The Effects of IQOS Use on Cigarette Smoking Behaviors
Phase: EARLY_PHASE1
Conditions: Smoking, Cigarette Smoking, Tobacco Use
Sponsor: University of Pennsylvania

 
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sponsor 
CLINICAL 
RESEARCH 
PROTOCOL 
 
 
 
 
 
 
 
 
The Effects of IQOS Use on Cigarette Smoking Behaviors 
 
 
 
 
 
Regulatory Sponsor: 
Janet Audrain-McGovern, Ph.D. 
Psychiatry- Center for Interdisciplinary Research on Nicotine 
Addiction (CIRNA)  
3535 Market St.- Suite 4100 
215-746-7145 
 
Funding Sponsor: 
 
National Cancer Institute (NCI) 
 
IRB Protocol Number: 
843646 
Version # (Date): 
Version 7 (8.4.21) 
 
    NCT Number:                           NCT05076708 
 
 
 
 
 
 
 
 
Initial version # (Date): Version 1 (7.6.2020) 
Amended: Version 2 (7.29.20) 
Amended: Version 3 (8.17.20) 
Amended: Version 4 (10.14.20) 
Amended: Version 5 (12.3.20) 
Amended: Version 6 (6.28.21) 
Amended: Version 7 (8.4.21) 
 
 

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Table of Contents 
1      STUDY SUMMARY ………………………………………………………………………………………….. 1 
2       INTRODUCTION .................................................................................................................................. 2 
2.1 
BACKGROUND ................................................................................................................................ 2 
3 
STUDY OBJECTIVES ......................................................................................................................... 2 
4 
STUDY DESIGN ................................................................................................................................... 3 
4.1 
GENERAL DESIGN .......................................................................................................................... 3 
4.2 
STUDY DURATION…………………………………………………………………………………………4 
4.3 
RATIONALE .................................................................................................................................... 4 
    4.1.1 Rationale for within-subject design…………………………………………………………………….....4 
    4.1.2     Rationale for non treatment-seeking smokers………………………………………………………..4 
    4.1.3     Rationale for study duration……………………………………………………………………………4 
   4.1.4  Rationale for providing IQOS, but not smokers' own brand of cigarettes…………….………...……5 
5 
CHARACTERISTICS OF THE STUDY POPULATION ....................................................................... 5 
5.1 
TARGET POPULATION ..................................................................................................................... 5 
5.2 
ACCRUAL ....................................................................................................................................... 5 
5.3 
INCLUSION CRITERIA ...................................................................................................................... 5 
5.4 
EXCLUSION CRITERIA ..................................................................................................................... 5 
5.5 
VULNERABLE POPULATIONS ........................................................................................................... 6 
5.6 
SUBJECT RECRUITMENT ................................................................................................................. 6 
5.7 
EARLY WITHDRAWAL OF SUBJECTS ................................................................................................ 7 
5.7.1 
When and How to Withdraw Subjects ..................................................................................... 7 
6 
STUDY-PROVIDED IQOS DEVICE AND HEATSTICKS .................................................................... 7 
6.1 
DESCRIPTION ................................................................................................................................. 7 
6.2 
DISTRIBUTION SCHEDULE ............................................................................................................... 8 
6.3 
PARTICIPANT COMPLIANCE MONITORING ......................................................................................... 8 
6.4 
RECEIVING, STORAGE, DISPENSING AND RETURN ............................................................................ 8 
6.4.1 
Receipt of IQOS and HeatSticks ............................................................................................. 8 
6.4.2 
Storage .................................................................................................................................... 8 
6.4.3 
IQOS and HeatStick Accountability ......................................................................................... 8 
6.4.4 
Return or Destruction of IQOS and HeatSticks ....................................................................... 8 
7 
STUDY PROCEDURES ....................................................................................................................... 9 
7.1 
TELEPHONE ELIGIBILITY SCREEN .................................................................................................... 9 
7.2 
IN-CENTER VISITS .......................................................................................................................... 9 
7.2.1 
Visit Reminders ....................................................................................................................... 9 
7.2.2 
Intake Visit ............................................................................................................................... 9 
7.2.3 
Day 6 Visit ............................................................................................................................. 10 
7.2.4 
Day 7 Visit ............................................................................................................................. 11 
7.2.5 
Day 11 Visit ........................................................................................................................... 11 
7.2.6 
Day 14 Visit ........................................................................................................................... 11 
7.2.7 
Day 17 Visit ........................................................................................................................... 12 
7.2.8 
Day 21 Visit ........................................................................................................................... 12 
7.2.9 
Day 22 Visit ........................................................................................................................... 12 
7.3 
TABLE 1. STUDY MEASURES AND TIME POINTS .............................................................................. 13 
7.4 
DESCRIPTION OF STUDY MEASURES ............................................................................................. 14 
7.4.1 
Screening/Covariates .............................................................. Error! Bookmark not defined. 
7.4.2 
Predictor Variables ................................................................................................................ 15 
7.4.3 
Outcome Variables ................................................................................................................ 16 
7.5 
ANALYTIC PLAN............................................................................................................................ 16 
8 
RISKS / BENEFITS ............................................................................................................................ 16 

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8.1 
POTENTIAL STUDY RISKS ............................................................................................................. 16 
8.2 
POTENTIAL STUDY BENEFITS ........................................................................................................ 18 
8.3 
RISK/BENEFIT ASSESSMENT ......................................................................................................... 18 
 
8.3.1 
Adequacy of Protection against Risks…………………………………………………………18 
9 
SAFETY AND ADVERSE EVENTS ................................................................................................... 19 
9.1 
DEFINITIONS ................................................................................................................................ 19 
9.2 
COLLECTION AND RECORDING OF ADVERSE EVENTS ..................................................................... 21 
9.2.1 
AE Collection Methods .......................................................................................................... 21 
9.2.2 
AE/SAE Documentation and Internal Reporting Procedures ................................................ 21 
9.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ................................. 23 
9.3.1 
Investigator reporting: notifying NCI and FDA ....................................................................... 23 
9.3.2 
Investigator reporting: notifying the Penn IRB ....................................................................... 23 
9.4 
MEDICAL MONITORING ................................................................................................................. 24 
10 
DATA MANAGEMENT ...................................................................................................................... 24 
10.1 
DATA MANAGEMENT SYSTEM DEVELOPMENT ................................................................................ 25 
10.2 
DATA SECURITY ........................................................................................................................... 25 
10.3 
DATA PROCESSING ...................................................................................................................... 25 
10.4 
DATA QUALITY ASSURANCE .......................................................................................................... 26 
10.5 
SUBJECT AND SPECIMEN TRACKING .............................................................................................. 26 
10.6 
DATA HANDLING AND RECORD KEEPING ....................................................................................... 26 
10.6.1 Confidentiality ........................................................................................................................ 26 
10.6.2 Subject Privacy/Protected Health Information ....................................................................... 27 
11 
DATA AND SAFETY MONITORING ................................................................................................. 27 
11.1 
RESEARCH ROLES ....................................................................................................................... 27 
11.2 
STAFF TRAINING .......................................................................................................................... 28 
11.3 
MONITORING ACTIVITIES ............................................................................................................... 28 
11.3.1 
AE/SAE Monitoring ........................................................................................................... 28 
11.3.2 
Initial Assessment (Intake) Monitoring .............................................................................. 28 
11.3.3 
Protocol Monitoring ........................................................................................................... 28 
11.3.4 
Database Auditing ............................................................................................................. 29 
11.3.5 
Data Security ..................................................................................................................... 29 
11.4 
FREQUENCY OF DATA AND SAFETY MONITORING ........................................................................... 29 
11.5 
AUDITING AND INSPECTING ........................................................................................................... 29 
12 
ETHICAL CONSIDERATIONS .......................................................................................................... 29 
12.1 
INFORMED CONSENT .................................................................................................................... 30 
13 
RESOURCES NECESSARY FOR HUMAN RESEARCH PROTECTION ........................................ 30 
13.1 
RESEARCH STAFF ........................................................................................................................ 30 
13.2 
STUDY FACILITIES ........................................................................................................................ 30 
14 
STUDY FINANCES ............................................................................................................................ 31 
14.1 
FUNDING SOURCE ........................................................................................................................ 31 
14.2 
CONFLICT OF INTEREST ................................................................................................................ 31 
14.3 
SUBJECT COMPENSATION............................................................................................................. 31 
14.3.1 
Table 2. Study Compensation ........................................................................................... 31 
15 
REFERENCES ................................................................................................................................... 32 
 
 

The Effects of IQOS Use on Cigarette Smoking Behaviors 
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1 Study Summary 
Title 
The Effects of IQOS Use on Cigarette Smoking Behaviors 
Short Title 
IQOS 
IRB Number 
843646 
Methodology 
This within-subjects study aims to evaluate the effects of IQOS use on 
combustible cigarette smoking behaviors among 160 cigarette 
smokers. 
After 
measuring 
baseline 
cigarette 
smoking 
rate, 
participants will receive an IQOS device and be instructed to use it 
(versus cigarettes) over a 14-day period. We will also examine which 
objective and subjective effects of IQOS use predict a complete and 
incomplete switch from cigarettes to IQOS. 
Study Center(s) 
Single-center  
Objectives 
Aim 1: To evaluate the effects of IQOS use on cigarette smoking 
behaviors. 
Aim 2: To examine which subjective and objective effects of IQOS 
predict cigarette smoking. 
Number of 
Participants  
Forty participants 
Main Inclusion and 
Exclusion Criteria 
Main Inclusion:  
1. Male and female current cigarette smokers who are between 
18 and 65 years old and self-report smoking at least 5 
cigarettes per day for at least the last 12 months. 
2. Not currently undergoing smoking cessation treatment or 
planning to quit smoking within the next 30 days. 
3. Report an interest in quitting smoking within the next 6 months. 
 
Main Exclusion:  
1. Regular use of nicotine containing products other than 
cigarettes.  
2. Current enrollment or plan to enroll in a smoking cessation 
program over the duration of the study. 
3. History of substance abuse (other than nicotine dependence) 
in the past 12 months and/or currently receiving medical 
treatment for substance abuse. 
4. Alcohol use greater than 20 standard drinks/week. 
5. Women who are pregnant, breast feeding, or planning a 
pregnancy over the duration of the study period. 
6. Serious or unstable disease within the past year (e.g. cancer, 
heart disease). 
7. Lifetime history of schizoprenia or psychosis. 
 
The complete list of study inclusion and exclusion criteria is 
included within the Characteristics of the Study Population 
section of this protocol.  
 

