Effect of Switching From Cigarette Smoking to IQOS on Exercise Capacity

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

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03887117

Enrollment

Registered

2019-03-22

Start date

2019-02-01

Completion date

2020-03-16

Last updated

2021-12-27

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Exercise Capacity, Smoking

Keywords

IQOS, Heated Tobacco

Brief summary

This exploratory study is part of the global clinical assessment program of IQOS. It was designed to provide scientific evidence to further substantiate the reduced risk potential of using a heated tobacco product (the Tobacco Heating System \[THS\] marketed as IQOS) as compared to smoking cigarettes. The main goals of this exploratory study were to assess whether switching from cigarette smoking to using IQOS would influence 1) maximum oxygen uptake during incremental exercise (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.

Detailed description

This exploratory study, with healthy adult smokers, was designed without product use restrictions (ad libitum product use) in order to replicate as closely as possible real life conditions. Subjects randomized to the cigarette and IQOS arms were asked to buy their own cigarettes or HeatSticks, respectively. Subjects randomized to the smoking abstinence (SA) arm were instructed to stay smoking abstinent until the end of the study. Subjects in the SA arm received smoking abstinence support and, in order to prevent relapse to cigarette smoking during the training program, were also allowed to use nicotine replacement therapy. Mobile health technology was 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 enabled non-invasive recording of physical activity in an objective manner throughout the study. However, results collected from this device will be reported separately. It should be noted that some study outcomes were reported graphically, rather than numerically. Consequently, these outcomes have not been included in this results disclosure.

Interventions

OTHERIQOS + Exercise Training Program

Switch to IQOS use + participation in a training program

OTHERIQOS without Exercise Training Program

Switch to IQOS use only, without participation in a training program

OTHERCigarette Smoking + Exercise Training Program

Continue to smoke cigarettes + participation in a training program

OTHERSmoking Abstinence + Exercise Training Program

Switch to smoking abstinence + participation in a training program

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

BASIC_SCIENCE

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

21 Years to 65 Years

Healthy volunteers

Yes

Inclusion criteria

* Smoking, healthy subject based on safety laboratory, ECG, spirometry, vital signs, physical examination, medical history and Investigator's assessment. * Subject has been smoking for at least three years prior to V1. * 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 both at V1 and V2. * Subject does not plan to quit smoking within 6 months after V1.

Exclusion criteria

* Subject has a clinically relevant disease which requires medication (including but not limited to gastrointestinal, renal, hepatic, 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. * Subject performs more than 45 min of vigorous physical activity per week. * Subject takes medication influencing blood volume such as erythropoietin, diuretics and beta blockers, or diabetic medications. * 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) * For women only: subject is pregnant (does not have negative pregnancy tests at V1 and at V2) or is breastfeeding. * For women of childbearing potential : female subject who does not agree to using an acceptable method of effective contraception during the entire study. * Subject has a BMI \< 18.5 kg/m2 or BMI ≥ 30 kg/m2. * Subject has a positive urine drug screen. * Subject has been previously screened for this study. * Subject, or one of their family members (e.g., spouse, parent, sibling or child), is a current or former employee of the tobacco industry. * 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. * 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).

Design outcomes

Primary

Measure	Time frame	Description
Respiratory Exchange Ratio	Measured at Baseline (V3), at week 1 (V4), and at week 12 (V43).	To measure the respiratory exchange ratio (VCO2/VO2) at VO2max
Maximal Oxygen Uptake (VO2max, Absolute Values)	Measured at baseline (V3), at week 1 (V4), and at week 12 (V43).	To measure VO2max during maximal cycle ergometer exercise (expressed in absolute values \[mL\*min-1\]).
Maximal Oxygen Uptake (VO2max, Weight-adjusted Values)	Measured at baseline (V3), at week 1 (V4), and at week 12 (V43).	To measure VO2max during maximal cycle ergometer exercise (expressed in weight-adjusted \[mL\kg-1\min-1\] values).
Maximal Oxygen Uptake (VO2max, Fat-free Weight Adjusted Values)	Measured at baseline (V3), at week 1 (V4), and at week 12 (V43).	To measure VO2max during maximal cycle ergometer exercise (expressed in fat-free weight adjusted values \[mL\kg-1\min-1\]).
Resting Pulse Rate	Measured at Baseline (V3), week 6 (V14), week 10 (V28), and week 12 (V43).	To measure resting heart rate in bpm.
Exercise Capacity	Measured at baseline (V3), at week 1 (V4), and at week 12 (V43)	To measure exercise capacity, by measuring 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 (seconds).
Exercise Training Intensity: Cumulative Work	Measured during 38 exercise training sessions of 40 minutes duration, conducted approximately 3 times a week, over 12 weeks.	To measure cumulative work (calories) produced during each 40 minute exercise training session, performed on a stationary bike, over 12 weeks.
Exercise Training Intensity: Average Work Rate	Measured during 38 exercise training sessions of 40 minutes duration, conducted approximately 3 times a week, over 12 weeks.	To measure the average work rate (watt) during each 40 minute exercise training session, performed on a stationary bike, over 12 weeks.
Exercise Training Intensity: Average Heart Rate	Measured during 38 exercise training sessions of 40 minutes duration, conducted approximately 3 times a week, over 12 weeks.	To measure the average heart rate (bpm) during each 40 minute exercise training session, performed on a stationary bike, over 12 weeks.
Exercise Training Intensity: Time Spent at Maximal Heart Rate	Measured during 38 exercise training sessions of 40 minutes duration, conducted approximately 3 times a week, over 12 weeks.	To measure the time (seconds) spent at 0-50%, 50-60%, 60-70%, 70-80 % and \>80% of maximal heart rate during each 40 minute exercise training session, performed on a stationary bike, over 12 weeks.
Hemoglobin Mass	Measured at Baseline (V3) and week 12 (V43).	To measure Hemoglobin mass (g), measured with the carbon monoxide-rebreathing method.
Red Blood Cell Volume	Measured at Baseline (V3) and week 12 (V43).	To measure Red blood cell volume (mL), measured with the carbon monoxide-rebreathing method.
Plasma Volume	Measured at Baseline (V3) and week 12 (V43).	To measure Plasma volume (mL), measured with the carbon monoxide-rebreathing method.
Total Blood Volume	Measured at Baseline (V3) and week 12 (V43).	To measure total blood volume (mL), measured with the carbon monoxide-rebreathing method.
Capillary Blood Lactate Levels	Measured at Baseline and week 15.	To measure changes from baseline of Capillary blood lactate levels (mmol/L), measured (with a portable lactate analyzer) during VO2max test.
Ventilation at VO2 Max	Measured at Baseline (V3), at week 1 (V4), and at week 12 (V43).	To measure ventilation (L/min) at VO2max.
Respiratory Rate	Measured at Baseline (V3), at week 1 (V4), and at week 12 (V43).	To measure respiratory rate (breaths per minute) at VO2max.
VCO2	Measured at Baseline (V3), at week 1 (V4), and at week 12 (V43).	To measure VCO2 (L/min) at VO2 max.
Rating of Perceived Capacity by Sex	Measured at Baseline (V3), at week 1 (V4), and at week 12 (V43).	To measure Rating of Perceived Capacity (RPC), determined by using the RPC scale. The RPC scale is a list of physical activities arranged in order, with a scale of values from least strenuous (1) to most exhausting (18 for women, 20 for men). Subjects choose the most strenuous activity, with corresponding value, which they could sustain for 30 minutes.
Rating of Perceived Exertion	Measured at Baseline (V3), at week 1 (V4), and at week 12 (V43).	To measure changes from baseline of the Rating of Perceived Exertion, determined by using the Borg scale. The Borg RPE scale is a numerical scale that ranges from 6 to 20, where 6 means no exertion at all and 20 means maximal exertion. Subjects choose a number from the scale that best describes their level of exertion during a physical activity.
Heart Rate	Measured at Baseline, at week 1, and at week 15.	To measure changes from baseline of heart rate (bpm) during VO2max test.
Oxygen Uptake	Measured at Baseline, at week 1, and at week 15.	To measure changes from baseline of Oxygen uptake during VO2max test. (mL/min)
High Density Lipoprotein (HDL)	Measured at Baseline (V3), week 6 (V14), week 10 (V28), and week 12 (V43).	To measure HDL concentrations in serum (mg/dL).
Low Density Lipoprotein (LDL)	Measured at Baseline (V3), week 6 (V14), week 10 (V28), and week 12 (V43).	To measure LDL concentrations in serum (mg/dL).
Very Low Density Lipoprotein (VLDL)	Measured at Baseline (V3), week 6 (V14), week 10 (V28), and week 12 (V43).	To measure VLDL concentrations in serum (mg/dL).
High Sensitivity C-reactive Protein (Hs-CRP)	Measured at Baseline (V3), week 6 (V14), week 10 (V28), and week 12 (V43).	To measure hs-CRP concentrations in serum (mg/dL).
Growth Hormone	Measured at Baseline (V3), week 6 (V14), week 10 (V28), and week 12 (V43).	To measure growth hormone concentrations in serum (ng/mL).
Hemoglobin A1c (HbA1c)	Measured at Baseline (V3), week 6 (V14), week 10 (V28), and week 12 (V43).	To measure glycosylated hemoglobin (HbA1c in whole blood).
Resting Systolic Blood Pressure	Measured at Baseline (V3), week 6 (V14), week 10 (V28), and week 12 (V43).	To measure resting systolic blood pressure in mmHg.
Body Fat	Measured at Baseline (V3), at week 1 (V4), and at week 12 (V43).	To measure body fat as a percentage.
Waist Circumference	Measured at Baseline (V3), at week 1 (V4), and at week 12 (V43).	To measure waist circumference in cm.
Body Weight	Measured at each visit, starting from Baseline (V3) until week 12 (V43).	To measure body weight in kilograms.
Exhaled Carbon Monoxide	Measured at each visit, starting from Baseline (V3) until week 12 (V43).	To measure exhaled carbon monoxide (ppm).
Carboxyhemoglobin	Measured at Baseline (V3), week 1 (V4), week 6 (V14), week 10 (V28), and week 12 (V43).	To measure Carboxyhemoglobin (COHb), assayed from whole blood. Expressed as % of saturation of hemoglobin.
NEQ	Measured at Baseline (V3), week 1 (V4), week 6 (V14), week 10 (V28), and week 12 (V43).	To measure Nicotine equivalents (NEQ) concentrations, measured in spot urine and expressed as concentration adjusted for creatinine.
Total NNAL	Measured at Baseline (V3), week 1 (V4), week 6 (V14), week 10 (V28), and week 12 (V43).	To measure Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) concentrations, measured in spot urine and expressed as concentration adjusted for creatinine.
CEMA	Measured at Baseline (V3), week 1 (V4), week 6 (V14), week 10 (V28), and week 12 (V43).	To measure 2-cyanoethylmercapturic acid (CEMA) concentrations, measured in spot urine and expressed as concentration adjusted for creatinine.
Nicotine/Tobacco Product Use (Cigarettes)	Recorded daily by subject, in product use diary, from study enrollment for 16 weeks.	To measure self-reported number of any nicotine/tobacco product used on a daily basis.
Nicotine/Tobacco Product Use (HeatSticks)	Recorded daily by subject, in product use diary, from study enrollment for 16 weeks.	To measure self-reported number of any nicotine/tobacco product used on a daily basis.
Nicotine/Tobacco Product Use (E-cigarettes)	Recorded daily by subject, in product use diary, from study enrollment for 16 weeks.	To measure self-reported number of any nicotine/tobacco product used on a daily basis.

Countries

Germany

Participant flow

Pre-assignment details

94 subjects were enrolled into the study, but 1 subject was not randomized. 26 subjects were randomized to Cigarette arm, 25 subjects were randomized to IQOS-1 arm, 15 subjects to IQOS-2 arm, and 27 subjects to the Smoking Abstinence (SA) arm. Subjects were requested to use the product allocated to their respective study arm, but it was considered acceptable that not all subjects randomized to the IQOS arms or to the cigarette arm exclusively used the randomized product during the study.

Participants by arm

Arm	Count
IQOS-1 IQOS + Exercise Training Program Subjects randomized to IQOS use will switch to IQOS use and participate in an exercise training program. IQOS + Exercise Training Program: Switch to IQOS use + participation in a training program	24
IQOS-2 No Training Subjects randomized to IQOS use will switch to IQOS use, but will not participate in an exercise training program. No Training: Switch to IQOS use only, without participation in a training program	14
Cigarette Smoking Cigarette Smoking + Exercise Training Program Subjects randomized to continued cigarette smoking and participation in an exercise training program. Cigarette Smoking + Exercise Training Program: Continue to smoke cigarettes + participation in a training program	25
Smoking Abstinence Smoking Abstinence + Exercise Training Program Subjects randomized to smoking abstinence and participation in an exercise training program. Smoking Abstinence + Exercise Training Program: Switch to smoking abstinence + participation in a training program	27
Total	90

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Overall Study	Discontinued prematurely	0	1	1	2

Baseline characteristics

Characteristic	IQOS-2	Cigarette Smoking	IQOS-1	Smoking Abstinence	Total
Age, Continuous	40.5 years STANDARD_DEVIATION 13.4	40.0 years STANDARD_DEVIATION 10.9	38.8 years STANDARD_DEVIATION 12.8	40.2 years STANDARD_DEVIATION 10.3	39.8 years STANDARD_DEVIATION 11.5
Cigarettes smoked/day (last year)	17.2 cigarettes/day STANDARD_DEVIATION 4.3	18.0 cigarettes/day STANDARD_DEVIATION 4.69	18.8 cigarettes/day STANDARD_DEVIATION 5.51	18.9 cigarettes/day STANDARD_DEVIATION 6.66	18.4 cigarettes/day STANDARD_DEVIATION 5.46
Height (cm)	171 cm STANDARD_DEVIATION 10.4	171 cm STANDARD_DEVIATION 8.25	171 cm STANDARD_DEVIATION 10.3	171 cm STANDARD_DEVIATION 9.19	171 cm STANDARD_DEVIATION 9.27
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	14 Participants	25 Participants	24 Participants	27 Participants	90 Participants
Sex: Female, Male Female	7 Participants	14 Participants	12 Participants	16 Participants	49 Participants
Sex: Female, Male Male	7 Participants	11 Participants	12 Participants	11 Participants	41 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	0 / 22	0 / 22	0 / 13	0 / 24	0 / 12
other Total, other adverse events	12 / 22	10 / 22	8 / 13	12 / 24	5 / 12
serious Total, serious adverse events	0 / 22	0 / 22	1 / 13	1 / 24	0 / 12

Outcome results

Primary

Body Fat

To measure body fat as a percentage.

