures and be discharged from the study. 
All subjects will report their CPD (Control and Test groups) and Test product use 
(Test groups only) daily using a SMS, i.e., text message, based system (Med-Quest). 
The self-reported CPD, use of other tobacco products, and measurements of eCO and 
NNN taken during the in-clinic visits will be used to monitor subject compliance with 
exclusive use of the Test products. All subjects will return to the study sites for four 
visits at Weeks 15, 18, 21, and 24. 
Throughout this protocol, Screening refers to Visit 1 and/or Visit 2 of the 12-week 
ALCS-RA-16-06-EV study (CA20130), and study weeks are relative to Week 1 
(Visit 3) of the 12-week ALCS-RA-16-06-EV study. Baseline values reported on 
Day 1 (Week 1) or at Screening (for spirometry only) of the 12-week 
ALCS-RA-16-06-EV study (CA20130) will be used. 

 
 
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The overall design of the study is shown below. 
 
 
Study Duration 
3.2
The expected duration of this study, from first subject, first visit (Visit 1, Week 12), 
through last subject, last visit will be approximately 12 weeks. The expected study 
duration from Screening (of the 12-week ALCS-RA-16-06-EV study) to End of 
Study for each individual subject is approximately 28 weeks. 
 
Clinical Safety Evaluations 
3.3
Clinical safety evaluations will be performed to ensure that subjects meet the 
requirements of the study and to monitor subject safety. Visit 1 (Week 12, which is 
the same as Visit 7 of the 12-week ALCS-RA-16-06-EV study) safety evaluations 
will include the following: physical examination (symptom-driven); vital signs; body 
weight, BMI; 12-lead ECGs; clinical chemistry, hematology, and urinalysis; and 
pregnancy testing (all females). At Visits 2, 3, and 4, safety evaluations will include 
vital signs and physical examination (symptom-driven). Visit 5/EOS (or early 
termination) 
safety 
evaluations 
will 
include 
a 
physical 
examination 
(symptom-driven); vital signs; body weight; BMI; 12-lead ECG; clinical chemistry, 
hematology, and urinalysis; and pregnancy testing (all females). 
AEs will be monitored and recorded from the time of the test e-vapor product trial at 
Screening, Visit 2 of the 12-week ALCS-RA-16-06-EV study until Week 24/EOS (or 
upon early termination). Events occurring after the initial informed consent signing at 

 
 
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Screening, Visit 1 of the 12-week ALCS-RA-16-06-EV study and before the test 
e-vapor product trial will be recorded and considered baseline signs and symptoms.  
Any concomitant medications taken from 30 days prior to Screening, Visit 1 of the 
12-week ALCS-RA-16-06-EV study through Week 24/EOS (or upon Early 
Termination) will also be recorded. 
4.0 
SUBJECT SELECTION 
 
Inclusion Criteria 
4.1
Subjects must satisfy the following criteria before being enrolled into the study. 
Subject must: 
1) have participated in and completed the 12-week ALCS-RA-16-06-EV study and 
have Baseline biomarker samples collected; 
2) demonstrate willingness to participate by signing an IRB-approved ICF for the 
study; 
3) have demonstrated consistent daily reporting of product use in the 12-week 
ALCS-RA-16-06-EV (≥ 75% reporting compliance); 
4) if randomized to a Test group, have reported an average of no more than 10% of 
Baseline cigarette smoking per day through Week 11 of the 12-week 
ALCS-RA-16-06-EV study; 
5) if randomized to a Test group, have reported use of at least two Test product 
cartridges per week in the 12-week ALCS-RA-16-06-EV study; 
6) if randomized to a Test group, have eCO measurements of ≤ 8 ppm at the 6-, 9-, 
and 12-week post-Baseline time points in the 12-week ALCS-RA-16-06-EV 
study; 
7) have daily access to text messaging capable cellular phone for daily product use 
reporting;  
8) if female (all females), have a negative urine pregnancy test at Week 12 (Visit 1) 
through Week 24 (Visit 5), inclusive; 
9) if female, heterosexually active, and of childbearing potential (i.e., not surgically 
sterile or 2 years naturally postmenopausal), must have used a medically accepted 
method of contraception (listed below in a) and b)) prior to Screening, Visit 1 of 
the 12-week ALCS-RA-16-06-EV study and must agree to continue to use such 
method(s) through Week 24 (EOS); 

 
 
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a) Surgically sterile includes bilateral tubal ligation, Essure, hysterectomy, or 
bilateral oophorectomy at least 6 months prior to Screening, Visit 1 of the 
12-week ALCS-RA-16-06-EV study. Naturally postmenopausal is defined as 
women having 2 years without menses. 
b) Acceptable methods of contraception are: hormonal (i.e., oral, transdermal 
patch, implant, or injection) consistently for at least 3 months prior to 
Screening, Visit 1 of the 12-week ALCS-RA-16-06-EV study; double barrier 
(i.e., condom with spermicide or diaphragm with spermicide) consistently for 
at least 4 weeks prior to Screening, Visit 1 of the 12-week 
ALCS-RA-16-06-EV study; and intrauterine device for at least 3 months prior 
to Screening, Visit 1 of the 12-week ALCS-RA-16-06-EV study; or only have 
a partner who has been vasectomized for at least 6 months prior to Screening, 
Visit 1 of the 12-week ALCS-RA-16-06-EV study. 
10) Be willing and able to comply with the requirements of the study. 
 
Exclusion Criteria 
4.2
Subjects may be excluded from the study if there is evidence of any of the following. 
Exceptions may be permitted at the discretion of the Investigator and in consultation 
with the Sponsor or designee provided there would be no additional risk to the 
subject. Any exceptions will be documented.  
1) Have clinically significant abnormal findings on the physical examination, vital 
signs, or ECG at the EOS visit (Visit 7) of the 12-week ALCS-RA-16-06-EV 
study that would jeopardize the safety of the subject, in the opinion of the 
Investigator;  
2) Female subjects who are pregnant (as determined at the EOS visit [Visit 7] of the 
12-week study), lactating, or intend to become pregnant from Visit 1 (Week 12) 
through Week 24 (EOS); 
3) Use of any medication for depression, asthma, or diabetes at any time during the 
study; 
4) Use of HDL-C raising medication / supplements (e.g., niacin, gemfibrozil, 
fenofibrate, etc.) at any time during the study; 
5) Subject or a first-degree relative (i.e., parent, spouse, sibling, or child) is a current 
or former employee of the tobacco industry or a named party or class 
representative in litigation with any tobacco company; 
6) Subject or a first-degree relative (i.e., parent, spouse, sibling, or child) is a current 
or former employee of Celerion or any of the clinical study sites. 

 
 
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Restrictions  
4.3
• No participation in other studies or blood (other than for this study) or 
plasma donations while taking part in this study.  
• Subjects will be instructed not to use any tobacco or nicotine-containing 
products other than manufactured cigarettes and/or test e-vapor product 
(according to their group assignment) (e.g., roll-your-own cigarettes, 
e-cigarette or e-vapor products, Bidis, snuff, nicotine inhaler, pipe, cigar, 
chewing tobacco, nicotine patch, nicotine spray, nicotine lozenge, or 
nicotine gum) during the study. 
• Medications with therapeutic effect on HDL-C, or medications for 
depression, asthma or diabetes, are not allowed during the study. 
 
Concomitant Medications 
4.4
Any concomitant medications taken through Week 24 (EOS) or upon Early 
Termination will be recorded. 
Stable doses of prescription or over-the-counter medications required to treat an 
Investigator-approved disease or condition (e.g., hypertension) are permitted at the 
discretion of the Investigator. Hormonal contraceptives (e.g., oral, transdermal patch, 
implant, injection) and hormonal replacement therapy are permitted. Occasional use 
of over-the-counter analgesics (e.g., acetaminophen, ibuprofen), antihistamines, and 
nasal decongestants are permitted. Exceptions may be permitted at the discretion of 
the Investigator in consultation with the Sponsor or designee, providing the 
medication in question would have no impact on the study. Any exceptions will be 
documented.  
5.0 
TEST PRODUCTS 
 
Test e-Vapor Products 
5.1
• Product XLCB = Test EVP (currently marketed by Nu Mark LLC as 
MarkTen® XL Bold Classic [4.0% NBW]) [CVR2.6.8] Formula: 10381-
44-B; Name: “Rosetta”; Label: B44 
• Product XLMB = Test EVP (currently marketed by Nu Mark LLC as 
MarkTen® XL Bold Menthol [4.0% NBW]) [CVR2.6.8] Formula: 10381-
40-E; Name: “Spencer”; Label: 40E 
The test e-vapor products are identified as Product XLCB for the Rosetta (Bold 
Classic) flavor and Product XLMB for the Spencer (Bold Menthol) flavor in this 
study. Each test e-vapor product consists of a battery and a cartridge. Each cartridge 
contains approximately 800 mg solution consisting of propylene glycol, glycerol, 

 
 
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flavors, and 4.0% USP grade tobacco-derived nicotine by weight. Once the battery is 
close to being fully discharged, the LED will blink indicating that the battery needs to 
be recharged. When a cartridge is almost empty there is a noticeable reduction in 
vapor and flavor. 
 
Study Material Accountability 
5.2
5.2.1 
Test e-Vapor Products 
The test e-vapor products will be provided and shipped by the Sponsor or designee to 
each of the study sites. The staff at each study site will coordinate shipping of all test 
e-vapor products from the Sponsor or designee. The staff will document the date each 
shipment was received in the inventory records.  
All test e-vapor products will be stored in a locked, limited-access area in the study 
site. The test e-vapor products will be kept at controlled room temperature (defined as 
20˚-25˚C [68˚ - 77˚F], with excursions permitted to 15˚C - 30˚C [59˚ - 86˚F] for up to 
15 minutes).  
The study site will document and reconcile the total number of test e-vapor products 
shipped to the study site, the total number of test e-vapor products dispensed, the total 
number of used test e-vapor products collected during the study, and the total number 
of unused test e-vapor products remaining at the end of the study.  
It is the responsibility of the Investigator to ensure that a current record of test 
e-vapor product accountability is maintained at each study site where test e-vapor 
product is inventoried and dispensed. Records or logs must include: 
• 
Number received/placed in storage area 
• 
Date dispensed 
• 
Amount dispensed to and returned by each subject, including unique 
subject identifiers 
• 
Amount re-dispensed to each subject, including unique subject identifiers 
• 
Number dispensed but not returned (e.g., lost by subject) 
• 
Amount returned to Sponsor 
Individual test e-vapor product dispensing records will be maintained by the study 
site for each subject. Test e-vapor products will be prepared for use by the study site 
according to the Study Procedures Manual.  