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2 Introduction 
This document is a protocol for a human research 
study. This study is to be conducted in compliance with 
this research protocol, as well as according to US and 
international standards of Good Clinical Practice (FDA 
Title 21 part 312 and International Conference on 
Harmonization guidelines), applicable government 
regulations, and institutional research policies and 
procedures.  
2.1 
Background 
Combustible cigarette smoking results in the rapid delivery of nicotine, contributing to smoking 
persistence, as well as long-term exposure to numerous toxins and carcinogens. Heat-not-burn 
(HNB) tobacco products are an emerging nicotine delivery innovation designed to deliver nicotine 
without the toxins associated with combustion. In 2019, the FDA approved the sale of IQOS, the 
first HNB tobacco product available in the U.S. Manufactured by Philip Morris International, IQOS 
is a rechargeable electronic device that produces a nicotine-containing aerosol by heating a 
disposable tobacco stick called HEETS or HeatSticks.  
Since entering the market in 2014, global sales of IQOS have increased with millions of users 
across 50 countries. In 2017, 1 in 10 smokers in the U.S. was aware of HNB tobacco products 
such as IQOS. Awareness increased by 33% across the following 12 months. Among those 
aware, 18% had ever used IQOS, while almost 9% were current users, a 50% increase from the 
previous year. Current smokers had six times the odds of ever use compared to never smokers, 
suggesting the potential for dual product use. Tobacco scientists and market analysts forecast 
rapid growth in IQOS sales in the U.S. over the next few years. 
While demand for IQOS is expected to increase among cigarette smokers, the lack of scientific 
studies evaluating the impact of IQOS use on cigarette smoking behaviors renders us unable to 
predict how an increase in IQOS sales will affect public health and regulatory actions. The 
proposed research will examine: 1) whether cigarette smokers switch completely to IQOS or dual-
use two tobacco products; 2) whether IQOS use affects smokers’ motivation to quit smoking 
cigarettes; and 3) how risk perceptions of IQOS and IQOS use impact cigarette smoking 
behaviors. 
The proposed study will fill gaps in the evidence base by recruiting combustible cigarette smokers 
to a 21-day protocol using a within-subjects design. Baseline smoking rate will be established 
during days 1-5. After overnight cigarette smoking abstinence, laboratory visits on days 6 and 7 
will assess IQOS-associated craving relief, withdrawal relief, subjective reward, and the 
reinforcing value of IQOS relative to combustible cigarettes. Participants will switch from cigarette 
smoking to IQOS use for the following 14 days (days 8-21). Participants will collect their spent 
cigarette filters and their used IQOS HeatSticks daily in order to assess consumption of cigarettes 
per day (cpd) and tobacco HeatSticks per day (spd). The primary outcome measure will be the 
longitudinal daily count of cigarettes from baseline to the end of the 14-day IQOS switch phase.  
Changes in motivation to quit smoking will be a secondary outcome. 
3 Study Objectives 
 
Aim 1: To evaluate the effects of IQOS use on cigarette smoking behaviors.  
 
1
Primary Outcome
Avg. # cigs per day 
(days 8-21)
Secondary Outcomes
•
Avg. # IQOS sticks 
per day (days 8-21)
•
Quitting Intentions
Lab
Visits
5
14*
FIGURE 1
Intake
* Visit: CO, # cigs/per day,
# IQOS sticks/per day
7
Baseline
Smoking 
Rate
8
22*
Switch to 
IQOS
17*
11*
6
21*
Study
End

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H1a:  IQOS use will decrease the number of cigarettes smoked per day relative to baseline.  We 
do not expect IQOS to replace all cigarettes, and we will measure IQOS only use (complete 
switching), cigarette smoking only, and dual use.   
H1b: The reduction in number of cigarettes smoked per day will be associated with the number 
of IQOS sticks used.   
 
H1c: IQOS use will decrease smokers’ motivation to quit cigarette smoking. 
 
Aim 2: To examine which subjective and objective effects of IQOS predict cigarette smoking.   
H2: Participants with lower IQOS risk perceptions, greater craving and withdrawal relief, greater 
IQOS subjective reward, and a higher relative reinforcing value of IQOS will smoke fewer 
cigarettes per day during the 14-day switching phase.  
This will be the first independent and prospective study to examine the subjective, objective, and 
behavioral effects of IQOS use on cigarette smoking behaviors (i.e., switching, dual use and 
smoking cessation-related behaviors). As the only HNB tobacco product available in the US, 
demand for IQOS presents tobacco control challenges such as encouraging the long-term use of 
combustible cigarettes and foregoing the benefits of cessation, while risking the unknown effects 
of dual use. A greater understanding of IQOS use and its relationship to cigarette smoking will be 
fundamental to address these challenges and to inform appropriate public health and regulatory 
actions. The findings will directly address CTP’s Rapid Response priority #4 (Behavior) to assess 
the likely impact of heated tobacco products on cigarette smoking behaviors (i.e., switching, use, 
dual use and smoking cessation-related behaviors).   
4 Study Design 
4.1 
General Design 
We propose to conduct a within-subjects study of the impact of IQOS use on smoking behavior 
among 160 combustible cigarette smokers. Eligible smokers will participate in 8 visits across a 
21-day protocol. Participants who are eligible based on telephone screening will complete an in-
person Intake Visit (day 0). Those eligible will complete measures of demographics, smoking 
history, and motivation to quit smoking. Baseline cigarette smoking rate will be established during 
days 1-5 by instructing participants to smoke as usual for the following five days (days 1-5), while 
collecting their spent cigarette filters each day.  Participants will return to the lab on day 6 after 
overnight smoking abstinence (CO < 10). Participants will be required to use the IQOS device in 
the lab, then complete an assessment of IQOS-associated craving relief, withdrawal relief, 
subjective rewarding value of IQOS, and IQOS-associated risk perceptions. Participants will also 
return to the Center on day 7 after overnight smoking abstinence (CO value 50% of Intake visit’s 
CO value) for an assessment of the Relative Reinforcing Value of IQOS (RRVI) after required use 
of the IQOS device in the lab. See Figure 1. 
   
Participants will then be instructed to use IQOS (versus cigarettes) for the following 14 days (days 
8-21). Participants will collect their used cigarette filters and their used IQOS HeatSticks daily in 
order to assess consumption of cigarettes per day and sticks per day. Participants will return to 
the Center on days 11, 14, 17, and 21 to have their carbon monoxide (CO, exhaled breath) 
measured, and to return their used tobacco sticks and any spent cigarette filters. Cigarette 
smoking status will be assessed via self-report, spent cigarette filters, and biochemically verified 
(CO value 50% of Intake visit’s CO value). Changes in motivation to quit smoking will be measured 
at study end, and all remaining used sticks and spent cigarette filters will be returned on Day 22. 
 
On Day 22, participants will be: (1) informed of the lack of data supporting IQOS as a smoking 
cessation aid or harm reduction tool; (2) cautioned on the likelihood of dual use and the risks 

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associated with dual use; (3) advised to either quit using IQOS or to quit smoking cigarettes if 
they are using both; and (4) referred to a smoking cessation program if interested in quitting 
smoking. The primary outcome measure will be the longitudinal daily count of cigarettes from 
baseline to the end of the 14-day IQOS switch phase.  Changes in motivation to quit smoking 
from baseline to study end will be a secondary outcome. 
4.2 
Study Duration 
 
Recruitment/enrollment for the pilot version of this study  began in November 2020 and and will 
continue until July 2021. Recruitment/enrollment for the full version of this study is anticipated to 
begin in August 2021 and will continue until January 2024. We estimate that up to 40 participants 
will have completed the pilot version of the study by July 2021, and we estimate that up to 120 
participants will have completed the study by August 2024, for a total of 160 participants 
completing the study. Each participant will be considered “active” within the study for 21 days per 
the study design. 
4.3 
Rationale 
4.1.1 
Rationale for within-subject design 
We chose a within-subjects design for several reasons. First, our proposed aims and hypotheses 
reflect intra-individual change across time. Baseline smoking rate will be established across five 
days of ad-libitum smoking. Cigarette smoking subsequent to the introduction of IQOS will be 
compared to each participant’s baseline smoking rate (Day 1-5 vs. Day 8-21, see Figure 1). 
Randomly assigning smokers to continue to smoke their own cigarettes or to switch to IQOS in a 
between-subjects design is inconsistent with our aims. Second, we do not expect daily cigarette 
consumption to change in a group of smokers instructed to continue smoking as usual. Third, 
utilizing a within-subjects design allows us to maximize statistical power and take advantage of 
the high within-individual correlation of the primary outcome measure so that we can detect 
differences in smoking behaviors as participants switch to IQOS. 
4.1.2 
Rationale for nontreatment-seeking smokers 
Consistent with previous studies of IQOS use among cigarette smokers, we will recruit smokers 
who are not seeking smoking cessation treatment. The goals of this study are to evaluate the 
effects of IQOS use on cigarette smoking behaviors and to examine which subjective and 
objective effects of IQOS predict greater IQOS use relative to cigarette smoking. Because the 
proposed study is not a smoking cessation treatment study, and we are thus not providing 
treatment, it would be inappropriate to recruit smokers wishing to quit. However, to increase the 
likelihood that participants will represent smokers likely to use IQOS, eligible smokers will include 
smokers who would like to quit smoking cigarettes within the next six months, but not within the 
next 30 days. Smokers reporting a desire to quit in the next 30 days are typically treatment 
seekers. 
4.1.3 
Rationale for study duration 
We have previously conducted research on the effects of progressively decreasing nicotine levels 
on cigarette smoking behaviors and subjective effects across 10-day duration periods. Significant 
decreases in smoking behavior and subjective ratings of cigarette characteristics were observed 
within this 10-day period. We have also observed significant effects on smoking behaviors in 
menthol cigarette smokers who switched to a non-menthol brand across a 15-day period, 
especially between days 10-12. In previous studies, we observed that most daily cigarette change 
occurs within the first 12 days of product use and then remains unchanged for at least the next 4 
weeks. Phillip Morris conducted the only longitudinal study of IQOS use among cigarette smokers 
under naturalistic conditions. Across six weeks of observation, the majority of change occurred in 

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the first weeks of IQOS use, with little to no change thereafter. Given these findings, we expect 
to detect the majority of change in IQOS use and cigarette smoking across 14 days. 
4.1.4 
Rationale for providing IQOS, but not smokers’ own brand of cigarettes 
IQOS will be provided to participants at no cost, but cigarettes will not. This decision is based on 
methodological, budgetary, and logistical reasons. One, it is not feasible to maintain every variety 
of cigarette brand that smokers use.  Two, we are interested in how IQOS use impacts smoking 
behavior.  By providing cigarettes, we may alter cigarette smoking behavior by implying that we 
expect participants to smoke their usual brand in addition to IQOS.  Three, smokers who purchase 
IQOS in the natural environment are likely to have a limited supply of cigarettes available, because 
their intent is to switch to IQOS.  As such, not providing a 14-day supply of cigarettes maximizes 
external validity. 
 
5 
CHARACTERISTICS OF THE STUDY POPULATION  
5.1 
Target Population 
Participants will be males and females between the ages of 18-65 who report smoking at least 5 
cigarettes/day for at least the past 12 months. 
5.2 
Accrual 
We propose to recruit 160 total participants (40 pilot study participants, 120 full study participants) 
to complete a 21-day duration protocol over an 8 month period. Their six laboratory visits will 
occur about every three days. This will allow approximately four to five participants to be recruited 
every month, accounting for scheduling of visits at about the same time of day (within 1 hour), as 
there is diurnal variation in smoking behaviors. We will use several, proven strategies to 
encourage completion of the study, such as providing: (1) each participant with a calendar of their 
appointments throughout the study; (2) reminder calls the day prior to coming in; (3) incentives 
for each visit; and (4) a bonus for completion of the entire study such that total compensation 
equals $500. 
5.3 
Inclusion Criteria 
1. Able to communicate fluently in English (i.e. speaking, writing, and reading). 
2. Male and female smokers who are between 18 and 65 years of age and self-report 
smoking at least 5 cigarettes (menthol and/or non-menthol) per day for at least the last 12 
months. 
3. Not currently undergoing smoking cessation treatment or planning to quit smoking within 
the next 30 days. 
4. Report an interest in quitting smoking within the next 6 months. 
5. Plan to live in the area for the duration of the study 
6. Willing to use study provided IQOS devices and HeatSticks during 2 laboratory visits and 
throughout study participation. 
7. Capable of giving written informed consent, which includes compliance with the 
requirements and restrictions listed in the combined consent and HIPAA form. 
5.4 
Exclusion Criteria 
Subjects who present and/or self-report with the following criteria will not be eligible to participate 
in the study:  
 
Smoking Behavior 

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1. Regular use of nicotine containing products other than cigarettes (e.g. chewing tobacco, 
snuff, snus, cigars, e-cigs, etc.). Participants agreeing to abstain from using nicotine 
containing products other than cigarettes for the duration of study will be considered 
eligible. 
2. Current enrollment or plans to enroll in a smoking cessation program over the duration of 
the study (i.e. 21 days/3 weeks). 
3. Provide a CO breath test reading less than 10 ppm at Intake. 
 
