Conditions: Smoking Cessation Harm Reduction
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 25
Healthy volunteers: yes

Brief summary:
This open-label study will explore the impact of varenicline on the process of switching from combustible cigarettes (CC) to an e-cigarette. Varenicline is currently the most efficacious single pharmacotherapy for smoking cessation, and through its actions as an agonist or partial agonist at various nicotinic acetylcholine receptor subtypes, serves to diminish the rewarding effects of cigarette smoking. Diminishing the rewarding effects of smoking might facilitate the transition from CC to e-cigarettes. On the other hand, varenicline might attenuate the rewarding effects of nicotine-containing e-cigarettes as well, which could hamper the transition. Thus, the study will provide important information about the actions of varenicline on CC as well as e-cigarettes. There is no therapeutic intent in that smokers' nicotine/tobacco dependence will not be treated; the goal is to switch from one form of nicotine/tobacco dependence (CC) to dependence on a different tobacco product (e-cigarettes).

Detailed description:

Arms:
arm 1: Participants enrolled in the study will receive a G6 e-cigarette at V2 for ad libitum use. The FDA approved starter kit of varenicline will be provided to participants at V3 (0.5 mg nightly for days 1-3, then 0.5 mg twice daily for days 4-7) along with additional G6 cartomizers. After the first week of varenicline, participants will receive the FDA-approved standard dose of varenicline (1 mg twice daily) and will continue to receive enough G6 cartomizers for the next 11 weeks.

Interventions: intervention 1: Varenicline intervention 2: e-cigarette
Intervention descriptions: intervention 1: 0.5 mg nightly for days 1-3, then 0.5 mg twice daily for days 4-7; then 1 mg twice daily for the remaining 11 weeks. intervention 2: Each G6 prefilled cartomizer contains a 50/50 blend nicotine salt with 35mg nicotine strength.

Protocol document:
Prot_SAP_000.pdf: 
Combination of E-cigarettes and Varenicline for 
Tobacco Harm Reduction 
 
 
NCT04210180 
 
Protocol V4.0 – 23 Mar 2020 


    
Main Office • 7920 ACC Blvd., Suite 110 • Raleigh, NC 27617 
 
 
Clinical Study Protocol 
 
 
Study Title: 
Combination of E-cigarettes and Varenicline for Tobacco Harm 
Reduction 
Sponsor: 
 
 
Foundation for a Smoke-Free World 
Version Number:   
Version 4.0 
Version Date:  
 
March 23, 2020 
Principal Investigator: 
Jed E. Rose, Ph.D. 
Medical Supervision:  
Perry Willette, MD 
Authors: 
Jed E. Rose, Ph.D.,  
President and CEO, 
Rose Research Center 
 
Perry Willette, MD 
Medical Director,  
Rose Research Center 
Tanaia Loeback 
Executive Vice President,  
Rose Research Center 
 
David Botts 
Executive Vice President,  
Rose Research Center 
 
Data and information contained in this document are considered to constitute trade secrets and confidential commercial 
information, and the legal protections provided to such trade secrets and confidential information are hereby claimed under 
the applicable provisions of United States law. No part of this document may be publicly disclosed without the written consent 
of the Rose Research Center, LLC. 
 
 


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TABLE OF CONTENTS 
List of Abbreviations ................................................................................................................................................... 5 
 
Introduction ........................................................................................................................................................ 7 
1.1 
Study Design and Plan ................................................................................................................................7 
1.2 
Background .................................................................................................................................................7 
 
Study Objectives and Endpoints ......................................................................................................................... 8 
2.1 
Complete Switching from CC to Halo G6 ....................................................................................................8 
2.2 
Point Abstinence (From CC) at Six Months Post Switch .............................................................................8 
2.3 
Change in Ankle-Brachial Index (ABI) .........................................................................................................8 
 
Investigational Plan ............................................................................................................................................ 8 
3.1 
Overall Study Design and Plan ....................................................................................................................8 
3.2 
General Study Procedures ....................................................................................................................... 10 
3.3 
Point of Enrollment ................................................................................................................................. 10 
3.4 
Study and Session Durations ................................................................................................................... 10 
 
Participant Involvement ................................................................................................................................... 10 
4.1 
Selection of Study Population ................................................................................................................. 10 
4.2 
Recruitment Strategies ............................................................................................................................ 12 
4.3 
Participant Retention in the Study .......................................................................................................... 12 
4.4 
Discontinuation of Participants from Study ............................................................................................ 12 
4.5 
Lost to Follow-up ..................................................................................................................................... 13 
4.6 
Violation of Inclusion/Exclusion Criteria ................................................................................................. 13 
4.7 
Participant Compensation ....................................................................................................................... 13 
4.8 
Session and Response Windows ............................................................................................................. 13 
 
HALO-G6 ELECTRONIC NICOTINE DELIVERY SYSTEM ....................................................................................... 14 
5.1 
Description of Halo G6............................................................................................................................. 14 
5.2 
DESCRIPTION OF E-LIQUID ...................................................................................................................... 14 
5.3 
Product Use Timeframe ........................................................................................................................... 14 
5.4 
Accountability and Compliance ............................................................................................................... 14 
 
Varenicline ........................................................................................................................................................ 15 
6.1 
Description of Varenicline ....................................................................................................................... 15 
6.2 
Dosage ..................................................................................................................................................... 15 
6.3 
Dose Adjustment Procedures .................................................................................................................. 15 


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6.4 
Accountability and Compliance ............................................................................................................... 15 
 
Study Procedures and Activities ....................................................................................................................... 16 
7.1 
Informed Consent and Guidance............................................................................................................. 16 
7.2 
Safety Laboratory and Other Assessments ............................................................................................. 16 
7.3 
5-Day Smoking Baseline Collection ......................................................................................................... 21 
7.4 
6-Month Follow Up .................................................................................................................................. 21 
7.5 
Schedule of Events .................................................................................................................................. 22 
7.6 
SMS Messaging ........................................................................................................................................ 23 
 
Risk / Benefit Information ................................................................................................................................ 23 
8.1 
Potential Risks ......................................................................................................................................... 23 
8.2 
Protection Against Risks .......................................................................................................................... 24 
 
Quality Control and Quality Assurance ............................................................................................................ 25 
9.1 
Training of Staff ....................................................................................................................................... 25 
9.2 
Audits and Inspections ............................................................................................................................ 25 
 Reporting of Adverse Events ............................................................................................................................ 25 
10.1 
Definitions ............................................................................................................................................... 25 
10.2 
Collection of Safety Events from Participants ......................................................................................... 26 
10.3 
Assessment of Adverse Events ................................................................................................................ 27 
10.4 
Follow-up of Non-serious and Serious Adverse Events ........................................................................... 27 
10.5 
Reporting of Safety Events to IRB ............................................................................................................ 27 
10.6 
Reporting of Safety Events to FDA .......................................................................................................... 27 
10.7 
Reporting and Follow-Up of Pregnancies ................................................................................................ 27 
10.8 
Adverse Event Leading to Discontinuation .............................................................................................. 28 
 Data Management ............................................................................................................................................ 28 
11.1 
Data Collection Procedures ..................................................................................................................... 28 
11.2 
Protocol Deviations / Noncompliance ..................................................................................................... 28 
11.3 
Data Capture ............................................................................................................................................ 28 
11.4 
Data Handling .......................................................................................................................................... 29 
 Planned Statistical Methods ............................................................................................................................. 29 
12.1 
Outcomes ................................................................................................................................................ 30 
12.2 
Interim Analysis ....................................................................................................................................... 30 
 Ethics and Regulations ...................................................................................................................................... 31 
13.1 
IRB Approval ............................................................................................................................................ 31 


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13.2 
Investigational New Drug Application ..................................................................................................... 31 
13.3 
Investigational Tobacco Product Application .......................................................................................... 31 
13.4 
GCP and Regulatory Requirements ......................................................................................................... 31 
13.5 
Participant Information and Consent ...................................................................................................... 31 
13.6 
Amendment to Informed Consent Form ................................................................................................. 32 
 Administrative Considerations ......................................................................................................................... 32 
14.1 
Participant Confidentiality ....................................................................................................................... 32 
14.2 
Record Retention ..................................................................................................................................... 32 
 References ........................................................................................................................................................ 33 
 
APPENDIX 
Appendix 1 - Patient Health Questionnaire (PHQ-9) ............................................................................................... 35 
Appendix 2 - Fagerström Test for Nicotine Dependence (FTND) ............................................................................ 36 
Appendix 3 - Research Participant Payment Verification Form .............................................................................. 37 
Appendix 4 - Smoking History ................................................................................................................................. 38 
Appendix 5 - Registration Form ............................................................................................................................... 39 
Appendix 6 - Medical History Form ......................................................................................................................... 40 
Appendix 7- Review of Systems Form ..................................................................................................................... 45 
Appendix 8 - Employment History ........................................................................................................................... 47 
Appendix 9 - modified Cigarette Evaluation Questionnaire (mCEQ) …………………………………………………………………..49 
Appendix 10 - modified Electronic Cigarette Evaluation Questionnaire (mECEQ) ………………………………………………50 
Appendix 11 - Halo G6 Flavor Assessment Questionnaire ………………………………………………………………………………….51 
Appendix 12 - Participant Instructions for Varenicline ……………………………………………………………………………………….52 
Appendix 13 - SMS Baseline Cigarette Data Collection Survey (after screening prior to V2) ……………………………...53 
Appendix 14 - SMS Daily Survey …………………………………………………………………………………………………………………………54 
Appendix 15 - 6 Month Follow Up Survey ………………………………………………………………………………………………………….55 
Appendix 16 - Assessment of Behavioral OUTcomes (ABOUT) ..…………………………………………………………………………56 
Appendix 17 - Session Payment Form .……………………………………………………………………………………………………………….58 
Appendix 18 - Reasons To Smoke .…………………………………………………………………………………………………………….……….59 
 
 
 


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LIST OF ABBREVIATIONS 
ABI 
Ankle Brachial Index 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AP 
Alkaline phosphatase 
ASP 
Application Service Provider 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CC 
Conventional cigarette 
CDC 
Center for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CO 
Carbon monoxide 
CRF 
Case report form 
CRM 
Customer relationship management 
ECG 
Electrocardiogram 
EOS 
End of Study 
FDA 
Food and Drug Administration  
FTND 
Fagerström test for nicotine dependence 
GCP 
Good Clinical Practice 
HCG 
Human chorionic gonadotropin 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation  
IRB 
Institutional Review Board 
Kg 
Kilograms 
Lbs 
pounds 
QTc 
Corrected QT interval 
mCEQ 
Modified Cigarette Evaluation Questionnaire. 
MCH 
Mean corpuscular hemoglobin 


