Reduce Tobacco Use in People Living With HIV in Switzerland: A Pragmatic Randomized Trial Within the Swiss HIV Cohort Study
Phase: NA
Conditions: HIV, Smoking
Sponsor: University Hospital, Basel, Switzerland

Version 1.2, 08/08/2025 
 
 
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RETUNE  
Study ID 
 
Study Protocol 
 
 
Reduce tobacco use in people living with HIV in Switzerland: A pragmatic 
randomized trial within the Swiss HIV Cohort Study (RETUNE) 
 
 
 
 
 
 
Study Type: 
 Other Clinical Trial according to ClinO, Chapter 4 
 
Risk Categorisation:  
Risk category A according to ClinO, Art. 61 
 
Study Registration: 
NCT06789692 
 
Sponsor Investigator:  
Prof. Matthias Briel, MD PhD 
 
 
 
 
Division of Clinical Epidemiology, 
 
 
 
 
University Hospital Basel  
 
 
 
 
Totengässlein 3, 4051 Basel  
 
 
 
 
+41 61 265 38 15 
 
 
 
 
Matthias.Briel@usb.ch 
 
Investigated Intervention: 
Offer of a menu of different tobacco smoking substitution products 
(nicotine pouches, electronic nicotine delivery systems, and nicotine 
patches)  
 
Protocol ID 
 
 
2024-02417 
 
Version and Date: 
 
Version 1.2 (dated 08.08.2025) 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document is confidential and the property of the sponsor. The 
information may not - in full or in part - be transmitted, reproduced, published, or disclosed to 
others than the applicable Competent Ethics Committee(s) and Regulatory Authority(ies) without 
prior written authorisation from the sponsor except to the extent necessary to obtain informed 
consent from those who will participate in the study. 

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LIST OF PROJECT LEADERS AND OTHER KEY PERSONS INVOLVED IN THE TRIAL 
Title 
Names 
Institution 
Position 
Role and 
Function/Responsibility 
in the project 
MD PhD 
Matthias Briel 
Division of Clinical 
Epidemiology, University 
Hospital Basel, University 
of Basel 
Unit head and 
research 
group leader 
Sponsor Investigator; 
Responsible for the overall 
trial implementation 
MD PhD 
Alain Amstutz 
Division of Clinical 
Epidemiology, University 
Hospital Basel, University 
of Basel 
Post-doctoral 
researcher 
and project 
leader 
Co-Principal Investigator; 
Responsible for the overall 
trial implementation 
MD 
Christof Manuel 
Schönenberger 
Division of Clinical 
Epidemiology, University 
of Basel, University 
Hospital Basel 
PhD 
Candidate 
Co-Principal Investigator; 
Coordinating all aspects of 
the trial 
MD 
Niklaus 
Labhardt 
Division of Clinical 
Epidemiology, University 
Hospital Basel, University 
of Basel 
Chief 
physician and 
division head 
Collaborator; Cohort 
physician and PhD 
supervisor 
PhD 
Frédérique 
Chammartin 
Division of Clinical 
Epidemiology, University 
Hospital Basel, University 
of Basel 
Statistician 
and project 
leader 
Trial Statistician; Input on 
the data analysis 
MD 
Reto Auer 
Institute of Primary Health 
Care (BIHAM), University 
of Bern 
Unit head and 
research 
group leader 
Collaborator; Input on 
smoking cessation aspects 
as well as methodological 
aspects of smoking 
cessation trials 
PhD 
Katharina 
Kusejko 
SHCS Data center, 
University of Zurich 
Head of the 
SHCS data 
center 
Collaborator; Implementing 
the trial data infrastructure 
in the SHCS 
PhD 
Sandra 
Chaudron 
SHCS Data center, 
University of Zurich 
Deputy head 
of the SHCS 
data center 
Collaborator; Implementing 
the trial data infrastructure 
in the SHCS 
PhD 
David Jackson-
Perry 
Lausanne University 
Hospital 
Project 
coordinator 
Member of the Participant 
Advisory Board; Input on all 
aspects of the trial, focus 
on lived experiences 
 
David Haerry 
Positivrat Schweiz 
President 
Member of the Participant 
Advisory Board; Input on all 
aspects of the trial, focus 
on lived experiences 
 
Ellen Cart 
La Maison du Pèlerin 
Chief nursing 
director 
Member of the Participant 
Advisory Board; Input on all 
aspects of the trial, focus 
on lived experiences 

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MD 
Maja Weisser 
Rohacek 
Department for Infectious 
Diseases and Hospital 
Hygiene, University 
Hospital Basel 
Senior 
physician 
Collaborator; Cohort 
physician; Input on local 
site implementation 
procedures (Basel) 
PhD 
Aurélie Berthet 
Unisanté, University of 
Lausanne 
Research 
group leader 
Collaborator; Leading 
Biomarker sub study 
PhD 
Benjamin 
Speich 
Division of Clinical 
Epidemiology, University 
Hospital Basel, University 
of Basel 
Senior 
researcher 
and project 
leader 
Collaborator; Input on trial 
methodology 
MD 
Bernard Surial 
Clinic for Infectious 
Diseases, University 
Hospital Bern 
Senior 
physician 
Collaborator; Cohort 
physician; Input on local 
site implementation 
procedures (Bern) 
MD 
Julia Notter 
Department for Infectious 
Diseases and Hospital 
Hygiene, University 
Hospital Basel 
Senior 
physician 
Collaborator; Cohort 
physician; Input on local 
site implementation 
procedures (Basel) 
MD PhD 
Irene Abela 
Clinic for Infectious 
Diseases and Hospital 
Hygiene, University 
Hospital Zurich 
Senior 
physician 
Collaborator; Cohort 
physician; Input on local 
site implementation 
procedures (Zurich) 
MD 
Christoph Fux 
Clinic for Infectious 
Diseases and Prevention, 
Cantonal Hospital Aarau 
Chief 
physician 
Local investigator Aarau 
site; Input on local site 
implementation procedures 
and responsible for local 
recruitment and follow-up 
MD 
Huldrych F. 
Günthard 
Clinic for Infectious 
Diseases and Hospital 
Hygiene, University 
Hospital Zurich 
Senior 
physician 
Collaborator; Cohort 
physician; Input on overall 
implementation in the 
cohort 
MD 
Andri Rauch 
Clinic for Infectious 
Diseases, University 
Hospital Bern 
SHCS 
President 
Collaborator; Cohort 
physician; Input on overall 
implementation in the 
cohort 
MD 
Marcel Stöckle 
Department for Infectious 
Diseases and Hospital 
Hygiene, University 
Hospital Basel 
SHCS center 
head 
Local investigator Basel 
site; Input on local site 
implementation procedures 
and responsible for local 
recruitment and follow-up 
MD 
Gilles Wandeler 
Clinic for Infectious 
Diseases, University 
Hospital Bern 
SHCS center 
head 
Local investigator Bern 
site; Input on local site 
implementation procedures 
and responsible for local 
recruitment and follow-up 
MD 
Johannes 
Nemeth 
Clinic for Infectious 
Diseases and Hospital 
SHCS center 
head 
Local investigator Zurich 
site; Input on local site 

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Hygiene, University 
Hospital Zurich 
implementation procedures 
and responsible for local 
recruitment and follow-up 
MD 
Patrick Schmid 
Clinic for Infectious 
Diseases, Cantonal 
Hospital St. Gallen 
SHCS center 
head 
Local investigator St. 
Gallen site; Input on local 
site implementation 
procedures and 
responsible for local 
recruitment and follow-up 
MD 
Matthias 
Cavassini 
Clinic for Infectious 
Diseases, University 
Hospital Lausanne 
SHCS center 
head 
Local investigator 
Lausanne site; Input on 
local site implementation 
procedures and 
responsible for local 
recruitment and follow-up 
MD PhD 
Alexandra 
Calmy 
Clinic for Infectious 
Diseases, University 
Hospital Geneva 
SHCS center 
head 
Local investigator Geneva 
site; Input on local site 
implementation procedures 
and responsible for local 
recruitment and follow-up 
 
 

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PROTOCOL SIGNATURE FORM    
 
 
Study Title 
Reduce tobacco use in people living with HIV in Switzerland: 
A pragmatic randomized trial within the Swiss HIV Cohort 
Study  
Study ID 
NCT06789692 
 
The Sponsor-investigator, the other principal investigators, and all site-investigators have 
approved the protocol version 1.2 (dated 08/08/2025) and confirm hereby to conduct the study 
according to the protocol, current version of the World Medical Association Declaration of 
Helsinki, and ICH-GCP guidelines as well as the local legally applicable requirements. 
 
 
Principal investigators: 
 
Name: Prof. Matthias Briel, MD PhD 
Date: _______________________ 
Signature: _________________________ 
 
 
 
Name: Alain Amstutz, MD PhD  
Date: _______________________ 
Signature: _________________________ 
 
 
 
Name: Christof Manuel Schönenberger, MD 
Date: _______________________ 
Signature: _________________________ 
 
 
 
 
Statistician: 
 
Name: Frédérique Chammartin, PhD 
Date: _______________________ 
Signature: _________________________ 
 
 
 
 
 
 
 
 
 

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Local Investigator at study site: 
 
 
Site: University Hospital Basel 
Local Investigator: Marcel Stöckle, MD 
Date: _______________________ 
Signature: _________________________ 
 
 
 
 
 
Site: University Hospital Zurich  
Local Investigator: PD. Johannes Nemeth, MD  
Date: _______________________ 
Signature: _________________________ 
 
Site: Inselspital Bern  
Local Investigator: Prof. Gilles Wandeler, MD PhD 
Date: _______________________ 
Signature: _________________________ 
 
 
Site: Cantonal Hospital St. Gallen   
Local Investigator: Patrick Schmid, MD  
Date: _______________________ 
Signature: _________________________ 
 
 
 
Site: University Hospital Lausanne  
Local Investigator: Prof. Matthias Cavassini, MD 
Date: _______________________ 
Signature: _________________________ 
 
 
 

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Site: University Hospital Geneva   
Local Investigator: Prof. Alexandra Calmy, MD PhD 
Date: _______________________ 
Signature: _________________________ 
 
Site: Cantonal Hospital Aarau 
Local Investigator: Christoph Fux, MD 
Date: _______________________ 
Signature: _________________________ 
 
 

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TABLE OF CONTENTS 
Table of Contents ........................................................................................................................................................................ 7 
1 
STUDY SYNOPSIS ............................................................................................................................................................ 10 
2 
BACKGROUND and rationale ..................................................................................................................................... 14 
2.1 People living with HIV in Switzerland – addressing the shift of mortality and morbidity ................................... 14 
2.2 Tackling a major health burden among PLWH ...................................................................................................................... 14 
2.3 Electronic nicotine delivery systems ............................................................................................................................................ 15 
2.4 Nicotine pouches ................................................................................................................................................................................... 16 
2.5 Nicotine patches .................................................................................................................................................................................... 17 
2.6 New ways to include more smokers in smoking cessation programs ............................................................................ 17 
2.7 Using an innovative design to generate randomized evidence in cohort studies ..................................................... 18 
2.8 Inequality in smoking cessation research regarding low socioeconomic status and HIV .................................... 18 
2.9 Scientific impact.................................................................................................................................................................................... 18 
3 
Study OBJECTIVES and Design .................................................................................................................................. 19 
3.1 Hypothesis and objectives ................................................................................................................................................................. 19 
3.2 Primary and secondary endpoints ................................................................................................................................................ 21 
3.3 Study design ............................................................................................................................................................................................ 22 
3.3.1 Allocation concealment and blinding ............................................................................................................................... 23 
3.3.2 Randomization ............................................................................................................................................................................ 23 
4 
Study POPULATION and Study procedures .......................................................................................................... 23 
4.1 Inclusion and exclusion criteria, justification of study population ................................................................................. 23 
4.1.1 Inclusion criteria ........................................................................................................................................................................ 23 
4.1.2 Exclusion criteria ....................................................................................................................................................................... 23 
4.1.3 Justification of the study population ................................................................................................................................ 24 
4.2 Recruitment, screening, and informed consent procedure ................................................................................................. 24 
4.2.1 Screening and recruitment.................................................................................................................................................... 24 
4.2.2 Informed consent ....................................................................................................................................................................... 24 
4.3 Study intervention ................................................................................................................................................................................ 25 
4.3.1 Description of electronic nicotine delivery system (e-cigarettes) ................................................................................ 25 
4.3.2 Description of nicotine pouches ......................................................................................................................................... 25 
4.3.3 Description of nicotine patches .......................................................................................................................................... 25 
4.3.4 Comparator ................................................................................................................................................................................... 25 
4.4 Study procedures .................................................................................................................................................................................. 26 
4.4.1 General Setting ............................................................................................................................................................................ 26 
4.4.2 Trial procedures and data collection................................................................................................................................ 26 
4.4.3 Storage conditions and supply of intervention products ....................................................................................... 29 
4.5 Withdrawal and discontinuation .................................................................................................................................................. 29 
4.6 Compliance with the intervention ................................................................................................................................................. 29 

