A Randomized, Controlled, Open-label, 4-arm Parallel Group Study to Evaluate the Effect of Switching From Cigarette Smoking to the Use of IQOS in Healthy Adult Current Smokers on Exercise Capacity and Trainability
Phase: NA
Conditions: Smoking, Exercise Capacity
Sponsor: Philip Morris Products S.A.

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Data and information contained in this document are considered to constitute trade secrets and confidential 
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Clinical Study Protocol
Study title:
A randomized, controlled, open-label, 4-arm parallel group 
study to evaluate the effect of switching from cigarette smoking 
to the use of IQOS in healthy adult current smokers on exercise 
capacity and trainability
Study number
P1-EXC-01-EU 
Short title
Effect of switching from cigarette smoking to IQOS on exercise 
capacity
Registration number:
NCT03887117
Product name:
IQOS
Sponsor:
Philip Morris Products SA
Quai Jeanrenaud 5
2000 Neuchâtel
Switzerland
Version number:
3.0
Date:
2 May 2019
Authors:
, Clinical Scientist
, Biostatistician
, Medical Safety Officer
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SUMMARY OF CHANGES 
Clinical Study Protocol 
P1-EXC-01-EU 
 
Version 
Date 
Amendment 
Second 
updated 
protocol 
3.0 
 2 May 2019 
Substantial changes.  
The cut-off for the exhaled CO level 
applied to confirm cigarette smoking 
status at V1 and V2, in addition to self-
report and urine cotinine measurement, 
was lowered from >10ppm to >6ppm as 
supported by literature. Due to the 2-8 
hours half-life of CO, confirmed smokers 
may have levels below >10 ppm 
especially in the morning after overnight 
abstinence (56,57).  
First updated 
protocol 
2.0 
22 November 
2018 
Substantial changes. 
The mHealth device included in the first 
version of the protocol (Everion, 
Biovotion) has been replaced with another 
device (Vivofit 3, Garmin). Endpoints and 
protocol sections concerned have been 
updated. 
Original 
protocol 
1.0 
14 September 
2018 
 
 
The main purpose of the table above is to summarize the major update(s) between original 
clinical study protocol P1-EXC-01-EU (Final Version 1.0) dated 14 September 2018 , signed 
18 September and  its first updated version (Final Version 2.0) dated and signed 22 November 
2018, and the changes between the first updated version dated and signed 22 November 2018 
and its second updated version dated 2 May 2019 
More precise details on the protocol sections changed are provided in the Appendix 5, with the 
list of changes, including the previous and the amended texts, as well as the reasons to change. 
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The new text has been highlighted in bold (e.g. new text) and deleted text has been crossed 
out (e.g. deleted text). 
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SYNOPSIS 
Sponsor: 
Philip Morris Products SA 
Quai Jeanrenaud 5 
2000 Neuchâtel 
Switzerland 
Name of Product: 
IQOS 
Study Title: 
A randomized, controlled, open-label, 4-arm parallel group study to evaluate the effect of 
switching from cigarette smoking to the use of IQOS in healthy adult current smokers on 
exercise capacity and trainability 
Study Number: 
P1-EXC-01-EU 
Short Title: 
Effect of switching from cigarette smoking to IQOS on exercise capacity 
Registration number: 
Not assigned 
Study Location: 
Germany  
Objectives and Endpoints: 
Objective 
1. To evaluate changes in VO2max in subjects switching to IQOS (with and without 
training), continuing to smoke cigarettes (with training)  and being smoking abstinent 
(with training) 
Endpoint (V3, V4 and V43)  
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x VO2max as determined during maximal cycle ergometer exercise (expressed in absolute 
[mL*min-1], weight-adjusted [mL*kg-1*min-1] and fat-free weight adjusted values 
[mL*kg-1*min-1]) 
 
2. To evaluate changes in exercise capacity in subjects switching to IQOS (with and 
without training), continuing to smoke cigarettes (with training) and being smoking 
abstinent (with training) 
Endpoints (V3, V4 and V43) 
x Exercise capacity: time to complete a pre-defined work  on a cycle ergometer 
(min:sec). 
 
3. To assess the intensity of the exercise training in subjects participating in a training 
program switching to IQOS, continuing to smoke cigarettes and being smoking 
abstinent 
Endpoints (V5-V42)  
x Cumulative work produced during each training session (calories and calories/kg body 
weight) 
x Average work rate during each training session (watt and watt/kg body weight) 
x Average work rate during each interval during each training session (watt and watt/kg 
body weight) 
x Time spent at 0-50%, 50-65%, 65-75%, 75-90%, >90% of maximal work rate during 
each training session (min:sec) 
x Average heart rate (HR) during each training session (bpm) 
x Time spent at 0-50%, 50-60%, 60-70% , 70-80 % and >80% of maximal HR during 
each training session (min:sec) 
 
4. To evaluate changes in physiological parameters and perception of exertion and 
capacity in subjects switching to IQOS (with and without training), continuing to 
smoke cigarettes (with training) and being smoking abstinent (with training) 
Endpoints (V3, V43) 
x Blood composition: Hemoglobin mass (g), red blood cell volume (mL), plasma volume 
(mL) and total blood volume (mL) as determined by CO re-breathing method  
x Capillary blood lactate levels during VO2max test (mmol/L) 
x Perceived rate of exertion during VO2max test (Borg Rating of Perceived Exertion 
(RPE) scale)  
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Endpoints (V3, V4 and V43) 
x Respiratory parameters at VO2max: Ventilation (L/min), respiratory rate, VCO2 
(L/min), Respiratory exchange ratio (RER) (VCO2 / VO2)  
x Rating of Perceived Capacity (RPC) scale 
x Heart rate (bpm) and oxygen uptake (mL/min) during VO2max test 
 
5. To monitor trends of daily physical activity levels during the study in subjects 
switching to IQOS (with and without training), continuing to smoke cigarettes (with 
training) and being smoking abstinent (with training) 
Endpoints (from V2 until V43) 
x Aggregated data derived from the mobile health (mHealth) wearable for: 
 Cumulative number of steps per day 
 Sedentary minutes per day and % of time sedentary 
 Active minutes per day and % of time active 
 Very active minutes per day and  % of time very active 
 
6. To explore trends and changes in activity and sleep parameters through continuous 
measurements during the study* 
Endpoints (from V2 until V43) 
mHealth wearable measurements of steps, activity, distance, energy expenditure, sleep* 
Reporting of data for this objective will be subject to a separate report(s) (not part of the 
Clinical Study Report [CSR]). 
 
7. To describe changes in biological health markers in subjects switching to IQOS (with 
and without training), continuing to smoke cigarettes (with training) and being 
smoking abstinent (with training) 
Endpoints (V3, V14, V28 and V43) 
x High density lipoprotein (HDL), low density lipoprotein (LDL) and very low density 
lipoprotein (VLDL) (mg/dL) 
x High sensitivity C-reactive protein (hs-CRP) (mg/L) 
x Growth hormone  (GH) (ng/mL) 
x Hemoglobin A1C (HbA1c) (%) 
x Resting blood pressure (mmHg) 
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x Resting HR (bpm) 
 
8. To describe changes in weight, body fat and waist circumference in subjects 
switching to IQOS (with and without training), continuing to smoke cigarettes (with 
training) and being smoking abstinent (with training) 
Endpoints (V3, V4 and V43) 
x Body fat percentage (%) 
x Waist circumference (cm) 
Endpoints V3-V43 
x Body weight (kg) 
 
9. To monitor levels of exposure to CO, nicotine, nitrosamines and acrylonitrile in 
subjects switching to IQOS (with and without training), continuing to smoke 
cigarettes (with training) and being smoking abstinent (with training) 
Endpoints  
At all visits:  
x Exhaled carbon monoxide (CO) (ppm)  
 
At V3, V4, V14, V28 and V43 
x Carboxyhemoglobin (COHb%) in blood (%) 
x Nicotine equivalents (NEQ) in urine (adjusted for creatinine) 
x  Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in urine (adjusted for 
creatinine) 
x 2-cyanoethylmercapturic acid (CEMA) in urine (adjusted for creatinine) 
 
10. To describe the self-reported nicotine and tobacco containing product use over the 
duration of the study 
Endpoints (measured daily from V2 to V43) 
x Self-reported number of any nicotine/tobacco product used on a daily basis as reported 
in the product use diary 
x Product use exposure 
 
11. To monitor safety during the study 
Endpoints 
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x Incidence of adverse events (AEs), serious adverse events (SAEs) 
x Frequency of AEs, SAEs 
x Incidence of IQOS device events including malfunction/misuse   
x Frequency of IQOS device events including malfunction/misuse 
x Vital signs changes from baseline (systolic and diastolic blood pressure, pulse rate and 
respiratory rate) 
x Physical examination changes from baseline 
x Electrocardiogram (ECG) changes from baseline (heart rate, PR, QRS, QT, QTcB, 
QTcF intervals)  
x Spirometry changes from screening visit (V1) used as baseline (FEV1, FEV1 % 
predicted, FVC, FVC % predicted, and FEV1/FVC) 
x Cough assessment changes from baseline (VAS and three Likert scales) 
x Changes from baseline in clinical chemistry, hematology, and urine analysis safety 
panel 
x Concomitant medications 
 
12. To assess perception of health and functioning in subjects switching to IQOS, 
continuing to smoke cigarettes and being smoking abstinent ** 
Endpoints (first interview between V2 and V3, second interview between V42 and V43) 
x Changes in subjects’ perception of health and functioning as determined by  qualitative 
interviews based on the World Health Organization’s International Classification of 
Functioning, Disability, and Health  
** This objective will be assessed as a sub-study with a separate section of the Informed 
Consent Form (ICF), and the reporting will be subject of an appendix to the main CSR. 
Study Hypothesis: 
The study is descriptive; no statistical hypothesis will be tested. 
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Study Design:   
This is a randomized, controlled, open-label, 4-arm parallel group study with stratification 
by daily cigarette consumption over the past 12 months prior to V1 as reported during V1 
(i.e. 10 to 19 cigarettes or >19 cigarettes per day) and sex (Figure 1).  
A sufficient number of healthy adult smokers will be screened and enrolled after checking 
that all eligibility criteria have been met, in order to reach 90 randomized subjects.  
Smokers will be randomized as follows with a 5:5:5:3 ratio according to strata:  
1. switch to IQOS use + participation in training program: IQOS-1 arm, 25 subjects 
2. continue cigarette smoking + participation in training program: Cigarette arm, 25 
subjects 
3. smoking abstinence + participation in training program:  SA arm, 25 subjects 
4. switch to IQOS use only: IQOS-2 arm, 15 subjects 
When 90 randomized subjects are reached, further enrollment will be stopped. Subjects 
already enrolled in the study will still be eligible for randomization. From randomization, 
subjects will be instructed to use their allocated product or stay smoking abstinent until the 
end of the study. Drop-outs will not be replaced. 
Acute effect on VO2max and exercise capacity of switching to IQOS will be assessed one 
week after randomization before initiating the training program, and the combined effect of 
switching and exercise training will be assessed one week after completion of the 12-week 
training program. 
Figure 1 
Study Design 
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Subjects will have serial visits at the investigational site as follows: 
Screening, V1 (within 28 days prior to V2): No study-specific procedures will be performed 
before the Informed Consent Form (ICF) has been signed. The subject will also be invited 
to participate in a sub-study on perception of health and functioning and will sign a separate 
optional section of  the ICF for this part of the study. Subjects will be invited to sign a 
separate optional consent form for collection of samples for biobanking. 
A demonstration of IQOS and the mHealth wearable will be done by the site staff during the 
screening visit. All inclusion and exclusion criteria will be assessed. A VO2max test will be 
performed as part of eligibility assessments. All eligible subjects will be invited to come to 
V2.  
Enrollment and Familiarization, V2 (7±1 days prior to V3): Enrollment will take place after 
confirmation of smoking status (urine cotinine and exhaled CO) and negative urine 
pregnancy test, alcohol breath test and urine drug screen. After enrollment, vital signs will 
be assessed and subjects will perform an exercise capacity test for the purpose of 
familiarization. The exercise test consists of completing a pre-defined work (calories) on a 
bike ergometer (1). Before leaving the investigational site the subject will receive an 
mHealth wearable kit and will be trained on how to handle the device. Subjects will be 
instructed to wear the device all the time. Subjects will also receive a diary to record the 
daily use of tobacco and nicotine containing products.  
 
Between V2 and V3, subjects having signed the optional section of the ICF will have an 
interview (by phone or computer) on the topic of health and functioning lasting around 60 
minutes. 
 
Baseline and Randomization, V3: Baseline assessments will be performed as listed in 
Appendix 1. Then, 30-60 min before start of the VO2max test all subjects will smoke a 
cigarette (only if they are willing to). During the VO2max test at rest and at each 25 W 
increase, the subject’s lactate levels will be determined by capillary blood sampling and the 
rate of perceived exertion (RPE) will be assessed using the Borg RPE scale. After completing 
the VO2max test, the subject will rest for 60±5min, after which the exercise capacity test 
will be performed. After completing exercise tests, total blood volume will be determined. 
Subjects will thereafter be randomized into one of the 4 arms. Subjects randomized into 
IQOS arms will receive their IQOS starter kit and be trained on how to use the device. 
Subjects randomized into the SA arm will receive smoking abstinence support and will be 
allowed to use NRT upon request. 
Acute effect, V4 (7±2 days after V3): Before the VO2 max test, vital signs, exhaled CO, 
weight, body-fat and waist circumference measurements will be performed. 30-60 min 
before start of the VO2max test subjects in cigarette and IQOS arms will smoke a cigarette 
or use a HeatStick, respectively (only if they are willing to). Subjects’ VO2max, maximal 
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heart rate and maximal work rate will be determined. After completing the VO2max test, 
subjects will rest for 60±5min after which the exercise capacity test will be performed.  
Training program, from V5 (15±2 days after V3) until V42 (99±2 days after V3): Subjects 
randomized into IQOS-1, cigarette and SA arms will participate in 38 supervised training 
sessions during a 12-week period using three different training protocols (Appendix 2).  
 
Subjects randomized to the IQOS-2 arm will come for visits once a week for all assessments 
except the training. Subjects in the IQOS-2 arm will consequently only attend the following 
visits: V5, V7, V9, V14, V16, V19, V23, V28, V30, V33, V35 and V39.  
 
At V14 and V28 (medical visits), safety, biological health marker and exposure marker 
assessments will be performed for all subjects. 
Before each training, the following assessments will be conducted; 
x Weight 
x Exhaled CO  
x 30-60 min before start of the training subjects in cigarette and IQOS arms will smoke 
a cigarette or use a HeatStick, respectively (only if they are willing to).  
All trainings will be performed on a bike ergometer. The training intensity will be adjusted 
according to the subject’s resting heart rate as determined by ECG at V3, and maximal heart 
rate as determined at the VO2max test at V4 (acute test) . The work produced, the work rate 
and heart rate will be recorded for each training (as described in Objective 3).  
 
Between V42 and V43, subjects having signed the optional section of the ICF will have an 
interview (by phone or computer) on the topic of health and functioning lasting around 60 
minutes. 
 
Training effect, V43 (106±2 days after V3):  
Before the VO2max test, biological health markers, exposure markers, vital signs, exhaled 
CO, weight, body-fat percentage and waist circumference measurements will be performed.  
Then, 30-60 min before start of the VO2max test subjects in cigarette and IQOS arms will 
smoke a cigarette or use a HeatStick, respectively (only if they are willing to). Subjects’ 
VO2max will be determined as described for V3, including determination of lactate levels 
and perceived exertion rate. After completing the VO2max test, the subject will rest for 
60±5min, after which the exercise capacity test will be performed.  
After completing exercise tests, total blood volume will be determined. Subjects will return 
the mHealth wearable, the product use diary and the IQOS device (if applicable). 
Discharge, V44 (107±2 days after V3): Safety assessments will be conducted as listed in 
Appendix 1.  
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Safety follow-up period (from discharge at V44 or early termination plus 28 days): 
After discharge on V44 or after early termination, subjects will enter a 28-day safety 
follow-up period during which AE/SAEs spontaneously reported by the subjects will be 
collected. Any non-serious AE that is ongoing at the time of discharge or early 
discontinuation will be followed-up by the Investigator or designee during the safety follow-
up period until it has been resolved, stabilized (i.e., no worsening of the condition), or an 
acceptable explanation has been found (e.g., a chronic condition) or lost to follow up. The 
follow-up of the ongoing non-serious AEs will be done via a phone call performed until the 
end of the Safety Follow-Up Period. At the end of the safety follow-up period, all ongoing 
non-serious AEs will be documented as “ongoing” and no further follow-up information will 
be sought for them by the Investigator or designee. At that point, the Investigator will assess 
whether the subject should be referred to his/her General Practitioner to have their ongoing 
AEs addressed accordingly. SAEs will be followed up by the Investigator until resolution, 
stabilization or the determination of a plausible explanation for them was found, regardless 
of the end of the safety follow-up period.  All subjects discontinued from the study at any 
time after enrollment, will enter the 28-day safety follow-up period. 
Study population and Main Inclusion Criteria: 
Inclusion criteria 
1. Subject has signed the ICF. 
2. Smoking, healthy subject based on safety laboratory, ECG, spirometry, vital signs, 
physical examination, medical history and Investigator’s assessment. 
3. Subject has been smoking for at least three years prior to V1. 
4. Subject has been smoking ≥ 10 cigarettes per day over the last 12 months. Smoking 
status will be verified by a urinary cotinine ≥ 200 ng/mL and CO exhaled breath 
test > 6 ppm at both V1 and V2. 
5. Subject does not plan to quit smoking within 6 months after V1. 
6. Subject is aged between 21 and 65 years (inclusive). 
7. Subject is available for the entire study period and willing to comply with study 
procedures. 
Exclusion criteria 
1. Subject performs more than 45 min of vigorous physical activity per week. 
2. Inability to perform a VO2max test at V1. 
3. VO2max > 50 mL.min-1 kg-1 for men and VO2max > 40 mL.min-1 kg-1 for women 
as determined at V1. 
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4. For women only: subject is pregnant (does not have negative pregnancy tests at V1 
and at V2) or is breastfeeding.  
5. For women of childbearing potential: Female subject who does not agree to using 
an acceptable method of effective contraception during the entire study. 
6. Subject has a BMI < 18.5 kg/m2 or BMI ≥ 30 kg/m2. 
Investigational Products; Dose; and Mode of Administration: 
IQOS arm: IQOS starter kit (IQOS device and packs of marketed HeatSticks of different 
variants) will be supplied to the subjects randomized to IQOS-1 and IQOS-2 arms at the end 
of V3. The short time between the randomization and the distribution of the device (same 
visit) does not allow subjects to purchase the device on-line and have it delivered on time 
(there is no physical shop in the study area). The distribution of the device by the study staff 
will also allow the subjects to benefit from the on-site guided trial to understand how to use 
the device properly. Subjects allocated to IQOS arms will be asked to buy their variant of 
choice of HeatSticks for their own use during the entire investigational period as HeatSticks 
will not be provided by the Sponsor.  
Cigarette arm (comparator product): Subjects’ own preferred brand of commercially 
available cigarettes will not be provided by the Sponsor but purchased by the subjects for 
their own use for the duration of the study. 
Duration of Study: 
The study duration per subject will be between approximately 20-25 weeks depending on 
length of visit windows. The study consists of  a 1-28-day screening period (V1), a 1-day 
familarization visit (V2), up to 7±1 days interval between V2 and V3, followed by a 1-day 
baseline and randomization visit (V3). A 1-day acute effect test visit (V4) will be scheduled 
7±2 days after V3, followed by a 12-week training program with training sessions 2-4 times 
per week (V5-V42) starting 15±2 days after V3 until 99±2 days after V3. A 1-day training 
effect test visit (V43) will be scheduled up to 7±2 days after V42 (106±2 days after V3), 
followed by a discharge visit (V44) up to 1±2 days after V43 (107 ±2 days after V3), and 
followed by a 28-week safety follow-up period. The end of the study for an individual 
subjects will be defined as V44 or the date of early termination plus the 28 days for the safety 
follow-up period. The end of the entire study is the latest date that an individual subject 
reaches the end of the study. 
Statistical Methods: 
Sample Size and Evaluation: 
The sample size of 20 per arm (smoking abstinence with training, IQOS with training, 
continued cigarette smoking with training) was determined based on previously published 
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results, which reported a standard deviation of 14 mL/kg/min in VO2max in the change 
between groups which continued smoking and those who were smoking abstinent after 
participating in a 12-week training program (2). This sample size allows a probability 
(power) of 90% that the half-width of the 95% confidence intervals between two arms have 
a precision of approximately 10.3 mL/kg/min. For example, if the mean difference in change 
between the cigarette arm and smoking abstinence arm was 12 mL/kg/min after training, we 
expect that if the experiment were repeated many times then on average 90% of the time the 
95% confidence intervals of the mean differences between two arms will be within 1.7 and 
22.3. To allow for a dropout rate of approximately 20%, the sample size will be 25 per arm. 
The IQOS-2 arm without training will mainly serve as a secondary analysis  to the IQOS-1 
arm with training, and the drop-out rate in this arm is expected to be lower. Therefore, only 
15 subjects will be randomized to this arm.  
Analysis Populations: 
The main population for non-safety analysis will be the As Exposed Exercise Compliant 
Set.  
Safety will be analyzed using the Safety Set.  
1. As Exposed Exercise Compliant Set  
The As Exposed Exercise Compliant Set (AEECS) consists of all randomized subjects who 
have at least one valid non-safety assessment after randomization, specifically we have  
x post-randomization product (cigarette or IQOS) use experience if randomized to 
IQOS, IQOS-2 or cigarette arm or 
x no product use if randomized to the SA arm, 
and who attended at least 34 of 38 (~90%) of the exercise training sessions except the 
subjects in IQOS-2 arm. The AEECS will be analyzed by actual exposure (product use 
exposure). 
 
2. Full Analysis Set 
The Full Analysis Set (FAS) consists of all randomized subjects who have at least one post-
randomization product (cigarette or IQOS) use experience if randomized to IQOS, IQOS-2 
or cigarette arm, and who have at least one valid non-safety assessment after randomization. 
All subjects in the SA arm who fulfil these requirements, except the product use experience, 
are part of this set as well. The FAS will be analyzed by randomized study arm. 
 