Time frame: Measured at Baseline (V3), at week 1 (V4), and at week 12 (V43).

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	Body Fat	Baseline (V3)	27.8 % (body fat)
Cigarette Smoking	Body Fat	Training Effect (V43)	30.6 % (body fat)
Cigarette Smoking	Body Fat	Acute Effect (V4)	28.1 % (body fat)
IQOS-1	Body Fat	Acute Effect (V4)	28.6 % (body fat)
IQOS-1	Body Fat	Baseline (V3)	28.2 % (body fat)
IQOS-1	Body Fat	Training Effect (V43)	27.5 % (body fat)
IQOS-2	Body Fat	Acute Effect (V4)	25.4 % (body fat)
IQOS-2	Body Fat	Baseline (V3)	25.6 % (body fat)
IQOS-2	Body Fat	Training Effect (V43)	28 % (body fat)
Smoking Abstinence	Body Fat	Baseline (V3)	27.3 % (body fat)
Smoking Abstinence	Body Fat	Training Effect (V43)	29.9 % (body fat)
Smoking Abstinence	Body Fat	Acute Effect (V4)	28.1 % (body fat)
Dual-1	Body Fat	Acute Effect (V4)	28 % (body fat)
Dual-1	Body Fat	Baseline (V3)	20.5 % (body fat)
Dual-1	Body Fat	Training Effect (V43)	30.1 % (body fat)

Primary

Body Weight

To measure body weight in kilograms.

Time frame: Measured at each visit, starting from Baseline (V3) until week 12 (V43).

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	Body Weight	Month 2 (V14 - V27)	72 kg
Cigarette Smoking	Body Weight	Baseline (V3)	72 kg
Cigarette Smoking	Body Weight	Month 3 (V28 - V43)	72 kg
Cigarette Smoking	Body Weight	Acute Effect (V4)	72.2 kg
Cigarette Smoking	Body Weight	Month 1 (V5 - V13)	72 kg
IQOS-1	Body Weight	Month 2 (V14 - V27)	75.8 kg
IQOS-1	Body Weight	Month 1 (V5 - V13)	75.7 kg
IQOS-1	Body Weight	Acute Effect (V4)	75.7 kg
IQOS-1	Body Weight	Month 3 (V28 - V43)	75.8 kg
IQOS-1	Body Weight	Baseline (V3)	75.7 kg
IQOS-2	Body Weight	Month 1 (V5 - V13)	75.7 kg
IQOS-2	Body Weight	Baseline (V3)	75.5 kg
IQOS-2	Body Weight	Acute Effect (V4)	75.5 kg
IQOS-2	Body Weight	Month 2 (V14 - V27)	76.1 kg
IQOS-2	Body Weight	Month 3 (V28 - V43)	76.6 kg
Smoking Abstinence	Body Weight	Month 3 (V28 - V43)	78.3 kg
Smoking Abstinence	Body Weight	Baseline (V3)	77.5 kg
Smoking Abstinence	Body Weight	Month 2 (V14 - V27)	78.1 kg
Smoking Abstinence	Body Weight	Month 1 (V5 - V13)	77.9 kg
Smoking Abstinence	Body Weight	Acute Effect (V4)	77.6 kg
Dual-1	Body Weight	Month 1 (V5 - V13)	69.8 kg
Dual-1	Body Weight	Month 2 (V14 - V27)	70.2 kg
Dual-1	Body Weight	Baseline (V3)	69.3 kg
Dual-1	Body Weight	Month 3 (V28 - V43)	70.5 kg
Dual-1	Body Weight	Acute Effect (V4)	69.6 kg

Primary

Capillary Blood Lactate Levels

To measure changes from baseline of Capillary blood lactate levels (mmol/L), measured (with a portable lactate analyzer) during VO2max test.

Time frame: Measured at Baseline and week 15.

Primary

Carboxyhemoglobin

To measure Carboxyhemoglobin (COHb), assayed from whole blood. Expressed as % of saturation of hemoglobin.

Time frame: Measured at Baseline (V3), week 1 (V4), week 6 (V14), week 10 (V28), and week 12 (V43).

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (GEOMETRIC_MEAN)
Cigarette Smoking	Carboxyhemoglobin	Week 10 (V28)	3.01 % (of saturation of hemoglobin)
Cigarette Smoking	Carboxyhemoglobin	Baseline (V3)	1.92 % (of saturation of hemoglobin)
Cigarette Smoking	Carboxyhemoglobin	Week 12 (V43)	2.04 % (of saturation of hemoglobin)
Cigarette Smoking	Carboxyhemoglobin	Week 1 (V4)	3.29 % (of saturation of hemoglobin)
Cigarette Smoking	Carboxyhemoglobin	Week 6 (V14)	2.51 % (of saturation of hemoglobin)
IQOS-1	Carboxyhemoglobin	Week 10 (V28)	0.338 % (of saturation of hemoglobin)
IQOS-1	Carboxyhemoglobin	Week 6 (V14)	0.350 % (of saturation of hemoglobin)
IQOS-1	Carboxyhemoglobin	Week 1 (V4)	0.422 % (of saturation of hemoglobin)
IQOS-1	Carboxyhemoglobin	Week 12 (V43)	0.187 % (of saturation of hemoglobin)
IQOS-1	Carboxyhemoglobin	Baseline (V3)	2.37 % (of saturation of hemoglobin)
IQOS-2	Carboxyhemoglobin	Week 6 (V14)	0.109 % (of saturation of hemoglobin)
IQOS-2	Carboxyhemoglobin	Baseline (V3)	1.71 % (of saturation of hemoglobin)
IQOS-2	Carboxyhemoglobin	Week 1 (V4)	0.372 % (of saturation of hemoglobin)
IQOS-2	Carboxyhemoglobin	Week 10 (V28)	0.285 % (of saturation of hemoglobin)
IQOS-2	Carboxyhemoglobin	Week 12 (V43)	0.0674 % (of saturation of hemoglobin)
Smoking Abstinence	Carboxyhemoglobin	Week 12 (V43)	0.0864 % (of saturation of hemoglobin)
Smoking Abstinence	Carboxyhemoglobin	Baseline (V3)	1.74 % (of saturation of hemoglobin)
Smoking Abstinence	Carboxyhemoglobin	Week 10 (V28)	0.189 % (of saturation of hemoglobin)
Smoking Abstinence	Carboxyhemoglobin	Week 6 (V14)	0.110 % (of saturation of hemoglobin)
Smoking Abstinence	Carboxyhemoglobin	Week 1 (V4)	0.272 % (of saturation of hemoglobin)
Dual-1	Carboxyhemoglobin	Week 6 (V14)	0.272 % (of saturation of hemoglobin)
Dual-1	Carboxyhemoglobin	Week 10 (V28)	0.432 % (of saturation of hemoglobin)
Dual-1	Carboxyhemoglobin	Baseline (V3)	2.50 % (of saturation of hemoglobin)
Dual-1	Carboxyhemoglobin	Week 12 (V43)	0.132 % (of saturation of hemoglobin)
Dual-1	Carboxyhemoglobin	Week 1 (V4)	0.426 % (of saturation of hemoglobin)

Primary

CEMA

To measure 2-cyanoethylmercapturic acid (CEMA) concentrations, measured in spot urine and expressed as concentration adjusted for creatinine.

Time frame: Measured at Baseline (V3), week 1 (V4), week 6 (V14), week 10 (V28), and week 12 (V43).

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (GEOMETRIC_MEAN)
Cigarette Smoking	CEMA	Week 10 (V28)	148 ng/mg creat
Cigarette Smoking	CEMA	Baseline (V3)	140 ng/mg creat
Cigarette Smoking	CEMA	Week 12 (V43)	141 ng/mg creat
Cigarette Smoking	CEMA	Week 1 (V4)	147 ng/mg creat
Cigarette Smoking	CEMA	Week 6 (V14)	139 ng/mg creat
IQOS-1	CEMA	Week 10 (V28)	23.6 ng/mg creat
IQOS-1	CEMA	Week 6 (V14)	26.6 ng/mg creat
IQOS-1	CEMA	Week 1 (V4)	39.5 ng/mg creat
IQOS-1	CEMA	Week 12 (V43)	24.8 ng/mg creat
IQOS-1	CEMA	Baseline (V3)	170 ng/mg creat
IQOS-2	CEMA	Week 6 (V14)	15.3 ng/mg creat
IQOS-2	CEMA	Baseline (V3)	135 ng/mg creat
IQOS-2	CEMA	Week 1 (V4)	28.1 ng/mg creat
IQOS-2	CEMA	Week 10 (V28)	12.7 ng/mg creat
IQOS-2	CEMA	Week 12 (V43)	8.67 ng/mg creat
Smoking Abstinence	CEMA	Week 12 (V43)	12.7 ng/mg creat
Smoking Abstinence	CEMA	Baseline (V3)	128 ng/mg creat
Smoking Abstinence	CEMA	Week 10 (V28)	11.0 ng/mg creat
Smoking Abstinence	CEMA	Week 6 (V14)	12.1 ng/mg creat
Smoking Abstinence	CEMA	Week 1 (V4)	25.3 ng/mg creat
Dual-1	CEMA	Week 6 (V14)	33.1 ng/mg creat
Dual-1	CEMA	Week 10 (V28)	19.3 ng/mg creat
Dual-1	CEMA	Baseline (V3)	144 ng/mg creat
Dual-1	CEMA	Week 12 (V43)	16.5 ng/mg creat
Dual-1	CEMA	Week 1 (V4)	37.5 ng/mg creat

Primary

Exercise Capacity

To measure exercise capacity, by measuring 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 (seconds).

Time frame: Measured at baseline (V3), at week 1 (V4), and at week 12 (V43)

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	Exercise Capacity	Acute Effect (V4)	2205 seconds
Cigarette Smoking	Exercise Capacity	Training Effect (V43)	1985 seconds
Cigarette Smoking	Exercise Capacity	Acute Baseline (V3)	2283 seconds
IQOS-1	Exercise Capacity	Acute Effect (V4)	2189 seconds
IQOS-1	Exercise Capacity	Acute Baseline (V3)	2366 seconds
IQOS-1	Exercise Capacity	Training Effect (V43)	2123 seconds
IQOS-2	Exercise Capacity	Acute Effect (V4)	2170 seconds
IQOS-2	Exercise Capacity	Acute Baseline (V3)	2330 seconds
IQOS-2	Exercise Capacity	Training Effect (V43)	2374 seconds
Smoking Abstinence	Exercise Capacity	Acute Baseline (V3)	2156 seconds
Smoking Abstinence	Exercise Capacity	Acute Effect (V4)	2210 seconds
Smoking Abstinence	Exercise Capacity	Training Effect (V43)	1849 seconds
Dual-1	Exercise Capacity	Acute Baseline (V3)	2110 seconds
Dual-1	Exercise Capacity	Acute Effect (V4)	2402 seconds
Dual-2	Exercise Capacity	Acute Baseline (V3)	2871 seconds
Dual-2	Exercise Capacity	Acute Effect (V4)	3006 seconds
Other	Exercise Capacity	Training Effect (V43)	1982 seconds
Other	Exercise Capacity	Acute Effect (V4)	2190 seconds
Other	Exercise Capacity	Acute Baseline (V3)	2147 seconds

Primary

Exercise Training Intensity: Average Heart Rate

To measure the average heart rate (bpm) during each 40 minute exercise training session, performed on a stationary bike, over 12 weeks.

Time frame: Measured during 38 exercise training sessions of 40 minutes duration, conducted approximately 3 times a week, over 12 weeks.