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4.6.1 Compensation for participants............................................................................................................................................ 30 
4.6.2. Compensation for participating trial centers .............................................................................................................. 30 
4.7 Participation in other clinical trials ............................................................................................................................................. 30 
4.8 Patient and public involvement and the participant advisory board ............................................................................ 30 
5 
STATISTICS AND METHODOLOGY............................................................................................................................ 30 
5.1 Sample size calculation ...................................................................................................................................................................... 30 
5.2 Adaptive readjustment ....................................................................................................................................................................... 31 
5.3 Internal pilot study .............................................................................................................................................................................. 32 
5.4 Description of statistical methods ................................................................................................................................................. 33 
5.4.1 Dataset to be analyzed............................................................................................................................................................. 33 
5.4.2 Primary analysis ......................................................................................................................................................................... 33 
5.4.3 Secondary analyses ................................................................................................................................................................... 33 
5.4.4 Interim analysis .......................................................................................................................................................................... 37 
5.4.5 Subgroup analysis...................................................................................................................................................................... 37 
5.5 Handling of missing data and drop-outs .................................................................................................................................... 37 
6 
Regulatory Aspects AND SAFETY ............................................................................................................................. 38 
6.1 Local regulations / Declaration of Helsinki .............................................................................................................................. 38 
6.2 (Serious) Adverse Events: Definitions, collection, and assessment ................................................................................. 38 
6.2.1 Adverse Events (AE) ................................................................................................................................................................. 38 
6.2.2 Adverse Events of Special Interest (AESI) ..................................................................................................................... 38 
6.2.3 Serious Adverse Event (SAE) ............................................................................................................................................... 38 
6.2.4 Collection of AE, SAE, AESI .................................................................................................................................................... 39 
6.2.5 Assessment of causality and severity ............................................................................................................................... 39 
6.2.6 Reporting of SAEs (see ClinO, Art. 63)97 ......................................................................................................................... 39 
6.3 (Periodic) safety reporting and reporting of general progress ........................................................................................ 39 
6.4 Pregnancy ................................................................................................................................................................................................ 40 
6.5 Amendments ........................................................................................................................................................................................... 40 
6.6 Notification and reporting upon completion, discontinuation or interruption of the study ............................... 40 
6.7 Insurance.................................................................................................................................................................................................. 40 
7 
FURTHER Aspects........................................................................................................................................................... 41 
7.1 Overall ethical considerations ........................................................................................................................................................ 41 
7.2 Risk-benefit assessment ..................................................................................................................................................................... 41 
7.3 Time plan and trial duration ........................................................................................................................................................... 42 
7.4 Process evaluation ............................................................................................................................................................................... 42 
8 
Quality CONTROL AND Data protection ................................................................................................................ 42 
8.1 Quality measures .................................................................................................................................................................................. 42 
8.2 Data recording and source data .................................................................................................................................................... 43 
8.3 Confidentiality and coding ............................................................................................................................................................... 43 

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8.4 Retention and destruction of study data and biological material .................................................................................. 45 
9  
Monitoring and Registration ..................................................................................................................................... 45 
10. 
Funding / Publication / declaration of Interest ............................................................................................ 45 
11. 
REFERENCES ................................................................................................................................................................ 47 
 
GLOSSARY OF ABBREVIATIONS 
 
AE  
 Adverse Event  
AESI 
 Adverse Event of Special Interest  
BASEC 
 Business Administration System for Ethical Committees 
CACE 
 Complier Average Causal Effect  
CVD 
 Cardiovascular Disease  
DAG 
 Directed Acyclic Graph  
e-cigarettes 
 electronic cigarettes 
eCRF 
 electronic Case Report Form  
EKNZ  
 Ethic committee of Northern and Central Switzerland  
FOPH 
 Federal Office of Public Health 
FSVA 
 Federal Food Safety and Veterinary Office 
HDL  
High Density Lipoprotein 
ITT 
 Intention-To-Treat 
LDL  
 Low Density Lipoprotein 
PLWH 
 People Living With HIV 
PPI 
 Patient and Public Involvement  
RCT 
 Randomized Clinical Trial  
SAE  
 Serious Adverse Events  
SHCS  
 Swiss HIV Cohort Study  
TwiCs 
 Trial within Cohorts  
 
 

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1 
STUDY SYNOPSIS 
Sponsor 
/ 
Sponsor-
Investigator 
Division of Clinical Epidemiology, University Hospital Basel  
Totengässlein 3, 4051 Basel  
Represented by: Prof. Matthias Briel, MD PhD  
+ 4161 61 265 38 15 
Matthias.Briel@usb.ch 
Study Title 
Reduce tobacco use in people living with HIV in Switzerland: A pragmatic 
randomized trial within the Swiss HIV Cohort Study   
Short Title / Study 
ID 
RETUNE  
Protocol Version 
and Date 
Version 1.2 (dated 08.08.2024) 
Study 
Registration 
NCT06789692 
Study 
Category 
and Rationale 
Risk category A, Other clinical trials 
Nicotine pouches and electronic cigarettes (electronic nicotine delivery systems and 
liquids) are regulated by the law on alimentary goods in Switzerland. We therefore 
follow the rules of the Federal Office of Public Health (FOPH) and the Federal Food 
Safety and Veterinary Office (FSVA) for the import and use of nicotine-containing e-
liquids. The risk is considered to be low.  
Nicotine patches are an authorized, established, low risk medical product.  
Background and 
Rationale  
Due to highly effective antiretroviral therapy, people living with HIV (PLWH) in 
Switzerland have a close-to-normal life expectancy. Among PLWH, there has been 
a shift of focus from HIV-related health issues to non-communicable diseases, 
especially cardiovascular diseases (CVDs) and cancer. Smoking, a prominent risk 
factor for both diseases, takes a key role in view of the high number of smokers 
among PLWH.  
New approaches to smoking cessation focus on harm reduction by substituting 
tobacco cigarettes by less harmful alternatives. Conventional nicotine replacement 
therapy like nicotine patches is well established and effective against withdrawal 
symptoms after quitting. However, these products are exceptionally expensive and 
the missing “nicotine hit” often limits therapy adherence. The long-term abstinence 
rate remains low. Electronic cigarettes (e-cigarettes) and nicotine pouches as 
alternative nicotine replacement therapies have the potential to overcome these 
problems and are accessible. 
E-cigarettes play a growing role in smoking cessation therapy. Evidence from 
randomized trials shows superiority over conventional nicotine replacement 
therapies, which is probably based on the better imitation of the smoking experience. 
Although e-cigarettes are not without concerns, there is consensus that they are 
significantly less harmful than tobacco cigarettes. 
Tobacco-free nicotine pouches, delivering nicotine through oral mucosa, are a 
relatively novel option for nicotine substitution. Similar to e-cigarettes, nicotine 
pouches are relatively affordable and can address the limitation of poor imitation of 
the “nicotine hit” seen with traditional nicotine replacement therapy. To the best of 
our knowledge, no trials have investigated the potential of nicotine pouches for 
smoking cessation so far.  
With this trial, we also want to address frequent shortcomings of smoking cessation 
trials, such as restrictive inclusion criteria and highly controlled interventions, by 

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offering a menu of different nicotine substitute products (e-cigarettes or nicotine 
pouches or nicotine patches) and by using a novel pragmatic trial design, the Trials 
within Cohorts (TwiCs) design. We plan to recruit tobacco smokers in the Swiss HIV 
Cohort Study (SHCS), regardless of their willingness to quit. This so called “opt-out-
approach” has been suggested as a new promising approach for smoking cessation 
trials to increase generalizability of the results. The TwiCs design optimally allows to 
implement and evaluate the “opt-out” approach embedded in the SHCS.  
Risk 
/ 
Benefit 
Assessment 
This trial investigates a low-risk intervention in a pragmatic way. The risk for the trial 
participants will be low and the application of the different products reflect real-life 
practice.  
All interventions used in this trial (e-cigarettes, nicotine pouches and nicotine 
patches) are approved by the Swiss authorities and freely available on the market. 
The nicotine patches are a drug and approved by Swissmedic.  
All products may cause local reactions and irritation of the skin or mucous membrane. 
Accordingly, the trial participants will be informed to discontinue the products and to 
contact their treating physician in case of corresponding side effects. Adverse events 
will be collected using surveys and routinely collected data from the SHCS.   
The intervention is designed to help trial participants quit smoking tobacco cigarettes. 
Given the major health burden caused by tobacco smoking, especially in PLWH, the 
potential benefit of the trial intervention clearly outweighs the potential low risks. If 
proven effective, our intervention can be translated directly into clinical practice (in 
PLWH and possibly other settings) to reduce the burden of tobacco smoking in terms 
of morbidity and mortality.  
Objective(s) 
Primary objective: The purpose of this trial is to test the effectiveness of offering a 
menu of different nicotine substitute products (e-cigarettes, nicotine pouches, 
nicotine patches in addition to usual of care) for tobacco smokers in the SHCS in 
achieving self-reported 7-day tobacco cigarette abstinence at 6 months. 
 
Secondary objectives:  
● 
To assess the effect of offering the preference-based smoking cessation 
intervention on tobacco smoking cessation (defined as 7-day tobacco 
cigarette abstinence) at 12 and 24 months. 
● 
To assess the effect of offering the preference-based smoking cessation 
intervention on (i) reduction of smoked tobacco cigarettes per day; (ii) 
reduction of cardiovascular risk and (iii) occurrence of cardiovascular events 
or death. 
Endpoint(s) 
Primary endpoint 
Tobacco smoking status (yes/no) measured as self-reported abstinence in the last 7 
days at 6-month visit (window: 120-270 days) 
Secondary endpoints 
1. Tobacco smoking status (yes/no) measured as self-reported abstinence in 
the last 7 days at 12-month visit (window: 271-450 days) and 24-month visit 
(window: 630-810 days).  
2. Mean change in the self-reported number of tobacco-based cigarettes 
smoked per day at 6,12, and 24 months.  
3. Self-reported use of any nicotine containing product other than tobacco 
cigarettes (yes/no). If yes, self-reported use of e-cigarettes (yes/no) or 
nicotine pouches (yes/no) or patches (yes/no) or other (yes/no) after 6 

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(window: 120-270 days), 12 (window: 271-450 days) and 24 (window: 630-
810 days) months.  
4. Self-reported abstinence of any nicotine containing product (yes/no) after 12 
(window: 271-450 days) and 24 (window: 630-810 days) months.    
5. Mean change in High Density Lipoprotein (HDL), Low Density Lipoprotein 
(LDL), and total Cholesterol (mmol/l) at 6,12, and 24 months.  
6. Mean change in systolic and diastolic blood pressure (mmHg) at 6,12, and 
24 months.  
7. Mean change in body weight (kg) from baseline to 6,12 and 24 months.  
8. Mean change in SCORE2 score at 6, 12, and 24 months.  
9. Occurrence of cardiovascular events (myocardial infarction, coronary 
angioplasty/stenting, 
coronary 
artery 
by-pass 
grafting, 
carotid 
endarterectomy, stroke, deep vein thrombosis, pulmonary embolism, heart 
transplantation) at 6,12, and 24 months.    
Study Design 
Randomized clinical trial according to the “Trials within Cohorts” (TwiCs) design 
approach. Individual 1:1 randomization, stratified by minimization variables (see 
below). 
Statistical 
Considerations 
The primary analysis will use the intention-to-treat set and a logistic regression model 
adjusted for the minimization variables (region (French vs. German speaking part of 
Switzerland), men having sex with man (yes/no), current drug user (yes/no), and the 
number of cigarettes per day) to test for superiority of the intervention (vs control) at 
a significance alpha level of 0.05.  
In secondary analyses, we will assess per protocol estimates for the primary endpoint 
using observational causal inference methods. No interim analysis is planned. 
Inclusion- 
/ 
Exclusion Criteria 
Inclusion criteria: SHCS participants aged 18 or older, living with HIV, accessing 
routine HIV care at one of the involved trial sites, who smoke one or more tobacco-
based cigarettes per day at the day of trial inclusion and signed the randomization 
consent.  
Exclusion criteria: SHCS participants who are, besides tobacco cigarettes, already 
using e-cigarettes or nicotine pouches or nicotine patches. Pregnant women are 
excluded.  
Number 
of 
Participants with 
Rationale 
We assume a smoking cessation rate of 8.5% in the control arm (based on SHCS 
data), a 20% cessation rate in the intervention arm (based on external evidence of 
similar trials), and an attrition rate of 3% (based on SHCS data). Considering a low 
uptake of only 50% in the intervention and thus dilution of the intervention effect, we 
aim at enrolling a total 972 participants to achieve 80% power for a two-sided alpha 
level at 5%. We will update our sample size during recruitment depending on 
observed uptake rates, monitored at predefined recruitment timepoints. 
Study 
Intervention 
Offer of menu of different nicotine substitute products, consisting of e-cigarettes or 
nicotine pouches or nicotine patches in addition to standard of care. This menu will 
be offered by the treating physician during the routine cohort visit and the participant 
can choose one product to test as an alternative to tobacco smoking. The products 
will be handed out directly after the consultation and are provided free of charge for 
6 months.  
Control 
Intervention 
Standard smoking cessation counselling according to routine care in the SHCS. The 
treating physician is allowed to prescribe medication or further smoking cessation 
counselling, if indicated or wished by the participant. However, participants in the 
control group will not be offered the intervention menu and no recommendations to 
use e-cigarettes or nicotine pouches will be made.  