3. Safety Set 
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The Safety Set consists of all subjects enrolled with signed ICF who have at least one valid 
safety assessment during the course of the study. The Safety Set will be analyzed by actual 
exposure (product use exposure).  
Endpoint analysis 
A linear mixed effects model will be used to estimate the VO2max values between each arm 
(IQOS-1, SA arm) versus cigarette arm one week after randomization (V4) and after 
completion of the 12-week training program (V43). The dependent variable will be VO2max 
with baseline VO2max, arm, sex, age and cigarette consumption as covariates. Appropriate 
contrasts will be constructed to report an estimate of the difference in VO2max and its 95% 
confidence intervals within and between each arm. The same analysis will be performed for 
SA vs IQOS-1 arm. Other covariates may be added as deemed appropriate.  
To estimate the VO2max values between IQOS-1 and IQOS-2 arms, the same linear mixed 
effects model will be used to model the VO2max at V43. The same analysis will be repeated 
for weight-adjusted and fat-free weight adjusted VO2max.  
A linear mixed model will be used to estimate the difference in exercise capacity between 
each arm (IQOS-1, SA arm) versus cigarette arm one week after randomization (V4) and 
after completion of the 12-week training program (V43). The dependent variable will be the 
time  to complete the test in seconds with baseline exercise capacity (in seconds), arm, sex, 
age and cigarette consumption as fixed effects. Appropriate contrasts will be constructed to 
report an estimate of the difference in change in exercise capacity time at V3 and V43 and 
its 95% confidence intervals as an estimate of the acute effect and training effect, 
respectively. Other covariates may be added as deemed appropriate. The same analysis will 
be performed for SA vs IQOS-1 arm as well. To estimate the change in exercise capacity 
between IQOS-1 and IQOS-2 arm the same linear model will be used to model the change 
between arms at V43. 
An appropriate statistical model will be used to estimate the intensity of exercise training in 
the various arms over time. Further details will be provided in the SAP. 
Estimates of variability from the statistical model (VO2max, exercise capacity, intensity of 
exercise training) will be reported and may be used to power future similar studies. 
Descriptive statistics will be used to present various measures assessing the VO2max, 
exercise capacity, intensity of exercise training in each arm.  
An appropriate statistical model will be used to estimate the changes in physiological 
parameters and perception of exertion and capacity whilst adjusting for covariates such as 
age, sex, cigarette consumption or any other clinically relevant covariates of interest. The 
difference between arms will be estimated and reported together with its 95% confidence 
intervals. Other covariates may be added as needed. 
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Descriptive statistics of the various measures of physical activity as measured by the 
mHealth wearable device will be reported. An appropriate statistical (linear or non-linear) 
model will be used to estimate the levels of activity taking into account clinically relevant 
covariates and repeated measures over time. Comparisons of physical activity levels for 
IQOS-1 and IQOS-2 arm will be reported based on the chosen statistical model. 
For each of the biological markers descriptive statistics will be employed to assess the 
difference between arms. An appropriate statistical model may be employed to estimate 
differences across arms at V43. 
For weight, body fat and waist circumference, descriptive statistics will be employed to 
assess the changes for each arm. An appropriate statistical model may be employed to 
estimate differences across arms at V43. 
To monitor levels of exposure to CO descriptive statistics of exhaled CO will be summarized 
and presented for each arm. Descriptive statistics of COHb% in blood, NEQ, NNAL and 
CEMA in urine will be summarized and presented for each arm. An appropriate statistical 
model may be employed to estimate differences across arms during the visits where these 
are measured.  
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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................4 
TABLE OF CONTENTS .........................................................................................................17 
ABBREVIATIONS AND DEFINITIONS OF TERMS .........................................................23 
1 
ETHICS AND REGULATIONS .....................................................................................27 
1.1 
Independent Ethics Committee (IEC) Approval ....................................................27 
1.2 
Ethical Conduct of the Study .................................................................................28 
1.3 
Subject Information and Consent...........................................................................28 
1.3.1 
Informed Consent Form for Study Participation .........................................28 
1.3.2 
Informed Consent Form for Biobanking......................................................29 
1.3.3 
Amendment to the Informed Consent Form ................................................29 
1.4 
Good Clinical Practice and Regulatory Requirements ..........................................29 
2 
INTRODUCTION ...........................................................................................................31 
2.1 
Background ............................................................................................................31 
2.1.1 
Smoking and Exercise Capacity ..................................................................31 
2.1.2 
Description of the Product and Scientific Findings .....................................32 
2.2 
Purpose of the Study ..............................................................................................34 
2.3 
Anticipated Benefits and Risks ..............................................................................34 
2.3.1 
Anticipated Benefits.....................................................................................34 
2.3.2 
Anticipated Foreseeable Risks due to Study Procedures .............................34 
2.3.3 
Anticipated Foreseeable Risks due to Investigational Product 
(IQOS/Cigarette) ..........................................................................................35 
2.3.4 
Unforeseeable Risks.....................................................................................35 
3 
STUDY OBJECTIVES ....................................................................................................36 
3.1 
Objectives and Endpoints ......................................................................................36 
4 
INVESTIGATIONAL PLAN ..........................................................................................40 
4.1 
Overall Study Design and Plan ..............................................................................40 
4.2 
Rationale for Study Design ....................................................................................43 
4.3 
Appropriateness of Measurements .........................................................................44 
4.4 
Study Duration .......................................................................................................45 
5 
STUDY POPULATION ..................................................................................................46 
5.1 
Selection of Study Population ................................................................................46 
5.1.1 
Inclusion Criteria .........................................................................................46 
5.1.2 
Exclusion Criteria ........................................................................................46 
5.2 
Discontinuation of Subjects from the Study ..........................................................49 
5.3 
Lost to Follow-up ...................................................................................................50 
5.4 
Violation of Selection Criteria ...............................................................................51 
6 
INVESTIGATIONAL PRODUCTS/ REFERENCE ARM ............................................52 
6.1 
Description of Investigational Products .................................................................52 
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6.1.1 
Test Product .................................................................................................52 
6.1.2 
Comparator and Baseline Product ...............................................................53 
6.2 
Packaging and Labeling .........................................................................................53 
6.3 
Use of Investigational Product(s)...........................................................................54 
6.3.1 
From Enrollment to Randomization ............................................................54 
6.3.2 
Investigational Period ..................................................................................54 
6.3.3 
Safety Follow-up Period ..............................................................................55 
6.3.4 
Stopping rules for Investigational Product ..................................................55 
6.4 
Method for Assigning Subjects to Study Arms .....................................................55 
6.5 
Blinding..................................................................................................................56 
6.5.1 
Blinding of site staff.....................................................................................56 
6.5.2 
Blinding of data............................................................................................56 
6.6 
Investigational Product Accountability and Adherence ........................................56 
6.6.1 
Dispensing Investigational Product .............................................................56 
6.6.2 
Storage and Accountability ..........................................................................57 
6.6.3 
Investigational Product Retention ................................................................57 
6.6.4 
Adherence to Investigational Products and Reference Arm ........................57 
6.7 
Restrictions ............................................................................................................58 
6.7.1 
Product Use Restrictions ..............................................................................58 
6.7.2 
Dietary Restrictions .....................................................................................58 
6.8 
Concomitant Medication ........................................................................................58 
7 
STUDY PROCEDURES .................................................................................................59 
7.1 
Informed Consent...................................................................................................59 
7.2 
Information on the Risk of Smoking and Smoking Cessation Advice and 
Debriefing on IQOS ...............................................................................................59 
7.3 
Questions on Smoking History/Habits and Plan to Quit Smoking. .......................60 
7.4 
Demonstration of IQOS .........................................................................................60 
7.5 
Clinical Assessments .............................................................................................60 
7.5.1 
Demographic Data .......................................................................................60 
7.5.2 
Medical History, Concomitant Disease, Previous and Ongoing 
Medications ..................................................................................................60 
7.5.3 
Physical Examination...................................................................................61 
7.5.4 
Body Height, Weight and Body Mass Index (BMI) ....................................61 
7.5.5 
Vital Signs ....................................................................................................61 
7.5.6 
Spirometry....................................................................................................61 
7.5.7 
Electrocardiogram ........................................................................................62 
7.5.8 
Body-fat Percentage and Waist Circumference ...........................................62 
7.5.9 
Determination of Blood Composition and Volume .....................................62 
7.6 
Exercise Testing and Training ...............................................................................63 
7.6.1 
VO2max Test and Blood Lactate Levels ......................................................63 
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7.6.2 
Exercise Capacity Test .................................................................................64 
7.6.3 
Exercise Training .........................................................................................64 
7.7 
Biomarker Assessment...........................................................................................64 
7.7.1 
Exhaled Carbonmonoxide (CO) ..................................................................64 
7.7.2 
Carboxyhemoglobin (COHb).......................................................................64 
7.7.3 
Urine Biomarkers of Exposure ....................................................................65 
7.7.4 
Biological Health Markers in Blood ............................................................65 
7.8 
Laboratory Assessments ........................................................................................65 
7.8.1 
Clinical Chemistry, Hematology, and Urinalysis for Safety Panel .............65 
7.8.2 
Serology .......................................................................................................66 
7.8.3 
Urine Drug Screening ..................................................................................66 
7.8.4 
Urine Cotinine Screening .............................................................................66 
7.8.5 
Alcohol Breath Test .....................................................................................67 
7.8.6 
Urine Pregnancy Test ...................................................................................67 
7.9 
Sample Handling, Storage, and Shipment .............................................................67 
7.9.1 
Blood Samples .............................................................................................67 
7.9.2 
Urine Samples ..............................................................................................67 
7.9.3 
Long-Term Storage (Biobanking) ................................................................68 
7.10 
Mobile Health (mHealth) Wearable .......................................................................68 
7.11 
Questionnaires........................................................................................................69 
7.11.1 
Fagerström Test for Nicotine Dependence (Revised Version) ....................69 
7.11.2 
Product preference .......................................................................................69 
7.11.3 
Lifestyle questionnaire .................................................................................70 
7.11.4 
Assessment of Cough-VAS and Likert Scales.............................................70 
7.11.5 
International Physical Activity Questionnaire (IPAQ) - short form ............70 
7.11.6 
Borg Rate of Perceived Exertion (RPE) Scale .............................................71 
7.11.7 
Rate of Perceived Capacity (RPC) Scale .....................................................71 
7.11.8 
Product Use Diary ........................................................................................71 
7.11.9 
Qualitative Interviews on Health and Functioning (sub-study) ...................71 
8 
ADVERSE EVENTS .......................................................................................................73 
8.1 
Definitions..............................................................................................................73 
8.1.1 
Adverse Events ............................................................................................73 
8.1.2 
Serious Adverse Events ...............................................................................73 
8.2 
Assessment of Adverse Events ..............................................................................74 
8.2.1 
Collection of Information ............................................................................74 
8.2.2 
Period of Collection .....................................................................................74 
8.2.3 
Intensity of Adverse Event...........................................................................75 
8.2.4 
Relationship to Investigational Product and Relationship to Study 
Procedures ....................................................................................................75 
8.2.5 
Expectedness ................................................................................................75 
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8.2.6 
Follow-up of Non-Serious and Serious Adverse Events .............................76 
8.3 
Reporting of Serious Adverse Events ....................................................................76 
8.4 
Reporting and of Other Events Critical to Safety Evaluation ................................77 
8.4.1 
Abnormal Results of Laboratory Tests ........................................................77 
8.4.2 
Reporting other abnormal findings ..............................................................78 
8.5 
Reporting and Follow-Up of Pregnancies..............................................................79 
8.5.1 
Period of Collection and Follow-up .............................................................79 
8.5.2 
Reporting of Pregnancies .............................................................................79 
8.6 
Adverse Events Leading to Discontinuation..........................................................79 
8.7 
Investigational Product Malfunction and Misuse ..................................................80 
9 
STUDY ACTIVITIES .....................................................................................................81 
9.1 
Screening................................................................................................................81 
9.2 
Enrollment and Familiarization with Exercise Test...............................................83 
9.3 
Baseline and Randomization..................................................................................85 
9.4 
Exposure Period .....................................................................................................87 
9.4.1 
Acute Effect Exercise Tests .........................................................................87 
9.4.2 
Exercise Training Program ..........................................................................89 
9.4.3 
Training Effect Exercise Tests .....................................................................91 
9.5 
Safety Follow-Up Period .......................................................................................94 
9.6 
Early Termination Procedures ...............................................................................94 
10 QUALITY CONTROL AND QUALITY ASSURANCE ...............................................96 
10.1 
Monitoring .............................................................................................................96 
10.2 
Training of Collaborators .......................................................................................96 
10.3 
Audits and Inspections ...........................................................................................97 
11 DATA MANAGEMENT ACTIVITIES..........................................................................98 
11.1 
Data Capture ..........................................................................................................98 
11.1.1 
Case Report Forms and Study Records .......................................................98 
11.1.2 
Protocol Deviations ......................................................................................98 
11.2 
Data Handling ........................................................................................................99 
11.2.1 
Data Validation ............................................................................................99 
11.2.2 
Coding ..........................................................................................................99 
11.2.3 
Database Lock ............................................................................................100 
12 PLANNED STATISTICAL METHODS ......................................................................101 
12.1 
General Considerations ........................................................................................101 
12.1.1 
Stratification Criteria .................................................................................101 
12.1.2 
Definitions for Statistical Data Analysis....................................................101 
12.1.3 
Descriptive Statistics ..................................................................................101 
12.1.4 
Handling of Missing Values and of Values outside the Detection or 
Quantification Limits .................................................................................101 
12.1.5 
Significance Level for Inferential Analysis ...............................................102 
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12.2 
Determination of Sample Size and Power Consideration ....................................102 
12.3 
Product Use ..........................................................................................................103 
12.4 
Analysis Populations ............................................................................................103 
12.4.1 
As Exposed Exercise Compliant Set..........................................................103 
12.4.2 
Full Analysis Set ........................................................................................103 
12.4.3 
Safety Set ...................................................................................................104 
12.5 
Endpoint Analysis ................................................................................................104 
12.6 
Demographics and Baseline Characteristics ........................................................106 
12.7 
Interim Analysis ...................................................................................................106 
13 ADMINISTRATIVE CONSIDERATIONS ..................................................................107 
13.1 
Investigator’s and Study Administrative Structure ..............................................107 
13.1.1 
Investigator ................................................................................................107 
13.1.2 
Sponsor ......................................................................................................107 
13.1.3 
Other Responsibilities ................................................................................107 
13.2 
Subject Confidentiality ........................................................................................108 
13.3 
Access to Source Documentation ........................................................................108 
13.4 
Record Retention .................................................................................................109 
13.5 
Clinical Study Report ...........................................................................................110 
13.6 
Financial Disclosure.............................................................................................110 
13.7 
Publication and Disclosure Policy .......................................................................110 
13.8 
Insurance ..............................................................................................................111 
14 REFERENCE LIST .......................................................................................................112 
APPENDIX 1 SCHEDULE OF EVENTS ............................................................................120 
APPENDIX 2 
EXERCISE TRAINING PROGRAM .......................................................126 
APPENDIX 3 - LABORATORY VALUES .........................................................................128 
APPENDIX 4 -  SUB-STUDY PROTOCOL ........................................................................132 
APPENDIX 5 CHANGES IN PROTOCOL AMENDMENT...............................................133 
 
LIST OF IN-TEXT TABLES 
Table 1 
Test Product (IQOS) ..................................................................................53 
Table 2 Blinding ................................................................................................................56 
Table 3 
Clinical Laboratory Parameters for Safety Panel .......................................66 
Table 4 
 Principles for assessing and reporting abnormal laboratory test results ...78 
Table 5 
Time Schedule – V1 ...................................................................................81 
Table 6 
Time Schedule – V2 Enrollment and Exercise Capacity Test ...................84 
Table 7 
Time Schedule – V3 Baseline ....................................................................85 
Table 8 
Time Schedule – V4 Acute Effect .............................................................87 
Table 9 
Time Schedule – ExerciseTrainings V5 to V42 ........................................89 
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Table 10 
Time Schedule – Medical Visits V14 and V28 .........................................90 
Table 11 
Time Schedule – V43 Training Effect Exercise Tests ...............................91 
Table 12 
Time Schedule – V44 Discharge Safety Assessments ...............................93 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Design ................................................................................................9 
Figure 2 
Study Design ..............................................................................................40 
 
LIST OF APPENDICES 
Appendix 1 Schedule of Events .......................................................................................120 
Appendix 2 
Exercise Training Program ......................................................................126 
Appendix 3 - Laboratory Values ......................................................................................128 
Appendix 4 -  Sub-study Protocol ....................................................................................132 
Appendix 5 Changes in Protocol Amendment .................................................................133 
 
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ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations  
AE 
Adverse event 
AEECS 
As Exposed Exercise Compliant Set 
BMI 
Body mass index 
BoExp 
Biomarker of exposure 
Bpm 
Beat per minute 
CEMA 
2-cyanoethylmercapturic acid 
CI 
Confidence interval 
CO 
Carbon monoxide 
COHb 
Carboxyhemoglobin 
CRF 
Case report form 
CRO 
Contract research organization 
CSR 
Clinical study report 
CTCAE 
Common terminology criteria for adverse events and common 
toxicity criteria  
CTMS 
Clinical trial management system 
CV (documentation) 
Curriculum vitae 
CV (statistics) 
Coefficient of variation 
DMP 
Data management plan 
ECG 
Electrocardiogram 
EOS 
End of study 
FAS 
Full analysis set 
FEV1  
Forced expiratory volume in 1 second 
FTND 
Fagerström test for nicotine dependence (revised version) 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GH 
Growth hormone 
Hb 
Hemoglobin 
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HbA1c
Hemoglobin A1c
HDL
High-density lipoprotein
HIV
Human immunodeficiency virus
HPHCs
Harmful and potentially harmful constituents
HR
Heart rate
hs-CRP
High sensitivity C-reactive protein
ICF
Informed consent form
ICH
International Conference on Harmonization 
IEC
Independent Ethics Committee
IP
Investigational product
IPAQ
International Physical Activity Questionnaire
LDL
Low-density lipoprotein
LLN
Lower limit of the normal range
LLOQ
Lower limit of quantification
MedDRA
Medical dictionary for regulatory activities
NEQ
Nicotine equivalents
NNAL
Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol
NRT
Nicotine replacement therapy
PMI
Philip Morris International
QC
Quality control
RPC
Rating of Perceived Capacity
RPE
Rate of Perceived Exertion
SA
Smoking abstinence
SAE
Serious adverse event
SAP
Statistical analysis plan
SOP
Standard operating procedure
SPI
Summary of Product Information
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ULN 
Upper limit of the normal range 
ULOQ 
Upper limit of quantification 
VAS 
Visual analogue scale 
VLDL 
Very low density lipoprotein 
VO2max 
Maximal oxygen uptake  
WBC 
White blood cell (count) 
WHO 
World Health Organization 
 
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Explanation of Terms 
The following special terms are used in this protocol:  
Cigarette  
The term ‘cigarette’ refers to commercially available cigarettes 
(manufactured) and excludes cigars, pipes, bidis, and other 
nicotine-containing products. 
End of study (EOS) 
The EOS for a subject is defined as discharge on Visit 44 or the 
date of early termination of the subject plus the 28 days for the 
safety follow-up period. The EOS of the entire study is the end of 
the safety follow-up period of the last subject. 
Randomization  
Allocation of the respective product at any time on V3 utilizing an 
interactive web and voice response system (IxRS). In the end of 
V3, the subjects will be individually informed about the product 
they are randomized to prior to the first product use.  
Screening failure 
All subjects that are not enrolled because they violate the entry 
criteria prior to enrollment are considered as screening failures. 
Re-screening of these subjects will not be permitted. 
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Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
1 
ETHICS AND REGULATIONS 
1.1 
Independent Ethics Committee (IEC) Approval 
Prior to the start of the study, the study protocol, together with its associated documents 
(informed consent form [ICF] including the subject information sheet and the informed 
consent, subject recruitment procedures [e.g., advertisements], written information including 
questionnaires and written instructions to be provided to the subjects, Summary of Product 
Information [SPI] including available safety information, curriculum vitae of the Investigator 
and/or other evidence of qualifications and any other documents requested by an Independent 
Ethics Committee [IEC]), will be submitted for review and approval to the relevant IEC. The 
IEC shall be appropriately constituted and perform its functions in accordance with the 
International Conference on Harmonization (ICH) Tripartite Guidance for Good Clinical 
Practice (GCP) (3) and local requirements, as applicable. 
In accordance with GCP, a written confirmation of the IEC approval should be provided to the 
Sponsor. This should identify the study (name of the Investigator, study number, and title) and 
the documents that have been approved by the IEC, with dates and version numbers, as well 
as the date of approval. The composition of the IEC, including the name and occupation of the 
chairperson, will be supplied to the Sponsor together with a GCP compliance statement. 
The written approval from the IEC will be filed in the Investigator Site File (ISF), and a copy 
will be filed in the Study Master File (SMF) at the Sponsor or designated organization. The 
study must not start at an investigational site before the Sponsor has obtained written 
confirmation of favorable opinion/approval from the concerned IEC. 
Any substantial change or addition to this protocol will require a written protocol amendment 
that must be approved by the Sponsor and the Investigator. All amendments will be submitted 
to the IEC, and substantial amendments will only be implemented after approval by the IEC. 
These requirements for approval should in no way prevent any action from being taken by the 
Investigator or by the Sponsor in order to eliminate immediate hazards to the subjects. If such 
a change to the protocol is felt to be necessary by the Investigator, and is implemented for 
safety reasons, the Sponsor and the IEC should be informed immediately. The Investigator is 
responsible for local reporting (e.g., to the IEC) of serious adverse events (SAEs) that occur 
during the study, according to local regulations. 
Relevant safety information should be submitted to the IEC during the course of the study in 
accordance with national regulations and requirements. Medically qualified study personnel 
will be available during the study. 
 
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Confidentiality Statement 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
1.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki (4) and are consistent with ICH/GCP guidelines (3) and applicable 
regulatory principles. 
The Investigator agrees to conduct the study in compliance with the protocol agreed with the 
Sponsor and approved by the IEC. The Investigator and the Sponsor must sign the protocol 
(and protocol amendments, if applicable) to confirm this agreement. A copy of the Declaration 
of Helsinki should be located in the ISF. 
1.3 
Subject Information and Consent 
1.3.1 
Informed Consent Form for Study Participation 
At the beginning of V1, the Investigator will ensure that each subject has been given full and 
adequate oral and written information about the nature, purpose, possible risks and benefits of 
the study, and the Investigator will answer all questions the subject might have to his/her full 
satisfaction. The subject will have sufficient time for consideration of his/her participation in 
the study and will be notified that he/she is free to withdraw his/her participation at any time 
without penalty or loss of benefits to which she/he may be otherwise entitled. 
Once the subject has received all the necessary information and sufficient time for 
consideration, and if he/she agrees to participate in the study, the subject and the person who 
conducted the informed consent discussion during V1 will both sign, date and time the ICF. 
The ICF includes both the subject information sheet and informed consent. No study-specific 
procedures will be performed before informed consent is obtained and the ICF has been signed 
(including date and time). All subjects will be invited to participate in an optional sub-study 
on health and functioning and will sign a separate section of the ICF for this part. 
The original, dated and signed ICF must be kept by the Investigator and filed in the ISF at the 
investigational site or with the subject’s files and a copy must be given to the subject. 
The subject will be informed that if he/she withdraws from the study, the data collected until 
the point of withdrawal will be maintained as part of the study data and the samples collected 
prior to withdrawal will be analyzed, unless he/she refuses in writing. The subject will be 
informed that additional data analyses not mentioned in the protocol or the statistical analysis 
plan might be performed with the collected data at a later time. If any additional analyses will 
be performed, they will fully be covered by data confidentiality, as for the main analyses 
described in this protocol. 
For the purpose of exploratory digital biomarker scientific research the subjects will need to 
consent that data collected continuously throughout the study with the mHealth wearable 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
device will be stored by the Sponsor. The subjects will be informed that following completion 
of this study, analysis of these data of exploratory nature will be conducted to provide better 
understanding of changes in  activity and sleep patterns in healthy smokers switching to IQOS 
or being smoking abstinent vs continued cigarette smoking.  
1.3.2 
Informed Consent Form for Biobanking 
In addition to the ICF for the participation in the study, each subject will be asked to provide 
his/her separate optional consent for the collection of samples and storage for long-term 
biobanking. Samples to be collected include blood, urine, saliva and sweat samples. 
Biobanking samples will be collected using commonly accepted methods for the purpose of 
identification and validation of new biomarkers indicative of the underlying biological 
processes related to the exposure to potentially harmful compounds, disease risk and health 
status. A part of the biobanking samples will also be used for the development and validation 
of methods to perform the measurements under the quality management system. The 
biobanking samples will be analyzed using non-targeted analytical methods such as molecular, 
metabolomics, proteomics, lipidomics, and transcriptomics profiling. The identified biomarker 
quantification will subsequently be confirmed using established targeted methods. The 
analyses performed will be covered by data confidentiality, as for the main analyses described 
in this protocol. 
Subjects will be given full and adequate oral and written information about the purpose of 
biobanking, and the Investigator will answer all questions the subject might have to their full 
satisfaction. The subject will be notified that he/she is free to withdraw consent at any time. 
Once the subject has received all the necessary information, and if he/she agrees to participate, 
this will be documented by the date, time and signature of both, the subject and the Investigator 
who conducted the informed consent discussion. The subject’s consent to collection of any 
samples for long-term storage in a biobank is not a requirement for participation in the study.  
1.3.3 
Amendment to the Informed Consent Form 
If a protocol amendment is required, an amendment may be required to the ICF. If revision of 
the ICF is necessary, the Investigator or designee will, with the support of the Sponsor or 
authorized representative, ensure that the documents have been reviewed and approved by the 
IEC before study participants are required to re-sign and time and date the ICF. 
1.4 
Good Clinical Practice and Regulatory Requirements 
The procedures set out in this clinical study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that the Sponsor, its authorized 
representative, and Investigator abide by the principles of the current version of the ICH 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
guidelines on GCP and will carry out the clinical study in accordance with these principles if 
applicable. Although these guidelines were written specifically to set a standard for 
pharmaceutical development, they nevertheless provide a robust and ethical framework for 
conducting clinical studies of tobacco products. 
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Confidentiality Statement 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
2 
INTRODUCTION 
2.1 
Background 
2.1.1 
Smoking and Exercise Capacity 
Insufficient physical activity is a leading risk factor for global mortality, and according to 
WHO 23% of adults are being insufficiently physically active (5). Improvement in 
cardiorespiratory fitness, quantified by measuring the maximal oxygen uptake (VO2max) is 
independently associated with 13% reduction in all-cause mortality, highlighting the clinical 
benefit associated with exercise training and physical activity (6) . Exercise training is the most 
effective lifestyle intervention for increasing cardiorespiratory fitness. 
In addition to causing adverse health effects and disease, cigarette smoking has been shown to 
adversely affect cardiorespiratory fitness and exercise performance, and lower VO2max values 
have been reported in smokers as compared to non-smokers. The carbon monoxide (CO) 
present in the cigarette smoke has >200 times stronger affinity for hemoglobin (Hb) as 
compared to oxygen thus in the presence of CO the formation of carboxyhemoglobin (COHb) 
easily occurs (7), which consequently limits oxygen transport to the exercising skeletal 
muscles. While it has been suggested that COHb% levels below 4% only exerts mild effects 
on VO2max, there is a marked decrease in VO2max above this threshold (8). In smokers, 
COHb% values of 3-15 is within the expected range (9), and upon smoking abstinence, these 
values decrease to levels found in non-smokers (10, 11).  
Beyond limiting exercise capacity, it has likewise been demonstrated that cigarette smoking 
limits the training response associated to exercise training, i.e. exercise trainability (7). Cooper 
et al. assessed the effect of 6 weeks of training on a 12-minute field test and showed that the 
training response was significantly impaired in the smoking as compared to the non-smoking 
participants (12). Another study, assessing the effect of smoking cessation on exercise 
performance in 109 female smokers, demonstrated that women who underwent a 12-week 
exercise training program and quit smoking improved exercise performance over those who 
continued smoking (2). 
The other main component in cigarettes that may influence exercise is nicotine. In regard to 
exercise, the main line of action of nicotine is exerted through an increase in adrenaline and 
noradrenaline release from peripheral nerve endings and the adrenal medulla. While this 
increases submaximal heart rate and contractility, and thereby cardiac minute volume, it has 
no consequences on submaximal exercise performance, as the O2 extraction in the skeletal 
muscle will decrease in order to keep the total oxygen uptake constant (13). Bolinder et al., 
assessed the influence of prolonged nicotine exposure on maximal physical working capacity, 
and cardiovascular response to exercise in 144 smokeless tobacco users, smokers and non-
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
tobacco users. Smokeless tobacco users had similar VO2max as non-users whereas 
significantly lower VO2max was found for smokers. The findings indicate that use of 
smokeless tobacco not generating CO does not significantly influence exercise capacity in 
healthy, physically well-trained men (14). Results from a randomized controlled cross-over 
study on a tobacco heating device (previous prototype of IQOS), with CO reduced by > 90% 
(15), indicated acute improvements in exercise performance parameters, such as maximal 
workload and heart rate response, in 18 male smokers switching to this product or being 
smoking abstinent (16). Altogether, these studies suggest that the effects of cigarette smoking 
on exercise performance and trainability are mainly triggered by an induced elevation in 
COHb% whereas the effect of nicotine is minor.  
Studies have also suggested that smokers stopping smoking tend to maintain a healthier 
physical activity level compared to those continuing to smoke (17). Physical activity is 
commonly assessed using self-reported questionnaires, which are limited by recall and 
response biases. Thus, activity tends to be over- or underestimated with regards to activity 
frequency, duration, and intensity (18). Recent advancements in mobile health (mHealth) 
wearable technology have provided clinicians and researchers with new opportunities to collect 
objective data from research participants with greater frequency than conventional data 
collection methods, outside of structured research settings during activities of daily living in a 
non-invasive manner. 
2.1.2 
Description of the Product and Scientific Findings 
Philip Morris International’s Tobacco Heating System IQOS is a novel tobacco product that 
heats a specifically designed tobacco stick (HeatSticks) within a precisely controlled 
temperature range rather than burning it. Lowering the temperature below 400 °C substantially 
reduces levels of harmful and potentially harmful constituents (HPHCs) including a reduction 
of CO > 95% (19). IQOS is composed of the Holder and dedicated HeatSticks. In this 
document, unless otherwise specified, IQOS refers to the device with HeatSticks. No other 
tobacco sticks should be used with the device. A Charger allows to recharge the Holder after 
each use. Unlike cigarettes, the HeatSticks do not burn down during their consumption and 
their lengths remain constant after use. IQOS has been commercialized in Germany since 2016. 
With this product, the heating of the tobacco is maintained below 350°C, a temperature much 
lower than what is observed for cigarette, which can reach 900°C.  
PMI has undertaken a comprehensive assessment program on IQOS, including pre-clinical and 
clinical studies, aiming to demonstrate that IQOS is a reduced risk product1. The non-clinical 
                                                 
1 Reduced risk products (“RRPs”) is the term used by PMI to refer to products that present, are likely to present, 
or have the potential to present less risk of harm to smokers who switch to these products versus continued 
smoking. 
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without the written consent of Philip Morris Products S.A 
assessment of IQOS, consisting of the aerosol chemistry analysis, in vitro and in vivo studies, 
supported the initiation of clinical studies, as no new or increased toxicological hazard in the 
product’s aerosol was detected when compared with cigarette smoke. Results from pre-clinical 
in vivo studies comparing cigarette smoke with IQOS aerosol in continuous inhalation show 
that exposure to IQOS aerosol, at multiple concentrations, results in a dramatically lower 
systemic toxicity, extensively reduced lung inflammation and reduced histopathological 
changes in the nasal epithelium as well as lung tissue compared to cigarette smoking (20, 21). 
Furthermore, exposure to IQOS aerosol in mice does not enhance cardiovascular disease or 
emphysema, as cigarette smoke does, and switching from cigarette smoke to IQOS aerosol 
exposure halts e.g., aortic plaque growth in a similar manner as smoking cessation (22, 23).  
 
Several clinical studies have been conducted with IQOS, in Europe, Asia and the United States, 
in order to evaluate the nicotine pharmacokinetics (PK) profile (24-28), to demonstrate reduced 
exposure (29, 30), and to determine functional and biological changes when adult smokers 
from cigarettes to IQOS use compared to smokers continuing smoking cigarettes (31-33). The 
PK studies demonstrated similar nicotine absorption in subjects using IQOS and subjects 
smoking cigarettes (34). The Reduced Exposure studies showed reductions from 47% to 98% 
in the controlled 5-day (10, 11), and from 32% to 94% (35) in the 3-month ambulatory settings, 
in the levels of biomarkers of exposure (BoExp) to selected HPHCs in subjects using IQOS 
compared to subjects continuing smoking cigarettes. Importantly, the magnitude of reductions 
in the BoExp levels when using IQOS were comparable to those observed when smokers 
stopped smoking cigarettes (10, 11, 35). The 3-month studies also indicated favorable 
biological and functional changes in clinical risk endpoints linked to smoking-related diseases 
(36).  A 6-month Exposure Response study (33) with the specific aim to demonstrate favorable 
changes in clinical risk endpoints in smokers switching from cigarettes to IQOS succeeded to 
meet its primary objective: all eight of the primary clinical risk endpoints moved in the same 
direction as observed for smoking cessation in the group who switched to IQOS, with 
statistically significant changes in five of the eight endpoints compared with on-going 
smoking. These clinical risk endpoints are associated with diseases including heart and lung 
diseases, covering multiple organ systems, disease pathways, and biological mechanisms such 
as inflammation and oxidative stress (37). The reporting of the 6-month extension of the 
Exposure Response study (38) is ongoing.  
Post-marketing studies have been initiated in order to have a better understanding of the 
product use behaviors (39). Safety data available from the clinical studies conducted to date 
show a similar short-term safety profile for IQOS than for cigarettes. PMI is now launching a 
series of new clinical studies to better understand whether switching to IQOS can have 
beneficial effects on health outcomes (40). Further product information can be found in the 
Summary of Product Information (SPI) (41). 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
2.2 
Purpose of the Study 
This study is part of the global clinical assessment program of IQOS which is designed to 
provide scientific evidence to further substantiate the potential of reduced risk of using IQOS 
as compared to smoking cigarettes. The main goals of this exploratory study are to assess 
whether switching from cigarette smoking to using IQOS will influence 1) VO2max and 
exercise capacity, 2) ability to perform exercise training and thereby influence 3) VO2max after 
12 weeks of exercise training, 4) physiological parameters and biological health markers, and 
finally 5) physical activity levels in daily life. 
2.3 
Anticipated Benefits and Risks 
2.3.1 
Anticipated Benefits 
Subjects who participate in this study will benefit from repeated, detailed health check-ups. 
The VO2max test  performed for screening purpose will allow subject to know their maximum 
exercise capacity and their level of cardiorespiratory fitness as compared to norms adjusted for 
sex and age. Advice on health risk associated with tobacco smoking, and smoking cessation 
advice will be provided at V1 and V2 and then on a monthly basis until the end of the study. 
Subjects who are motivated to quit using tobacco-containing products (e.g. IQOS and/or 
cigarette) are to be referred for additional smoking cessation counselling and the standard of 
care to support smoking cessation will be applied. 
Subject being randomized into an arm including participation in the training program 
(cigarette, SA and IQOS-1 arms) will benefit from a personalized 12-week exercise training 
program.  
2.3.2 Anticipated Foreseeable Risks due to Study Procedures 
x Risks related to blood sampling (e.g., excessive bleeding, fainting, hematoma, paresthesia 
or infection). 
x Risk related to spirometry testing procedures (e.g., dizziness or fainting). Administration 
of salbutamol for the spirometry testing may potentially elevate blood pressure, increase 
the heart rate and cause tremor, inner agitation, palpitation due to sinus tachycardia, muscle 
cramps or headaches. However, these effects are limited after single use and only more 
frequent following repeated use and oral administration. 
x Risk related to VO2max test may include muscle cramps, muscle strain, delayed muscle 
soreness (1 to 2 days afterwards), light headedness, fatigue, and in rare instances, heart 
attack. These symptoms are expected physiological responses and are similar to what may 
occur if the subject undertakes a strenuous run or bike-ride by him- or herself. 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
x Risks related to exercise training include muscle cramps, muscle strain and delayed muscle 
soreness 1 to 2 days afterwards, fatigue. These symptoms are expected physiological 
responses and are similar to what may occur if the subject undertakes a strenuous run or 
bike-ride by him- or herself. 
All risks related to study procedures will be explained in detail to the subjects. Mitigation will 
include: 
x 
Using accepted research and scientific standards, (e.g., blood samples not to exceed 
local blood donation standards). 
x 
Before performing the first VO2max test at V1, subjects will undergo medical 
examinations and their medical history will be assessed. All exercise testing will be 
performed by trained study personnel and be medically supervised. 
x Exercise training sessions will be supervised and performed on stationary bikes. During 
stationary bike ergometer exercise, the exerted loads on especially the knee joints and 
back will be smaller than during running exercise (42). 
x Medical assessment of all study participants with follow-up of those who have 
experienced an AE/SAE. 
2.3.3 
Anticipated Foreseeable Risks due to Investigational Product 
(IQOS/Cigarette)  
A substantial body of evidence already exists on IQOS and its development product, Tobacco 
Heating System (THS) (please refer to SPI (41)). Adverse events (AEs) reported so far seem 
to be mostly in line with the side effects that can be observed while using NRT. Cigarette 
smoking causes pulmonary, cardiovascular diseases and other serious diseases in smokers.   
 