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MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
Mg 
Milligram 
mL 
Milliliter 
nAChR 
Nicotinic Acetylcholine Receptor 
MNWS 
Minnesota Nicotine Withdrawal Scale 
PHQ-9 
The Patient Health Questionnaire 
PPM 
Parts per million 
RBC 
Red blood cell (count) 
RCT 
Randomized Control Trial 
RRC 
Rose Research Center, LLC. 
SaaS 
Software-as-a-Service 
SAE 
Serious adverse event 
SMS 
Short Message Service 
SOP 
Standard operating procedure 
SSL 
Secure Sockets Layer 
STAI 
State-Trait Anxiety Inventory 
TLS 
Transport Layer Security 
V 
Voltage 
W 
Wattage 
WBC 
White blood cell (count) 
WHO 
World Health Organization 
WI-PREPARE 
The Wisconsin Predicting Patients' Relapse Questionnaire 
 
 


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 INTRODUCTION 
1.1 STUDY DESIGN AND PLAN 
This open-label study will explore the impact of varenicline on the process of switching from combustible 
cigarettes (CC) to an e-cigarette. Varenicline is currently the most efficacious single pharmacotherapy for 
smoking cessation, and through its actions as an agonist or partial agonist at various nicotinic acetylcholine 
receptor subtypes, serves to diminish the rewarding effects of cigarette smoking. Diminishing the rewarding 
effects of smoking might facilitate the transition from CC to e-cigarettes. On the other hand, varenicline might 
attenuate the rewarding effects of nicotine-containing e-cigarettes as well, which could hamper the transition. 
Thus, the study will provide important information about the actions of varenicline on CC as well as e-cigarettes. 
There is no therapeutic intent in that smokers’ nicotine/tobacco dependence will not be treated; the goal is to 
switch from one form of nicotine/tobacco dependence (CC) to dependence on a different tobacco product (e-
cigarettes). 
1.2 BACKGROUND 
The burden of disease and death attributable to combustible cigarette (CC) smoking is enormous, with an 
estimated 540,000 premature deaths annually in the United States [1]. Considerable progress has been made 
toward reducing the prevalence of smoking, through education about the harms of smoking, increased 
taxation/regulation and the greater availability of cessation treatments. However, despite a gradual reduction in 
smoking prevalence over the years, in 2015, 15% of the adult U.S. population, or 35 million individuals, 
continued to smoke [2]. 
The 2010 U.S. Surgeon General’s Report [3] implicated combustion products, rather than nicotine, in 
contributing to the major smoking-related diseases. Therefore, e-cigarettes may reduce health risks to the user 
by avoiding combustion. Instead, they heat a solution (usually a mixture of propylene glycol and glycerol) that 
also contains nicotine and flavorings, in order to generate an aerosol at much lower temperatures than burning 
cigarettes [4]. Measures of constituents in e-cigarette aerosol show substantial reductions in most toxicants, 
including carbon monoxide, carcinogens (including tobacco-specific nitrosamines and polycyclic aromatic 
hydrocarbons), and volatile organic compounds such as acrolein, acrylamide, acrylonitrile, 1,3-butadiene and 
ethylene oxide [5, 6]. This reduction in toxicant yield could potentially translate into a marked reduction in risk 
to the smoker. Recent studies of smokers and e-cigarette users have shown 90-100% reductions in many of the 
harmful and potentially harmful constituents of cigarette smoke [7]. Preliminary studies also indicate 
improvements in lung function among e-cigarette users [8]. However, many smokers continue to smoke 
combustible cigarettes along with using e-cigarettes, which undermines any reduction in health risks that might 
be achieved. Hence, it is important to identify methods to facilitate the complete switching from CC to e-
cigarettes. 


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 STUDY OBJECTIVES AND ENDPOINTS 
2.1 COMPLETE SWITCHING FROM CC TO HALO G6 
The primary switching outcome will be smoking abstinence during weeks 8-11 post-quit date. This will be 
defined as self-report of no cigarette smoking (not even a puff), confirmed by an expired air CO reading of less 
than 5 ppm. 
2.2 POINT ABSTINENCE (FROM CC) AT SIX MONTHS POST SWITCH 
A secondary outcome will be 7-day point abstinence at 6 months post-switch. Assessed by self-report utilizing an 
automated SMS messaging system. 
2.3 CHANGE IN ANKLE-BRACHIAL INDEX (ABI) 
The Ankle-Brachial Index (ABI) is the most common test used for screening and detection of Peripheral Arterial 
Disease (PAD) in the clinical setting. The ABI is the ratio of highest systolic blood pressure obtained from the 
brachial arteries (arms) versus the highest systolic blood pressure obtained from the posterior tibial or dorsalis 
pedis arteries (ankles/feet).  
This study will utilize this simple test to evaluate changes in arterial flow when smokers change from 
combustible cigarettes to electronic cigarettes over a 13-week period. Measurements will be obtained using a 
manual sphygmomanometer and an 8- to 10- MHz doppler ultrasound probe. Subjects will undergo this testing 
at Visit 1 (baseline data) and at the end of study (Visit 7). All values will be reviewed by licensed medical 
providers. Subjects with values indicative of mild to moderate peripheral artery disease (less than 0.90, but 
greater than 0.40) will be referred to their primary care provider for follow up and will be enrolled in the study. 
Subjects with severe disease (less than or equal to 0.40) at baseline will be excluded from the study and referred 
to their primary care providers [9]. 
 INVESTIGATIONAL PLAN 
3.1 OVERALL STUDY DESIGN AND PLAN 
This single-group, small-scale, open-label study (N= 25 to 50) will evaluate the impact of varenicline on the 
process of switching from combustible cigarettes (CC) to an e-cigarette. There will be a data collection period of 
at least five days to obtain baseline data on use of combustible cigarettes. Participants enrolled in the study will 
receive a G6 e-cigarette at V2 for ad libitum use. The FDA approved starter kit of varenicline will be provided to 
participants at V3 (0.5 mg nightly for days 1-3, then 0.5 mg twice daily for days 4-7) along with additional G6 
cartomizers. After the first week of varenicline, participants will receive the FDA-approved standard dose of 
varenicline (1 mg twice daily) and will continue to receive enough G6 cartomizers to last until their next study 
visit. Halo G6 and varenicline use will continue until the participant returns for the End-of-Study visit. 


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Figure 1 - Overall Study Design 
The outcome of varenicline on the process of switching from combustible cigarettes (CC) to an e-cigarette will 
be compared to the following benchmarks. Initial results will fall into one of the following three categories: 
3.1.1 Complete switching rate of 64% 
If this study achieves at least a 64% (16/25) switching rate to Halo G6 for the first 25 smokers tested at visit 7, it 
will be viewed as having considerable promise, and will immediately be advanced to larger-scale (~N=200) 
randomized controlled clinical trials (RCTs) to provide a rigorous evaluation of its efficacy and effectiveness in 
helping smokers switch to e-cigarettes. These trials may include both double-blind efficacy trials and unblinded, 
pragmatic, real-world effectiveness trials. Future trials will be submitted to the Institutional Review Board (IRB) 
as new protocols.  
3.1.2 Complete switching rate of 52% to 60% 
If this study achieves switching to Halo G6 in 52%-60% (13/25 to 15/25) of the first 25 smokers tested at visit 7, 
then an additional sample of 25 smokers will be enrolled (total N=50) to obtain a more precise estimate of the 
switching rate. If, cumulatively, complete switching to G6 is achieved in at least 56% (28/50) at visit 7, the use of 
varenicline as an aid to switching will then be advanced to larger RCTs.  
3.1.3 Switching Thresholds Not Achieved 
If either of the above switching rate thresholds is not met in the first 25-50 smokers tested, the use of 
varenicline as an aid to switching will be considered unpromising, and further subjects will not be enrolled.  
In choosing these thresholds, Monte Carlo simulations were conducted to determine the significance thresholds 
for both the N=25 and N=50 one-tailed binomial tests so that the overall false positive (Type I error) rate across 
all tests would be approximately 10%. Conversely, the overall false negative (Type II error) rate, whereby a 
promising procedure is discarded prematurely, would be approximately 20%. The diagram below depicts the 
stepwise evaluation algorithm. 
 
Scr
Baseline 
Assessment of 
CC Use
Intro to G6
WK8
WK9
WK10
Varenicline 
Starter Pack
with G6
V2
V3
V4
V5
WK1
WK2
WK3
WK4
Target Day for 
Complete 
Switching
WK13
Varenicline Standard Dose with G6
V7
WK5
WK6
WK7
V6
WK11
WK12


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3.2 GENERAL STUDY PROCEDURES 
At each session, expired air CO will be measured along with blood pressure, heart rate, respiratory rate and 
body weight. Participants will also complete questionnaires rating subjective effects of smoking and e-cigarette 
use. Subjects will be given enough cartomizers to last until their next scheduled session, along with an extra 4 
days’ worth to allow for flexibility in case sessions need to be rescheduled. E-cigarette usage will be tracked not 
only by self-reported number of occasions used, but also by cartomizer counts (used or unused). 
3.3 POINT OF ENROLLMENT 
Participants will be enrolled after all safety laboratory results have been received and reviewed by the medical 
staff (MD or PA). The Halo G6 and the cartomizers will be dispensed starting at V2, and at each subsequent visit 
until the End-Of-Study. Study drugs will be dispensed starting at V3, and at each subsequent visit until the End-
Of-Study. 
3.4 STUDY AND SESSION DURATIONS 
The total duration for a participant will be approximately 14-16 weeks. The Screening Session (Visit 1) will last 
approximately 2 ½ to 3 hours. The other study sessions will last approximately one hour. 
 PARTICIPANT INVOLVEMENT 
4.1 SELECTION OF STUDY POPULATION 
Healthy, cigarette smoking adults, age 21-65 years, with no restriction on gender, race and ethnicities, or social-
economic status, who have smoked an average of at least 10 commercially available cigarettes per day for the 
last 12 months will be screened for enrollment in this study. 
The study will screen and enroll at both Rose Research Center locations, located in Raleigh and Charlotte, North 
Carolina. 
4.1.1 Inclusion Criteria 
Each participant must meet all the following inclusion criteria before enrollment: 
Inclusion Criteria 
1. Has signed the ICF and is able to read and understand the information provided in the ICF.  
2. Is 21 to 65 years of age (inclusive) at screening.  
3. Smokes at least 10 commercially available cigarettes per day (no brand restrictions), for the last 12 months. 
4. Has an expired air CO reading of at least 10 ppm at screening. 
5. Interested in switching to an electronic cigarette. 
6. Willing and able to comply with the requirements of the study. 
7. Owns a smart phone with text message and data capabilities compatible with necessary surveys. 