 
 
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Upon completion or termination of the study, all used and unused test e-vapor 
products will be reconciled at the study site. The test products will then be returned to 
ALCS or designee (return address and instruction will be provided separately). 
Twenty-four cartridges (one box) of each lot of flavored test e-vapor product will be 
retained by each study site until final Clinical Study Report is issued (even if within 
1 month of product expiration). 
All test e-vapor products returned to ALCS or designee must be accompanied by the 
appropriate documentation and be clearly identified by protocol number and study 
site number on outermost shipping container. If test product is returned and never 
dispensed to subjects, the supply should be in the original packaging.  
 
Study Material Dispensing 
5.3
5.3.1 
Test e-Vapor Products  
Prior to dispensing, the study site will ensure that the test e-vapor product packaging 
is labelled to disclose, at minimum, the protocol number and unique subject 
identifiers, date it was dispensed, the statements of “For study use only, not for sale” 
and “Keep out of reach of children”.  
Subjects should be reminded at Visit 1/Week 12, Visit 2/Week 15, Visit 3/Week 18, 
Visit 4/Week 21, and Visit 5/Week 24, when test e-vapor products are distributed, to 
keep test e-vapor products out of the reach of children and that they must keep all 
used and unused cartridges from the time of dispensing until the next visit and bring 
them to the study site at the following visit.  
When handling or dispensing test e-vapor products, study site personnel will be 
instructed to wear gloves.  
5.3.2 
Conventional Cigarettes 
Subjects randomized to the Control group will continue to supply their own 
conventional cigarettes, at their own cost, for the duration of the study. 
There will be no restrictions on cigarette brand at any time during the study. 
6.0 
VISIT 1 (WEEK 12 / DAY 84 ±3) 
Visit 1 should be arranged in the morning to accommodate fasting blood sampling. 
Subjects should be reminded to maintain their product use during the morning of the 
study visit; abstinence is not required. Visit 1 of this study is the same as Visit 7 of 
the 12-week ALCS-RA-16-06-EV (CA20130) study. Study procedures scheduled at 
this visit should be performed only once (with the exception of rechecks). 

 
 
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Informed Consent 
6.1
All prospective subjects will have the study explained by the Investigator or his/her 
designee. 
All prospective subjects will be required to read, sign, and date the study ICF prior to 
any study procedures being performed. Written acknowledgment of the receipt of the 
full informed consent and the subject’s freely tendered offer to participate will be 
obtained from each subject in the study and documented in the source documents. 
Each subject will receive a signed and dated copy of his/her ICF. 
 
Review of Inclusion / Exclusion Criteria 
6.2
A brief assessment (medical/medication questionnaire) to affirm that the applicable 
inclusion and exclusion criteria/restrictions have not been violated will be performed. 
Subjects who do not meet the inclusion/exclusion criteria required at Visit 1 
(Week 12/Day 84 +/- 3) will not be enrolled in this study; data to be captured will 
include subject demographics and reason(s) for screen failure. 
 
Review of Concomitant Medications 
6.3
The study site staff will document any concomitant medications taken by subjects. 
 
Review of Tobacco and Nicotine Restrictions 
6.4
Subjects will be asked about any tobacco / nicotine containing products they are using 
and the results will be documented. If non-permissible tobacco or nicotine containing 
products have been used, the study site staff will remind the subjects of the 
importance of compliance with study instructions. 
 
Review of Adverse Events 
6.5
All AEs occurring during this clinical trial after the subject has signed the ICF must 
be recorded in the electronic case report form (eCRF). 
 
Test e-Vapor Product Dispensation  
6.6
Subjects randomized to a Test group will be given enough of their assigned test 
e-vapor product to last until they return to the study site at Visit 2 (Week 15) based on 
previous use (estimated to be approximately 3 batteries, 3 battery chargers and 
66 cartridges assuming 3 per day). Subjects should be instructed to contact the study 
site to make arrangements to pick up additional supplies if it looks like they will run 
out of supplies prior to the next scheduled visit. All test e-vapor product dispensed 
and returned must be documented by the study site.  

 
 
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Prior to dispensing, the study site will ensure the test e-vapor product packaging is 
labelled to disclose, at minimum, the protocol number and unique subject identifiers, 
date it was dispensed, the statements of “For study use only, not for sale” and “Keep 
out of reach of children”. 
Subjects will be asked to bring back all used and unused products (cartridges) at each 
subsequent study visit. Study sites will perform accountability on the returned 
product. 
Unused cartridges may be re-dispensed to the same subject. Only unused cartridges 
with the seal intact and at least 1 month to the expiration date should be dispensed to 
the subject. 
During product dispensing, subjects will be reminded to keep the product out of reach 
of children. 
The subjects will be instructed to store the cartridges in a cool and dry place 
preferably between 15 and 25oC (59 – 77 oF) and not to leave the product(s) in 
extreme conditions (e.g., in a car parked in the heat/cold, freezer, etc.). 
 
Reminder Calls 
6.7
Study site personnel should make a phone call within 24 – 72 hours to subjects prior 
to their Visits to remind them the date and time of the visits (Visits 1 - 5), and 
collecting and bringing the first void of day urine samples to study site and fasting for 
at least 8 hours prior to the study visit (Visits 3 and 5). Subjects should be reminded 
to maintain their usual smoking/vaping behavior during the morning of the study 
visits; abstinence is not required. 
 
SMS System Use 
6.8
Subjects will be instructed to continue to record their daily cigarette or test e-vapor 
product use via the SMS system. Compliance and the need for retraining may be 
performed as necessary. 
 
Changes in Your Health and Well-Being Questionnaire 
6.9
Subjects will fill out the Changes in Your Health and Well-Being Questionnaire 
(Appendix 6A). 
7.0 
VISIT 2 (WEEK 15 / DAY 105 ±3) 
Subjects should be reminded to maintain their usual smoking/vaping behavior during 
the day of the study visit; abstinence is not required. 

 
 
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Review of Inclusion / Exclusion Criteria 
7.1
A brief assessment (medical/medication questionnaire) to affirm that the applicable 
inclusion and exclusion criteria/restrictions have not been violated since Visit 1 
(Week 12) will be performed. 
 
Vital Signs 
7.2
Respiratory rate, pulse rate, blood pressure, and oral temperature in the sitting 
position after at least 5 minutes of rest and at least 15 minutes after the last cigarette 
smoked or nicotine-containing product used. 
 
Review of Concomitant Medications 
7.3
The study site staff will document any concomitant medications taken by subjects. 
 
Review of Tobacco and Nicotine Restrictions 
7.4
Subjects will be asked about any tobacco / nicotine containing products they are using 
and the results will be documented. If non-permissible tobacco or nicotine containing 
products have been used, the study site staff will remind the subjects of the 
importance of compliance with study instructions. 
 
Physical Examination (Symptom-Driven) 
7.5
A symptom-driven physical examination will be conducted. 
 
Urine Pregnancy Test 
7.6
Female subjects will complete a urine pregnancy test and only those who have a 
negative test result will continue to be eligible. 
 
Review of Adverse Events 
7.7
All AEs occurring during this clinical trial after the subject has signed the ICF must 
be recorded in the eCRF. 
 
Confirm Cigarette Brand / Photocopy Cigarette Pack 
7.8
The study site staff will confirm that the subject’s regular brand of cigarettes (Control 
group) has not changed. If the regular brand has changed, the change will be 
documented and a photocopy of the pack made.  

 
 
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Test e-Vapor Product Collection  
7.9
The study site staff will collect and document all used and unused products 
(cartridges) at each study visit. The study site will perform accountability on the 
returned product. 
 
Test e-Vapor Product Dispensation  
7.10
Subjects randomized to a Test group will be given enough of their assigned test 
e-vapor product to last until they return to the study site at Visit 3 (Week 18) based on 
previous use (estimated to be approximately 3 batteries, 3 battery chargers and 
66 cartridges assuming 3 per day). Subjects should be instructed to contact the study 
site to make arrangements to pick up additional supplies if it looks like they will run 
out of supplies prior to the next scheduled visit. All test e-vapor product dispensed 
and returned must be documented by the study site.  
Prior to dispensing, the study site will ensure the test e-vapor product packaging is 
labelled to disclose, at minimum, the protocol number and unique subject identifiers, 
date it was dispensed, the statements of “For study use only, not for sale” and “Keep 
out of reach of children”. 
Subjects will be asked to bring back all used and unused products (cartridges) at each 
subsequent study visit. Study sites will perform accountability on the returned 
product. 
Unused cartridges may be re-dispensed to the same subject. Only unused cartridges 
with the seal intact and at least 1 month to the expiration date should be dispensed to 
the subject. 
During product dispensing, subjects will be reminded to keep the product out of reach 
of children. 
The subjects will be instructed to store the cartridges in a cool and dry place 
preferably between 15 and 25oC (59 – 77 oF) and not to leave the product(s) in 
extreme conditions (e.g., in a car parked in the heat/cold, freezer, etc.). 
 
Reminder Calls 
7.11
Study site personnel should make a phone call within 24 – 72 hours to subjects prior 
to their Visits to remind them the date and time of the visits, and collecting and 
bringing the first void of day urine samples to study site and fasting for at least 
8 hours prior to the study visit (Visits 3 and 5). Subjects should be reminded to 
maintain their usual smoking/vaping behavior during the morning of the study visits; 
abstinence is not required. 

 
 
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Dispense First Urine Void Collection Containers 
7.12
Study site personnel will dispense first void of the day urine collection containers to 
all subjects still qualifying for the study at Visit 2 (Week 15) for collecting the first 
void urine sample in the morning of Visit 3 (Week 18), and instruct subjects on 
collection, storage, and returning the sample at the subsequent visit; subjects will be 
instructed that urine collection should occur at least 4 hours after the prior void. 
 
SMS System Use 
7.13
Subjects will be instructed to continue to record their daily cigarette or test e-vapor 
product use via the SMS system. Compliance and the need for retraining may be 
performed as necessary. 
 
Exhaled CO Measurement 
7.14
Exhaled CO measurements will be performed by the clinic staff using the Micro+ 
basic™ Smokerlyzer® monitor (coVita). Subjects in the Control and Test groups are 
expected to have eCO measurements consistent with recent cigarette smoking or 
e-vapor use, respectively. Subjects in the Test groups with eCO measurements 
> 5 ppm will be counseled on the importance of study compliance. Subjects in the 
Test groups with eCO measurements > 8 ppm will be recorded as non-compliant at 
the Visit. 
8.0 
VISIT 3 (WEEK 18 / DAY 126 ±3) 
Subjects should be reminded to maintain their usual smoking/vaping behavior during 
the day of the study visit; abstinence is not required. 
 