2.3.4 
Unforeseeable Risks 
The possibility of unforeseeable events/risks will be explained at V1. Non-expected 
malfunction of IQOS may lead to unforeseeable risks. Subjects will be informed that IQOS is 
not demonstrated yet to be less harmful than cigarettes. Mitigation will include close 
monitoring and medical supervision to detect any unforeseeable risks or safety signals at the 
earliest time possible. 
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3 
STUDY OBJECTIVES 
3.1 
Objectives and Endpoints 
The objectives of this study are: 
Objective 
1. To evaluate changes in VO2max in subjects switching to IQOS (with and without 
training), continuing to smoke cigarettes (with training) and being smoking abstinent 
(with training) 
Endpoint (V3, V4 and V43)  
x VO2max as determined during maximal cycle ergometer exercise (expressed in absolute 
[mL*min-1], weight-adjusted [mL*kg-1*min-1] and fat free weight-adjusted [mL*kg-1*min-
1] values) 
 
2. To evaluate changes in exercise capacity in subjects switching to IQOS (with and 
without training), continuing to smoke cigarettes (with training) and being smoking 
abstinent (with training) 
Endpoints (V3, V4 and V43) 
x Exercise capacity: time to complete a pre-defined work on a cycle ergometer (min:sec) 
 
3. To assess the intensity of the exercise training in subjects participating in a training 
program and switching to IQOS, continuing to smoke cigarettes and being smoking 
abstinent  
Endpoints (V5-V42)  
x Cumulative work produced during each training session (calories and calories/kg body 
weight) 
x Average work rate during each training session (watt and watt/kg body weight) 
x Average work rate during each interval during each training session (watt and watt/kg 
body weight) 
x Time spent at 0-50%, 50-65%, 65-75%, 75-90%, >90% of maximal work rate during 
each training session (min:sec) 
x Average heart rate (HR) during each training session (bpm) 
x Time spent at 0-50%, 50-60%, 60-70% , 70-80 % and >80 % of maximal HR during each 
training session (min:sec) 
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4. To evaluate changes in physiological parameters and perception of exertion and 
capacity in subjects switching to IQOS (with and without training), continuing to smoke 
cigarettes (with training) and being smoking abstinent (with training) 
Endpoints (V3, V43) 
x Blood composition: Hemoglobin mass (g), red blood cell volume (mL), plasma volume 
(mL) and total blood volume (ml) as determined by CO re-breathing method  
x Capillary blood lactate levels during VO2max test (mmol/L) 
x Perceived rate of exertion during VO2max test (Borg Rating of Perceived Exertion (RPE)  
scale)  
 
Endpoints (V3, V4 and  V43) 
x Respiratory parameters at VO2max: Ventilation (L/min), respiratory rate, VCO2 (L/min), 
Respiratory exchange ratio (RER) (VCO2 / VO2)  
x Rating of Perceived Capacity (RPC) scale 
x Heart rate (bpm) and oxygen uptake (mL/min) during VO2max test 
 
5. To monitor trends of daily physical activity levels during the study in subjects 
switching to IQOS (with and without training), continuing to smoke cigarettes (with 
training) and being smoking abstinent  (with training) 
Endpoints (from V2 until V43) 
Aggregated data derived from the mobile health (mHealth) wearable for:  
 Cumulative number of steps per day 
 Sedentary minutes per day and % of time sedentary 
 Active minutes per day and % of time active 
 Very active minutes per day and % of time very active 
 
6. To explore trends and changes in activity and sleep parameters through continuous 
measurements during the study* 
Endpoints (from V2 until V43) 
mHealth wearable measurements of steps, activity, distance, energy expenditure, sleep* 
Reporting of data for this objective will be subject to a separate report(s) (not part of the 
Clinical Study Report [CSR]). 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
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without the written consent of Philip Morris Products S.A 
 
7. To describe changes in biological health markers in subjects switching to IQOS (with 
and without training), continuing to smoke cigarettes (with training) and being smoking 
abstinent (with training) 
Endpoints (V3, V14, V28 and V43) 
x High density lipoprotein (HDL), low density lipoprotein (LDL) and very low density 
lipoprotein (VLDL) (mg/dL) 
x High sensitivity C-reactive protein (hs-CRP) (mg/L) 
x Growth hormone  (GH) (ng/mL) 
x Hemoglobin A1C (HbA1c) (%) 
x Resting blood pressure (mmHg) 
x Resting HR (bpm) 
 
8. To describe changes in weight, body fat and waist cirumference in subjects switching 
to IQOS (with and without training), continuing to smoke cigarettes (with training) and 
being smoking abstinent (with training) 
Endpoints (V3, V4 and V43) 
x Body fat percentage (%) 
x Waist circumference (cm) 
Endpoints (V3- V43) 
x Body weight (kg) 
 
9. To monitor levels of exposure to CO, nitrosamines and acrylonitrile in subjects 
switching to IQOS (with and without training), continuing to smoke cigarettes (with 
training) and being smoking abstinent (with training) 
Endpoints  
At all visits:  
x Exhaled carbon monoxide (CO) (ppm)  
 
At V3, V4, V14, V28 and V43 
x COHb% in blood (%) 
x Nicotine equivalents (NEQ) in urine (adjusted for creatinine) 
x Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in urine (adjusted for 
creatinine) 
x 2-cyanoethylmercapturic acid (CEMA) in urine (adjusted for creatinine) 
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hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
 
10. To describe the self-reported nicotine and tobacco containing product use over the 
duration of the study 
Endpoints (measured daily from V2 to V43) 
x Self-reported number of any nicotine/tobacco product use on a daily basis as reported in 
the product use diary 
x Product use exposure 
 
11. To monitor safety during the study 
Endpoints 
x Incidence of adverse events (AEs), serious adverse events (SAEs) 
x Frequency of AEs, SAEs 
x Incidence of IQOS device events including malfunction/misuse   
x Frequency of IQOS device events including malfunction/misuse 
x Vital signs changes from baseline (systolic and diastolic blood pressure, pulse rate and 
respiratory rate) 
x Physical examination changes from baseline 
x Electrocardiogram (ECG) changes from baseline (heart rate, PR, QRS, QT, QTcB, QTcF 
intervals)  
x Spirometry changes from screening visit (V1) used as  baseline (FEV1, FEV1 % 
predicted, FVC, FVC % predicted, and FEV1/FVC) 
x Cough assessment changes from baseline (VAS and three Likert scales) 
x Changes from baseline in clinical chemistry, hematology, and urine analysis safety panel 
x Concomitant medications 
 
12. To assess perception of health and functioning in subjects switching to IQOS, 
continuing to smoke cigarettes and being smoking abstinent ** 
Endpoints (first interview between V2 and V3, second interview between V42 and V43) 
x Changes in subjects’ perception of health and functioning as determined by  qualitative 
interviews based on the World Health Organization’s International Classification of 
Functioning, Disability, and Health  
** This objective will be assessed as a sub-study with a separate section of the Informed 
Consent Form (ICF), and the reporting will be subject of an appendix to the main CSR. 
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4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan 
This is a randomized, controlled, open-label, 4-arm parallel group study with stratification by 
daily cigarette consumption over the last 12 months prior to V1 as reported during V1 (i.e., 10 
to 19 cigarettes or >19 cigarettes per day) and sex (Figure 2). 
A sufficient number of healthy adult smokers will be screened and enrolled after checking that 
all eligibility criteria have been met, in order to reach 90 randomized subjects.  
Smokers will be randomized as follows with a 5:5:5:3 ratio according to strata:  
1. switch to IQOS use + participation in training program: IQOS-1 arm, 25 subjects 
2. continue cigarette smoking + participation in training program: Cigarette arm, 25 
subjects 
3. smoking abstinence + participation in training program:  SA arm, 25 subjects 
4. switch to IQOS use only: IQOS-2 arm, 15 subjects 
  
When 90 randomized subjects are reached, further enrollment will be stopped. Subjects already 
enrolled in the study will still be eligible for randomization. From randomization, subjects will 
be instructed to use their allocated product or stay smoking abstinent until the end of the study. 
Drop-outs will not be replaced. 
 
 
Figure 2 
Study Design 
 
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Subjects will have serial visits at the investigational site as follows: 
Screening, V1 (within 28 days prior to V2): No study-specific procedures will be performed 
before informed consent is obtained and the ICF has been signed. The subject will also be 
invited to participate in a sub-study on perception of health and functioning and will sign a 
separate optional section of the ICF for this part of the study. Subjects will be invited to sign a 
separate optional consent form for collection of samples for biobanking. 
All inclusion and exclusion criteria will be assessed. A demonstration of IQOS and the mHealth 
wearable will be done by the site staff during the screening visit. A VO2max test will be 
performed as part of eligibility assessments. All eligible subjects will be invited to come to V2.  
Enrollment and Familiarization 1, V2 (7±1 days prior to V3): Enrollment will take place after 
confirmation of smoking status (urine cotinine and exhaled CO) and negative urine pregnancy 
test, alcohol breath test and urine drug screen. After enrollment, vital signs will be assessed 
and subjects will perform an exercise capacity test for the purpose of familiarization. The 
exercise test consists of completing a pre-defined work (calories) on a bike ergometer (1). 
Before leaving the investigational site the subject will receive an mHealth wearable kit and 
will be trained on how to handle the device. Subjects will be instructed to wear the device all 
the time. Subjects will also receive a diary to record the daily use of tobacco and nicotine 
containing products. 
 
Between V2 and V3, subjects having signed the optional section of the ICF will have an 
interview (by phone or computer) on the topic of health and functioning lasting around 60 
minutes. 
 
Baseline and Randomization, V3: Baseline assessments will be performed as listed in 
Appendix 1. Then, 30-60 min before start of the VO2max test all subjects will smoke a cigarette 
(only if they are willing to). During the VO2max test at rest and at each 25 W increase, the 
subject’s lactate levels will be determined by capillary blood sampling and the rate of perceived 
exertion will be assessed using the Borg RPE scale. After completing the VO2max test, the 
subject will rest for 60±5min, after which the exercise capacity test will be performed. After 
completing exercise tests, total blood volume will be determined. 
Subjects will thereafter be randomized into one of the 4 arms. Subjects randomized into IQOS 
arms will receive their IQOS starter kit and be trained on how to use the device. Subjects 
randomized into the SA arm will receive smoking abstinence support and will be allowed to 
use NRT upon request. 
Acute effect 1, V4 (7±2 days after V3): Before the VO2 max test, vital signs, exhaled CO, 
weight, body-fat and waist circumference measurements will be performed. 30-60 min before 
start of the VO2max test subjects in cigarette and IQOS arms will smoke a cigarette or use a 
HeatStick, respectively (only if they are willing to). Subjects’ VO2max, maximal heart rate and 
maximal work rate will be determined. After completing the VO2max test, the subject will rest 
for 60±5min after which the exercise capacity test will be performed.  
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Training program, from V5 (15±2 days after V3) until V42 (99±2 days after V3): Subjects 
randomized into IQOS-1, cigarette and SA arms will participate in 38 supervised training 
sessions during a 12-week period using three different training protocols (Appendix 2).  
 
Subjects randomized to the IQOS-2 arm will come for visits once a week for all assessments 
except the training. Subjects in the IQOS-2 arm will consequently only attend the following 
visits: V5, V7, V9, V14, V16, V19, V23, V28, V30, V33, V35 and V39. 
 
At V14 and V28 (medical visits), safety and biological health marker and exposure marker 
assessments will be performed for all subjects. 
Before each training, the following assessments will be conducted; 
x Weight 
x Exhaled CO  
x 30-60 min before start of the training subjects in cigarette and IQOS arms will smoke 
a cigarette or use a HeatStick, respectively (only if they are willing to).  
All trainings will be performed on a bike ergometer. The training intensity will be adjusted 
according to the subject’s resting heart rate as determined by ECG at V3 and maximal heart 
rate as determined at the VO2max test at V4 (acute test). The work produced, the work rate and 
heart rate will be recorded for each training (as described in Objective 3). 
Between V42 and V43, subjects having signed the optional section of the ICF will have an 
interview (by phone or computer) on the topic of health and functioning lasting around 60 
minutes. 
Training effect, V43 (106±2 days after V3):  
Before the VO2max test, biological health markers, exposure markers, vital signs, exhaled CO, 
weight, body-fat percentage and waist circumference measurements will be performed. Then, 
30-60 min before start of the VO2max test subjects in cigarette and IQOS arms will smoke a 
cigarette or use a HeatStick, respectively (only if they are willing to). Subjects’ VO2max will 
be determined as described for V3, including determination of lactate levels and perceived 
exertion rate. After completing the VO2max test, the subject will rest for 60±5min, after which 
the exercise capacity test will be performed. After completing exercise tests, total blood 
volume will be determined. 
Subjects will return the mHealth wearable, the product use diary and the IQOS device (if 
applicable). 
Discharge, V44 (107±2 days after V3): Safety assessments will be conducted as listed in 
Appendix 1.  
Safety follow-up period (from discharge at V44 or early termination plus 28 days): 
After discharge on V44 or after early termination, subjects will enter a 28-day safety follow-up 
period during which AE/SAEs spontaneously reported by the subjects will be collected. Any 
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non-serious AE that is ongoing at the time of discharge or early discontinuation will be 
followed-up by the Investigator or designee during the safety follow-up period until it has been 
resolved, stabilized (i.e., no worsening of the condition), or an acceptable explanation has been 
found (e.g., a chronic condition) or lost to follow up. The follow-up of the ongoing non-serious 
AEs will be done via a phone call performed until the end of the Safety follow-up period.  At 
the end of the safety follow-up period, all ongoing non-serious AEs will be documented as 
“ongoing” and no further follow-up information will be sought for them by the Investigator or 
designee. At that point, the Investigator will assess whether the subject should be referred to 
his/her General Practitioner to have their ongoing AEs addressed accordingly. SAEs will be 
followed up by the Investigator until resolution, stabilization or the determination of a plausible 
explanation for them was found, regardless of the end of the safety follow-up period. All 
subjects discontinued from the study at any time after enrollment, will enter the 28-day safety 
follow-up period. 
4.2 
Rationale for Study Design  
PMI is now launching a series of new clinical studies to better understand the additional 
benefits the reduced exposure of IQOS can offer to its consumers. Because of the recognized 
adverse effects of smoking on exercise capacity, this exploratory study is part of the program. 
The overall objective of the IQOS design is to provide an acceptable alternative to cigarettes 
for current, adult smokers, with substantial reduction of exposure to HPHCs by its aerosol 
compared to cigarette smoke. 
Based on the well-known role of hemoglobin in blood oxygen transport and the formation of 
COHb upon CO exposure, it is assumed that when cigarette smokers switch to a smoke- and 
CO-free product, such as IQOS, their exercise capacity and response to exercise training will 
increase as a consequence of normalization of COHb levels and increased blood oxygenation.  
In order to explore this assumption, and to further assess the role of CO, smokers will be 
randomized to switching to IQOS use (IQOS-1, IQOS-2), continuing cigarette smoking and 
smoking abstinence (SA). In a previous study an effect on VO2max already after 8h of smoking 
abstinence has been reported (9). In this study the acute effect of switching to IQOS will be 
assessed one week after randomization. In order to assess the impact on the response to exercise 
training, all subjects besides the IQOS-2 arm, will participate in a 12-week exercise training 
program. Whereas a reduced CO exposure in the SA-arm and the IQOS-1 arm is thought to 
favorably impact response to training, continued exposure to CO in the cigarette arm would 
reduce the training effect in sedentary healthy smokers.  
The training program designed for this study is based on previous studies demonstrating that 
in order to achieve improvements in cardiorespiratory fitness the optimal training frequency 
consists of at least 3 training sessions at a moderate intensity (~65% of maximal workload) per 
week (43). A bike exercise is recommended as compared to running due to the lower risk of 
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injuries (42, 44.) The IQOS-2 arm will allow to assess the impact on simply switching to a 
smoke-free product on VO2max and exercise capacity.  
This study is designed as an ad libitum study without product use restriction in order to mimic 
as closely as possible “real life” conditions. Subjects randomized to the cigarette  and IQOS 
arms will be asked to buy their own cigarettes or HeatSticks respectively, according to their 
needs for the study, in order to minimize any changes in their smoking behavior. Subject 
randomized to the SA arm will be instructed to stay smoking abstinent until the end of the 
study. Subjects in the SA arm will receive smoking abstinence support and, in order to prevent 
relapse to cigarette smoking (i.e. CO exposure) during the intense training program, subjects 
will be allowed to use nicotine replacement therapy. Other drugs to aid smoking abstinence 
have been approved in Germany (e.g., bupropion and varenicline). However, since information 
on their effect on the study endpoints is sparse, their use will not be allowed in this study. 
Similarly to smoking cessation (45), there is evidence that physical activity and exercise 
training have a favorable impact on biological health markers, such as markers for 
inflammation (46), lipid metabolism (47, 48) and blood glucose regulation (49). In this study 
the impact of switching to IQOS, alone or in combination with participation in an exercise 
training program, on a selected number of health markers will be assessed. It is expected that 
IQOS effects will be close to the ones observed in the SA arm. 
Mobile health technology will be used in the study to explore the impact on switching from 
smoking to using IQOS on physical activity in daily real-world living conditions. The wearable 
will enable non-invasive recording of physical activity in an objective manner throughout the 
study.   
4.3 
Appropriateness of Measurements 
The VO2max test is the only direct test to determine maximal oxygen uptake in humans and is 
considered to be the metric that defines the limits of the cardiopulmonary system (50). To 
assess exercise performance in this study, a laboratory-based exercise capacity test will be 
performed which includes the advantages of the controlled settings provided in a laboratory. 
The combination of these two tests provide a complete evaluation of exercise capacity. The 
determination of blood lactate levels during incremental exercise (51) and blood volume before 
and after the exercise interventions (52) provides an additional measure of exercise capacity 
but which is independent of subject motivation.    
All laboratory-based exercise tests will be conducted on a bike ergometer and not on a treadmill 
since 1) all exercise training sessions will be performed on bike ergometers 2) workloads can 
be determined more accurately, 3) the test procedure itself is easier as subject movement is 
smaller and 4) it may be difficult for especially untrained individuals to coordinate their limbs 
during fast maximal treadmill running which can lead to false low values. 
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In addition to self-reporting of product use, to assess exposure to CO, nicotine, tobacco-
specific nitrosamines and acrylonitrile (a tobacco combustion constituent), exhaled CO and 
COHb levels, and NEQ, NNAL and CEMA concentrations in urine will be measured 
throughout the study. 
4.4 
Study Duration 
The study duration per subject will be between approximately 20-25 weeks depending on 
length of visit windows. The study consists of  a 1-28-day screening period (V1), a 1-day 
familarization visit (V2), up to 7±1 days interval between V2 and V3, followed by a 1-day 
baseline and randomization visit (V3). A 1-day acute effect test visit (V4) will be scheduled 
7±2 days after V3, followed by a 12-week training program with training sessions 2-4 times 
per week (V5-V42) starting 15±2 days after V3 until 99±2 days after V3. A 1-day training 
effect test visit (V43) will be scheduled up to 7±2 days after V42 (106 ±2 days after V3), 
followed by a discharge visit (V44) up to 1±2 days after V43 (107 ±2 days after V3), and 
followed by a 28-day safety follow-up period. The end of the study for an individual subjects 
will be defined as V44 or the date of early termination plus the 28 days for the safety follow-
up period. The end of the entire study is the latest date that an individual subject reaches the 
end of the study. 
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5 
STUDY POPULATION 
5.1 
Selection of Study Population 
5.1.1 
Inclusion Criteria 
Subjects who meet all the following inclusion criteria can be enrolled into the study: 
Inclusion Criteria 
Rationale 
Screening  Enrollment 
V2 
1. Subject has signed the ICF. 
Administrative 
x 
 
2. Smoking, healthy subject based on safety 
laboratory, ECG, spirometry, vital signs, physical 
examination, medical history and Investigator’s 
assessment. 
Safety 
x 
 
3. Subject has been smoking for at least three years 
prior to V1. 
Effect 
x 
 
4. Subject has been smoking ≥ 10 cigarettes per 
day over the last 12 months. Smoking status will 
be verified by a urinary cotinine ≥ 200 ng/mL and 
CO exhaled breath test > 6 ppm both at V1 and 
V2. 
Effect 
x 
x 
5. Subject does not plan to quit smoking within 6 
months after V1. 
Safety 
x 
 
6. Subject is aged between 21 and 65 years 
(inclusive). 
Safety 
x 
 
7. Subject is available for the entire study period 
and willing to comply with study procedures. 
Effect 
x 
 
5.1.2 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria must not be enrolled into the 
study: 
Exclusion Criteria 
Rationale 
Screening  
Enrollment 
V2 
1. Subject has a clinically relevant disease 
which requires medication (including but not 
limited to gastrointestinal, renal, hepatic, 
Safety 
x 
 
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Exclusion Criteria 
Rationale 
Screening  
Enrollment 
V2 
neurological, hematological, endocrine, 
oncological, urological, immunological, 
pulmonary [such as but not limited to 
pulmonary oedema, asthma], and 
cardiovascular [such as, but not limited to 
myocardial infarction, unstable angina, 
uncontrolled arrhythmias, heart failure],  
disease) or any other clinically significant 
medical condition (including abnormal safety 
laboratory result as per CTCAE), which as 
per the judgment of the Investigator would 
jeopardize the safety of the subject.  
2. Subject who has forced expiratory volume in 1 
second/forced vital capacity (FEV1/FVC) <0.7 
and FEV1 <80% predicted value at post-
bronchodilator spirometry (GOLD, 2017).  
Safety 
x 
 
3. Subject with asthma condition (FEV1/FVC < 
0.75 and reversibility in FEV1 (in both > 12% 
and > 200 mL) from pre to post-bronchodilator 
values. 
Safety 
x 
 
4. Subject has clinical significant abnormalities of 
ECG at V1. 
Safety 
x 
 
5. Subject performs more than 45 min of 
vigorous physical activity per week. 
Effect 
x 
 
6. Inability to perform a VO2max test at V1. 
Safety 
x 
 
7. VO2max >50 mL.min-1kg-1 for men and 
VO2max >40 mL.min-1kg-1 for women as 
determined at V1. 
Effect 
x 
 
8. Subject takes medication influencing blood 
volume such as erythropoietin, diuretics and 
beta blockers, or diabetic medications. 
Effect 
x 
 
9. Subject cannot participate in the study for any 
reason other than medical as per the 
Investigator’s judgment (e.g. psychological 
and/or social reason) 
Administrative 
x 
 
10. For women only: subject is pregnant (does not 
have negative pregnancy tests at V1 and at 
V2) or is breastfeeding.  
Safety 
x 
x 
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Exclusion Criteria 
Rationale 
Screening  
Enrollment 
V2 
11. For women of childbearing potential2: female 
subject who does not agree to using an 
acceptable method of effective contraception 3 
during the entire study. 
Safety 
x 
 
12. Subject has a BMI < 18.5 kg/m2 or BMI ≥ 30 
kg/m2. 
Safety 
x 
 
13. Subject has positive serology test for HIV, 
Hepatitis B or Hepatitis C. 
Safety 
x 
 
14. Subject has a positive alcohol breath test 
and/or a history of alcohol use disorder (both 
V1 and V2). 
Administrative 
x 
x 
15. Subject has a positive urine drug screen. 
Administrative 
x 
x 
16. The subject has been previously screened for 
this study. 
Administrative 
x 
 
17. The subject, or one of their family members 
(e.g., spouse, parent, sibling or child), is a 
current or former employee of the tobacco 
industry. 
Administrative 
x 
 
18. The subject, or one of their family members 
(e.g. spouse, parent, sibling or child), is an 
employee of the investigational site or any 
other parties involved in the study. 
Administrative 
x 
 
19. Subject is legally incompetent, or physically or 
mentally incapable of giving consent (e.g., 
emergency situation, under guardianship, 
prisoners, or subjects who are involuntarily 
incarcerated). 
Administrative 
x 
 
                                                 
2 Women who are not of childbearing potential meet at least one of the following criteria:  Have undergone 
hysterectomy or bilateral tubal ligation,  Have medically confirmed ovarian failure, or  Are medically confirmed 
to be post-menopausal (cessation of regular menses for at least 12 consecutive months with no alternative 
pathological or physiological cause). 
3 Intrauterine device, intrauterine system, barrier methods of contraception (condoms, occlusive caps) with 
spermicidal foam/gel/film/suppository, hormonal contraception containing progesterone only, vasectomized 
partner(s), from screening until the end of the safety follow-up period. 
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Exclusion Criteria 
Rationale 
Screening  
Enrollment 
V2 
20. Subject has donated or received whole blood 
or blood products within 3 months prior to V1. 
Safety/ Effect 
x 
 
 
5.2 
Discontinuation of Subjects from the Study 
Discontinued subjects will include both, subjects who withdraw from the study (subject’s 
decision) and subjects who are discontinued from the study by the decision of the Investigator. 
A subject can only be discontinued from the study after enrollment. 
Subjects will be informed that they are free to withdraw from the study at any time. Subjects 
should be questioned for the reason of withdrawal from the study, although they are not obliged 
to disclose it.  
If the subject withdraws from the study, he/she will be asked to perform the early termination 
procedures (Section 9.6) as soon as possible after the time of withdrawal unless the subjects 
refuses to do it in writing.  
If a subject expressed his/her wish to quit the study during a visit planned for clinical 
assessments, he/she will be asked whether he/she would agree to still do the clinical 
assessments planned for this visit, but with no obligation.  
After the time of study termination, independent of the reason of discontinuation (for example, 
withdrawal of consent, or at the Investigator’s decision etc.), the subject will enter into the 28-
day period of safety follow-up.  
 
Discontinuation from the study  
Subjects  must be discontinued from the study for any of the following reasons:  
 
1. Withdrawal of informed consent.  
2. Discontinuation is considered to be in the interest of the subjects from a safety 
perspective as judged by the Investigator.  
3. Positive or unclear pregnancy test.  
4. The Sponsor or Investigator terminates the study or the study terminates at the 
investigational site. If the Sponsor or the Investigator decides to prematurely terminate 
the study, the subject will be promptly informed. The Investigator should report the fact 
and the reason in writing to the IEC.  
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5. Subjects becomes an employee of the investigational site or any other parties involved in 
the study.  
6. Lost to follow-up.  
 
7. Violation of eligibility criteria after enrolment (i.e. if an eligibility criteria violation is 
retrospectively discovered after enrolment during the course of a study). 
 