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	Exercise Training Intensity: Average Heart Rate	Baseline (V5)	125 beats/minute
Cigarette Smoking	Exercise Training Intensity: Average Heart Rate	V14	119 beats/minute
Cigarette Smoking	Exercise Training Intensity: Average Heart Rate	V29	124 beats/minute
Cigarette Smoking	Exercise Training Intensity: Average Heart Rate	V41	125 beats/minute
IQOS-1	Exercise Training Intensity: Average Heart Rate	V14	127 beats/minute
IQOS-1	Exercise Training Intensity: Average Heart Rate	V29	124 beats/minute
IQOS-1	Exercise Training Intensity: Average Heart Rate	V41	122 beats/minute
IQOS-1	Exercise Training Intensity: Average Heart Rate	Baseline (V5)	127 beats/minute
IQOS-2	Exercise Training Intensity: Average Heart Rate	V29	121 beats/minute
IQOS-2	Exercise Training Intensity: Average Heart Rate	V14	121 beats/minute
IQOS-2	Exercise Training Intensity: Average Heart Rate	V41	123 beats/minute
IQOS-2	Exercise Training Intensity: Average Heart Rate	Baseline (V5)	123 beats/minute
Smoking Abstinence	Exercise Training Intensity: Average Heart Rate	V41	120 beats/minute
Smoking Abstinence	Exercise Training Intensity: Average Heart Rate	V14	125 beats/minute
Smoking Abstinence	Exercise Training Intensity: Average Heart Rate	Baseline (V5)	110 beats/minute
Smoking Abstinence	Exercise Training Intensity: Average Heart Rate	V29	123 beats/minute

Primary

Exercise Training Intensity: Average Work Rate

To measure the average work rate (watt) during each 40 minute exercise training session, performed on a stationary bike, over 12 weeks.

Time frame: Measured during 38 exercise training sessions of 40 minutes duration, conducted approximately 3 times a week, over 12 weeks.

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	Exercise Training Intensity: Average Work Rate	Baseline (V5)	70.7 Watt
Cigarette Smoking	Exercise Training Intensity: Average Work Rate	V14	81.7 Watt
Cigarette Smoking	Exercise Training Intensity: Average Work Rate	V29	74.0 Watt
Cigarette Smoking	Exercise Training Intensity: Average Work Rate	V41	76.9 Watt
IQOS-1	Exercise Training Intensity: Average Work Rate	V14	78.7 Watt
IQOS-1	Exercise Training Intensity: Average Work Rate	V29	80.4 Watt
IQOS-1	Exercise Training Intensity: Average Work Rate	V41	82.1 Watt
IQOS-1	Exercise Training Intensity: Average Work Rate	Baseline (V5)	87.6 Watt
IQOS-2	Exercise Training Intensity: Average Work Rate	V29	90.9 Watt
IQOS-2	Exercise Training Intensity: Average Work Rate	V14	90.5 Watt
IQOS-2	Exercise Training Intensity: Average Work Rate	V41	85.8 Watt
IQOS-2	Exercise Training Intensity: Average Work Rate	Baseline (V5)	84.4 Watt
Smoking Abstinence	Exercise Training Intensity: Average Work Rate	V41	89.0 Watt
Smoking Abstinence	Exercise Training Intensity: Average Work Rate	V14	80.5 Watt
Smoking Abstinence	Exercise Training Intensity: Average Work Rate	Baseline (V5)	82.8 Watt
Smoking Abstinence	Exercise Training Intensity: Average Work Rate	V29	85.3 Watt

Primary

Exercise Training Intensity: Cumulative Work

To measure cumulative work (calories) produced during each 40 minute exercise training session, performed on a stationary bike, over 12 weeks.

Time frame: Measured during 38 exercise training sessions of 40 minutes duration, conducted approximately 3 times a week, over 12 weeks.

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	Exercise Training Intensity: Cumulative Work	Baseline (V5)	169 calorie
Cigarette Smoking	Exercise Training Intensity: Cumulative Work	V14	203 calorie
Cigarette Smoking	Exercise Training Intensity: Cumulative Work	V29	183 calorie
Cigarette Smoking	Exercise Training Intensity: Cumulative Work	V41	187 calorie
IQOS-1	Exercise Training Intensity: Cumulative Work	V14	196 calorie
IQOS-1	Exercise Training Intensity: Cumulative Work	V29	197 calorie
IQOS-1	Exercise Training Intensity: Cumulative Work	V41	199 calorie
IQOS-1	Exercise Training Intensity: Cumulative Work	Baseline (V5)	222 calorie
IQOS-2	Exercise Training Intensity: Cumulative Work	V29	223 calorie
IQOS-2	Exercise Training Intensity: Cumulative Work	V14	231 calorie
IQOS-2	Exercise Training Intensity: Cumulative Work	V41	211 calorie
IQOS-2	Exercise Training Intensity: Cumulative Work	Baseline (V5)	208 calorie
Smoking Abstinence	Exercise Training Intensity: Cumulative Work	V41	219 calorie
Smoking Abstinence	Exercise Training Intensity: Cumulative Work	V14	195 calorie
Smoking Abstinence	Exercise Training Intensity: Cumulative Work	Baseline (V5)	203 calorie
Smoking Abstinence	Exercise Training Intensity: Cumulative Work	V29	214 calorie

Primary

Exercise Training Intensity: Time Spent at Maximal Heart Rate

To measure the time (seconds) spent at 0-50%, 50-60%, 60-70%, 70-80 % and \>80% of maximal heart rate during each 40 minute exercise training session, performed on a stationary bike, over 12 weeks.

Time frame: Measured during 38 exercise training sessions of 40 minutes duration, conducted approximately 3 times a week, over 12 weeks.

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 29: 0-50%	83.1 seconds
Cigarette Smoking	Exercise Training Intensity: Time Spent at Maximal Heart Rate	V5 (Baseline): 0-50%	33.7 seconds
Cigarette Smoking	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 29: 50-60%	25.3 seconds
Cigarette Smoking	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 29: >80%	1411 seconds
Cigarette Smoking	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 29: 60-70%	120 seconds
Cigarette Smoking	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 14: 50-60%	25.3 seconds
Cigarette Smoking	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 29: 70-80%	731 seconds
Cigarette Smoking	Exercise Training Intensity: Time Spent at Maximal Heart Rate	V5 (Baseline): 70-80%	793 seconds
Cigarette Smoking	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 41: 70-80%	871 seconds
Cigarette Smoking	Exercise Training Intensity: Time Spent at Maximal Heart Rate	V5 (Baseline): >80%	1438 seconds
Cigarette Smoking	Exercise Training Intensity: Time Spent at Maximal Heart Rate	V5 (Baseline): 50-60%	29.7 seconds
Cigarette Smoking	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 14: 0-50%	12.4 seconds
Cigarette Smoking	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 41: 60-70%	99.3 seconds
Cigarette Smoking	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 14: 60-70%	145 seconds
Cigarette Smoking	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 41: >80%	1377 seconds
Cigarette Smoking	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 41: 50-60%	12.3 seconds
Cigarette Smoking	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 14: 70-80%	807 seconds
Cigarette Smoking	Exercise Training Intensity: Time Spent at Maximal Heart Rate	V5 (Baseline): 60-70%	86.1 seconds
Cigarette Smoking	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 14: >80%	1370 seconds
Cigarette Smoking	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 41: 0-50%	11.1 seconds
IQOS-1	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 41: 60-70%	308 seconds
IQOS-1	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 29: 0-50%	17.2 seconds
IQOS-1	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 41: 0-50%	22.6 seconds
IQOS-1	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 29: >80%	1201 seconds
IQOS-1	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 14: 0-50%	7.24 seconds
IQOS-1	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 29: 50-60%	32.9 seconds
IQOS-1	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 41: 70-80%	825 seconds
IQOS-1	Exercise Training Intensity: Time Spent at Maximal Heart Rate	V5 (Baseline): 50-60%	42.2 seconds
IQOS-1	Exercise Training Intensity: Time Spent at Maximal Heart Rate	V5 (Baseline): 60-70%	130 seconds
IQOS-1	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 29: 60-70%	236 seconds
IQOS-1	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 14: 50-60%	32.1 seconds
IQOS-1	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 29: 70-80%	887 seconds
IQOS-1	Exercise Training Intensity: Time Spent at Maximal Heart Rate	V5 (Baseline): 0-50%	26.1 seconds
IQOS-1	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 41: 50-60%	34.0 seconds
IQOS-1	Exercise Training Intensity: Time Spent at Maximal Heart Rate	V5 (Baseline): 70-80%	737 seconds
IQOS-1	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 41: >80%	1185 seconds
IQOS-1	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 14: 70-80%	783 seconds
IQOS-1	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 14: 60-70%	139 seconds
IQOS-1	Exercise Training Intensity: Time Spent at Maximal Heart Rate	V5 (Baseline): >80%	1405 seconds
IQOS-1	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 14: >80%	1424 seconds
IQOS-2	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 29: 60-70%	259 seconds
IQOS-2	Exercise Training Intensity: Time Spent at Maximal Heart Rate	V5 (Baseline): 0-50%	14.2 seconds
IQOS-2	Exercise Training Intensity: Time Spent at Maximal Heart Rate	V5 (Baseline): 50-60%	38.6 seconds
IQOS-2	Exercise Training Intensity: Time Spent at Maximal Heart Rate	V5 (Baseline): 60-70%	131 seconds
IQOS-2	Exercise Training Intensity: Time Spent at Maximal Heart Rate	V5 (Baseline): 70-80%	743 seconds
IQOS-2	Exercise Training Intensity: Time Spent at Maximal Heart Rate	V5 (Baseline): >80%	1415 seconds
IQOS-2	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 14: 0-50%	13.5 seconds
IQOS-2	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 14: 50-60%	38.0 seconds
IQOS-2	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 14: 60-70%	188 seconds
IQOS-2	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 14: 70-80%	880 seconds
IQOS-2	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 14: >80%	1260 seconds
IQOS-2	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 29: 0-50%	32.2 seconds
IQOS-2	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 29: 50-60%	43.0 seconds
IQOS-2	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 29: 70-80%	732 seconds
IQOS-2	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 29: >80%	1293 seconds
IQOS-2	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 41: 0-50%	6.60 seconds
IQOS-2	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 41: 50-60%	25.5 seconds
IQOS-2	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 41: 60-70%	171 seconds
IQOS-2	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 41: 70-80%	877 seconds
IQOS-2	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 41: >80%	1293 seconds
Smoking Abstinence	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 14: >80%	1386 seconds
Smoking Abstinence	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 14: 70-80%	888 seconds
Smoking Abstinence	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 41: 70-80%	1032 seconds
Smoking Abstinence	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 41: 0-50%	1.33 seconds
Smoking Abstinence	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 14: 60-70%	77.8 seconds
Smoking Abstinence	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 14: 50-60%	28.5 seconds
Smoking Abstinence	Exercise Training Intensity: Time Spent at Maximal Heart Rate	V5 (Baseline): 50-60%	162 seconds
Smoking Abstinence	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 41: 50-60%	5.33 seconds
Smoking Abstinence	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 14: 0-50%	7.0 seconds
Smoking Abstinence	Exercise Training Intensity: Time Spent at Maximal Heart Rate	V5 (Baseline): >80%	944 seconds
Smoking Abstinence	Exercise Training Intensity: Time Spent at Maximal Heart Rate	V5 (Baseline): 0-50%	361 seconds
Smoking Abstinence	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 41: 60-70%	271 seconds
Smoking Abstinence	Exercise Training Intensity: Time Spent at Maximal Heart Rate	V5 (Baseline): 70-80%	591 seconds
Smoking Abstinence	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 29: 60-70%	130 seconds
Smoking Abstinence	Exercise Training Intensity: Time Spent at Maximal Heart Rate	V5 (Baseline): 60-70%	301 seconds
Smoking Abstinence	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 29: 70-80%	855 seconds
Smoking Abstinence	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 29: 50-60%	54.7 seconds
Smoking Abstinence	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 29: 0-50%	30.0 seconds
Smoking Abstinence	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 41: >80%	1091 seconds
Smoking Abstinence	Exercise Training Intensity: Time Spent at Maximal Heart Rate	Visit 29: >80%	1286 seconds

Primary

Exhaled Carbon Monoxide

To measure exhaled carbon monoxide (ppm).

Time frame: Measured at each visit, starting from Baseline (V3) until week 12 (V43).

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	Exhaled Carbon Monoxide	Week 10 (V28)	20.6 ppm
Cigarette Smoking	Exhaled Carbon Monoxide	Baseline (V3)	20.8 ppm
Cigarette Smoking	Exhaled Carbon Monoxide	Week 12 (V43)	21.8 ppm
Cigarette Smoking	Exhaled Carbon Monoxide	Week 1 (V4)	25.4 ppm
Cigarette Smoking	Exhaled Carbon Monoxide	Week 6 (V14)	20.6 ppm
IQOS-1	Exhaled Carbon Monoxide	Week 10 (V28)	4.58 ppm
IQOS-1	Exhaled Carbon Monoxide	Week 6 (V14)	5.00 ppm
IQOS-1	Exhaled Carbon Monoxide	Week 1 (V4)	6.16 ppm
IQOS-1	Exhaled Carbon Monoxide	Week 12 (V43)	5.79 ppm
IQOS-1	Exhaled Carbon Monoxide	Baseline (V3)	20.8 ppm
IQOS-2	Exhaled Carbon Monoxide	Week 6 (V14)	8.38 ppm
IQOS-2	Exhaled Carbon Monoxide	Baseline (V3)	19.7 ppm
IQOS-2	Exhaled Carbon Monoxide	Week 1 (V4)	5.46 ppm
IQOS-2	Exhaled Carbon Monoxide	Week 10 (V28)	4.00 ppm
IQOS-2	Exhaled Carbon Monoxide	Week 12 (V43)	3.17 ppm
Smoking Abstinence	Exhaled Carbon Monoxide	Week 12 (V43)	3.05 ppm
Smoking Abstinence	Exhaled Carbon Monoxide	Baseline (V3)	18.6 ppm
Smoking Abstinence	Exhaled Carbon Monoxide	Week 10 (V28)	2.64 ppm
Smoking Abstinence	Exhaled Carbon Monoxide	Week 6 (V14)	2.77 ppm
Smoking Abstinence	Exhaled Carbon Monoxide	Week 1 (V4)	3.55 ppm
Dual-1	Exhaled Carbon Monoxide	Week 6 (V14)	2.60 ppm
Dual-1	Exhaled Carbon Monoxide	Week 10 (V28)	2.40 ppm
Dual-1	Exhaled Carbon Monoxide	Baseline (V3)	20.4 ppm
Dual-1	Exhaled Carbon Monoxide	Week 12 (V43)	2.00 ppm
Dual-1	Exhaled Carbon Monoxide	Week 1 (V4)	4.80 ppm

Primary

Growth Hormone

To measure growth hormone concentrations in serum (ng/mL).