Alcohol and Drug  
1. History of substance abuse (other than nicotine dependence) in the past 12 months and/or 
currently receiving medical treatment for substance abuse. Counseling and support 
groups (e.g. Alcoholics Anonymous and Narcotics Anonymous) will not be considered 
medical treatment for the purposes of this protocol.  
2. Current alcohol consumption that exceeds 20 standard drinks/week. 
3. Breath alcohol reading (BrAC) greater than .000 at Intake. 
 
Medical  
1. Women, including all individuals assigned as “female” at birth, who are pregnant, breast 
feeding, or planning a pregnancy over the duration of the study period.  
2. Serious or unstable disease within the past year (e.g. cancer, heart disease). Applicable 
conditions will be evaluated on a case-by-case basis by the Principal Investigator. 
 
Psychiatric 
1. Lifetime history of schizophrenia or psychosis. 
2. Lifetime history or current diagnosis of active major depression. Participants who maintain 
a diagnosis of major depression who have not experienced any major depressive 
episodes in the past 6 months and are stable on antidepressant medication(s) are eligible 
to participate.  
3. Lifetime history of a suicide attempt. 
 
General Exclusion 
1. Past, current, anticipated, or pending enrollment in another research program over the 
study period that could potentially impact subject safety, study data, and/or the study 
design as determined by the Principal Investigator. 
2. Any medical condition, illness, disorder, adverse event (AE), or concomitant medication 
that could compromise participant safety or significantly impact study performance as 
determined by the Principal Investigator.  Subjects may be deemed ineligible for any of 
the aforementioned reasons at any point throughout the study, as well as during the initial 
telephone screen. 
3. Significant non-compliance with protocol and/or study design as determined by the 
Principal Investigator and/o.  Subjects may be deemed ineligible at any point throughout 
the study.  
5.5 
Vulnerable Populations 
Children, pregnant women, fetuses, neonates, or prisoners are not included in this research study. 
Educationally or economically disadvantaged persons are included but not solely targeted for 
recruitment. Because of our recruitment efforts for this study, it is possible that University of 
Pennsylvania employees and students may be invited to participate. Status of participation in the 
current study will be independent of the participant’s work or school activities.  

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5.6 
Subject Recruitment  
Participants may be recruited from print, traditional, and social media advertisements, referrals, 
and/or from our database of previous participants who have agreed to be re-contacted for future 
studies. All advertising materials will be submitted to the UPENN IRB for approval prior to 
distribution/posting. Interested participants will first complete a telephone screen to assess their 
initial eligibility. Participants who are initially eligible will be screened against our registration 
database to confirm that they are not currently participating in another research study at our 
Center and have not previously reported a condition or circumstance that would make them 
ineligible for the current study. These participants who remain initially eligible will then be invited 
to attend an Intake Visit at our Center during which they will be presented with the IRB-approved 
combined informed consent and HIPAA Form and have their final eligibility confirmed. Initially 
eligible participants will also have the option to review and sign the combined informed consent 
and HIPAA Form electronically via REDCap prior to completing the rest of the Intake Visit at our 
Center.  
5.7 
Early Withdrawal of Subjects 
5.7.1 
When and How to Withdraw Subjects 
Participants are free to withdraw from the study on their own accord at any time. In addition, 
participants may be withdrawn by the Principal Investigator at any time per the exclusion criteria 
listed previously. No follow-up data collection is required for participants who withdraw or are 
deemed ineligible throughout the study. 
6. Study-Provided IQOS Device and HeatSticks 
6.1 Description 
Heat-not-burn (HNB) tobacco products are an emerging nicotine delivery innovation designed to 
deliver nicotine without the toxins associated with combustion. Powered by a rechargeable 
battery, HNB devices heat (~662 degrees Fahrenheit) rather than combust (~1,112 degrees 
Fahrenheit) leaf tobacco to produce a nicotine-containing aerosol for inhalation. In 2019, the Food 
and Drug Administration (FDA) approved the sale of IQOS, the first HNB tobacco product 
available in the U.S. [4].  Manufactured by Philip Morris International, IQOS consists of three 
components: (1) a disposable tobacco stick – HeatSticks or HEETS; (2) a holder that heats the 
tobacco stick via an electronically charged heating blade; and (3) a charger to recharge the holder 
after each use. To use IQOS, a tobacco stick is 
inserted into the heating blade within the 
holder, the holder is turned on, the heating 
blade is activated, and then the tobacco stick is 
heated 
producing 
a 
nicotine-containing 
aerosol. The tobacco stick is heated for 
approximately six minutes, allowing up to 14 
puffs to be taken, offering smokers the 
opportunity to self-administer nicotine without 
combustion. See Figures 2, 3. 
Figure 2. 

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6.2 Distribution Schedule 
At the Day 7 Visit, participants will be provided with an IQOS 3.0 holder and charger, a 7-day 
supply of regular and/or menthol HeatSticks, and fourteen date-stamped zipped baggies for daily 
collection (7 for spent cigarette filters, 7 for used HeatSticks). At the Day 14 Visit, participants will 
be provided with their second seven-day supply of Marlboro HeatSticks, as well as fourteen 
additional date-stamped zipped baggies (7 for spent cigarette filters, 7 for used HeatSticks). The 
Principal Investigator may approve a change to the distribution 
schedule on a case-by-case basis due to extenuating 
circumstances.  
6.3  Participant Compliance Monitoring 
Participants will be required to keep track of the IQOS device 
and all the HeatSticks provided to them. Therefore, 
participants will be instructed to return all used HeatSticks, 
unused HeatSticks within their original packaging, and empty 
HeatStick packages to the Center at each lab visit. Research 
staff will fill in a “Product Accountability Log” with the 
participants at each visit. Any discrepancy between the 
products dispensed versus the products returned will be 
discussed and recorded in the log. All unused study HeatSticks 
will be collected from participants at all visits. Unused 
HeatSticks returned by a given participant may be re-distributed to the same participant. At the 
Day 22 Visit, any remaining unused HeatSticks returned by the participants will be collected by 
the research staff for destruction.  
6.4  Receipt, Storage, Dispensing and Return 
6.4.1 Receipt of IQOS and Marlboro HeatSticks 
IQOS devices and HeatSticks will be shipped directly to the CIRNA and/or purchased from a 
commercial vendor. Upon receipt of IQOS devices and HeatSticks to the CIRNA, an inventory will 
be performed and a product receipt log will be filled out and signed by the person accepting the 
shipment/delivery. Study staff will verify that the shipment/delivery contains all the items noted in 
the shipment/delivery inventory. Any damaged or unusable IQOS devices and/or HeatSticks in a 
given shipment/delivery will be documented in the study files.    
6.4.2 Storage 
IQOS devices and HeatSticks will be held at room temperature in a double-locked location (e.g., 
a locked cabinet in a locked room).  
6.4.3 IQOS and HeatStick Accountability 
A master product accountability log will be maintained throughout the study. All product received, 
distributed to each unique participant, and destroyed will be documented per standardized 
product accountability procedures.  
6.4.4 Return or Destruction of IQOS and HeatSticks (trial completion) 
At the completion of the study, there will be a final reconciliation of IQOS devices and HeatSticks 
purchased, IQOS devices and HeatSticks dispensed, and IQOS devices and HeatSticks 
remaining. This reconciliation will be logged on a study completion reconciliation form.  Any 
notable discrepancies will be investigated, documented, and resolved if possible. 
 
Figure 3. 

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7 Study Procedures 
7.1  Telephone Eligibility Screen  
Individuals interested in study participation will be screened by a qualified member of the research 
team to determine initial study eligibility. If the participant meets preliminary eligibility, they will be 
invited to schedule an Intake Visit at which their final eligibility will be confirmed. 
 
7.2  In-Center Visits  
 
7.2.1 Visit Reminders 
Participants will typically receive study visit reminders 24 hours prior to their scheduled study visits 
via phone call, email, and text message (if applicable).  
 
7.2.2 Intake Visit 
During Intake, (Duration: ~1.5 hours) participants will: 
1. Either hear an informed consent and HIPAA presentation where all the study procedures 
and institutional policies will be reviewed OR complete a virtual IRB-approved informed 
consent and HIPAA presentation via REDCap where all the study procedures and 
institutional policies will be reviewed prior to coming in to complete the remainder of their 
Intake Visit. The Principal Investigator will determine whether in-person or electronic 
consent will be collected based on University COVID-19-related guidelines. The in-
person consent procedures will proceed as follows: the combined informed consent and 
HIPAA form will be read verbatim. All participant questions will be answered as 
appropriate after which the combined informed consent and HIPAA form will be 
completed (signed and dated) by both the participant and a qualified member of the 
research team. The electronic consent process will involve the following procedures:  
a. The participant will be required to view the entire combined informed consent and 
HIPAA form on REDCap prior to signing the document. Upon completing their 
reading of the consent, the participant will be offered the opportunity to indicate if 
they have any questions and a staff member will call the participant to complete a 
consent discussion via the telephone. All participant questions will be recorded and 
answered as appropriate after which the combined informed consent and HIPAA 
form will be completed (virtually signed and dated) by both the participant and a 
qualified member of the research team. 
b. The staff will print a signed copies of this completed record, and provide one 
copy to the participant and save one copy for our records. 
2. Confirm the accuracy of information (i.e. name, address, phone number, email [if 
applicable], date of birth, age, gender, ethnicity, and race) provided during the initial 
Telephone Eligibility Screen. 
3. Complete a UDS (at least 30ml [two tablespoons] of urine). The UDS will assess the use 
of any study-prohibited medications/recreational drugs (See Key Exclusionary Criteria; 
Alcohol and Drug).  
4. Participants who test positive for any exclusionary medications or recreational drugs per 
this protocol will be deemed ineligible. 
5. Female participants only: Self-administer a CLIA-waived urine pregnancy test.  
6. Female participants are advised that participation of pregnant women in this study is 
prohibited and that they may withdraw at any time. 
7. Have height and weight measured. 
8.  Perform a BrAC assessment to control for alcohol consumption.  
9. Participants with a BrAC greater than 0.000 at Intake Visit will be ineligible. 

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10. Perform a CO breath assessment and collect self-report smoking behavior over the past 
24 hours to control for prior tobacco exposure.  
11. Participants with a CO reading less than 10 ppm will be deemed ineligible. 
12. Be asked questions about use of marijuana, other tobacco products (besides cigarettes), 
or vaping of any substance including tobacco/nicotine or other drugs in the past month. 
13. Complete a Medical History Form with a member of the research team to review for 
applicable contraindications, including psychiatric exclusions, previously listed under 
Inclusion and Exclusion Criteria (section 4.3 and 4.4). 
14. Complete a baseline concomitant medication review (if applicable).  
15. Complete questionnaires: 
16. Demographics 
17. Smoking History (e.g., duration, rate, regular and/or menthol) 
18. Nicotine Dependence (FTND) 
19. Motivation to quit smoking (Contemplation Ladder) 
20. Provide instructions to smoke as usual for the first five days of the study protocol 
(assessment of baseline smoking rate). 
21. Be provided with five date-stamped zipped baggies by the research staff. 
22. Review a written instruction card for the collection and storage of used cigarette filters with 
the research staff. 
23. Be instructed to engage in overnight smoking abstinence (10-hours) the night of Day 5 in 
preparation for the Day 6 Visit. 
24. Tentatively schedule study visits with a member of the research team. 
 