Subjects may be discontinued from the study for the following reasons:  
 
1. Non-compliance with the study procedures based on the judgment of the Investigator.  
 
For subjects who are discontinued, the reason for discontinuation should be documented in the 
source documents and in the CRF and subjects will undertake early termination procedures 
(Section 9.6). 
IQOS and cigarette arms: 
The switch to different variants of HeatSticks as well as the use of other tobacco- or nicotine-
containing products will not lead to discontinuation. 
SA arm: 
The use of any tobacco- or nicotine-containing products will not lead to discontinuation. 
5.3 
Lost to Follow-up 
The date of the last contact with the subject (e.g., last visit, last phone call) should be recorded 
in the source document. 
After the last contact, reasonable number of attempts to contact the subject (including written 
correspondence and phone calls) should be done and documented in the source documents by 
the site. Following the contact attempts, if the Investigator(s) or designee(s) decides to 
discontinue the subject with the reason of lost to follow-up, the discontinuation date will be 
recorded. The discontinuation date for the subjects will be the date the subject was determined 
to be lost to follow-up and will correspond to the date of the EOS of the subject. 
If the site has lost track of the subject, the discontinuation date cannot exceed the maximum 
number of study weeks (i.e. 25), then the Investigator(s) or designee(s) will discontinue the 
subject with reason as lost to follow-up. 
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5.4 
Violation of Selection Criteria 
Subjects who violate the entry criteria prior to enrollment will be considered as screening 
failures. Re-screening of these subjects will not be permitted. 
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6 
INVESTIGATIONAL PRODUCTS/ REFERENCE ARM 
6.1 
Description of Investigational Products 
6.1.1 
Test Product  
The product tested in this study is the Tobacco Heating System with Heatsticks, marketed in 
Germany under the brand name IQOS and referred to as IQOS in this protocol. All versions of 
IQOS and Heatsticks available for sale in Germany at the time of study start or becoming 
available during the course of the study are allowed to be used in the context of this study. The 
IQOS is composed of the following components: a tobacco HeatStick, a Holder and a Charger 
(Table 1), as well as a cleaning tool, a power supply, and a USB cable. The product user guide 
will be provided as part of the IQOS starter kit. 
 The product is provided to study subjects free of charge in the framework of the study due to 
the short time between the randomization and the distribution of the device (same visit) which 
does not allow subjects to purchase the device on-line and have it delivered on time (there is 
no physical shop in the study area). The distribution of the device by the study staff will also 
allow the subjects to benefit from the on-site guided trial to understand how to use the device 
properly. Subjects will then buy their preferred variant of Heatsticks by themselves. 
 
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Table 1 
Test Product (IQOS) 
HeatStick: 
The HeatStick is designed to function with the Holder. The HeatStick is 
made up of: tobacco plug, hollow acetate tube, polymer-film filter, mouth 
piece filter, outer and mouth-end papers. 
All materials have been evaluated with regards to their toxicological 
potential and have been approved for use. 
The tobacco plug is made from tobacco, glycerin, water, guar gum, 
cellulose, propylene glycol, natural and artificial flavorings. 
The average amount of nicotine in the tobacco plug is 4.3-5.4 mg/stick per 
HeatStick. 
Holder: 
The Holder is a slim electrical heating unit that heats the HeatStick in a 
controlled manner by using a heater blade. 
The Holder stores enough energy for a single experience, delivering puffs 
over a period of about 6 minutes or 14 puffs (whichever comes first). A 
Light Emitting Diode indicates the end of the experience. 
Once this cycle is complete, the Holder must be recharged before a new 
HeatStick can be used. 
Charger: 
The power supply for the Holder is the Charger. 
The Charger holds enough energy for approximately 20 uses of the Holder 
and can be recharged from household power. 
The Charger stores the Holder when not in use, and provides a secure 
environment for the cleaning process of the heater blade. 
 
The overall objective of the product design is to provide an acceptable experience in which the 
HPHCs levels in the aerosol are substantially reduced in comparison with the smoke of a 
cigarette (19, 53). A summary of description of the product, pre-clinical and clinical data 
available on IQOS is provided in the SPI (41). 
6.1.2 
Comparator and Baseline Product 
Cigarette (comparator product): subjects’s own preferred brand of commercially available 
cigarettes.  
6.2 
Packaging and Labeling 
An IQOS starter kit (i.e., IQOS device and a selection of HeatSticks variants available on the 
German market) will be supplied to the site by the Sponsor or authorized representative in 
packages that protect against deterioration during transport and storage.  
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The Sponsor or authorized representative will label the IQOS starter kit in local language 
ensuring adherence to local regulatory requirements. This will include at least the following 
information: 
x 
Statement ‘For investigational use only’ 
x 
Name and address of the Sponsor (if the Sponsor resides outside Germany, name of 
the Sponsor and name of the country where the Sponsor is located, and name and 
address of the clinical trial in-country representative) 
x 
IQOS device serial number. 
6.3 
Use of Investigational Product(s) 
The study is designed as an ad libitum use study. The subjects will be allowed to use their 
allocated products (cigarette or IQOS) according to their need. There will be no restrictions on 
the variants of HeatSticks used.  
6.3.1 From Enrollment to Randomization  
From screening visit (V1) to randomization (V3), all subjects will be allowed to continue 
smoking ad libitum their preferred usual brand of cigarettes. 30-60 min before start of baseline 
VO2 max at V3, subjects will smoke a cigarette. However, subjects will never be forced to 
smoke, and will only smoke if they are willing to.  
At randomization, subjects allocated to the IQOS arm, since they will not be able to purchse 
the device on time to start the trial (there is no physical store in the study area),  will be supplied 
with an IQOS starter kit (i.e., IQOS device and a selection of HeatStick variants available on 
the German market). Subjects will benefit from a guided trial to understand how to properly 
use the device and will have to return it at the end of the trial. Subjects will have to purchase 
their own HeatSticks for use during the study (available throughout the country).  
6.3.2 Investigational Period 
6.3.2.1 
IQOS arms  
IQOS arm: subjects randomized into IQOS-1 and IQOS-2 arms will be instructed to use 
exclusively IQOS ad libitum. The switch to different variants of HeatSticks as well as the use 
of other tobacco- or nicotine-containing products will not lead to discontinuation (see Section 
5.2). 30-60 min before start of VO2 max at V4, and V43 and 30-60 min before start of each 
training V5-V42, subjects will use a HeatStick. However, subjects will never be forced to use 
IQOS, and will only use a HeatStick if they are willing to.   
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6.3.2.2 
Cigarette arm 
Cigarette arm: subjects randomized to the cigarette arm will be instructed to continue smoking 
their cigarettes ad libitum. The switch to different cigarette brands and the use of other tobacco- 
or nicotine-containing products will not lead to discontinuation (see Section 5.2). 30-60 min 
before start of VO2 max at V4 and V43 and before each training V5-V42,  subjects will smoke 
a cigarette.  However, subjects will never be forced to smoke, and will only smoke if they are 
willing to.  
6.3.2.3 
SA arm 
SA arm: As of randomization on V3 until V43, subjects in the SA arm will be instructed to 
abstain from smoking cigarettes or using any other tobacco- or nicotine-containing products. 
Use of NRT will be allowed as per subjects request and will be provided by the site. If NRT 
patches are used they should be removed before and during exercise tests and trainings. 
6.3.3 
Safety Follow-up Period  
During the safety follow-up period (i.e. as of V44 or prematurely discontinued), all subjects 
will be free to smoke their own cigarettes, or use  any other nicotine-containing product of 
their choice. 
6.3.4 
Stopping rules for Investigational Product 
For safety purposes, use of the IP should be temporarily reduced or stopped in the event of any 
signs suggesting nicotine overexposure, e.g., gastrointestinal disturbance (nausea, vomiting, 
diarrhea, stomach, or abdominal pain), cold sweats, headache, dizziness, and breathing 
problems or any reasons at the discretion of the Investigator. 
6.4 
Method for Assigning Subjects to Study Arms 
Randomization will be done through the Interactive Web and Voice Response System (IXRS) 
at any time during the visit. Subjects will be informed about their study arm allocation at the 
end of V3. Subjects will be randomized in one of the four study arms: 
x Cigarette arm with training program  
x IQOS-1 arm with training program 
x SA arm with training program  
x IQOS-2 arm without training  
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in a 5:5:5:3 ratio using a stratified randomization based on daily cigarette consumption over 
the 12 months prior to V1 (10-19 cigarettes/day vs. >19 cigarettes/day), and sex. All subjects 
will be instructed to adhere to their assigned product/regimen until they complete the study. 
6.5 
Blinding 
6.5.1 
Blinding of site staff  
This is an open-label study and the site staff performing study assessments will therefore not 
be blinded by the smoking status. 
6.5.2 
Blinding of data 
There will be additional, even though limited, degree of blinding during the conduct of the 
study, including the data review and data analysis process. In particular, PMI and contract 
research organization (CRO) personnel will be blinded as summarized in Table 2  
Table 2 Blinding 
Blinded Study Personnel 
Blinded data 
End of Blinding Period 
PMI and CRO Study 
Statisticians 
VO2max and exercise 
capacity test results after 
randomization 
After database lock.  
PMI Clinical Scientist 
VO2max and exercise 
capacity test results after 
randomization 
After the finalization of PMI blind 
database review. Can be actively 
un-blinded when appropriate. 
Any PMI and CRO personnel who are not listed in Table 2 will be unblinded by default.  
Unblinded information will not be shared with the blinded study team, until the end of the 
blinding period. PMI will receive blinded and unblinded data for the pre-analysis data review 
as planned in the data review plan. Unblinded data will only be reviewed by the unblinded 
study team. 
6.6 
Investigational Product Accountability and Adherence 
6.6.1 
Dispensing Investigational Product 
Due to the lack of availability of the device in physical stores in the study area subjects 
allocated to the IQOS arms will be supplied with an IQOS starter kit (IQOS device and a 
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selection of HeatStick variants available on the German market) at V3 after randomization. 
Subjects randomized to the IQOS arms will purchase their HeatSticks variants, as it will not 
be provided by the Sponsor. 
In case the device needs replacement due to a device malfunction or in case of loss/theft of the 
device, the subjects will need to contact the site. In case a subject decides to purchase their 
own device, these will not be replaced by the site. Subjects allocated to the cigarette arm will 
buy cigarettes for their own use for the entire duration of the study. 
6.6.2 
Storage and Accountability  
The Investigator or a designated study collaborator will be responsible for the storage and 
accountability of the IQOS devices and HeatSticks to be distributed only once at V3, together 
with the device. The IQOS devices (charger and holder) as well as HeatSticks (to be distributed 
only once at V3, together with the device) will be stored in a secured storage site with access 
limited to authorized personnel only.  
A sufficient number of IQOS starter kit will be stored at site, to be delivered to subjects 
allocated to the two IQOS arms only. A few additional devices will be stored in case a subject 
needs to have his/her IQOS device replaced. Full accountability of the distributed IQOS starter 
kit and replacement devices, if any, will be ensured by the designated study collaborator and 
recorded in IP accountability logs. This includes but is not limited to the record of the device 
serial number, HeatSticks batch number, the quantity of devices and HeatStick packs delivered 
per subject, date of delivery, total quantity available at site, the quantity of devices returned to 
the site at the end of the study. 
Except for the initial packs of HeatSticks delivered within the IQOS starter kit at V3, neither 
HeatSticks nor cigarettes will be stored at site during the study as they will be bought by the 
subjects throughout the study.  
6.6.3 
Investigational Product Retention 
The subjects will return the IQOS device (Charger and Holder), including replacement devices 
to the study site at V43 or upon early discontinuation. The study site will return to the Sponsor 
or authorized representative the IQOS device (Charger and Holder) upon study completion. 
This does not apply to devices purchased by the subjects. 
6.6.4 
Adherence to Investigational Products and Reference Arm 
Adherence to the allocated product or reference arm will be monitored using self-reported 
tobacco and nicotine containing product use as reported in the product use diary (Section 
7.11.8).  
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6.7 
Restrictions 
6.7.1 
Product Use Restrictions 
There will be no restriction on allocated product use. 
6.7.2 
Dietary Restrictions 
Subejcts will be asked not to consume any caffeine- or alcohol-containing products 12 h prior 
to VO2max and exercise capacity test.  
Before safety laboratory and biological health markers blood collections at V3, V14, V28, V43 
and V44 subjects will be required to fast for at least 8 h. 
6.8 
Concomitant Medication 
Medications will be allowed and carefully monitored during the study by the Investigator or 
designee. The Investigator or designee is responsible for the medical care including medication 
of the subjects during their participation in the study.  Any decisions regarding the prescription 
of medication will be taken in the best interest of the subject. The use of any concomitant 
medication must be fully documented in the source document and transcribed into the CRF. 
All medication taken within 4 weeks prior to the ICF signature will be considered prior 
medication. All medication taken from screening visit to end of the safety follow-up period 
will be considered concomitant medication. 
Records of medication taken include the drug name (preferably both generic and trade name), 
route of administration (e.g., oral, intravenous), total daily dose/unit (e.g., expressed in mg, 
mL or IU), indication, the start and if applicable, the stop date (day, month and year). Any 
therapy changes (including changes of regimen) during the study have to be documented.   
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7 
STUDY PROCEDURES 
Personnel performing or recording study measurements must have appropriate and fully 
documented training. Quality control (QC) measures must be defined, implemented and 
documented. All study procedures are provided as an overview in the schedule of events 
(Appendix 1).  
In this section, only the expected/planned time points for the various measurements are given. 
Considering that not all study participants can have a procedure at the same time point, 
adequate time windows are given for each study procedure and each time point in Section 9. 
Site personnel will adhere to the site’s standard operating procedures (SOPs) for all activities 
relevant to the quality of the study. Appropriate medical advice will be provided to the subjects 
in case of any medical findings requiring health care. 
7.1 
Informed Consent 
Prior to any study assessment being performed, the subjects will be asked to provide his/her 
written consent to participate to the study (ICF) (Section 1.3.). During the consent process, the 
Investigator or designee obtaining consent must inform each subject of the nature, risks and 
benefits of, and alternatives to study participation. In addition, each subject must review the 
ICF and must have sufficient time to understand and have adequate opportunity to ask 
questions. The ICF must be signed and dated (date and time) prior to undertaking any study 
specific procedures. A copy of the signed ICF must be given to the subject. 
Subjects will be invited to participate in an optional sub-study assessing health and functioning 
through qualitative interviews (Section 7.11.9) and will sign a separate section of the ICF if 
they wish to participate. 
In addition to the ICF for study participation, the subject will be asked to provide his/her 
separate optional consent for the collection and storage of samples for long-term biobanking. 
7.2 
Information on the Risk of Smoking and Smoking Cessation 
Advice and Debriefing on IQOS 
All subjects included in the study will be advised that the best way of preventing the 
development of smoking-related diseases is to stop smoking. Only subjects who are not 
planning to quit smoking cigarettes will be eligible for the study.  
From V1 onwards, information on the risks of smoking and smoking cessation advice will be 
given to all subjects (Appendix 1). This will take the form of a brief interview according to 
WHO recommendations (54). In addition, a debriefing of subjects will be done to address any 
intended or unintended beliefs participants have about IQOS. The goal of the debriefing is to 
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ensure that subjects have an accurate understanding of IQOS risks including an understanding 
that IQOS has not yet been demonstrated to be less harmful than cigarettes.  
Any enrolled subject, who is willing to attempt quitting during the study will be encouraged to 
do so and will be referred to appropriate medical services. 
7.3 
Questions on Smoking History/Habits and Plan to Quit 
Smoking.  
Subject will be questioned for their smoking history and self-reported current tobacco and 
nicotine containing product use over the past 12 months at V1. The subject will also be asked 
if he/she is planning to quit smoking within 6 months after V1. This information will be used 
to assess their eligibility for the study. 
7.4 
Demonstration of IQOS  
IQOS including HeatSticks will be presented to all subjects by the Investigator or designated 
study collaborator at V1.  
7.5 
Clinical Assessments 
7.5.1 
Demographic Data 
Demographic data (sex, date of birth, race) will be recorded at V1. 
7.5.2 
Medical History, Concomitant Disease, Previous and Ongoing Medications 
Relevant medical history and any concomitant disease will be documented at V1. Medical 
history is defined as any condition that started and ended prior to ICF signature. A concomitant 
disease is defined as any condition that started prior to ICF signature and is still ongoing at V1. 
The final status of any concomitant disease (i.e stop date or ongoing) should be verified at each 
visit.  
Prior medication taken within 4 weeks prior to screening and any ongoing medication at 
screening needs to be documented. Any medication which is started prior to screening and is 
still being taken by the subject at screening or thereafter will be considered as concomitant 
medication. Medication initiated after the screening visit will also be referred to as concomitant 
medication. This applies to both prescription and over-the-counter products. If the use of a 
concomitant medication cannot be avoided for the subject’s safety, it must be fully documented 
in the Source Document and CRF (see Section 6.8).  
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7.5.3 
Physical Examination 
A full physical examination will include review of general appearance, skin, head, eyes, ears, 
nose and throat, thyroid gland, chest, lungs, back, abdomen, dentition, cardiovascular, 
gastrointestinal, musculoskeletal and neurological systems. The physical examination is to be 
conducted by the Investigator or a designated fully trained representative. 
7.5.4 
Body Height, Weight and Body Mass Index (BMI) 
Body height and weight will be recorded and BMI will be calculated using the following 
formula: 
BMI =  
weight in kilograms 
————————  
(kg/m² ) 
height in meters² 
The BMI will be used to assess eligibility for enrollment at V1. 
The fat-free weight is defined as: 
Fat-free 
weight =   
Weight in kilograms * (100 – body 
fat percentage)/100 kg 
 
Weight will be recorded throughout the study (Appendix 1). 
7.5.5 
Vital Signs 
Systolic and diastolic blood pressure, pulse rate and respiratory rate will be recorded. All 
measurements will be made in supine position after the subject has rested for at least 5 minutes 
in a supine position. The subject should have abstained from smoking or using IQOS for at 
least 15 minutes prior to measurement. 
7.5.6 
Spirometry 
All personnel performing spirometry testing must have the appropriate training with the record 
of the training. Quality control measures should be available and be properly documented.  
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The spirometry test will be performed in accordance with the 2005 guideline of the American 
Thoracic Society (ATS)/European Respiratory Society (ERS) Joint Task Force on the 
standardization of spirometry (55).  
Pre and post- bronchodilator spirometry assessments will be performed. Each assessment 
requires at least three valid spirometry tests. The ratio of forced expiratory volume in one 
second (FEV1) / forced vital capacity (FVC) will be calculated from the highest acceptable 
FEV1 and the highest acceptable FVC, respectively.  
The results from FEV1 and the ratio FEV1 to FVC at V1 will be used for eligibility criteria to 
assess COPD and asthma conditions. All spirometry testing will be recorded in sitting position 
after resting for at least 15 minutes in sitting position. The subject should have abstained from 
smoking or using IQOS for at least 1 hour prior to testing. All post-bronchodilator spirometry 
testing will be performed 15-30 minutes post administration of around 400 μg of 
salbutamol/albuterol (usually equivalent to 4 puffs assuming 100 μg/puff). The time of 
salbutamol/albuterol inhalation and time of spirometry assessment will be recorded in the 
source document. 
7.5.7 
 Electrocardiogram 
ECG testing will be performed as per the site’s local practice. A standard 12-lead ECG will be 
recorded after the subject has rested for at least 10 minutes in a supine position. 
The following parameters will be documented: heart rate, PR interval, QRS interval, QT 
interval, and QT interval corrected according to Bazett’s formula and Fridericia’s formula. 
Every ECG has to be assessed as normal, abnormal – clinically not relevant, or abnormal – 
clinically relevant. A diagnosis has to be provided on the CRF for all ECGs assessed as 
abnormal – clinically relevant. All ECG print-outs will be interpreted by a qualified physician. 
Any print-outs of ECGs on thermo-sensitive paper must be photocopied. 
7.5.8 
Body-fat Percentage and Waist Circumference  
Body-fat percentage based on skinfold caliper measurements and waist circumference will be 
performed as per the site’s practice. Mesurements should be performed by the same trained 
site collaborator and using the same instrument.  
7.5.9 
Determination of Blood Composition and Volume 
Hemoglobin mass (Hbmass) will be quantified using an automated system (e.g. OpCO, Detalo 
Instruments, Denmark or similar). First, a venous blood sample will be drawn to measure 
hemoglobin, hematocrit and COHb, after which the CO re-breathing procedure will be 
performed. Using the system a precise volume of CO is inhaled and re-breathed by the subject 
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for 10 min. During the re-breathing period 100% O2 is administered to the subject on a demand 
basis, and  due to the small volume of CO administered and the continuous O2 supplementation 
arterial O2 is barely affected. After completion of the re-breathing procedure COHb will be 
measured again. Then based on the resulting increase in COHb, the mass of hemoglobin will 
be calculated. Red blood cell volume, plasma volume and blood volume will be derived from 
measures of Hbmass, [Hb] and hematocrit.  
7.6 
Exercise Testing and Training 
7.6.1 VO2max Test and Blood Lactate Levels 
Subjects will perform an incremental cycling test to volitional fatigue on an electronically 
braked cycle ergometer (such as Monark E839, Varberg, Sweden). To measure oxygen uptake 
and determine VO2max an online gas collection system (e.g. COSMED CPET) will be used 
where O2 and CO2 concentration in the expired gas are continuously measured and monitored 
as breath-by-breath values.  
Subjects will be asked to refrain from heavy exercise 24h prior to the test, and consuming 
caffeine or alcohol 12h prior to the test. Measurements will begin with the subjects resting for 
3 min seated on the bike ergometer whereafter the workload will be increased by 25W every 
60 sec until volitional fatigue. Subjects should keep cadence between 60 and 90 rpm during 
the test. Mean VO2max will be determined as the highest O2 value averaged over 30 s for each 
subject. At VO2max the following parameters will be recorded: ventilation (l/min) respiratory 
rate, VCO2 (l/min), respiratory exchange ratio (RER, [VCO2 / VO2]).  
In addition at V4, the maximal heart rate and the maximal work rate will be recorded in order 
to design the training program. 
At V3 and V43, capillary (fingertip or earlobe) blood samples will be obtained at rest and at 
each 25W workload increased and analysed for lactate (e.g. Radiometer ABL80 or similar). 
Blood collection should be started 40-45 seconds into the workload and no blood sample 
should be obtained at maximal effort. The final blood sample should be obtained within 5 
minutes after termination of the bike exercise. Heart rate and oxygen uptake (VO2) will be 
recorded at rest at each 25W increase. 
After the test subjects will rest for 60±5 min and will be offered water ad libitum and a light 
snack e.g. fruit, chocolate or bar. The snack has to be consumed at least 30 min before the 
upcoming exercise capacity test (not applicable for V1). 
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7.6.2 
Exercise Capacity Test 
Subjects will perform an exercise capacity test during which they will complete a given 
workload as quickly as possible. The criteria for completion of the test is the completing of a 
pre-defined relative work determined based on the highest wattage level reached at VO2max 
test times 1.25 (i.e. 200 W x 1.25 = 250; 250 kcal to be completed). The highest wattage 
reached at the VO2max test at V1 will be used for the test at V2, and at the VO2max test V3 
will be used for the tests at V3, V4 and V43. This relative workload determination is selected 
for the exercise capacity tests because it i.) controls for differences in baseline aerobic capacity 
across subjects, and ii.) standardizes the time of completion of all baseline tests at 
approximately 20 minutes. 
7.6.3 
Exercise Training 
Subjects randomized into the IQOS-1, cigarette and SA arms will participate in a 12-week 
training program consisting of 38 training sessions (V5-V42). All training sessions will be 
performed at the investigational site using stationary bikes, and will be supervised by 
designated site personnel.  
Different training programs will be circulated to provide the study participants with 
differentiated training inputs and make the training sessions less monotonous. Each training 
session will last 40 min with a training intensity ranging between 60-85%. The target exercise 
heart rates are based on the subject’s resting (HRrest; obtained  during ECG at V3) and maximal 
heart rate (HRmax)  obtained during the acute effect VO2max test at V4. The formula to be used 
for exercise heart rates is: Target exercise heart rate = ((HRmax – HRrest) * intensity) + HRrest 
with intensity as fraction of 1.   
7.7 
Biomarker Assessment 
7.7.1 
Exhaled Carbonmonoxide (CO) 
Carbon monoxide (CO) in exhaled breath will be measured using the a Smokerlyzer® device, 
such as the Micro 4 Smokerlyzer® or similar. At V1 and V2, a cut-off  of >6 ppm for 
confirming cigarette smoking status will be applied (56)(57). 
7.7.2 
Carboxyhemoglobin (COHb) 
Venous blood samples will be collected and COHb measured by a designated laboratory. 
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7.7.3 
Urine Biomarkers of Exposure 
Spot urine will be collected to measure concentrations of NEQ, NNAL, CEMA and creatinine. 
The urine collection should be performed as late as possible during the day. 
7.7.4 
Biological Health Markers in Blood 
Venous blood samples will be collected for measurement of HDL, LDL, VLDL, hs-CRP, GH 
and HbA1c (%). Blood samples will be taken after at least 8 hours of fasting (Section 6.7.2). 
7.8 
Laboratory Assessments 
7.8.1 
Clinical Chemistry, Hematology, and Urinalysis for Safety Panel 
Hematology, clinical chemistry, serology and urinalysis safety panel will be measured at local 
laboratory except for urine drug screening, urine cotinine screening,, alcohol breath test and 
urine pregnancy test, these tests will be performed at site 
Blood samples will be taken after at least 8 hours of fasting (Section 6.7.2) except at screening 
(V1) and early termination. Parameters to be measured are listed in Table 3. 
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Table 3 
Clinical Laboratory Parameters for Safety Panel 
Hematology 
Clinical Chemistry 
Urinalysis    
• 
Hematocrit 
• 
Hemoglobin 
• 
Mean corpuscular hemoglobin 
(MCH) 
• 
Mean corpuscular hemoglobin 
concentration (MCHC) 
• 
Mean corpuscular volume 
(MCV) 
• 
Platelet count 
• 
Red blood cell (RBC) count•
 
White blood cell (WBC) count 
• 
Differential WBC count: 
- 
Neutrophils 
- 
Basophils 
- 
Eosinophils 
- 
Lymphocytes 
- 
Monocytes 
 
• 
Albumin 
• 
Total protein 
• 
Alkaline phosphatase (AP) 
• 
Alanine aminotransferase (ALT) 
• 
Aspartate aminotransferase (AST) 
• 
Blood urea nitrogen (BUN) 
• 
Creatinine 
• 
Gamma-glutamyl transferase 
(GGT) 
• 
Glucose 
• 
Lactate dehydrogenase (LDH) 
• 
Potassium 
• 
Sodium 
• 
Total bilirubin 
• 
Direct bilirubin 
• 
Total cholesterol (TC) 
• 
Triglycerides (TG) 
• 
pH 
• 
Bilirubin 
• 
Glucose 
• 
Nitrite 
• 
Red blood cell 
traces 
• 
Protein 
• 
Specific gravity 
 
 
7.8.2 
Serology 
At V1, a test for hepatitis B (HbsAg), hepatitis C (HCV antibody), and human 
immunodeficiency virus (anti-HIV1/2) will be performed. In case of positive results, the 
subject will be referred to appropriate medical care. 
7.8.3 
Urine Drug Screening 
At V1 and V2, urine drug screen (amphetamines, barbiturates, benzodiazepines, cannabinoids, 
cocaine, opiates, methadone, methamphetamines, phencyclidine, tricyclic antidepressants) will 
be performed by the personnel at the investigational site. 
7.8.4 
Urine Cotinine Screening 
At V1 and V2, a urine dip-stick cotinine test with a threshold of ≥ 200 ng/mL will be performed 
at the investigational site to confirm subject’s smoking status. 
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7.8.5 Alcohol Breath Test 
At V1 and V2, a breath alcohol test will be performed at the investigational site using a 
breathalyzer device. 
7.8.6 
Urine Pregnancy Test 
A urine pregnancy test will be done at the investigational site for all female subjects at V1-V3 
V5, V14, V28 and V44.  
Subjects with a positive pregnancy test at V1 or at V2 will not be enrolled and will be 
considered screening failures. In any case of a positive urine pregnancy test, the Investigator 
will inform the subject about the risks associated with smoking during pregnancy. 
All pregnancies detected during the study must be reported and handled as described in Section 
8.5. Pregnancies detected after enrollment will lead to discontinuation from the study.  
 
