Effect of Switching From Cigarette Smoking to IQOS on Exercise Capacity

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Smoking, Exercise Capacity

Intervention / Treatment
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* Other: IQOS + Exercise Training Program
* Other: IQOS without Exercise Training Program
* Other: Cigarette Smoking + Exercise Training Program
* Other: Smoking Abstinence + Exercise Training Program


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: IQOS-1<br>IQOS + Exercise Training Program Subjects randomized to IQOS use will switch to IQOS use and participate in an exercise training program. | Other: IQOS + Exercise Training Program<br>* Switch to IQOS use + participation in a training program<br>|
| Active Comparator: IQOS-2<br>IQOS without Exercise Training Program Subjects randomized to IQOS use will switch to IQOS use, but will not participate in an exercise training program. | Other: IQOS without Exercise Training Program<br>* Switch to IQOS use only, without participation in a training program<br>|
| Active Comparator: Cigarette Smoking<br>Cigarette Smoking + Exercise Training Program Subjects randomized to continued cigarette smoking and participation in an exercise training program. | Other: Cigarette Smoking + Exercise Training Program<br>* Continue to smoke cigarettes + participation in a training program<br>|
| Active Comparator: Smoking Abstinence<br>Smoking Abstinence + Exercise Training Program Subjects randomized to smoking abstinence and participation in an exercise training program. | Other: Smoking Abstinence + Exercise Training Program<br>* Switch to smoking abstinence + participation in a training program<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal Oxygen Uptake (VO2max, Absolute Values) | To measure VO2max during maximal cycle ergometer exercise (expressed in absolute values [mL*min-1]). | Measured at baseline (V3), at week 1 (V4), and at week 12 (V43). | 
| 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). | Measured at baseline (V3), at week 1 (V4), and at week 12 (V43). | 
| 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]). | Measured at baseline (V3), at week 1 (V4), and at week 12 (V43). | 
| 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). | Measured at baseline (V3), at week 1 (V4), and at week 12 (V43) | 
| 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. | Measured during 38 exercise training sessions of 40 minutes duration, conducted approximately 3 times a week, over 12 weeks. | 
| 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. | Measured during 38 exercise training sessions of 40 minutes duration, conducted approximately 3 times a week, over 12 weeks. | 
| 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. | Measured during 38 exercise training sessions of 40 minutes duration, conducted approximately 3 times a week, over 12 weeks. | 
| 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. | Measured during 38 exercise training sessions of 40 minutes duration, conducted approximately 3 times a week, over 12 weeks. | 
| Hemoglobin Mass | To measure Hemoglobin mass (g), measured with the carbon monoxide-rebreathing method. | Measured at Baseline (V3) and week 12 (V43). | 
| Red Blood Cell Volume | To measure Red blood cell volume (mL), measured with the carbon monoxide-rebreathing method. | Measured at Baseline (V3) and week 12 (V43). | 
| Plasma Volume | To measure Plasma volume (mL), measured with the carbon monoxide-rebreathing method. | Measured at Baseline (V3) and week 12 (V43). | 
| Total Blood Volume | To measure total blood volume (mL), measured with the carbon monoxide-rebreathing method. | Measured at Baseline (V3) and week 12 (V43). | 
| 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. | Measured at Baseline and week 15. | 
| Ventilation at VO2 Max | To measure ventilation (L/min) at VO2max. | Measured at Baseline (V3), at week 1 (V4), and at week 12 (V43). | 
| Respiratory Rate | To measure respiratory rate (breaths per minute) at VO2max. | Measured at Baseline (V3), at week 1 (V4), and at week 12 (V43). | 
| VCO2 | To measure VCO2 (L/min) at VO2 max. | Measured at Baseline (V3), at week 1 (V4), and at week 12 (V43). | 