7.2.3 Day 6 Visit 
During the Day 6 Visit, (Duration: ~1.25 hours) participants will: 
1. Arrive at the Center at 9:00 AM after having abstained from smoking overnight. 
2. Perform a CO breath assessment and concomitant medication review. 
3. Be asked questions about use of marijuana, other tobacco products (besides cigarettes), 
or vaping of any substance including tobacco/nicotine or other drugs in the past month. 
4. Have their overnight smoking abstinence (10-hours) verified by a CO measurement of 
50% of Intake visit’s CO value 
5. Return five date-stamped zipped baggies containing all spent cigarette filters from Days 
1-5. 
6. Receive instructions on how to use the IQOS prior to two IQOS HeatStick exposures 
(one regular, one menthol). 
7. Be required to use the IQOS device in the lab, where they will be exposed to two IQOS 
HeatSticks (one regular, one menthol) 
• 
Participants will take 14 puffs from the regular HeatStick, then take 14 puffs from 
the menthol HeatStick. These two exposures will be separated by 45 minutes. 

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8. Complete questionnaires after each 
exposure: 
• 
Adverse Events Form 
(Open-Ended AEs) 
• 
Questionnaire of Smoking 
• 
Withdrawal Symptoms 
(MNWS) 
• 
IQOS Risk Perceptions 
• 
Subjective Reward of IQOS 
(CES adapted for IQOS use) 
9. Be reminded to engage in overnight 
smoking abstinence (10-hours) in 
preparation for the Day 7 Visit. 
 
7.2.4 Day 7 Visit 
During the Day 7 Visit, (Duration: ~2 hours) participants will: 
1. Arrive at the Center at 9:00 AM after having abstained from smoking overnight. 
2. Perform a CO breath assessment and concomitant medication review. 
3. Have their overnight smoking abstinence (10-hours) verified by a CO measurement of 
50% of Intake visit’s CO value  
4. Be asked questions about use of marijuana, other tobacco products (besides cigarettes), or vaping 
of any substance including tobacco/nicotine or other drugs in the past month. 
5. Complete questionnaires: 
• 
Adverse Events Form (Open-Ended AEs) 
6. Be introduced to and briefly practice the Relative Reinforcing Value of IQOS (RRVI) 
computerized lab task. 
7. Complete computerized lab task: Relative Reinforcing Value of IQOS (RRVI).  
8. Complete a standardized one-hour wait period in the laboratory, then complete required 
IQOS use in the lab.  
9. Review instructions for IQOS use with a member of the research staff. 
10. Receive an IQOS 3.0 holder and charger, a 7-day supply of regular and/or menthol 
HeatSticks, and 14 date-stamped zipped baggies for daily collection of spent filters and 
HeatSticks (7 for spent cigarette filters, 7 for used HeatSticks).  
11. Be provided with instructions to switch completely from smoking combustible cigarettes to 
using IQOS. 
12. Review written instructions for the collection and storage of used tobacco HeatSticks with 
a member of the research staff. 
7.2.5 Day 11 Visit 
During the Day 11 Visit (duration: ~30 min), participants will: 
1. Perform a CO breath assessment and concomitant medication review. 
2. Be asked questions about use of marijuana, other tobacco products (besides cigarettes), 
or vaping of any substance including tobacco/nicotine or other drugs in the past month. 
3. Complete questionnaires: 
• 
Adverse Events Form (Open-Ended AEs) 
4. Return used HeatSticks (and cigarette filters, if applicable) in date-stamped zipped 
baggies provided by the research staff. 
 
7.2.6 Day 14 Visit 
During the Day 14 visit (duration: ~30 min) participants will: 
1. Perform a CO breath assessment and concomitant medication review. 
Figure 4. 

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2. Be asked questions about use of marijuana, other tobacco products (besides cigarettes), 
or vaping of any substance including tobacco/nicotine or other drugs in the past month. 
3. Complete questionnaires: 
• 
Adverse Events Form (Open-Ended AEs) 
4. Return used HeatSticks (and cigarette filters, if applicable) in date-stamped zipped 
baggies provided by the research staff. 
5. Receive second seven-day supply of HeatSticks, and 14 date-stamped zipped baggies 
for daily collection of spent filters and HeatSticks (7 for spent cigarette filters, 7 for used 
HeatSticks). 
 
7.2.7 Day 17 Visit 
During the Day 17 visit (duration: ~30 min) participants will: 
1. Perform a CO breath assessment and concomitant medication review. 
2. Be asked questions about use of marijuana, other tobacco products (besides cigarettes), 
or vaping of any substance including tobacco/nicotine or other drugs in the past month. 
3. Complete questionnaires: 
• 
Adverse Events Form (Open-Ended AEs) 
4. Return used HeatSticks (and cigarette filters, if applicable) in date-stamped zipped 
baggies provided by the research staff. 
 
7.2.8 Day 21 Visit 
During the Day 21 visit (duration: ~30 min) participants will: 
1. Perform a CO breath assessment and concomitant medication review. 
2. Be asked questions about use of marijuana, other tobacco products (besides cigarettes), 
or vaping of any substance including tobacco/nicotine or other drugs in the past month. 
3. Complete questionnaires: 
• 
Adverse Events Form (Open-Ended AEs) 
4. Return used HeatSticks (and cigarette filters, if applicable) in date-stamped zipped 
baggies provided by the research staff. 
 
7.2.9 Day 22 Visit 
During the Day 22 visit (Duration: ~30 min) participants will: 
1. Complete questionnaires: 
• 
Adverse Events Form (Open-Ended AEs) 
• 
Concomitant medication review 
• 
Changes in motivation to quit smoking (Contemplation Ladder) 
2. Return all remaining used HeatSticks and spent cigarette filters 
3. Be informed of the lack of data supporting IQOS as a smoking cessation aid or harm 
reduction tool 
4. Cautioned on the likelihood of dual use and the risks associated with dual use 
5. Advised to either quit using IQOS or quit smoking cigarettes if they are using both 
6. Referred to a smoking cessation program if interested in quitting smoking 

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7.3 Table 1. Study Measures and Time Points 
 
 
 
 
 
Table 1. Measures 
Bio-behavioral Laboratory Visits 
Description of Time Point 
Intake 
 
 
Days 8-21: Switch to IQOS 
End of 
study 
Day # 
Day 0 
Day 
6 
Day 
7 
Day 
11 
Day 
14 
Day 
17 
Day 
21 
Day 
22 
Demographic & Baseline Covariates 
Demographics 
X 
 
 
 
 
 
 
 
Smoking History 
X 
 
 
 
 
 
 
 
Nicotine Dependence 
X 
 
 
 
 
 
 
 
Cigarettes per day (days 1-5) 
 
X 
 
 
 
 
 
 
CO 
X 
X 
X 
X 
X 
X 
X 
 
Predictor Variables 
Craving Relief 
 
X 
 
 
 
 
 
 
Withdrawal Relief 
 
X 
 
 
 
 
 
 
Subjective Reward of IQOS 
 
X 
 
 
 
 
 
 
IQOS Risk Perceptions 
 
X 
 
 
 
 
 
 
Relative Reinforcing Value of 
IQOS 
 
 
X 
 
 
 
 
 
IQOS sticks per day 
 
 
 
X 
X 
X 
X 
X 
Outcome Variables  
Cigarettes per day  
 
 
 
X 
X 
X 
X 
X 
Quitting Motivation 
X 
 
 
 
 
 
 
X 

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7.4  Description of Study Measures 
7.4.1 Screening/Covariates 
Urine Drug Screen: A urine sample (~20-30ml) will be collected at the Intake Visit to conduct a 
urine drug screen. The urine drug screen indicates whether the subject has recently taken any of 
the following recreational drugs or medications: THC, cocaine, opiates, amphetamines, 
methamphetamines, phencyclidine (PCP), ecstasy (MDMA), barbiturates, benzodiazepines, 
methadone, tricyclic antidepressants, and/or oxycodone. Participants with a positive urine drug 
screen for any substance listed above other than THC or tricyclic antidepressants will be deemed 
ineligible. A urine sample that doesn’t register a temperature reading of at least 90 degrees 
Fahrenheit will not be considered a valid sample. In an effort to remain CLIA-compliant, results 
from urine drug screen will not be shared with participants. Participants will be informed that the 
testing is for research purposes only and that they will be informed of their eligibility status, but 
not of the specific testing results. In order to document inclusion/exclusion criteria for regulatory 
purposes, results of the urine drug screens (test cup) will be retained in research charts and in an 
electronic research record within our local data management system (Access). These results are 
not and will not be entered into a participant’s electronic medical record. 
 
Urine Pregnancy Test: At the Intake Visit, female participants will be supplied with a simple, CLIA-
waived hCG pregnancy test strip and a urine sample cup. Female participants will be informed 
that pregnant women are not advised to participate in this research study. Participants will then 
be instructed to self-administer the pregnancy test and inform the study staff if they would like to 
continue participation after they have reviewed the results of the pregnancy test. Participants will 
be informed that there is no penalty for discontinuing participation at this point in the visit and that 
they will still receive travel reimbursement for the visit.  
  
Breath Alcohol Concentration (BrAC): Participants will complete a BrAC assessment at the Intake 
Visit. Participants will be made aware of the BrAC assessment prior to the visit and asked to avoid 
alcohol and alcohol-based products (e.g. mouthwash, breath spray, etc.) the evening and morning 
before the Intake Visit. The BrAC monitor is a handheld device that uses a disposable mouthpiece 
and reports the concentration of alcohol in exhaled breath. Any reading greater than 0.000 
indicates alcohol consumption within the last 14 hours. Participants with a BrAC greater than 
0.000 at the Intake Visit will be deemed ineligible.  
 
Medical History Form: A medical history form (led by the research staff) will be completed to review 
for applicable contraindications previously listed under Key Inclusion/Exclusion Criteria at the 
Intake Visit.   
 
Demographics and Smoking History (FTND): Standard surveys will collect demographics 
information such as age, sex, race, ethnicity, education level, and income [7,10,12]. Standard 
survey questions will assess smoking history (e.g., age at initiation, current smoking rate). 
Nicotine dependence will be assessed with the Fagerstrom Test for Nicotine Dependence 
(FTND). This 6-item measure has good internal consistency (α = .64) and high test-retest reliability 
(r = .88) [44]. 
 
Smoking Urges/Craving (QSU-B): The well-validated and reliable 10-item brief Questionnaire of 
Smoking Urges will assess craving for cigarettes. The QSU-B utilizes a “right now” frame of 
reference. 
Adverse Events Form (Open-Ended AEs): Participants will be asked an open-ended question about 
any symptom or medical event that may be related to their study participation. These events will 
documented as unanticipated (unexpected) AEs unless they are otherwise outlined in the protocol 
and/or consent form (i.e. related to withdrawal, assessments, etc.). The reporting period for each 

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assessment will inquire about any event(s) or symptom(s) experienced since the last in-person visit.  
If a participant reports a symptom or medical event, they will be asked to rate the severity of the 
event utilizing the following severity scale: 0 (None=No Concerns), 1 (Mild=Issue does not 
interfere with usual daily activities), 2 (Moderate=Issue does interfere with some activities), and 3 
(Severe=No normal activities are possible). See section 8.2.1: AE Collection Methods for further 
details. 
 
Carbon Monoxide (CO) will be measured using a Vitolograph CO monitor (Lenexa, KS). A CO > 
5 is indicative of combustible cigarette smoking [25,45,46]. HNB products are expected to result 
in significantly lower increases in CO compared to a combustible cigarettes [47].  Five minutes of 
IQOS use did not result in clinically significant increases in CO (0.3 ppm) after overnight 
abstinence compared to five minutes of combustible cigarette [27]. We will include CO as a 
covariate in our statistical models. 
 