7.9 
Sample Handling, Storage, and Shipment 
Detailed procedures for sample collection and handling of samples are described in the 
laboratory manual. Safety laboratory samples will be destroyed as per the laboratory’s standard 
procedures. For blood and urine samples collected for biological health marker and exposure 
marker analysis at least one sample should be kept at least up until the finalization of the 
bioanalytical reports and the database is locked unless stability for analysis is exceeded. 
7.9.1 
Blood Samples 
Venous blood samples will be collected by qualified and trained site personnel. Subjects should 
be in a seated position during blood collection. The maximal volume of blood drawn for each 
subject will be approximately 235 mL, which includes approximately 55 mL for safety and 
serology analysis, approximately 100 mL for biological health markers, COHb, and blood 
volume determination and  80 mL for biobanking.  
Capillary blood sampling will be performed for determination of lactate levels and will be 
analyzed on-site. 
7.9.2 
Urine Samples 
Spot urine samples will be used for the urine drug screen, urine cotinine screen, urine 
pregnancy test, safety urinalysis, NEQ, NNAL, CEMA and creatinine analysis, and for 
biobanking.  
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7.9.3 
Long-Term Storage (Biobanking)  
If a subject gives consent for biobanking, additional samples of urine, blood, plasma, saliva 
will be collected at V3, V14, V28 and V43, and sweat at V3 and V43. 
 
Urine: 
Samples will be collected from the spot urine for: 
x lipidomic profiling: 2 x approximately 2 mL  
x proteomic profiling: 2 x approximately 10 mL 
x metabolomics profiling: 2 x approximately 10 mL 
 
Whole blood: 
x transcriptomic profiling: 2 x 2,5 mL will be collected  
x proteomic profiling: 5 mL will be collected to obtain 4 x 0.5 mL of plasma  
x metabolomics profiling: 5 mL will be collected to obtain 4 x 0.5 mL of plasma  
x lipidomics profiling: 5 mL will be collected to obtain 2 x 1 mL of plasma   
 
Saliva: 
x 4  x approximately 1mL saliva will be collected using a dedicated saliva collection kit 
for molecular profiling. 
 
Sweat: 
x 2 x at least approximately 40μL will be collected using a sweat collection system 
(Macroduct®Sweat Collection system, ELITechGroup) for molecular profiling. 
 
Samples will be sent to the designated biobank facility and stored for 10 years as of final CSR. 
The biobank facility will follow their procedures for destruction of banked samples if a subject 
withdraws consent for long-term biobanking.  
7.10 Mobile Health (mHealth) Wearable 
Subjects will wear a mHealth device (Vivofit 3, Garmin), which is worn on the wrist, for the 
recording of their physical activity including daily step count and intensity minutes. Three 
intensity levels of physical activity will be recorded; 1) sedentary - little to no activity 
monitored (e.g. minimal movement, sitting, resting, or sleeping); 2) active – some activity 
monitored (e.g. a brisk walk); 3) very active- high activity monitored (e.g.running or speed 
walking). 
The wearable will simultaneously record energy expenditure, distance and sleep as described 
in objective 6, however the analysis and reporting of this data will not be part of the CSR but 
reported separately.  
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Subjects will be trained on how to wear (i.e. correct positioning) and handle the device in 
accordance with the user guide. Subjects will be instructed to wear the device on their non-
dominant wrist and to wear it all the time. As part of the wearable device kit subjects will also 
receive a mobile phone with Bluetooth and wireless internet connectivity through which data 
will be transferred from the wearable device. Between V2 and V3, baseline data will be 
collected, and as of randomization at V3 data will be collected during the investigational period 
until V43.  
The Vivofit 3 device records accelerometer data continuously and transfers data aggregated on 
a 15-min basis to the data storage cloud. For the parameters to be analyzed as part of the study 
(objective 5; steps and activity) data transferred from the wearable device to the clinical 
database will be aggregated on a per 24-hour level. In addition, wear time per day will be 
monitored. Parameters listed in objective 6 will be transferred from the wearable device on a 
per 15-min level to the storage cloud. Further details on device set-up, subject account creation, 
device pairing and mapping, and data flow and storage will be given in a dedicated plan. 
7.11 Questionnaires 
7.11.1 Fagerström Test for Nicotine Dependence (Revised Version) 
Subjects will complete the FTND questionnaire in its revised version (58). 
The questionnaire consists of six questions. The FTND total score determines the subject’s 
dependence on nicotine in three levels: mild (0-3 points), moderate (4-6 points), and severe (7-
10 points). 
7.11.2 Product preference 
On V3, the following question will be asked to all subjects  
 
“Which product would you prefer to be randomized to?”  
x IQOS  
x Cigarette 
x Smoking abstinence  
x No preference 
 
The product preference question needs to be asked before randomization. As an instruction to 
answer this question, subjects will be informed that their response will not influence the 
randomization process. 
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7.11.3 Lifestyle questionnaire 
Subjects will be asked questions to capture baseline covariates such as, diet, alcohol intake, 
sleep deficit, and exposure to passive smoking at V3. 
7.11.4 Assessment of Cough-VAS and Likert Scales 
Subjects will assess cough on a Visual Analogue Scale (VAS) and on three Likert scales. 
Subjects will be asked if they have experienced a regular need to cough (e.g., whether they 
have coughed several times in the previous 24 hours prior to assessment). If the answer is ‘yes’, 
subjects will be asked to complete a VAS and 3 Likert scales. On the VAS, subjects will assess 
how bothersome their cough was during the previous 24 hours. The VAS ranges from “not 
bothering me at all” to “extremely bothersome”. Furthermore, subjects will assess the intensity 
and frequency of cough and the amount of sputum production during the previous 24 hours on 
Likert scales. 
• The intensity of cough will be assessed on a 5-point Likert scale ranging from 1 to 5, with 
1 = very mild – 2 = mild – 3 = moderate – 4 = severe – 5 = very severe. 
• The frequency of cough will be assessed on a 5-point Likert scale ranging from 1 to 5, with 
1 = rarely – 2 = sometimes – 3 = fairly often – 4 = often – 5 = almost always. 
• The amount of sputum production will be assessed on a 4-point Likert scale ranging from 
0 to 3, with 0 = no sputum – 1 = a moderate amount of sputum – 2 = a larger amount of 
sputum – 3 = a very large amount of sputum. 
Symptoms or worsening of symptoms documented in the VAS do not need to be documented 
as additional AEs because the VAS will be analyzed as part of the final report. However, it is 
at the discretion of the Investigator to decide whether to document such symptoms as additional 
AEs. The main source for AE collection will be the face-to-face interview between the subject 
and investigational site staff using, open, non-directive questions (see Section 8.2.1). 
7.11.5 International Physical Activity Questionnaire (IPAQ) - short form 
At V1 subjects’ physical activity levels will be assessed using the short version of the IPAQ. 
This questionnaire was developed by a group of experts in 1998 to facilitate surveillance of 
physical activity based on a global standard (59). The IPAQ has since become the most widely 
used physical activity questionnaire (60) with two versions available: the 31 item long form 
(IPAQ-LF) and the 9 item short form (IPAQ-SF). The short form records the activity of four 
intensity levels: 1) vigorous-intensity activity such as aerobics, 2) moderate-intensity activity 
such as leisure cycling, 3) walking, and 4) sitting. 
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7.11.6 Borg Rate of Perceived Exertion (RPE) Scale  
During VO2max test (only at V3 and V43) subjects will rate their perceived exertion on the 
Borg RPE scale at rest and then at each 25W increase (61). The Borg RPE scale is a way of 
measuring physical activity intensity level. It is based on the physical sensations a person 
experiences during physical activity, including increased heart rate, increased respiration or 
breathing rate, increased sweating, and muscle fatigue.  
The scale ranges from  
x 6- no exertion at all,  
x 7.5 – extremely light,  
x 9 – very light,  
x 11 – light,  
x 13 somewhat hard, 
x 15- hard,  
x 17-very hard,  
x 19- extremely hard, to 
x 20- maximal exertion. 
A high correlation exists between a person's perceived exertion rating times 10 and the actual 
heart rate during physical activity (61). 
7.11.7 Rate of Perceived Capacity (RPC) Scale 
To predict maximal exercise capacity, the rating of perceived capacity (RPC) scale was 
developed based on metabolic equivalents (METs) (62). MET values from 1 to 20 for men and 
1 to 18 for women are listed on a progressive scale and linked to physical activities. Subjects 
will rate their perceived capacity by choosing the most strenuous activity and the 
corresponding MET value that they could sustain for 30 min. 
7.11.8 Product Use Diary 
Subjects will enter the number of HeatSticks, cigarettes, or/and other tobacco and nicotine-
containing products used per day in a product use diary from V2 until the discharge at V43. 
Before the diary is delivered to the subjects, subjects will be trained by site staff on how to 
complete it. The product use diary will be supplied by Sponsor and distributed to the subjects 
by the investigational site personnel.  
7.11.9 Qualitative Interviews on Health and Functioning (sub-study) 
Subjects that have signed the optional section of the ICF for the sub-study on health on 
functioning will have a one-hour, qualitative interview over the phone or computer between 
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V2 and V3, and at the end of the study between V42 and V43. Questions during the interview 
will be open-ended and will focus on subjects’ current state of health and functioning, 
experiences during the training program, and changes in health and functioning as a result of 
the training program. The protocol for the sub-study is available in Appendix 4. 
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8 
ADVERSE EVENTS 
8.1 
Definitions 
8.1.1 
Adverse Events 
An adverse event is defined as any health-related event which is adverse or unfavorable and 
which either starts after ICF signature or represents a worsening of a health – related condition 
that existed at the time of that signature. Careful medical judgment is required to establish 
whether a clinical finding (including an abnormal laboratory result) is a true AE or just a 
manifestation of a preexisting health – related condition. An AE may or may not have a causal 
relationship with the study procedures or with the use of investigational product (cigarette  or 
IQOS). 
8.1.2 
Serious Adverse Events 
A serious adverse event (SAE) is defined as an AE that: 
x Results in death, 
x Is life-threatening, 
x Requires inpatient hospitalization or prolongation of existing hospitalization, 
x Results in persistent or significant disability/incapacity,  
x Is a congenital anomaly/birth defect, or 
x Is an important medical event. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based on appropriate medical judgment, they 
may jeopardize the subject or the subject may require medical or surgical intervention to 
prevent one of the outcomes listed in the above definitions. 
"Life-threatening" means that the subject was at immediate risk of death from the event. It 
might have caused death if it had occurred in a more serious form. 
 
7.1.3. Conditions Existent Before the Start of the Period of Collection of AEs (ICF 
Signature) 
Clinical conditions that existed before the start of the period of collection of AEs  and still 
ongoing at V1 (concomitant disease), and whose severity remained unchanged after that point, 
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should not be considered AEs and should not be captured as such. This includes medical 
therapies or surgical interventions that had been planned before the start of the period of 
collection  of AEs regardless of involving admissions to hospital, if the medical condition to 
be addressed did not worsen after the start of the collection period. Otherwise, any medical 
condition that existed before the start of the period of collection and still ongoing at V1 
(concomitant disease) and whose severity increased after that point is to be captured as a non-
serious AE or an SAE, depending on the seriousness criteria met. 
8.2 
Assessment of Adverse Events 
8.2.1 
Collection of Information 
Any non-serious AE occurrence during the study must be documented in the subject’s medical 
records in accordance with the Investigator’s normal clinical practice and on the AE page of 
the CRF. SAEs that occur during the study must be documented in the subject’s medical record, 
on the AE CRF, and on the SAE form. 
AEs should be collected mainly via face-to-face interview with the subject through 
spontaneous reporting or by the use of consistent, open, non-directive questions from the 
Investigator or designee(s) (e.g., “Have you had any health problems since you were last 
asked? or “How have you been feeling since you were last asked?”).  
Information recorded will include: verbatim description of the AE/SAE, start and stop dates, 
seriousness, severity (intensity), action taken (e.g., whether or not the AE/SAE led to the 
subject’s withdrawal from the study), and outcome (e.g., resolved, stabilized).  
Information to be recorded about an SAE should also include, whenever possible, onset and 
resolution dates and times, circumstances leading up to the event, clinical elements such as 
clinical course, specific vital signs and test results that may explain the pathophysiology of the 
event, as well as alternative explanations to its occurrence. 
Whenever a medically meaningful diagnosis is available to comprise a set of reported signs 
and/or symptoms, it should be preferentially provided as the AE or SAE term, rather than the 
individual signs and/or symptoms. Otherwise, each one of those signs and/or symptoms should 
be reported separately as event terms. 
8.2.2 
Period of Collection 
AEs (including SAEs) will be collected from the time of ICF signature until the EOS. 
Any AEs which occur during the screening period will be captured by the study site staff and 
assessed by the Investigator or designee(s) in order to establish relationship to study 
procedures.  
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During a 28-day safety follow-up period there will be recording of spontaneously reported new 
AEs/SAEs and the active follow-up of ongoing AEs/SAEs by the study site. In general, all 
AEs will be followed-up until resolved, stabilized (i.e., no worsening of the event), or a 
plausible explanation for the event has been found and until the end of the study. The follow-
up of the ongoing non-serious AEs will be done via a phone call performed until the end of the 
Safety follow-up period. Any AEs or SAEs that are ongoing at the end of the safety follow-up 
period will be managed as described in Section  8.2.6. 
SAEs spontaneously reported to the Investigator after the end of the safety follow-up period 
and considered related to the IQOS must also be reported to the Sponsor.  
8.2.3 Intensity of Adverse Event 
The Investigator must assess the intensity of each reported AE according to the following 
grading scale: 
Mild: Easily tolerated, not interfering with normal everyday activities. 
Moderate: Interferes with normal everyday activities, but the subject is still able to function.  
Severe: Incapacitating and requires medical intervention. 
8.2.4 Relationship to Investigational Product and Relationship to Study 
Procedures 
The Investigator must assess the causal relationship between the exposure to the IP (cigarette 
or IQOS) and each of the reported AEs, using the classification system and the criteria 
described below. The same assessment must be made separately regarding the causal 
relationship between the study procedures and each of the reported AEs: 
Not related: The temporal relationship of the adverse event to IP administration or study 
procedure(s) makes a causal relationship unlikely, or concomitant medication, therapeutic 
interventions, or underlying conditions provide a sufficient explanation for the observed event. 
Related: The temporal relationship of the adverse event to IP administration or study 
procedure(s) makes a causal relationship possible, and concomitant medication, therapeutic 
interventions, or underlying conditions do not provide a sufficient explanation for the observed 
event. 
8.2.5 
Expectedness 
Any AE assessed as related to the IP (cigarette or IQOS) will be assessed for its expectedness. 
An AE will be regarded as “unexpected” if its nature or severity is not consistent with 
information already recorded about IQOS in current version of SPI. The assessment of 
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without the written consent of Philip Morris Products S.A 
expectedness with the cigarette will be based on the judgement of the PI relying on the 
available safety information on cigarette in the literature. 
8.2.6 
Follow-up of Non-Serious and Serious Adverse Events 
Any non-serious AE that is ongoing at the time of discharge or early termination will be  
followed-up by the Investigator during the follow-up period until it has been resolved, 
stabilized (i.e., no worsening of the condition), or an acceptable explanation has been found 
(e.g., a chronic condition). The follow-up of the ongoing non-serious AEs will be done via a 
phone call performed until the end of the Safety follow-up period. 
At the end of the safety follow-up period, all ongoing non-serious AEs will be documented as 
“ongoing” and no follow-up information will be sought on them anymore by the Investigator. 
At that point, the Investigator will assess whether the subject should be referred to his/her 
General Practitioner to have their ongoing AEs addressed accordingly. 
All SAEs will be followed up by the Investigator or designee, despite their continuation after 
the end of the safety follow-up period, until their resolution, stabilization (i.e., no worsening 
of the condition), or an acceptable explanation has been found (e.g., a chronic condition). 
8.3
Reporting of Serious Adverse Events
Any SAE observed during the  study, whether or not attributable to the IP (cigarette or IQOS),
or to any study procedures, must be reported within 24 hours of first awareness to 
 
 and Sponsor, as described in the respective safety management plan 
(SMP). 
SAEs considered related to the IQOS and spontaneously reported after the  end of study must 
also be reported within 24 hours of first awareness to
and Sponsor 
for safety surveillance purposes 
All the SAE report forms must be sent as an attachment to an e-mail message to 
 
 and Sponsor: 
:
E-mail:
Fax:
Address:
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
Sponsor:
E-mail:
Phone:
@pmi.com
+ 41 
Address:
Philip Morris Products S.A.
R&D Innovation Cube
5 Quai Jeanrenaud
2000 Neuchâtel
Switzerland
As further information regarding an already reported SAE becomes available to any of the 
parties involved in this study, such follow-up information should be reported on a new SAE 
report form, marked as a follow-up report and submitted to 
 and 
Sponsor according to the same timelines described above. The follow-up SAE report form 
must include the minimum information required for form completion and only changed/new 
information needs to be specified. Information provided in the follow-up SAE report form 
supersedes any information that was initially reported.  The SAE report form to be used in this 
study is provided as a separate document. All SAEs will also be recorded on the relevant CRF 
page, in addition to the SAE report form.  
The Investigator or designee is responsible for submitting the relevant reports of SAEs that 
occur during the study to the local IEC, according to local regulations and in accordance with 
the respective safety management plan (SMP). 
8.4
Reporting and of Other Events Critical to Safety Evaluation 
8.4.1 
Abnormal Results of Laboratory Tests 
Any clinical safety laboratory test result that is outside of the normal reference range will be 
reviewed by the Investigator and assessed for clinical significance according to its severity.
The severity of abnormal laboratory test result must be assessed using CTCAE version 4.03 
grading scales (Appendix 3).
Any clinical safety laboratory test result that is outside of the normal reference range will be 
reviewed by the Investigator and assessed for clinical significance according to its severity. 
Whenever that grading scheme is not available for the laboratory result of concern, the 
Investigator should assess the severity and the clinical significance of that result using his/her 
medical judgment.  
Subjects with clinically significant abnormal laboratory values at Screening will not be 
enrolled. Abnormal laboratory test results detected at the Screening Visit whose CTCAE 
grades are 2 or higher or still are CTCAE grade 1 and deemed clinically significant are usually 
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concomitant disease or a manifestation of one and must be recorded accordingly. However, in 
some instances, they may be assessed as AEs (and therefore must be handled according to the 
directions in Section 8.2) or as manifestations of already reported AEs. This decision will 
require a careful assessment of the abnormal result within the clinical context on a case-bycase 
basis and will depend on the Investigator's medical judgment. 
Abnormal laboratory test results detected after the screening visit whose CTCAE grades are 2 
or higher or still are CTCAE grade 1 and deemed clinically significant must be either recorded 
as AEs (and handled according to the directions in Section 8.2) or linked to a concomitant 
disease or still to an already reported AE.   
The principles for assessing and reporting abnormal laboratory test results, emerging after the 
screening Visit, using CTCAE 4.03 grading scales are set up in Table 4:  
Table 4 
 Principles for assessing and reporting abnormal laboratory test results 
Grading 
Clinically 
significant? 
Is it a grade increase 
from previous 
results in study?§ 
Report? 
Grade 1 
No 
Not applicable 
No 
Grade 1 
Yes 
No 
No* 
Grade 1 
Yes 
Yes 
Yes, as AE or linked to 
an already reported 
AE 
Grade 2 or higher 
No/Yes 
No 
No* 
Grade 2 or higher 
No/Yes 
Yes 
Yes, as AE or linked to 
an already reported 
AE 
*in this situation, this abnormal lab test result is either a manifestation of a concomitant disease or of 
an already reported AE. 
§ grade increase in this context means the value is higher  than the one from the screening visit. 
In general, laboratory values will be recorded as “increased <lab parameter>” or “decreased 
<lab parameter>” to ensure consistency of recording/coding. 
8.4.2 
Reporting other abnormal findings 
The other abnormal findings (except abnormal results of laboratory tests) discovered during 
different clinical assessments (e.g., ECG, spirometry, physical examination, vital signs, body 
weight) should be evaluated for the clinical significance by the Investigator/designee based on 
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his/her medical judgement. All abnormal clinical significant test results or clinical examination 
findings can, at the discretion of the Investigator, be reported as AEs and handled according to 
the directions from Section 8.2. 
8.5 
Reporting and Follow-Up of Pregnancies 
8.5.1 
Period of Collection and Follow-up 
In case of pregnancies detected between the time of signature of the ICF  and enrollment of 
the subject, the subject will be considered as a screening failure. In that situation, the pregnancy 
will not be reported to the Sponsor, however, the identified pregnancy(ies) must be captured 
in the screening failure CRF. No pregnancy form will be filled.  
In case of pregnancies detected between enrollment and prior to randomization, subject will 
be discontinued, and reported as “enrolled but not randomized” subject. Early termination 
procedures shall apply. No pregnancy form will be filled. 
 Any pregnancy detected after randomization must be reported by the Investigator within 24 
hours. This also includes pregnancies spontaneously reported to the Investigator after the end 
of the study for a subject.  
Any pregnancy that was potentially associated with exposure to IP (IQOS or cigarette) will be 
followed-up until an outcome is reached (e.g., normal delivery, spontaneous abortion, or 
voluntary termination) and also until 8 weeks after delivery.   
Any pregnancy complication, adverse pregnancy outcome or maternal complications will be 
recorded as an AE accordingly. 
8.5.2 
Reporting of Pregnancies  
A dedicated pregnancy form will be used to report pregnancy cases.  
The procedure to report a pregnancy and provide any additional/follow-up information to UBC 
Pharmacovigilance and Sponsor is the same and performed within the same timelines as the 
one described for an SAE (Section 8.3).  
The Investigator is responsible for informing the corresponding IEC of any pregnancy case 
that was reported during the study, as determined by local regulations. 
8.6 
Adverse Events Leading to Discontinuation 
Subjects who are discontinued from the study because of an AE will undergo the early 
termination procedures (Section 9.6), as soon as practical after discontinuation, and will enter 
the 28-day safety follow-up period. In general, AEs will be followed-up until resolved, 
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stabilized (i.e., no worsening of the event), or a plausible explanation has been found and until 
the end of the study. Any AEs or SAEs that are ongoing at the end of the safety follow-up 
period will be managed as described in Section 8.2.6. 
8.7 
Investigational Product Malfunction and Misuse 
Any occurrences of device events, including IQOS malfunction (e.g., holder does not charge 
when inserted into the charger) or misuse by a subject (use not in accordance with its label and 
instructions), will be documented by the Investigator or his/her designee using a device issue 
log.  
Investigational product misuse may result in use-related hazards (Section 2.3.4).  
Furthermore, any misuse or malfunction of IQOS that leads to an AE/SAE will follow the same 
processes as described above for the reporting of the AE/SAE. 
 
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9 
STUDY ACTIVITIES 
The procedure can be performed at any time during the visit, unless otherwise specified. 
Assessments will be conducted only by qualified and trained site personnel.  
9.1 
Screening  
The screening visit can be performed on  more than one day but has to be completed (including 
safety laboratory results) within 28 days prior to V2. The sequence of assessments/events 
before VO2max test is given for illustrative purposes. The VO2max test should only be 
performed after all clinical assessment have been performed and the subject is judged healthy 
without any contraindication to perform exercise testing as per the Investigator’s judgement. 
If the inclusion and exclusion criteria are satisfactorily met, the site staff will contact the subject 
to arrange his/her next visit (V2) to the site. 
Table 5 shows the procedures that will be performed at V1: 
Table 5 
Time Schedule – V1 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
V1 
 
 
 
Informed consent for study 
participation  
Including section on optional 
participation in sub-study 
interviews 
 
 
Informed consent for biobanking 
Optional 
After ICF 
signature 
 
Information on the risk of 
smoking, smoking cessation 
advice and debriefing on IQOS 
 
 
 
Demographic data collected 
(sex, date of birth/age, and 
race) 
 
 
 
Medical history/concomitant 
disease 
 
 
 
Prior medication (within 4 weeks 
prior to V1) and concomitant 
medication 
 
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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
V1 
 
 
 
Questionnaire on tobacco and 
nicotine containing product use 
history and habits to assess 
smoking history 
 
 
 
IPAQ-short 
 
 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
After resting for at least 5 minutes 
in supine position 
 
 
Collection of spot urine for: 
x 
Urinalysis safety panel 
x 
Urine drug screen 
x 
Urine cotinine test 
x 
Urine pregnancy test  
 
 
√ 
Clinical laboratory parameters 
(hematology, clinical chemistry) 
 
 
√ 
Serology (HIV, hepatitis B and 
C) 
 
 
 
Physical examination 
 
 
 
Height, weight, calculation of 
BMI 
 
 
 
IQOS demonstration 
Without product use 
 
 
mHealth wearable 
demonstration 
 
 
 
Alcohol breath test  
 
 
 
CO breath test 
 
 
 
Spirometry 
Has to be done at least 1 hour 
after smoking  
After resting in sitting position for 
at least 15 minutes prior to 
testing. 
 
 
 
ECG 
After resting for at least 10 
minutes in supine position prior to 
recording. 
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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
V1 
 
After having 
performed all 
clinical 
assessments  
 
VO2max test 
Exercise testing should be 
performed at least 30 min after 
spirometry assessments.  
VO2max and the work produced 
will be recorded. 
After completing the test water 
will be provided ad libitum. 
 
 
AE/SAE recording 
At any time during the day. 
If the V1 is performed on two 
separate days, the AE/SAE 
questions will be asked again 
 
 
Readiness to comply with study 
procedures 
 
 
 
Inclusion/exclusion criteria 
check 
 
Abbreviations:  
AE = Adverse event; BMI = Body mass index; CO = Carbon monoxide; ECG = Electrocardiogram; HIV = Human 
immunodeficiency virus; IPAQ= International Physical Activity Questionnaire; SAE = Serious adverse event. 
9.2 
Enrollment and Familiarization with Exercise Test 
Visit 2 (V2) will be scheduled 7±1 days prior to V3 (randomization).  
Table 6 shows the procedures that will be performed at V2. 
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Table 6 
Time Schedule – V2 Enrollment and Exercise Capacity Test 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
V2 
 
Prior to 
enrollment 
 
Collection of spot urine for: 
x 
Urine cotinine test  
x 
Urine drug screen  
x 
Urine pregnancy test  
Confirmation of smoking status 
by CO breath test. 
Alcohol breath test 
Confirmation of eligibility. 
Has to be done in the morning 
prior to enrollment 
 
 
Enrollment 
 
After 
enrollment 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
After resting for at least 5 minutes 
in supine position 
 
 
Information on the risk of 
smoking, smoking cessation 
advice  
 
 
 
Exercise capacity test – bike 
ergometer 
Work to complete will be based 
on the highest wattage level 
reached  during VO2max test 
during V1. After completing the 
test water will be provided ad 
libitum. 
 
 
mHealth wearable kit 
distribution and training on how 
to wear, handle and charge the 
device 
 
 
 
Product use diary distribution 
 
 
 
Concomitant medication 
 
 
 
AE/SAE recording 
At any time during the day. 
Abbreviations:  
AE = Adverse event; CO = Carbon monoxide; SAE = Serious adverse event. 
 
During the 7±1 days between V2 and V3, subjects having signed the optional section of the 
ICF will have an interview (by phone or computer) on the topic of health and functioning 
lasting around 60 minutes. 
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9.3 
Baseline and Randomization 
Table 7 shows the procedures that will be performed at V3. All baseline assessments should 
be performed before randomization.  
Table 7 
Time Schedule – V3 Baseline 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
V3 
 
 
 
Urine pregnancy test 
 
Before 
breakfast/ 
snack 
√ 
Clinical laboratory parameters 
(hematology, clinical chemistry 
and urinalysis) 
At least 8 hours of fasting  
Hematocrit and Hemoglobin 
results will also be used to 
calculate blood volume 
 
√ 
Biological health markers 
At least 8 hours of fasting  
 
√ 
Biobank blood collection 
Only if optional ICF signed 
At least 8 hours of fasting 
 
 
Breakfast/Snack  
 
 
 
Biobank saliva and sweat 
collection 
Only if optional ICF signed 
 
 
FTND questionnaire 
 
 
 
Lifestyle questionnaire 
 
 
 
RPC scale 
 
 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
After resting for at least 5 minutes 
in supine position 
 
 
ECG 
After resting for at least 10 
minutes in supine position prior to 
recording. 
 