Time frame: Measured at Baseline (V3), week 6 (V14), week 10 (V28), and week 12 (V43).

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	Growth Hormone	Baseline (V3)	2.15 ng/mL
Cigarette Smoking	Growth Hormone	Week 6 (V14)	1.25 ng/mL
Cigarette Smoking	Growth Hormone	Week 10 (V28)	1.45 ng/mL
Cigarette Smoking	Growth Hormone	Week 12 (V43)	1.98 ng/mL
IQOS-1	Growth Hormone	Baseline (V3)	1.37 ng/mL
IQOS-1	Growth Hormone	Week 12 (V43)	1.44 ng/mL
IQOS-1	Growth Hormone	Week 6 (V14)	1.49 ng/mL
IQOS-1	Growth Hormone	Week 10 (V28)	0.907 ng/mL
IQOS-2	Growth Hormone	Week 12 (V43)	1.94 ng/mL
IQOS-2	Growth Hormone	Week 6 (V14)	1.22 ng/mL
IQOS-2	Growth Hormone	Week 10 (V28)	1.31 ng/mL
IQOS-2	Growth Hormone	Baseline (V3)	2.49 ng/mL
Smoking Abstinence	Growth Hormone	Baseline (V3)	4.03 ng/mL
Smoking Abstinence	Growth Hormone	Week 6 (V14)	1.30 ng/mL
Smoking Abstinence	Growth Hormone	Week 12 (V43)	1.55 ng/mL
Smoking Abstinence	Growth Hormone	Week 10 (V28)	1.97 ng/mL
Dual-1	Growth Hormone	Week 12 (V43)	0.492 ng/mL
Dual-1	Growth Hormone	Week 10 (V28)	0.536 ng/mL
Dual-1	Growth Hormone	Week 6 (V14)	1.13 ng/mL
Dual-1	Growth Hormone	Baseline (V3)	2.02 ng/mL

Primary

Heart Rate

To measure changes from baseline of heart rate (bpm) during VO2max test.

Time frame: Measured at Baseline, at week 1, and at week 15.

Primary

Hemoglobin A1c (HbA1c)

To measure glycosylated hemoglobin (HbA1c in whole blood).

Time frame: Measured at Baseline (V3), week 6 (V14), week 10 (V28), and week 12 (V43).

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	Hemoglobin A1c (HbA1c)	Baseline (V3)	5.44 % (of red blood cells)
Cigarette Smoking	Hemoglobin A1c (HbA1c)	Week 6 (V14)	5.41 % (of red blood cells)
Cigarette Smoking	Hemoglobin A1c (HbA1c)	Week 10 (V28)	5.38 % (of red blood cells)
Cigarette Smoking	Hemoglobin A1c (HbA1c)	Week 12 (V43)	5.40 % (of red blood cells)
IQOS-1	Hemoglobin A1c (HbA1c)	Baseline (V3)	5.39 % (of red blood cells)
IQOS-1	Hemoglobin A1c (HbA1c)	Week 12 (V43)	5.35 % (of red blood cells)
IQOS-1	Hemoglobin A1c (HbA1c)	Week 6 (V14)	5.35 % (of red blood cells)
IQOS-1	Hemoglobin A1c (HbA1c)	Week 10 (V28)	5.34 % (of red blood cells)
IQOS-2	Hemoglobin A1c (HbA1c)	Week 12 (V43)	5.34 % (of red blood cells)
IQOS-2	Hemoglobin A1c (HbA1c)	Week 6 (V14)	5.41 % (of red blood cells)
IQOS-2	Hemoglobin A1c (HbA1c)	Week 10 (V28)	5.38 % (of red blood cells)
IQOS-2	Hemoglobin A1c (HbA1c)	Baseline (V3)	5.38 % (of red blood cells)
Smoking Abstinence	Hemoglobin A1c (HbA1c)	Baseline (V3)	5.53 % (of red blood cells)
Smoking Abstinence	Hemoglobin A1c (HbA1c)	Week 6 (V14)	5.50 % (of red blood cells)
Smoking Abstinence	Hemoglobin A1c (HbA1c)	Week 12 (V43)	5.50 % (of red blood cells)
Smoking Abstinence	Hemoglobin A1c (HbA1c)	Week 10 (V28)	5.49 % (of red blood cells)
Dual-1	Hemoglobin A1c (HbA1c)	Week 12 (V43)	5.34 % (of red blood cells)
Dual-1	Hemoglobin A1c (HbA1c)	Week 10 (V28)	5.28 % (of red blood cells)
Dual-1	Hemoglobin A1c (HbA1c)	Week 6 (V14)	5.28 % (of red blood cells)
Dual-1	Hemoglobin A1c (HbA1c)	Baseline (V3)	5.36 % (of red blood cells)

Primary

Hemoglobin Mass

To measure Hemoglobin mass (g), measured with the carbon monoxide-rebreathing method.

Time frame: Measured at Baseline (V3) and week 12 (V43).

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	Hemoglobin Mass	Baseline (V3)	861 g
Cigarette Smoking	Hemoglobin Mass	Week 12 (V43)	1194 g
IQOS-1	Hemoglobin Mass	Baseline (V3)	796 g
IQOS-1	Hemoglobin Mass	Week 12 (V43)	1176 g
IQOS-2	Hemoglobin Mass	Baseline (V3)	905 g
IQOS-2	Hemoglobin Mass	Week 12 (V43)	1224 g
Smoking Abstinence	Hemoglobin Mass	Week 12 (V43)	1217 g
Smoking Abstinence	Hemoglobin Mass	Baseline (V3)	883 g
Dual-1	Hemoglobin Mass	Baseline (V3)	766 g
Dual-1	Hemoglobin Mass	Week 12 (V43)	900 g

Primary

High Density Lipoprotein (HDL)

To measure HDL concentrations in serum (mg/dL).

Time frame: Measured at Baseline (V3), week 6 (V14), week 10 (V28), and week 12 (V43).

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	High Density Lipoprotein (HDL)	Week 6 (V14)	48.6 mg/dL
Cigarette Smoking	High Density Lipoprotein (HDL)	Week 12 (V43)	47.8 mg/dL
Cigarette Smoking	High Density Lipoprotein (HDL)	Week 10 (V28)	51.0 mg/dL
Cigarette Smoking	High Density Lipoprotein (HDL)	Baseline (V3)	49.3 mg/dL
IQOS-1	High Density Lipoprotein (HDL)	Week 12 (V43)	48.7 mg/dL
IQOS-1	High Density Lipoprotein (HDL)	Week 6 (V14)	53.3 mg/dL
IQOS-1	High Density Lipoprotein (HDL)	Week 10 (V28)	49.0 mg/dL
IQOS-1	High Density Lipoprotein (HDL)	Baseline (V3)	48.2 mg/dL
IQOS-2	High Density Lipoprotein (HDL)	Week 6 (V14)	51.0 mg/dL
IQOS-2	High Density Lipoprotein (HDL)	Baseline (V3)	47.1 mg/dL
IQOS-2	High Density Lipoprotein (HDL)	Week 12 (V43)	50.1 mg/dL
IQOS-2	High Density Lipoprotein (HDL)	Week 10 (V28)	51.8 mg/dL
Smoking Abstinence	High Density Lipoprotein (HDL)	Week 6 (V14)	53.6 mg/dL
Smoking Abstinence	High Density Lipoprotein (HDL)	Baseline (V3)	52.1 mg/dL
Smoking Abstinence	High Density Lipoprotein (HDL)	Week 12 (V43)	55.6 mg/dL
Smoking Abstinence	High Density Lipoprotein (HDL)	Week 10 (V28)	53.3 mg/dL
Dual-1	High Density Lipoprotein (HDL)	Week 12 (V43)	49.1 mg/dL
Dual-1	High Density Lipoprotein (HDL)	Week 6 (V14)	54.7 mg/dL
Dual-1	High Density Lipoprotein (HDL)	Week 10 (V28)	56.2 mg/dL
Dual-1	High Density Lipoprotein (HDL)	Baseline (V3)	55.4 mg/dL

Primary

High Sensitivity C-reactive Protein (Hs-CRP)

To measure hs-CRP concentrations in serum (mg/dL).

Time frame: Measured at Baseline (V3), week 6 (V14), week 10 (V28), and week 12 (V43).

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	High Sensitivity C-reactive Protein (Hs-CRP)	Baseline (V3)	2.10 mg/L
Cigarette Smoking	High Sensitivity C-reactive Protein (Hs-CRP)	Week 6 (V14)	1.40 mg/L
Cigarette Smoking	High Sensitivity C-reactive Protein (Hs-CRP)	Week 10 (V28)	1.67 mg/L
Cigarette Smoking	High Sensitivity C-reactive Protein (Hs-CRP)	Week 12 (V43)	1.55 mg/L
IQOS-1	High Sensitivity C-reactive Protein (Hs-CRP)	Baseline (V3)	2.19 mg/L
IQOS-1	High Sensitivity C-reactive Protein (Hs-CRP)	Week 12 (V43)	2.79 mg/L
IQOS-1	High Sensitivity C-reactive Protein (Hs-CRP)	Week 6 (V14)	1.84 mg/L
IQOS-1	High Sensitivity C-reactive Protein (Hs-CRP)	Week 10 (V28)	2.57 mg/L
IQOS-2	High Sensitivity C-reactive Protein (Hs-CRP)	Week 12 (V43)	1.69 mg/L
IQOS-2	High Sensitivity C-reactive Protein (Hs-CRP)	Week 6 (V14)	1.24 mg/L
IQOS-2	High Sensitivity C-reactive Protein (Hs-CRP)	Week 10 (V28)	0.815 mg/L
IQOS-2	High Sensitivity C-reactive Protein (Hs-CRP)	Baseline (V3)	0.804 mg/L
Smoking Abstinence	High Sensitivity C-reactive Protein (Hs-CRP)	Baseline (V3)	1.80 mg/L
Smoking Abstinence	High Sensitivity C-reactive Protein (Hs-CRP)	Week 6 (V14)	1.43 mg/L
Smoking Abstinence	High Sensitivity C-reactive Protein (Hs-CRP)	Week 12 (V43)	1.61 mg/L
Smoking Abstinence	High Sensitivity C-reactive Protein (Hs-CRP)	Week 10 (V28)	2.38 mg/L
Dual-1	High Sensitivity C-reactive Protein (Hs-CRP)	Week 12 (V43)	1.26 mg/L
Dual-1	High Sensitivity C-reactive Protein (Hs-CRP)	Week 10 (V28)	1.43 mg/L
Dual-1	High Sensitivity C-reactive Protein (Hs-CRP)	Week 6 (V14)	1.37 mg/L
Dual-1	High Sensitivity C-reactive Protein (Hs-CRP)	Baseline (V3)	1.17 mg/L

Primary

Low Density Lipoprotein (LDL)

To measure LDL concentrations in serum (mg/dL).

Time frame: Measured at Baseline (V3), week 6 (V14), week 10 (V28), and week 12 (V43).

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	Low Density Lipoprotein (LDL)	Baseline (V3)	124 mg/dL
Cigarette Smoking	Low Density Lipoprotein (LDL)	Week 6 (V14)	127 mg/dL
Cigarette Smoking	Low Density Lipoprotein (LDL)	Week 10 (V28)	131 mg/dL
Cigarette Smoking	Low Density Lipoprotein (LDL)	Week 12 (V43)	133 mg/dL
IQOS-1	Low Density Lipoprotein (LDL)	Baseline (V3)	111 mg/dL
IQOS-1	Low Density Lipoprotein (LDL)	Week 12 (V43)	105 mg/dL
IQOS-1	Low Density Lipoprotein (LDL)	Week 6 (V14)	108 mg/dL
IQOS-1	Low Density Lipoprotein (LDL)	Week 10 (V28)	105 mg/dL
IQOS-2	Low Density Lipoprotein (LDL)	Week 12 (V43)	118 mg/dL
IQOS-2	Low Density Lipoprotein (LDL)	Week 6 (V14)	126 mg/dL
IQOS-2	Low Density Lipoprotein (LDL)	Week 10 (V28)	122 mg/dL
IQOS-2	Low Density Lipoprotein (LDL)	Baseline (V3)	122 mg/dL
Smoking Abstinence	Low Density Lipoprotein (LDL)	Baseline (V3)	115 mg/dL
Smoking Abstinence	Low Density Lipoprotein (LDL)	Week 6 (V14)	104 mg/dL
Smoking Abstinence	Low Density Lipoprotein (LDL)	Week 12 (V43)	109 mg/dL
Smoking Abstinence	Low Density Lipoprotein (LDL)	Week 10 (V28)	106 mg/dL
Dual-1	Low Density Lipoprotein (LDL)	Week 12 (V43)	123 mg/dL
Dual-1	Low Density Lipoprotein (LDL)	Week 10 (V28)	140 mg/dL
Dual-1	Low Density Lipoprotein (LDL)	Week 6 (V14)	136 mg/dL
Dual-1	Low Density Lipoprotein (LDL)	Baseline (V3)	155 mg/dL

Primary

Maximal Oxygen Uptake (VO2max, Absolute Values)

To measure VO2max during maximal cycle ergometer exercise (expressed in absolute values \[mL\*min-1\]).