Review of Inclusion / Exclusion Criteria 
8.1
A brief assessment (medical/medication questionnaire) to affirm that the applicable 
inclusion and exclusion criteria/restrictions have not been violated since Visit 1 
(Week 12) will be performed. 
 
Vital Signs 
8.2
Respiratory rate, pulse rate, blood pressure, and oral temperature in the sitting 
position after at least 5 minutes of rest and at least 15 minutes after the last cigarette 
smoked or nicotine-containing product used. 
 
Spirometry 
8.3
All subjects will undergo spirometry tests (FEV1, FVC, and FEV1/FVC ratio) at the 
study site. Spirometry measurements will be conducted in accordance with the 2005 
American Thoracic Society / European Respiratory Society Joint Task Force on the 

 
 
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standardization of spirometry. The spirometry tests will be performed on a study 
specific spirometer provided by a central vendor. The spirometry predicted values 
will be standardized by the Third National Health and Nutrition Examination Survey 
predicted set. Study site staff performing spirometry tests must receive appropriate 
training by the central vendor. The quality of the tests will be reviewed by a 
centralized over-reader. The spirometry tests should be performed at least one hour 
from the last cigarette smoked or last e-vapor product use and in sitting position. The 
subjects will be instructed on how to correctly perform spirometry tests prior to the 
measurements being recorded by appropriately trained study staff. 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 from an albuterol metered-dose inhaler at 
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. Spirometry results 
will be captured in the source document. 
 
Review of Concomitant Medications 
8.4
The study site staff will document any concomitant medications taken by subjects. 
 
Review of Tobacco and Nicotine Restrictions 
8.5
Subjects will be asked about any tobacco / nicotine containing products they are using 
and the results will be documented. If non-permissible tobacco or nicotine containing 
products have been used, the study site staff will remind the subjects of the 
importance of compliance with study instructions. 
 
Physical Examination (Symptom-Driven) 
8.6
A symptom-driven physical examination will be conducted. 
 
Urine Pregnancy Test 
8.7
Female subjects will complete a urine pregnancy test and only those who have a 
negative test result will continue to be eligible. 
 
Review of Adverse Events 
8.8
All AEs occurring during this clinical trial after the subject has signed the ICF must 
be recorded in the eCRF. 
 
QGEN and TQOLIT Questionnaires 
8.9
Subjects will complete the QGEN and TQOLIT questionnaires (Appendix 1, 
Appendix 1A for Control Group, Appendix 1B for Test Groups).  

 
 
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Cough Questionnaire 
8.10
Subjects will complete the Cough Questionnaire (Appendix 2). 
 
Confirm Cigarette Brand / Photocopy Cigarette Pack 
8.11
The study site staff will confirm that the subject’s regular brand of cigarettes (Control 
group) has not changed. If the regular brand has changed, the change will be 
documented and a photocopy of the pack made.  
 
Test e-Vapor Product Collection  
8.12
The study site staff will collect and document all used and unused products 
(cartridges) at each study visit. The study site will perform accountability on the 
returned product. 
 
Test e-Vapor Product Dispensation  
8.13
Subjects randomized to a Test group will be given enough of their assigned test 
e-vapor product to last until they return to the study site at Visit 4 (Week 21) based on 
previous use (estimated to be approximately 3 batteries, 3 battery chargers and 
66 cartridges assuming 3 per day). Subjects should be instructed to contact the study 
site to make arrangements to pick up additional supplies if it looks like they will run 
out of supplies prior to the next scheduled visit. All test e-vapor product dispensed 
and returned must be documented by the study site.  
Prior to dispensing, the study site will ensure the test e-vapor product packaging is 
labelled to disclose, at minimum, the protocol number and unique subject identifiers, 
date it was dispensed, the statements of “For study use only, not for sale” and “Keep 
out of reach of children”. 
Subjects will be asked to bring back all used and unused products (cartridges) at each 
subsequent study visit. Study sites will perform accountability on the returned 
product. 
Unused cartridges may be re-dispensed to the same subject. Only unused cartridges 
with the seal intact and at least 1 month to the expiration date should be dispensed to 
the subject. 
During product dispensing, subjects will be reminded to keep the product out of reach 
of children. 
The subjects will be instructed to store the cartridges in a cool and dry place 
preferably between 15 and 25oC (59 – 77oF) and not to leave the product(s) in 
extreme conditions (e.g., in a car parked in the heat/cold, freezer, etc.). 

 
 
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Reminder Calls 
8.14
Study site personnel should make a phone call within 24 – 72 hours to subjects prior 
to their Visits to remind them the date and time of the visits, and collecting and 
bringing the first void of day urine samples to study site and fasting for at least 
8 hours prior to the study visit (Visits 3 and 5). Subjects should be reminded to 
maintain their usual smoking/vaping behavior during the morning of the study visits; 
abstinence is not required. 
 
BOE and BOPH Urine Sample Collection 
8.15
First Urine Void for BOEs and BOPHs 
On the morning of Visit 3 (Week 18), subjects will collect their first urine void of the 
day, between 4:00am and 7:00am, and at least 4 hours after the prior void, in the 
dispensed container as instructed and bring it with them to the study site. Sample 
should be kept refrigerated until packed for transport to the study site. An ice pack 
should be placed in the package with the urine sample at the same time. Upon receipt, 
study staff should document the volume (mL) of the urine sample, status of the ice 
pack (present – not/or partially melted; present – fully melted; not present). 
 
BOPH and COHb Blood Sample Collection 
8.16
Blood Collection for BOPH and COHb 
Blood will be collected after overnight fasting (at least 8 hours). 
 
SMS System Use 
8.17
Subjects will be instructed to continue to record their daily cigarette or test e-vapor 
product use via the SMS system. Compliance and the need for retraining may be 
performed as necessary. 
 
Exhaled CO Measurement 
8.18
Exhaled CO measurements will be performed by the clinic staff using the Micro+ 
basic™ Smokerlyzer® monitor (coVita). Subjects in the Control and Test groups are 
expected to have eCO measurements consistent with recent cigarette smoking or 
e-vapor use, respectively. Subjects in the Test groups with eCO measurements 
> 5 ppm will be counseled on the importance of study compliance. Subjects in the 
Test groups with eCO measurements > 8 ppm will be recorded as non-compliant at 
the Visit. 

 
 
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9.0 
VISIT 4 (WEEK 21 / DAY 147 ±3) 
Subjects should be reminded to maintain their usual smoking/vaping behavior during 
the day of the study visit; abstinence is not required. 
 
Review of Inclusion / Exclusion Criteria 
9.1
A brief assessment (medical/medication questionnaire) to affirm that the applicable 
inclusion and exclusion criteria/restrictions have not been violated since Visit 1 
(Week 12) will be performed. 
 
Vital Signs 
9.2
Respiratory rate, pulse rate, blood pressure, and oral temperature in the sitting 
position after at least 5 minutes of rest and at least 15 minutes after the last cigarette 
smoked or nicotine-containing product used. 
 
Review of Concomitant Medications 
9.3
The study site staff will document any concomitant medications taken by subjects. 
 
Review of Tobacco and Nicotine Restrictions 
9.4
Subjects will be asked about any tobacco / nicotine containing products they are using 
and the results will be documented. If non-permissible tobacco or nicotine containing 
products have been used, the study site staff will remind the subjects of the 
importance of compliance with study instructions. 
 
Physical Examination (Symptom-Driven) 
9.5
A symptom-driven physical examination will be conducted. 
 
Urine Pregnancy Test 
9.6
Female subjects will complete a urine pregnancy test and only those who have a 
negative test result will continue to be eligible. 
 
Review of Adverse Events 
9.7
All AEs occurring during this clinical trial after the subject has signed the ICF must 
be recorded in the eCRF. 
 
Confirm Cigarette Brand / Photocopy Cigarette Pack 
9.8
The study site staff will confirm that the subject’s regular brand of cigarettes (Control 
group) has not changed. If the regular brand has changed, the change will be 
documented and a photocopy of the pack made.  

 
 
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Test e-Vapor Product Collection  
9.9
The study site staff will collect and document all used and unused products 
(cartridges) at each study visit. The study site will perform accountability on the 
returned product. 
 
Test e-Vapor Product Dispensation  
9.10
Subjects randomized to a Test group will be given enough of their assigned test 
e-vapor product to last until they return to the study site at Visit 5 (Week 24) based on 
previous use (estimated to be approximately 3 batteries, 3 battery chargers and 
66 cartridges assuming 3 per day). Subjects should be instructed to contact the study 
site to make arrangements to pick up additional supplies if it looks like they will run 
out of supplies prior to the next scheduled visit. All test e-vapor product dispensed 
and returned must be documented by the study site.  
Prior to dispensing, the study site will ensure the test e-vapor product packaging is 
labelled to disclose, at minimum, the protocol number and unique subject identifiers, 
date it was dispensed, the statements of “For study use only, not for sale” and “Keep 
out of reach of children”. 
Subjects will be asked to bring back all used and unused products (cartridges) at each 
subsequent study visit. Study sites will perform accountability on the returned 
product. 
Unused cartridges may be re-dispensed to the same subject. Only unused cartridges 
with the seal intact and at least 1 month to the expiration date should be dispensed to 
the subject. 
During product dispensing, subjects will be reminded to keep the product out of reach 
of children. 
The subjects will be instructed to store the cartridges in a cool and dry place 
preferably between 15 and 25oC (59 – 77 oF) and not to leave the product(s) in 
extreme conditions (e.g., in a car parked in the heat/cold, freezer, etc.). 
 
Reminder Calls 
9.11
Study site personnel should make a phone call within 24 – 72 hours to subjects prior 
to their Visits to remind them the date and time of the visits, and collecting and 
bringing the first void of day urine samples to study site and fasting for at least 
8 hours prior to the study visit (Visits 3 and 5). Subjects should be reminded to 
maintain their usual smoking/vaping behavior during the morning of the study visits; 
abstinence is not required. 

 
 
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Dispense First Urine Void Collection Containers 
9.12
Study site personnel will dispense first void of the day urine collection containers to 
all subjects still qualifying for the study at Visit 4 (Week 21) for collecting the first 
void urine sample in the morning of Visit 5 (Week 24), and instruct subjects on 
collection, storage, and returning the sample at the subsequent visit; subjects will be 
instructed that urine collection should occur at least 4 hours after the prior void. 
 
SMS System Use 
9.13
Subjects will be instructed to continue to record their daily cigarette or test e-vapor 
product use via the SMS system. Compliance and the need for retraining may be 
performed as necessary. 
 