Concomitant Medications: At the Intake Visit, participants will be asked to list all medications 
(prescription or non-prescription) and NRTs currently taken and/or recently discontinued (within 
the past 14 days) as a baseline collection. All information will be collected on a Concomitant 
Medication Log that will be maintained within the participant’s study chart. At every subsequent 
in-person visit, participants will be asked if they have taken any additional medications 
(prescription or non-prescription), NRTs, and/or changed the dosage or stopped taking any 
previously reported medications since their last in-person visit. Participants who report taking 
contraindicated medication(s) over the course of the study period may only remain eligible if the 
Principal Investigator determine that the contraindicated medication(s) did not impact the study 
design, data quality, and/or participant safety and welfare.  
7.4.2 Predictor variables 
Motivation to Quit Smoking (Contemplation Ladder): The contemplation ladder will be used to 
assess readiness to consider smoking cessation [59]. The contemplation ladder is designed  to 
measure a smokers position on an 11-point scale (0-10) range, from having no thought of quitting 
to taking action to quit, and has been successfully employed in several diverse smoking 
populations [60-62]. We will assess changes in quitting motivation from Intake to Day 22 (end of 
study). 
Craving: Craving will be measured on Day 6 with the well-validated and reliable 10-item brief 
Questionnaire of Smoking Urges [48-50]. Items are scored from (1=strongly disagree to 
7=strongly agree).   
Withdrawal symptoms will be measured on Day 6 with the Minnesota Nicotine Withdrawal Scale 
[51]. This 15-item scale assess withdrawal symptoms with respect to a specific frame of time 
(0=none to 4=severe). 
Subjective rewarding value of IQOS will be measured on Day 6 with the Cigarette Evaluation 
Scale (CES) adapted for IQOS use [15-18,27]. The CES is an 11 item Likert-format (1=not at all 
to 7=extremely) self-report instrument with established validity and reliability (α > .80)  
[22,23,32,33,52]. We will focus on the Satisfaction Subscale for the measurment of subjective 
reward [23]. 
IQOS Risk perceptions will be measured on Day 6 with 12 items. Four items drawn from prior 
studies will assess absolute health risk and addictive potential [53-56]. Response options include 
1=no risk, 2=low risk, 3=moderate risk, 4= high risk, and 5=very high risk.  Eight previously 
validated tobacco use risk perception items will assess risk relative to combustible cigarettes 
[57,58]. Instructions are “Compared to your own cigarettes that you usually smoke, IQOS is lower 
in nicotine, lower in tar, are less addictive, are less likely to cause cancer, have fewer chemicals, 
are healthier, make tobacco use safer, and help people quit smoking.” The Likert-style response 
options range from 1=definitely untrue to 5=definitely true [57,58]. 

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Relative reinforcing value of IQOS will be measured on Day 7 with a validated choice paradigm, 
evaluating the preference for IQOS versus cigarettes [34,36,37]. RRVI will be defined in relation 
to responding for cigarette puffs. Working for cigarette puffs on < 5 trials out of the 10 trials is 
indicative of reinforcer indifference or less reinforcing value of cigarette puffs relative to IQOS 
puffs [41,42]. We will also measure overall responding for IQOS versus cigarette puffs [41,42].  
IQOS Use  will be determined by counting the daily spent tobacco HeatSticks returned for each 
of the 14 days (days 8 – 21) [12] [24,25]. HeatSticks per day will be included as a time-varying 
covariate in the Aim 1 models. 
7.4.3 Outcome variables 
Cigarette Consumption (primary outcome): The primary outcome is the longitudinal daily count of 
cigarettes from Intake to the end of the IQOS switch phase. Daily cigarette consumption will be 
determined by counting the daily spent cigarette filters returned for each of the 14 days (days 8-
21). 
 
Motivation for smoking cessation (secondary outcome): The contemplation ladder will be used to 
assess readiness to consider smoking cessation. The contemplation latter is designed to measure 
a smoker’s position on an 11-point scale (0-10) range, from having no thought of quitting to taking 
action to quit, and has been successfully employed in several diverse smoking populations [60, 
62]. We will assess changes in quitting motivation from baseline to day 21 (end of study). 
7.5  Analytic Plan 
Sample size.  Hypotheses will be tested with 80% power using a two-sided type-1 error of 5%. 
The primary outcome is the longitudinal daily count of cigarettes from baseline to the end of the 
IQOS switch phase.  Using simulation methods, with correlated negative-binomial random 
numbers (r=0.6 within subject) and a longitudinal (GEE) negative binomial model, we calculated 
that we can detect a slope (change per day) of 0.1 cigarettes, or a change of 1.5 cigarettes per 
day across the two-week switch period.  With a lower correlation (r=0.3), that detectable effect 
becomes a slope of 0.15 (change per day) or 2.0 cigarettes per day across the switch period.  The 
secondary outcome is motivation to quit smoking (contemplation ladder), which will also be 
modeled longitudinally.  The contemplation ladder itself has a historical standard deviation of 
approximately 3.0, and a correlation of 0.3.  Our sample of 100 will allow us to detect a change of 
0.7 in the contemplation scale in a baseline to end of study comparison. 
Data analysis. Prior to analyses, we will: (a) screen the data for data entry errors, (b) check for 
outliers, and (c) assess the extent and type of missing data, and select the most appropriate 
method for dealing with the missing data. We will create all summary scores needed for the 
analysis, and check that the distributional assumptions are met.  We will assess for participation 
biases and differences between participants retained and lost.  Analyses will be conducted using 
Stata software (StataCorp, College Station, Texas). 
The primary outcome is a daily count variable, the number of cigarettes smoked each day. The 
distribution of cigarettes smoked per day is expected to be over-dispersed (and perhaps zero 
inflated), because of the study instructions for participants to switch to IQOS heat-sticks for a 14-
day period, and the expectation that the majority of participants will have various levels of dual 
use.  The number of IQOS HeatSticks used each day is also a count variable. Participants may 
have days where they only use IQOS HeatSticks, only smoke cigarettes, and days where they 
use both.  We will accomplish the measurement portion of Aim 1 by summarizing the daily 
frequencies of cigarettes only, partial switching, and complete switching.  Distributional 
assumptions of all regression methods will be examined in the data set ahead of the analysis to 
ensure that the best and most representative error model is used.  We will examine demographic 
and other variables for any association with the outcomes or predictors. Those found to be 

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associated with outcomes (p=0.2) will be included in the model either to correct for confounding 
or to control error. 
The goal of Aim 1 is to evaluate the effects of IQOS use on cigarette smoking 
behaviors.  For the primary analysis, we will analyze the longitudinal counts of cigarettes using 
mixed models (Gaussian or negative binomial as appropriate).  The model will include predictors 
of time (continuous or discrete), and study phase (baseline versus switch period).  We will also 
include candidate controlling variables (demographic and clinical).   
 
H.1.a. states that IQOS use will decrease the number of cigarettes smoked per day relative to 
baseline.  We do not expect IQOS to replace all cigarettes, and we will measure the use of 
cigarette smoking only, dual use, and IQOS only use (complete switching). H.1.a. will be tested 
using the z-score corresponding to the contrast between baseline and switch periods (phase).  
H.1.b.  states that the reduction in number of cigarettes smoked per day will be associated with 
the number of IQOS HeatSticks used.  For H.1.b., we will add the daily IQOS use to the model 
predicting cigarette use, and test using the z-score corresponding to the daily IQOS HeatStick 
count by phase interaction.   
H.1.c. will test whether IQOS use decreases smokers’ motivation to quit cigarette smoking. This 
hypothesis will be examined using mixed models.  Predictors will include time (baseline, end of 
study), and H1c will be tested using the z-score corresponding to the baseline to end of study 
comparison.  Secondarily, we will test cumulative IQOS use as the predictor for change in 
motivation to quit smoking as measured by the contemplation ladder.   
 
The goal of Aim 2 is to examine which subjective and objective effects of IQOS predict 
cigarette smoking.  H.2. will test whether participants who report lower IQOS risk 
perceptions, greater craving relief, greater withdrawal relief, greater IQOS subjective reward, and 
have a higher relative reinforcing value of IQOS will smoke fewer cigarettes per day during the 
14-day switching period. For H.2., we will remove the daily IQOS counts from the model to avoid 
confounding, and evaluate the laboratory measures from days 6 and 7 (i.e., IQOS risk 
perceptions, craving relief, withdrawal relief, subjective reward, and reinforcing value of IQOS 
relative to cigarettes) for entry in to the model as predictors, using the significance of the 
corresponding z-score.   
 
8 Risks / Benefits 
8.1  Potential Study Risks 
The potential risks to participants, their likelihood and seriousness, and strategies to mitigate risks 
are described below. Participants can choose, as an alternative, to not enroll in this study. Overall, 
there is minimal risk for serious adverse reactions as a consequence of enrolling in this study. 
Adverse reactions/AEs will be collected, assessed, and reported as per the study protocol (see 
section 8: Safety and Adverse Events), federal law, and University of Pennsylvania regulations.  
Reproductive Risks: Smoking can cause serious harm to unborn children or children who are 
breast-feeding. Female participants are asked to use a medically accepted method of birth control 
(such as IUD, birth control pills, condoms, etc.) while participating in the study. Further, female 
participants, and those assigned as female at birth, will be asked to administer a simple, one-step 
hCG pregnancy test and informed that if they are (or believe they may be) pregnant that they will 
not be eligible to participate in the research study. If a female participant becomes pregnant over 
the course of the trial, they will be immediately withdrawn. It will also be recommended that the 
participant seek consult from an obstetrician or maternal-fetal specialist about the dangers of 
smoking while pregnant. 
 

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Withdrawal Symptoms: Participants may experience uncomfortable withdrawal symptoms during 
their overnight smoking abstinence. In preparation for the overnight abstinence, participants will 
receive tips for remaining abstinent (e.g., coping with withdrawal and craving, smoking triggers, 
coping with stress).  Participants will also be reminded that these symptoms will be short-lived 
and that they will be able to self administer nicotine in the laboratory the following morning. 
 
Assessments: Some participants may experience some emotional distress during the 
assessments due to learning their carbon monoxide levels or seeing how many cigarettes and/or 
HeatSticks they smoke. These events happen very rarely and in almost all cases are short-lived 
and of low intensity. If a participant does exhibit a high level of emotional distress, however, they 
will be offered contact information for mental health services in the area. 
 
Cigarette Smoking and IQOS use: Although cigarette smoking is associated with many diseases, 
we do not believe the risk is beyond every day risk as all participants must be current cigarette 
smokers to be eligible. We will inform participants that cigarette smoking has been shown to cause 
diseases such as emphysema and cancer. There will be a phase of the study where participants 
will be instructed to switch completely to IQOS. If participants don’t completely switch from 
smoking cigarettes to using IQOS, their risks from smoking will remain the same. 
 
Important safety information regarding IQOS: IQOS works exclusively with HeatSticks. Never 
use IQOS with a cigarette or any other tobacco sticks or accessories. Do not remove a tobacco 
stick (HeatStick) while in use. Tobacco sticks (HeatSticks) are single use only and should never 
be reused. Tobacco sticks (HeatSticks) should never be lit with a match, lighter, or any other 
flame source. Keep tobacco sticks out of reach of children and pets. If tobacco sticks are 
swallowed, seek medical attention immediately due to risk of nicotine ingestion. Store your 
tobacco sticks in a cool, dry place. Do not expose product to high humidity conditions or direct 
sunlight. Do not use IQOS during hot conditions or in periods of high humidity. Pay attention to 
signs that your battery may be leaking. The IQOS Holder and Pocket Charger are powered 
with sealed Lithium-ion batteries. Under normal conditions of use, the battery is sealed. If you 
notice fluid leaking from the battery, follow these precautions, discontinue using the product 
immediately and contact Shannon at 215-746-7164, or Stephen at 215-746-2100. In case of 
contact with skin, wash hands and do not touch eyes. In case of contact with eyes, immediately 
flush with running water for at least 15 minutes and seek medical attention. If fluid is inhaled, get 
fresh air and seek medical attention. If you swallow fluid, seek medical attention immediately. Do 
not induce vomiting or ingest food or drink. Stop using IQOS and seek medical attention 
immediately if you experience any symptoms that may indicate a serious allergic reaction: 
swelling of the face, lips, tongue, gums, throat, or body; difficulty breathing, or wheezing. 
 