Time frame: Measured at baseline (V3), at week 1 (V4), and at week 12 (V43).

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	Maximal Oxygen Uptake (VO2max, Absolute Values)	Acute Effect (V4)	1823 mL/min
Cigarette Smoking	Maximal Oxygen Uptake (VO2max, Absolute Values)	Training Effect (V43)	1977 mL/min
Cigarette Smoking	Maximal Oxygen Uptake (VO2max, Absolute Values)	Acute Baseline (V3)	1878 mL/min
IQOS-1	Maximal Oxygen Uptake (VO2max, Absolute Values)	Acute Effect (V4)	2062 mL/min
IQOS-1	Maximal Oxygen Uptake (VO2max, Absolute Values)	Acute Baseline (V3)	2027 mL/min
IQOS-1	Maximal Oxygen Uptake (VO2max, Absolute Values)	Training Effect (V43)	2178 mL/min
IQOS-2	Maximal Oxygen Uptake (VO2max, Absolute Values)	Acute Effect (V4)	2156 mL/min
IQOS-2	Maximal Oxygen Uptake (VO2max, Absolute Values)	Acute Baseline (V3)	2197 mL/min
IQOS-2	Maximal Oxygen Uptake (VO2max, Absolute Values)	Training Effect (V43)	2150 mL/min
Smoking Abstinence	Maximal Oxygen Uptake (VO2max, Absolute Values)	Acute Baseline (V3)	1950 mL/min
Smoking Abstinence	Maximal Oxygen Uptake (VO2max, Absolute Values)	Acute Effect (V4)	2071 mL/min
Smoking Abstinence	Maximal Oxygen Uptake (VO2max, Absolute Values)	Training Effect (V43)	2292 mL/min
Dual-1	Maximal Oxygen Uptake (VO2max, Absolute Values)	Acute Baseline (V3)	2750 mL/min
Dual-1	Maximal Oxygen Uptake (VO2max, Absolute Values)	Acute Effect (V4)	2770 mL/min
Dual-2	Maximal Oxygen Uptake (VO2max, Absolute Values)	Acute Baseline (V3)	1620 mL/min
Dual-2	Maximal Oxygen Uptake (VO2max, Absolute Values)	Acute Effect (V4)	1770 mL/min
Other	Maximal Oxygen Uptake (VO2max, Absolute Values)	Training Effect (V43)	2182 mL/min
Other	Maximal Oxygen Uptake (VO2max, Absolute Values)	Acute Effect (V4)	2094 mL/min
Other	Maximal Oxygen Uptake (VO2max, Absolute Values)	Acute Baseline (V3)	2103 mL/min

Primary

Maximal Oxygen Uptake (VO2max, Fat-free Weight Adjusted Values)

To measure VO2max during maximal cycle ergometer exercise (expressed in fat-free weight adjusted values \[mL\*kg-1\*min-1\]).

Time frame: Measured at baseline (V3), at week 1 (V4), and at week 12 (V43).

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	Maximal Oxygen Uptake (VO2max, Fat-free Weight Adjusted Values)	Acute Effect (V4)	37.0 mL/(kg*min)
Cigarette Smoking	Maximal Oxygen Uptake (VO2max, Fat-free Weight Adjusted Values)	Training Effect (V43)	40.3 mL/(kg*min)
Cigarette Smoking	Maximal Oxygen Uptake (VO2max, Fat-free Weight Adjusted Values)	Acute Baseline (V3)	37.5 mL/(kg*min)
IQOS-1	Maximal Oxygen Uptake (VO2max, Fat-free Weight Adjusted Values)	Acute Effect (V4)	39.8 mL/(kg*min)
IQOS-1	Maximal Oxygen Uptake (VO2max, Fat-free Weight Adjusted Values)	Acute Baseline (V3)	38.4 mL/(kg*min)
IQOS-1	Maximal Oxygen Uptake (VO2max, Fat-free Weight Adjusted Values)	Training Effect (V43)	39.8 mL/(kg*min)
IQOS-2	Maximal Oxygen Uptake (VO2max, Fat-free Weight Adjusted Values)	Acute Effect (V4)	37.6 mL/(kg*min)
IQOS-2	Maximal Oxygen Uptake (VO2max, Fat-free Weight Adjusted Values)	Acute Baseline (V3)	38.3 mL/(kg*min)
IQOS-2	Maximal Oxygen Uptake (VO2max, Fat-free Weight Adjusted Values)	Training Effect (V43)	38.1 mL/(kg*min)
Smoking Abstinence	Maximal Oxygen Uptake (VO2max, Fat-free Weight Adjusted Values)	Acute Baseline (V3)	34.8 mL/(kg*min)
Smoking Abstinence	Maximal Oxygen Uptake (VO2max, Fat-free Weight Adjusted Values)	Acute Effect (V4)	37.0 mL/(kg*min)
Smoking Abstinence	Maximal Oxygen Uptake (VO2max, Fat-free Weight Adjusted Values)	Training Effect (V43)	42.0 mL/(kg*min)
Dual-1	Maximal Oxygen Uptake (VO2max, Fat-free Weight Adjusted Values)	Acute Baseline (V3)	44.1 mL/(kg*min)
Dual-1	Maximal Oxygen Uptake (VO2max, Fat-free Weight Adjusted Values)	Acute Effect (V4)	45.3 mL/(kg*min)
Dual-2	Maximal Oxygen Uptake (VO2max, Fat-free Weight Adjusted Values)	Acute Baseline (V3)	34.3 mL/(kg*min)
Dual-2	Maximal Oxygen Uptake (VO2max, Fat-free Weight Adjusted Values)	Acute Effect (V4)	40.2 mL/(kg*min)
Other	Maximal Oxygen Uptake (VO2max, Fat-free Weight Adjusted Values)	Training Effect (V43)	44.7 mL/(kg*min)
Other	Maximal Oxygen Uptake (VO2max, Fat-free Weight Adjusted Values)	Acute Effect (V4)	34.1 mL/(kg*min)
Other	Maximal Oxygen Uptake (VO2max, Fat-free Weight Adjusted Values)	Acute Baseline (V3)	34.4 mL/(kg*min)

Primary

Maximal Oxygen Uptake (VO2max, Weight-adjusted Values)

To measure VO2max during maximal cycle ergometer exercise (expressed in weight-adjusted \[mL\*kg-1\*min-1\] values).

Time frame: Measured at baseline (V3), at week 1 (V4), and at week 12 (V43).

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	Maximal Oxygen Uptake (VO2max, Weight-adjusted Values)	Acute Effect (V4)	26.6 mL/(kg*min)
Cigarette Smoking	Maximal Oxygen Uptake (VO2max, Weight-adjusted Values)	Training Effect (V43)	27.9 mL/(kg*min)
Cigarette Smoking	Maximal Oxygen Uptake (VO2max, Weight-adjusted Values)	Acute Baseline (V3)	27.3 mL/(kg*min)
IQOS-1	Maximal Oxygen Uptake (VO2max, Weight-adjusted Values)	Acute Effect (V4)	27.9 mL/(kg*min)
IQOS-1	Maximal Oxygen Uptake (VO2max, Weight-adjusted Values)	Acute Baseline (V3)	27.4 mL/(kg*min)
IQOS-1	Maximal Oxygen Uptake (VO2max, Weight-adjusted Values)	Training Effect (V43)	28.8 mL/(kg*min)
IQOS-2	Maximal Oxygen Uptake (VO2max, Weight-adjusted Values)	Acute Effect (V4)	28.2 mL/(kg*min)
IQOS-2	Maximal Oxygen Uptake (VO2max, Weight-adjusted Values)	Acute Baseline (V3)	28.9 mL/(kg*min)
IQOS-2	Maximal Oxygen Uptake (VO2max, Weight-adjusted Values)	Training Effect (V43)	27.7 mL/(kg*min)
Smoking Abstinence	Maximal Oxygen Uptake (VO2max, Weight-adjusted Values)	Acute Baseline (V3)	25.1 mL/(kg*min)
Smoking Abstinence	Maximal Oxygen Uptake (VO2max, Weight-adjusted Values)	Acute Effect (V4)	26.7 mL/(kg*min)
Smoking Abstinence	Maximal Oxygen Uptake (VO2max, Weight-adjusted Values)	Training Effect (V43)	29.6 mL/(kg*min)
Dual-1	Maximal Oxygen Uptake (VO2max, Weight-adjusted Values)	Acute Baseline (V3)	34.7 mL/(kg*min)
Dual-1	Maximal Oxygen Uptake (VO2max, Weight-adjusted Values)	Acute Effect (V4)	34.5 mL/(kg*min)
Dual-2	Maximal Oxygen Uptake (VO2max, Weight-adjusted Values)	Acute Baseline (V3)	24.4 mL/(kg*min)
Dual-2	Maximal Oxygen Uptake (VO2max, Weight-adjusted Values)	Acute Effect (V4)	27.0 mL/(kg*min)
Other	Maximal Oxygen Uptake (VO2max, Weight-adjusted Values)	Training Effect (V43)	30.9 mL/(kg*min)
Other	Maximal Oxygen Uptake (VO2max, Weight-adjusted Values)	Acute Effect (V4)	25.4 mL/(kg*min)
Other	Maximal Oxygen Uptake (VO2max, Weight-adjusted Values)	Acute Baseline (V3)	25.8 mL/(kg*min)

Primary

NEQ

To measure Nicotine equivalents (NEQ) concentrations, measured in spot urine and expressed as concentration adjusted for creatinine.

Time frame: Measured at Baseline (V3), week 1 (V4), week 6 (V14), week 10 (V28), and week 12 (V43).

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (GEOMETRIC_MEAN)
Cigarette Smoking	NEQ	Week 10 (V28)	14.3 mg/g creat
Cigarette Smoking	NEQ	Baseline (V3)	14.9 mg/g creat
Cigarette Smoking	NEQ	Week 12 (V43)	13.8 mg/g creat
Cigarette Smoking	NEQ	Week 1 (V4)	13.2 mg/g creat
Cigarette Smoking	NEQ	Week 6 (V14)	13.2 mg/g creat
IQOS-1	NEQ	Week 10 (V28)	11.4 mg/g creat
IQOS-1	NEQ	Week 6 (V14)	10.9 mg/g creat
IQOS-1	NEQ	Week 1 (V4)	10.9 mg/g creat
IQOS-1	NEQ	Week 12 (V43)	12.3 mg/g creat
IQOS-1	NEQ	Baseline (V3)	14.2 mg/g creat
IQOS-2	NEQ	Week 6 (V14)	7.08 mg/g creat
IQOS-2	NEQ	Baseline (V3)	10.5 mg/g creat
IQOS-2	NEQ	Week 1 (V4)	7.08 mg/g creat
IQOS-2	NEQ	Week 10 (V28)	8.66 mg/g creat
IQOS-2	NEQ	Week 12 (V43)	5.93 mg/g creat
Smoking Abstinence	NEQ	Week 12 (V43)	2.70 mg/g creat
Smoking Abstinence	NEQ	Baseline (V3)	12.9 mg/g creat
Smoking Abstinence	NEQ	Week 10 (V28)	1.59 mg/g creat
Smoking Abstinence	NEQ	Week 6 (V14)	4.40 mg/g creat
Smoking Abstinence	NEQ	Week 1 (V4)	4.40 mg/g creat
Dual-1	NEQ	Week 6 (V14)	9.03 mg/g creat
Dual-1	NEQ	Week 10 (V28)	11.6 mg/g creat
Dual-1	NEQ	Baseline (V3)	14.0 mg/g creat
Dual-1	NEQ	Week 12 (V43)	5.87 mg/g creat
Dual-1	NEQ	Week 1 (V4)	8.49 mg/g creat

Primary

Nicotine/Tobacco Product Use (Cigarettes)

To measure self-reported number of any nicotine/tobacco product used on a daily basis.

Time frame: Recorded daily by subject, in product use diary, from study enrollment for 16 weeks.