| Respiratory Exchange Ratio | To measure the respiratory exchange ratio (VCO2/VO2) at VO2max | Measured at Baseline (V3), at week 1 (V4), and at week 12 (V43). | 
| 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. | Measured at Baseline (V3), at week 1 (V4), and at week 12 (V43). | 
| 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. | Measured at Baseline (V3), at week 1 (V4), and at week 12 (V43). | 
| Heart Rate | To measure changes from baseline of heart rate (bpm) during VO2max test. | Measured at Baseline, at week 1, and at week 15. | 
| Oxygen Uptake | To measure changes from baseline of Oxygen uptake during VO2max test. (mL/min) | Measured at Baseline, at week 1, and at week 15. | 
| High Density Lipoprotein (HDL) | To measure HDL concentrations in serum (mg/dL). | Measured at Baseline (V3), week 6 (V14), week 10 (V28), and week 12 (V43). | 
| Low Density Lipoprotein (LDL) | To measure LDL concentrations in serum (mg/dL). | Measured at Baseline (V3), week 6 (V14), week 10 (V28), and week 12 (V43). | 
| Very Low Density Lipoprotein (VLDL) | To measure VLDL concentrations in serum (mg/dL). | Measured at Baseline (V3), week 6 (V14), week 10 (V28), and week 12 (V43). | 
| High Sensitivity C-reactive Protein (Hs-CRP) | To measure hs-CRP concentrations in serum (mg/dL). | Measured at Baseline (V3), week 6 (V14), week 10 (V28), and week 12 (V43). | 
| Growth Hormone | To measure growth hormone concentrations in serum (ng/mL). | Measured at Baseline (V3), week 6 (V14), week 10 (V28), and week 12 (V43). | 
| Hemoglobin A1c (HbA1c) | To measure glycosylated hemoglobin (HbA1c in whole blood). | Measured at Baseline (V3), week 6 (V14), week 10 (V28), and week 12 (V43). | 
| Resting Systolic Blood Pressure | To measure resting systolic blood pressure in mmHg. | Measured at Baseline (V3), week 6 (V14), week 10 (V28), and week 12 (V43). | 
| Resting Pulse Rate | To measure resting heart rate in bpm. | Measured at Baseline (V3), week 6 (V14), week 10 (V28), and week 12 (V43). | 
| Body Fat | To measure body fat as a percentage. | Measured at Baseline (V3), at week 1 (V4), and at week 12 (V43). | 
| Waist Circumference | To measure waist circumference in cm. | Measured at Baseline (V3), at week 1 (V4), and at week 12 (V43). | 
| Body Weight | To measure body weight in kilograms. | Measured at each visit, starting from Baseline (V3) until week 12 (V43). | 
| Exhaled Carbon Monoxide | To measure exhaled carbon monoxide (ppm). | Measured at each visit, starting from Baseline (V3) until week 12 (V43). | 
| Carboxyhemoglobin | To measure Carboxyhemoglobin (COHb), assayed from whole blood. Expressed as % of saturation of hemoglobin. | Measured at Baseline (V3), week 1 (V4), week 6 (V14), week 10 (V28), and week 12 (V43). | 
| NEQ | To measure Nicotine equivalents (NEQ) concentrations, measured in spot urine and expressed as concentration adjusted for creatinine. | Measured at Baseline (V3), week 1 (V4), week 6 (V14), week 10 (V28), and week 12 (V43). | 
| 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. | Measured at Baseline (V3), week 1 (V4), week 6 (V14), week 10 (V28), and week 12 (V43). | 
| CEMA | To measure 2-cyanoethylmercapturic acid (CEMA) concentrations, measured in spot urine and expressed as concentration adjusted for creatinine. | Measured at Baseline (V3), week 1 (V4), week 6 (V14), week 10 (V28), and week 12 (V43). | 
| Nicotine/Tobacco Product Use (Cigarettes) | To measure self-reported number of any nicotine/tobacco product used on a daily basis. | Recorded daily by subject, in product use diary, from study enrollment for 16 weeks. | 
| Nicotine/Tobacco Product Use (HeatSticks) | To measure self-reported number of any nicotine/tobacco product used on a daily basis. | Recorded daily by subject, in product use diary, from study enrollment for 16 weeks. | 
| Nicotine/Tobacco Product Use (E-cigarettes) | To measure self-reported number of any nicotine/tobacco product used on a daily basis. | Recorded daily by subject, in product use diary, from study enrollment for 16 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IQOS, Heated Tobacco