 
Email Communications: In this research study participants may prefer to receive appointment 
reminders via email or submit questions related participation via email.  Email is not a secure 
means of communication. Email messages travel across the Internet passing through multiple 
computers before reaching their final destination.  It is not possible to know whether an email a 
participant sends will be viewed along the way.  Additionally, if sent messages are not deleted, 
an email provider may have an archive of everything that is sent. If someone gets access to an 
email account (for example, a participant’s family member), they could see archived messages.  
There are many other ways in which emails are not secure—these are only selected examples. 
To manage this risk the informed consent form will include specific language to educate research 
participants on the privacy risks involved in email communications. Participants will also be 

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explicitly instructed to only use email communications for routine matters and never for personal 
or confidential messages or questions. 
 
Confidentiality and Loss of Privacy: See section 9.6.1 and 9.6.2 for methods in which 
Confidentiality and Subject Privacy/Protected Health Information will be secured and maintained. 
8.2  Potential Study Benefits 
Cigarette smokers may benefit from participation by knowing that they are contributing to research 
that can help determine if (1) IQOS is an acceptable alternative to combustible cigarette smoking 
among smokers like themselves, (2) IQOS fully replace cigarettes, and (3) IQOS lessens 
motivation to quit smoking. The proposed study is expected to yield new knowledge regarding the 
subjective, objective, and behavioral impact of IQOS on cigarette smoking behaviors.  The 
findings will inform public health interventions and regulatory actions to educate and protect 
smokers if they choose to use IQOS. 
8.3  Risk/Benefit Assessment 
The potential benefits of this study outweigh the potential risks. There is only a minimal risk of 
experiencing study-related AEs or SAEs by enrolling in this trial. The findings from this study will 
inform public health interventions and regulatory actions to educate and protect smokers if they 
choose to use IQOS. 
8.3.1 Adequacy of Protection against Risks 
Informed Consent. Informed consent/HIPPA forms will be signed electronically on REDCap or at 
the Intake Visit before any research activities are completed.  Trained staff will provide a study 
overview, including the risk and benefits of being in the study.  Staff will respond to all questions 
and inform potential participants that participation is voluntary.  Preliminarily eligible smokers 
adults will be asked to provide informed consent for participation.    After receiving informed 
consent, participants will provide a urine sample to assess drug use and/or pregnancy, which are 
exclusions for participation. Participants will receive a copy of their signed consent form. 
 
Oversight and Monitoring. The Institutional Review Board at the University of Pennsylvania will 
monitor the protection of human subjects and the safe and secure collection and storage of data.  
This committee will assess the study before initiation and then annually at the time of Continuing 
Review.  The IRB will ensure the scientific, technical, and statistical soundness of the research 
and guarantee that methods for the ethical and safe treatment of human subjects are in place. 
 
Participant Safety.  Eligibility criteria for this study will exclude any individual who would be at risk 
of adverse effects from participation in this study.  Participant safety begins with the PI’s thorough 
training and ongoing supervision of the project staff and study procedures. Weekly meetings will 
ensure an understanding and adherence to the study goals and data collection and management 
procedures.  Personnel training by the PI will be considered to be of the highest priority and will 
be addressed prior to the start of the study and on an ongoing basis.  Training will help ensure 
that all processes and procedures for data collection and management are correctly applied and 
utilized.  Specifically, but not exclusively, this training will ensure that research personnel 
understand the study’s goals and objectives, data collection process, confidentiality, participant 
safety, all case report forms (CRFs), the manual of procedures (MOP), database software and 
the data management system (DMS), and all applicable standard operating procedures (SOPs) 
to attest that the study is conducted in a proper manner. Training will span study recruitment 
approaches, screening, assessment, follow-up of rescheduled participants, data entry and 
storage, and tracking study incentives. 
 

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Data Management. The CIRNA Data Management Core will be responsible for the data 
management system, the operational facets of this study, quality assurance, and data storage.   
 
Data Collection, Processing, and Management.  All data collection, processing, and management 
procedures will be standardized in a detailed Manual of Procedures (MOP).  Hard-copy surveys 
will serve as source documents.  All data are entered into a database located upon the secure 
server with dedicated uninterrupted power at the CIRNA.  All indicated data entry and processing 
operations will be performed using Data Management System (DMS) software.  Study personnel 
will access the menu driven DMS software to perform specific operations.  For example, the DMS 
functionality will include subject tracking, data entry, data validation, and query tracking, standard 
reports, and tracking of all major study milestones (e.g., assessment and visit disposition), and 
the counterbalanced sequence of the order of IQOS flavors on the day 6 laboratory visit.  
 
Quality and Data Safety Assurance Practices.  The PI will conduct training to ensure that all 
processes and procedures for data collection and procedures for data collection, processing, and 
storage are correctly applied and utilized.  Confidential participant information will be collected 
and entered into the database.  When this information exists on paper (e.g., updated contact 
information, alternative contact information) it will always be filed under lock and key.  Upon entry 
of this data into the database, an auto-study ID will be generated.  The auto-study ID will then 
generate and be linked to a participant ID in a separate table.  Thus, contact information will never 
exist in the same DMS table as a participant ID.  No one can gain access to an individual database 
unless they have been explicitly granted a user ID and password.  The Center’s database server 
and individual study databases have never been compromised as a result of the extremely 
rigorous and secure network firewall technologies.  The secure servers are located in a specially 
designed, highly secured facility with dedicated uninterrupted power supply.  Access to this server 
facility is strictly limited.   
 
Adverse Event Reporting.  In accordance with NIH and IRB guidelines, this protocol will employ 
the following mechanisms for adverse event reporting:  (1) alert the IRB of any and all reports of 
serious adverse events; (2) inform all members of the study team of any and all reports of serious 
adverse events; (3) notify the NIH of any actions taken by IRB with regard to data safety 
monitoring. 
 
9 Safety and Adverse Events 
9.1  Definitions 
Unanticipated Problems Involving Risk to Subjects or Others: 
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in nature, severity, or frequency (i.e. not described in study-related documents 
such as the IRB-approved protocol or consent form, the investigators brochure, etc.) 
• Related or possibly related to participation in the research (i.e. possibly related means 
there is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research) 
• Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm). 
 
Adverse Event: 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study (regardless if study-related). Intercurrent illnesses or 

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injuries should be regarded as adverse events.  Abnormal results of diagnostic procedures are 
considered to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
Serious Adverse Event: 
Adverse events are classified as serious or non-serious.  A serious adverse event (SAE) is any 
AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly 
of major clinical significance.   They may jeopardize the subject, and may require intervention to 
prevent one of the other serious outcomes noted above.  For example, drug overdose or abuse, 
a seizure that did not result in in-patient hospitalization, or intensive treatment of bronchospasm 
in an emergency department would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-
serious adverse events.  
 
Adverse Event Reporting Period: 
The study period during which AEs/SAEs will be reported is from the initiation of any study 
procedures until the end of the study.  Any event(s) that the subject, or the subject’s personal 
physician, believes might reasonably be related to participation in the study after the final time 
point will be assessed and reported as appropriate.   
 
Preexisting Condition: 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 
 
Post-study Adverse Event: 
All unresolved adverse events should be followed by the investigator until the events are resolved, 
the subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled 
visit, the investigator should instruct each subject to report any subsequent event(s) that the 
subject, or the subject’s personal physician, believes might reasonably be related to participation 
in this study.   
 
Hospitalization, Prolonged Hospitalization or Surgery: 
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as a SAE unless specifically instructed otherwise in this protocol.  Any condition 
responsible for surgery should be documented as an AE if the condition meets the criteria for an 
AE.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances: 

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• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for a preexisting condition. Surgery should not be reported as an outcome of an adverse 
event if the purpose of the surgery was elective or diagnostic and the outcome was 
uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 
9.2  Collection and Recording of Adverse Events 
9.2.1 AE Collection Methods 
 
All AEs and SAEs occurring during the study period will be captured through the methods 
described below: 
1. Open-Ended AE Form: Participants will be asked an open-ended question about any 
symptom or medical event that may be related to their study participation. These events will 
be documented as unanticipated (unexpected) AEs unless they are otherwise outlined in 
the protocol or consent (i.e. related to withdrawal, assessments, etc.). The reporting period 
for each assessment will inquire about any event(s) or symptom(s) experienced since the 
last in-person visit.  If a participant reports a symptom or medical event, they will be asked to 
rate the severity of the event utilizing the following severity scale: 0 (None=No Concerns), 
1 (Mild=Issue does not interfere with usual daily activities), 2 (Moderate=Issue does 
interfere with some activities), and 3 (Severe=No normal activities are possible). Any report 
on the Open-Ended AE Form will require additional follow up per the AE documentation and 
internal reporting procedures outlined below in section 8.2.2.  
2. Spontaneous Assessment: Once enrolled, participants will be instructed to inform the 
research team about any notable symptom or medical event/concern throughout their 
participation in the study. A participant may also request the Principal Investigator be 
consulted about any reported medical event or concern of any severity at any time 
throughout their participation.  
3. An “AE Note” template will be available to the research staff to collect supporting AE 
information and will function as the source document. However, research staff may collect 
AE information on any source document available to them and transfer the relevant 
information to a formal AE Note at a later time. Any notable AE reported spontaneously will 
require additional follow up per the AE documentation and internal reporting procedures 
outlined below in section 8.2.2. 
9.2.2 AE/SAE Documentation and Internal Reporting Procedures 
 
AE/SAE Documentation: At a minimum, follow-up information will include AE/SAE 
onset/resolution, description of event/course, severity, action taken, outcome, and possible 
relation to study participation. 
 
Information surrounding AEs and SAEs will be initially recorded on the appropriate source 
document such as the SEC Form, an “AE Note” or SAE Form, and/or any document in which the 
AE/SAE information was originally recorded. All applicable AEs and SAEs will then be 
documented on a cumulative AE and SAE log maintained within the regulatory binder.   
 