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	Nicotine/Tobacco Product Use (Cigarettes)	Up to month 2 (V3-V26	17.1 cigarettes per day
Cigarette Smoking	Nicotine/Tobacco Product Use (Cigarettes)	Pre-randomization (V2-V3)	16.8 cigarettes per day
Cigarette Smoking	Nicotine/Tobacco Product Use (Cigarettes)	Overall (V3-V43)	17.1 cigarettes per day
Cigarette Smoking	Nicotine/Tobacco Product Use (Cigarettes)	Week 1 (V3-V4)	17.5 cigarettes per day
Cigarette Smoking	Nicotine/Tobacco Product Use (Cigarettes)	Up to month 1 (V3-V14)	17.3 cigarettes per day
IQOS-1	Nicotine/Tobacco Product Use (Cigarettes)	Up to month 2 (V3-V26	0.0196 cigarettes per day
IQOS-1	Nicotine/Tobacco Product Use (Cigarettes)	Up to month 1 (V3-V14)	0.0351 cigarettes per day
IQOS-1	Nicotine/Tobacco Product Use (Cigarettes)	Week 1 (V3-V4)	0.206 cigarettes per day
IQOS-1	Nicotine/Tobacco Product Use (Cigarettes)	Overall (V3-V43)	0.0142 cigarettes per day
IQOS-1	Nicotine/Tobacco Product Use (Cigarettes)	Pre-randomization (V2-V3)	19.0 cigarettes per day
IQOS-2	Nicotine/Tobacco Product Use (Cigarettes)	Up to month 1 (V3-V14)	0.0623 cigarettes per day
IQOS-2	Nicotine/Tobacco Product Use (Cigarettes)	Pre-randomization (V2-V3)	17.4 cigarettes per day
IQOS-2	Nicotine/Tobacco Product Use (Cigarettes)	Week 1 (V3-V4)	0.242 cigarettes per day
IQOS-2	Nicotine/Tobacco Product Use (Cigarettes)	Up to month 2 (V3-V26	0.0369 cigarettes per day
IQOS-2	Nicotine/Tobacco Product Use (Cigarettes)	Overall (V3-V43)	0.0273 cigarettes per day
Smoking Abstinence	Nicotine/Tobacco Product Use (Cigarettes)	Overall (V3-V43)	0.000858 cigarettes per day
Smoking Abstinence	Nicotine/Tobacco Product Use (Cigarettes)	Pre-randomization (V2-V3)	17.7 cigarettes per day
Smoking Abstinence	Nicotine/Tobacco Product Use (Cigarettes)	Up to month 2 (V3-V26	0.00132 cigarettes per day
Smoking Abstinence	Nicotine/Tobacco Product Use (Cigarettes)	Up to month 1 (V3-V14)	0.00222 cigarettes per day
Smoking Abstinence	Nicotine/Tobacco Product Use (Cigarettes)	Week 1 (V3-V4)	0.0136 cigarettes per day
Dual-1	Nicotine/Tobacco Product Use (Cigarettes)	Up to month 1 (V3-V14)	8.86 cigarettes per day
Dual-1	Nicotine/Tobacco Product Use (Cigarettes)	Up to month 2 (V3-V26	8.38 cigarettes per day
Dual-1	Nicotine/Tobacco Product Use (Cigarettes)	Pre-randomization (V2-V3)	24.1 cigarettes per day
Dual-1	Nicotine/Tobacco Product Use (Cigarettes)	Overall (V3-V43)	8.34 cigarettes per day
Dual-1	Nicotine/Tobacco Product Use (Cigarettes)	Week 1 (V3-V4)	9.72 cigarettes per day

Primary

Nicotine/Tobacco Product Use (E-cigarettes)

To measure self-reported number of any nicotine/tobacco product used on a daily basis.

Time frame: Recorded daily by subject, in product use diary, from study enrollment for 16 weeks.

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	Nicotine/Tobacco Product Use (E-cigarettes)	Pre-randomization (V2-V3)	0 e-cigarettes per day
Cigarette Smoking	Nicotine/Tobacco Product Use (E-cigarettes)	Week 1 (V3-V4)	0 e-cigarettes per day
Cigarette Smoking	Nicotine/Tobacco Product Use (E-cigarettes)	Up to month 1 (V3-V14)	0 e-cigarettes per day
Cigarette Smoking	Nicotine/Tobacco Product Use (E-cigarettes)	Up to month 2 (V3-V26	0 e-cigarettes per day
Cigarette Smoking	Nicotine/Tobacco Product Use (E-cigarettes)	Overall (V3-V43)	0 e-cigarettes per day
IQOS-1	Nicotine/Tobacco Product Use (E-cigarettes)	Overall (V3-V43)	0 e-cigarettes per day
IQOS-1	Nicotine/Tobacco Product Use (E-cigarettes)	Pre-randomization (V2-V3)	0 e-cigarettes per day
IQOS-1	Nicotine/Tobacco Product Use (E-cigarettes)	Up to month 1 (V3-V14)	0 e-cigarettes per day
IQOS-1	Nicotine/Tobacco Product Use (E-cigarettes)	Up to month 2 (V3-V26	0 e-cigarettes per day
IQOS-1	Nicotine/Tobacco Product Use (E-cigarettes)	Week 1 (V3-V4)	0 e-cigarettes per day
IQOS-2	Nicotine/Tobacco Product Use (E-cigarettes)	Up to month 1 (V3-V14)	0 e-cigarettes per day
IQOS-2	Nicotine/Tobacco Product Use (E-cigarettes)	Up to month 2 (V3-V26	0 e-cigarettes per day
IQOS-2	Nicotine/Tobacco Product Use (E-cigarettes)	Pre-randomization (V2-V3)	0.0952 e-cigarettes per day
IQOS-2	Nicotine/Tobacco Product Use (E-cigarettes)	Week 1 (V3-V4)	0 e-cigarettes per day
IQOS-2	Nicotine/Tobacco Product Use (E-cigarettes)	Overall (V3-V43)	0 e-cigarettes per day
Smoking Abstinence	Nicotine/Tobacco Product Use (E-cigarettes)	Week 1 (V3-V4)	0 e-cigarettes per day
Smoking Abstinence	Nicotine/Tobacco Product Use (E-cigarettes)	Up to month 1 (V3-V14)	0 e-cigarettes per day
Smoking Abstinence	Nicotine/Tobacco Product Use (E-cigarettes)	Overall (V3-V43)	0 e-cigarettes per day
Smoking Abstinence	Nicotine/Tobacco Product Use (E-cigarettes)	Up to month 2 (V3-V26	0 e-cigarettes per day
Smoking Abstinence	Nicotine/Tobacco Product Use (E-cigarettes)	Pre-randomization (V2-V3)	0 e-cigarettes per day
Dual-1	Nicotine/Tobacco Product Use (E-cigarettes)	Pre-randomization (V2-V3)	0 e-cigarettes per day
Dual-1	Nicotine/Tobacco Product Use (E-cigarettes)	Week 1 (V3-V4)	0 e-cigarettes per day
Dual-1	Nicotine/Tobacco Product Use (E-cigarettes)	Up to month 1 (V3-V14)	0 e-cigarettes per day
Dual-1	Nicotine/Tobacco Product Use (E-cigarettes)	Overall (V3-V43)	0 e-cigarettes per day
Dual-1	Nicotine/Tobacco Product Use (E-cigarettes)	Up to month 2 (V3-V26	0 e-cigarettes per day

Primary

Nicotine/Tobacco Product Use (HeatSticks)

To measure self-reported number of any nicotine/tobacco product used on a daily basis.

Time frame: Recorded daily by subject, in product use diary, from study enrollment for 16 weeks.

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	Nicotine/Tobacco Product Use (HeatSticks)	Up to month 2 (V3-V26	0 heatsticks per day
Cigarette Smoking	Nicotine/Tobacco Product Use (HeatSticks)	Pre-randomization (V2-V3)	0 heatsticks per day
Cigarette Smoking	Nicotine/Tobacco Product Use (HeatSticks)	Overall (V3-V43)	0 heatsticks per day
Cigarette Smoking	Nicotine/Tobacco Product Use (HeatSticks)	Week 1 (V3-V4)	0 heatsticks per day
Cigarette Smoking	Nicotine/Tobacco Product Use (HeatSticks)	Up to month 1 (V3-V14)	0 heatsticks per day
IQOS-1	Nicotine/Tobacco Product Use (HeatSticks)	Up to month 2 (V3-V26	18.7 heatsticks per day
IQOS-1	Nicotine/Tobacco Product Use (HeatSticks)	Up to month 1 (V3-V14)	18.6 heatsticks per day
IQOS-1	Nicotine/Tobacco Product Use (HeatSticks)	Week 1 (V3-V4)	17.7 heatsticks per day
IQOS-1	Nicotine/Tobacco Product Use (HeatSticks)	Overall (V3-V43)	19.0 heatsticks per day
IQOS-1	Nicotine/Tobacco Product Use (HeatSticks)	Pre-randomization (V2-V3)	0 heatsticks per day
IQOS-2	Nicotine/Tobacco Product Use (HeatSticks)	Up to month 1 (V3-V14)	14.0 heatsticks per day
IQOS-2	Nicotine/Tobacco Product Use (HeatSticks)	Pre-randomization (V2-V3)	0 heatsticks per day
IQOS-2	Nicotine/Tobacco Product Use (HeatSticks)	Week 1 (V3-V4)	14.1 heatsticks per day
IQOS-2	Nicotine/Tobacco Product Use (HeatSticks)	Up to month 2 (V3-V26	14.1 heatsticks per day
IQOS-2	Nicotine/Tobacco Product Use (HeatSticks)	Overall (V3-V43)	14.1 heatsticks per day
Smoking Abstinence	Nicotine/Tobacco Product Use (HeatSticks)	Overall (V3-V43)	0 heatsticks per day
Smoking Abstinence	Nicotine/Tobacco Product Use (HeatSticks)	Pre-randomization (V2-V3)	0 heatsticks per day
Smoking Abstinence	Nicotine/Tobacco Product Use (HeatSticks)	Up to month 2 (V3-V26	0 heatsticks per day
Smoking Abstinence	Nicotine/Tobacco Product Use (HeatSticks)	Up to month 1 (V3-V14)	0 heatsticks per day
Smoking Abstinence	Nicotine/Tobacco Product Use (HeatSticks)	Week 1 (V3-V4)	0 heatsticks per day
Dual-1	Nicotine/Tobacco Product Use (HeatSticks)	Up to month 1 (V3-V14)	4.97 heatsticks per day
Dual-1	Nicotine/Tobacco Product Use (HeatSticks)	Up to month 2 (V3-V26	4.97 heatsticks per day
Dual-1	Nicotine/Tobacco Product Use (HeatSticks)	Pre-randomization (V2-V3)	0 heatsticks per day
Dual-1	Nicotine/Tobacco Product Use (HeatSticks)	Overall (V3-V43)	5.08 heatsticks per day
Dual-1	Nicotine/Tobacco Product Use (HeatSticks)	Week 1 (V3-V4)	5.81 heatsticks per day

Primary

Oxygen Uptake

To measure changes from baseline of Oxygen uptake during VO2max test. (mL/min)

Time frame: Measured at Baseline, at week 1, and at week 15.

Primary

Plasma Volume

To measure Plasma volume (mL), measured with the carbon monoxide-rebreathing method.

Time frame: Measured at Baseline (V3) and week 12 (V43).

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	Plasma Volume	Week 12 (V43)	4840 mL
Cigarette Smoking	Plasma Volume	Baseline (V3)	3429 mL
IQOS-1	Plasma Volume	Baseline (V3)	3156 mL
IQOS-1	Plasma Volume	Week 12 (V43)	4938 mL
IQOS-2	Plasma Volume	Week 12 (V43)	4959 mL
IQOS-2	Plasma Volume	Baseline (V3)	3558 mL
Smoking Abstinence	Plasma Volume	Baseline (V3)	3521 mL
Smoking Abstinence	Plasma Volume	Week 12 (V43)	5281 mL
Dual-1	Plasma Volume	Week 12 (V43)	4272 mL
Dual-1	Plasma Volume	Baseline (V3)	3252 mL

Primary

Rating of Perceived Capacity by Sex

To measure Rating of Perceived Capacity (RPC), determined by using the RPC scale. The RPC scale is a list of physical activities arranged in order, with a scale of values from least strenuous (1) to most exhausting (18 for women, 20 for men). Subjects choose the most strenuous activity, with corresponding value, which they could sustain for 30 minutes.

Time frame: Measured at Baseline (V3), at week 1 (V4), and at week 12 (V43).