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Study procedures 
The trial endpoints will be collected during regular cohort visits, which take place 
every 6 months.  
The following parameters will be collected (part of routine care): smoking status, 
number of cigarettes smoked in the last 7 days, use of nicotine patches, nicotine 
chewing gums, snus, nicotine pouches, pipe, snuff, IQOS, and e-cigarettes. In 
addition, information on systolic and diastolic blood pressure (mmHg), body weight 
(kg), HDL-, LDL-, and total Cholesterol (mmol/l), hospitalizations and death are 
routinely collected during SHCS visits and used for trial purposes. 
Additional safety endpoints and adherence information in the intervention group are 
collected retrospectively (not part of the SHCS routine data collection).  
Study 
Duration 
and Schedule 
3 years  
First patient in: February 2025 
Last patient out: December 2027 
Sponsor 
Investigator 
Prof. Matthias Briel, MD PhD 
Deputy Head of Division 
Division of Clinical Epidemiology   
University Hospital Basel  
Totengaesslein 3, 4051 Basel, Switzerland 
+ 4161 265 3815 
Mathias.briel@usb.ch 
Study Center(s) 
In this multicenter trial 7 institutions will be involved:  
University Hospital Basel (Klinik für Infektiologie und Spitalhygiene, Petersgraben 
4, 4031 Basel and Division of Clinical Epidemiology, Totengässlein 3, 4051 Basel) 
University Hospital Zurich (Klinik für Infektionskrankheiten und Spitalhygiene, 
Rämistrasse 100, 8091 Zürich) 
Inselspital Bern (Universitätsklinik für Infektiologie, Freiburgstrasse 16, 3010 Bern) 
Cantonal Hospital St. Gallen (Klinik für Infektiologie und Spitalhygiene, 
Rorschacherstrasse 95, 9007 St. Gallen) 
University Hospital Lausanne (Service des maladies infectieuses, Rue de Bugnon 
46, 1011 Lausanne) 
University Hospital Geneva (Service des maladies infectieuses, Rue Gabrielle-
Perret-Gentil 4, 1205 Genève) 
Cantonal Hospital Aarau (Klinik für Infektiologie und Infektionsprävention, Haus 7, 
Tellstrasse 25, 5001 Aarau) 
Data privacy 
The data of the participants will be kept encrypted. Identifying patient data will only 
be visible for the principal investigators and for staff at the respective SHCS sites. 
Coding keys will be kept at the treating SHCS site, according to the SHCS protocol.  
No blood sampling will be collected as part of this study. 
Ethical 
consideration 
This project will be conducted in accordance with the research plan outlined in this 
protocol and with principles according to the current version of the Declaration of 
Helsinki as well as all national legal requirements and guidelines as applicable.  
This protocol will be reviewed by the Ethikkommission Nordwest- und Zentralschweiz 
(EKNZ, Ethics Committee of Northern and Central Switzerland) as the leading ethics 
committee before the start of the trial. 
All participants in the SHCS and in the RETUNE trial are participating voluntarily. All 
intervention products can be declined and discontinued, and participants will 
continue receiving best available care as part of the SHCS. It is possible to not 

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participate in the RETUNE trial but be a participant in the SHCS. The treating study 
centers, who have many years of experience, ensure the best possible care for the 
trial participants. 
The nicotine substitute products may have potential risks and participants will be 
informed about these. Only products that are approved and freely available will be 
used. However, the health benefit of reducing tobacco smoking outweighs potential 
side-effects from the harm reduction products. 
The evidence generated by this trial will help improve national and international 
guidelines with respect to smoking cessation for PLWH.  
GCP Statement 
This study will be conducted in compliance with the protocol, the current version of 
the Declaration of Helsinki, the ICH-GCP, the HRA as well as other locally relevant 
legal and regulatory requirements.  
 
2 
BACKGROUND AND RATIONALE  
2.1 People living with HIV in Switzerland – addressing the shift of mortality and morbidity 
People living with HIV (PLWH) have a close-to-normal life expectancy due to highly effective 
antiretroviral therapy that has been rolled out over the last decades.1 Among PLWH, there has 
been a shift of focus from HIV-related health issues to non-communicable diseases, especially 
cardiovascular diseases (CVDs)1-4 and cancer.5,6 By 2030, an estimated 84% of PLWH will suffer 
from a non-communicable disease, and 78% will have a CVD.7 Two meta-analyses, including 
predominantly PLWH from Europe and North America, conclude a doubled overall risk for CVDs 
in this population compared to the general population.2,8,9  Moreover, the incidence of lung cancer, 
which is heavily driven by tobacco smoking, is higher in PLWH.10,11 While HIV-related morbidity 
and mortality have significantly decreased, non-communicable diseases and their risk factors 
represent the most documented health burden among PLWH, especially in high-income countries 
such as Switzerland.12  
The Swiss HIV Cohort Study (SHCS) (Business Administration System of Ethic Committees 
(BASEC) number 2023-02080) established in 1988, is a multicenter, prospective, observational, 
nationwide cohort study.13 PLWH are recruited at all university hospitals in the country and at 
various other clinics and practices. The cohort included about 9’500 active participants.14 
2.2 Tackling a major health burden among PLWH 
Smoking is one of the leading causes of death and is responsible for approximately 7.7 million 
deaths per year worldwide.15 Tobacco smoking is also a key contributor for CVD and thus overall 
a major health burden among PLWH.5,16 In 2017, 34% of participants in the SHCS smoked 3 or 
more cigarettes per day.17 Today, smokers with HIV lose more life years to smoking than to HIV.5 
There is widespread consensus that nicotine, while addictive, is not responsible for smoking-
associated diseases such as CVD and cancer.18,19 Therefore, harm reduction interventions using 
nicotine substitute products have become a mainstay of tobacco smoking cessation programs. 
Conventional nicotine replacement therapy, such as patches or gums, are well established and 
effective against withdrawal symptoms after quitting, but these products are exceptionally 
expensive in Switzerland and are highly regulated.20 Furthermore, the missing “nicotine hit” due 
to the slow release of nicotine often limits therapy adherence. Electronic cigarettes (e-cigarettes) 
and nicotine pouches as alternative nicotine substitute products have the potential to overcome 

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some of these problems and are already in widespread but unregulated use. Their effectiveness 
needs to be assessed in high-quality, randomized, large-scale, clinical trials. 
2.3 Electronic nicotine delivery systems  
E-cigarettes, also referred as vapors or electronic nicotine delivery systems, are devices imitating 
tobacco cigarettes in their use and properties. E-cigarettes heat up nicotine containing liquids to 
inhale nicotine in the form of aerosols (vapor) in contrast to smoke like in traditional tobacco 
cigarettes. The liquids are usually available in different flavors and components. By avoiding 
burning tobacco, e-cigarettes produce a significantly lower amount of harmful chemicals than 
tobacco cigarettes.21 Despite potential risks of e-cigarettes, there is widespread agreement that 
replacing traditional tobacco cigarettes with e-cigarettes can significantly reduce exposure to 
toxins and carcinogens.22 
Furthermore, in Switzerland e-cigarettes are considered to be alimentary goods and fall under 
the “Lebensmittel- und Gebrauchsgegenständeverordnung” (LGV SR 817.02). Currently, e-
cigarettes are not classified as medicine or medical devices in any country in the world.21 The 
resulting competitive market keeps the prices of e-cigarettes low, especially when compared with 
traditional nicotine replacement therapies like nicotine patches, gums, sprays, lozenges or 
inhalers. E-cigarettes should be understood as a heterogeneous group of devices across different 
generations with different characteristics, such as different capacities in delivering nicotine. Newer 
generations of e-cigarettes proved to be more effective in delivering nicotine.23 
While nicotine is mainly responsible for the neuropharmacological dependence on tobacco 
smoking, bio-behavioral factors and smoking related stimuli also play important roles in smoking 
cessation.24 This seems an obvious reason for the mediocre success of conventional nicotine 
replacement products, which substitute nicotine but poorly mimic the smoking experience. E-
cigarettes come closer to the smoking routine and mimic experiences of smoking, such as the 
feeling of holding a cigarette, or inhaling smoke into the throat (“throat hit”) or exhaling the cloud 
of smoke.25 Moreover, nicotine is absorbed with e-cigarettes at a similar fast rate as with 
conventional tobacco cigarettes, which enables the “nicotine hit” that plays an important role for 
an addictive behavior. By meeting the needs of smokers better than conventional nicotine 
replacement therapies, e-cigarettes also carry the potential to act as a long-term substitute.26 
Although there is still a lack of empirical data (especially long-term), the current evidence 
suggests that e-cigarettes are notably less harmful than conventional cigarettes with respect to 
the development of cancer and lung disease.27 A danger that should not be underestimated is the 
strong addiction potential of e-cigarettes, which may tempt people to smoke and needs to be 
tackled in the smoking prevention programs among adolescents. This makes the correct use of 
e-cigarettes in smoking prevention even more important. 
A Cochrane review from 2024, which included 88 studies, 47 of which were randomized clinical 
trials (RCT), showed that e-cigarettes improved cessation rates compared with conventional 
nicotine replacement therapy and did not lead to more adverse events.28 While e-cigarette use is 
still controversial among health professionals and policy makers, the evidence is pointing in 
direction of promoting e-cigarettes as a reasonable smoking cessation tool to save lives from 
smoking. For these reasons, the accessible and low-cost e-cigarettes represent an important 
pillar for our smoking cessation intervention. 
 
 

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Figure 1: E-cigarette (Endura T20-S-Kit) 
 
2.4 Nicotine pouches  
Tobacco-free nicotine pouches are nicotine products for oral use. They consist of a small pouch, 
which is filled with a nicotine-containing matrix. The nicotine comes either from tobacco plants or 
is produced synthetically. In contrast to the widespread used snus in Scandinavia, nicotine 
pouches do not contain tobacco. In the application, however, they do not differ, the pouches are 
clamped between the lip and the palate and provide the nicotine through the oral mucosa. 
Similarly to e-cigarettes, nicotine pouches are available in different flavors. 
Following the concept of harm reduction, the use of nicotine pouches has grown as a tool for 
nicotine substitution. Nicotine pouches offer several advantages over conventional nicotine 
replacement therapy. Nicotine pouches are comparatively affordable, both in comparison with 
tobacco cigarettes and with nicotine replacement therapy and they are convenient in use. 
According to a 2022 study by Jakub et al., nicotine pouches are the cheapest form of nicotine 
delivery in Switzerland.29 
Regarding the safety of nicotine pouches, it is difficult to draw sound conclusions due to the small 
number of studies. However, the available evidence from pharmacokinetic studies suggests that 
nicotine pouches were safe and well tolerated in healthy participants. No serious adverse events 
were recorded.30,31 In 2013, McNeill et al. introduced the concept of the risk continuum for various 
nicotine products. Classical tobacco cigarettes and other forms of inhaled tobacco (combustible 
tobacco products) represent the most dangerous form. Oral tobacco products (non-combustible 
tobacco products) represent an intermediate stage and non-combustible nicotine products like 
traditional nicotine replacement therapies represent the least dangerous stage.32 A study based 
on nicotine pouches chemical analysis of the most common toxicants found in smokeless tobacco 
products suggests that nicotine pouches should be positioned similarly to nicotine replacement 
therapies in this continuum.33 Further, an in vitro study assessing the influence of nicotine 
pouches on gingiva organotypic cultures classified them as non-mutagenetic, non-genotoxic and 
non-cytotoxic compared to conventional cigarettes.34 A described problem of nicotine pouches 
are occasionally high nicotine concentrations, which have a large dependence potential.35 
Currently, no data are available on long-term effects.36 

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Despite these concerns, but especially because of the unanimously recognized harmfulness of 
tobacco cigarettes, nicotine pouches are an increasingly accepted tool for harm reduction in 
smokers. When substituting nicotine, it is important to consider at what rate and in what amounts 
nicotine is being absorbed. Conventional cigarette smoking is particularly effective in absorbing 
nicotine. A major reason why many smokers do not accept nicotine replacement therapy is that 
they deliver nicotine much slower than cigarettes.37 Nicotine pouches overcome this weakness 
and deliver nicotine faster in higher doses to achieve satisfactory plasma nicotine 
concentrations.30,31 To the best of our knowledge, so far no trials have investigated the potential 
of nicotine pouches for smoking cessation. 
 