Exhaled CO Measurement 
9.14
Exhaled CO measurements will be performed by the clinic staff using the Micro+ 
basic™ Smokerlyzer® monitor (coVita). Subjects in the Control and Test groups are 
expected to have eCO measurements consistent with recent cigarette smoking or 
e-vapor use, respectively. Subjects in the Test groups with eCO measurements 
> 5 ppm will be counseled on the importance of study compliance. Subjects in the 
Test groups with eCO measurements > 8 ppm will be recorded as non-compliant at 
the Visit. 
10.0 
VISIT 5, END OF STUDY (WEEK 24 / DAY 168 ±3) 
Visit 5 should be arranged in the morning to accommodate fasting blood sampling. 
Subjects should be reminded to maintain their usual smoking/vaping behavior during 
the morning of the study visit; abstinence is not required. 
 
Review of Inclusion / Exclusion Criteria 
10.1
A brief assessment (medical/medication questionnaire) to affirm that the applicable 
inclusion and exclusion criteria/restrictions have not been violated since Visit 1 
(Week 12) will be performed. 
 
Vital Signs 
10.2
Respiratory rate, pulse rate, blood pressure, and oral temperature in the sitting 
position after at least 5 minutes of rest and at least 15 minutes after the last cigarette 
smoked or nicotine-containing product used. 

 
 
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Body Weight and Body Mass Index 
10.3
Weight (kg) recorded in indoor clothing without shoes. BMI will be calculated as 
weight (kg)/height (meters) squared (height from Screening, Visit 1 of the 12-week 
ALCS-RA-16-06-EV study will be used to calculate BMI). 
 
Spirometry 
10.4
All subjects will undergo spirometry tests (FEV1, FVC, and FEV1/FVC ratio) at the 
study site. Spirometry measurements will be conducted in accordance with the 2005 
American Thoracic Society / European Respiratory Society Joint Task Force on the 
standardization of spirometry. The spirometry tests will be performed on a study 
specific spirometer provided by a central vendor. The spirometry predicted values 
will be standardized by the Third National Health and Nutrition Examination Survey 
predicted set. Study site staff performing spirometry tests must receive appropriate 
training by the central vendor. The quality of the tests will be reviewed by a 
centralized over-reader. The spirometry tests should be performed at least one hour 
from the last cigarette smoked or last e-vapor product use and in sitting position. The 
subjects will be instructed on how to correctly perform spirometry tests prior to the 
measurements being recorded by appropriately trained study staff. 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 from an albuterol metered-dose inhaler at 
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. Spirometry results 
will be captured in the source document. 
 
Smoking Cessation Information 
10.5
The Investigator or designee will advise all subjects that to reduce the health effects 
of smoking, the best thing to do is to quit. The Investigator or designee also will offer 
all participants the Quit Assist™ brochure or referral to the Quit Assist™ web site, 
which contains citations to a number of third-party information sources, including 
web sites, telephone resources, and other organizations with additional information. 
 
Clinical Laboratory Tests 
10.6
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 study site using 
CLIA-waived kits or procedures. Values for the laboratory parameters are to be 
within the laboratory normal ranges or deemed not clinically significant in the 
opinion of the Investigator; clinically significant findings will be followed up as 
described for Adverse Events (Section 11.2). 

 
 
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10.6.1 
Clinical Chemistry 
Clinical chemistry will be performed, after at least 8 hours fasting, consisting of 
sodium, potassium, chloride, bicarbonate, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), blood urea nitrogen (BUN), alkaline phosphatase (ALP), 
total bilirubin, glucose, creatinine (at Screening, creatinine clearance will be 
calculated using Cockcroft-Gault formula), total protein, uric acid, and albumin. 
10.6.2 
Hematology 
Hematology will be performed, after at least 8 hours fasting, consisting of 
hemoglobin, hematocrit, RBC, WBC with differential, and platelet count. 
10.6.3 
Urinalysis 
Routine clinical urinalysis consisting of bilirubin, blood, glucose, ketones, leukocyte 
esterase, nitrite, pH, protein, specific gravity, and urobilinogen will be evaluated. 
Microscopic examination will be conducted if protein, leukocyte esterase, nitrite 
and/or blood are detected. Microscopic analysis will include RBC, WBC, casts, and 
bacteria.  
 
Review of Concomitant Medications 
10.7
Any concomitant medications taken through the End of Study (or upon Early 
Termination) will be recorded. 
 
Physical Examination (Symptom-Driven) 
10.8
A symptom-driven physical examination will be conducted. 
 
12-Lead ECG 
10.9
A 12-lead ECG will be completed after at least 5 minutes in the supine position. 
 
Urine Pregnancy Test 
10.10
Female subjects will complete a urine pregnancy test. 
 
Review of Adverse Events 
10.11
All AEs occurring during this clinical trial after the subject has signed the ICF must 
be recorded in the eCRF. 
 
QGEN and TQOLIT Questionnaires 
10.12
Subjects will complete the QGEN and TQOLIT questionnaires (Appendix 1, 
Appendix 1A for Control Group, Appendix 1B for Test Groups).  

 
 
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Cough Questionnaire 
10.13
Subjects will complete the Cough Questionnaire (Appendix 2). 
 
mCEQ Questionnaire 
10.14
Subjects will complete the appropriate mCEQ Questionnaire (Appendix 3A for Test 
groups, Appendix 3B for the Control group). 
 
Reasons of Use/Not-Use Test Product Questionnaire (Test group only) 
10.15
Subjects will fill out the Reasons of Use/Not-Use Test Product Questionnaire 
(Appendix 4). 
 
Confirm Cigarette Brand / Photocopy Cigarette Pack 
10.16
The study site staff will confirm that the subject’s regular brand of cigarettes (Control 
group) has not changed. If the regular brand has changed, the change will be 
documented and a photocopy of the pack made.  
 
Test e-Vapor Product Collection  
10.17
The study site staff will collect and document all used and unused products 
(cartridges) at each study visit. The study site will perform accountability on the 
returned product. 
 
Reminder Calls 
10.18
Study site personnel should make a phone call within 24 – 72 hours to subjects prior 
to Visit 5 to remind them the date and time of the visit, and collecting and bringing 
the first void of day urine samples to study site and fasting for at least 8 hours prior to 
Visit 5. Subjects should be reminded to maintain their usual smoking/vaping behavior 
during the morning of the study visits; abstinence is not required. 
 
BOE and BOPH Urine Sample Collection 
10.19
First Urine Void for BOEs and BOPHs 
On the morning of Visit 5 (Week 24), subjects will collect their first urine void of the 
day, between 4:00am and 7:00am, and at least 4 hours after the prior void, in the 
dispensed container as instructed and bring it with them to the study site. Sample 
should be kept refrigerated until packed for transport to the study site. An ice pack 
should be placed in the package with the urine sample at the same time. Upon receipt, 
study staff should document the volume (mL) of the urine sample, status of the ice 
pack (present – not/or partially melted; present – fully melted; not present). 

 
 
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BOPH and COHb Blood Sample Collection 
10.20
Blood Collection for BOPH and COHb 
Blood will be collected after overnight fasting (at least 8 hours). 
 
SMS System Use 
10.21
The day prior to Visit 5 will be the final product use entry. 
 
Exhaled CO Measurement 
10.22
Exhaled CO measurements will be performed by the clinic staff using the Micro+ 
basic™ Smokerlyzer® monitor (coVita). Subjects in the Control and Test groups are 
expected to have eCO measurements consistent with recent cigarette smoking or 
e-vapor use, respectively. Subjects in the Test groups with eCO measurements 
> 5 ppm will be counseled on the importance of study compliance. Subjects in the 
Test groups with eCO measurements > 8 ppm will be recorded as non-compliant at 
the Visit. 
 
Changes in Your Health and Well-Being Questionnaire 
10.23
Subjects will fill out the Changes in Your Health and Well-Being Questionnaire 
(Appendix 6B). 
 
End of Study Questionnaire 
10.24
Subjects will fill out the End of Study Questionnaire Appendix 5A (Control group) 
and Appendix 5B (Test group). 
11.0 
ADVERSE EVENTS 
The following is the definition for an AE: 
Any unfavorable or unintended sign (including an abnormal laboratory 
findinga), symptom, or diseaseb temporally associated with the use of a study 
product, whether or not related to the study products.3, 4 
a For this study, a laboratory AE is defined as an abnormal laboratory finding that is 
determined by the Investigator to be clinically significant for that subject. 
b ‘Disease’ includes a newly developed, worsened preexisting, recurring intermittent or 
intercurrent illness, injury, or condition. 
All AEs occurring during this clinical trial after the subject has signed the ICF 
document must be recorded in the eCRF, including the date and time of onset and 
outcome of each event. 

 
 
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Surgical procedures themselves are not AEs; they are therapeutic measures for 
conditions that require surgery. The condition for which the surgery is required may 
be an AE. Planned surgery permitted by the clinical study protocol and the 
condition(s) leading to this surgery are not AEs. 
No causal relationship with the study products or with the clinical study itself is 
implied by the use of the term “adverse event.” 
The Investigator will review each event and rate each reported sign or symptom on a 
3-point severity scale. The following definitions for rating severity (ICH Guideline 
for Clinical Safety Data Management) will be used: 
Mild: 
The AE is easily tolerated and does not interfere with daily activity. 
Moderate: 
The AE interferes with daily activity, but the subject is still able to 
function. 
Severe: 
The AE is incapacitating and requires medical intervention. Note: 
This is not the same as “serious,” which is based on the outcome or 
action criteria usually associated with events that pose a threat to life 
or functioning.  
Each AE will also be assessed by the Investigator for relationship to study product 
(causality) using the following grades of certainty [the strength of a causal association 
may be revised as more information becomes available]: 
Not related:  Clearly and definitely due to extraneous cause (e.g., disease, 
environment) 
Unlikely:  
a. Does not follow a probable temporal (i.e., time) sequence from 
use of study product. 
b. Does not follow a known pattern of response to the study 
product. 
c. Could plausibly have been produced by the subject’s clinical 
state/underlying disease or other drugs or chemicals the subject 
received. 
d. Does not reappear or worsen when the study product is 
re-administered. 
Possible: 
a. Follows a reasonable temporal (i.e., time) sequence from use of 
study product. 
b. Follows a known pattern of response to the study product. 