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	Rating of Perceived Capacity by Sex	Training Baseline - Female (V3)	6.92 Rating of Perceived Capacity
Cigarette Smoking	Rating of Perceived Capacity by Sex	Training Effect - Female (V43)	8.58 Rating of Perceived Capacity
Cigarette Smoking	Rating of Perceived Capacity by Sex	Acute Effect - Female (V4)	7.15 Rating of Perceived Capacity
Cigarette Smoking	Rating of Perceived Capacity by Sex	Training Effect - Male (V43)	8.33 Rating of Perceived Capacity
Cigarette Smoking	Rating of Perceived Capacity by Sex	Acute Baseline - Male (V3)	8.00 Rating of Perceived Capacity
Cigarette Smoking	Rating of Perceived Capacity by Sex	Training Baseline - Male (V3)	7.67 Rating of Perceived Capacity
Cigarette Smoking	Rating of Perceived Capacity by Sex	Acute Effect - Male (V4)	6.86 Rating of Perceived Capacity
Cigarette Smoking	Rating of Perceived Capacity by Sex	Acute Baseline - Female (V3)	7.77 Rating of Perceived Capacity
IQOS-1	Rating of Perceived Capacity by Sex	Acute Effect - Female (V4)	7.22 Rating of Perceived Capacity
IQOS-1	Rating of Perceived Capacity by Sex	Acute Effect - Male (V4)	9.13 Rating of Perceived Capacity
IQOS-1	Rating of Perceived Capacity by Sex	Acute Baseline - Male (V3)	8.25 Rating of Perceived Capacity
IQOS-1	Rating of Perceived Capacity by Sex	Acute Baseline - Female (V3)	8.22 Rating of Perceived Capacity
IQOS-1	Rating of Perceived Capacity by Sex	Training Baseline - Male (V3)	8.30 Rating of Perceived Capacity
IQOS-1	Rating of Perceived Capacity by Sex	Training Baseline - Female (V3)	8.22 Rating of Perceived Capacity
IQOS-1	Rating of Perceived Capacity by Sex	Training Effect - Female (V43)	9.11 Rating of Perceived Capacity
IQOS-1	Rating of Perceived Capacity by Sex	Training Effect - Male (V43)	10.1 Rating of Perceived Capacity
IQOS-2	Rating of Perceived Capacity by Sex	Training Effect - Female (V43)	8.60 Rating of Perceived Capacity
IQOS-2	Rating of Perceived Capacity by Sex	Acute Baseline - Female (V3)	8.17 Rating of Perceived Capacity
IQOS-2	Rating of Perceived Capacity by Sex	Acute Effect - Female (V4)	7.83 Rating of Perceived Capacity
IQOS-2	Rating of Perceived Capacity by Sex	Training Baseline - Male (V3)	9.71 Rating of Perceived Capacity
IQOS-2	Rating of Perceived Capacity by Sex	Acute Effect - Male (V4)	10.7 Rating of Perceived Capacity
IQOS-2	Rating of Perceived Capacity by Sex	Training Baseline - Female (V3)	7.67 Rating of Perceived Capacity
IQOS-2	Rating of Perceived Capacity by Sex	Acute Baseline - Male (V3)	9.71 Rating of Perceived Capacity
IQOS-2	Rating of Perceived Capacity by Sex	Training Effect - Male (V43)	9.14 Rating of Perceived Capacity
Smoking Abstinence	Rating of Perceived Capacity by Sex	Acute Effect - Male (V4)	9.90 Rating of Perceived Capacity
Smoking Abstinence	Rating of Perceived Capacity by Sex	Acute Baseline - Female (V3)	8.00 Rating of Perceived Capacity
Smoking Abstinence	Rating of Perceived Capacity by Sex	Acute Effect - Female (V4)	7.90 Rating of Perceived Capacity
Smoking Abstinence	Rating of Perceived Capacity by Sex	Acute Baseline - Male (V3)	9.70 Rating of Perceived Capacity
Smoking Abstinence	Rating of Perceived Capacity by Sex	Training Baseline - Female (V3)	8.00 Rating of Perceived Capacity
Smoking Abstinence	Rating of Perceived Capacity by Sex	Training Effect - Female (V43)	8.91 Rating of Perceived Capacity
Smoking Abstinence	Rating of Perceived Capacity by Sex	Training Baseline - Male (V3)	9.36 Rating of Perceived Capacity
Smoking Abstinence	Rating of Perceived Capacity by Sex	Training Effect - Male (V43)	11.8 Rating of Perceived Capacity
Dual-1	Rating of Perceived Capacity by Sex	Acute Baseline - Male (V3)	8.00 Rating of Perceived Capacity
Dual-1	Rating of Perceived Capacity by Sex	Acute Effect - Male (V4)	9.00 Rating of Perceived Capacity
Dual-2	Rating of Perceived Capacity by Sex	Acute Baseline - Female (V3)	5.00 Rating of Perceived Capacity
Dual-2	Rating of Perceived Capacity by Sex	Acute Effect - Female (V4)	5.00 Rating of Perceived Capacity
Other	Rating of Perceived Capacity by Sex	Acute Effect - Female (V4)	8.50 Rating of Perceived Capacity
Other	Rating of Perceived Capacity by Sex	Acute Baseline - Female (V3)	8.50 Rating of Perceived Capacity
Other	Rating of Perceived Capacity by Sex	Training Effect - Female (V43)	9.60 Rating of Perceived Capacity
Other	Rating of Perceived Capacity by Sex	Training Baseline - Female (V3)	10.4 Rating of Perceived Capacity
Other	Rating of Perceived Capacity by Sex	Acute Effect - Male (V4)	6.25 Rating of Perceived Capacity
Other	Rating of Perceived Capacity by Sex	Acute Baseline - Male (V3)	7.00 Rating of Perceived Capacity

Primary

Rating of Perceived Exertion

To measure changes from baseline of the Rating of Perceived Exertion, determined by using the Borg scale. The Borg RPE scale is a numerical scale that ranges from 6 to 20, where 6 means no exertion at all and 20 means maximal exertion. Subjects choose a number from the scale that best describes their level of exertion during a physical activity.

Time frame: Measured at Baseline (V3), at week 1 (V4), and at week 12 (V43).

Primary

Red Blood Cell Volume

To measure Red blood cell volume (mL), measured with the carbon monoxide-rebreathing method.

Time frame: Measured at Baseline (V3) and week 12 (V43).

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	Red Blood Cell Volume	Baseline (V3)	2541 mL
Cigarette Smoking	Red Blood Cell Volume	Week 12 (V43)	3523 mL
IQOS-1	Red Blood Cell Volume	Baseline (V3)	2353 mL
IQOS-1	Red Blood Cell Volume	Week 12 (V43)	3478 mL
IQOS-2	Red Blood Cell Volume	Baseline (V3)	2681 mL
IQOS-2	Red Blood Cell Volume	Week 12 (V43)	3618 mL
Smoking Abstinence	Red Blood Cell Volume	Week 12 (V43)	3605 mL
Smoking Abstinence	Red Blood Cell Volume	Baseline (V3)	2605 mL
Dual-1	Red Blood Cell Volume	Baseline (V3)	2269 mL
Dual-1	Red Blood Cell Volume	Week 12 (V43)	2623 mL

Primary

Respiratory Exchange Ratio

To measure the respiratory exchange ratio (VCO2/VO2) at VO2max

Time frame: Measured at Baseline (V3), at week 1 (V4), and at week 12 (V43).

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	Respiratory Exchange Ratio	Acute effect (V4)	1.20 ratio
Cigarette Smoking	Respiratory Exchange Ratio	Training Effect (V43)	1.16 ratio
Cigarette Smoking	Respiratory Exchange Ratio	Acute baseline (V3)	1.18 ratio
IQOS-1	Respiratory Exchange Ratio	Acute effect (V4)	1.17 ratio
IQOS-1	Respiratory Exchange Ratio	Acute baseline (V3)	1.16 ratio
IQOS-1	Respiratory Exchange Ratio	Training Effect (V43)	1.16 ratio
IQOS-2	Respiratory Exchange Ratio	Acute effect (V4)	1.18 ratio
IQOS-2	Respiratory Exchange Ratio	Acute baseline (V3)	1.19 ratio
IQOS-2	Respiratory Exchange Ratio	Training Effect (V43)	1.18 ratio
Smoking Abstinence	Respiratory Exchange Ratio	Acute baseline (V3)	1.16 ratio
Smoking Abstinence	Respiratory Exchange Ratio	Acute effect (V4)	1.17 ratio
Smoking Abstinence	Respiratory Exchange Ratio	Training Effect (V43)	1.18 ratio
Dual-1	Respiratory Exchange Ratio	Acute baseline (V3)	1.17 ratio
Dual-1	Respiratory Exchange Ratio	Acute effect (V4)	1.18 ratio
Dual-2	Respiratory Exchange Ratio	Acute baseline (V3)	1.05 ratio
Dual-2	Respiratory Exchange Ratio	Acute effect (V4)	1.19 ratio
Other	Respiratory Exchange Ratio	Training Effect (V43)	1.21 ratio
Other	Respiratory Exchange Ratio	Acute effect (V4)	1.14 ratio
Other	Respiratory Exchange Ratio	Acute baseline (V3)	1.14 ratio

Primary

Respiratory Rate

To measure respiratory rate (breaths per minute) at VO2max.

Time frame: Measured at Baseline (V3), at week 1 (V4), and at week 12 (V43).

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	Respiratory Rate	Acute Effect (V4)	34.1 breaths/minute
Cigarette Smoking	Respiratory Rate	Training Effect (V43	33.8 breaths/minute
Cigarette Smoking	Respiratory Rate	Acute Baseline (V3)	34.5 breaths/minute
IQOS-1	Respiratory Rate	Acute Effect (V4)	37.8 breaths/minute
IQOS-1	Respiratory Rate	Acute Baseline (V3)	37.5 breaths/minute
IQOS-1	Respiratory Rate	Training Effect (V43	37.0 breaths/minute
IQOS-2	Respiratory Rate	Acute Effect (V4)	35.4 breaths/minute
IQOS-2	Respiratory Rate	Acute Baseline (V3)	37.1 breaths/minute
IQOS-2	Respiratory Rate	Training Effect (V43	33.8 breaths/minute
Smoking Abstinence	Respiratory Rate	Acute Baseline (V3)	35.2 breaths/minute
Smoking Abstinence	Respiratory Rate	Acute Effect (V4)	36.1 breaths/minute
Smoking Abstinence	Respiratory Rate	Training Effect (V43	36.3 breaths/minute
Dual-1	Respiratory Rate	Acute Baseline (V3)	36.0 breaths/minute
Dual-1	Respiratory Rate	Acute Effect (V4)	38.0 breaths/minute
Dual-2	Respiratory Rate	Acute Baseline (V3)	29.0 breaths/minute
Dual-2	Respiratory Rate	Acute Effect (V4)	37.0 breaths/minute
Other	Respiratory Rate	Training Effect (V43	38.4 breaths/minute
Other	Respiratory Rate	Acute Effect (V4)	34.1 breaths/minute
Other	Respiratory Rate	Acute Baseline (V3)	35.6 breaths/minute

Primary

Resting Pulse Rate

To measure resting heart rate in bpm.

Time frame: Measured at Baseline (V3), week 6 (V14), week 10 (V28), and week 12 (V43).

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	Resting Pulse Rate	Baseline (V3)	68.8 beats/minute
Cigarette Smoking	Resting Pulse Rate	Week 6 (V14)	65.1 beats/minute
Cigarette Smoking	Resting Pulse Rate	Week 10 (V28)	65.1 beats/minute
Cigarette Smoking	Resting Pulse Rate	Week 12 (V43)	70.5 beats/minute
IQOS-1	Resting Pulse Rate	Baseline (V3)	68.2 beats/minute
IQOS-1	Resting Pulse Rate	Week 12 (V43)	65.8 beats/minute
IQOS-1	Resting Pulse Rate	Week 6 (V14)	60.0 beats/minute
IQOS-1	Resting Pulse Rate	Week 10 (V28)	60.3 beats/minute
IQOS-2	Resting Pulse Rate	Week 12 (V43)	69.5 beats/minute
IQOS-2	Resting Pulse Rate	Week 6 (V14)	63.3 beats/minute
IQOS-2	Resting Pulse Rate	Week 10 (V28)	60.7 beats/minute
IQOS-2	Resting Pulse Rate	Baseline (V3)	67.9 beats/minute
Smoking Abstinence	Resting Pulse Rate	Baseline (V3)	65.8 beats/minute
Smoking Abstinence	Resting Pulse Rate	Week 6 (V14)	60.1 beats/minute
Smoking Abstinence	Resting Pulse Rate	Week 12 (V43)	63.9 beats/minute
Smoking Abstinence	Resting Pulse Rate	Week 10 (V28)	59.9 beats/minute
Dual-1	Resting Pulse Rate	Week 12 (V43)	73.2 beats/minute
Dual-1	Resting Pulse Rate	Week 10 (V28)	65.4 beats/minute
Dual-1	Resting Pulse Rate	Week 6 (V14)	62.2 beats/minute
Dual-1	Resting Pulse Rate	Baseline (V3)	73.8 beats/minute

Primary

Resting Systolic Blood Pressure

To measure resting systolic blood pressure in mmHg.

Time frame: Measured at Baseline (V3), week 6 (V14), week 10 (V28), and week 12 (V43).

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	Resting Systolic Blood Pressure	Baseline (V3)	118 mmHg
Cigarette Smoking	Resting Systolic Blood Pressure	Week 6 (V14)	117 mmHg
Cigarette Smoking	Resting Systolic Blood Pressure	Week 10 (V28)	117 mmHg
Cigarette Smoking	Resting Systolic Blood Pressure	Week 12 (V43)	116 mmHg
IQOS-1	Resting Systolic Blood Pressure	Baseline (V3)	121 mmHg
IQOS-1	Resting Systolic Blood Pressure	Week 12 (V43)	119 mmHg
IQOS-1	Resting Systolic Blood Pressure	Week 6 (V14)	124 mmHg
IQOS-1	Resting Systolic Blood Pressure	Week 10 (V28)	121 mmHg
IQOS-2	Resting Systolic Blood Pressure	Week 12 (V43)	116 mmHg
IQOS-2	Resting Systolic Blood Pressure	Week 6 (V14)	120 mmHg
IQOS-2	Resting Systolic Blood Pressure	Week 10 (V28)	113 mmHg
IQOS-2	Resting Systolic Blood Pressure	Baseline (V3)	118 mmHg
Smoking Abstinence	Resting Systolic Blood Pressure	Baseline (V3)	122 mmHg
Smoking Abstinence	Resting Systolic Blood Pressure	Week 6 (V14)	122 mmHg
Smoking Abstinence	Resting Systolic Blood Pressure	Week 12 (V43)	122 mmHg
Smoking Abstinence	Resting Systolic Blood Pressure	Week 10 (V28)	124 mmHg
Dual-1	Resting Systolic Blood Pressure	Week 12 (V43)	109 mmHg
Dual-1	Resting Systolic Blood Pressure	Week 10 (V28)	110 mmHg
Dual-1	Resting Systolic Blood Pressure	Week 6 (V14)	111 mmHg
Dual-1	Resting Systolic Blood Pressure	Baseline (V3)	108 mmHg

Primary

Total Blood Volume

To measure total blood volume (mL), measured with the carbon monoxide-rebreathing method.