Figure 2: Nicotine pouches33  
 
2.5 Nicotine patches  
Nicotine-containing transdermal patches are a widely used form of nicotine replacement therapy 
and an established standard of care against withdrawn symptoms.38 Due to the simple 
application, they achieve a high compliance rate. They are equally effective as other traditional 
nicotine replacement therapy (e.g. nicotine gums, nicotine inhalers) and more effective than 
placebo for smoking cessation.39,40 The transdermal nicotine uptake is slow and nicotine patches 
need about one hour to reach the maximum nicotine concentration. Afterwards, they create a 
steady state for up to 24 hours. Therefore, nicotine patches do not imitate any of the 
pharmacodynamic and behavioral properties of smoking.40  This may limit their effectiveness. The 
most common side effects are skin reactions.   
2.6 New ways to include more smokers in smoking cessation programs 
Smoking cessation trials often struggle with suboptimal recruitment and limited applicability of the 
results. A common problem is often the strict inclusion criteria, only allowing smokers willing to 
quit in a specific timeframe to participate in the trial. This selection leads to a lack of applicability 
of trial results in clinical practice and establishes a hurdle for smokers to receive smoking 
cessation support. This problem is present in many large completed and ongoing smoking 
cessation trials investigating the potential of e-cigarettes in nicotine substitution.41-44  
One possible solution is the so called “opt-out” approach, in which all smokers are provided with 
smoking cessation aids and counseling, not only those who express a willingness to quit as in the 

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classic “opt-in” approach.45-47 It has been shown that smokers who want to quit and smokers 
without this explicit intention have similar quit rates, provided they receive appropriate support.48,49  
Smoking cessation studies according to the "opt-out" design can be more easily translated into 
clinical practice. The goal of our trial is to provide evidence for a future large-scale public health 
intervention that may be offered to all smokers during a consultation. The “Trials within Cohorts” 
(TwiCs) design (see section 2.7) is the ideal trial design to implement and evaluate the “opt-out” 
approach embedded in a cohort study. 
2.7 Using an innovative design to generate randomized evidence in cohort studies 
RCTs represent the gold standard in terms of evidence generation on therapeutic or prophylactic 
interventions in clinical research.50 However, RCTs are expensive and often challenging to plan 
and conduct and findings from RCTs using highly controlled procedures are often difficult to 
translate into routine care.51 Therefore, more efficient and applicable trial designs are needed. 
TwiCs is a randomized trial design whereby participants are recruited within a prospective cohort 
study and give their consent not only to regular data collection at cohort visits, but at the same 
time, they are asked for their consent to be randomized into future pragmatic trials, evaluating 
low-risk interventions, nested in the cohort.52,53 Participants are informed that they will be 
contacted in case they are randomized into the intervention arm and may accept or decline the 
intervention. In case they are randomized to the control arm (usual care), they will not be 
contacted but followed continuously in the frame of the cohort study. Participants in both arms 
are not aware of the other arm, which reduces disappointment effects, cross-over and 
withdrawals.54 The multistep consent procedure in TwiCs mimics a usual care setting in which 
people are asked to consent to treatment options while not being told about treatments they 
cannot access. Published evidence suggests that TwiCs are efficient in terms of enhanced 
recruitment and completeness of follow-up, and provide better external validity due to the 
pragmatic approach of the trial.55 The TwiCs design has been adopted by several cohorts across 
the world and in a variety of medical fields such as breast cancer, bone metastases, mental 
health, or care of elderly people – and recently in the SHCS.56 
2.8 Inequality in smoking cessation research regarding low socioeconomic status and HIV 
Despite consensus about the need for effective smoking cessation interventions, PLWH represent 
a neglected population with respect to smoking cessation studies.57 Furthermore, it is known that 
people with low-socioeconomic status suffer more severely from the burden of smoking and 
encounter various barriers to smoking cessation.58,59 Thus, there is still a lack of effective smoking 
cessation interventions for these people.60 Data on the effectiveness of offering a preference-
based smoking cessation intervention taking into account socioeconomic parameters are lacking, 
as is knowledge about disadvantaged groups within PLWH in relation to smoking cessation 
interventions. The SHCS with its representative population holds the opportunity to close some 
of these knowledge gaps. 
2.9 Scientific impact 
TwiCs is a pragmatic trial design with the goal to mimic a real-life situation and testing 
interventions that can be adopted into everyday medical practice. Tobacco smoking represents a 
major health burden in PLWH. Quitting tobacco smoking is the key to reduce mortality.67 There is 
consensus among patient representatives, researchers, and clinicians that new and effective 
smoking cessation interventions are needed. Further, we will challenge the established pattern of 

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smoking cessation trials, which presupposes smokers' willingness to quit. Evidence from the 
literature shows that (1) the lengthy process of participating in a smoking cessation program (opt-
in principle) discourages many smokers from quitting and that (2) smokers who have the intention 
to quit and those without this intention show similar quit rates with appropriate support. With this 
trial, we expect to achieve a doubling of smoking cessation rates compared to the control group. 
Additionally, we aim to generate needed evidence to better assess the effectiveness and safety 
of e-cigarettes and nicotine pouches.  
With the implementation of the TwiCs for the first time in Switzerland, we hope to pave the way 
to improve randomized evidence generation within a large-scale national cohort study. The SHCS 
will thus play a pioneering role both nationally and internationally and increase its image of an 
innovative nationwide cohort study. 
3 
STUDY OBJECTIVES AND DESIGN  
3.1 Hypothesis and objectives 
Hypothesis: The offer of a preference-based smoking cessation intervention menu, consisting of 
e-cigarettes, nicotine pouches and nicotine patches, in addition to usual care is safe and superior 
to reduce tobacco smoking among PLWH in the SHCS after 6 months compared with usual care 
alone.  
 
Primary estimand: The primary estimand is described in Table 1. Intercurrent events and their 
handling are described in Table 2. The description of the primary estimand follows current 
guidelines.68,69   
 
Table 1: Definition of the primary estimand (primary analysis) 
Attribute  
Definition 
Population 
Adults living with HIV, smoking one or more tobacco 
cigarettes per day 
Treatment condition 
 
Intervention 
Offer of a preference-based smoking substitute menu 
(consisting of e-cigarettes, nicotine pouches and 
nicotine patches) free of charge for the participants.  
Control  
Standard smoking cessation practice in the SHCS  
Endpoint 
Self-reported abstinence from tobacco smoking in the 
past 7 days after 6 months  
Summary measure 
Odds ratio between groups, adjusted for key 
prognostic baseline covariates 
Handling of intercurrent events  
See table 2 
 
 
 
 
 

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Table 2: Definition and handling of intercurrent events for the primary estimand/analysis 
Intercurrent event (type)  
Strategy  
Explanation  
Death (truncating event)  
While-alive strategy  
Only outcomes before the occurrence 
of the death are considered.  
Non-uptake 
of 
any 
smoking 
cessation 
product 
in 
the 
intervention group and 
uptake of an intervention 
smoking 
cessation 
product in the control 
group 
(treatment-
modifying event) 
Treatment policy strategy  The occurrence of these intercurrent 
event is part of the treatment condition. 
Participants stay in the intention-to-
treat analysis set as randomized at 
baseline regardless of (non-)uptake 
thereafter. 
 
Stop or switch of use of s 
smoking 
cessation 
product 
at 
any 
time 
during the intervention 
due 
to 
any 
reason 
(treatment-modifying 
event) 
Treatment policy strategy The occurrence of the intercurrent 
event is part of the treatment condition. 
Participants stay in the intention-to-
treat analysis set, regardless of their 
adherence to the intervention.  
Attrition 
from 
SHCS 
(truncating event) 
Principal stratum strategy  Participants dropping out of the SHCS 
are excluded from the analysis set, 
assuming 
missing 
completely 
at 
random (no common cause between 
outcome and attrition), occurring at 
similar frequency across both groups 
and considered as such in the power 
calculation 
 
Primary objective: The purpose of this trial is to test the effectiveness of offering a menu of 
different nicotine substitute products (e-cigarettes, nicotine pouches, nicotine patches in addition 
to usual care) for smokers in the SHCS in terms of self-reported tobacco cigarette abstinence at 
6 months. 
 
Secondary objectives:  
● To assess the effect of offering the preference-based smoking cessation intervention on 
tobacco smoking cessation at 12 and 24 months. 
● To assess the effect of offering the preference-based smoking cessation intervention on 
(i) reduction of smoked tobacco cigarettes per day; (ii) reduction of cardiovascular risk and 
(iii) occurrence of cardiovascular events or death. 
 
Explanatory and implementation objectives:  
● To investigate preferences and uptake of the different smoking cessation tools across 
various sociodemographic factors.  
● To evaluate the safety and side-effects of nicotine pouches 

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3.2 Primary and secondary endpoints 
The primary endpoint was chosen based on a smoking cessation core outcome set,70,71 previous 
smoking cessation trials,47 discussions with the Participant Advisory Board (see section 4.8), and 
the availability of routinely collected data in the SHCS. Secondary endpoints will generate 
evidence on long-term smoking cessation rates and broader health outcomes. Results from large 
scale randomized trials indicate that relative estimates from 7-day self-reported abstinence rates 
are similar to biochemically verified abstinence rates.42,44,64 Moreover, the self-reported primary 
outcome will minimize missing and incomplete outcome data, because biochemical validation 
additionally requires urine or blood samples and a biobanking consent from participants.  
Of note, by design (see section 3.3 about the TwiCs design), all trial endpoints (randomized 
comparisons) are routinely collected data, measured at cohort visits of the SHCS, regularly taking 
place approximately every 6 months. For the endpoint assessments at six months (180 days), a 
range of 120 to 270 days applies. For the endpoint assessments at twelve months, a range of 
271 to 450 days after enrolment applies. If several measurements within the time window are 
available, the one closest to 6 months will be used. Additionally, we will collect information on the 
safety and usage of the interventional products via retrospective surveys only in the intervention 
group (see section 4.2.2).   
Primary endpoint 
● Tobacco smoking status (yes/no) measured as self-reported abstinence in the last 7 day 
at 6-month visit (window: 120-270 days) 
Secondary endpoints 
● Tobacco smoking status (yes/no) measured as self-reported abstinence in the last 7 day 
at 12-month visit (window: 271-450 days) and 24-month visit (window: 630-810 days).  
● Mean change in the self-reported number of tobacco-based cigarettes smoked per day 
at 6,12, and 24 months.  
● Self-reported use of any nicotine containing product other than tobacco cigarettes 
(yes/no). If yes, self-reported use of e-cigarettes (yes/no) or nicotine pouches (yes/no) or 
patches (yes/no) or other (yes/no) after 6 (window: 120-270 days), 12 (window: 271-450 
days) and 24 (window: 630-810 days) months.  
● Self-reported abstinence of any nicotine containing product (yes/no) after 12 (window: 
271-450 days) and 24 (window: 630-810 days) months.  
● Mean change in High Density Lipoprotein (HDL) and Low Density Lipoprotein (LDL) 
Cholesterol (mmol/l) at 6,12, and 24 months.  
● Mean change in systolic and diastolic blood pressure (mmHg) at 6,12, and 24 months.  
● Mean change in body weight (kg) from baseline to 6,12 and 24 months.  
● Mean change in SCORE272-risk prediction algorithm at 6, 12, and 24 months.  
● Occurrence 
of 
cardiovascular 
events 
(myocardial 
infarction, 
coronary 
angioplasty/stenting, coronary artery by-pass grafting, carotid endarterectomy, stroke, 
deep vein thrombosis, pulmonary embolism, heart transplantation) and all-cause death 
at 6,12, and 24 months.   
Safety endpoint 
● Serious Adverse events (SAEs) are collected after 6, 12, and 24 months and are 
described in section 6.2. 
 
 

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3.3 Study design  
We plan to conduct a multicenter, national, open-label, superiority, two-arm, randomized 
controlled trial using the TwiCs design approach, embedded in the SHCS. At least seven SHCS 
centers will participate (University Hospital Basel, University Hospital Bern, University Hospital 
Geneva, University Hospital Lausanne, Cantonal Hospital St. Gallen, University Hospital Zurich, 
and Cantonal Hospital Aarau). TwiCs is a relatively novel randomized trial design that was first 
described in 2010.52 The overarching idea is to integrate a pragmatic randomized trial into an 
observational cohort study with randomization consent of participants to gain efficiency and mimic 
clinical practice. To do so, TwiCs uses a multistep consent procedure.  
The consent procedure includes three levels. The first consent level is to collect longitudinal data 
as part of the SHCS (“cohort consent”). A signed cohort consent is a requirement to be eligible 
for the RETUNE trial. On a second level, cohort participants are asked for their consent to be 
randomized into future, not yet defined randomized comparisons (“randomization consent”). 
These first two consent steps are integral parts of the SHCS under the newly amended SHCS 
protocol (BASEC-Nr. 2023-02080, approved 05.07.2024) and currently the collection of the 
randomization consent is underway. 
A signed randomization consent is also a requirement to be eligible for the RETUNE trial. If 
participants are randomized into the intervention group, they will be informed about being selected 
for the RETUNE trial and they can accept or decline the offered intervention (“intervention 
consent”). Participants randomized to the control group are not approached and will receive 
usual care according to the cohort procedure. If participants randomized into the intervention 
group accept the offered intervention (they can select one nicotine substitute product), they 
document their decision in written form (“intervention consent”) and receive the products. The 
whole recruitment process including checking for eligibility will be integrated in the SHCS and all 
needed information is routinely collected data.   
 