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4.1.2 Exclusion Criteria 
Potential participants who show or report indications of or self-report a diagnosis of conditions listed below may 
be excluded from the study. If the study physician (or designee) determines through the course of pre-screening, 
or a physical screen, medical history, physical findings, current medications, ECG, or laboratory findings suggests 
one of the conditions listed below, or findings reveal other information that may potentially jeopardize the 
participants’ safe participation, then they may be excluded. For medical conditions that do not appear below, 
the participant may be enrolled if the study physician (or designee) does not feel that the medical condition 
would jeopardize safe study participation or data validity. 
Exclusion Criteria 
1. Is unhealthy or cannot participate in the study for any reason (e.g., medical, psychiatric, and/or social 
reason) as judged by the Investigator or designated medical staff based on all available assessments from 
the screening period (e.g., safety laboratory, vital signs, physical examination, Ankle-Brachial Index, ECG, 
concomitant medications and medical history).   
2. PHQ-9 score greater than 9, or a score greater than 0 on item #9 (“Thoughts that you would be better off 
dead, or of hurting yourself in some way”) at screening. 
3. Planned use of an FDA-approved smoking cessation product during the study. 
4. High blood pressure (systolic > 150 mmHg or diastolic >95 mmHg) at screening.  
5. Body mass index (BMI) less than 15.0 kg/m2 or greater than 40.0 kg/m2. 
6. Coronary heart disease, structural cardiac disease (including, but not limited to valvular heart disease or 
cardiac murmurs), cardiac dysrhythmias, syncope, cardiac chest pain, or history of heart attack or heart 
failure. 
7. Has received psychotherapy or behavioral treatments potentially impacting symptoms of depression, 
anxiety, or nicotine withdrawal within 30 days of screening, or during the study.  
8. Taking antidepressants, psychoactive medications (e.g. antipsychotics, benzodiazepines, hypnotics) or 
medications that prolong QTc. 
9. Use of any of these products in the past 30 days:  
a. Illegal drugs (or if the urine drug screen is positive for cocaine, THC, amphetamines, methamphetamines, 
or opiates);  
b. Experimental (investigational) drugs that are unknown to subject;  
c. Chronic opiate use. 
10. Use of smokeless tobacco (chewing tobacco, snuff), cigars (except for “Black & Mild” cigars or Cigarillos), 
pipes, hookah, e-cigarettes, nicotine replacement therapy or other smoking cessation treatments within 
14 days of screening. 
11. Pregnant or nursing (by self-report) or has a positive pregnancy test. 
12. Enrollment requirements met. 


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4.1.3 Women of Childbearing Potential 
Pregnant or breastfeeding women will be excluded from the study. All females will undergo a serum pregnancy 
test at screening (Visit 1) and a urine pregnancy test at each subsequent visit. Heterosexually active females of 
childbearing potential (not post-menopausal) must agree to use medically acceptable contraceptives during the 
study. Medically acceptable contraceptives include: (1) surgical sterilization (such as a tubal ligation, 
hysterectomy, or Essure), (2) approved hormonal contraceptives (such as birth control pills, patches, implants or 
injections), (3) barrier methods (such as a condom or diaphragm) used with a spermicide, or (4) an intrauterine 
device (IUD).  Contraceptive measures such as Plan BTM, sold for emergency use after unprotected sex, are not 
acceptable methods for routine use. Female participants will be encouraged in the consent form to notify study 
staff if they believe a change in their pregnancy status has occurred during the trial.  
Post-menopause is defined as the time after which a woman has experienced 12 consecutive months of 
amenorrhea (lack of menstruation). 
4.2 RECRUITMENT STRATEGIES 
Participants will be selected through IRB approved generic recruitment advertisements which are specifically 
designed to recruit participants into the volunteer database for future smoking and tobacco use related research 
at the Rose Research Center. For this database, many of the participants have provided basic smoking history 
data along with demographic information, which will allow selection of potentially interested participants. 
Participants who call in will be screened into the volunteer database, and if they pre-qualify, will be offered the 
option to prescreen for this protocol. 
Participants will be contacted only with IRB approved appropriate materials and information submitted along 
with this protocol. These documents will include a brief description of the study and information on how to 
prescreen for participation. Participants will be contacted by phone, email and text message prompting 
interested participants to prescreen through an electronic screen form. 
4.2.1 
Pre-Screening 
Pre-screening will be completed prior to V1 for all participants. Participants will be provided with a set of IRB 
approved questions directly related to the inclusion and exclusion criteria. Based upon the outcome of these 
questions, potential participants may be scheduled for a screening visit (V1). 
4.3 PARTICIPANT RETENTION IN THE STUDY 
All candidates who schedule a screening visit (V1) will receive a series of email, text, and telephone reminders; 
participants are also permitted through these communications to confirm, cancel, or reschedule all their 
appointments. 
4.4 DISCONTINUATION OF PARTICIPANTS FROM STUDY 
Discontinued participants will include both participants who withdraw from the study (participant’s decision) or 
participants who are discontinued from the study (following Investigator’s decision). A participant can only be 
discontinued from the study after enrollment. Participants that are not enrolled are considered screen failures. 
Participants will be informed that they are free to withdraw from the study at any time. Participants should be 
questioned for the reason of premature withdrawal from the study, although they are not obliged to disclose it.  


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Participants discontinued from the study cannot re-enter the study.  
4.4.1 
Participants will be discontinued from the study for any of the following reasons: 
• Withdrawal of informed consent. 
• Any adverse effect or condition that would jeopardize continued safe study participation. 
• Pregnancy test is positive.  
• Discontinuation is considered to be in the best interest for the participant or for other participants 
participating in the study, as judged by the Investigator or designee. 
4.4.2 
Subjects may be discontinued from the study for any of the following reasons based on the judgment of 
the Investigator: 
• No-show to appointments and unable to reschedule within the visit window. 
• The misuse or abuse of study related equipment. 
• Unwilling or unable to comply with study procedures. 
4.5 LOST TO FOLLOW-UP 
For subjects lost to follow-up, a reasonable number of attempts to contact the subject (including written 
correspondence and/or phone calls) will be made and documented in the source documents. The date of the 
last contact (e.g. last visit, last phone call) will be recorded in the source document. When the PI(s) or 
designee(s) declare(s) a subject is lost to follow-up, the lost to follow-up date will be recorded and will 
correspond to the date of the end of study (EOS) of the subject. 
4.6 VIOLATION OF INCLUSION/EXCLUSION CRITERIA 
Participants who, after signing the ICF, do not meet the inclusion and exclusion criteria will not be enrolled in 
the study and will be considered screen failures. Re-screening for the study is not permitted. 
4.7 PARTICIPANT COMPENSATION 
There will be a payment of $25 for the Screening Session (V1) and $75 at the completion of each study session 
V2 through V7. Subjects will also receive an additional payment of $5/day for responding to daily text messages 
during the 13-week product use period. 
If subjects are asked by study staff to return to the center to complete or redo parts of the screening in 
situations of equipment malfunctions or other circumstances that are beyond the subjects’ control, subjects 
may be reimbursed for mileage. 
Subjects who decide to withdraw from the study will be paid for the part of the study they have completed.  
4.8 SESSION AND RESPONSE WINDOWS 
4.8.1 
V2 Session Window 
Participants may attend V2 up to 30 days post Screening Session (V1).  
4.8.2 
All other visit Windows 
Participants may attend sessions up to four-calendar day’s pre or post the scheduled visit. 


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4.8.3 
SMS Response Window 
The SMS response window will be open until the next SMS message is sent.  
 HALO-G6 ELECTRONIC NICOTINE DELIVERY SYSTEM 
5.1 DESCRIPTION OF HALO G6 
The Halo G6 is a breath-actuated, rechargeable e-cigarette that comes with prefilled e-liquid cartomizers. This e-
cigarette was chosen over other tank-based or pod-based e-cigarette models because of its similarity in shape 
and size to a cigarette. Because one of the goals is to provide habit substitution for smoking that varenicline 
cannot provide, this “cigalike” design is considered advantageous.  
5.2 DESCRIPTION OF E-LIQUID 
Each G6 prefilled cartomizer contains a 50/50 blend nicotine salt with 35mg nicotine strength. The 3.5% nicotine 
concentration was chosen over higher (e.g. 5%) concentrations to reduce the likelihood of nausea, given that 
nausea is a side effect of varenicline. The cartomizers come in packs of five. All Halo brand e-liquids undergo 
independent testing and they are manufactured by Nicopure labs.  
This study will use “Tribeca” (tobacco) and “Menthol” flavored cartomizers, with subjects choosing their 
preferred one of these flavors. At Visit 2, subjects will be allowed to use the two different flavors ad libitum, 
presented in counterbalanced order (randomly assigned), with a 10-minute period between each trial use. 
Research staff will inquire whether the subjects are willing and able to use the Halo G6 (either flavor) during the 
study, to determine eligibility. 
5.3 PRODUCT USE TIMEFRAME 
The maximum amount of time the G6 will be in use will be for 13 weeks, plus up to an additional four days (to 
allow for the scheduling window). Subjects will be instructed on how to use the e-cigarette prior to dispensing. 
5.4 ACCOUNTABILITY AND COMPLIANCE 
The G6 will be dispensed by the Investigator or designated study staff, as per study design. Subjects will be 
dispensed cartomizers initially at 125% based on their daily smoking habits as reported at baseline (one per pack 
of cigarettes smoked per day). Subjects may come into the office between visits to get additional supplies if 
needed. Each dispensation and collection of the product will be recorded.  
5.4.1 
Storage and Accountability 
All products will be stored in a locked, limited-access area at the study site and kept at a controlled room 
temperature (defined as 20 - 25C [68 - 77F], with excursions permitted to 15 - 30C [59 - 86F]). Halo products 
should not be exposed to extreme heat or cold.  
5.4.2 
Compliance 
Compliance will be ensured by strict distribution of the product and collection of devices (used and unused) 
which will be documented in appropriate logs.  