Completed documentation of applicable AEs will include the following information: 

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• 
Protocol Title and IRB# 
• 
Subject Identifier  
• 
Event Title 
• 
Date Site Notified  
• 
Event Start Date and Time  
• 
Event Stop Date and Time 
• 
Description of Event/Course (including sequelae) 
• 
Severity: 
o None = No concerns 
o Mild = Side effect or issue does not interfere with usual daily activities 
o Moderate = Side effect or issue interferes with some activities 
o Severe = No normal activities are possible 
• 
Relatedness to the study procedures (PI): 
o Unrelated = Definitely not related   
o Unlikely = Doubtfully related 
o Possibly = May be related  
o Probably = Likely related 
o Definitely = Related 
• 
Expectedness per protocol and/or consent  
o Expected/Anticipated 
o Unexpected/Unanticipated 
• 
Action(s) taken (if appropriate) 
• 
Outcome (if appropriate) 
 
Documentation of SAEs will include the following information on a standardized SAE Form: 
• 
Protocol name and number 
• 
Subject identifiers 
• 
Demographic data 
• 
Date Site Notified  
• 
Date and time of SAE onset 
• 
Date and time of SAE resolution, if available 
• 
Course/Description of Event (including sequelae) 
• 
Action Taken 
• 
Outcome 
• 
Follow-up plan 
• 
Serious Status (What makes the event an SAE) 
• 
Severity of the event 
o None = No concerns 
o Mild = Side effect or issue does not interfere with usual daily activities 
o Moderate = Side effect or issue interferes with some activities 
o Severe = No normal activities are possible 
• 
Relatedness to the study procedures (PI): 
o Unrelated = Definitely not related   

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o Unlikely = Doubtfully related 
o Possibly = May be related  
o Probably = Likely related 
o Definitely = Related 
• 
Clinical assessment of subject conducted at time of SAE (if appropriate) 
• 
Results of any laboratory tests and/or diagnostic procedures (if appropriate) 
• 
Autopsy findings (if appropriate) 
• 
Concomitant medications and therapies  (excluding treatment of event) 
• 
Relevant Medical History (if appropriate) 
 
Internal Reporting Procedures:  All relevant follow-up information outlined above (see AE/SAE 
documentation) concerning applicable AEs, including all information regarding the occurrence of 
previously reported event(s), will be reported to the Study Coordinator (or other senior personnel) 
and Principal Investigator to determine a course of action (e.g. continue to monitor, reduce 
medication dose, stop medication), relatedness (causality) to the study, and expectedness (if not 
already established). This consult will be documented via email. The clinical course of each event 
will be followed until resolution, stabilization, or until it has been determined that the study 
treatment or participation is not (or unlikely) to be the cause.  
 
SAEs that are still ongoing at the end of the study period must be followed up to determine the 
final outcome unless it has been determined that the study treatment or participation is not the 
cause. Any SAE that occurs after the study period and is considered to be possibly related to the 
study treatment or study participation should be recorded and reported immediately per this 
protocol. 
9.3  Reporting of Serious Adverse Events and Unanticipated Problems  
The reporting requirements of applicable SAEs and/or Unanticipated Problems including 
reportable AEs (see section 8.1 for definitions) to external entities are detailed in the following 
sub-sections:   
9.3.1 Investigator reporting: notifying NCI and FDA 
The following events/reports will be submitted to the FDA and NCI Project/Program Officer in a 
narrative format or on FDA Form 3500A: 
• 
Unexpected fatal or life-threatening suspected adverse reactions (in relation to study-
provided IQOS and HeatSticks) will be reported as soon as possible, but in no case later 
than 7 calendar days after the initial receipt of the information. 
9.3.2 Investigator reporting: notifying the Penn IRB 
This section describes the requirements for safety reporting by investigators who are Penn faculty, 
affiliated with a Penn research site, or otherwise responsible for safety reporting to the Penn IRB. 
The University of Pennsylvania IRB (Penn IRB) requires expedited reporting of those events 
related to study participation that are unforeseen and indicate that participants or others are at 
increased risk of harm.  The Penn IRB will not acknowledge safety reports or bulk adverse event 
submissions that do not meet the criteria outlined below. The Penn IRB requires researchers to 
submit reports of the following problems within 10 working days from the time the investigator 
becomes aware of the event: 
• Any AE (regardless of whether the event is serious or non-serious, on-site or off-site) that 
occurs any time during or after the research study, which in the opinion of the Principal 
Investigator is: 

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Unexpected (An event is “unexpected” when its specificity and severity are not accurately 
reflected in the protocol-related documents, such as the IRB-approved research protocol, 
any applicable investigator brochure, and the current IRB-approved informed consent 
document and other relevant sources of information, such as product labeling and package 
inserts.) 
 
 
AND 
Related to the research procedures (According to the Penn IRB standard operating 
procedures [SOPs], an event is “related to the research procedures” if the event is deemed 
probably or definitely related to the procedures.”) 
 
Reporting Process: 
Unanticipated problems posing risks to subjects or others as noted above will be reported to the 
Penn IRB using the form: “Unanticipated Problems Posing Risks to Subjects or Others Including 
Reportable Adverse Events” or as a written report of the event (including a description of the event 
with information regarding its fulfillment of the above criteria, follow-up/resolution and need for 
revision to consent form and/or other study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical 
Investigator’s study file. 
 
Reporting Deaths (more rapid reporting requirements): 
Deaths that occur during the course of a research study and that are:  
• 
Unexpected; AND  
• 
Related to the research study; AND  
• 
When other participants are believed to be at an increased risk of harm 
 
Must be reported to the IRB within 3 days from the time the investigator becomes aware of the 
death.  
9.4  Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study. This safety 
monitoring will include careful assessment and appropriate reporting of AEs/SAEs as noted 
above, as well as adherence to the study data and safety monitoring plan outlined in sections 8 
and 10.   
10  Data Management 
The CIRNA Data Management Team has developed a data management system (DMS) that will 
facilitate the operational facets of this study, including determination of entry eligibility, production 
of lists of subjects for telephone contacts for scheduling, and data entry. The DMS uses the 
relational database product Microsoft Access as the primary software platform for data entry and 
validation, storage, retrieval, modification, and security. The DMS ensures data integrity through 
range and validity checks during the data entry process. Daily backups are performed to protect 
data against accidental destruction or corruption. 
10.1 Data Management System Development  
The CIRNA Data Manager will work closely with the trial investigators to develop an 
understanding of the data collection, storage, and quality assessment needs for the trial. This 
includes the design and development of the trial data collection forms and any additional 
administrative CRFs, to ensure that standardized, uniform data collection and data management 

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procedures are implemented and sustained throughout the trial. The data collection forms will 
serve as templates for designing the data entry screens. The Data Manager will work closely with 
trial investigators and senior personnel to design, develop, and test an appropriate database 
structure to support the requirements of the DMS and to promote data security and integrity. 
Electronic audit trails of changes to database contents are incorporated into the design and will 
capture and record those changes automatically. In addition to the trial database where actual 
results will be maintained, a development database will be created. The development database 
is a working environment that facilitates the development, testing, troubleshooting, enhancement, 
and training for the DMS without adversely affecting the integrity of the collected project data. 
 
Prior to deployment and use by the research staff, the database and DMS will be subjected to 
extensive functional testing. This testing is conducted according to a written test plan and is 
intended to verify the proper functioning of all components of the DMS. Any components that do 
not function as they were intended will be identified and evaluated by the development team to 
determine appropriate corrective action. Testing will also include an evaluation by user 
representatives for adherence to the requirements established by the intended users for the DMS. 
Successful completion of these user acceptance tests will mark the end of development and 
predicate the deployment of the DMS for use in storing and managing active trial data. Any 
modifications made to the DMS will be conducted in accordance with change control procedures. 
10.2 Data Security  
All research data for the trial will be stored in an electronic Access database that is managed by 
the Data Manger. The database will be hosted on a secure computing server and will be restricted 
to only those individuals who are authorized to work on the trial. Individual user accounts with 
passwords will be used to restrict access to the database. Specific privilege assignments within 
the database will also be employed to limit the types of functions that authorized users can 
perform to those functions that are appropriate for their role in the trial. Additional measures to 
prevent unauthorized external access to the database environment will be employed using 
network firewall technologies. The Data Manager will maintain the database in an appropriate 
manner for the retention period required by regulation. Database administration includes user 
account maintenance, database security, performance monitoring, and database change 
management. 
10.3 Data Processing  
The data entry screens will resemble the data collection forms as closely as possible to allow 
visual referencing during data entry. This data entry module will be configured for single data 
entry. Participant data will be collected by research staff, recorded on study-specific CRFs, and 
scanned in or entered directly into the appropriate DMS module. Data entry checks will be 
included in the entry screen designs where appropriate to limit the opportunity for erroneous 
entries due to mistyping. Such data entry checks would include value range comparisons, valid 
data type checks, required value checks, and/or skip pattern enforcement. Following telephone 
eligibility screening, research staff will perform subject registration. Following the Intake Visit, 
research staff will randomize eligible subjects. The randomization module will allow the research 
staff to randomize subjects into one of the two trial arms. At the randomization attempt, the DMS 
will check the eligibility data to confirm that randomization is valid. A randomization assignment 
will then be provided.  
10.4 Data Quality Assurance        
A data quality module will be developed to assess data entered into the database in relation to a 
set of rules that describe expectations for those data items. This set of data validation rules will 
be defined by the data manager, working closely with trial investigators, to identify data items that 
may have been collected incorrectly or entered into the database inaccurately. The module will 
run automatically to inspect all newly entered or modified data. The research staff will review the 
results of the data validation and take any required corrective action for invalid data. Queries will 
be recorded and tracked in the data quality module. Corrections identified for individual data items 

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will be managed by the research staff. All changes made will be recorded in an electronic audit 
trail and documented using change control procedures. 
 
Monitoring of trial progress will be accomplished, in part, through the use of standard reports. The 
Data Manager will program a set of standard enrollment, tracking, quality review, and safety 
monitoring reports. Data audits will occur after the first few participants are enrolled and 
periodically during the trial to detect errors in data entry. Eligible participants will have 100% of 
their source document information compared with the data entered in the database. Any errors 
will be investigated, resolved, and a plan will be implemented to prevent further errors should 
concerning patterns emerge. 
10.5 Subject and Specimen Tracking  
The Data Manager will develop a module to assist research staff in recruitment and retention 
tracking for trial subjects. This module will accept and store contact information for potential 
subjects and will include data items to indicate the completion status of significant events. The 
tracking module will include information about contact and visit schedules to assist in preparing 
communications to potential subjects and trial participants concerning scheduled events. The 
module will also allow for incentive-related inventory management.  
10.6 Data Handling and Record Keeping 
10.6.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those 
regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. Note in 
the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.  
 
Confidentially of study data will be maintained in the following manner: 
• 
Paper-based records will be kept in a secure location and only be accessible to personnel 
involved in the study. 
• 
Computer-based files will only be made available to personnel involved in the study 
through the use of access privileges and passwords. 
• 
Prior to access to any study-related information, personnel will be required to review and 
sign statements agreeing to protect the security and confidentiality of identifiable 
information. 
• 
Whenever feasible, identifiers will be removed from study-related information. 
• 
Precautions are in place to ensure the data is secure by using passwords and encryption. 
 
Since self-report data will be collected and stored as part of this study, it is possible that subject 
privacy or confidentiality can be threatened. To address this concern, the data management 
system has set up several safeguards to prevent unauthorized access to participant data. In the 
subject map table, an automatically generated index number is assigned to a subject’s study 
identification number. A linked subject identification table is created to store subject name, 
address, and telephone contact information. This table uses the automatically generated index 
number rather than the study identification number. The master subject map and subject 
identification information are maintained in separate locations. Using this method, no identifying 

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subject information is directly linked to bio-samples or results. Any publication of data will not 
identify participants by name or with an identifier that could be used to reveal identity. 
 
All subject data that can be linked to the study ID will be stored in the secure data management 
system, which has limited, password-required access. The aforementioned precautions and 
procedures will be applied to protecting subject privacy and the protected health information 
detailed in Section 9.6.2 below. 
10.6.2 Subject Privacy/Protected Health Information 
The following protected health information (PHI) may be collected as part of this study: 
1. Name 
2. Street address, city, county, zip code 
3. All elements of dates (except year) for dates directly related to an individual and all ages 
over 89 
4. Date of birth 
5. Social Security Number 
6. Telephone number, email address 
7. Any other unique identifying number, characteristic, or code  
8. Results from all questionnaires, tests, and procedures  
 
Potential participants will be contacted over the phone after responding to recruitment efforts or 
having agreed to be contacted for future studies. Only individuals who have responded to 
recruitment efforts or who have agreed to be contacted regarding research studies at our Center 
will be contacted. If an individual cannot be reached immediately, staff members will identify 
themselves only as calling from the University of Pennsylvania; no mention will be made of the 
inquiry regarding study participation. Participants will undergo an initial telephone screening 
where preliminary eligibility for the research study will be determined. Only if a participant is 
initially eligible, will they be asked to attend an in-person Intake Visit to confirm eligibility. All data 
collected over the phone and during in-person visits will be collected by research staff that have 
completed the CITI-Protection of Human Subjects Research Training as well as HIPAA 
Compliance Training. Once enrolled, information will never be recorded with identifiers other than 
study ID. A separate list of names with ID numbers will be accessible only by authorized 
personnel. All records will be kept in locked filing cabinets to maintain confidentiality. All analyses 
will be conducted on de-identified data.  
 