 
 
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c. Could also have been produced by the subject’s clinical 
state/concurrent disease or other drugs or chemicals the subject 
received. 
Likely:  
a. Follows a reasonable temporal (i.e., time) sequence from use of 
study product. 
b. Follows a known pattern of response to the study product. 
c. Could not readily have been produced by the subject’s clinical 
state/concurrent disease or other drugs or chemicals. 
d. Follows a clinically reasonable response on withdrawal 
(dechallenge), i.e., disappears or decreases when the study 
product is stopped or reduced. 
e. Rechallenge information is not required to fulfill this 
definition. 
Definitely: 
a. Follows a reasonable temporal (i.e., time) sequence from use of 
study product. 
b. Follows a known pattern of response to the stduy product. 
c.  Cannot be explained by the subject’s clinical state/concurrent 
disease or other drugs or chemicals. 
d. Follows a clinically reasonable response on withdrawal 
(dechallenge), i.e., disappears or decreases when the study 
product is stopped or reduced. 
e. Recurs with re-exposure to study product (rechallenge). NOTE: 
Re-exposure of the subject is NOT required, but the 
“certainly/definitely related” category may only be used when 
recurrence is observed. 
 
Serious Adverse Events 
11.1
The following is the definition for a serious adverse event (SAE): 
An SAE is any adverse study experience that results in any of the following 
outcomes:  
• death 
• a life-threatening adverse study experiencea 

 
 
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• in-patient hospitalization or prolongation of existing hospitalization 
• a persistent or significant disability/incapacityb  
• a congenital anomaly/birth defect (ICH Guideline for Good Clinical Practice4).  
a “Life-threatening” means that the subject was at immediate risk of death at the time of the SAE; it 
does not refer to a SAE that hypothetically might have caused death if it were more severe. 
b “Persistent or significant disability/incapacity” means that there is a substantial disruption 
of a person’s ability to carry out normal life functions. 
Important medical events that may or may not result in death, be life-threatening, or 
require hospitalization may be considered an SAE when, based upon appropriate 
medical judgment, it may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. An example is 
allergic bronchospasm requiring intensive treatment in an emergency room or at 
home. 
All SAEs, whether or not considered study product-related, must be reported by 
telephone to the Medical Monitor within 24 hours of the study site’s learning of the 
SAE or, at the latest, on the following workday. The Medical Monitor must inform 
ALCS within 24 hours of Medical Monitor’s notification. The Sponsor-designated 
Medical Monitor to contact about this study is: 
Dr. Kathy Smith 
Drug Safety Solutions 
Raleigh, NC 27613 USA 
Phone: +1 (919) 264-5626 
Fax: +1 (919) 844-6948 
Email: ksmith@drugsafety.biz 
Additionally, an SAE Report Form must be completed for all SAEs with as much 
information as is available and e-mailed or faxed within 24 hours of the event to 
Medical Monitor at email or phone. The Investigator must also inform the IRB, in 
compliance with GCP reporting guidelines, and the study site monitor of an SAE, 
whether or not considered study-related. The initial report must be as complete as 
possible, including an assessment of the causal relationship between the event and the 
study product. Information not available at the time of the initial report (e.g., end 
date, laboratory values) must be documented on a follow-up SAE form. SAEs will be 
reported for up to 48 hours following a subject’s completion of the study and 
followed for 30 days from onset or to a final outcome. Final outcome may be 
classified as resolved, improved, unchanged, worse, fatal, or unknown (lost to 
follow-up).  

 
 
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Adverse Events / Serious Adverse Events Follow Up 
11.2
AEs, including clinically significant laboratory abnormalities, will be followed for up 
to 7 days or to a final outcome, regardless of whether the subject is still participating 
in the study. SAEs will be followed for up to 30 days from onset or to a final 
outcome, regardless of whether the subject is still participating in the study. Final 
outcome may be classified as resolved, improved, unchanged, worse, fatal, or 
unknown (lost to follow-up). Where appropriate, medical tests and examinations will 
be performed to document the outcome of the AE. Appropriate supportive and/or 
definitive therapy will be administered as required. 
 
Pregnancy 
11.3
Pregnancy occurring after test e-vapor product use in the study will be documented 
on a pregnancy form, as a protocol deviation, and reported in accordance with IRB 
guidance. Pregnancy itself is not a SAE. Pregnancies occurring after enrolling into 
this study must be reported by telephone to the sponsor designated Medical Monitor 
within 24 hours of the study site’s learning of the pregnancy or, at the latest, on the 
following workday. The Medical Monitor must inform ALCS within 24 hours of 
Medical Monitor’s notification. 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. The Investigator also will offer all 
participants the Quit Assist™ brochure or referral to the Quit Assist™ web site, 
which contains citations to a number of third-party information sources, including 
web sites, telephone resources and other organizations with additional information. 
Advice given will be documented in the subject’s source document. 
The study site clinical staff will request the pregnant subject to notify the study site of 
the outcome of the pregnancy (i.e., birth, loss, or termination). To help ensure this, 
the study site clinical staff will follow up with the subject until the end of pregnancy, 
if in compliance with the study 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. 
12.0 
SUBJECT EARLY TERMINATION 
Subjects will be advised that they are free to withdraw from the study at any time. 
The Investigator may remove a subject if s/he feels this action is in the best interest of 
the subject. At the discretion of the Investigator, and in consultation with the Sponsor, 
a subject may be removed for failure to adhere to the requirements of the protocol. 
If a subject terminates early from the study and has used test e-vapor product 
provided by the Sponsor, all used and unused test products (cartridges) should be 
returned if assigned to the Test group, and all of the safety data normally required at 
the End of Study, Visit 5 (Week 24) should, if possible, be obtained. Subjects with 
AEs will be followed per Section 11.2. 

 
 
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Subjects who terminate early from the study, through their own choice to withdraw or 
at the discretion of the Investigator, will be considered dropouts and will not be 
replaced.  
13.0 
SUBJECT DISCONTINUATION 
Subjects will be advised that they are free to not participate or withdraw from the 
study at any time and for any reason. The Investigator may remove a subject if s/he 
feels this action is in the best interest of the subject. 
Investigators are urged to enroll only those eligible subjects who are likely to 
complete the entire study and who are willing to comply with the requirements of the 
protocol. Subjects who are discontinued from the study for any reason (including 
study completion) cannot re-enter. 
Subjects will be informed during the informed consent process that all biologic 
samples collected up to the point of withdrawal are intended for analysis but that they 
may notify the Investigator if they choose to withdraw consent for analysis of these 
samples prior to use. 
Subject Discontinuation Criteria 
Subject participation in this trial may be discontinued for any of the following 
reasons: 
• withdrawal of informed consent; 
• clinical AE, laboratory abnormality, or other medical condition (including 
pregnancy) that indicates to the Investigator that continued participation is 
not in the best interest of the subject; 
• failure to meet Inclusion/Exclusion criteria; 
• noncompliance with study procedures, e.g.; 
o failure to comply with daily CPD/cartridge recording requirements 
(> 5 consecutive days without recording). 
o failure to appear within required window for study visits 
o eCO > 8 ppm on consecutive visits (Test groups only) 
• termination of the study by the Sponsor, US Food and Drug 
Administration (FDA), or other regulatory authorities; or 
• lost to follow-up. 
Protocol deviations 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. Subject compliance with study product use and reporting is a critical 

 
 
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component of this study; however, given the duration and ambulatory nature of the 
study, 100% compliance is an unrealistic expectation. During each study visit, the 
study site staff will stress the importance of compliance with the study requirements 
and honestly reporting product use. Subjects who regularly fail to complete the daily 
product use entries or who have eCO measurements inconsistent with use of the study 
product assigned may be identified by the Investigator as individuals whose 
noncompliance may jeopardize the integrity of the study data. Disqualification for 
noncompliance with product use may occur with consultation with the Sponsor.  
Discontinuation Procedures 
If premature withdrawal from the study occurs for any reason, the Investigator must 
determine the primary reason and record this information in the eCRF. Subjects 
withdrawing or dismissed by the Investigator will be instructed to return all used and 
unused test products (if assigned to one of the Test groups) and will undergo EOS 
safety procedures as feasible. 
If a subject becomes lost to follow-up, a reasonable effort will be made to contact the 
subject and perform the End-of-Study procedures. A reasonable effort is considered, 
at minimum, two attempts via phone (at least 1 day apart) followed by a certified 
letter to the subject’s last known address requesting their return to the study site for a 
safety evaluation and return of any study products. 
Subjects who are discontinued from the study for any reason will not be replaced. 
14.0 
CLINICAL LABORATORY SAMPLES 
Values for the clinical laboratory parameters will be determined by a central 
laboratory facility accredited by the Centers for Medicare and Medicaid Services 
(CLIA-88). Hematology, clinical chemistry, and urinalysis will be analyzed using 
standard clinical laboratory procedures.  
15.0 
BIOANALYTICAL LABORATORY 
Biomarkers (BOEs and BOPHs) as noted below will be analyzed using validated 
analytical methods, and if applicable, with appropriate quality controls according to 
the FDA Guidance for Industry: Bioanalytical Method Validation (May, 2001)5 and 
in accordance with SOPs which are written to meet applicable portions of Good 
Laboratory Practice regulations (21 CFR Part 58)4. 
Full sample collection methods, processing, storage, and shipping instructions will be 
provided in the sample handling manual. An overview of sample requirements is as 
follows: 

 
 
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Urine markers: 
Biomarker 
Number of 
Aliquots/Volume 
Required 
Container Type 
Total NNAL / NNN 
2 aliquots of 10 mL each 
UV shielded HDPP 
Creatinine 
2 aliquots of 5 mL each 
HDPP 
8-epi-prostaglandin F2α 
2 aliquots of 5 mL each 
HDPP 
11-dehydrothromboxane B2 
2 aliquots of 5 mL each 
HDPP 
Nicotine equivalents  
2 aliquots of 5 mL each 
HDPP 
Bio-banking 
Remaining volume after 
aliquots above have been 
taken 
HDPE 
All aliquots will be prepared within 120 minutes from the time that the subject 
presents the sample and then stored at -20 ±10°C until shipped to Celerion for 
analysis. 
Blood markers: 
Biomarker 
Volume and Collection Tube 
Comments 
COHb 
4 mL sodium heparin 
store refrigerated until shipped 
sICAM 
4 mL sodium heparin 
centrifuge and freeze plasma 
at -20°C 
WBC 
4 mL EDTA 
standard whole blood 
HDL 
3.5 mL SST 
allow to clot for 30 minutes, 
centrifuge, and freeze serum 
at -20°C 
Bio-banking 
3.5 mL SST 
allow to clot for 30 minutes, 
centrifuge, and freeze serum 
at -20°C 
Approximately 51 mL of blood will be required for the planned assessments during 
the entire study. Details regarding the processing, storage, and shipping instructions 
for the bio-banking samples will be provided in the sample handling guidance 
document prepared by Celerion. 