Time frame: Measured at Baseline (V3) and week 12 (V43).

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	Total Blood Volume	Baseline (V3)	5970 mL
Cigarette Smoking	Total Blood Volume	Week 12 (V43)	8363 mL
IQOS-1	Total Blood Volume	Baseline (V3)	5508 mL
IQOS-1	Total Blood Volume	Week 12 (V43)	8416 mL
IQOS-2	Total Blood Volume	Baseline (V3)	6239 mL
IQOS-2	Total Blood Volume	Week 12 (V43)	8577 mL
Smoking Abstinence	Total Blood Volume	Week 12 (V43)	8886 mL
Smoking Abstinence	Total Blood Volume	Baseline (V3)	6126 mL
Dual-1	Total Blood Volume	Baseline (V3)	5521 mL
Dual-1	Total Blood Volume	Week 12 (V43)	6896 mL

Primary

Total NNAL

To measure Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) concentrations, measured in spot urine and expressed as concentration adjusted for creatinine.

Time frame: Measured at Baseline (V3), week 1 (V4), week 6 (V14), week 10 (V28), and week 12 (V43).

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (GEOMETRIC_MEAN)
Cigarette Smoking	Total NNAL	Week 10 (V28)	221 pg/mg creat
Cigarette Smoking	Total NNAL	Baseline (V3)	170 pg/mg creat
Cigarette Smoking	Total NNAL	Week 12 (V43)	214 pg/mg creat
Cigarette Smoking	Total NNAL	Week 1 (V4)	147 pg/mg creat
Cigarette Smoking	Total NNAL	Week 6 (V14)	177 pg/mg creat
IQOS-1	Total NNAL	Week 10 (V28)	81.3 pg/mg creat
IQOS-1	Total NNAL	Week 6 (V14)	90.2 pg/mg creat
IQOS-1	Total NNAL	Week 1 (V4)	88.3 pg/mg creat
IQOS-1	Total NNAL	Week 12 (V43)	82.5 pg/mg creat
IQOS-1	Total NNAL	Baseline (V3)	239 pg/mg creat
IQOS-2	Total NNAL	Week 6 (V14)	62.7 pg/mg creat
IQOS-2	Total NNAL	Baseline (V3)	164 pg/mg creat
IQOS-2	Total NNAL	Week 1 (V4)	69.9 pg/mg creat
IQOS-2	Total NNAL	Week 10 (V28)	74.6 pg/mg creat
IQOS-2	Total NNAL	Week 12 (V43)	37.9 pg/mg creat
Smoking Abstinence	Total NNAL	Week 12 (V43)	41.3 pg/mg creat
Smoking Abstinence	Total NNAL	Baseline (V3)	166 pg/mg creat
Smoking Abstinence	Total NNAL	Week 10 (V28)	26.1 pg/mg creat
Smoking Abstinence	Total NNAL	Week 6 (V14)	17.4 pg/mg creat
Smoking Abstinence	Total NNAL	Week 1 (V4)	45.8 pg/mg creat
Dual-1	Total NNAL	Week 6 (V14)	93.4 pg/mg creat
Dual-1	Total NNAL	Week 10 (V28)	83.3 pg/mg creat
Dual-1	Total NNAL	Baseline (V3)	244 pg/mg creat
Dual-1	Total NNAL	Week 12 (V43)	62.3 pg/mg creat
Dual-1	Total NNAL	Week 1 (V4)	97.9 pg/mg creat

Primary

VCO2

To measure VCO2 (L/min) at VO2 max.

Time frame: Measured at Baseline (V3), at week 1 (V4), and at week 12 (V43).

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	VCO2	Acute Effect (V4)	2.19 L/min
Cigarette Smoking	VCO2	Training Effect (V43)	2.36 L/min
Cigarette Smoking	VCO2	Acute Baseline (V3)	2.21 L/min
IQOS-1	VCO2	Acute Effect (V4)	2.41 L/min
IQOS-1	VCO2	Acute Baseline (V3)	2.36 L/min
IQOS-1	VCO2	Training Effect (V43)	2.53 L/min
IQOS-2	VCO2	Acute Effect (V4)	2.53 L/min
IQOS-2	VCO2	Acute Baseline (V3)	2.58 L/min
IQOS-2	VCO2	Training Effect (V43)	2.53 L/min
Smoking Abstinence	VCO2	Acute Baseline (V3)	2.24 L/min
Smoking Abstinence	VCO2	Acute Effect (V4)	2.41 L/min
Smoking Abstinence	VCO2	Training Effect (V43)	2.67 L/min
Dual-1	VCO2	Acute Baseline (V3)	3.23 L/min
Dual-1	VCO2	Acute Effect (V4)	3.28 L/min
Dual-2	VCO2	Acute Baseline (V3)	1.70 L/min
Dual-2	VCO2	Acute Effect (V4)	2.10 L/min
Other	VCO2	Acute Effect (V4)	2.38 L/min
Other	VCO2	Training Effect (V43)	2.63 L/min
Other	VCO2	Acute Baseline (V3)	2.39 L/min

Primary

Ventilation at VO2 Max

To measure ventilation (L/min) at VO2max.

Time frame: Measured at Baseline (V3), at week 1 (V4), and at week 12 (V43).

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	Ventilation at VO2 Max	Acute Effect (V4)	72.0 L/min
Cigarette Smoking	Ventilation at VO2 Max	Training Effect (V43)	72.7 L/min
Cigarette Smoking	Ventilation at VO2 Max	Baseline (V3)	74.8 L/min
IQOS-1	Ventilation at VO2 Max	Acute Effect (V4)	79.1 L/min
IQOS-1	Ventilation at VO2 Max	Baseline (V3)	78.9 L/min
IQOS-1	Ventilation at VO2 Max	Training Effect (V43)	79.2 L/min
IQOS-2	Ventilation at VO2 Max	Acute Effect (V4)	81.3 L/min
IQOS-2	Ventilation at VO2 Max	Baseline (V3)	87.3 L/min
IQOS-2	Ventilation at VO2 Max	Training Effect (V43)	82.5 L/min
Smoking Abstinence	Ventilation at VO2 Max	Baseline (V3)	71.9 L/min
Smoking Abstinence	Ventilation at VO2 Max	Acute Effect (V4)	77.2 L/min
Smoking Abstinence	Ventilation at VO2 Max	Training Effect (V43)	80.3 L/min
Dual-1	Ventilation at VO2 Max	Baseline (V3)	109 L/min
Dual-1	Ventilation at VO2 Max	Acute Effect (V4)	110 L/min
Dual-2	Ventilation at VO2 Max	Baseline (V3)	55.7 L/min
Dual-2	Ventilation at VO2 Max	Acute Effect (V4)	78.6 L/min
Other	Ventilation at VO2 Max	Training Effect (V43)	72.0 L/min
Other	Ventilation at VO2 Max	Acute Effect (V4)	76.1 L/min
Other	Ventilation at VO2 Max	Baseline (V3)	77.2 L/min

Primary

Very Low Density Lipoprotein (VLDL)

To measure VLDL concentrations in serum (mg/dL).

Time frame: Measured at Baseline (V3), week 6 (V14), week 10 (V28), and week 12 (V43).

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	Very Low Density Lipoprotein (VLDL)	Baseline (V3)	14.7 mg/dL
Cigarette Smoking	Very Low Density Lipoprotein (VLDL)	Week 6 (V14)	15.6 mg/dL
Cigarette Smoking	Very Low Density Lipoprotein (VLDL)	Week 10 (V28)	14.7 mg/dL
Cigarette Smoking	Very Low Density Lipoprotein (VLDL)	Week 12 (V43)	10.7 mg/dL
IQOS-1	Very Low Density Lipoprotein (VLDL)	Baseline (V3)	13.7 mg/dL
IQOS-1	Very Low Density Lipoprotein (VLDL)	Week 12 (V43)	12.4 mg/dL
IQOS-1	Very Low Density Lipoprotein (VLDL)	Week 6 (V14)	8.30 mg/dL
IQOS-1	Very Low Density Lipoprotein (VLDL)	Week 10 (V28)	13.7 mg/dL
IQOS-2	Very Low Density Lipoprotein (VLDL)	Week 12 (V43)	12.1 mg/dL
IQOS-2	Very Low Density Lipoprotein (VLDL)	Week 6 (V14)	11.1 mg/dL
IQOS-2	Very Low Density Lipoprotein (VLDL)	Week 10 (V28)	12.0 mg/dL
IQOS-2	Very Low Density Lipoprotein (VLDL)	Baseline (V3)	15.8 mg/dL
Smoking Abstinence	Very Low Density Lipoprotein (VLDL)	Baseline (V3)	13.7 mg/dL
Smoking Abstinence	Very Low Density Lipoprotein (VLDL)	Week 6 (V14)	11.4 mg/dL
Smoking Abstinence	Very Low Density Lipoprotein (VLDL)	Week 12 (V43)	12.3 mg/dL
Smoking Abstinence	Very Low Density Lipoprotein (VLDL)	Week 10 (V28)	6.56 mg/dL
Dual-1	Very Low Density Lipoprotein (VLDL)	Week 12 (V43)	10.8 mg/dL
Dual-1	Very Low Density Lipoprotein (VLDL)	Week 10 (V28)	10.3 mg/dL
Dual-1	Very Low Density Lipoprotein (VLDL)	Week 6 (V14)	9.82 mg/dL
Dual-1	Very Low Density Lipoprotein (VLDL)	Baseline (V3)	12.5 mg/dL

Primary

Waist Circumference

To measure waist circumference in cm.

Time frame: Measured at Baseline (V3), at week 1 (V4), and at week 12 (V43).

Population: AEECS: As Exposed Exercise Compliant Set. Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm	Measure	Group	Value (MEAN)
Cigarette Smoking	Waist Circumference	Baseline (V3)	82.6 cm
Cigarette Smoking	Waist Circumference	Training Effect (V43)	85.8 cm
Cigarette Smoking	Waist Circumference	Acute Effect (V4)	82.1 cm
IQOS-1	Waist Circumference	Acute Effect (V4)	81.6 cm
IQOS-1	Waist Circumference	Baseline (V3)	83.7 cm
IQOS-1	Waist Circumference	Training Effect (V43)	86.6 cm
IQOS-2	Waist Circumference	Acute Effect (V4)	83.6 cm
IQOS-2	Waist Circumference	Baseline (V3)	84.4 cm
IQOS-2	Waist Circumference	Training Effect (V43)	87.3 cm
Smoking Abstinence	Waist Circumference	Baseline (V3)	84.9 cm
Smoking Abstinence	Waist Circumference	Training Effect (V43)	89.5 cm
Smoking Abstinence	Waist Circumference	Acute Effect (V4)	85.2 cm
Dual-1	Waist Circumference	Acute Effect (V4)	77.6 cm
Dual-1	Waist Circumference	Baseline (V3)	78.4 cm
Dual-1	Waist Circumference	Training Effect (V43)	86 cm

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026

Effect of Switching From Cigarette Smoking to IQOS on Exercise Capacity

Conditions

Keywords

Brief summary

Detailed description

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Countries

Participant flow

Pre-assignment details

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

Body Fat

Body Weight

Capillary Blood Lactate Levels

Carboxyhemoglobin

CEMA

Exercise Capacity

Exercise Training Intensity: Average Heart Rate

Exercise Training Intensity: Average Work Rate

Exercise Training Intensity: Cumulative Work

Exercise Training Intensity: Time Spent at Maximal Heart Rate

Exhaled Carbon Monoxide

Growth Hormone

Heart Rate

Hemoglobin A1c (HbA1c)

Hemoglobin Mass

High Density Lipoprotein (HDL)

High Sensitivity C-reactive Protein (Hs-CRP)

Low Density Lipoprotein (LDL)

Maximal Oxygen Uptake (VO2max, Absolute Values)

Maximal Oxygen Uptake (VO2max, Fat-free Weight Adjusted Values)

Maximal Oxygen Uptake (VO2max, Weight-adjusted Values)

NEQ

Nicotine/Tobacco Product Use (Cigarettes)

Nicotine/Tobacco Product Use (E-cigarettes)

Nicotine/Tobacco Product Use (HeatSticks)

Oxygen Uptake

Plasma Volume

Rating of Perceived Capacity by Sex

Rating of Perceived Exertion

Red Blood Cell Volume

Respiratory Exchange Ratio

Respiratory Rate

Resting Pulse Rate

Resting Systolic Blood Pressure

Total Blood Volume

Total NNAL

VCO2

Ventilation at VO2 Max

Very Low Density Lipoprotein (VLDL)

Waist Circumference