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 VARENICLINE 
6.1 DESCRIPTION OF VARENICLINE 
Varenicline is one of two FDA-approved non-nicotine medications prescribed as a smoking cessation aid. It is a 
partial agonist of the α4β2 nACHR, activating receptors; however, compared to nicotine, varenicline also acts as 
an antagonist, blocking occupied receptors from additional stimulation from nicotine. Recognized as the most 
effective monotherapy treatments for tobacco dependence, the medication increases the odds of quitting 
smoking by nearly fourfold compared with placebo. Hays et al. found varenicline to be generally safe and well 
tolerated as a smoking cessation aid [10].  Effective treatment of nicotine addiction is essential for reducing the 
substantial current and predicted morbidity and mortality associated with tobacco smoking. Despite the 
availability of effective treatments for smoking cessation, such as nicotine replacement therapy and bupropion 
sustained-release (SR), abstinence rates remain less than optimal. Varenicline is the first in a new class of agents 
for smoking cessation, the alpha(4)beta(2) nicotinic acetylcholine receptor (nAChR) partial agonists. Nicotine 
addiction is mediated by stimulation of central alpha(4)beta(2) nAChRs by nicotine, which causes the release of 
dopamine, ultimately leading to the pleasurable effects of smoking. As a nAChR partial agonist, varenicline 
attenuates the craving and withdrawal symptoms that occur with abstinence from nicotine and also reduces the 
rewarding effects of nicotine obtained from smoking in patients who lapse. Thus, varenicline offers a new 
therapeutic option for the treatment of nicotine addiction. Clinical trials have demonstrated superior efficacy of 
this agent over placebo and bupropion-SR for achieving abstinence from smoking, and varenicline has also been 
shown to significantly delay smoking relapse. As the newest agent approved for smoking cessation, the 
mechanism of action, efficacy, and safety of varenicline. Common adverse events associated with varenicline 
(occurring 10% or more) include nausea, insomnia, abnormal dreams, headaches, and nasopharyngitis.[11] 
Nausea, the most common side effect of varenicline, has been reported as high as 30%. Abnormal dreams and 
insomnia have been reported by over 10% of users.[12–14] 
6.2 DOSAGE 
• 0.5 mg tablet orally once a day for 3 days. 
• Starting on the fourth day, 0.5 mg tablet twice a day, orally. 
• After one week, 1.0 mg tablet twice a day, orally, for 11 weeks. 
6.3 DOSE ADJUSTMENT PROCEDURES 
Dose adjustments for varenicline will be performed by licensed medical providers based on adverse effects 
reported by participants (e.g. insomnia, abnormal dreams, mood disturbances, anxiety, in which case the dose 
will be decreased to 0.5 mg twice a day for moderate to severe side effects). Participants will be re-evaluated 
within one week of any dose adjustment. 
6.4 ACCOUNTABILITY AND COMPLIANCE 
6.4.1 
Dispensing Product 
The varenicline will be dispensed by the Investigator or designated study staff utilizing blister-pack technology to 
enhance compliance and accountability. Each dispense and collection of the product will be recorded during 


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each laboratory visit (Visit 2 through Visit 6). All study-related drug will be collected at the End-Of-Study (Visit 7 
or early termination). 
Prior to dispensing, the site will ensure that the product packaging is labelled with the protocol number and 
unique participant identifiers, date it was dispensed, and the statements “For investigational use only” and 
“Keep out of reach of children”. 
6.4.2 
Storage and Accountability 
Varenicline will be stored in a climate-controlled secured-storage site with access limited to the authorized 
personnel only. Full accountability of the distributed products will be ensured by designated staff.  
6.4.3 
Compliance 
Compliance will be ensured by strict distribution of the product, daily SMS messages, and collection of unused 
products at each study session. This information will be documented in appropriate logs.  
 STUDY PROCEDURES AND ACTIVITIES 
Personnel performing study assessments must have appropriate and documented training. An overview of all 
study assessments is shown in the schedule of events (Section 7.5). Study personnel will adhere to standard 
operating procedures (SOPs) for all activities. Appropriate medical advice will be provided by qualified staff 
(licensed providers) to the subject in case of any medical findings requiring health care. 
7.1 INFORMED CONSENT AND GUIDANCE 
Prior to any study assessments being performed, the subject will be asked to provide their written consent to 
participate in the study on an informed consent form (ICF). All assessments must start after the time of ICF 
signature by the subject for study participation. 
Designated staff, under the supervision of the Principal Investigator, will obtain informed consent from each 
participant. The person obtaining consent provides the participants with a printed document that explains the 
procedures and risks. Designated staff will answer any questions. A signed copy of the informed consent form 
will be given to each participant. Participants are informed that they may withdraw from participation in the 
study at any time without penalty.  
Because of the nature of this study and the number of questionnaires that subjects are expected to complete, 
we do not recruit potential subjects who do not read, are blind, or who do not understand English. We are not 
equipped to validate alternate versions of our questionnaires, most of which are not published. Questionnaires 
cannot be administered orally by a translator or by technicians to illiterate or blind subjects because the data 
obtained would not be comparable to self-administered questionnaires. 
7.2 SAFETY LABORATORY AND OTHER ASSESSMENTS 
An overview of all assessments is provided in the schedule of events (Section 7.5). 
Non-fasting blood samples and urine samples will be collected by qualified and trained site personnel. 
Participants will be in a seated or in a supine position during blood collection. 


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The maximal total volume of blood drawn for each subject will be around 30 mL for clinical chemistry, 
hematology, and serum pregnancy (for females). 
Samples for clinical chemistry, hematology, and serum pregnancy test will be sent to LabCorp for analysis. 
Urinalysis will also be performed by LabCorp. 
The results of the clinical chemistry, hematology and urine analysis safety panel will not routinely be given to 
subjects to send or be sent to their physician to include in their medical record. However, if the subject’s 
laboratory results are clinically relevant (including positive pregnancy tests), the research medical staff will send 
the subject a copy of the laboratory results. Subjects who are accepted into the study but need medical follow-
up due to minor abnormalities in laboratory results (at any session) will also receive a copy of the laboratory 
results. 
7.2.1 
Safety Laboratory  
Safety laboratory includes clinical chemistry, hematology, and urinalysis and will be assessed at Visit 1. 
 
Clinical Chemistry 
Clinical Chemistry 
Sodium  
Chloride 
Potassium  
Carbon dioxide 
Blood urea nitrogen (BUN) 
Creatinine  
Glucose 
Calcium 
Total protein 
Albumin  
Bilirubin 
Alkaline phosphatase (AP) 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
 
Hematology 
Hematology 
Red blood cell (RBC) count  
WBC count  
Hemoglobin  
Differential white blood cell (WBC) count  
Hematocrit 
Platelet count  
Mean corpuscular volume (MCV) 
Mean corpuscular hemoglobin concentration (MCHC) 
Mean corpuscular hemoglobin (MCH) 
 
7.2.2 
Urine Samples 
Urine samples will be collected for the urine drug screen (at screening session), urine pregnancy test (at all 
sessions except screening), and safety urinalysis (at screening session). The urine drug screen and pregnancy 
tests will be performed by study personnel at the study site. The urine sample collected for urinalysis will be 
sent to LabCorp for testing. 
In case of any positive pregnancy test, the Investigator or designee will inform the participant about the risks 
associated with smoking during pregnancy. 
In the event of a positive urine drug test for cocaine, THC, opiates, amphetamines, or methamphetamines at the 
screening visit (V1), subjects are notified that they have been excluded from study participation because of a 
positive drug test. 


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Urinalysis 
pH 
Red blood cell traces 
Bilirubin 
Protein 
Glucose 
Specific gravity 
Nitrite 
WBC Esterase 
Table 1 - Urinalysis Assessments 
Drug Screening 
Amphetamine 
Cocaine 
THC 
Methamphetamine 
Opiates 
Table 2 - Drug Screening 
7.2.3 
Serum Pregnancy Test 
Serum pregnancy test will be performed during the screening visit for all females. 
Serum Pregnancy Test 
Quantitative human chorionic gonadotropin (HCG) 
test 
7.2.4 
Urine Pregnancy Test 
The urine pregnancy test will be performed by study personnel on site for all females at each visit (except 
screening). 
7.2.5 
Electrocardiogram (ECG) 
ECG recording will be performed as per the site’s standard operating procedures. A standard 12-lead ECG will be 
recorded after the subject has rested for at least 5 minutes in a supine position.  
The following parameters will be documented: heart rate, PR interval, QRS interval, QT interval, and QTc 
interval. Every ECG has to be assessed as normal, abnormal – not clinically significant, or abnormal – clinically 
significant. 
ECG print-outs will be interpreted by a qualified physician or licensed medical provider. Any print-outs of ECGs 
on thermo-sensitive paper must be photocopied and stapled together for inclusion in the source documents and 
signed by the Investigator or designee.  
7.2.6 
Vital Signs 
Vital signs (systolic and diastolic blood pressure, pulse rate, temperature and respiratory rate), will be measured 
in sitting position after the subject has rested for at least 5 minutes. After two minutes of standing, a second 
blood pressure reading (systolic and diastolic) and pulse rate will be obtained at the screening visit (V1). 