Figure 3: TwiCs design figure 
 
To be part of the SHCS, all participants need to sign the “cohort consent”. Since the amendment of the SHCS protocol 
in August 2024 participants are also routinely asked for an additional “randomization consent”. Smokers who signed 
the “randomization consent” and without exclusion criteria will become eligible for the RETUNE trial. They are 
randomized in a 1:1 ratio. Participants in the intervention group may accept or decline the offered intervention. If they 

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accept the intervention, they will sign an “intervention consent”. The primary analysis will be conducted using an 
intention-to-treat analysis set. All trial endpoints are collected within the routine cohort visits.  
3.3.1 Allocation concealment and blinding 
The SHCS physicians who perform the randomization have no access to the random allocation 
sequence. The SHCS physicians who offer the intervention and collect the outcomes are aware 
of the group assignment. Participants in the control group are not aware of the trial (as per TwiCs 
design) Participants in the intervention are aware of the trial and their allocation to the intervention.  
The primary endpoint will be self-reported and entered in the eCRF by the treating physician as 
part of routinely collected data during SHCS visits.  
The data analysist who prepares the data and runs the analysis is aware of the group allocation. 
3.3.2 Randomization  
Cohort participants who have consented to be randomized to future interventions (see section 
4.2.2) and meet the inclusion and exclusion criteria of the study will be assigned in a 1:1 ratio to 
the intervention and control groups. We will use a dynamic procedure using a stochastic treatment 
allocation algorithm based on the variance method to minimize imbalances simultaneously for 
region (French vs German speaking part of Switzerland), men having sex with men (yes/no), 
current drug user (yes/no), number of cigarettes smoked per day.73 These variables – seen as 
the most important predictors of smoking cessation - were selected based on routine data 
availability and completeness, and expert knowledge.  
The randomization will be conducted centralized via the SCHS data collection tool, by the SHCS 
data center located at the University Hospital Zurich.  
4 
STUDY POPULATION AND STUDY PROCEDURES 
4.1 Inclusion and exclusion criteria, justification of study population 
The RETUNE trial will include 972 PLWH who smoke tobacco cigarettes from the SHCS. Details 
on the sample size calculation are provided in section 5.1.  
According to its pragmatic design, RETUNE will use broad and inclusive eligibility criteria, to 
ensure a high level of generalizability of the results for similar populations.  
 
4.1.1 Inclusion criteria  
● Signed informed consent for the data collection and participation in the SHCS (Cohort 
consent). 
● Signed informed consent to be randomized to future interventions (Randomization 
consent). 
● Age 18 years or older.  
● Smoked one or more tobacco cigarettes per day (smoking status = yes) at the time of 
enrolment.  
 
4.1.2 Exclusion criteria  
● Currently using e-cigarettes or nicotine pouches or nicotine patches.  
● Pregnant women.  
 

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4.1.3 Justification of the study population  
As described in the background, PLWH have an increased risk for CVD and cancer, driven by 
life-style factors such as tobacco smoking. In Switzerland, PLWH are more likely to smoke 
tobacco cigarettes than people not living with HIV.  
4.2 Recruitment, screening, and informed consent procedure 
4.2.1 Screening and recruitment  
RETUNE will use the SHCS as a platform to recruit participants according to the TwiCs design. 
All SHCS participants who have signed an informed consent to participate in future TwiCs 
(randomization consent, see section 4.2.2) will be screened for eligibility.  
The eligibility criteria for the trial will automatically be checked using routinely asked questions 
within the SHCS visit procedure. During the consultation, the treating physicians (or a delegate) 
routinely ask SHCS participants about current smoking habits. If the tobacco smoking status is 
confirmed and no exclusion criteria are present, the participant will be eligible for the trial. On a 
separate page of the cohort data collection tool, the treating physician (or a delegate) is then 
prompted to press a button to randomize the participant into the intervention or control group. A 
randomization module is integrated in the SHCS data collection tool and will be set up by a data 
manager not involved in the trial. More details on the randomization process are available in 
section 3.3.2.  
4.2.2 Informed consent  
Informed consent is obtained in three different steps (cohort consent, randomization consent, 
intervention consent) according to the TwiCs design.  
The “cohort consent” (to be part of the SHCS and its data collection) and “randomization consent” 
(to be randomized into future trials using the TwiCs design) are part of the SHCS protocol which 
was recently approved (BASEC-Nr. 2023-02080, approved 05.07.2024)  
All eligible participants (tobacco smoker, cohort consent and randomization consent signed, and 
no exclusion criteria present) are randomized either to the control group or the intervention group. 
In the case of allocation to the control group, participants will receive standard smoking cessation 
counselling as part of routine care.   
In the case of allocation to the intervention group, the treating physician (or a delegate) will offer 
the menu of the different nicotine substitute products to the participant. The participant will be 
encouraged to choose and try one of the products. If the participant is willing to accept any of the 
products, the physician (or a delegate) will briefly explain the usage, the planned duration of the 
intervention, and potential side-effects of the respective product and the participant will sign an 
additional informed consent form (“intervention consent”). The treating physician (or a delegate) 
will document the uptake of the respective interventional product. The “intervention consent” form 
will be signed and dated by the investigator or his designee at the same time as the participant 
signs. A copy of the signed informed consent will be given to the participant. The consent form 
will be retained as part of the trial records. Participants are informed that they can be contacted 
by the RETUNE trial team exclusively for the purpose of this trial. They are asked to provide their 
phone number and, if preferred, their email address. The contact details will only be used for the 
purpose of the trial (supply of interventional products, collection of adverse events of special 
interest, and retrospective reported use of interventional products) and deleted afterwards (see 
section 8.3 for details). Participants are told that they can withdraw from the intervention at any 

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time. However, they remain part of the SHCS and its data collection unless they also withdraw 
cohort participation. 
4.3 Study intervention 
The intervention consists of a menu of different nicotine substitute products from which trial 
participants can choose in the cohort consultation with the treating physician. Available are e-
cigarettes, nicotine pouches, and nicotine patches, which are described in more detail below. All 
products are provided free of charge for 24 weeks. The participants will also receive an 
information brochure, how to use the product, which side effects should be reported, and how 
they receive supply. 
4.3.1 Description of electronic nicotine delivery system (e-cigarettes)  
This trial will use the Aspire© pod system OBY. The OBY e-cigarette will come in a user packet 
with a 500 mAh internal Li-Po battery, a fix integrated 1.2-ohm atomizer with 2ml capacity, a USB-
C cable, and an instruction manual in French, German, Italian, English, Spanish and Dutch. The 
device is authorized for sale in Switzerland. The devices will be ordered via aspire-shop.de and 
fourtwenty.ch. Upon inclusion in the RETUNE trial, the devices will be given to the trial 
participants, and they will be informed about their use. Study nurses and treating physicians at 
the respective centers can provide additional support for the handling of the products.  
We will use e-liquids from the company Gaiatrend© in France (alpha liquids). The liquids will be 
available in two different flavors (classic, menthol) and different nicotine concentrations (0 mg/ml, 
3 mg/ml, 6 mg/ml, 12 mg/ml, 16 mg/ml). E-liquids are ordered via fourtwenty.ch and freevap.ch. 
The liquids were already tested in pre-clinical studies and used in a large-scale, multicenter, 
clinical trial in Switzerland and have proven to be safe.64 
4.3.2 Description of nicotine pouches  
We will use the Edelsnus© for this trial. We will have two different flavors with different nicotine 
content on offer (cold, 20 mg/g and onyx, 25 mg/g). The product is distributed by the Swiss 
company Edelsnus© and we will buy it via snushus.ch. Edelsnus are produced by the company 
MultiFill AG, which does not belong to any international tobacco company. The product is 
authorized for sale in Switzerland.  
4.3.3 Description of nicotine patches  
The nicotine patches (traditional nicotine replacement therapy) will be purchased from the 
company Nicotinell©. The nicotine patches are available in three different nicotine concentrations 
(21 mg, 14 mg, 7 mg). There are two different application schemes for heavy or moderate and 
mild smokers. The scheme for heavy smokers uses patches for a total of 12 weeks, reducing the 
dose of nicotine subsequently. The scheme for moderate and mild smokers lasts over a total of 
9 weeks. These patches are classified as a drug, have been approved by Swissmedic (approval 
number 50582) and have been used in clinical practice for many years.  
4.3.4 Comparator  
This pragmatic trial will use the standard smoking cessation counselling in the SHCS as the 
comparator. To prevent contamination bias, the treating physicians will be trained not to offer the 
intervention menu (products) to the control group. At the smokers’ request, further steps towards 
smoking cessation can be initiated, such as prescribing medication or referring them to special 
consultations. Of note, no interventional products from the trial will be dispensed to the control 

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group. Likewise, participants are not directed to use e-cigarettes or nicotine pouches on their own 
costs. Standardization of the control group with a rigid protocol is not intended. The different 
approaches of the individual centers and physicians will continue to be applied.  
4.4 Study procedures 
4.4.1 General Setting  
RETUNE will be embedded in the SHCS and the regular cohort visits. The cohort visits take place 
approximately every 6 months and involve laboratory and clinical monitoring of the HIV infection, 
its medication as well as any comorbidities or concomitant diseases and their treatment. Further, 
preventive measures of common diseases in PLWH are also offered during the visits. For more 
detailed information regarding SHCS cohort visits and data collection, we refer to the latest 
version of the SHCS protocol (BASEC-Nr. 2023-02080, version 6.1).  
4.4.2 Trial procedures and data collection  
Cohort of the SHCS will take place approximately every 6 months. Table 3 provides an overview 
of the trial procedure.  
According to the TwiCs design, most relevant baseline data (inclusive demographic information) 
and trial endpoints are covered by the SHCS routinely collected data. Additional data collection 
exclusively for the RETUNE trial is restricted to the intervention group. Table 4 provides an 
overview of the data collection.  
 
 

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Table 3: Trial procedures  
Procedure  
Baseline 
visit  
4-week 
Pilot study1 
 
 
+/- 6 weeks 
8-week 
supply2 
16-week 
supply2 
Outcome 
visit month 
6 
 
+/- 6 weeks 
Outcome 
visit month 
12 
 
+/- 6 weeks 
Outcome 
visit month 
24 
 
+/- 6 weeks 
Enrollment 
Eligibility 
screening  
x 
 
 
 
 
 
 
Randomization 
x 
 
 
 
 
 
 
Offering 
of 
intervention 
x 
 
 
 
 
 
 
Informed 
consent 
(“intervention 
consent”) 
x 
 
 
 
 
 
 
Intervention 
Opportunity 
to 
switch products3 
 
x 
x 
x 
 
 
 
Intervention  
 
 
 
 
 
 
 
Control  
 
 
 
 
 
 
 
Data collection 
Routine 
data 
collection 
x 
 
 
 
x 
x 
x 
RETUNE-
specific 
additional data 
collection in the 
intervention 
group 
 
x 
 
 
x 
 
 
1 Only among the 30 participants included in the internal pilot study.  
2 Only among participants randomized to the intervention group who accepted an intervention product.  
3 These data are only collected in the intervention group 

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Table 4: Data collection 
The routinely collected data used for RETUNE are marked in green. Data additionally collected for 
RETUNE are marked in orange.  
Procedure  
Baseline 
visit  
4-week 
Pilot 
study1 
Outcome visit 
month 6 
Outcome visit 
month 12 
Outcome 
visit 
month 24 
Visit window  
 
+/- 2 weeks  
+/- 6 weeks  
+/- 6 weeks 
+/- 6 weeks 
Smoking 
status 
(yes/no) 
x 
 
x 
x 
x 
Number of cigarettes 
per day 
x 
 
x 
x 
x 
Use of e-cigarettes 
(yes/no) 
x 
 
x 
x 
x 
Use of other nicotine 
containing products 
(Nicotine 
patches, 
Chewing 
gums, 
Snus, 
Nicotine 
pouches, 
Pipe, 
Snuff, IQOS) 
x 
 
x 
x 
x 
Cannabis use  
x 
 
x 
x 
x 
Body weight  
x 
 
x 
x 
x 
LDL-, HDL-, and total 
Cholesterol 
x 
 
x 
x 
x 
Blood pressure  
x 
 
x 
x 
x 
Cardiovascular 
event2  
 
 
x 
x 
x 
Safety 
assessment 
(SAE collection)3 
 
x 
x 
x 
x 
Adverse 
event 
of 
special 
interest 
collection 
(see 
section 6.2.2)4  
 
x 
x 
 
 
Retrospective 
assessment of the 
product use (quantity 
of use)4  
 
 
x 
 
 
Uptake 
and 
acceptability of the 
different components 
of the offered menu4 
x 
x 
 
 
 
Usage 
experience 
(quality of use)4  
 
x 
x 
 
 
1 Only in the subgroup of participants included in the internal pilot study.  
2 Myocardial infarction, coronary angioplasty/stenting, coronary artery by-pass grafting, carotid endarterectomy, stroke, 
deep vein thrombosis, pulmonary embolism, heart transplantation  
3 A serious adverse event is any untoward medical occurrence that results in death or is life-threatening, requires in-
patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or 
incapacity, or causes a congenital anomaly or birth defect.  
4 These data are only collected in the intervention group  