Data will be accessible only to the Study Investigators, study staff, applicable Center staff, UPenn 
IRB, Office of Clinical Research, authorized UPENN staff (e.g. accounting and billing matters, 
provide treatment, etc.), National Cancer Institute, and the FDA.  
 
11 Data and Safety Monitoring 
11.1 Research Roles 
During the course of the study, data and safety monitoring will be performed on an ongoing basis 
by the Principal Investigator, research staff, and the IRB. The research staff are responsible for 
collecting and recording all clinical data. This includes ensuring that all source documents exist 
for the data on the case report forms (CRFs), ensuring all fields are completed appropriately, and 
all error corrections are done according to GCPs. Any inconsistencies/deviations will be 
documented and addressed as appropriate. The research staff will perform regular chart reviews 
to verify data integrity. The Study Coordinator (or senior personnel) and Principal Investigator will 
maintain the study regulatory binder/essential documents per GCP. Research staff will meet and 
communicate on a regular basis to reconcile data queries and safety concerns. The IRB will 

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review the trial on an on-going basis per institutional and federal regulations until the study is 
formally closed-out.   
11.2 Staff Training 
Staff training will consist of an initial explanation and review of the protocol, informed consent 
form, CRFs and laboratory tasks, sample collection protocols, data management system, adverse 
event collection and reporting, and all study-specific SOPs. In addition, during a standardized 
training period, the duties of each staff member will be clearly outlined and all applicable 
regulations will be reviewed. Training interactions will be documented in a training log, which will 
be maintained within the regulatory binder. Senior personnel will supervise junior staff and provide 
re-training as needed.   
 
All personnel working on this project will complete required training in the protection of human 
subjects and the protection of personal identifiable information (i.e. HIPAA) before interacting with 
study data or research participants.  All human subject and privacy protections certifications will 
be maintained in the regulatory binder. 
11.3 Monitoring Activities 
11.3.1 AE/SAE Monitoring  
Monitoring and management of AEs/SAEs will be conducted in real-time by the Principal 
Investigator and the research team at regular time points as per the methods and procedures 
detailed in section 8: Safety and Adverse Events. 
11.3.2 Initial Assessment (Intake) Monitoring  
The study staff will conduct a manual review of source documents and CRFs for all subjects 
determined to be eligible at telephone screen and again prior to the Intake Visit. Eligibility data 
will be reviewed in real-time at the Intake Visit by the research staff. In addition, The Study 
Coordinator (or senior personnel) will verify that all data have been collected and, when 
applicable, meet the eligibility criteria on a “Final Eligibility Checklist.” The Final Eligibility Checklist 
will be signed and dated by the Study Coordinator (or senior personnel) to formally document 
review. In addition to confirming eligibility, a brief, internal report describing the findings will be 
compiled and distributed to study staff (if applicable). If the Study Coordinator (or senior 
personnel) notes a pattern of improper data collection or deviations, additional trainings will occur. 
11.3.3 Protocol Monitoring  
Protocol monitoring includes a survey of those activities that are associated with protocol 
adherence such as identifying, reporting, and rectifying protocols deviations, reviewing for 
violations of inclusion/exclusion criteria, and ensuring the adherence to study-specific SOPs, 
GCP, and other federal and institutional regulations. Protocol monitoring will be performed on an 
ongoing basis through the following methods: 
1. Checklists will be utilized at all time points to ensure all data is collected per protocol and 
procedures are followed as appropriate. 
2. A Final Eligibility Checklist will be completed after the Intake Visit for all participants who 
enroll (i.e. sign consent) in the study. The Final Eligibility Checklist will serve as final 
confirmation of eligibility status. 
3. A complete chart review of a randomly selected participant charts. The chart review 
procedure is a thorough review of all source documentation to ensure the integrity of the 
data, all study paperwork is present, all fields are completed per GCP, and all study-specific 
SOPs have been followed appropriately.  
11.3.4 Database Auditing  
As outlined in Section 9: Data Management, the study DMS will be equipped with internal 
validation checks to ensure data is entered within reasonable ranges. Error messages will be 

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displayed in real-time if data appears inaccurate. Staff will have to respond to these error 
messages before data can be saved. In addition, The Study Coordinator (or senior personnel) will 
perform regular milestone quality assurance checks. 
11.3.5 Data Security 
As outlined in section 9: Data Management, study data will be secured through controlled user 
access and accessible to authorized personnel only.  Source documents will be secured in locked 
filing cabinets.  
11.4 Frequency of Data and Safety Monitoring  
Data will be reviewed internally on a regular basis. Specifically: 
 
1. At data capture, the research staff will review data for completeness and integrity. 
2. At data entry, the DMS will include multiple internal validity checks which will prompt the 
staff if an entry was made that is out of range or in an unacceptable format. 
3. Eligibility data will be reviewed in real-time at the Intake Visit. In addition, the Study 
Coordinator (or senior personnel) will review and verify that all data have been collected 
and, when applicable, meets the eligibility criteria on a “Final Eligibility Checklist.”  
4. On a regular basis, the project staff will review data through an internal chart review 
procedure supported by the DMS.  A random subset of eligible participants will be 
reviewed. 
5. All CRFs for eligible subjects are 100% source-data verified through an internal data 
management system (Data Entry/Quality Assurance) on an ongoing basis.   
6. The study statistician will review data prior to analysis to ensure integrity and validity. 
11.5 Auditing and Inspecting 
The Principal Investigator will permit study-related monitoring, audits, and inspections by the 
EC/IRB, the sponsor, government regulatory bodies, and University compliance and quality 
assurance groups of all study related documents (e.g. source documents, regulatory documents, 
data collection instruments, study data, etc.).  The Principal Investigator will ensure the capability 
for inspections of applicable study-related facilities. Participation as an investigator in this study 
implies acceptance of potential inspection by government regulatory authorities and applicable 
University compliance and quality assurance offices. 
12  Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent Ethics 
Committee (EC) or Institutional Review Board (IRB), in agreement with local legal prescriptions, 
for formal approval of the study conduct.  The decision of the EC/IRB concerning the conduct of 
the study will be made in writing to the investigator and a copy of this decision will be provided to 
the sponsor before commencement of this study.   
12.1 Informed Consent 
A fully trained staff member will obtain informed consent using the combined consent and HIPAA 
form approved by the IRB (UPENN).  The consent process will take place prior to the initiation of 
any study procedures. The consent process will occur electronically via REDCap OR in person at 
the CIRNA and will involve a discussion of the study requirements and procedures. During in-
person consent, the combined consent and HIPAA form will be read verbatim to participants. 

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During electronic consent, the combined consent and HIPAA form will be completed virtually via 
REDCap. Participants will be required to read the entire consent in order to participate in the 
research study. Participants will have an opportunity to ask any questions and/or express 
concerns. Participants can elect not to participate and may withdraw at any time without penalty. 
Participants will receive a copy of the combined consent and HIPAA form for their records. In 
addition, participants will be given the Principal Investigator’s contact information (located on pg.1 
of the consent) should they wish to speak to the Investigator during the course of the study 
regarding their consent or the study procedures.  The consent process will take place in English, 
there will be no waiting period, no coercion to participate, and all participants will be considered 
competent to provide informed consent (i.e., they will be asked if they understand what they are 
consenting for). The consent form must be signed and dated by the participant and the 
investigator-designated research professional obtaining the consent. The original signed 
combined consent and HIPAA form will be centrally stored in regulatory binders (consent). 
13  RESOURCES NECESSARY FOR HUMAN RESEARCH PROTECTION 
13.1 Research Staff  
The following research staff will be directly involved with the implementation and execution of the 
current study:   
 
• 
Janet Audrain-McGovern, Ph.D., Principal Investigator  
• 
Andrew A. Strasser, Ph.D., Collaborating Investigator 
• 
Melissa Mercincavage, Ph.D., Collaborating Investigator 
• 
Shannon Testa, Research Staff 
• 
Stephen Pianin, Research Staff 
• 
Stephanie Messiha, Research Staff 
• 
Fodie Koita, Research Staff 
• 
Susan Ware, Database Developer/Manager 
• 
Paul Sanborn, Research Staff   
13.2 Study Facilities 
This project will be conducted at and through the CIRNA. The CIRNA has successfully conducted 
similar protocols and has well-developed procedures for staff training, data collection and storage, 
and study completion. The facilities available for this project include a large and small conference 
room, individual consulting rooms with computer/internet access, storage rooms, office space for 
study personnel, and data management facilities. 
 
If participants require referral for psychological services, information about such programs at 3535 
Market Street and/or the Philadelphia area will be provided; we have a form with specific 
information about such programs already in use in other CIRNA studies. 
 
14  Study Finances 
14.1 Funding Source 
This study is financed through a grant from the U.S. National Cancer Institute. 
14.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 

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reviewed by a properly constituted Conflict of Interest Committee with a Committee-sanctioned 
conflict management plan that has been reviewed and approved by the study sponsor prior to 
participation in this study. All University of Pennsylvania investigators will follow the University 
conflict of interest policy. 
14.3 Subject Compensation 
Participants will be compensated for each in-person visit they attend and can receive up to 
$500.00 (including travel reimbursement) for successfully completing all of the study requirements 
in their entirety as per the Study Compensation table (Table 2) below. 
 
All cases of non-compliance in regards to task and visit completion compensation will be reviewed 
on a case-by-case basis by senior personnel. A detailed compensation breakdown will be 
reviewed during the informed consent presentation and throughout the course of the trial.   
 
Participants will be asked to complete a W-9 tax form (includes social security number) at the 
conclusion of Intake because the University of Pennsylvania is required to report to the Internal 
Revenue Service (IRS) any cumulative payments for participation in research studies at the 
University of Pennsylvania that exceed a total of $600.00 in a calendar year. A W-9 will aid the 
Center and University in tracking and reporting those who participate in multiple projects and 
accrue over $600.00 in a calendar year. Further, a social security number is required to register 
each participant for a Greenphire ClinCard (described below).  
 
At the end of the Intake Visit, eligible participants will be issued a Greenphire ClinCard, which is 
a reloadable, pre-paid card for the purposes of study compensation. Compensation will be loaded 
onto the ClinCard at the end of successfully completed visits. Participants may opt to receive a 
text message alert when a payment has been loaded onto the ClinCard. 
 
14.3.1  
Table 2. Study Compensation 
Visit 
Visit 
Compensation 
Compensation for Used 
Cigarettes/HeatSticks 
Travel 
Reimbursement 
Total 
Intake 
$10.00 
N/A 
N/A 
$10.00 
Day 6 Visit 
$35.00 
$35.00 
$5.00 
$75.00 
Day 7 Visit 
$40.00 
N/A 
$5.00 
$45.00 
Day 11 Visit 
$20.00 
$45.00 
$5.00 
$70.00 
Day 14 Visit 
$20.00 
$45.00 
$5.00 
$70.00 
Day 17 Visit 
$20.00 
$45.00 
$5.00 
$70.00 
Day 21 Visit 
$20.00 
$60.00 
$5.00 
$85.00 
Day 22 Visit 
$55.00 BONUS 
$15.00 
$5.00 
$75.00 
 
Study Total: 
$500.00 
 
 
 
 
15  References 
See the NCI grant proposal for references.