 
 
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BOEs Urine (1st void of the day):  
15.1
1) Total NNAL in urine with creatinine adjusted (ng/g Cr) 
2) NNN in urine with creatinine adjusted (ng/g Cr) 
3) NE (mg/g Cr) 
Samples of all BOE urine collections will be banked for potential future additional 
BOE and/or BOPH assessments 
 
BOE Blood (after overnight fasting, at least 8 hours): 
15.2
1) COHb in whole blood (% sat) 
 
BOPHs Urine (1st void of the day): 
15.3
1) 8-epi-prostaglandin F2α in urine with creatinine adjusted (ng/g Cr) 
2) 11-dehydrothromboxane B2 with creatinine adjusted (ng/g Cr) 
 
BOPHs Blood (after overnight fasting, at least 8 hours): 
15.4
1) WBC in whole blood (103µ/L) 
2) HDL-C in serum (mg/dL) 
3) sICAM-1 in serum (ng/mL) 
Samples of all BOPH blood collections will be banked for potential future BOPH 
and/or BOE assessments 
 
Urine Creatinine (1st void of the day) 
15.5
Urine Creatinine levels (mg/mL) will also be measured for each urine sample and 
used to adjust for all urinary biomarkers. 
16.0 
STATISTICAL METHODS  
 
Statistical Analysis Plan 
16.1
The contents of this section are the basis for the SAP of this study. The SAP may be 
revised during the study to accommodate potential amendments of the clinical study 
protocol that are needed to adapt to unexpected issues in study conduct and may 
affect the planned SAP. 

 
 
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Sample Size Estimation 
16.2
The 12-week ALCS-RA-16-06-EV study (CA20130) was designed to detect a 
statistically significant difference in change from baseline to the end of the study in 5 
out of the 7 primary biomarkers between the Test and the Control groups. Total 
NNAL, COHb, 11-dehydrothromboxane B2, 8-epi-prostaglandin F2α, WBC, and HDL 
values from a previous PMUSA longitudinal study (Study #: EHCJLI/02/02)6 for the 
Electronic Heating Cigarette Smoking System and sICAM values from another 
source7 were used for the sample size calculation. A total of 450 subjects (300 in the 
Test groups and 150 in the Control group) were randomized. 
In the current study, a total of up to 250 subjects (up to 100 in each of the Test groups 
and 50 in the Control group) who were compliant with the requirements of the 
12-week ALCS-RA-16-06-EV study and continue to satisfy all inclusion/exclusion 
criteria of that study will be enrolled. The number of subjects is based on the 
anticipated number of protocol-compliant subjects in the Test groups rather than the 
power required to discriminate between Test and Control groups. 
 
Criteria for Evaluation 
16.3
16.3.1 
Primary Endpoints 
The primary endpoints are the following biomarkers measured at Baseline (Day 1 of 
the 12-week ALCS-RA-16-06-EV study) and Week 24 (EOS): 
• WBC in whole blood (103 µg/L) 
• HDL-C in serum (mg/dL) 
• 8-epi-prostaglandin F2α in urine with creatinine adjusted (ng/g Cr) 
• 11-dehydrothromboxane B2 in urine with creatinine adjusted (ng/g Cr) 
• sICAM-1 in serum (ng/mL) 
• Total NNAL in urine with creatinine adjusted (ng/g Cr) 
• COHb in whole blood (% sat) 
16.3.2 
Secondary Endpoints  
The secondary endpoints are: 
1) FEV1 (% predicted), FCV, and FEV1/FVC measured at Screening (Visit 2 of 
the 12-week ALCS-RA-16-06-EV study), Week 18, and Week 24 (EOS) 

 
 
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2) Levels of selected biomarkers (same as the primary endpoints) and the 
following additional biomarkers measured at Baseline, Week 18, and Week 24 
(EOS): 
a) Creatinine-adjusted NNN in urine (ng/g Cr) and eCO 
3) The average daily cigarettes smoked and Test Product use reported by 
subjects from Baseline through Week 24 (EOS) 
a) Test Products used per day, as determined by the number of new 
cartridges used and the average number of puffs taken (1 – 20 or >20), to 
be documented through text message 
b) The number of cigarettes smoked per day will be documented by the 
subjects through text message 
16.3.3 
Exploratory Endpoints 
The exploratory endpoints are: 
1) Assess changes in BOPHs and BOEs (same as in the primary objective) measured 
at Baseline, Week 18, and Week 24 (EOS) between the subgroups that used 
different flavored Test e-vapor products  
2) NE (nicotine, cotinine, trans-3'-hydroxycotinine, trans-3'-hydroxycotinine-O-
glucuronide, nicotine-N-glucuronide, and cotinine-N-glucuronide) in urine with 
creatinine adjustment (mg/g Cr) measured at Baseline, Week 18, and Week 24 
(EOS) 
3) Responses (Score) to the QGEN and TQOLIT questionnaires and the Cough 
Questionnaire recorded at Baseline, Week 18, and Week 24 (EOS) 
4) Reponses to Reasons for Use and Not-use of Test Product (Week 24 [EOS]) and 
mCEQ questionnaires (Baseline and Week 24) (Test group only) 
16.3.4 
Clinical Safety Endpoints  
Clinical safety analyses will be conducted on the clinical safety population. Clinical 
safety endpoints are: 
• AEs and SAEs  
• Blood pressure, ECG, vital signs, clinical chemistry, urinalysis, and hematology 

 
 
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Analyses Data Set  
16.4
The intent to treat (ITT) population includes every subject who is randomized 
according to the randomization schedule. 
The modified intent to treat (MITT) population includes those subjects in the ITT 
population for which there is a baseline and at least one post-baseline biomarker 
measure after Week 12.  
The clinical safety population (CSP) will consist of all subjects who record at least 
one use of study products (i.e., conventional cigarettes or test e-vapor products) after 
Week 12. 
The per-protocol (PP) population is defined as a subset of the MITT population, 
which is comprised of subjects who completed the study without any major protocol 
violations, which are defined as: 
• Control group: subjects who quit smoking 
• Test groups: subjects who self-report use of > 10% of baseline CPD over the 
course of the study, subjects with an eCO > 8 ppm at Visits 2 - 5, or subjects 
whose NNN levels are consistent with smoking cigarettes 
The ITT and PP populations will be used for the analyses of subject demographics, 
baseline characteristics and tobacco product use. 
The MITT and PP populations will be used for the analyses of the primary endpoint, 
secondary endpoints of biomarkers, and exploratory endpoints. 
The CSP will be used for the analyses of AEs, vital signs, clinical laboratory findings 
and other study safety related variables. 
Deviations from the approved SAP will be reported in the final study report.  
16.4.1 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics collected at Screening will be summarized 
by study group with descriptive statistics (the number of non-missing values, the 
number of missing values mean, median, standard deviation [SD], minimum, 
maximum, and 95% confidence interval, as appropriate) for continuous variables 
(e.g., BMI) and frequency counts for categorical variables (e.g., gender).  
16.4.2 
Endpoint Analyses 
Descriptive statistics will be provided for all analysis variables by study group and 
visit. The number of subjects with non-missing data, number of subjects with missing 

 
 
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data, mean, standard deviation, median, minimum and maximum will be provided for 
continuous variables, and counts and percentages for categorical variables. 
All statistical analyses will be performed with SAS® software version 9.3 or above. 
16.4.2.1 
Primary Endpoint Analyses 
A linear MMRM analysis will be used for comparing each Test group to the Control 
group in the mean absolute change from Baseline to Week 24 (EOS) for each primary 
endpoint. In the model, study group, visit, and study group by visit interaction, 
gender, age class, race, and BMI class are the fixed effect factors. The baseline value 
of the response biomarker is the covariate and subject is the random effect factor. The 
unstructured covariance structure will be used for modeling covariance. The 
least-squares mean difference, 95% confidence interval, and p-value will be provided 
for the group difference. The analysis will be conducted on the MITT population. 
To assess the robustness of the primary MMRM analysis to the possible violation of 
the MAR assumption, the pattern mixture model based on the non-future dependent 
missing value restriction will be applied. In addition, a supportive analysis based on 
the PP population will also be conducted. 
Descriptive statistics (the number of subjects with non-missing data, number of 
subjects with missing data, mean, standard deviation, median, minimum, and 
maximum) will be used to summarize the raw values (creatinine-adjusted raw values 
for urine variables) and absolute change from baseline values. 
16.4.2.2 
Secondary Endpoint Analyses 
• Changes in FEV1, FVC, and FEV1/FVC ratios from Baseline to Week 18 and to 
Week 24 (EOS) in the Test and Control groups.  
• The MMRM as used for the primary endpoints will be used to test the differences 
in the mean absolute change from Baseline to Week 18 for the selected 
biomarkers (WBCs, HDL-C, COHb, total NNAL, 8-epi-prostaglandin F2α, 
11-dehydrothromboxane B2, and sICAM-1) between each Test group and the 
Control group.  
• Descriptive statistics (the number of subjects with non-missing data, number of 
subjects with missing data, mean, standard deviation, median, minimum, and 
maximum) will be used to summarize the average cigarettes per day and the 
average number of e-vapor cartridge used per day by group from Week 12 
through Week 18 and from Week 19 through Week 24 (EOS). Frequency tables 
will also be used to summarize the number and percent of subjects with a 
reduction, no change, or increase in cigarette or e-vapor cartridge use from 
Baseline to Week 24 (EOS) for each study group. 

 
 
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• A frequency table (n and %) will be used to summarize use of other tobacco 
products, eCO and NNN for assessment of compliance and noncompliance for 
each study group. 
16.4.2.3 
Exploratory Endpoints Analyses 
The MMRM approach will be used to provide the estimates for: 
• changes in BOPHs and BOEs from Baseline to Week 24 (EOS) between the 
subgroups that used different flavored Test e-vapor products  
• changes in urine NE from Baseline to Week 18 and Week 24 (EOS) within each 
test group and between the Test and Control groups 
• changes in the QGEN and TQOLIT questionnaires and the Cough Questionnaire 
from Baseline to Week 24 (EOS) in the Test and Control groups 
 
Dealing with Missing Data 
16.5
In general, missing data will remain as missing in data description, i.e., no attempt 
will be made to impute missing values and only observed values will be used in 
descriptive statistics. For the primary endpoint analyses, missing data will be handled 
using the MMRM. Likewise, for all other endpoints using the MMRM analysis, 
missing data will be handled by the model. For sensitivity analyses using ANCOVA 
models, missing data will be imputed using multiple imputation with pattern-mixture 
model. For secondary or exploratory analyses using the missing data, no imputation 
will be used. Details about missing data imputation for the primary endpoints will be 
provided in the statistical analysis plan. 
 