 
Physical examination 
 
 
 
Weight, body fat percentage 
and waist circumference 
 
 
 
Cough assessment 
questionnaire (VAS scale, and 3 
Likert scales) 
 
 
 
CO breath test 
 
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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
V3 
 
30-60 min 
before 
VO2max test 
 
Smoke a cigarette 
Only subjects willing to 
After all 
clinical 
assessments 
 
VO2max test 
HR and VO2 will be recorded at 
rest and at each 25W increase 
During 
VO2max test 
 
Borg RPE scale  
At rest and at each 25W increase  
During 
VO2max test 
√ 
Capillary blood lactate sampling 
to measure lactate levels 
At rest and at each 25W increase 
Before start of 
exercise 
capacity 
 
Snack and water ad libitum 
Snack to be consumed at least 30 
min before start of exercise 
capacity test 
60±5min after 
VO2max test 
 
Exercise capacity test – bike 
ergometer 
Work to complete will be based 
on the highest wattage level 
reached during VO2max test at 
V3. After completing the test 
water will be provided ad libitum. 
After exercise 
capacity test 
Before CO-
rebreathing 
√ 
COHb  
Results will be used to assess 1) 
CO exposure and 2) to calculate 
blood volume 
After exercise 
capacity test 
√ 
Determination of blood volume 
by CO-rebreathing 
Blood will be sampled after CO-
rebreathing for COHb 
determination 
As late as 
possible 
during the 
day/visit 
 
Spot urine collection for urinary 
exposure markers and 
biobanking 
Collection of urine for biobanking 
only if optional ICF signed 
 
 
Concomitant medication 
 
 
 
AE/SAE recording 
At any time during the day. 
Before 
randomization 
 
Product preference question 
As an instruction to answer this 
question, subjects will be 
informed that their response will 
not influence the randomization 
process. 
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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
V3 
 
 
 
Randomization 
 
 
 
IQOS-1 and IQOS-2 arms: 
Distribution of IOQS starter kit 
to subjects randomized into and 
training on how to use the 
device. 
SA arm: Upon subject’s request 
provision of NRT 
 
 
Abbreviations:  
AE = Adverse event; CO = Carbon monoxide; COHb = Carboxyhemoglobin; ECG= Electrocardiogram; FTND = 
Fagerström Test for Nicotine Dependence (revised version); HR = Heart rate; NRT = Nicotine Replacement theray; RPC 
= Rating of Perceived Capacity; RPE = Rate of Perceived Exertion; SAE = Serious adverse event; VAS = Visual 
analogue scale 
9.4 
Exposure Period 
9.4.1 
Acute Effect Exercise Tests 
Visit 4 (V4) will be scheduled up to 7±2 days after V3. 
Table 8 shows the procedures that will be performed at V4: 
Table 8 
Time Schedule – V4 Acute Effect 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
V4 
 
 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
After resting for at least 5 minutes 
in supine position 
 
√ 
COHb  
 
 
 
RPC scale 
 
 
 
Weight, body fat percentage 
and waist circumference 
 
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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
V4 
 
 
 
CO breath test 
 
30-60 min 
before 
VO2max test 
 
Subjects in IQOS-1 and IQOS-2 
arms will use a HeatStick. 
Subjects in cigarette arm will 
smoke a cigarette. 
Only subjects willing to. 
 
 
VO2max test 
HR and VO2 will be recorded at 
rest and at each 25W increase 
HR at rest and maximal HR 
during VO2max test will  be 
recorded and used to set exercise 
training program intensities. 
Maximal work rate during 
VO2max test will recorded and 
used to assess the work rates 
during exercise training program. 
After VO2max 
test 
 
Snack and water ad libitum 
Snack to be consumed at least 30 
min before start of exercise 
capacity test. 
60±5min after 
VO2max test 
 
Exercise capacity test – bike 
ergometer 
Work to complete will be based 
on the highest wattage level 
reached during VO2 max test at 
V3. After completing the test 
water will be provided ad libitum. 
As late as 
possible 
during the 
day/visit 
 
Spot urine collection for urinary 
exposure markers 
 
 
 
Concomitant medication 
 
 
 
AE/SAE and device event 
recording 
At any time during the day. 
Abbreviations:  
AE = Adverse event; CO = Carbon monoxide; COHb = Carboxyhemoglobin;  HR = Heart rate; RPC = Rating of 
Perceived Exertion; SAE = Serious adverse event. 
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9.4.2 
Exercise Training Program 
7±1 days after V4 all subjects besides those who are randomized to the IQOS-2 (no training) 
arm, will start a 12-week exercise training program, from V5 (15±2 days after V3) until V42 
(99±2 days after V3) . 
Subjects will attend trainings sessions 2-4 times per week and three different training programs 
will be circulated as described in Appendix 2. All trainings will be performed indoor on 
stationary bikes.  
Subjects in the IQOS-2 arm will only attend V5, V7, V9, V14, V16, V19, V23, V28, V30, 
V33, V35 and V39 but not for training sessions. 
Table 9 shows the procedures that will be performed at each training from V5 to V42. 
Table 9 
Time Schedule – ExerciseTrainings V5 to V42 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
V5-V42 
 
Before training 
 
Urine pregnancy test  
V5 only  
Before training 
 
Weight 
 
Before training 
 
CO breath test 
 
30-60 min 
before the 
training 
 
Subjects in IQOS-1 and IQOS-2 
arms will use a HeatStick. 
Subjects in cigarette arm will 
smoke a cigarette 
Only subjects willing to 
 
 
40-min bike exercise training 
As per training program schedule 
in Appendix 2. The training 
intensity will be adapted for each 
subject based on the resting and 
maximal HR.  
 
 
Concomitant medication 
 
 
 
AE/SAE and device event 
recording 
At any time during the day. 
Abbreviations:  
AE = Adverse event; CO = Carbon monoxide; HR = Heart rate; SAE = Serious adverse event. 
 
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Table 10 describes the procedures that will be performed at medical visits after 4-week and 8-
week of the training program. For subjects in IQOS-1, cigarette and SA arms medical 
assessments will be performed in conjunction with the training session on V14 and V28. 
Subjects in the IQOS-2 arm will attend these visits for medical assessments only. 
V14 and V28 will be scheduled in the end of the 4th week (40±2 days after V3) and 8th week 
(68±2 days after V3) of the training program, respectively. 
Table 10 
Time Schedule – Medical Visits V14 and V28 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
V14 and V28 
 
 
 
Urine pregnancy test  
 
Before 
breakfast/ 
snack 
√ 
Clinical laboratory parameters 
(hematology, clinical chemistry 
and urinalysis) 
At least 8 hours of fasting  
 
√ 
Biological health markers 
At least 8 hours of fasting  
 
√ 
Biobank blood collection 
Only if optional ICF signed 
At least 8 hours of fasting 
 
 
Breakfast/snack 
 
 
 
Biobank saliva collection 
Only if optional ICF signed 
 
 
Weight 
 
 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
After resting for at least 5 minutes 
in supine position 
 
√ 
COHb  
 
 
 
ECG 
After resting for at least 10 
minutes in supine position prior to 
recording. 
 
 
Physical examination 
 
 
 
CO breath test 
 
 
 
Cough assessment 
questionnaire (VAS scale, and 3 
Likert scales) 
 
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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
V14 and V28 
 
As late as 
possible 
during the 
day/visit 
 
Spot urine collection for urinary 
exposure markers and 
biobanking 
Collection of urine for biobanking 
only if optional ICF signed 
 
 
Information on the risk of 
smoking, smoking cessation 
advice  
 
 
 
AE/SAE and device event 
recording 
At any time during the day. 
 
 
Concomitant medication 
 
Abbreviations:  
AE = Adverse event; CO = Carbon monoxide; COHb = Carboxyhemoglobin; SAE = Serious adverse event; VAS = 
Visual Analogue Scale 
During the 7±1 days between V42 and V43, subjects having signed the optional section of the 
ICF will have an interview (by phone or computer) on the topic of health and functioning 
lasting around 60 minutes. 
9.4.3 
Training Effect Exercise Tests 
Visit 43 (V43) will be scheduled 106±2 days after V3, and 7±2 days after V42. 
Table 11 shows the procedures that will be performed at V43 
Table 11 
Time Schedule – V43 Training Effect Exercise Tests 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
V43 
 
Before 
breakfast/ 
snack 
√ 
Biological health markers 
At least 8 hours of fasting  
 
√ 
Biobank blood collection 
Only if optional ICF signed 
At least 8 hours of fasting 
 
 
Breakfast/snack 
 
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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
V43 
 
 
 
Biobank saliva and sweat 
collection 
Only if optional ICF signed 
 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
After resting for at least 5 minutes 
in supine position 
 
 
Weight,body fat percentage and 
waist circumference 
 
 
 
RPC scale 
 
 
 
CO breath test 
 
30-60 min 
before 
VO2max test 
 
Subjects in IQOS-1 and IQOS-2 
arms will use a HeatStick. 
Subjects in the cigarette arm will 
smoke a cigarette. 
Only subjects willing to. 
After all 
clinical 
assessments 
 
VO2max test 
HR and VO2 will be recorded at 
rest and at each 25W increase 
During 
VO2max test 
 
Borg RPE scale  
At  rest and at each 25W increase 
During 
VO2max test 
√ 
Capillary blood lactate sampling 
to measure lactate levels 
At rest and at each 25W increase 
After VO2max 
test 
 
Snack and water ad libitum 
Snack to be consumed at least 30 
min before start of exercise 
capacity test 
60±5min after 
VO2max test 
 
Exercise capacity test – bike 
ergometer 
Work to complete will be based 
on the highest wattage level 
reached during VO2max test at 
V3. After completing the test 
water will be provided ad libitum. 
After exercise 
capacity test 
Before CO-
rebreathing 
√ 
COHb 
Results will be used to assess 1) 
CO exposure and 2) to calculate 
blood volume 
After exercise 
capacity test 
√ 
Determination of blood volume 
by CO-rebreathing 
Blood will be sampled before CO-
rebreathing to for Hematocrit and 
Hemoglobin and after CO-
rebreathing for COHb 
determination 
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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
V43 
 
As late as 
possible 
during the 
day/visit 
 
Spot urine collection for urinary 
exposure markers 
 
 
 
Return of IQOS device 
 
 
 
Return of mHealth wearable  
 
 
 
Return of product use diary 
 
 
 
Concomitant medication 
 
 
 
AE/SAE and device event  
recording 
At any time during the day. 
Abbreviations:  
AE = Adverse event; CO = Carbon monoxide; HR = Heart rate; RPC = Rating of Percieved Capacity; RPE = Rate of 
Exertion; SAE = Serious adverse event. 
 
Visit 44 (V44) will be scheduled 107±2 days after V3. Table 12 shows the procedures that will 
be performed at V44. 
Table 12 
Time Schedule – V44 Discharge Safety Assessments 
Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
V44 
 
 
 
Urine pregnancy test 
 
Before 
breakfast/ 
snack 
√ 
Clinical laboratory parameters 
(hematology, clinical chemistry 
and urinalysis) 
At least 8 hours of fasting  
 
 
Information on the risk of 
smoking, smoking cessation 
advice and debriefing on IQOS 
 
 
 
Cough assessment 
questionnaire (VAS scale, and 3 
Likert scales) 
 
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Time 
Blood 
Sample 
Procedures 
Additional Information 
Start of 
Procedure 
 
V44 
 
 
 
Vital signs (blood pressure, 
pulse rate, respiratory rate) 
After resting for at least 5 minutes 
in supine position 
 
 
Physical examination 
 
 
 
Spirometry 
Has to be done at least 1 hour 
after smoking  
After resting in sitting position for 
at least 15 minutes prior to 
testing. 
 
 
ECG 
After resting for at least 10 
minutes in supine position prior to 
recording. 
 
 
Concomitant medication 
 
 
 
AE/SAE recording 
At any time during the day. 
Abbreviations:  
AE = Adverse event; CO = Carbon monoxide; SAE = Serious adverse event. 
9.5 
Safety Follow-Up Period    
After the procedures of discharge or at the time of early termination, subjects will enter a 28-
day safety follow-up period during which new AE/SAEs spontaneously reported by the subject 
and concomitant medication used as treatment for AE/SAEs will be recorded. The follow-up 
of ongoing AEs/SAEs will be conducted by the study investigational site as described in 
Section 8.2.6.  
9.6 
Early Termination Procedures 
The following early termination procedures will be performed if a subject is discontinued from 
the study unless the subject refuses to perform the assessments: 
• AE/SAE recording 
• Device event recording 
• Concomitant medications 
• Clinical laboratory parameters (hematology, clinical chemistry, and urinalysis safety 
panel) 
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• Physical examination 
• Spirometry 
• Urine pregnancy test 
• Vital signs 
• ECG 
• Information on the risk of smoking, smoking cessation advice, and debriefing on IQOS 
• Return of IQOS device, mHealth wearable and product use diary. 
Safety laboratory (hematology and clinical chemistry) may be done in non-fasting or fasting 
state. If subjects withdraw from the study or are discontinued during a planned visit, 
assessments required as per protocol for early termination that have been already performed 
during the planned visit should not be conducted again. 
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10 QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 Monitoring 
The Clinical Research Associate (“Monitor”) will be responsible for the monitoring of the 
study. Monitoring will be performed according to CRO’s Standard Operating Procedures 
(SOPs) and as per the agreed monitoring plan with the Sponsor.  
The Investigator shall permit the Monitor to review study data as frequently as considered 
necessary to ensure that data are being recorded in an adequate manner and that protocol 
adherence is satisfactory.  
The Investigator shall access medical records for the Monitor in order that entries in the CRFs 
may be verified. The Investigator, as part of their responsibilities, is expected to ensure that 
the study adheres to GCP requirements.  
An Investigator’s meeting will be held prior to the site initiation visit. During this meeting, the 
general training of the study procedures and specific training on selected procedures will be 
done and documented.  
Subsequent to the Investigator’s meeting, and before the first subject is screened into the study, 
site initiation visit will be conducted by the Monitor and, if necessary, with the Sponsor or its 
authorized representative. The purpose of the site initiation visit will be detailed in the 
monitoring plan.  
Communication by telephone, mail, and e-mail may be used as needed to supplement site 
visits. The Investigator and study personnel will cooperate with the Monitor, provide all 
appropriate documentation, and will be available to discuss the study.  
The Monitor and the Sponsor’s personnel will be available between visits, should the 
Investigator or other study collaborator at the sites need information and advice. Site visits 
will be made at regular intervals during the study. The frequency of the monitoring visits will 
be defined in the monitoring plan agreed with the Sponsor.  
The Investigator, or a designated member of the Investigator’s study collaborator, must be 
available during the monitoring visit to review the data and resolve any queries, and to allow 
direct access to the subject’s records for source data verification. 
10.2 Training of Collaborators 
A formal meeting (Investigator meeting) will be conducted prior to site initiation. During this 
meeting, the Sponsor or its authorized representative will discuss the requirements of the 
clinical study protocol and related documents and will also provide training in the relevant 
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systems and other study-specific procedures. The activities of the Investigator meeting will be 
described in the monitoring plan. 
In addition to the Investigator meeting, the Investigator will ensure that appropriate training 
relevant to the study is provided to all study collaborators involved in the study, and that any 
new information relevant to the performance of this study is forwarded to the study 
collaborator involved in a timely manner. The record of all individuals involved in the study 
will be maintained in the Site Investigator File. 
10.3 Audits and Inspections 
Good Clinical Practice regulations require that there are independent inspections of clinical 
program activities. Such inspections may be performed at any time before, during and/or after 
the study.  
Authorized representatives of the Sponsor, regulatory agencies and/or the IEC may perform 
audits or inspections, including source data verification. The purpose of an audit or inspection 
is to systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, ICH/GCP guidelines, and any applicable 
regulatory requirements. The Investigator will contact the Sponsor or the authorized 
representative immediately, if contacted by a regulatory agency about an inspection at their 
site.  
The Investigator and study collaborator are responsible for maintaining a comprehensive and 
accurate filing system of all study-related documentation that will be suitable for inspection at 
any time by the Sponsor, its authorized representative, and/or regulatory agencies. In signing 
this protocol, the Investigator understands and agrees to provide access to the necessary 
documentation and files. 
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11 DATA MANAGEMENT ACTIVITIES 
All Data Management activities will be described in detail in the Data Management Plan 
(DMP) and documents specified therein. 
11.1 Data Capture 
11.1.1 Case Report Forms and Study Records 
Data Collection Procedures:  
The results from the clinical assessments will be recorded in the source data file by the 
Investigator or their authorized designee and then captured in the CRFs.  
Trained study personnel will be responsible for capturing the data from the observations, tests, 
and assessments specified in the protocol and in the source documents, and transferring the 
data to the CRF according to the CRF Completion Guidelines.  
The Investigator has ultimate responsibility for the collection and reporting of all data related 
to the clinical study and ensuring that the data are accurate, authentic/original, legible, timely 
(contemporaneous), enduring, and available when required. The CRF must be signed by the 
Investigator to attest that the data contained on the CRF are true and accurate. Any corrections 
made to source documents must be clearly recorded, without obscuring the original values and 
be accompanied by the date of change, reason for change, and identification of the person 
making the change. The CRF data will be verified against the source documents at the study 
site by the clinical research associate. Instances of missing or unclear data will be discussed 
with the Investigator for resolution. 
11.1.2 Protocol Deviations 
All protocol deviations will be entered into the Clinical Trial Management System (CTMS) or 
other approved format.  
Information from the source documents will represent the primary source of protocol 
deviations. Information following site monitoring and other manual reviews will be 
documented in the site visit reports, follow-up letters, audit documentation, or other manual 
review and will be recorded and tracked in the CTMS or other approved format. 
Telecommunications and other verbal communications regarding deviations will be considered 
and handled as important communication, and documented and tracked as protocol deviations, 
as necessary.  
Individual entries for protocol deviations that are recorded in the CTMS, or other approved 
format, following site monitoring and other manual reviews will be reviewed against the 
individual data points in the CRF database but will not be formally reconciled with the CRF 
database (e.g., their description or occurrence date). The overall procedures for managing 
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protocol deviations are described in the SOPs of the CRO Data Management Team. All 
deviations will be reviewed periodically, as determined at study start, to identify trends to 
improve monitoring and/or potential impact on the statistical analysis. 
11.2 Data Handling 
All study data will be managed by the Data Management Team at the CRO. The overall 
procedures for quality assurance of clinical study data are described in the SOPs of the CRO 
Data Management Team. The Data Management Team at CRO will prepare a DMP, to be 
reviewed and approved by the Sponsor, prior to the start of the study. This document will 
describe, in detail, the Data Management related procedures and processes.  
All data of all subjects enrolled and screening failures who experience an AE during the study 
(from time of informed consent) will be captured. All data collected during the study is 
property of the Sponsor irrespective of the location of the database and the Data Management 
CRO. 
11.2.1 
 Data Validation 
The data will be validated as defined in the DMP and Data Validation Specifications. 
Discrepancies will be reported as defined in DMP and Data Validation Specifications.  
Data queries will be raised for discrepant or missing data. All changes to data will be captured 
in the database with a comprehensive audit trail. 
11.2.2 Coding 
AEs, medical/surgical history, and prior/concomitant medication will be classified according 
to the terminology of the latest version of the following Dictionaries, at time of coding the first 
entry: 
Medical history: 
Medical Dictionary for Regulatory Activities (MedDRA®) 
Adverse events / 
Procedures: 
MedDRA® 
Medications: 
WHODrug Global 
IQOS device issues 
and/or malfunctions: 
C54451/Medical_Device_Problem_Codes_FDA_CDRH 
 
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11.2.3  Database Lock 
When all outstanding Data Management issues have been resolved and all validation, quality 
review, and cleaning activities are complete, the database or selected data is/are declared soft 
locked. Access to change data in the soft-locked database or to change selected data at this 
time is limited. 
After the data is reviewed by the Sponsor, resolution of all raised queries and QC of the 
changed data, database, or selected data upon Sponsor approval as applicable, is declared 
locked. 
Any changes to the database after that time can only be made by written agreement between 
the Sponsor and the Data Management and Statistical Teams at the CRO. Any of those changes 
must be documented in the database log file. 
After study completion, the study database will be transferred to the Sponsor in the format 
specified in the DMP and compliant with CDISC Study Data Tabulation Model (SDTM). 
 
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12 PLANNED STATISTICAL METHODS 
12.1 General Considerations 
Full details of the statistical analysis will be given in the Statistical Analysis Plan (SAP). Any 
changes to the planned statistical methods will be documented in the study report. The 
statistical evaluation will be performed using SAS®, version 9.2 or later. 
12.1.1 Stratification Criteria 
For the analysis of VO2max and  exercise capacity, the following stratification criteria will be 
used: 
x Cigarette consumption at V1 (10 to 19 cigarettes, more than 19 cigarettes per day) 
x Sex (male, female) 
Additional stratified presentations (e.g. for demographic data by age and BMI) will be defined 
in the SAP.  
12.1.2 
Definitions for Statistical Data Analysis 
In general, baseline value for any given variable will be the last assessment prior to 
randomization for the subjects randomized to either IQOS, cigarette  or SA arms. Further 
details will be described in the SAP.  
12.1.3 Descriptive Statistics 
Descriptive statistics for continuous variables will include the number of subjects, number and 
percent of subjects with missing data, the mean and standard deviation, geometric means and 
coefficient of variation (CV), median, first and third quartiles, minimum and maximum, and 
95% confidence interval (CI; based on a t-distribution if not otherwise stated) on the mean for 
each product use group, and summary across all subjects. For categorical variables descriptive 
statistics will provide the number of observations, absolute frequencies, and relative 
frequencies (percentages) of the observed values. In addition, the results may be presented as 
a stratified summary as defined in the SAP. 
12.1.4 Handling of Missing Values and of Values outside the Detection or 
Quantification Limits 
For laboratory parameters outside the limit of detection or quantification, the following 
imputation will be performed: 
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x Values below the lower limit of detection (LLOD) or quantification (LLOQ) will be 
imputed as 0.5 x LLOD or LLOQ.  
x Values above the upper limit of detection (ULOD) or quantification (ULOQ) will be 
imputed as the ULOD or ULOQ. 
The number of values below LLOD (or LLOQ) or above ULOD (or ULOQ) will be presented 
in each summary table, as well as the statistics on the other quantitative values.  
However, if 50% or more data are below the lower limit or above the upper limit, only the 
number of values below the lower limit and above the upper limit will be reported in the 
summaries, together with minimum (if no value below the lower limit is present) and maximum 
(if no value above the upper limit is present) of the observed values, and no other statistics will 
be reported. 
There will be no imputation of missing laboratory parameters. 
For mHealth parameters that are missing: 
x There will be no imputation and all available data will be analyzed as is.  
12.1.5 Significance Level for Inferential Analysis 
This study is of exploratory in nature and therefore no statistical hypothesis will be tested.  
12.2 Determination of Sample Size and Power Consideration 
The sample size of 20 per arm (smoking abstinence with training, IQOS with training, 
continued cigarette smoking with training) was determined based on previously published 
results, which reported a standard deviation of 14 mL/kg/min in VO2max in the change 
between groups which continued smoking and those who were smoking abstinent after 
participating in a 12-week training program (2). This sample size allows a probability of 90% 
that the half-width of the 95% confidence intervals between two arms have a precision of 
approximately 10.3 mL/kg/min. For example, if the mean difference in change between the 
cigarette arm and smoking abstinence arm was 12 mL/kg/min after training, we expect that if 
the experiment were repeated many times then on average 90% of the time the 95% confidence 
intervals of the mean differences between two arms will be within 1.7 and 22.3. To allow for 
a dropout rate of approximately 20%, the sample size will be 25 per arm. The IQOS-2 arm 
without training will mainly serve as a secondary analysis  to the IQOS-1 arm with training, 
and the drop-out rate in this arm is expected to be lower. Therefore, only 15 subjects will be 
randomized to this arm. 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
12.3 Product Use 
Although subjects are being requested to use solely the product allocated to their respective 
study arm, it is considered that not all subjects randomized to the IQOS arms or to the cigarette 
arm will exclusively use the randomized product at all times during the study. Subjects may 
concomitantly use IQOS and cigarettes (dual use). To account for dual use of IOQS and 
cigarettes, adjustments for cigarette or IQOS use outside of the intended arms will be done 
statistically. Similarly, it is expected that subjects in the SA arm who should stay abstinent 
during the study may relapse to the use of tobacco or nicotine-containing tobacco products 
(e.g., cigarette  or IQOS). 
Actual product use exposure within an analysis period will be categorized based on self-
reporting; further details will be provided in the SAP. 
12.4 Analysis Populations 
The main population for non-safety analysis will be the As Exposed Exercise Compliant Set. 
Safety will be analyzed using the Safety Set.  
12.4.1 As Exposed Exercise Compliant Set  
The As Exposed Exercise Compliant Set (AEECS) consists of all randomized subjects who 
have at least one valid non-safety assessment after randomization, specifically we have  
x post-randomization product (cigarette or IQOS) use experience if randomized to IQOS, 
IQOS-2 or cigarette arm or 
x no product use if randomized to the SA arm, 
and who attended at least 34 of 38 (~90%) of the exercise training sessions except the subjects 
in IQOS-2 arm. The AEECS will be analyzed by actual exposure (product use exposure). 
12.4.2 Full Analysis Set 
The Full Analysis Set (FAS) consists of all randomized subjects who have at least one post-
randomization product (cigarette or IQOS) use experience if randomized to IQOS, IQOS-2 or 
cigarette arm, and who have at least one valid non-safety assessment after randomization. All 
subjects in the SA arm who fulfil these requirements, except the product use experience, are 
part of this set as well. The FAS will be analyzed by randomized study arm. 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
12.4.3 Safety Set 
The Safety Set consists of all subjects enrolled with signed ICF who have at least one valid 
safety assessment during the course of the study. The Safety Set will be analyzed by actual 
exposure (product use exposure).  
12.5 Endpoint Analysis 
To evaluate changes in VO2max in subjects switching to IQOS, continuing to smoke 
cigarettes and being smoking abstinent. 
A linear mixed effects model will be used to estimate the difference in VO2max between each 
arm (SA arm, IQOS-1 arm) versus cigarette arm one week after randomization (V4) and after 
completion of the 12-week training program (V43). The dependent variable will be the  
VO2max with baseline VO2max, arm, sex, age and baseline cigarette consumption as 
covariates. Self-reported cigarette consumption and/or IQOS use will be added as a covariate 
as well.  Appropriate contrasts will be constructed to report an estimate of the VO2max and its 
95% confidence intervals within each arm and also between SA arm, IQOS-1 arm vs cigarette 
arm. The comparison between SA vs IQOS-1 arm will be calculated as well.  
To estimate the difference in VO2max between IQOS-2 and other arms, the same model will 
be used to model the change between arms only at V43.  
Other covariates may be added as deemed appropriate. The same analysis will be repeated for 
weight-adjusted and fat-free weight adjusted VO2max. Estimates of variability from the 
statistical model will be reported and may be used to power future similar studies.  
To evaluate changes in exercise capacity in subjects switching to IQOS, continuing to smoke 
cigarettes and being smoking abstinent  
The linear mixed effects model as described above for VO2max  will be used to estimate the 
difference in exercise capacity between the IQOS-1 or SA arm versus cigarette arm one week 
after randomization (V4) and after completion of the 12-week training program (V43). The 
dependent variable will be the time to complete the test in seconds with baseline exercise 
capacity (in seconds) as a covariate.   
Other covariates may be added as deemed appropriate. Estimates of variability from the 
statistical model will be reported and may be used to power future similar studies. 
To assess the intensity of the exercise training in subjects switching to IQOS, continuing to 
smoke cigarettes and being smoking abstinent  
An appropriate statistical model will be used to estimate the intensity of exercise training in 
the various (cigarette, IQOS-1 and SA) arms over time. The exercise intensity will be the 
endpoint with baseline exercise intensity, age, visit, sex and arm as covariates. Self reported 
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hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
cigarette consumption and/or IQOS may also be used as a covariate. Further details will be 
provided in the SAP. 
Estimates of variability from the statistical model will be reported and may be used to power 
future similar studies.  
Descriptive statistics will be used to present various measures assessing the intensity of 
exercise training in each arm. This includes the cumulative work produced (calories and 
calories/kg body weight)), average work rate during each training session (watt and watt/kg 
body weight), average work rate during each interval during each training session (watt and 
watt/kg body weight), time spent at 0-50%, 50-65%, 65-75%, 75-90%, >90% of maximal work 
rate during each training session (min:sec), average heart rate (HR) during each training 
session (bpm) and time spent at 0-50%, 50-60%, 60-70% , 70-80 % and >80 % of maximal 
HR during each training session (min:sec). 
To evaluate changes in physiological parameters and perception of exertion and capacity in 
subjects switching to IQOS, continuing to smoke cigarettes and being smoking abstinent  
An appropriate statistical model will be used to estimate the differences in physiological 
parameters and perception of exertion and capacity whilst adjusting for covariates such as age, 
sex, cigarette consumption and/or IQOS use or any other clinically relevant covariates of 
interest. The difference between arms (IQOS-1/SA vs cigarette) will be estimated and reported 
together with its 95% confidence intervals. All other pairwise comparisons between arms will 
be estimated and reported as well.  
To monitor trends of daily physical activity levels during the study in subjects switching to 
IQOS, continuing to smoke cigarettes and being smoking abstinent  
Descriptive statistics of the various measures of physical activity as measured by the mHealth 
wearable device will be reported. An appropriate statistical (linear or non-linear) model will 
be used to estimate the levels of activity taking into account clinically relevant covariates such 
as sex, cigarette consumption and age, and repeated measures over time. Estimates for each 
arm and all pairwise comparisons between arms will be reported using an appropriate statistical 
model as defined in the SAP. 
To describe changes in biological health markers in subjects switching to IQOS, continuing 
to smoke cigarettes and being smoking abstinent  
For each of the biological markers descriptive statistics will be employed to assess the changes 
from baseline for each arm. An appropriate (linear or non-linear) statistical model may be 
employed to estimate differences across arms at V14, V28 and V43. Covariates such as age, 
sex, cigarette consumption and/or IQOS use or any other clinically relevant covariates of 
interest will be adjusted statistically and further defined in the SAP. 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
To describe changes in weight, body fat and waist circumference in subjects switching to 
IQOS, continuing to smoke cigarettes and being smoking abstinent  
For weight, body fat and waist circumference, descriptive statistics will be employed to assess 
the changes for each arm. An appropriate statistical model may be employed to estimate 
differences across arms at V4 and V43. Covariates such as age, sex, cigarette consumption 
and/or IQOS use or any other clinically relevant covariates of interest will be adjusted 
statistically and further defined in the SAP. 
To monitor levels of exposure to CO, nicotine, nitrosamines and acrylonitrile in subjects 
switching to IQOS, continuing to smoke cigarettes and being smoking abstinent  
Descriptive statistics of exhaled CO will be summarized and presented for each arm. An  
appropriate statistical model may be employed to estimate differences across arms at the end 
of the study. Covariates such as age, sex, cigarette consumption and/or IQOS use or any other 
clinically relevant covariates of interest will be adjusted statistically and further defined in the 
SAP. Descriptive statistics of COHb% in blood, NEQ, NNAL and CEMA in urine will be 
summarized and presented for each arm. An appropriate statistical model may be employed to 
estimate differences across arms during the visits where these are measured.  
 