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4.4.3 Storage conditions and supply of intervention products  
The e-cigarettes (Aspire© pod system OBY) are purchased via aspire-shop.de and fourtwenty.ch. 
The e-liquids are purchased fourtwenty.ch and feevap.ch. The nicotine pouches are purchased 
via snushus.ch. By purchasing all products independently from the producers, we want to avoid 
conflicts of interest. The products are stored in the respective SHCS centers in a room with 
restricted access.  
Trial participants will be instructed to store the products out of reach of children and pets. At the 
end of the study period, unused products may be retained by the trial participants. 
In the case of a defective e-cigarette, a replacement product can be obtained from the SHCS 
center or from the Division of Clinical Epidemiology Basel. 
A starter package of the chosen product (e-cigarettes, nicotine pouches or nicotine patches) will 
be given to trial participants during the inclusion visit. This should cover the required quantity for 
8 weeks. After 6 weeks, the trial participants will receive a phone call or email (whatever they 
prefer). The participants are asked if they want to continue the product, switch to another product 
or stop their participation.  If they do not actively decline, for example if we don’t reach them in 
the time window, we will send a new supply for another 8 weeks. After 16 weeks, we will contact 
the participants again for the final delivery. They can decline the delivery, but this time they have 
not the possibility to switch the product again. Finally, the participants will receive the products 
for a total of 24 weeks free of charge. If there is a problem with a product between the fixed 
deliveries, the participants will receive a replacement product after contacting the trial team via 
phone or email or reach out to their treating physician.  
To facilitate this supply chain, the participants will be asked to provide their phone number, e-mail 
address and postal address when entering the trial (part of the intervention consent). The 
information will be recorded in “RETUNE intervention group form” in REDCap®. The access to 
this information will be restricted to the RETUNE core team at the Division of Clinical 
Epidemiology Basel. All contact information will be deleted after completion of the trial. See 
section 8.3 for more detail.  
4.5 Withdrawal and discontinuation 
The trial intervention may be discontinued at any time. Participants who discontinue the trial 
intervention continue regular cohort visits within the SHCS.  
4.6 Compliance with the intervention  
Study personnel who recruit trial participants will be trained on the delivery of the intervention and 
of the potential benefits and harms of the products. The handling of e-cigarettes and nicotine 
pouches will be explained to the participants in a structured manner. They will also be made 
aware of possible side effects (see section 6.2.2.). To increase the compliance of the trial 
participants and to create an intervention that is as close to reality as possible, they can choose 
between the different nicotine replacement products. Furthermore, they can choose between 
different flavors of e-liquids and nicotine pouches.  
The use of the administered products will be monitored retrospectively after the trial period using 
a survey.   
Cross-over use of the interventional products in the control group will be monitored in the routine 
data collection of the SHCS.  

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4.6.1 Compensation for participants   
No financial compensation or payments will be given to the participants.  
4.6.2. Compensation for participating trial centers 
The RETUNE trial will create additional work for the treating physicians and for the participating 
SHCS centers. This is compensated with a fixed fee of 105 CHF per included participant. In 
addition, this is intended to create an incentive for the trial centers to participate. 
4.7 Participation in other clinical trials  
Participants of the RETUNE trial are allowed to participate in other observational and 
interventional studies in the SHCS if there is no interference with the intervention or outcomes 
investigated in RETUNE. The scientific board of the SHCS and the RETUNE study team will 
ensure this.  
4.8 Patient and public involvement and the participant advisory board  
Based on the guiding principle of patient and public involvement (PPI)74, this trial was planned 
together with patient representatives from the SHCS, collaborating with them in every phase of 
our trial. As a first step, we have conducted informal interviews with three patient representatives 
(2 men, 1 woman) from the German and French speaking regions of Switzerland and we have 
discussed and incorporated their initial thoughts and comments on the study design, the 
intervention, the study procedures, and the study endpoints. We have drafted a PPI agreement 
(based on the Swiss Clinical Trial Organization template75) to outline responsibilities, 
expectations, timelines as well as remuneration details to formalize the PPI and establish a formal 
Participant Advisory Board for this project. To provide more details, the agreement is available as 
a supplement to this protocol. The PPI will be reported using the GRIPP2 reporting guidelines in 
the final manuscript.76  
5 
STATISTICS AND METHODOLOGY 
5.1 Sample size calculation  
We assume a smoking cessation rate of 8.5% in the control arm (based on SHCS data), a 20% 
cessation rate in the intervention arm (based on external evidence of similar trials41-43), and an 
attrition rate of 3% (based on SHCS data).13  
Taking into account a low uptake of only 50% in the intervention and thus dilution of the 
intervention effect, we aim at enrolling a total 972 participants (486 in each arm) to achieve 80% 
power for a two-sided alpha level at 5%. We will update our sample size during recruitment 
depending on observed uptake rates, monitored at pre-defined recruitment timepoints. 
The 
full 
R 
code 
for 
the 
sample 
size 
calculation 
is 
available 
on 
GitHub 
(https://github.com/alainamstutz/TwiCs_samplesize/blob/main/TwiCs_samplesize.md) 
Due to the integration of the trial in the SHCS, eligibility of cohort participants can be pre-
assessed. Table 7 shows the current situation regarding smoking behavior in the SHCS. The 
SHCS includes 9470 PLWH under active follow-up, of which 4873 are under treatment in one of 
the RETUNE trial centers (Data from December 05, 2022). At the last follow-up visit, 1576/4873 

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(32.3%) PLWH reported smoking tobacco cigarettes. The median number of tobacco cigarettes 
smoked per day was 12 (IQR = 7 -20). 
Table 5: Eligible participants for RETUNE 
Center 
Smoking 
Non-smoking 
Zurich 
541 
1171 
Basel 
205 
394 
Bern 
232 
496 
Geneva 
115 
319 
Lausanne 
272 
588 
St. Gallen 
211 
329 
Total 
1576 
3297 
5.2 Adaptive readjustment 
The uptake of the offered intervention plays a key role in the sample size calculation of trials using 
the TwiCs design. We start with a conservative scenario of 50% uptake. As per guidance from 
the literature and conducted by other TwiCs, we will re-evaluate this critical assumption at pre-
specified timepoints (after 100, 200, and 300 randomized participants).55,77 If the uptake is higher 
than expected, we will reduce the target total sample size (see figure 4 below for the correlation 
of uptake and the needed sample size). Since we will not analyze outcomes at the sample size 
re-evaluation time points, these are not formal interim analyses with alpha spending and no 
correction for multiplicity is needed. If uptake falls well below 45%, we will include more sites or 
decide to discontinue based on available budget and operational resources. 
Figure 4: Influence of effect size on target sample size  
 
The effect size is influenced by the uptake of the offered intervention. If the uptake is lower, then the effect 
size becomes exponentially smaller, influencing the target sample size. For our calculation we used a two-

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sided alpha of 5%, a power of 80%, and an attrition rate of 3%. A Cohen’s effect size of 0.18 corresponds 
to a cessation rate of 8.5% in the control group and a diluted intervention effect of 14.25% (instead of 20%) 
in the intervention group, accounting for an uptake of 50% in the intervention group. 
5.3 Internal pilot study 
Pilot studies are a subset of feasibility studies in which the feasibility of an RCT, or a sub-aspect 
of an RCT, is tested on a usually smaller scale, i.e. with fewer participants.78 The goal of a pilot 
study is to evaluate important logistical aspects of a future trial and optimally integrate them into 
the trial design. This helps to avoid errors in trial conduct and makes pilot studies a valuable 
contribution to optimizing the internal validity of high-quality clinical trials.79 Two types of pilot 
studies can be distinguished, external pilot studies and internal pilot studies. In an external pilot 
study, the participants are excluded from the final outcome data set. Consequently, participants 
who would be eligible for the trial are no longer available. In an internal pilot study, participants 
and their outcome data can be transferred from the “pilot phase” to the main trial with its final 
analysis.80  
The internal pilot study will include the enrolment of at least 30 people randomized to the 
intervention group which are accepting the offered intervention. The internal pilot study will recruit 
participants at the center in Basel and in at least one other center.  
The pilot study will investigate logistical challenges and generate knowledge about the popularity 
of the different components (nicotine patches, e-cigarettes, nicotine pouches) of the preference-
based smoking cessation menu. Based on this, we can tailor our supply. After 30 days, the pilot 
participants of the intervention group will be interviewed by telephone about their use behavior. 
We will offer two to a maximum of three different flavors and nicotine concentrations of e-
cigarettes and nicotine pouches, which will be further tailored according to their popularity after 
the pilot study phase. Details regarding the criteria studied during the pilot phase are listed in 
Table 3. If we observe major concerns regarding the feasibility of the trial during the internal pilot 
study, we will reconsider the continuation of the trial.  
 
Table 6: Aims of the internal pilot study  
Aim  
Measurement  
Explanation  
To assess the safety of the 
interventional products  
After 
30 
days, 
the 
participants 
in 
the 
intervention group will be 
asked if they experienced 
any safety issues (Adverse 
events of special interest, 
see also section 6.2.2) with 
the products.   
The tested intervention products 
are of low risk for the participants, 
since they are all available on the 
free market. We will test this 
assumption and modify the offered 
menu if needed.  
To assess the uptake, 
acceptability/preference of 
the different components 
of 
the 
intervention 
package. 
 
Uptake of the different 
components of the offered 
menu measured.  
Based on this information, we will 
adapt the supply of products. For 
example, if e-cigarettes should be 
more 
popular 
than 
nicotine 
pouches, we will order more e-
cigarettes for the full trial.  

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To assess the preferences 
regarding 
the 
different 
products and flavors and 
the 
experience 
of 
the 
participants regarding the 
handling of products.  
After 
30 
days, 
the 
participants 
in 
the 
intervention group will be 
asked 
regarding 
their 
usage experiences of the 
different products and their 
preferences for flavors of 
nicotine pouches and e-
cigarettes.  
We 
are 
interested 
in 
the 
experiences of the participants with 
the respective products. Moreover, 
nicotine pouches and e-cigarettes 
are available in different flavors. 
The collected knowledge will help 
us to further optimize the offered 
products and better instruct the 
participants reading the usage.  
5.4 Description of statistical methods  
The analysis of the trial will be conducted at the Division of Clinical Epidemiology at the University 
Hospital Basel. Before the recruitment will be completed, a statistical analysis plan will be written, 
detailing the steps of data processing and statistical analyses.   
All analyses will be performed using Stata81 or R82. 
5.4.1 Dataset to be analyzed  
The primary analysis set will be an intention-to-treat analysis set. It will include all randomized 
participants as they were randomized (see also definition of primary estimand in section 3.1). 
Participants randomized to intervention are analyzed as such, i.e., regardless of product uptake. 
Participants randomized to the control group are analyzed as such, i.e., regardless of any 
intervention product use outside of the study (cross-over).  
5.4.2 Primary analysis  
The primary outcome will be assessed in the intention-to-treat set as defined in section 5.4.1., 
using a logistic regression model adjusted for the variables used in the minimization (region 
[French vs. German speaking part of Switzerland], men having sex with men [yes/no], current 
drug user [yes/no], number of cigarettes per day ) and will be reported as an adjusted odds ratio 
with 95% Wald confidence interval.83-85 Superiority of the intervention vs control will be assessed 
according to the two-tailed p-value of the intervention regression coefficient and an alpha level 
set to 0.05. Additionally, absolute risk difference and proportions of smoking cessation under 
intervention and control will be estimated using marginal standardization, with 95% percentile 
interval calculated from 1,000 bootstrap samples. Hypothesis testing will only be conducted for 
primary.  
5.4.3 Secondary analyses  
Table 7 summarizes the statistical analysis of the secondary endpoints. For the secondary 
outcomes we will use the same model as for the primary outcome but use linear regression in 
case of continuous outcomes and add baseline adjustment of the outcome where appropriate. 
The secondary outcomes will be reported with 95% confidence intervals to support descriptive 
interpretation and are of exploratory nature.  Further details are provided in the statistical analysis 
plan. 
 