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7.2.7 
Ankle-Brachial Index 
Measurements will be obtained using a manual sphygmomanometer and an 8- to 10- MHz doppler ultrasound 
probe. Subjects will undergo this testing at Visit 1 (baseline data) and at the end of study (Visit 7). All values will 
be reviewed by licensed medical providers. Subjects with values indicative of mild to moderate peripheral artery 
disease (less than 0.90, but greater than 0.40) will be referred to their primary care provider for follow up and 
will be enrolled in the study. Subjects with severe disease (less than or equal to 0.40) at baseline will be 
excluded from the study and referred to their primary care providers. 
7.2.8 
Physical Examination 
A complete physical examination, including auscultation and palpation will be performed. A complete physical 
examination will include review of general appearance, hair and skin, head, eyes, ears, nose and throat, neck, 
chest, abdomen, dentition, cardiovascular, musculoskeletal and neurological systems. The physical examination 
is to be conducted by a designated fully trained representative. 
Appropriate medical recommendations will be provided to the subject if any medical findings requiring health 
care are identified. 
7.2.9 
Expired Air CO Breath Test 
Carbon Monoxide (CO) in participant’s exhaled breath (expressed as ppm) will be measured using a Vitalograph 
CO Monitor. Participants must have an expired air CO reading at V1 of at least 10 ppm for inclusion into this 
study. This test will be repeated at each of the sessions. 
7.2.10 Medical History and Concomitant Disease 
Relevant medical history and concomitant disease will be documented at the screening visit (V1). Medical 
history is defined as any condition that started and ended prior to screening. A concomitant disease is defined as 
any condition that started prior to screening and is still ongoing at V1 (this may also include findings detected 
during the screening visit (V1)). 
7.2.11 Prior and Concomitant Medication 
All medication taken 30 days prior to the screening visit (V1) and during the study will be documented. 
Medications which are stopped before the screening visit (V1) will be considered as prior medication. 
Medications which are started prior to the screening visit (V1) and which are still being taken by the subject 
during the study, as well as medications that are initiated after the screening visit (V1) will be considered as 
concomitant medications. This applies to both prescription and over-the-counter products (e.g., vitamins). 
Records of prior and concomitant medications taken include the drug name (preferably both generic and trade 
name), route of administration, dose/unit, frequency of use, indication, the start and, if applicable, the stop 
date. Any therapy changes (including changes of regimen) during the study have to be documented. 
7.2.12 Body Height and Body Weight 
Body weight will be measured at each visit. Height and weight will be measured at screening, and body mass 
index (BMI) will be calculated. 
7.2.13 Demographics 
Sex, date of birth, race and ethnicity will be recorded for each participant according to Section 8.5. 


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7.2.14 AE/SAE Reporting 
AEs/SAEs will be assessed using questionnaires and face-to-face interviews at the indicated time points and 
spontaneous reporting from the time of ICF signature until the EOS for the participant (see Section 8.5). 
7.2.15 Questionnaires 
The questionnaires will be administered to the participants using paper questionnaires and/or an electronic data 
collection system. The questionnaires will be asked according to Section 8.5. 
 PHQ-9 -- The Patient Health Questionnaire 
The Patient Health Questionnaire PHQ-9 for Depression will be used to screen for current (within 2 weeks) 
depression. Potential participants who score >9 (or who score >0 on item #9 (“Thoughts that you would be 
better off dead, or of hurting yourself in some way”)) will be excluded from study participation, and, at the 
discretion of the study physician/physician assistants, referred to appropriate psychiatric treatment. Participants 
will respond to this questionnaire at all visits. This questionnaire will be administered at every visit, including the 
screening visit (V1 through V7). 
 Modified Cigarette Evaluation Questionnaire (mCEQ) and Modified Electronic Cigarette Evaluation 
Questionnaire (mECEQ) 
The Cigarette Evaluation Questionnaire was initially developed in the PI's laboratory and used in numerous 
studies to assess the effects of pharmacological treatments on the rewarding effects of cigarette smoking. The 
mCEQ (Appendix 9) is a widely used and validated questionnaire that will be utilized to assess the degree to 
which subjects experience the reinforcing of smoking, providing five subscale scores: smoking satisfaction 
(satisfying, tastes good, enjoy smoking), psychological rewards (calms down, more awake, less irritable, helps 
concentrate, reduces hunger), aversion (dizziness, nauseated), enjoyment of respiratory tract sensations (single-
item assessment), craving reduction (single-item assessment). Subjects will be asked to assess the 12 items of 
the questionnaire on a 7-point scale, ranging from “not at all” to “extremely”. The e-cigarette version of this 
questionnaire (mECEQ, Appendix 10) will also be used. 
 Reasons to Smoke 
The Reasons to Smoke questionnaire (Appendix 17) is used to determine the most important reasons to smoke 
for each subject. 
 FTND -- The Fagerström Test for Nicotine Dependence 
The Fagerström Test for Nicotine Dependence is a six-item questionnaire developed by Karl-Olov Fagerström 
and is used to determine someone’s level of nicotine dependence. The scores obtained on the test allow the 
classification of nicotine dependence in three different levels: mild (0-3 points), moderate (4-6 points), and 
severe (7 -10 points).  
 ABOUT – Assessment of Behavioral Outcomes 
The ABOUT is a self-report instrument that measures dependence in a directly comparable way across different 
tobacco- and nicotine-containing products.  
 Prior and Concomitant Medication 
At each visit, participants will report any changes in medication use, including the use of supplements, vitamins, 
over-the-counter medications, and prescription medications.  


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 Smoking History Questionnaire 
The Smoking History is a questionnaire designed to help assess the participant’s current and past smoking 
habits. This questionnaire will be administered at screening (V1) and will include questions about the number of 
years participants have smoked combustible cigarettes (CC), the number of CCs per day smoked over the last 12 
months, brand of CCs, use of other tobacco products and use of nicotine replacement therapy or other smoking 
cessation treatments. This questionnaire will also be used to check eligibility criteria. 
 Registration Form 
This form is an internal questionnaire designed to collect demographic information about participants. It will be 
administered at screening (V1). 
 Medical History Form 
The Medical History form is an internal questionnaire designed to help assess the participant’s current health 
and any health history. This questionnaire also includes questions about all medications (include prescription 
medications, other-the-counter medications or supplements) taken in the past 30 days. It is designed to help 
assess the participant’s current health and health history and is used to help determine eligibility. This form is 
administered at the initial screening visit (V1). 
 Review of Systems 
The Review of Systems is an internal questionnaire administered at screening (V1) to help assess the 
participant’s current health and health history by asking about the presence of a list of symptoms. 
 Employment History 
The Employment History is an internal questionnaire designed to collect information about a participants’ social 
economic status. Participants will be presented this questionnaire after enrollment, at the second visit (V2). 
 Medication Compliance 
Participants will be queried via SMS text messages whether they have been compliant with taking the study 
specific medications. These messages will commence after the second visit and continue through the End of 
Study (see Section 8.8). 
 Smoking Status 
SMS text messages will be sent to participants starting after enrollment, through the End of Study, to ascertain 
the participants smoking status (see Section 7.6). 
7.3 5-DAY SMOKING BASELINE COLLECTION 
After verification of eligibility (approximately two days after screening), participants will commence a five-day 
smoking baseline data collection. Participants will be called and given instructions on the use of the SMS system 
which will administer questions about smoking status in order to collect baseline data prior to start of the Halo 
and the study drug. 
7.4 6-MONTH FOLLOW UP 
Participants who complete the study will be contacted six months after the complete switch day utilizing an 
automated SMS messaging system, to ascertain their current smoking status and use of e-cigarettes. 


7.5 SCHEDULE OF EVENTS 
12 Weeks
V1
V2
V3
V4
V5
V6
V7
PM  SM S
•
•
•
•
•
•
•
•
•
•
Smoking History Questionnaire
•
Registration Form
•
Employment History
•
Medical History/Review of Systems
•
Payment Verification Form
•
•
•
•
•
•
•
Reasons to Smoke
•
•*
Modified Cigarette Evaluation Questionnaire (mCEQ)
•
•
•
•
•
•
The Fagerström Test for Nicotine Dependence (FTND)
•
•
•
Assessment of Behavioral OUTcomes (ABOUT)
•
•
•
Patient Health Questionnaire (PHQ-9)
•
•
•
•
•
•
•
e-Cigarette Usage  (via daily SMS text)
•
Smoking Status (via daily SMS text)
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Blood Pressure
•
•
•
•
•
•
•
Heart rate
•
•
•
•
•
•
•
Temperature
•
Respiratory rate
•
•
•
•
•
•
•
Weight
•
•
•
•
•
•
•
•
•
•#
•#
•#
•#
•#
•#
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
#  Targeted examination as needed
* Based on current product use
Collect Used/Unused Blister Packs
Dispense Study Drugs in Blister Packs
Ankle-Brachial Index (ABI)
Screening 
Session
5-Day 
Baseline 
Cig Data 
Collection
Dispense Halo products
Inclusion/Exclusion Criteria
Enrollment/Randomization
Halo Flavor Assessment and Questionnaire
Collect Used/Unused Halo products
Product 
Use Period
Height
Physical Examination
Vitals
Laboratory Sessions
CO Breath Test
ECG
Questionnaires
Urine Drug Screen
Prior and Concomitant Medication
Visit Assessments and Procedures
Urine Pregnancy Test (Females)
Safety Laboratories
Serum Pregnancy Test (Females)
Informed Consent and Guidance


7.6 SMS MESSAGING 
7.6.1 
Daily SMS Message (after screening, prior to V2) – Participants will receive a text with a link to a 
survey to access the following: 
• 
How soon after you woke up did you smoke your first cigarette? 
 1-Within 5 Minutes, 2-6 to 30 Minutes, 3-31 to 60 Minutes, 4-After 60 Minutes 
• 
How many cigarettes did you smoke today? 
7.6.2 
Daily SMS Message (From Visit 2) -- Participants will receive a text with a link to a survey to assess 
the following: 
• Have you smoked any combustible cigarettes today? 
o If yes, how soon after you woke up did you smoke your first cigarette? 
1-Within 5 Minutes, 2-6 to 30 Minutes, 3-31 to 60 Minutes, 4-After 60 Minutes  
o How many cigarettes did you smoke today? 
• Have you used your e-cigarette today? 
o If yes, how soon after you woke up did you use it? 
1-Within 5 Minutes, 2-6 to 30 Minutes, 3-31 to 60 Minutes, 4-After 60 Minutes  
• How many times did you use your e-cigarette today? 
• Did you take your study drug this morning? (After Visit 3) 
• Did you take your study drug this evening? (After Visit 3) 
7.6.3 
6-Month follow up SMS Message -- Participants will receive a text with a link to a survey to assess 
the following: 
• Have you smoked a combustible cigarette since your last visit? 
o If yes, are you still smoking combustible cigarettes right now? 
o How many combustible cigarettes do you smoke per day on average? 
• Have you used an e-cigarette since your last visit? 
o If yes, are you still using an e-cigarette? 
o How often do you use an e-cigarette? 
 RISK / BENEFIT INFORMATION 
8.1 POTENTIAL RISKS 
Continuing to smoke carries significant health risks; however, the participants in the studies will have 
expressed an interest in switching from smoking combustible cigarettes to using an electronic cigarette 
during the brief study duration, and hence will not be exposed to significant additional risks.  
8.1.1 
Varenicline 
Varenicline is one of the most widely used prescription medications for smoking cessation. Common 
adverse events associated with varenicline include nausea, insomnia, abnormal dreams, headaches, and 
nasopharyngitis.[11] The most common adverse reaction reported is nausea, with 30-40% of 
participants in randomized control trials reporting mild to moderate levels of nausea.[15] 
Discontinuation/drop-out rates of nearly 10% have been noted during clinical trials due to these adverse 