In the paragraphs above we mention “any other clinically relevant covariates of interest”. This 
may for example refer to spot urine concentrations of CEMA adjusted for creatinine that may 
be considered as a covariate because they serve as biochemical verification of product use or 
smoking abstinence. The self reported cigarette use of each subject may be used in addition to 
CEMA. A subject’s product preference prior to randomization may also be used as a clinically 
relevant covariate of interest. 
 
Safety endpoints collected during the course of the study will be reported and details will be 
given in the SAP. 
12.6 Demographics and Baseline Characteristics 
Demographic and other baseline characteristics will be summarized as reported in Section 
12.1.3 for the Full Analysis Set. Summaries will also be provided for other analysis sets if they 
differ from FAS and each other. There will be no formal comparison of baseline data, that is, 
no statistical hypothesis testing will be performed. 
12.7 Interim Analysis 
No interim analysis will be performed for this study. 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
13 ADMINISTRATIVE CONSIDERATIONS 
13.1
Investigator’s and Study Administrative Structure 
13.1.1 Investigator 
Investigator:
Dr. med. Dr. rer. nat. Armin Schultz
13.1.2 Sponsor 
Sponsor:
Philip Morris Products S.A.
Quai Jeanrenaud 5
2000 Neuchâtel
Switzerland
Tel: +41 58 242 2111
Fax: +41 58 242 2811
Clinical Scientist
Phone: +41 
E-mail: 
Biostatistician
Phone: +41 
E-mail: 
Medical Safety Officer
Phone: +41 
E-mail: 
13.1.3 Other Responsibilities 
Any SAEs or pregnancies will be handled by: 
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Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
Switzerland. 
Phone: +41 
Fax: 
+41 
E-mail: 
Any SAEs or pregnancies will be handled as per the instructions listed in Section 8.3. 
13.2
Subject Confidentiality
All information obtained during the conduct of the study with respect to the subjects and state 
of their health will be regarded as confidential. A statement to this effect will be written in the 
information provided to the subject. An agreement to disclose any such information will be 
obtained from the subjects in writing and signed by the subject, in compliance with all 
applicable data protection and privacy legislation. 
The anonymity of subjects participating in this study will be maintained. Subjects will be 
identifiable by the Sponsor (or Sponsor’s authorized representative) on CRFs and other 
documents by their subject (or randomization) number/code, sex and date of birth, but not by 
name, initial, or any other details relating to identifiable person (e.g., address, health insurance 
ID card, medical chart number, etc.). The assignment of a subject number/code for subject 
identification will be based on the appropriate data protection rules. 
Any documents that allow full identification of the subject (e.g., the subjects’s signed study 
participation ICF) must be maintained in confidence by the Investigator. If any document 
relating to this study shows a subject’s name or any other details relating to an identifiable 
person (e.g., address, health insurance ID card, medical chart number, etc.), the name or other 
identifiable details must be obscured before a copy of that document is supplied to the Sponsor 
or the Sponsor’s authorized representative.
13.3 Access to Source Documentation 
Subjects will be informed that, during the course of the clinical study, the Sponsor, any 
authorized representatives of the Sponsor, IEC, or regulatory authorities may inspect their 
medical records to verify the information collected, and ensure that all personal information 
made available for inspection is handled in the strictest confidence and in accordance with 
applicable data protection and privacy legislation. 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
The Investigator and all study site collaborators involved with the study must permit direct 
access to source data/documents for study related monitoring, audits, IEB review, and 
regulatory inspection(s). 
13.4 Record Retention 
 
Essential study documents/records, which individually and collectively permit evaluation of 
the conduct of a study and the quality of the data produced, are described in Section 8 of the 
ICH GCP Guidelines (3). 
Essential documents must be retained by the Investigator for a minimum of: 
x 
At least 15 years after completion or discontinuation of the study. 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by an agreement with the Sponsor. 
Examples of essential records/documents include, but are not limited to: 
x 
Signed informed consent documents for all subjects and study participation ICF. 
x 
Subject identification code list, Screening Log and Enrollment Log (if applicable). 
x 
Record of all communications between the Investigator and the IEC, composition of 
the IEC. 
x 
Record of all communications/contact between the Investigator, Sponsor, and its 
authorized representatives. 
x 
List of sub-Investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in 
the study. 
x 
Investigator Logs. 
x 
CRFs, study specific questionnaires (and associated data/scoring), subject diaries. 
x 
AE reports and details of follow-up investigations, details of concomitant medication. 
x 
All other source documents or any electronically captured study source data. 
x 
Original medical/hospital records, if applicable (the medical files of study subjects 
must be retained in accordance with local legislation and in accordance with the 
maximum period of time permitted by the hospital or investigational site). 
x 
Record of any body fluids or tissue samples collected and retained. 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
x 
Device Issue Log, IP Accountability Logs, dispensing records. 
x 
Information regarding subjects’ discontinuation and any follow-up. 
It is the responsibility of the Sponsor to inform the Investigator as to when these documents 
no longer need to be retained. 
The Investigator must take measures to prevent accidental or premature destruction of these 
documents. 
If the Investigator wishes to assign the study records to another party or move them to another 
location, the Sponsor must be notified in advance. 
The Investigator must obtain written approval from the Sponsor before destruction of any 
records. Normally, these records will be held in the Investigator’s archives. If the Investigator 
is unable to meet this obligation, they must ask the Sponsor for permission to make alternative 
arrangements. Details of these arrangements must be documented. 
The Sponsor or Sponsor’s authorized representative will maintain documentation relating to 
the study as long as the IP is on the market, and/or for 15 years after the CSR has been finalized. 
13.5 Clinical Study Report 
The Sponsor must ensure that a CSR for this study is prepared regardless of whether the study 
is completed or prematurely terminated. 
The CSR will be written based on standards of the ICH Guideline for the Structure and Content 
of Clinical Study Reports. In certain circumstances, an abbreviated CSR may be acceptable. 
Submission of the CSR to the IEC will be complied with as requested by local requirements. 
The results of the additional variables for analysis will be presented in reports separate from 
the CSR. 
13.6 Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor. In 
addition, the Investigators must provide to the Sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and for 1 year 
following the completion of the study. 
13.7 Publication and Disclosure Policy 
This document contains data, information and trade secretes that are confidential and 
proprietary to the Sponsor. This document is being provided solely for the purpose of 
evaluation and/or conducting this clinical study for the Sponsor. Disclosure of the content of 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
this document is allowed only to study personnel, IEC, or duly authorized representatives of 
regulatory agencies for this purpose under the condition that confidentiality is maintained. The 
contents of this document may not be used in any other clinical study or disclosed to any other 
person or entity without the prior written permission of the Sponsor. The foregoing shall not 
apply to disclosure required by any regulations; however, prompt notice will be given to the 
Sponsor prior to any such disclosure. 
The Sponsor plans to disclose details of the study protocol on a web-based, publicly available, 
clinical trial register database (e.g., ClinicalTrials.gov). 
13.8 Insurance 
The Sponsor is responsible for AEs and health damage of the subjects who are associated with 
the IQOS product which are used during the study, except for AEs and health damage of the 
subjects caused by a negligent or an intentional misconduct and/or significant deviation to 
the protocol of the Investigator or the Investigational site or the subjects. The Sponsor has 
taken out insurance to cover any bodily injury and property damage caused by the operations 
carried out by the insured. 
 
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without the written consent of Philip Morris Products S.A 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
18. Gresham G, Schrack J, Gresham LM, Shinde AM, Hendifar AE, Tuli R, et al. Wearable 
activity monitors in oncology trials: Current use of an emerging technology. Contemp Clin 
Trials. 2018;64:13-21. Epub 2017/11/14. doi: 10.1016/j.cct.2017.11.002. PubMed PMID: 
29129704. 
19. Schaller J-P, Keller D, Poget L, Pratte P, Kaelin E, McHugh D, et al. Evaluation of the 
Tobacco Heating System 2.2. Part 2: Chemical composition, genotoxicity, cytotoxicity, and 
physical properties of the aerosol. Regul Toxicol Pharmacol. 2016;Suppl 2. Available from: 
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toxicology endpoints demonstrates reduced exposure effects compared with cigarette smoke. 
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without the written consent of Philip Morris Products S.A 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
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without the written consent of Philip Morris Products S.A 
[ZRHR-REXC-04-JP]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of 
Medicine 
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commercial information, and the legal protections provided to such trade secrets and confidential information are 
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without the written consent of Philip Morris Products S.A 
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Appendix 1 SCHEDULE OF EVENTS 
 
Screening 
Familiarization 
Baseline 
Exercise Tests  
Acute Effect 
Training 
Visits 
Medical 
Visit 
Training 
Visits 
Medical 
Visit 
Training 
Visits 
Exercise Tests 
Training Effect 
Discharge / Early 
Termination 
28-day Safety 
follow-up 
Visit 
1 
2 
3 
4 
5-14 
14 
15-28 
28 
29-42 
43 
44 
 
Informed consent4 
• 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
• 
•5 
 
 
 
 
 
 
 
 
 
 
Advice on the risks of 
smoking/smoking cessation 
advice and debriefing on 
IQOS 
• 
• 
 
 
 
• 
 
• 
 
 
•• - if ET 
 
Demographics 
• 
 
 
 
 
 
 
 
 
 
 
 
Fagerstrom’s test for nicotine 
dependence (FTND) 
 
 
• 
 
 
 
 
 
 
 
 
 
Tobacco and nicotine 
containing product use 
history and habits 
• 
 
 
 
 
 
 
 
 
 
 
 
Cotinine urine test  
• 
• 
 
 
 
 
 
 
 
 
 
 
Exhaled CO 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
 
 
International Physical 
Activity Questionnaire 
(IPAQ-short) 
• 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen6 
• 
• 
 
 
 
 
 
 
 
 
 
 
Alcohol breath test 
• 
• 
 
 
 
 
 
 
 
 
 
 
         
4 ICF for study participation including section for optional participation in sub-study interviews, and separate ICF for optional biobanking. 
5 Urine pregnancy test, cotinine urine test, exhaled CO, alcohol breath test, urine drug screen will be performed at V2 before enrollment. 
6 Amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates, methadone, methamphetamines, phencyclidine, tricyclic antidepressants,. 
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Data and information contained in this document are considered to constitute trade secrets and confidential commercial information, and the legal protections 
provided to such trade secrets and confidential information are hereby claimed under the provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A 
 
Screening 
Familiarization 
Baseline 
Exercise Tests  
Acute Effect 
Training 
Visits 
Medical 
Visit 
Training 
Visits 
Medical 
Visit 
Training 
Visits 
Exercise Tests 
Training Effect 
Discharge / Early 
Termination 
28-day Safety 
follow-up 
Visit 
1 
2 
3 
4 
5-14 
14 
15-28 
28 
29-42 
43 
44 
 
HIV, Hepatitis B and C  
• 
 
 
 
 
 
 
 
 
 
 
 
Safety laboratory 
hematology, clinical 
chemistry and urinalysis  
• 
 
• 
 
 
• 
 
• 
 
 
•• - if ET 
 
Cough assessment 
questionnaire (VAS scale, 
and 3 Likert scales) 
 
 
• 
 
 
• 
 
• 
 
 
• 
 
Urine pregnancy test 
• 
• 
• 
 
•7 
• 
 
• 
 
 
•• - if ET 
 
Physical examination 
• 
 
• 
 
 
• 
 
• 
 
 
•• - if ET 
 
ECG 
• 
 
• 
 
 
• 
 
• 
 
 
•• - if ET 
 
Spirometry 
• 
 
 
 
 
 
 
 
 
 
•• - if ET 
 
Vital signs8 
• 
• 
• 
• 
 
• 
 
• 
 
• 
•• - if ET 
 
Height  
• 
 
 
 
 
 
 
 
 
 
 
 
Weight 
• 
 
• 
• 
• 
• 
• 
• 
• 
• 
 
 
BMI 
• 
 
 
 
 
 
 
 
 
 
 
 
Medical history and 
concomitant diseases 
• 
 
 
 
 
 
 
 
 
 
 
 
Concomitant disease status 
 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
 
AE/SAE recording 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
•• - if ET 
•9 
         
7 Urine pregnancy test will not be performed at each training but at V5 only. 
8 Systolic and diastolic blood pressure, respiratory rate, pulse rate.  
9 Spontaneous reporting of new AEs and active follow-up of AEs ongoing at V44. 
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Data and information contained in this document are considered to constitute trade secrets and confidential commercial information, and the legal protections 
provided to such trade secrets and confidential information are hereby claimed under the provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A 
 
Screening 
Familiarization 
Baseline 
Exercise Tests  
Acute Effect 
Training 
Visits 
Medical 
Visit 
Training 
Visits 
Medical 
Visit 
Training 
Visits 
Exercise Tests 
Training Effect 
Discharge / Early 
Termination 
28-day Safety 
follow-up 
Visit 
1 
2 
3 
4 
5-14 
14 
15-28 
28 
29-42 
43 
44 
 
Prior and concomitant 
medications 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
•• - if ET 
•10 
Lifestyle questionnaire 
 
 
• 
 
 
 
 
 
 
 
 
 
Rating of Perceived Capacity 
(RPC) scale 
 
 
• 
• 
 
 
 
 
 
• 
 
 
Product preference11 
 
 
• 
 
 
 
 
 
 
 
 
 
Smoke a cigarette/Heatstick 
before VO2max test/exercise 
training12 
 
 
• 
• 
• 
 
• 
 
• 
• 
 
 
Snack and water after 
VO2max test 
• 
 
• 
• 
 
 
 
 
 
• 
 
 
Bike ergometer – VO2max 
test13 
• 
 
• 
• 
 
 
 
 
 
• 
 
 
Readiness to comply with 
study procedures 
• 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
 
• 
 
 
 
 
 
 
 
 
 
 
         
10 Only concomitant medications used for treatment of AE/SAEs ongoing at discharge at V43. 
11 Will be asked before randomization. As an instruction to answer this question, subjects will be informed that their response will not influence the randomization 
process. 
12 As per randomized arm before exercise tests and trainings. Only applies for exercise tests for subjects in IQOS-2 arm. 
13 The VO2max test will be performed on a bike ergometer using a mouthpiece and nose clip. Measurements will begin with the subjects resting for 3 min seated 
on the bike ergometer whereafter the workload will be increased by 25W every 60 sec until volitional fatigue. Subjects should keep cadence between 60 and 90 
rpm during the test.  At V3, V4 and V43, heart rate and VO2 will be recorded at rest and at each 25W increase. 
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provided to such trade secrets and confidential information are hereby claimed under the provisions of applicable law. No part of this document may be publicly 
disclosed without the written consent of Philip Morris Products S.A 
 
Screening 
Familiarization 
Baseline 
Exercise Tests  
Acute Effect 
Training 
Visits 
Medical 
Visit 
Training 
Visits 
Medical 
Visit 
Training 
Visits 
Exercise Tests 
Training Effect 
Discharge / Early 
Termination 
28-day Safety 
follow-up 
Visit 
1 
2 
3 
4 
5-14 
14 
15-28 
28 
29-42 
43 
44 
 
Bike ergometer –  Exercise 
capacity14 
 
• 
• 
• 
 
 
 
 
 
• 
 
 
mHealth wearable 
demonstration  
• 
 
 
 
 
 
 
 
 
 
 
 
mHealth wearable 
distribution and training  
 
• 
 
 
 
 
 
 
 
 
 
 
mHealth wearable return 
 
 
 
 
 
 
 
 
 
• 
• - if ET 
 
Randomization 
 
 
• 
 
 
 
 
 
 
 
 
 
Demonstration of IQOS  
• 
 
 
 
 
 
 
 
 
 
 
 
IQOS starter kit distribution 
and device return 
 
 
• 
 
 
 
 
 
 
• 
•- if ET 
 
Product use diary 
Distribution/Return 
 
• 
 
 
 
 
 
 
 
• 
• - if ET 
 
Bike ergometer 40-min 
training session15 
 
 
 
 
• 
 
• 
 
• 
 
 
 
Body fat percentage  
 
 
• 
• 
 
 
 
 
 
• 
 
 
Waist circumference 
 
 
• 
• 
 
 
 
 
 
• 
 
 
Blood composition and 
volume (CO re-breathing 
method)  including blood 
sample for hematocrit Hb 
and COHb before  CO-
 
 
• 
 
 
 
 
 
 
• 
 
 
         
14 The time to complete a pre-defined work as fast as possible on a bike ergometer. The criteria for completion of the test is the completion of the pre-defined work 
(kcal) determined as 1.25 times the highest wattage reached  during the VO2max test at V1 for the test at V2, and at V3 for the tests at V3, V4 and V43.  
15 Training sessions will be performed according to Appendix 2 and will be adjusted according to the subject’s resting and maximal heart rate. 
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Screening 
Familiarization 
Baseline 
Exercise Tests  
Acute Effect 
Training 
Visits 
Medical 
Visit 
Training 
Visits 
Medical 
Visit 
Training 
Visits 
Exercise Tests 
Training Effect 
Discharge / Early 
Termination 
28-day Safety 
follow-up 
Visit 
1 
2 
3 
4 
5-14 
14 
15-28 
28 
29-42 
43 
44 
 
rebreathing, and COHb after 
CO-rebreathing. 
Perceived exertion - RPE 
Borg scale 16 
 
 
• 
 
 
 
 
 
 
• 
 
 
Blood COHb% 
 
 
• 
• 
 
• 
 
• 
 
• 
 
 
Capillary blood lactate 
levels17 
 
 
• 
 
 
 
 
 
 
• 
 
 
Blood sampling for 
biological health markers18 
 
 
• 
 
 
• 
 
• 
 
• 
 
 
Spot urine collection for 
urinary exposure markers 
(NEQ, NNAL, CEMA, 
creatinine)19  
 
 
• 
• 
 
• 
 
• 
 
• 
 
 
Biobanking sample 
collection– blood, urine, 
saliva 
 
 
• 
 
 
• 
 
• 
 
• 
 
 
Biobanking sample 
collection- sweat 
 
 
• 
 
 
 
 
 
 
• 
 
 
         
16 Rate of perceived exertion will be measured at rest and at every 25 W increase during the VO2 max test until the end of the test. 
17 Capillary (fingertip or earlobe) blood samples will be obtained at rest and at each workload and analysed for lactate. Blood collection should be started 40-45 
sec into the workload and no blood sample should be obtained at maximal effort. The final blood sample should be obtained 60 sec after termination of the bike 
exercise. 
18 Blood sampling will be performed on fasting state (at least 8 hours of fasting). 
19 Urine collection to be performed as late as possible during the day. 
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Screening 
Familiarization 
Baseline 
Exercise Tests  
Acute Effect 
Training 
Visits 
Medical 
Visit 
Training 
Visits 
Medical 
Visit 
Training 
Visits 
Exercise Tests 
Training Effect 
Discharge / Early 
Termination 
28-day Safety 
follow-up 
Visit 
1 
2 
3 
4 
5-14 
14 
15-28 
28 
29-42 
43 
44 
 
Qualitative interview on 
health and functioning20 
 
 
 
• 
 
 
 
 
 
 
• 
 
 
Discharge 
 
 
 
 
 
 
 
 
 
 
• 
 
         
20 Subjects that have signed the optional section of the ICF for the sub-study on health on functioning will have a one-hour, qualitative interview over the phone or 
computer between V2 and V3, and in the end of the study between V42 and V43.  
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Appendix 2 
Exercise Training Program 
A set of three different training programs will be used. Different programs will provide the 
study participants with differentiated training inputs and make the training sessions less 
monotonous. Each training session will last 40 min with a training intensity ranging between 
60-85%.The target exercise heart rates are based on the resting (HRrest; obtained during 
baseline ECG at V3) and maximal heart rate (HRmax)  obtained during the acute effect VO2max 
test at V4. The formula to be used for exercise heart rates is: target exercise heart rate = ((HRmax 
– HRrest) * intensity) + HRrest with intensity as fraction of 1. Training programs including 
intervals and intensities will be described in a dedicated manual. 
 
Training programs will be circulated as described below: 
 
 
Visit 
Training 1 
Training 2 
Training 3 
Week 1 
5 
• 
 
 
6 
 
• 
 
Week 2 
7 
 
 
• 
8 
• 
 
 
Week 3 
9 
 
• 
 
10 
 
 
• 
11 
• 
 
 
Week 4 
12 
 
• 
 
13 
 
 
• 
14 
• 
 
 
Week 5 
15 
 
• 
 
16 
 
 
• 
17 
• 
 
 
18 
 
• 
 
Week 6 
19 
 
 
• 
20 
• 
 
 
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21 
 
• 
 
22 
 
 
• 
Week 7 
23 
• 
 
 
24 
 
• 
 
Week 8 
25 
 
 
• 
26 
• 
 
 
27 
 
• 
 
28 
 
 
• 
Week 9 
29 
• 
 
 
30 
 
• 
 
31 
 
 
• 
32 
• 
 
 
Week 10 
33 
 
• 
 
34 
 
 
• 
Week 11 
35 
• 
 
 
36 
 
• 
 
37 
 
 
• 
38 
• 
 
 
Week 12 
39 
 
• 
 
40 
 
 
• 
41 
• 
 
 
42 
 
• 
 
 
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Appendix 3 - Laboratory Values 
ABNORMAL LABORATORY VALUES RATING: CLINICAL CHEMISTRY PARAMETERS 
Serum Chemistry 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Life-
Threatening 
 (Grade 4) 
Sodium – Hyponatremia (mmol/L) 0 
<LLN - 130 
- 
<130 - 120 
<120 
Sodium – Hypernatremia (mmol/L) 0 
>ULN - 150 
>150 - 155 
>155 - 160; 
hospitalization 
indicated 
>160 
Potassium – Hyperkalemia (mmol/L) 0 
>ULN - 5.5 
>5.5 - 6.0 
>6.0 -7.0; 
hospitalization 
indicated 
>7.0 
Potassium – Hypokalemia (mmol/L) 0 
<LLN - 3.0 
<LLN - 3.0; 
symptomatic; 
intervention 
indicated 
<3.0 - 2.5; 
hospitalization 
indicated 
<2.5 
Glucose – Hypoglycemia 0 
(mg/dL) 
(mmol/L)  
<LLN – 55; 
<LLN – 3.0 
<55 – 40; 
<3.0 – 2.2 
<40 – 30; 
<2.2 – 1.7 
<30; 
<1.7 
Glucose – Hyperglycemia: 0 
Fasting (mg/dL) 
(mmol/L) 
 
>ULN-160; 
>ULN-8.9 
 
>160-250; 
>8.9-13.9 
 
>250-500; 
>13.9-27.8; 
hospitalization 
indicated 
 
>500; 
>27.8 
Creatinine increased 0 
>1 – 1.5 x 
Baseline; 
>ULN – 1.5 
x ULN 
>1.5 – 3.0 x 
Baseline; 
>1.5 – 3.0 x ULN 
>3.0 x Baseline; 
>3.0 – 6.0 x ULN 
>6.0 x ULN 
Albumin - Hypoalbuminemia 0 
(g/dL) 
(g/L) 
<LLN – 3; 
<LLN - 30 
<3 – 2; 
<30 - 20 
<2; 
<20 
 
- 
- 
Alkaline phosphatase increased 0 
>ULN – 2.5 
x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
ALT / AST increased 0 
>ULN – 3.0 
x ULN 
>3.0 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
Gamma-glutamyl transferase (GGT) 
increased 0 
>ULN – 2.5 
x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
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Serum Chemistry 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Life-
Threatening 
 (Grade 4) 
Blood bilirubin increased  
(total and direct) 0 
>ULN – 1.5 
x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 10.0 x ULN 
>10.0 x ULN 
Cholesterol high 0 
(mg/dL) 
(mmol/L) 
 
>ULN - 
300; 
>ULN - 
7.75 
 
>300-400; 
>7.75-10.34 
 
>400-500; 
>10.34-12.92 
 
>500; 
>12.92 
Triglycerides - Hypertriglyceridemia 0 
(mg/dL) 
(mmol/L) 
150 – 300; 
1.71 – 3.42 
>300 – 500; 
>3.42 – 5.70 
>500 – 1000; 
>5.70 – 11.40 
 
>1000; 
>11.4  
Abbreviations: ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; BUN = Blood urea nitrogen; 
GGT = Gamma-glutamyl transferase; LLN = Lower limit of the normal range; ULN = Upper limit of the normal range. 
Data Sources: 
0 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, U.S. Department of Health and Human Services, 
FDA, Center for Biologics Evaluation and Research - Guidance for Industry. 
 
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ABNORMAL LABORATORY VALUES RATING: HEMATOLOGY PARAMETERS 
Hematology 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Life-
Threatening 
(Grade 4) 
Anemia (Hemoglobin) 0 
(g/dL) 
(mmol) 
(g/L) 
 
<LLN-10.0 
<LLN-6.2 
<LLN-100 
 
< 10-8.0 
< 6.2-4.9 
< 100-80 
 
<8.0 
<4.9 
<80 
Transfusion 
indicated 
 
Life threatening 
consequences; 
urgent intervention 
indicated 
Hemoglobin increase 0 – (g/dL) 
Increase in >0 – 
2 above ULN or 
above Baseline if 
Baseline is above 
ULN 
Increase in >2 – 
4 above ULN or 
above Baseline 
if Baseline is 
above ULN 
Increase in >4 
above ULN or 
above Baseline 
if Baseline is 
above ULN 
- 
WBC Decrease 0 - (cell/mm3)  
(109/L) 
 
<LLN – 3000; 
<LLN – 3.0 
 
<3000 - 2000; 
<3.0 – 2.0  
 
<2000 - 1000; 
<2.0 – 1.0  
 
<1000; 
<1.0  
Lymphocytes increase 0 
(cell/mm3)  
 
- 
 
>4,000 – 20,000 
 
>20,000 
 
- 
Lymphocytes decrease 0 
(cell/mm3)  
(109/L) 
 
<LLN – 800; 
<LLN – 0.8 
 
<800 - 500; 
<0.8 – 0.5 
 
<500 - 200; 
<0.5 – 0.2 
 
<200; 
<0.2 
Neutrophils Decrease 0 
(cell/mm3)  
(109/L) 
 
<LLN – 1500; 
<LLN – 1.5 
 
<1500 - 1000; 
<1.5 – 1.0 
 
<1000 - 500; 
<1.0 – 0.5 
 
<500; 
<0.5 
Platelets decrease 0 
(cell/mm3)  
(109/l) 
 
<LLN – 75,000; 
<LLN – 75.0 
 
<75,000 – 
50,000; 
<75.0 – 50.0 
 
<50,000 – 
25,000; 
<50.0 – 25.0 
 
<25,000; 
<25.0 
Abbreviations: LLN = Lower limit of the normal range; ULN = Upper limit of the normal range; WBC = White blood cell. 
Data Source: 
0 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, U.S. Department of Health and Human Services, 
FDA, Center for Biologics Evaluation and Research - Guidance for Industry. 
 
 
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ABNORMAL LABORATORY VALUES RATING: URINE ANALYSIS PARAMETERS 
Urine 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Life-
Threatening 
(Grade 4) 
Protein0 
1+ proteinuria; urinary 
protein <1.0 g/24 hours 
2+ proteinuria; urinary protein 
1.0-3.4 g/24 hours 
Urinary protein ≥3.5 
g/24 hours 
- 
Data Source: 
0 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, U.S. Department of Health and Human Services, 
FDA, Center for Biologics Evaluation and Research - Guidance for Industry. 
 
 
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Appendix 4 -  Sub-study Protocol 
Study Number: ABOUT-HF-ND-CE-01-GER 
Study Title: Exercise Capacity Clinical Trial Qualitative Interviews – Concept Elicitation 
Interviews Study to Inform the Development of a Health and Functioning Questionnaire for 
users of tobacco and nicotine products. 
 