 
 

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Table 7: Statistical analysis of secondary endpoints   
Tobacco smoking status (yes/no) measured 
as self-reported abstinence in the last 7 days 
at 12-month visit (window: 300-420 days) and 
24-month visit (window: 650-800 days).  
Logistic regression model adjusted for the 
variables used in the minimization (region 
[French 
vs. 
German 
speaking 
part 
of 
Switzerland], men having sex with men 
[yes/no], current drug user [yes/no], number of 
cigarettes per day) and will be reported as an 
adjusted odds ratio with 95% confidence 
interval. 
Mean change in the self-reported number of 
tobacco-based cigarettes smoked per day at 
6,12, and 24 months.  
Linear regression model adjusted for the 
variables used in the minimization (region 
[French 
vs. 
German 
speaking 
part 
of 
Switzerland], men having sex with men 
[yes/no], current drug user [yes/no], number of 
cigarettes per day) and will be reported as an 
adjusted odds ratio with 95% confidence 
interval. 
Self-reported use of any nicotine containing 
product other than tobacco cigarettes (yes/no). 
If yes, self-reported use of e-cigarettes 
(yes/no) or nicotine pouches (yes/no) or 
patches (yes/no) or other (yes/no) after 6 
(window: 120-270 days), 12 (window: 271-450 
days) and 24 (window: 630-810 days) months.  
Logistic regression model adjusted for the 
variables used in the minimization (region 
[French 
vs. 
German 
speaking 
part 
of 
Switzerland], men having sex with men 
[yes/no], current drug user [yes/no], number of 
cigarettes per day) and will be reported as an 
adjusted odds ratio with 95% confidence 
interval. 
Self-reported abstinence of any nicotine 
containing product (yes/no) after 12 (window: 
271-450 days) and 24 (window: 630-810 days) 
months. 
Logistic regression model adjusted for the 
variables used in the minimization (region 
[French 
vs. 
German 
speaking 
part 
of 
Switzerland], men having sex with men 
[yes/no], current drug user [yes/no], number of 
cigarettes per day) and will be reported as an 
adjusted odds ratio with 95% confidence 
interval. 
Mean change in HDL-, LDL- and total 
Cholesterol (mmol/l) at 6,12, and 24 months.  
Linear regression model adjusted for the 
variables used in the minimization (region 
[French 
vs. 
German 
speaking 
part 
of 
Switzerland], men having sex with men 
[yes/no], current drug user [yes/no], number of 
cigarettes per day) and will be reported as an 

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adjusted odds ratio with 95% confidence 
interval. 
Mean change in systolic and diastolic blood 
pressure (mmHg) at 6,12, and 24 months.  
Linear regression model adjusted for the 
variables used in the minimization (region 
[French 
vs. 
German 
speaking 
part 
of 
Switzerland], men having sex with men 
[yes/no], current drug user [yes/no], number of 
cigarettes per day) and will be reported as an 
adjusted odds ratio with 95% confidence 
interval. 
Mean change in body weight (kg) from 
baseline to 6,12 and 24 months.  
Linear regression model adjusted for the 
variables used in the minimization (region 
[French 
vs. 
German 
speaking 
part 
of 
Switzerland], men having sex with men 
[yes/no], current drug user [yes/no], number of 
cigarettes per day) and will be reported as an 
adjusted odds ratio with 95% confidence 
interval. 
Mean change in SCORE2 prediction algorithm 
at 6,12, and 24 months. 
Linear regression model adjusted for the 
variables used in the minimization (region 
[French 
vs. 
German 
speaking 
part 
of 
Switzerland], men having sex with men 
[yes/no], current drug user [yes/no], number of 
cigarettes per day) and will be reported as an 
adjusted odds ratio with 95% confidence 
interval. 
Occurrence 
of 
cardiovascular 
events 
(myocardial 
infarction, 
coronary 
angioplasty/stenting, coronary artery by-pass 
grafting, carotid endarterectomy, stroke, deep 
vein thrombosis, pulmonary embolism, heart 
transplantation) at 6,12, and 24 months. 
This endpoint will be presented descriptively.  
Serious Adverse events (SAEs) are collected 
after 6, 12, and 24 months. 
This endpoint will be presented descriptively.  
 
Since we expect low uptake of the intervention products at baseline (currently estimated at 50%), 
the intention-to-treat estimand will give us an unbiased estimate for offering the intervention to all. 
While this estimate is of interest to policy makers, it might be less so for patients and treating 
physicians.86 
We will apply two observational causal inference methods to inform possible per protocol effects 
of interest. As any statistical analysis, they rely on specific assumptions that need to be justified: 

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i) 
Estimation of the hypothetical per protocol “Effect of everyone had taken up a product 
at baseline vs no-one had taken up a product at baseline” (Average Treatment Effect) 
a. This per protocol effect will be estimated using data generated by the trial. We will 
compare outcomes of trial participants that received the intervention with those 
from participants that did not receive intervention (i.e., participants in the control 
group and non-uptakers in the intervention group). We will generate these pseudo-
populations using inverse probability of treatment weights to correct for potential 
imbalance of main confounders. Main confounders are the factors used for the 
minimization.  
b. The main assumption for this analysis (which does not rely on randomization 
anymore) is the usual core assumption of any standard observational analysis, 
i.e., no unmeasured confounding, that means that all confounders are measured 
and are controlled for. See Directed Acyclic Graph (DAG) in Figure 5. 
 
Figure 5: DAG – Confounding in observational analysis  
 
Notes: Confounders were defined based on expert knowledge: region (French vs 
German speaking part of Switzerland), men having sex with men (yes/no), current drug 
user (yes/no), Number of cigarettes smoked per day.  
Green arrow: Average causal effect to be estimated. 
Further details will be outlined in the statistical analysis plan.  
 
ii) 
Estimation of the hypothetical per protocol “Effect of the intervention for participants 
who complied with the treatment assigned to”” (Complier Average Causal Effect).  
a. This per protocol effect will be estimated using an instrumental variable approach. 
b. While instrumental variable methods do not rely on the core assumption of no 
unmeasured confounding, they however rely on a different set of assumptions. 
First, the three core assumptions of the instrumental variable need to hold:  
i. “Randomization 
is 
associated 
with 
product 
uptake” 
(relevance 
assumption). This can be proven from the data and will undoubtedly be 
true in RETUNE since it is an RCT and randomization the instrument. 
ii. “The randomization and smoking cessation do not share common causes” 
(independence assumption). This can be proven from the data and will 
indubitably be true in RETUNE since it is an RCT and randomization the 
instrument. 

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iii. “Randomization does not affect smoking cessation except through the 
potential effect of the intervention” (exclusion restriction assumption). This 
cannot be shown empirically but is reasonable to hold since both groups 
receive standard counselling and suggested in other similar RCT 
settings.87,88   
c. Second, to estimate the complier effect including a point estimate, a fourth 
assumption is needed. While the homogeneity assumption (the effect of the 
intervention on the outcome is exactly the same for all participants) is a rather 
strong assumption, we will choose instead the monotonicity assumption. The 
TwiCs design is a perfectly suited RCT design for this assumption to hold, because 
the control group is not aware of the intervention group and vice versa. In this 
sense, there is no possibility of defiers being present in the study population, 
meaning people who accept the intervention if not offered but deny the intervention 
if offered. This - plus the fact that TwiCs often have low uptake of their interventions 
- are the reasons why there is a prolific literature of using such methods as per 
protocol analyses in TwiCs.89-92  
 
Figure 6: DAG– Randomization as instrumental variable   
 
 
Notes: Since the effect of product uptake on smoking cessation is measured using 
randomization as the instrument, confounders are irrelevant.  
Green arrow: Complier Average Causal Effect to be estimated. 
Further details will be outlined in the statistical analysis plan.  
 
5.4.4 Interim analysis  
No interim analysis will be conducted.  
5.4.5 Subgroup analysis  
We plan exploratory subgroup analysis (no pre-specified hypothesis) for the baseline number of 
cigarettes smoked per day (continuous), age (continuous), and sex (binary). We will include 
corresponding interaction terms – one at a time - in the adjusted logistic regression model. If a p-
value of an interaction term turns out to be smaller than 0.1, we will assess the credibility of the 
effect using the ICEMAN tool.93 Further details will be outlined in the statistical analysis plan.  
5.5 Handling of missing data and drop-outs 
No missing covariates are expected since all adjusting factors are used for minimization and 

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therefore mandatory for randomization. Missing outcome data will be imputed using multiple 
imputation by chained equation techniques. Additionally, we will perform a sensitivity analysis 
where participants with missing outcomes will be excluded from the analysis (complete case 
analysis). Further details will be outlined in the statistical analysis plan.  
 
6 
REGULATORY ASPECTS AND SAFETY 
6.1 Local regulations / Declaration of Helsinki 
This study is conducted in compliance with the protocol, the current version of the Declaration of 
Helsinki94, the ICH-GCP95, the HRA96 as well as other locally relevant legal and regulatory 
requirements.  
6.2 (Serious) Adverse Events: Definitions, collection, and assessment  
6.2.1 Adverse Events (AE)  
An adverse event (AE) is any untoward medical occurrence in a patient which does not 
necessarily have a causal relationship with the trial procedure. An AE can therefore be any 
unfavorable or unintended finding, symptom, or disease temporally associated with a trial 
procedure, whether or not related to it. 
 
6.2.2 Adverse Events of Special Interest (AESI) 
Adverse events of special interest (AESI) are AEs probably related to the tested nicotine 
substitute products. We anticipate the following AESI, and RETUNE study team will ask them 
actively in a retrospective survey amongst participants in the intervention group (online or 
telephone based): 
- 
New or increased nausea after use of the investigational product  
- 
New or increased emesis after use of the investigational product  
- 
New or increased headache after the use of the investigational product  
- 
New or increased dizziness after the use of the investigational product 
- 
New or increased respiratory symptoms: cough, phlegm, wheezing, sore throat after the 
use of the investigational product 
- 
New or increased gingival pain after use of the investigational product 
- 
New or increased gingival bleeding after use of the investigational product 
- 
New or increased mouth ulcers after use of the investigational product 
- 
New or increased eczema / allergic skin reactions after use of the investigational product 
- 
New or increased mouth and tongue irritation / change of the oral mucosa after use of the 
investigational product 
6.2.3 Serious Adverse Event (SAE) 
A serious adverse event (SAE, ClinO, Art. 63)97 is any untoward medical occurrence that 
- 
Results in death or is life-threatening, 
- 
Requires in-patient hospitalization or prolongation of existing hospitalization, 
- 
Results in persistent or significant disability or incapacity, or 
- 
Causes a congenital anomaly or birth defect  

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6.2.4 Collection of AE, SAE, AESI 
As this is a pragmatic trial with a low-risk intervention, we propose a risk-based safety monitoring. 
SAEs will be collected in the routine data. AESI will be collected using a retrospective survey 
among the intervention group only. As such this will be a single-arm assessment without a 
randomized comparator and interpreted as such. We will not collect any other AEs. 
6.2.5 Assessment of causality and severity  
The causality assessment of all SAE will be performed by a trial physician using information from 
the retrospective survey in the intervention group and routinely collected data within the SHCS. 
An independent physician will provide a statement whether the SAE is definitely related, probably 
related, possibly related, unlikely related, or unrelated to the offered intervention.  
 
Table 8: Causality assessment  
Relationship 
Description 
Definitely 
Temporal relationship 
Improvement after dechallenge* 
Recurrence after rechallenge 
(or other proof of drug cause) 
Probably 
Temporal relationship 
Improvement after dechallenge 
No other cause evident 
Possibly 
Temporal relationship 
Other cause possible 
Unlikely 
Any assessable reaction that does not fulfill the above 
conditions 
Not related 
Causal relationship can be ruled out 
*Improvement after dechallenge only taken into consideration, if applicable to reaction 
 
An independent trial physician makes a severity assessment of the event as mild, moderate, or 
severe. Mild means the complication is tolerable, moderate means it interferes with daily activities 
and severe means it renders daily activities impossible.  
6.2.6 Reporting of SAEs (see ClinO, Art. 63)97 
All SAEs are documented and reported within a maximum of 24 hours after being aware of it to 
the Sponsor-Investigator.  
If it cannot be excluded that the SAE is attributable to the intervention under investigation, the 
Sponsor-Investigator reports it to the Ethics Committee via BASEC within 15 days. A 
corresponding template from Swiss Ethics will be used.  
6.3 (Periodic) safety reporting and reporting of general progress 

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All deaths and all other SAEs that are possibly or definitely related to the study intervention will 
be reported to the Ethics Committee of Northern and Central Switzerland (EKNZ) immediately 
(see section 6.2.6) and summarized on a yearly basis. The investigator also informs the Ethics 
Committee about the general progress of the clinical trial (ClinO, Art. 43). 
 
6.4 Pregnancy  
Pregnant women will be excluded from the trial. Pregnancy is usually collected as part of SHCS 
data collection. We will exclude pregnant women not because the intended intervention is 
particularly harmful in this population, especially compared to the known harms from tobacco 
smoking, but the ethics committee had concerns with nicotine replacement for pregnant women, 
and we followed the recommendation of the ethics committee.     
6.5 Amendments 
Substantial changes to the trial setup and organization, the protocol and relevant trial documents 
will be submitted to the Ethics Committee for approval before implementation. Under emergency 
circumstances, deviations from the protocol to protect the rights, safety and well-being of human 
subjects may proceed without prior approval of the Ethics Committee. Such deviations will be 
documented and reported to the Ethics Committee as soon as possible. 
Substantial amendments are changes that affect the safety, health, rights and obligations of 
participants, changes in the protocol that affect study objective(s) or central research topic, 
changes of trial site(s) or of trial leader and sponsor (ClinO, Art. 29). 
A list of substantial changes is also available on www.swissethics.ch. 
A list of all non-substantial amendments will be submitted once a year to the competent EC 
together with the yearly safety report. 
6.6 Notification and reporting upon completion, discontinuation or interruption of the 
study 
After enrolment of the first participant and upon regular trial completion, the Ethics Committee is 
notified via the BASEC within 30 days (ClinO, Art. 38).97 The sponsor-investigator may terminate 
the trial prematurely in case of:  
- 
Ethical concerns  
- 
Insufficient participant recruitment  
- 
When the safety of the participants is doubtful  
 
In case of premature trial termination or trial interruption, the Ethics Committee will be notified via 
BASEC within 15 days (ClinO, Art. 38).97 
A final report is submitted to the Ethics Committee via BASEC within a year after completion or 
discontinuation of the trial, unless a longer period is specified in the protocol (ClinO, Art. 38).97 
6.7 Insurance 
In the event of study-related damage or injuries, the liability of the University Hospital Basel 
provides compensation, except for claims that arise from misconduct or gross negligence.  