Subgroup Analysis 
16.6
A subgroup analysis will be conducted for the Week 24 (EOS) change from Baseline 
in the primary biomarkers for covariates including gender, age class, race, and BMI 
that prove to be statistically significant in the MMRM model.  
All subgroup analyses are exploratory in nature. 
17.0 
DATA MANAGEMENT 
Every effort will be made to ensure that data management practices adhere to ethical 
and scientific quality standards of clinical data management procedures. The Sponsor 
will contract with Celerion to manage the data for this investigation. Details about the 
data management activities will be specified in the Data Management Plan (DMP). 

 
 
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Database Design and Creation 
17.1
An appropriate database will be designed and created within a validated Clinical Data 
Management System (CDMS). Electric data capture will be used for this study and 
eCRFs will be developed according to the study protocol specifications. Clinical and 
analytical laboratory data will be collected external to CDMS as external data files. 
 
Data Coding 
17.2
Upon completion of the eCRF data entry by the study site, a secondary clinical 
review will be conducted by Celerion. Adverse events and medical history coding 
will be undertaken using MedDRA®. Concomitant medications coding will be 
undertaken using WHO-DD. Each dictionary version will remain the same 
throughout the trial. 
 
Data Entry and Verification 
17.3
Data will be entered directly or transmitted from other sources by the Investigator or 
Investigator’s staff into the eCRF. Ancillary data received from clinical and analytical 
laboratories (clinical laboratory results) will be integrated into the Clinical Data 
Interchange Standards Consortium study data tabulation model datasets. 
 
Study Results Data Transfer 
17.4
Study data transfers will be sent to ALCS or their designee, electronically on a 
schedule and in a format mutually agreed upon by ALCS or their designee, and 
Celerion for the analysis of these study data. No personally identifiable information 
will be transferred to ALCS at any point in the study. 
 
Data Validation 
17.5
After the data have been entered and verified, various edit checks (including manual 
review of listings) will be performed to ensure the accuracy, integrity and validation 
of the database against the eCRF. 
Inconsistencies that arise from these edit checks will be resolved with the Investigator 
or designee. 
 
Database Lock 
17.6
On study completion, after data entry is complete, the data has been pronounced 
clean, and the Principal Investigator has reviewed and provided approval via 
signature, the database will be locked and final write access will be removed. 
The final transfer of all study data (without subject personally identifying 
information) to the study sponsor will be in SAS format. 

 
 
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18.0 
MONITORING THE STUDY 
The responsible ALCS monitor or designee will contact and visit the Investigator as 
necessary, and he/she will be allowed, upon request, to inspect and verify various 
records of the study (e.g., source documents, ICFs, eCRFs) in a manner consistent 
with GCP and all other applicable state and federal laws. 
It will be the monitor or designee’s responsibility to review the eCRFs to verify the 
adherence to the protocol and the completeness, consistency, and accuracy of the data 
being entered. The monitor will verify that each subject has consented in writing. 
Where the terms of the informed consent, GCP, and all other applicable state and 
federal laws permit, the monitor should have access to laboratory test reports and 
other subject records needed to verify the entries in the eCRF. The Investigator (or 
his/her designee) agrees to co-operate with the monitor to ensure that any problems 
detected in the course of these reviews are resolved. 
19.0 
REPORTING FOR THE STUDY 
 
Case Report Forms 
19.1
Electronic CRFs will be used for each screened subject whether or not he/she has 
completed the study. All eCRFs will be reviewed and signed by the Investigator.  
 
Study Report 
19.2
A clinical study report will be written consistent with ICH guidelines and will include 
a description 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.  
The clinical study report will be audited against the SAS data and the raw data. At the 
completion of the audit, a QA report will be issued allowing any findings to be 
addressed. 
20.0 
GENERAL 
 
Confidentiality  
20.1
All study sites will have signed confidentiality agreements with Celerion. Celerion 
will regard all information provided to the Investigator dealing with the study and 
information obtained during the course of the study as confidential. 
Celerion will not supply to the Sponsor any subject names, initials, date of birth 
(except year), or other personal identifiers.8 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 

 
 
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separate from other source documentation. 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. 
 
Responsibility of the Investigator 
20.2
The Investigator is responsible for ensuring that the clinical study is performed in 
accordance with the Declaration of Helsinki and in a manner consistent with the ICH 
Guideline for GCP and the corresponding section of the US CFR governing 
Protection of Human Subjects (Title 21 CFR Part 50)9, and Institutional Review 
Boards (Title 21 CFR Part 56)3.  
The Investigator should ensure that all persons assisting with the study are qualified 
for the duties assigned, adequately informed and trained about the protocol and 
amendments to the protocol, the test e-vapor products, and their study-related duties 
and functions. 
The Investigator will maintain a list, including signatures, of sub-investigators and 
other appropriately qualified persons to whom significant study-related duties are 
delegated. Any personnel change in this list during the course of the study will be 
documented. All study related training will be documented. 
 
Procedure for Amendments to Protocol 
20.3
No deviations from this protocol will be permitted, except in a medical emergency, 
without the approval of the Sponsor. If agreement is reached concerning the need for 
modification, this agreement will be made in a formal amendment to the protocol. 
All revisions and/or amendments to the protocol must be approved in writing by the 
IRB, if applicable. 
All persons who are affected by the amendment to the protocol will be retrained if 
deemed necessary. 
 
Institutional Review Board 
20.4
Before study initiation and shipment of test e-vapor product to a study site, the 
Investigator must have written and dated approval from the IRB for the protocol, ICF, 
subject recruitment materials/process (e.g., advertisements), and any other written 
information that will be provided to subjects. The IRB approval should be obtained in 
writing, clearly identifying the trial, the documents reviewed, and the date of the 
review. 

 
 
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As applicable, amendments to the above stated documents must also be submitted and 
receive approval from the IRB prior to implementation at the study site. The IRB 
approval should be obtained in writing, clearly identifying the trial, the documents 
reviewed, and the date of the review. 
The Investigator or Sponsor should also provide the IRB with a copy of other 
information according to regulatory requirements or Institution procedures. 
 
Termination of Study 
20.5
The Sponsor reserves the right to discontinue this study at any time. The Investigator, 
in collaboration with the Sponsor, reserves the right to discontinue the study for 
safety reasons at any time. 
 
Study Records Retention 
20.6
Investigator-specific essential documents and all primary data, or copies thereof (e.g., 
eCRFs, laboratory records, data sheets, correspondence, photographs, computer 
records, photocopied government-issued ID to verify subject age), which are a result 
of the original observations and activities of the study and are necessary for the 
reconstruction and evaluation of any study report will be retained in the investigative 
study site’s archives for a minimum of 20 years after the completion or termination 
of the study. It is the responsibility of the Sponsor to inform the Investigator as to 
when these documents no longer need to be retained. The study report and final 
database will be retained in CRO NAME’s archives for a minimum of 20 years after 
the completion or termination of the study and will be available for inspection at any 
time by the Sponsor. At completion of the study (i.e., at issuance of final study 
report), the final database will be transferred to the Sponsor. Subject names, initials, 
date of birth (except year), and other personal identifiers (including photocopied 
government issued ID) will be redacted from this data transfer file; any such 
information removed will be documented at the time of transfer.  
 

 
 
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21.0 
REFERENCES  
1. U.S.Department of Health and Human Services. The Health Consequences of 
Smoking: 50 Years of Progress. A Report of the Surgeon General. Atlanta: U.S. 
Department of Health and Human Services, Centers for Disease Control and 
Prevention, National Center for Chronic Disease Prevention and Health 
Promotion, Office on Smoking and Health., 2014. 
2. Rodgman A, Smith CJ, Perfetti TA. The composition of cigarette smoke: a 
retrospective, with emphasis on polycyclic components. Hum Exp Toxicol. 
2000;19 (10):573-595 
3. ICH Guideline for Clinical Safety Data Management: Definitions and Standards 
for Expedited Reporting (E2A). Federal Register. Vol. 60, March 1, 1995, p. 
11284. 
4. ICH Guideline for Good Clinical Practice: Consolidated Guidance (E6). Federal 
Register. Vol. 62, May 9, 1997, p. 25692. 
5. FDA Guidance for Industry, Bioanalytical Method Validation. 2001 May. 
http://www.fda.gov/cder/guidance/4252fnl.pdf 
6. Roethig H, S Feng, Q Liang, J Liu, A. Rees, and B. Zedler. 2008. A 12-Month, 
Randomized, Controlled Study to Evaluate Exposure and Cardiovascular Risk 
Factors in Adult Smokers Switching From Conventional Cigarettes to a Second-
Generation Electrically Heated Cigarette Smoking System. J Clin Pharmacol. 48: 
580 -591. 
7. Scott DA, Stapleton, JA, Wilson RF, Sutherland G, Palmer RM, Coward PY, 
Gustavsson G. 2000. Dramatic decline in circulating intercellular adhesion 
molecule-1 concentration on quitting tobacco smoking. Blood Cells, Molecules, 
and Diseases 26(3):255-258. 
8. U.S. Department of Health and Human Services. HIPAA Privacy Rule. 
Information for Researchers. De-identifying Protected Health Information Under 
the Privacy Rule. Available online at http://privacyruleandresearch.nih.gov/ 
pr_08.asp#8a. Last accessed August 30, 2011.   
9. United States Department of Labor. Occupational Safety and Health 
Administration. 
Chemical 
Sampling 
Information. 
Glycidol. 
https://www.osha.gov/dts/chemicalsampling/data/CH_243700.html 
 
 

 
 
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APPENDICES 
Appendix 1: QGEN 
 

 
 
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Appendix 1A: TQOLIT (Control Group) 
 

 
 
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Appendix 1B: TQOLIT (Test Group) 
 
 

 
 
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Appendix 2: Cough Questionnaire 
I. 
Did you have a cough in the past 30 days? 
1. Yes – PROCEED TO QUESTION II. 
2. No – STOP. DO NOT ANSWER THE REST OF THE QUESTIONS. 
 