 
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Appendix 5 Changes in Protocol Amendment  
The changes made in the different protocol versions are listed in the below table, including 
previous and amended texts, as well as the reasons to change. The new text has been 
highlighted in bold (e.g. new text) and deleted text has been crossed out (e.g. old text). When 
text has been amended in several sections for the same reason, the reason for change is after 
the last section. 
Changes from Version 2.0 to Version 3.0 
Section 
Number 
Section Name 
Changes 
 
General  
The version number and the revision date were updated 
accordingly to the most current version and date. The 
clinical trials.gov registration number was added.  
The table containing the “Summary of changes” has been 
updated, referring to Appendix 5 for the detailed changes. 
Synopsis, 
3 
Synopsis, 
Objectives 
Old text 
Endpoints (V3, V4 and V43) 
x Exercise capacity: time to complete a pre-defined 
work (determined as 25% more work than the study 
subject produced during baseline VO2max test) on a 
cycle ergometer (min:sec). 
Amended text 
Endpoints (V3, V4 and V43) 
x Exercise capacity: time to complete a pre-defined 
work (determined as 25% more work than the study 
subject produced during baseline VO2max test) on a 
cycle ergometer (min:sec). 
7.6.2 
Exercise 
Capacity Test 
Old text 
The criteria for completion of the test is the completing of 
a pre-defined relative work determined as 25% more work 
than was completed during the VO2max test at V1 for the 
test at V2, and at the VO2max test V3 for the tests at V3, 
V4 and V43. 
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Amended text 
The criteria for completion of the test is the completing of 
a pre-defined relative work determined as 25% more work 
than was completed during based on the highest wattage 
level reached at VO2max test times 1. 25 (i.e. 200 W x 
1.25 = 250; 250 kcal to be completed). The highest 
wattage reached at the VO2max test at V1 will be used for 
the test at V2, and at the VO2max test V3 will be used for 
the tests at V3, V4 and V43. 
9.2  
 
 
 
9.3 
 
9.4.3 
Enrollment and 
Familarization 
with 
Exercise 
Test – Table 6 
Baseline 
and 
Randomization – 
Table 7 
Training 
Effect 
Exercise Tests – 
Table 11 
Old text  
Work to complete will be based on the work produced 
during VO2max test during V1.  
Amended text 
Work to complete will be based on the workhighest 
wattage level reached produced during VO2max test 
during V1.  
Appendix 
1 
Schedule 
of 
events 
Old text  
14 The time to complete a pre-defined work as fast as 
possible on a bike ergometer. The criteria for completion of 
the test is the completion of the pre-defined work 
determined as 25% more work than was completed  during 
the VO2max test at V1 for the test at V2, and at V3 for the 
tests at V3, V4 and V44. 
Amended text 
14 The time to complete a pre-defined work as fast as 
possible on a bike ergometer. The criteria for completion of 
the test is the completion of the pre-defined work (kcal) 
determined as 1.25 times the highest wattage reached % 
more work than was completed during the VO2max test at 
V1 for the test at V2, and at V3 for the tests at V3, V4 and 
V43V44. 
Reason for change: To clarify how the work to be 
completed for the Exercise Capacity test is determined 
based on the subject’s performance during the VO2max test, 
accounting for the output of the exercise equipement 
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installed on site. For the calculation of the work to be 
competed, the highest wattage reached at subject’s VO2max 
test is used and not the work produced during VO2max test. 
Synopsis, 
4.1  
Synopsis, 
Overall 
Study 
Design and Plan 
Old text 
The subject will also be invited to participate in a sub-study 
on perception of health and functioning and will sign a 
separate optional section of  the ICF for this part of the 
study.  
Amended text 
The subject will also be invited to participate in a sub-study 
on perception of health and functioning and will sign a 
separate optional section of  the ICF for this part of the 
study. Subjects will be invited to sign and separate 
optional consent form for collection of samples for 
biobanking. 
 
Reason for change: To add the mention of the optional 
biobanking ICF in the Study Design and Plan sections as 
this was missing in the previous version. 
Synopsis, 
5.1.1  
Synopsis, 
Inclusion criteria 
Old text 
Inclusion criteria 
[…] 
4. Subject has been smoking ≥ 10 cigarettes per day over 
the last 12 months. Smoking status will be verified by a 
urinary cotinine ≥ 200 ng/mL and CO exhaled breath test 
> 10 ppm at both V1 and V2. 
Amended text 
4. Subject has been smoking ≥ 10 cigarettes per day over 
the last 12 months. Smoking status will be verified by a 
urinary cotinine ≥ 200 ng/mL and CO exhaled breath test 
>610 ppm at both V1 and V2. 
7.7.1 
Exhaled 
Carbonmonoxide  
(CO) 
Old text 
- 
Amended text 
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At V1 and V2, a cut-off  of >6 ppm for confirming 
cigarette smoking status will be applied (56) (57). 
Reason for change: The cut-off for the exhaled CO level 
applied to confirm cigarette smoking status at V1 and V2, 
in addition to self-report and urine cotinine measurement, 
was lowered from >10ppm to >6ppm as supported by 
literature. Due to the 2-8 hours half-life of CO, confirmed 
smokers may have levels below >10 ppm especially in the 
morning after overnight abstinence (56, 57). 
7.6.3 
Exercise 
Training 
Old text 
Each training session will last 40 min with a training 
intensity ranging between 60-80%. 
Amended text 
Each training session will last 40 min with a training 
intensity ranging between 60-805%. 
Reason for change: Correction of typhographical error.  
7.9.3  
Long-Term 
Storage 
(Biobanking) 
Old text 
Urine: 
Samples will be collected from the spot urine for: 
x lipidomic profiling: 2 x 2 mL  
x proteomic profiling: 2 x 10 mL 
x metabolomics profiling: 2 x 10 mL 
 
Whole blood: 
x transcriptomic profiling: 2 x 2,5 mL will be 
collected  
x proteomic profiling:5 mL will be collected to 
obtain 4 x 0.5 mL of plasma  
x metabolomics profiling: 5 mL will be collected to 
obtain 4 x 0.5 mL of plasma  
x lipidomics profiling: 5 mL will be collected to 
obtain 2 x 1 mL of plasma   
 
Saliva: 
x 4  x 1mL saliva will be collected using a dedicated 
saliva collection kit for molecular profiling. 
 
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Sweat: 
x 2 x 75 μL will be collected using a sweat 
collection system (Macroduct®Sweat Collection 
system, ELITechGroup) for molecular profiling. 
Amended text 
Urine: 
Samples will be collected from the spot urine for: 
x lipidomic profiling: 2 x approximately 2 mL  
x proteomic profiling: 2 x approximately 10 mL 
x metabolomics profiling: 2 x approximately 10 mL 
 
Whole blood: 
x transcriptomic profiling: 2 x 2,5 mL will be 
collected  
x proteomic profiling:5 mL will be collected to 
obtain 4 x 0.5 mL of plasma  
x metabolomics profiling: 5 mL will be collected to 
obtain 4 x 0.5 mL of plasma  
x lipidomics profiling: 5 mL will be collected to 
obtain 2 x 1 mL of plasma   
 
Saliva: 
x 4  x approximately 1mL saliva will be collected 
using a dedicated saliva collection kit for 
molecular profiling. 
 
Sweat: 
x 2 x at least approximately 40-75 μL will be 
collected using a sweat collection system 
(Macroduct®Sweat Collection system, 
ELITechGroup) for molecular profiling. 
Reason for change: To clarify that volumes of urine, saliva 
and sweat are approximate as collection method of these 
fluids may be more variable as compared to a blood draw. 
9 
Study Activities 
Old text 
If no start time for the procedures is provided, then the 
procedure can be performed at any time during the visit. 
Amended text 
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without the written consent of Philip Morris Products S.A 
The procedure can be performed at any time during the
visit, unless other specified.
9.3
Baseline 
and 
Randomization
Old text
Table 7 shows the procedures that will be performed at V3
Amended text
Table 7 shows the procedures that will be performed at V3.
All baseline assessments should be performed before 
randomization.
Reason for change: To clarify order of assessments during 
visits.
13.1.2
Sponsor
Old text
Email
Amended text 
Email: 
Reason for change: Change in email adress.
Appendix 
3
ABNORMAL 
LABORATORY 
VALUES 
RATING: 
HEMATOLOGY 
PARAMETERS
Old text:
WBC Decrease 0 - (cell/mm3)
(10-9/L)
Lymphocytes increase 0
(cell/mm3)
Lymphocytes decrease 0
(cell/mm3)
(10-9/L)
Neutrophils Decrease 0
(cell/mm3)
(10-9/L)
Platelets decrease 0
(cell/mm3)
(10-9/l)
Amended text:
WBC Decrease 0 - (cell/mm3)
(109/L)
Lymphocytes increase 0
(cell/mm3)
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Lymphocytes decrease 0 
(cell/mm3)  
(10-9/L) 
Neutrophils Decrease 0 
(cell/mm3)  
(109/L) 
Platelets decrease 0 
(cell/mm3)  
(109/l) 
Reason for change: Correction of typographical error such 
as 109 instead of 10-9. 
Appendix 
4 
Sub-Study 
Protocol 
Please see summary of changes in the sub-study protocol.  
 
Changes from Version 1.0 to Version 2.0 
Section 
Number 
Section Name 
Changes 
 
General  
The version number and the revision date were updated 
accordingly to the most current version and date. 
A table containing the “Summary of changes” has been 
added, referring to this Appendix 5 for the detailed changes. 
Synopsis, 
3 
Synopsis, 
Objectives 
Old text 
5. To monitor trends of daily physical activity levels during 
the study in subjects switching to IQOS (with and without 
training), continuing to smoke cigarettes (with training) and 
being smoking abstinent (with training) 
Endpoints (from V2 until V43) 
• 
Aggregated data derived from the mobile health 
(mHealth) wearable for: 
 Cumulative number of steps per day 
 Energy expenditure (kcal) per day 
 Daily move score 
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Amended text 
5. To monitor trends of daily physical activity levels during 
the study in subjects switching to IQOS (with and without 
training), continuing to smoke cigarettes (with training) and 
being smoking abstinent (with training) 
Endpoints (from V2 until V43) 
x Aggregated data derived from the mobile health 
(mHealth) wearable for: 
 Cumulative number of steps per day 
 Energy expenditure (kcal) per day 
 Daily move score 
 Sedentary minutes per day and % of time 
sedentary 
 Active minutes per day and % of time active 
 Very active minutes per day and  % of time 
very active 
Synopsis, 
3 
Synopsis, 
Objectives 
Old text 
6. To explore trends and changes in subject-generated 
physiological and behavioral parameters through continuous 
measurements during the study* 
Endpoints (from V2 until V43) 
mHealth wearable measurements of : 
x physiological parameters: heart rate, heart rate variability, 
interbeat interval, blood pulse wave, blood perfusion 
index, blood oxygenation (SpO2), skin temperature, core 
temperature, blood pressure, respiratory rate, energy 
expenditure 
x behavioral parameters: steps, activity levels 
Amended text 
6. To explore trends and changes in subject-generated 
physiological and behavioral activity and sleep parameters 
through continuous measurements during the study* 
Endpoints (from V2 until V43) 
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mHealth wearable measurements of : 
x steps, activity, distance, energy expenditure, sleep 
physiological parameters: heart rate, heart rate variability, 
interbeat interval, blood pulse wave, blood perfusion 
index, blood oxygenation (SpO2), skin temperature, core 
temperature, blood pressure, respiratory rate, energy 
expenditure 
x behavioral parameters: steps, activity levels 
4.2 
Rationale 
for 
Study Design 
Old text 
The wearable will enable non-invasive recording of physical 
activity and energy expenditure in an objective manner 
throughout the study.   
Amended text 
The wearable will enable non-invasive recording of physical 
activity and energy expenditure in an objective manner 
throughout the study.   
Reason for change: Replacement of Biovotion device with 
Garmin device and consequent alignement of captured 
parameters. 
Synopsis, 
4.1  
Synopsis,  
Overall Study 
Design 
and 
Plan 
Old text 
Before leaving the investigational site the subject will receive 
an mHealth wearable kit and will be trained on how to handle 
and charge the device. 
Amended text 
Before leaving the investigational site the subject will receive 
an mHealth wearable kit and will be trained on how to handle 
and charge the device. 
Reason for change: Garmin device does not need to be 
charged. 
Synopsis 
4.1 
 
Synopsis 
Overall Study 
Design 
and 
Plan 
Old text 
Subjects’ VO2max, resting and maximal heart rate and 
maximal work rate will be determined. 
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[…] 
The training intensity will be adjusted according to the 
subject’s resting and maximal heart rate as determined at the 
VO2max test at V4 (acute test). 
Amended text 
Subjects’ VO2max, resting and maximal heart rate and 
maximal work rate will be determined. 
[…] 
The training intensity will be adjusted according to the 
subject’s resting heart rate as determined by ECG at V3, 
and maximal heart rate as determined at the VO2max test at 
V4 (acute test). 
7.6.1 
 
VO2max Test 
and 
Blood 
Lactate Levels 
 
Old text 
In addition at V4, the resting heart rate, the maximal heart rate 
and the maximal work rate will be recorded in order to design 
the training program 
Amended text 
In addition at V4, the resting heart rate the maximal heart rate 
and the maximal work rate will be recorded in order to design 
the training program 
7.6.3 
 
Exercise 
Training 
 
Old text 
The target exercise heart rates are based on the subject’s 
resting (HRrest;lowest value during 3 min supine rest on 
ergometer) and maximal heart rate (HRmax)  obtained during 
the acute effect VO2max test at V4. 
Amended text 
The target exercise heart rates are based on the subject’s 
resting (HRrest; obtained  during ECG at V3 lowest value 
during 3 min supine rest on ergometer) and maximal heart rate 
(HRmax)  obtained during the acute effect VO2max test at V4. 
9.4.2 
 
Table 9 
 
Old text 
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The training intensity will be adapted for each subject based 
on the resting and maximal HR recorded at VO2max test V4. 
Amended text 
The training intensity will be adapted for each subject based 
on the resting and maximal HR recorded at VO2max test V4. 
Appendix 
1 
 
Schedule 
of 
Events-
Footnote 
 
Old text 
15 Training sessions will be performed according to Appendix 
2 and will be adjusted according to the subject’s resting and 
maximal heart rate as determined at VO2max test at V4. 
Amended text 
15 Training sessions will be performed according to Appendix 
2 and will be adjusted according to the subject’s resting and 
maximal heart rate as determined at VO2max test at V4. 
Appendix 
2 
Exercise 
Training 
Program 
 
Old text 
The target exercise heart rates are based on the resting (HRrest; 
lowest value during supine rest on ergometer) and maximal 
heart rate (HRmax)  obtained during the acute effect VO2max 
test at V4. 
Amended text 
The target exercise heart rates are based on the resting (HRrest; 
lowest valueobtained duringsupine rest on ergometer 
baseline ECG at V3) and maximal heart rate (HRmax)  
obtained during the acute effect VO2max test at V4. 
Reason for change: Clarification that the resting heart rate 
should be determined by ECG at V3 and not at V4. 
Synopsis 
4.1 
 
4.4 
 
Synopsis 
Overall Study 
Design 
and 
Plan 
Study Duration 
Old text 
Acute effect, V4 (7±1days after V3) 
[…] 
Training effect, V43 (106±1 days after V3) 
[…] 
Discharge, V44 (107±1 days after V3) 
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[…] 
A 1-day acute effect test visit (V4) will be scheduled 7±1 days 
after V3, followed by a 12-week training program with 
training sessions 2-4 times per week (V5-V42) starting 15±2 
days after V3 until 99±2 days after V3. 
[…] 
A 1-day training effect test visit (V43) will be scheduled up 
to 7±1 days after V42 (106±1days after V3), followed by a 
discharge visit (V44) up to 1±1 days after V43 (107±1 days 
after V3), and followed by a 28-week safety follow-up period. 
Amended text 
Acute effect, V4 (7±12days after V3) 
[…] 
Training effect, V43 (106±12 days after V3) 
[…] 
Discharge, V44 (107±12 days after V3) 
[…] 
A 1-day acute effect test visit (V4) will be scheduled 7±21 
days after V3, followed by a 12-week training program with 
training sessions 2-4 times per week (V5-V42) starting 15±2 
days after V3 until 99±2 days after V3. 
[…] 
A 1-day training effect test visit (V43) will be scheduled up 
to 7±21 days after V42 (106±12 days after V3), followed by 
a discharge visit (V44) up to 1±21 days after V43 (107±21 
days after V3), and followed by a 28-week safety follow-up 
period. 
9.4.1 
9.4.3 
Acute 
Effect 
Exercise Tests 
Training Effect 
Exercise Tests 
Old text 
Visit 4 (V4) will be scheduled up to 7±2 days after V3. 
[…] 
Visit 43 (V43) will be scheduled 106±1days after V3, and 7±1 
days after V42. 
[…] 
Visit 44 (V44) will be scheduled 108±1 days after V3. 
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Amended text 
Visit 4 (V4) will be scheduled up to 7±12 days after V3. 
[…] 
Visit 43 (V43) will be scheduled 106±12 days after V3, and 
7±12 days after V42. 
[…] 
Visit 44 (V44) will be scheduled 1078±12 days after V3 
Reason for change: Visit windows were increased to allow 
more flexibility when scheduling site visits. 
Synopsis 
12.4.1 
Synopsis 
As 
Exposed 
Exercise 
Compliant Set 
Old text 
… and who attended at least 90% of the exercise training 
sessions except the subjects in IQOS-2 arm. The AEECS will 
be analyzed by actual exposure (product use exposure). 
Amended text 
and who attended at least 34 of 38 (~90%) of the exercise 
training sessions except the subjects in IQOS-2 arm. The 
AEECS will be analyzed by actual exposure (product use 
exposure). 
Reason for change: To precise how many visits can be missed 
corresponding to ~10%. 
1.3.1 
Informed 
Consent Form 
for 
Study 
Participation 
Old text 
The subjects will be informed that following completion of 
this study, analysis of these data of exploratory nature will be 
conducted to provide better understanding of physiological 
changes in healthy smokers switching to IQOS or being 
smoking abstinent vs continued cigarette smoking.  
Amended text 
The subjects will be informed that following completion of 
this study, analysis of these data of exploratory nature will be 
conducted to provide better understanding of physiological 
changes in  activity and sleep patterns in healthy smokers 
switching to IQOS or being smoking abstinent vs continued 
cigarette smoking.  
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Reason for change: Replacement of Biovotion device with 
Garmin device and consequent alignement of captured 
parameters. 
2.3.1  
Anticipated 
benefits 
Old text 
Subjects who participate in this study will benefit from 
repeated, detailed health check-ups which may help to 
uncover undiagnosed medical conditions. 
Amended text 
Subjects who participate in this study will benefit from 
repeated, detailed health check-ups which may help to 
uncover undiagnosed medical conditions. 
Reason to change: Alignement with wording in the ICF. 
7.5.2 
 
Medical 
History, 
Concomitqnt 
Disease, 
Previous 
and 
Ongoing 
Medications 
Old text 
A concomitant disease is defined as any condition that started 
prior to ICF signature and is still ongoing at V1.  
Amended text 
A concomitant disease is defined as any condition that started 
prior to ICF signature and is still ongoing at V1. The final 
status of any concomitant disease (i.e stop date or 
ongoing) should be verified at each visit.  
Appendix 
1 
Schedule 
of 
Events 
Old text 
- 
Amended text 
Concomitant disease status (line added in Schedule of 
Events) 
Reason for change: Clarifiy the concomitant disease status 
should be checked during the study. 
7.6.1 
VO2max Test 
and 
Blood 
Lactate Levels 
Old text 
The final blood sample should be obtained within 60 seconds 
after termination of the bike exercise. 
Amended text 
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The final blood sample should be obtained within 60 seconds 
5 minutes after termination of the bike exercise. 
Reason for change: To allow for more time to collect the final 
blood sample while the subject is cooling down. 
7.6.2 
Exercise 
Capacity Test 
Old text 
The criteria for completion of the test is the completing of a 
pre-defined relative work determined as 25% more work than 
was completed during the VO2max test at V1 for the test at 
V2, and at the VO2max test V3 for the tests at V3, V4 and 
V44. 
Amended text 
The criteria for completion of the test is the completing of a 
pre-defined relative work determined as 25% more work than 
was completed during the VO2max test at V1 for the test at 
V2, and at the VO2max test V3 for the tests at V3, V4 and 
V4443. 
Reason to change: Mistake in the text. 
7.8.3 
Appendix 
1 
Urine 
Drug 
Screening 
Schedule 
of 
Events 
– 
footnote 
Old text 
At V1 and V2, urine drug screen (amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine and opiates) will be 
performed by the personnel at the investigational site. 
Amended text 
At V1 and V2, urine drug screen (amphetamines, barbiturates, 
benzodiazepines, cannabinoids, 
cocaine, 
and opiates, 
methadone, methamphetamines, phencyclidine, tricyclic 
antidepressants) will be performed by the personnel at the 
investigational site. 
Old text  
6Amphetamines, 
barbiturates, 
benzodiazepines, 
cannabinoids, cocaine and opiates. 
Amended text 
6Amphetamines, 
barbiturates, 
benzodiazepines, 
cannabinoids, 
cocaine, 
and 
opiates, 
methadone, 
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methamphetamines, 
phencyclidine, 
tricyclic 
antidepressants. 
Reason for change: The list was updated to accommodate all 
substances tested for by the site’s standard test. 
7.9. 
Long-Term 
Storage 
(Biobanking) 
Old text 
Urine: 
Samples will be collected from the spot urine for: 
x lipidomic profiling: 2 x 2 mL  
x proteomic profiling: 4 x 10 mL 
x metabolomics profiling: 4 x 10 mL 
 
Saliva: 
x 6  x 1mL saliva will be collected using a dedicated 
saliva collection kit for molecular profiling. 
 
Amended text 
Urine: 
Samples will be collected from the spot urine for: 
x lipidomic profiling: 2 x 2 mL  
x proteomic profiling: 4 2 x 10 mL 
x metabolomics profiling: 4 2x 10 mL 
 
Saliva: 
x 6 4 x 1mL saliva will be collected using a dedicated 
saliva collection kit for molecular profiling. 
 
Reason for change: Urine volumes were reduced as the 
expected volume of the spot urine collection may not allow 
for collection of the initially planned volume. Saliva volume 
was reduced to alleviate subject and site burden. 
7.10 
Mobile Health 
(mHealth) 
Wearable 
Old text  
Subjects will wear an mHealth wearable device (Everion, 
Biovotion), which is worn on the upper arm, for the 
recording of their physical activity including daily step 
count and move score, and energy expenditure. Physical 
activity is routinely identified, analyzed, and evaluated on 
the basis of producing health benefits. The daily cumulative 
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move score produced uses a 0 to 100 feedback scale (0-30 = 
poor, 30-59 = moderate, and 60-100 = good health effects). 
The score achieved varies according to the duration and 
intensity of the activity. Intensity accounts for the subject’s 
heart rate,  espiratory rate (derived from R-R intervals, i.e. 
time etween 
successive heart beats) (56, 57). The wearable will 
simultaneously record a range of physiological parameters 
as described in objective 6, however the analysis and 
reporting of this data will not be part of the CSR but 
reported separately. 
Subjects will be trained on how to wear (i.e. correct 
positioning), charge and handle the device in accordance 
with the user guide. Subjects will be instructed to wear the 
device all the time (~22-23h per day) except while charging 
and when showering or swimming (as per user guide 
instructions). The device should be charged once daily, 
preferably at the same time everyday. As part of the 
wearable device kit (device, armband, charger) subjects will 
also receive a mobile phone with Bluetooth and wireless 
internet connectivity through which data will be transferred 
from the wearable device. Subjects will wear the device in a 
blinded manner, i.e. they will not be able to see the data 
collected in order not to influence their behavior but will 
only be able to monitor battery levels. Between V2 and V3, 
baseline data will be collected, and as of randomization at 
V3 data will be collected during the investigational period 
until V43. The Everion device records physiological signals 
continuously on a per second level. For the parameters to be 
analyzed as part of the study (objective 5; steps, energy 
expenditure and move 
score) data transferred from the wearable device to the  
clinical database will be aggregated on a per 24-hour level. 
In addition, wear time per day will be monitored. Parameters 
listed in objective 6 will be transferred from the wearable 
device on a per second level to the storage cloud. 
 
Amended text 
Subjects will wear an mHealth wearable device (Everion, 
BiovotionVivofit 3, Garmin), which is worn on the upper 
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arm wrist, for the recording of their physical activity 
including daily step count and move score, and energy 
expenditure intensity minutes. Three intensity levels of 
physical activity will be recorded; 1) sedentary - little to 
no activity monitored (e.g. minimal movement, sitting, 
resting, or sleeping); 2) active – some activity monitored 
(e.g. a brisk walk); 3) very active- high activity monitored 
(e.g.running or speed walking). Physical activity is 
routinely identified, analyzed, and evaluated 
on the basis of producing health benefits. The daily 
cumulative move score produced uses a 0 
to 100 feedback scale (0-30 = poor, 30-59 = moderate, and 
60-100 = good health effects). The 
score achieved varies according to the duration and intensity 
of the activity. Intensity accounts 
for the subject’s heart rate, respiratory rate (derived from R-
R intervals, i.e. time between 
successive heart beats) (56, 57). 
The wearable will simultaneously record a range of 
physiological parametersenergy expenditure, distance and 
sleep as described in objective 6, however the analysis and 
reporting of this data will not be part of the CSR but reported 
separately.  
Subjects will be trained on how to wear (i.e. correct 
positioning), charge and handle the device in accordance 
with the user guide. Subjects will be instructed to wear the 
device on their non-dominant wrist and to wear it all the 
time (~22-23h per day) except while charging and when 
showering or swimming (as per user guide instructions). The 
device should be charged once daily, preferably at the same 
time everyday. 
As part of the wearable device kit (device, armband, 
charger) subjects will also receive a mobile phone with 
Bluetooth and wireless internet connectivity through which 
data will be transferred from the wearable device. Subjects 
will wear the device in a blinded manner, i.e.they will not be 
able to see the data collected in order not to influence their 
behavior but willonly be able to monitor battery levels. 
Between V2 and V3, baseline data will be collected, and as 
This document is an uncontrolled copy of RD_SMF02_049133_CSP_P1-EXC-01-EU, 1.0,CURRENT
Total number of pages of the document doesn't include the signature page

Philip Morris Products SA 
Clinical Study Protocol  
Confidential 
P1-EXC-01-EU 
Version 3.0 / 2 May 2019 
Page 151 of 151 
 
 
 
 
Confidentiality Statement 
Data and information contained in this document are considered to constitute trade secrets and confidential 
commercial information, and the legal protections provided to such trade secrets and confidential information are 
hereby claimed under the provisions of applicable law. No part of this document may be publicly disclosed 
without the written consent of Philip Morris Products S.A 
of randomization at V3 data will be collected during the 
investigational period until V43.  
The Everion deviceVivofit 3 device records physiological 
signals accelerometer data continuously on a per second 
leveland transfers data aggregated on a 15-min basis to 
the data storage cloud. For the parameters to be analyzed as 
part of the study (objective 5; steps, energy expenditure and 
move scoreactivity) data transferred from the wearable 
device to the clinical database will be aggregated on a per 24-
hour level. In addition, wear time per day will be monitored. 
Parameters listed in objective 6 will be transferred from the 
wearable device on a per second15-min level to the storage 
cloud. 
Reason for change: Replacement of Biovotion device with 
Garmin device.  
9.3 
Baseline and 
Randomization 
Table 7  
Footnote 
 
Old text 
COHb = Carbon monoxide 
Amended text 
COHb= Carbon monoxideCarboxyhemoglobin 
Reason for change: Mistake in the abbreviation. 
Appendix 
2  
Exercise 
Training 
Program 
Old text  
Each training session will last 40 min with a training intensity 
ranging between 60-80%. 
Amended text 
Each training session will last 40 min with a training intensity 
ranging between 60-8580%. 
Training programs including intervals and intensities will 
be described in a dedicated manual. 
Reason for change: Clarification that a training manual will 
be prepared. 
 
 
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Document Information
Document Name
RD_SMF02_049133_CSP_P1-EXC-01-EU
Document Title
CSP_P1-EXC-01-EU_Version 3.0 Draft
Version
1.0
Lifecycle
Approved Lifecycle
Status
Approved
Signature Table
Approver
Date (UTC time)
Reason for signing
Outcome
08-May-2019 10:52:13
Author Approval
Approved
08-May-2019 11:51:11
Author Approval
Approved
08-May-2019 11:01:09
Author Approval
Approved
This document is an uncontrolled copy of RD_SMF02_049133_CSP_P1-EXC-01
01
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U 1.0
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.0,CURRENT
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