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7 
FURTHER ASPECTS 
7.1 Overall ethical considerations 
The purpose of this trial is to address the need to reduce tobacco smoking among SHCS 
participants. RETUNE follows the concept of harm reduction by substituting smoking tobacco 
cigarettes by less harmful alternatives.  
We propose to test a pragmatic intervention using an innovative trial design to minimize the hurdle 
for the participants and the treating physician to participate in the trial. We will generate real-life 
evidence about making new nicotine substitute products available on a low threshold to all 
smokers, regardless of their willingness to quit smoking. This intends to change the way of 
smoking cessation in clinical trials as well as in clinical routine. In case the intervention proves to 
be effective, it can be directly transferred into clinical practice.  
7.2 Risk-benefit assessment  
The investigational intervention is considered low risk. The intervention is designed to help trial 
participants quit smoking tobacco with the overarching idea of harm reduction by substitution. In 
case the intervention is effective, trial participants will benefit directly by reducing their risk of 
tobacco-related cardiovascular disease and cancer. Similarly, the society and smokers in other 
settings will profit from improved evidence about smoking cessation. Finally, the evidence 
generated in this trial may inform national and international clinical guidelines as well as 
policymakers to improve smoking cessation strategies.  
All interventions used in RETUNE (e-cigarettes, nicotine pouches and nicotine patches) are 
approved by the Swiss authorities and freely available. The nicotine patches, approved by the 
Swiss Agency of Medical Products (Swissmedic). All products may cause local reactions and 
irritation of the skin or mucous membrane and systemic reactions to the nicotine intake such as 
nausea and headache. We will try to minimize the risks associated with the incorrect application 
of the products by instructing the participants accordingly. The study participants will be informed 
to keep the products out of reach of children and pets.  
Even though e-cigarettes and nicotine pouches are not under the jurisdiction of Swissmedic, we 
will determine adverse events of special interest, serious adverse events, and risks with the same 
accuracy as if they were therapeutic products.  
 
 
 
 
 
 

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7.3 Time plan and trial duration  
Table 9: Overview trial duration  
We aim to start the recruitment in February 2025. SHCS follow-up visits take place every 6 
months. We anticipate completing the recruitment by the end of August 2026. The recruitment 
will start at the SHCS center Basel. Subsequently, the other involved centers will open to reach 
the full recruitment capacity.    
The primary outcome data will be collected at 6 months after inclusion during the following cohort 
visit. Considering the time of inclusion in the trial and a margin of 2 months, we expect to complete 
the collection of the primary endpoint by the end of February 2027.  
The secondary outcomes data will be collected 12 months after inclusion in the trial. Considering 
the same margin of 2 months, we expect to complete the data collection at the end of August 
2027. Given the outcome collection within the routine SHCS data collection, long term follow-up 
data (24 months after randomization) will be collected automatically without trial specific follow-
up. 
7.4 Process evaluation   
RETUNE tests a complex intervention that involves offering a menu of different nicotine substitute 
products to participants in the SHCS who smoke tobacco cigarettes. To better understand how 
this intervention works, we are planning a process evaluation study. This study will use a mixed-
methods design (combining qualitative and quantitative measures) to investigate the delivery 
(offer), uptake, adoption, and implementation of the intervention, as well as the contextual factors 
influencing these processes. The process evaluation study will be described in detail elsewhere. 
8 
QUALITY CONTROL AND DATA PROTECTION 
8.1 Quality measures  
The treating physicians of the participating SHCS centers will be trained by the RETUNE team 
regarding screening, recruitment, randomization procedure, consent procedures, and how to 
explain and deliver the intervention. We will emphasize the concept and importance of harm 
reduction in smoking cessation. This training will be conducted in person for each center 
Year 
2025 
2026 
2027 
Quarter 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
4 
Recruitment of  
Participants for RETUNE 
 
 
 
 
 
 
 
 
 
 
 
 
Internal pilot trial  
 
 
 
 
 
 
 
 
 
 
 
 
Primary outcome  
assessment 
 
 
 
 
 
 
 
 
 
 
 
 
Secondary outcome 
assessment  
 
 
 
 
 
 
 
 
 
 
 
 
Analyzing data & 
manuscript writing and 
submission 
 
 
 
 
 
 
 
 
 
 
 
 
Long term follow-up with 
subsequent analysis  
 
 
 
 
 
 
 
 
 
 
 
 

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individually to take local differences into account. Moreover, the study team will provide training 
material and leaflets for the treating physicians and study nurses.  
RETUNE will use the routinely collected data from the SHCS for most endpoints. Quality 
measures for the SHCS data collection are described in the SHCS protocol (BASEC-Nr. 2023-
02080). Additional data on (S)AE and use of the chosen products will be collected retrospectively 
via surveys sent out by the RETUNE team. This information will be collected via REDCap and 
stored on a server at the University Hospital Basel.  
The data records will be kept under protection to ensure the confidentiality of the trial participants. 
The principal investigators and their delegates will have access to the records. The principal 
investigators will permit access to the data records to regulatory agencies in case of audits.   
No independent Data- or Safety Monitoring Committee is planned due to the low risk of the tested 
intervention. Safety monitoring will be conducted as outlined above in section 6.2.  
8.2 Data recording and source data 
RETUNE will use routinely collected data from the SHCS. The SHCS eCRF is a Django-based 
web-application hosted at the University of Zürich (https://www.djangoproject.com). The 
application is based on PostgreSQL (https://www.postgresql.org). The application was developed 
by the SHCS and includes an audit trail, which means that it is traced who changed which data 
and when. A daily backup is done.  
Additional data like information on (S)AE, use of the individual products, and contact information 
of the participants to provide supply of the interventional products over the course of the trial will 
be recorded using REDCap (https://www.project-redcap.org/) surveys.  
The signed intervention consent forms represent the only source data in the RETUNE trial. They 
will be stored at the respective centers. For data recording and export we will work closely 
together with the SHCS data center at the University of Zurich. Details regarding the eCRF, the 
record of data and the data management are described in the SHCS protocol (BASEC-Nr. 2023-
02080).  
8.3 Confidentiality and coding 
At the inclusion cohort visit, the participants who accept the offered intervention are asked to 
provide their postal address and preferred communication channel (telephone number or email 
address). This information will be used to contact the participants for supply of the interventional 
products (see section 4.4.3) and to conduct retrospective surveys in the intervention group to 
collect intervention on potential SAEs and usage of the interventional products (see table 4 
section 4.4.2). This information will be stored in a REDCap based case report form. The REDCap 
is hosted by the Department of Clinical Research at the University Hospital Basel. Only the 
principal investigators and their delegates will have access to this data.   
When the participants sign the intervention consent, the treating physician writes by hand the 
REDCap identifier (unique for each participant) on the intervention consent sheet. The 
intervention consent sheets are stored at each cohort center. Using the signed consent sheets 
with the REDCap identifier, each center creates a decoding key (excel file) with the SHCS number 
and the REDCap identifier. This procedure ensures that identifying patient data (e.g. name, postal 
address) in combination with the SHCS identifier cannot be used outside of the respective SHCS 
center.  

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The information recorded in REDCap (stored at the University Hospital Basel) will be kept 
separate from the SHCS data collection (stored at the University of Zurich). After completion of 
the RETUNE trial, an anonymized data set with the results from the surveys, on SAE and usage 
of the products, will be exported from REDCap. No identifying patient data will be exported. This 
data set will then be merged with the routinely collected data from the SHCS using the de-coding 
key at each SHCS center.  
This procedure ensures that identifying participant data leaves the SHCS center only for the 
purpose of the RETUNE trial and without the corresponding SHCS identifier.  
 
On the SHCS eCRFs to collect the routine cohort data, participants are only identified by a unique 
participant number. The eCRFs are stored centrally on a server of the University Hospital Zurich. 
The SHCS eCRFs are password protected and only members of the SHCS have access. For 
detailed information we refer to the protocol of the SHCS. A list of participants identification will 
be stored in the investigator site file at each study site.  
 
No biological material is collected as part of this trial. For more detailed information about 
protection, storage, shipping (including transport to other centers or other countries) and 
processing of routine biological material in the SHCS we refer to the protocol of the SHCS 
(regarding the biobanking). For shipping of biological material outside of the SHCS centers (if 
needed), separate transfer agreements will be signed.  
 
Figure 7: Data collection, processing, export and decoding  
 
Routine SHCs data is collected at the different SHCS centers via Django and stored and processed 
centrally at the SHCS data center at the University of Zurich. Data additionally collected for RETUNE 
(including identifying personal data like phone number, Email address or postal address) is collected via 
REDCap and stored at the DKF at the University Hospital Basel. The decoding list which allows combining 
RETUNE data with SHCS data remains at the respective SHCS center. After completion of the trial, the 
RETUNE specific data is exported without identifying personal data. The decoding lists are used to combine 
the RETUNE data with the SHCS data at the respective centers.  

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DKF=Department Clinical Research, ICF=Informed Consent Form, ID=Identifier, RETUNE=Reduce 
Tobacco Use In People Living With HIV, SHCS=Swiss HIV Cohort Study 
8.4 Retention and destruction of study data and biological material 
At the end of the trial or in case of premature termination, all trial data will be locked and archived. 
Since most of the trial data are routinely collected within the SHCS, the data will be stored as 
described in the SHCS protocol on a server of the University of Zurich. Additional data not 
collected within the SHCS (retrospective surveys conducted via REDCap) are stored by the 
Department of Clinical Research at the University Hospital Basel on a secure server for a 
minimum of 20 years.  
9  MONITORING AND REGISTRATION 
Since the trial uses mostly data collected within the SHCS, data monitoring will be exclusively 
done centrally. All SHCS collected data will undergo SHCS quality control described in the SCHS 
protocol (BASEC-Nr. 2023-02080). In brief, high data quality will be ensured by three validations 
steps. First, the data is collected by trained SHCS study nurses or cohort physicians. Second, the 
data record is then validated, and if necessary supplemented by local research associates at the 
responsible SHCS centers. After validation, the data is sent to the SHCS data center at the 
University of Zurich. Third, at the data center, the data is validated and released for research 
purposes. Additionally, members of the data center conduct regular quality visits at the centers. 
For the RETUNE trial, members of the RETUNE study team will monitor recruitment numbers 
and routinely collected data used for the primary or the secondary endpoints on a weekly basis.  
As described in section 4.4, RETUNE will collect additional data only in the intervention group 
regarding usage and safety of the investigational products. These data will be collected via 
REDCap and managed by a member of the RETUNE study team (CS). A second member of the 
RETUNE study team will double check the data entry (AA).  
Before recruitment of the recruitment of the first participant at a respective site, the PI will perform 
an in-person site initiation visit. After follow-up of the last patient, the PI will perform an in-person 
site closure visit (can be performed remotely).  
The trial is registered on the Clinical Trials Registry Platform of the National Institute of Health 
(NCT06789692) as well as in the Swiss National Clinical trial Portal (BASEC-Nr. 2024-02417).  
10. FUNDING / PUBLICATION / DECLARATION OF INTEREST 
10.1 Funding  
This research project is funded by the Swiss National Science Foundation through the MD-PhD 
program, the Novartis Foundation for Medical-Biological Research and the Swiss Tobacco 
Control fund (Bundesamt für Gesundheit). The Division of Clinical Epidemiology and the 
University Hospital Basel provide parts of the needed infrastructure. The SHCS provides access 
to the cohort infrastructure and covers costs of the routine SHCS procedures.  
The funding sources are not involved in the trial design, data collection, data analysis, 
interpretation of the results, or writing the manuscript.  
 
 

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10.2 Declaration of Interests  
None of the investigators involved have any financial or other conflicts of interest with the 
proposed research project. In particular, there are no relationships with tobacco companies or 
manufacturers of alternative nicotine products to declare. 
 
10.2 Publication and dissemination policy  
To pursue a clear communication strategy, we will develop a detailed communication plan with 
our Participant Advisory Board (see section 4.8). Besides publication in peer-reviewed open-
access journals, the results will be shared at national and international conferences (e.g. the 
annual conference of the Society of Nicotine and Tobacco Research, European AIDS conference, 
Conference on Retroviruses and Opportunistic Infections), at meetings with other HIV cohorts 
outside of Switzerland, at the local sites, and in the SHCS newsletter in the form of lay summaries. 
This newsletter is regularly sent to SHCS participants and is published in German, French, and 
Italian. To increase accessibility, we may translate the results into English and Spanish.  
The sponsor enters and publishes a summary of the trial results in clinicaltrials.gov in accordance 
with ClinO Art. 65a within one year of completion or discontinuation of the trial. An interruption 
lasting more than two years is considered a discontinuation of the trial. 
For the purpose of publication in the public register the sponsor also ensures that a lay summary 
of the trial results is entered in BASEC within one year of completion or discontinuation of the 
trial. The entry is made at least in the national languages of Switzerland in which the study 
participants were recruited. 
 
 

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