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effects.[16] In addition to the potential drug-specific side effects noted, any medication may trigger a 
serious allergic reaction and may cause shock, seizures (convulsions, epilepsy, "fits"), loss of 
consciousness, tingling, swelling of the face, lips, tongue, throat and/or vocal cords, difficulty breathing, 
asthma, wheezing, rash, hives, itching, and possibly death. 
8.1.2 
Use of Halo G6 
The common risks associated with e-cigarette use include coughing, dry mouth, throat irritation, sore 
throat and shortness-of-breath. 
8.1.3 
Tobacco Withdrawal 
To the extent that nicotine or other tobacco smoke constituent intake is reduced or eliminated, 
participants may experience tobacco withdrawal symptoms, including craving, difficulty concentrating, 
mood disturbance and increased appetite/weight gain.  
8.1.4 
Nicotine Toxicity 
The e-cigarette may deliver less of various tobacco smoke constituents than participants’ usual brands 
of cigarettes, and in some cases, may deliver more nicotine. However, participants control their nicotine 
intake and many studies have shown that smokers effectively limit their nicotine intake from cigarettes 
to avoid symptoms of nicotine toxicity (e.g., nausea, vomiting, sweating, headache, dizziness, jittery, 
palpitations, or in the case of extreme cases of nicotine overdose, convulsions, respiratory paralysis and 
death). 
8.1.5 
Blood Draw 
The risks associated with venipuncture are minimal and include momentary discomfort and/or bruising. 
Infection, excess bleeding, clotting, and fainting are also possible, although unlikely. 
8.2 PROTECTION AGAINST RISKS 
The risks to which participants will be exposed are comparatively minor, because it is unlikely when 
using the e-cigarette that they will be exposed to higher levels of toxicants than when smoking their 
cigarettes. Smokers are very experienced in regulating their nicotine intake to avoid excessive amounts 
[17]. Additionally, participants will be screened medically and monitored throughout the study. 
Study participants will receive detailed instructions on the use of the tobacco products distributed to 
them, in order to minimize the possibility of misuse. Subjects will be instructed to keep all 
nicotine/tobacco products away from children and pets. 
Participants will be instructed to report any side effects to study staff, who will communicate these 
reports to the medical staff. The most appropriate course of action will be determined, which may 
include options for termination of exposure to study-related clinical materials (e.g., e-cigarettes), 
options for dose reductions to varenicline, or complete termination of varenicline. Participants will, 
however, be reminded that they have the option to withdraw from the study at any time. Subjects will 
also be given a 24-hour emergency contact number in the event that side effects or adverse events 
occur between sessions. 


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 QUALITY CONTROL AND QUALITY ASSURANCE 
9.1 TRAINING OF STAFF 
The Investigator or designee will ensure that appropriate training relevant to the study is provided to all 
staff involved in the study, and that any new information relevant to the performance of this study is 
forwarded in a timely manner to the staff.  
9.2 AUDITS AND INSPECTIONS 
Good Clinical Practice regulations require independent inspections of clinical program activities. Such 
inspections may be performed at any time before, during, and after the study. 
Authorized representatives of the Sponsor, regulatory agencies and/or an IRB may perform audits or 
inspections, including source data verification. The purpose of an audit or inspection is to systematically 
and independently examine all study-related activities and documents to determine whether these 
activities were conducted, and data were recorded, analyzed and accurately reported, according to the 
protocol, ICH/GCP guidelines and any applicable regulatory requirements. The Investigator or designee 
will contact the Sponsor immediately if contacted by a regulatory agency about an inspection at their 
site. 
The Investigator and study staff are responsible for maintaining a comprehensive and accurate filing 
system of all study-related documentation that will be suitable for inspection at any time by the 
Sponsor, its authorized representative, and other regulatory agencies.  
 REPORTING OF ADVERSE EVENTS 
10.1 DEFINITIONS 
10.1.1 Adverse Event 
An Adverse Event (AE) is defined as any untoward medical occurrence that may present during 
participation in the study and which may or may not have a causal relationship with study procedures 
and/or products tested in this study. An adverse event (AE) can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to the 
study procedures and/or products. 
Any increase in the severity and/or the frequency of a concomitant disease is considered an AE. 
10.1.2 Serious Adverse Event 
A Serious Adverse Event is any adverse event that: 
• results in death; 
• is life-threatening; 
• results in inpatient hospitalization or prolongation of existing hospitalization; 
• results in persistent or significant disability / incapacity; 


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• results in a congenital anomaly / birth defect; 
• requires immediate medical or surgical intervention. 
Important medical events that may not result in death, be life threatening, or require hospitalization 
may be considered an SAE, when, based on appropriate medical judgment, the event may jeopardize 
the participant, or the participant may require medical or surgical intervention to prevent one of the 
outcomes listed in the above definitions. 
The term "life-threatening" in the definition of "serious" refers to an event in which the participant was 
at risk of death at the time of the event; it does not refer to an event, which hypothetically might have 
caused death if it were more severe. 
Any pre-planned hospitalizations that are known at the time of signing the ICF will not be recorded as an 
SAE; however, they will be recorded as AE only. Any AE that occurs during this pre-planned 
hospitalization will be considered according to the above definitions. 
10.2 COLLECTION OF SAFETY EVENTS FROM PARTICIPANTS 
Information recorded when collecting AEs will include: thorough description of the AE, seriousness 
assessment, start and stop dates (if known), circumstances leading up to the event, clinical elements 
such as clinical course, specific vital signs and test results that may explain the pathophysiology of the 
event, as well as alternative explanations to its occurrence, the action taken with the investigation 
product/procedures due to the AE, the participant`s disposition in the study after the occurrence of the 
AE and the final outcome of the AE (if known). 
Any exacerbation/worsening or increased frequency of an AE or pre-existing condition shall be 
evaluated and recorded. 
AEs should be collected using face-to-face interviews with the subject.  
Whenever a medically meaningful diagnosis is available to comprise a set of reported signs and/or 
symptoms, it should be preferentially provided as the AE or SAE term, rather than the individual signs 
and/or symptoms. Otherwise, each one of those signs and/or symptoms should be reported separately 
as event terms. 
10.2.1 Period of Collection 
All existing health conditions identified during the Screening Period will be recorded as concomitant 
disease and the participant’s eligibility will be reviewed. Any AEs which occur during the screening 
session will be captured by the study site staff and assessed by the Investigator or designee in order to 
establish relationship or relatedness in respect to study procedures. 
Any new, clinically relevant, abnormal finding detected during the study or worsening of a pre-existing 
condition/concomitant disease will be documented as an AE or an SAE. 
All ongoing AEs at the end of study participation will be followed-up by the Investigator or designee until 
they have improved, resolved, stabilized (i.e., no worsening of condition), or until an acceptable 
explanation has been found. The Investigator or designee will refer the subject to their Primary Care 
Provider for follow up of those AE when appropriate. 


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10.3 ASSESSMENT OF ADVERSE EVENTS 
10.3.1 Intensity of Adverse Events 
For each AE/SAE, the intensity will be graded on a 3-point intensity scale: 
• Mild:  The AE is easily tolerated and does not interfere with daily activity. 
• Moderate: The AE interferes with daily activity, but the participant is still able to function. 
• Severe: The AE is incapacitating and requires medical intervention. 
10.3.2 Relationship to Study Procedures 
In general, all AEs and SAEs will be assessed by the Investigator or designee as either ‘related’ or ‘not 
related’.  
• Not related: The temporal relationship of the clinical event to study procedures and/or the 
study medication makes a causal relationship unlikely, or, concomitant medication, 
therapeutic interventions, or underlying conditions provide a sufficient explanation for the 
observed event. 
• Related: The temporal relationship of the clinical event to study procedures and/or the study 
medication makes a causal relationship possible, and concomitant medication, therapeutic 
interventions, or underlying conditions do not provide a sufficient explanation for the 
observed event. 
10.4 FOLLOW-UP OF NON-SERIOUS AND SERIOUS ADVERSE EVENTS 
All ongoing Non-Serious AEs at the end of study participation will be followed-up by the Investigator or 
designee until they have improved, resolved, stabilized (i.e., no worsening of condition), or until an 
acceptable explanation has been found. The Investigator or designee will refer the subject to their 
Primary Care Provider for follow up of those AE when appropriate. 
Serious AEs will be followed up by the Investigator or designee, despite their continuation after the end 
of study, until their resolution, stabilization (i.e., no worsening of the condition), or an acceptable 
explanation has been found (e.g. a chronic condition). 
10.5 REPORTING OF SAFETY EVENTS TO IRB 
The Principal Investigator will report all serious adverse events relating to the study in an expedited 
manner to the Institutional Review Board (IRB) office in accordance with the Center’s standard 
operating procedures and GCP reporting guidelines. 
10.6 REPORTING OF SAFETY EVENTS TO FDA 
The Principal Investigator will report any suspected adverse reaction to study treatment that is both 
serious and unexpected to the FDA following established Safety Reporting guidelines. 
10.7 REPORTING AND FOLLOW-UP OF PREGNANCIES 
All participants who are determined to be pregnant after enrollment will be discontinued from the 
study. Advice on the risk of smoking and smoking cessation will be provided by the study doctor (or 


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qualified staff) and participants will be referred to the respective health care facility/health care 
provider for further support. 
The Investigator is responsible for informing the IRB of any pregnancy that occurs during the study 
according to local regulations. 
10.8 ADVERSE EVENT LEADING TO DISCONTINUATION 
If a participant is discontinued from the study because of an AE, the Investigator or designee will follow 
up until the AE(s) has/have been resolved, stabilized (i.e., no worsening of condition), or until an 
acceptable explanation has been found. 
 DATA MANAGEMENT 
11.1 DATA COLLECTION PROCEDURES 
The results from the clinical assessments will be recorded in the source data file by the Investigator or 
their authorized designee and then captured in the case report forms (CRFs), unless specified otherwise 
in the final protocol. Trained study personnel will be responsible for capturing the data from the 
observations, tests, and assessments specified in the protocol and in the source documents and 
transferring the data to the CRFs. 
The Investigator has ultimate responsibility for the collection and reporting of all data related to the 
clinical study and ensuring that the data are accurate, authentic/original, legible, timely 
(contemporaneous), enduring, and available when required. Any corrections made to source documents 
must be clearly recorded, without obscuring the original values and be accompanied by the date of 
change, reason for change, and identification of the person making the change. CRF data will be verified 
against the source documents at the study site by appropriate staff. Instances of missing or unclear data 
will be discussed with the Investigator for resolution. 
11.2 PROTOCOL DEVIATIONS / NONCOMPLIANCE 
Protocol deviations are defined as deviations from the study procedures as defined in this document, 
whether intentional or unintentional that may affect the participant’s rights, safety, or well-being and/or 
the completeness, accuracy and reliability of the data. 
Noncompliance that meets the above definition must be reported to the IRB within 10 days of becoming 
aware of the noncompliance. 
11.3 DATA CAPTURE 
All data are collected from participants using paper documents or an electronic data capture system. All 
applicable data, as specified in the protocol, will be transferred to the database or applicable Case 
Report Forms. 