II. 
How long have you had the cough? (provide a number)  
1. ____ Days 
2. ____ Weeks 
3. ____ Months 
4. ____ Years 
 
III. 
When does the cough occur? (choose one)  
1. Middle of the night 
2. Daytime 
3. Anytime 
 
IV. 
Do you have a cough that comes mainly from your chest and NOT from your throat 
1. Yes, cough mainly comes from my chest 
2. No 
 
V. 
Do you cough up phlegm?  
1. Never 
2. Seldom 
3. Sometimes 
4. Often 
5. Always 
 
VI. 
Do you cough more than the average person?  
1. Yes 
2. No 
 
VII. 
Have you taken medications for your cough?  
1. Yes 
2. No 
 
VIII. 
Have you sought the help of a health care provider to treat your cough?  
1. Yes 
2. No 
 
IX. 
In the last 24-hours, has your cough disturbed your sleep?  
1. All of the time 
2. Most of the time 
3. A good bit of the time 
4. Some of the time 

 
 
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5. A little of the time 
6. Hardly any of the time 
7. None of the time 
 
X. 
In the last 24-hours, how many times have you had coughing bouts?  
1. All the time (continuously) 
2. Most times of during the day 
3. Several times during the day 
4. Some times during the day 
5. Occasionally through the day 
6. Rarely 
7. None 
 
 

 
 
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Appendix 3: mCEQ Questionnaires 
 
Appendix 3A: mCEQ-E Questionnaire (Test groups only) 
 
Please mark the number that best represents how using the test e-Vapor product made you 
feel (1—not at all, 2—very little, 3—a little, 4—moderately, 5—a lot, 6—quite a lot, 7—
extremely). 
---------------------------------------------------------------------------------------------------------------- 
1. Was using the test e-Vapor product satisfying?  ____  (1….7) 
 
 
 
2. Did the test e-Vapor product taste good?   ____  (1….7) 
3. Did you enjoy the sensations in your throat and chest?   ____  (1….7) 
4. Did using the test e-Vapor product calm you down?  ____ (1….7) 
5. Did using the test e-Vapor product make you feel more awake?  ____ (1….7) 
6. Did using the test e-Vapor product make you feel less irritable?  ____ (1….7) 
7. Did using the test e-Vapor product help you concentrate?  ____ (1….7) 
8. Did using the test e-Vapor product reduce your hunger for food?  ____ (1….7) 
9. Did using the test e-Vapor product make you dizzy?  ____ (1….7) 
10. Did using the test e-Vapor product make you nauseous?  ____ (1….7) 
11. Did using the test e-Vapor product immediately relieve your craving for a cigarette?  
____ (1….7) 
12. Did you enjoy using the test e-Vapor product? ____ (1….7) 
 
 
 

 
 
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Appendix 3B: mCEQ-C Questionnaire (Both Groups at Baseline, Control group only at 
EOS) 
 
Please mark the number that best represents how using the test e-Vapor product made you 
feel (1—not at all, 2—very little, 3—a little, 4—moderately, 5—a lot, 6—quite a lot,  
7—extremely). 
---------------------------------------------------------------------------------------------------------------- 
1. Is smoking cigarettes satisfying?  ____  (1….7)  
 
 
2. Does smoking cigarettes taste good?   ____  (1….7) 
3. Do you enjoy the sensations in your throat and chest?   ____  (1….7) 
4. Does smoking cigarettes calm you down?  ____ (1….7) 
5. Does smoking cigarettes make you feel more awake?  ____ (1….7) 
6. Does smoking cigarettes make you feel less irritable?  ____ (1….7) 
7. Does smoking cigarettes help you concentrate?  ____ (1….7) 
8. Does smoking cigarettes reduce your hunger for food?  ____ (1….7) 
9. Does smoking cigarettes make you dizzy?  ____ (1….7) 
10. Does smoking cigarettes make you nauseous?  ____ (1….7) 
11. Does smoking cigarettes immediately relieve your craving for a cigarette?  ____ (1….7) 
12. Do you enjoy smoking cigarettes? ____ (1….7) 
 

 
 
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Appendix 4: 
Reasons of Use/Not-Use Test Product Questionnaire (Test Group Only) 
 
1. How likely are you to use e-cigarettes exclusively in the next 30 days? 
Strongly Likely     Quite Likely 
  Somewhat Likely Neutral/Neither  
Strongly Unlikely   Quite Unlikely        Somewhat Unlikely 
 
2. How likely would you be to use the test product exclusively in the next 30 days? 
Strongly Likely     Quite Likely 
  Somewhat Likely Neutral/Neither  
Strongly Unlikely   Quite Unlikely        Somewhat Unlikely 
 
3. Why would you use the test product NOW? (CLICK ALL THAT APPLY) 
 
Smoking/Other Tobacco-Related Reasons 
To satisfy my nicotine cravings ......................................................................................................................... 1 
To help cut back or quit smoking/using other tobacco products ....................................................................... 1 
To help prevent relapse/return to smoking/using other tobacco products ......................................................... 1 
To use in places where I cannot or should not smoke/use other  tobacco products ........................................... 1 
To not smell like smoke .................................................................................................................................... 1 
To not bother other people with smoke/smell of cigarettes/other tobacco products .......................................... 1 
It might be less harmful than cigarettes/other tobacco products ........................................................................ 1 
To reduce negative smoking related health symptoms ...................................................................................... 1 
So I would not have to quit using tobacco products altogether ......................................................................... 1 
It might be less harmful for other people around me ......................................................................................... 1 
More affordable than cigarettes/other tobacco products .................................................................................... 1 
General Reasons 
Curiosity ............................................................................................................................................................ 1 
Offered/given/used by a friend/family member ................................................................................................. 1 
Enjoy the taste ................................................................................................................................................... 1 
Enjoy the effects ................................................................................................................................................ 1 
Advertising or promotion (e.g., magazine ad, in-store, coupon) ....................................................................... 1 
To meet other people or be part of a larger group ............................................................................................. 1 
To suppress appetite for food ............................................................................................................................ 1 
Other reason 
 ...................................................................................................................................... 1 
Don’t know (SP) 
 ...................................................................................................................................... 1 
 
 

 
 
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Appendix 5: End of Study Questionnaires 
 
Appendix 5A: End of Study Questionnaire (Control Group Only) 
 
The following questions are to help in the interpretation of this study and design of future studies, please be 
completely honest. Your answers will not affect your compensation or eligibility for future studies in any way. 
 
1. 
When you collected your 1st void of the day urine collections, were you able to always collect the first 
void of the day at least 4 hours since the prior void? 
 
_____Yes 
_____No 
 
2. 
Were you able to continue to smoke your average cigarettes per day every day over the past 3 months? 
 
_____Every day 
_____Most days 
_____Some days 
_____Rarely  
_____Not at all 
 
3. 
Did you smoke more than your average cigarettes per day over the past 3 months? 
 
_____Every day 
_____Most days 
_____Some days 
_____Rarely  
_____Not at all 
 
4. 
Did you smoke less than your average cigarettes per day over the past 3 months? 
 
_____Every day 
_____Most days 
_____Some days 
_____Rarely  
_____Not at all 
 
 
5. 
Were there any days when you did not smoke at all? 
 
_____Yes: If yes, how many days ____________ (please provide a single number) 
_____No 
 
 
 
 
 
 

 
 
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Appendix 5B: End of Study Questionnaire (Test Groups Only) 
 
The following questions are to help in the interpretation of this study and design of future studies, please be 
completely honest. Your answers will not affect your compensation or eligibility for future studies in any way. 
 
1. 
When you collected your 1st void of the day urine collections, were you able to always collect the first 
void of the day at least 4 hours after the prior void? 
 
_____Yes 
_____No 
 
2. 
Have you smoked cigarettes since you were instructed to completely replace your cigarettes with the 
test e-Vapor product? 
 
_____Yes: If yes, on how many days? ____________ (please provide a single number) 
 
 On the days that you smoked what was the average number of cigarettes?_____________ 
_____No 
 
3. 
Did you use the test e-Vapor product… 
 
_____Every day 
_____Most days 
_____Some days 
_____Rarely  
_____Not at all 
 
 
 

 
 
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Appendix 6: Changes in Your Health and Well-Being 
 
Appendix 6A: Changes in Your Health and Well-Being 
 
These questions are about your health and well-being now compared to when you 
enrolled in the study about 3 months ago.  
 
1. How much better or worse is your quality of life overall? 
 
 
Lot better now .............................................1  
 
Little better now...........................................2  
 
About the same now.....................................3  
 
Little worse now ..........................................4  
 
Lot worse now..............................................5  
 
2. How much more or less limited are you in your everyday physical activities, such as 
walking, climbing stairs, carrying groceries, or participating in sports? 
 
 
Lot more limited now...................................1  
 
Little more limited now ...............................2  
 
About the same now.....................................3  
 
Little less limited now..................................4  
 
Lot less limited now.....................................5  
 
3. How much more or less often do you have emotional problems, such as feeling 
anxious,depressed or irritable? 
 
 
Lot more often now......................................1  
 
Little more often now...................................2  
 
About the same now.....................................3  
 
Little less often now.....................................4  
 
Lot less often now........................................5  
 
4. How much better or worse is your health in general? 
 
 
Much better now ..........................................1  
 
Somewhat better now...................................2  
 
About the same now.....................................3  
 
Somewhat worse now ..................................4  
 
Much worse now..........................................5  
 

 
 
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5. How much more or less confident are you about your health in the future? 
 
 
Much more confident now ...........................1  
 
Somewhat more confident now ...................2  
 
About the same now......................................3  
 
Somewhat less confident now......................4  
 
Much less confident now .............................5  
 
 

 
 
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Appendix 6B: Changes in Your Health and Well-Being 
 
These questions are about your health and well-being now compared to when you 
enrolled in the study about 6 months ago.  
 
1. How much better or worse is your quality of life overall? 
 
 
Lot better now .............................................1  
 
Little better now...........................................2  
 
About the same now.....................................3  
 
Little worse now ..........................................4  
 
Lot worse now..............................................5  
 
2. How much more or less limited are you in your everyday physical activities, such as 
walking, climbing stairs, carrying groceries, or participating in sports? 
 
 
Lot more limited now...................................1  
 
Little more limited now ...............................2  
 
About the same now.....................................3  
 
Little less limited now..................................4  
 
Lot less limited now.....................................5  
 
3. How much more or less often do you have emotional problems, such as feeling 
anxious,depressed or irritable? 
 
 
Lot more often now......................................1  
 
Little more often now...................................2  
 
About the same now.....................................3  
 
Little less often now.....................................4  
 
Lot less often now........................................5  
 
4. How much better or worse is your health in general? 
 
 
Much better now ..........................................1  
 
Somewhat better now...................................2  
 
About the same now.....................................3  
 
Somewhat worse now ..................................4  
 
Much worse now..........................................5  
 

 
 
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HIGHLY CONFIDENTIAL 
VERSION: Amendment 2, Date 06 June, 2017 
 
5. How much more or less confident are you about your health in the future? 
 
 
Much more confident now ...........................1  
 
Somewhat more confident now ...................2  
 
About the same now......................................3  
 
Somewhat less confident now......................4  
 
Much less confident now .............................5