--> This is a substudy of the main ESTxENDS trial (NCT03589989). Pulmonary function outcomes should be considered secondary outcomes of the main smoking cessation outcome formulated in NCT03589989.

Cigarette smoking is the leading cause of preventable death in Switzerland and still more than a quarter of the Swiss population smokes cigarettes. Recently, electronic nicotine delivery systems (ENDS; also called vaporizer, e-cigarette or electronic cigarette) have become popular with smokers who want to stop smoking or reduce their exposure to inhaled chemicals since ENDS use appears to be safer than tobacco smoking. The inhaled ENDS aerosol appears safe in laboratory conditions, its long-term effects on pulmonary function remains unknown. This study will therefore investigate the impact of ENDS on lung function in smokers, who attempt to quit using ENDS compared with smokers, receiving only smoking cessation counseling with nicotine replacement therapy (NRT).

Multiple breath washout (MBW) is an established technique for assessment of peripheral airway function in pediatrics and its use is emerging in adult medicine, as it offers a better sensitivity to assess small airway disease before large airway involvement can be detected using conventional pulmonary function tests (PFT - spirometry, body plethysmography and diffusing capacity test). Preliminary evidence from limited studies suggest MBW parameters (LCI, Scond, Sacin) can be impaired in smokers with normal lung function and improve after smoking abstinence.

Primary objective of this substudy is to assess changes in LCI from baseline to 6 months post target quit date (TQD) in cigarette smokers randomized to the intervention group compared to the control group.

For the main ESTxENDS trial (NCT03589989), cigarette smokers motivated to quit smoking cigarettes will be included. Participants in the intervention group will receive an ENDS and nicotine-containing e-liquids, which they will be allowed to use ad libitum. Additionally, they will receive standard of care, i.e. smoking cessation counseling and encouragement to use NRT. Smoking cessation counseling will be provided in person at the first clinical visit and then over the phone at the target quit date and again at week 1, 2, 4 and 8 after the target quit date. Participants in the control group will receive only standard of care. All participants will be followed over a 6-month period. After 6 months, participants will be asked to come to a final clinical visit.

Inclusion Criteria:

• Informed Consent as documented by signature
• Persons aged 18 or older
• Currently smoking 5 or more cigarettes a day for at least 12 months
• Willing to try to quit smoking within the next 3 months
• Persons providing a valid phone number, a valid email address and/or a valid postal address.

Exclusion Criteria:

• Known hypersensitivity or allergy to contents of the e-liquid
• Participation in another study with investigational drug within the 30 days preceding the baseline visit and during the present study where interactions are to be expected
• Women who are pregnant or breast feeding
• Intention to become pregnant during the course of the scheduled study intervention, i.e. within the first 6-months of the study
• Persons having used ENDS or tobacco heating systems regularly in the 3 months preceding the baseline visit
• Persons having used nicotine replacement therapy (NRT) or other medications with demonstrated efficacy as an aid for smoking cessation such as varenicline or bupropion within the 3 months preceding the baseline visit
• Persons who cannot attend the 6-month follow-up visit for any reason
• Cannot understand instructions delivered in person or by phone, or otherwise unable to participate in study procedures

Statisticians and laboratory personnel will be blinded to group allocation