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11.3.1 Salesforce.com 
Data will be collected for recruitment and screening purposes as stated within an Advarra IRB generic 
recruitment protocol. Unrelated to that protocol, pre-screening questionnaires will be attached to 
potential participant’s records on whether they qualify or are disqualified for this study. Questionnaires 
utilized for this study will be permanently attached to that potential volunteer’s record unless that 
information is requested to be removed by the participant. 
11.3.2 Survey Monkey 
Survey Monkey uses some of the most advanced technology for Internet security that is commercially 
available today. This Security Statement is aimed at being transparent about our security infrastructure 
and practices, to help reassure that data is appropriately protected. Visit Survey Monkey privacy policy 
for more information on data handling. 
All Survey Monkey information systems and infrastructure are hosted in world-class data centers. These 
data centers include all the necessary physical security controls you would expect in a data center these 
days (e.g., 24×7 monitoring, cameras, visitor logs, entry requirements). SurveyMonkey has dedicated 
cages to separate our equipment from other tenants. In addition, these data centers are SOC 2 
accredited.  
11.3.3 Short Message Service (SMS) Messaging 
SMS Messaging will be utilized for the delivery of a hyperlink to a mobile device to collect study data. 
This data will be collected utilizing an electronic survey. The service utilized for these messages is 
textit.in. 
11.3.4 Medrio 
All smoking behavioral and self-report measures will be captured initially using Medrio. Medrio is an 
electronic data collection system that records and performs analysis and reporting of data. Participant 
data will be kept within Medrio’s secure servers and may only be transmitted through a secure (SSL) 
download to our local server. Medrio’s servers are protected by high-end firewall systems, with 
vulnerability scans performed regularly. All services have quick failover points with redundant hardware, 
and complete encrypted backups are performed regularly. Medrio uses Transport Layer Security (TLS) 
encryption (SSL or HTTPS) for all transmitted internet data. All information collected within Medrio is 
compliant with 21 CFR 11 requirements. 
11.4 DATA HANDLING 
Data of all participants enrolled including screening failures and AE/SAEs during the study (from the time 
of informed consent to the end of the study of the participant) will be captured in the source 
documents. 
 PLANNED STATISTICAL METHODS 
All data measures (e.g., withdrawal symptoms questionnaires, smoking history, smoking diaries, etc.) are 
captured initially using paper or an electronic data capture system. Verified data files will be analyzed 
using Statview or SAS (Statview, SAS Institute, Cary NC). Data will be inspected for outliers and if 


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sufficiently extreme (Chauvenet’s criterion, after verifying normality of distributions) will be censored 
from the data analysis.  
12.1 OUTCOMES 
12.1.1 Switching Outcome 
Complete switching from combustible cigarette use at each time point will be defined by a self-report of 
no cigarette smoking (not even a puff) since the prior session, confirmed by an expired air CO reading of 
less than 5 ppm. The primary switching outcome will be smoking abstinence during weeks 8-11 post-
switching date. An intent-to-treat approach will be taken in which any participants lost to follow-up 
after the point of randomization, or who have smoked during weeks 8-11 will be counted as having not 
completely switched to e-cigarette use.  A secondary outcome will be 7-day point abstinence at 6-
months post-switch. The main goal of the 6-month follow-up is to assess the persistence of switching to 
e-cigarettes for those who do switch (even partially) during the first 11 weeks. The main hypothesis to 
be evaluated in this pilot study is that the rate of complete switching to e-cigarette use will be greater 
than the historical benchmark of 45% smoking abstinence expected with varenicline when it is used in 
smoking cessation treatment.  
12.1.2 Ankle-Brachial Index  (ABI) 
The ABI is the ratio of highest systolic blood pressure obtained from the brachial arteries (arms) versus 
the highest systolic blood pressure obtained from the posterior tibial or dorsalis pedis arteries 
(ankles/feet). It is a simple test, requiring minimal operator training. The ABI has been shown to be a 
marker of atherosclerosis, as well as a predictor of mortality [18]. A study from 1999 by Yataco and 
Gardner demonstrated acute changes in ABI’s in chronic smokers with peripheral arterial occlusive 
disease (PAD) after smoking just two of their usual brand combustible cigarettes [19]. Another study 
published in 2013 demonstrated statistically significant improvements in ABIs at 12 months for subjects 
who quit smoking, which the authors associated with improved arterial stiffness with smoking cessation 
[20]. We propose to utilize this simple test to evaluate vascular changes when smokers change from 
combustible cigarettes to electronic cigarettes over a 13-week period. The ABI test could provide 
valuable information regarding macrovascular effects, including changes in arterial stiffness, associated 
with switching from a combustible cigarette to an electronic cigarette. It is hypothesized that the ABIs of 
participants who completely switch to e-cigarettes will increase, demonstrating an acute improvement 
in peripheral circulation after avoidance of the deleterious effects from inhaled combustible cigarette 
smoke. 
12.2 INTERIM ANALYSIS 
An interim analysis will be conducted after results are collected from the first 25 participants, in order to 
determine whether the trial will stop, or an additional 25 participants will be enrolled, as described above. 


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 ETHICS AND REGULATIONS 
13.1 IRB APPROVAL 
The protocol, informed consent document and relevant supporting information must be submitted to 
the IRB for review and must be approved before the study is initiated. In addition, any participant 
recruitment materials must be approved by the IRB prior to being used.  
Any change to the protocol must be submitted to the IRB for review and approval before 
implementation. A protocol change intended to eliminate an apparent immediate hazard to participants 
may be implemented immediately provided the reviewing IRB are notified within 10 working days. 
13.2 INVESTIGATIONAL NEW DRUG APPLICATION 
An Investigational New Drug (IND) application is not required for use of varenicline in this study. This 
study is not intended to support a new indication, support a change in labeling, support a change in 
advertising, nor does it involve a change in dosage level or route of administration. 
An Investigational New Drug (IND) application is not required for use of Halo G6 in this study because 
the G6 is not intended for use as a smoking cessation aid.  
13.3 INVESTIGATIONAL TOBACCO PRODUCT APPLICATION 
An Investigational Tobacco Product (ITP) application is not required for use of the Halo G6 in this study. 
The device and the cartomizers were marketed prior to August 8, 2016 and are not being modified for 
the investigation. 
13.4 GCP AND REGULATORY REQUIREMENTS 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki and that are consistent with Good Clinical Practice and applicable regulatory 
requirements. The study must be conducted in accordance with the regulations of the United States 
Food and Drug Administration (FDA) as described in 21 CFR 50 and 56, applicable laws and the IRB 
requirements.  
13.5 PARTICIPANT INFORMATION AND CONSENT 
It is the responsibility of the investigator to provide each participant with full and adequate verbal and 
written information using the IRB-approved informed consent form (ICF), including the objective and 
procedures of the study and the possible risks involved before inclusion in the study. Informed consent 
must be obtained prior to performing any study-related procedures.  
The signed and personally dated original and completed ICF(s) must be kept by the Investigator and filed 
in the Investigator study file at the site or with the participant’s files and a copy must be given to the 
participant. The participant will be informed that if they discontinue from the study, the data collected 
until the point of discontinuation will be maintained as part of the study data and the samples 
collected prior to discontinuation will be analyzed, unless they refuse in writing. 


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13.6 AMENDMENT TO INFORMED CONSENT FORM 
If a protocol amendment is required, an amendment may be required to the ICF. If revision of the ICF is 
necessary, the Investigator or designee will ensure that the documents have been reviewed and 
approved by the IRB before participants are informed and sign the amended ICF (including date and 
time). 
 ADMINISTRATIVE CONSIDERATIONS 
14.1 PARTICIPANT CONFIDENTIALITY 
All information obtained during the conduct of the study with respect to the participants' state of health 
will be regarded as confidential. A statement to this effect will be written in the information provided to 
the participant. An agreement to disclose any such information will be obtained from the participant in 
writing and signed by the participant, in compliance with all local and national data protection and 
privacy legislation. 
Study records that identify participants will be kept confidential as required by law. Except when 
required by law, participants will not be identified by name, social security number, address, telephone 
number, or any other direct personal identifier in study records disclosed outside of Rose Research 
Center. For records disclosed outside of Rose Research Center, participants will be assigned a unique 
code number. The key to the code will be kept separate from the locked file where the study records are 
stored. 
14.2 RECORD RETENTION 
All records of data, in any form, will be maintained by Rose Research Center as required by ICH/GCPs. 
Essential documents will be retained for at least 15 years after completion of the study. 
Appropriate measures will be taken to prevent accidental or premature destruction of these documents. 
 
 


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 REFERENCES 
1.  
Carter, B.D., Freedman, N.D., Jacobs, E.J.: Smoking and mortality--beyond established causes. N. 
Engl. J. Med. 372, 2170 (2015). https://doi.org/10.1056/NEJMc1503675 
2.  
Ward, B.W.: Early Release of Selected Estimates Based on Data From the 2015 National Health 
Interview Survey (05/2016). 120 (2015) 
3.  
Centers for Disease Control and Prevention (US), National Center for Chronic Disease Prevention 
and Health Promotion (US), Office on Smoking and Health (US): How Tobacco Smoke Causes 
Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the 
Surgeon General. Centers for Disease Control and Prevention (US), Atlanta (GA) (2010) 
4.  
Geiss, O., Bianchi, I., Barrero-Moreno, J.: Correlation of volatile carbonyl yields emitted by e-
cigarettes with the temperature of the heating coil and the perceived sensorial quality of the 
generated vapours. Int. J. Hyg. Environ. Health. 219, 268–277 (2016). 
https://doi.org/10.1016/j.ijheh.2016.01.004 
5.  
McRobbie, H., Phillips, A., Goniewicz, M.L., Smith, K.M., Knight-West, O., Przulj, D., Hajek, P.: 
Effects of Switching to Electronic Cigarettes with and without Concurrent Smoking on Exposure to 
Nicotine, Carbon Monoxide, and Acrolein. Cancer Prev. Res. Phila. Pa. 8, 873–878 (2015). 
https://doi.org/10.1158/1940-6207.CAPR-15-0058 
6.  
Tayyarah, R., Long, G.A.: Comparison of select analytes in aerosol from e-cigarettes with smoke 
from conventional cigarettes and with ambient air. Regul. Toxicol. Pharmacol. RTP. 70, 704–710 
(2014). https://doi.org/10.1016/j.yrtph.2014.10.010 
7.  
Goniewicz, M.L., Smith, D.M., Edwards, K.C., Blount, B.C., Caldwell, K.L., Feng, J., Wang, L., 
Christensen, C., Ambrose, B., Borek, N., Bemmel, D. van, Konkel, K., Erives, G., Stanton, C.A., 
Lambert, E., Kimmel, H.L., Hatsukami, D., Hecht, S.S., Niaura, R.S., Travers, M., Lawrence, C., 
Hyland, A.J.: Comparison of Nicotine and Toxicant Exposure in Users of Electronic Cigarettes and 
Combustible Cigarettes. JAMA Netw. Open. 1, e185937–e185937 (2018). 
https://doi.org/10.1001/jamanetworkopen.2018.5937 
8.  
Polosa, R., Morjaria, J.B., Prosperini, U., Russo, C., Pennisi, A., Puleo, R., Caruso, M., Caponnetto, 
P.: Health effects in COPD smokers who switch to electronic cigarettes: a retrospective-prospective 
3-year follow-up. Int. J. Chron. Obstruct. Pulmon. Dis. 13, 2533–2542 (2018). 
https://doi.org/10.2147/COPD.S161138 
9.  
Aboyans, V., Criqui, M.H., Abraham, P., Allison, M.A., Creager, M.A., Diehm, C., Fowkes, F.G.R., 
Hiatt, W.R., Jönsson, B., Lacroix, P., Marin, B., McDermott, M.M., Norgren, L., Pande, R.L., Preux, 
P.-M., Stoffers, H.E.J., Treat-Jacobson, D., American Heart Association Council on Peripheral 
Vascular Disease, Council on Epidemiology and Prevention, Council on Clinical Cardiology, Council 
on Cardiovascular Nursing, Council on Cardiovascular Radiology and Intervention, and Council on 
Cardiovascular Surgery and Anesthesia: Measurement and interpretation of the ankle-brachial 
index: a scientific statement from the American Heart Association. Circulation. 126, 2890–2909 
(2012). https://doi.org/10.1161/CIR.0b013e318276fbcb 
10.  Hays, J.T., Ebbert, J.O., Sood, A.: Efficacy and safety of varenicline for smoking cessation. Am. J. 
Med. 121, S32-42 (2008). https://doi.org/10.1016/j.amjmed.2008.01.017 
11.  Hays, J.T., Ebbert, J.O., Sood, A.: Efficacy and safety of varenicline for smoking cessation. Am. J. 
Med. 121, S32-42 (2008). https://doi.org/10.1016/j.amjmed.2008.01.017 
12.  Halperin, A.C., McAfee, T.A., Jack, L.M., Catz, S., McClure, J.B., Deprey, M., Richards, J., Zbikowski, 
S., Swan, G.E.: IMPACT OF SYMPTOMS EXPERIENCED BY VARENICLINE USERS ON TOBACCO 
TREATMENT IN A REAL WORLD SETTING. J. Subst. Abuse Treat. 36, 428–434 (2009). 
https://doi.org/10.1016/j.jsat.2008.09.001 


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13.  Varenicline Side Effects in Detail, https://www.drugs.com/sfx/varenicline-side-effects.html 
14.  Research, C. for D.E. and: Drug Safety and Availability - FDA Drug Safety Communication: Safety 
review update of Chantix (varenicline) and risk of cardiovascular adverse events, 
https://www.fda.gov/Drugs/DrugSafety/ucm330367.htm 
15.  CHANTIX® (varenicline tartrate) | Pfizer Medical Information - US, 
https://www.pfizermedicalinformation.com/en-us/chantix 
16.  Swan, G.E., Javitz, H.S., Jack, L.M., Wessel, J., Michel, M., Hinds, D.A., Stokowksi, R.P., McClure, J.B., 
Catz, S.L., Richards, J., Zbikowski, S.M., Deprey, M., McAfee, T., Conti, D.V., Bergen, A.W.: 
Varenicline for Smoking Cessation: Nausea Severity and Variation in Nicotinic Receptor Genes. 
Pharmacogenomics J. 12, 349–358 (2012). https://doi.org/10.1038/tpj.2011.19 
17.  Delnevo, C.D., Giovenco, D.P., Steinberg, M.B., Villanti, A.C., Pearson, J.L., Niaura, R.S., Abrams, 
D.B.: Patterns of Electronic Cigarette Use Among Adults in the United States. Nicotine Tob. Res. 
Off. J. Soc. Res. Nicotine Tob. 18, 715–719 (2016). https://doi.org/10.1093/ntr/ntv237 
18.  Miller, D., Pearsall, E., Johnston, D., Frecea, M., McKenzie, M., Ontario Provincial ERAS 
Enterostomal Therapy Nurse Network: Executive Summary: Enhanced Recovery After Surgery: Best 
Practice Guideline for Care of Patients With a Fecal Diversion. J. Wound Ostomy Cont. Nurs. Off. 
Publ. Wound Ostomy Cont. Nurses Soc. 44, 74–77 (2017). 
https://doi.org/10.1097/WON.0000000000000297 
19.  Yataco, A.R., Gardner, A.W.: Acute reduction in ankle/brachial index following smoking in chronic 
smokers with peripheral arterial occlusive disease. Angiology. 50, 355–360 (1999). 
https://doi.org/10.1177/000331979905000501 
20.  Yu-Jie, W., Hui-Liang, L., Bing, L., Lu, Z., Zhi-Geng, J.: Impact of smoking and smoking cessation on 
arterial stiffness in healthy participants. Angiology. 64, 273–280 (2013). 
https://doi.org/10.1177/0003319712447888 
 
 


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Appendix 1 - Patient Health Questionnaire (PHQ-9) 
 
 


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Appendix 2 – Fagerström Test for Nicotine Dependence (FTND) 
 
 
 
 


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Appendix 3 - Research Participant Payment Verification Form  
 
 
RESEARCH PARTICIPANT PAYMENT VERIFICATION FORM 
Receipt for Payment: 
In order for Rose Research Center to meet its obligations to the Internal Revenue Service we are required to obtain the 
following information. Payment received as compensation for participation in research is considered taxable income.  You are 
responsible for paying any state, federal or Social Security taxes on the money you receive.  If your total payment exceeds $600 
in any one calendar year, we are required to report this information to the Internal Revenue Service (IRS).   
The Payment Verification Form will be used in order to process your payments only. Once your information has been entered 
into the Greenphire payment system, this form will be destroyed. Until that time, the form will be kept in a secure and locked 
area at all times. Your information will not be connected to your responses to the interviews, surveys, questionnaires or with 
your participation in this study. 
 
Full Name: 
 
______________________________________________ 
 
Social Security Number: 
______________________________________________ 
 
Permanent Home Address:  
 
_________________________________________ 
 
_________________________________________ 
 
_________________________________________ 
 


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Appendix 4 – Smoking History 
 
 
 


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Appendix 5 – Registration Form 
 
 
 


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Appendix 6 – Medical History Form 
 


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Appendix 7- Review of Systems Form 
 
 


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Appendix 8 – Employment History 
 
 
 
 
 


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Appendix 9 – modified Cigarette Evaluation Questionnaire (mCEQ) 
 
 
 


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Appendix 10 – modified Electronic Cigarette Evaluation Questionnaire (mECEQ) 
 
 
 


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Appendix 11 – Halo G6 Flavor Assessment Questionnaire 
 
 
  
 


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Appendix 12 – Participant Instructions for Varenicline 
 
 


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Appendix 13 – SMS Baseline Cigarette Data Collection Survey (after screening – prior to V2) 
 
 
 
 
 


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Appendix 14 – SMS Daily Survey 
 
 


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Appendix 15 – 6-Month Follow Up Survey  
 


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Appendix 16 – Assessment of Behavioral OUTcomes (ABOUT)  
 


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Appendix 17 – Session Payment Form 
 
 
 


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Appendix 18 – Reasons To Smoke 
 
  
REASONS TO SMOKE 
 
Have you smoked any cigarettes since your switch day? 
 No: Skip questionnaire 
 Yes: Please answer the following questions based on the FIRST cigarette you smoked on the 
last day you smoked. 
 
INSTRUCTIONS: Listed below are thirteen common reasons why people like to smoke. Using the scale on the 
right, fill in the bubble for each statement which most closely describes how important that reason is to you.  
 
 
Least 
Important  
Hardly 
Important  
Not Really 
Important  
A Little 
Important  
More 
Important  
Really 
Important  
Most 
Important 
1. It calms me down  
  
  
  
  
  
  
  
2. It gives me something to do with 
my hands  
  
  
  
  
  
  
  
3. I like the taste and smell  
  
  
  
  
  
  
  
4. I like the sensations deep in my 
throat or chest  
  
  
  
  
  
  
  
5. It wakes me up when I am drowsy  
  
  
  
  
  
  
  
6. I like to watch the smoke  
  
  
  
  
  
  
  
7. It makes relaxing seem even better  
  
  
  
  
  
  
  
8. It satisfies my craving  
  
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9. It gives me a rush  
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10. It gives me more confidence 
around other people  
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11. It helps me control my weight  
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12. It’s is like a friend  
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13. It helps me concentrate  
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