Smoking Cessation Facilitated by Glucagon-like Peptide-1 (GLP-1) Analogues - a Randomized, Double-blind, Placebo-controlled Trial
Phase: PHASE2
Conditions: Glucagon-like Peptide-1, Smoking Cessation, Weight Change, Body, Craving
Sponsor: University Hospital, Basel, Switzerland

Smoking cessation by GLP-1 analogues - The SKIP-Study, Version 4 (12.03.2018) 
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Clinical Study Protocol 
 
Smoking cessation facilitated by glucagon-like peptide-1 (GLP-1) analogues – a randomized, 
double-blind, placebo-controlled trial 
 
 
Study Type: 
Clinical trial with Investigational Medicinal Product (IMP) 
Study Categorisation: 
Risk category B 
Study Registration: 
clinicaltrials.gov and kofam.ch intended  
 
 
Sponsor-Investigator: 
Prof. Mirjam Christ-Crain 
Universitätsspital Basel, Petersgraben 4, 4031 Basel 
 
Principal Investigator: 
 
Co-Investigators:  
 
 
 
 
Investigational Product: 
 
Dr. med. Bettina Winzeler 
 
Dr. med. Thilo Burkard 
Dr. med. Andrea Meienberg 
Dr. med. Nica Jeanloz 
 
Dr. med. Fabian Meienberg 
 
Dulaglutide (Trulicity®) 
 
Protocol Version and Date: 
 
Version 4, 12.03.2018 
Version 3, 13.10.2017 
Version 2, 03.05.2017 
Version 1, 16.02.2017 
 
 
 
 
 
 
 
 
 
 
 

Smoking cessation by GLP-1 analogues - The SKIP-Study, Version 4 (12.03.2018) 
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Signature Page 
 
Study number 
- BASEC 2017-00286 
Study Title 
The SKIP-Study 
 
The Sponsor-Investigator and trial statistician have approved the protocol version [4, 12.04.2018], and 
confirm hereby to conduct the study according to the protocol, current version of the World Medical 
Association Declaration of Helsinki, ICH-GCP guidelines and the local legally applicable requirements. 
 
 
 
 
 

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TABLE OF CONTENT 
STUDY SYNOPSIS ...................................................................................................................................... 7 
STUDY SUMMARY IN LOCAL LANGUAGE .............................................................................................. 11 
ABBREVATIONS ........................................................................................................................................ 11 
STUDY SCHEDULE ................................................................................................................................... 12 
1. STUDY ADMINISTRATIVE STRUCTURE .............................................................................................. 13 
1.1 Sponsor, Sponsor-Investigator .......................................................................................................... 13 
1.2 Principal Investigator ......................................................................................................................... 13 
1.3 Statistician ("Biostatistician") ............................................................................................................. 13 
1.4 Clinical Epidemiologists..................................................................................................................... 13 
1.5 Laboratory ......................................................................................................................................... 13 
1.6 Monitoring institution ......................................................................................................................... 13 
1.7 Data Safety Monitoring Committee .................................................................................................... 13 
1.8 Authors’ contributions ........................................................................................................................ 13 
2. ETHICAL AND REGULATORY ASPECTS ............................................................................................. 14 
2.1 Study registration .............................................................................................................................. 14 
2.2 Categorisation of study ..................................................................................................................... 14 
2.3 Competent Ethics Committee (CEC) ................................................................................................. 14 
2.4 Competent Authorities (CA) .............................................................................................................. 14 
2.5 Ethical Conduct of the Study ............................................................................................................. 14 
2.6 Declaration of interest ....................................................................................................................... 14 
2.7 Patient Information and Informed Consent ........................................................................................ 14 
2.8 Participant privacy and confidentiality ................................................................................................ 15 
2.9 Early termination of the study ............................................................................................................ 15 
2.10 Protocol amendments ..................................................................................................................... 15 
3. BACKGROUND AND RATIONALE ........................................................................................................ 15 
3.1 Background and Rationale ................................................................................................................ 15 
3.2 Investigational Product (treatment, device) and Indication ................................................................. 16 
3.3 Preclinical Evidence .......................................................................................................................... 16 
3.4 Clinical Evidence to Date .................................................................................................................. 16 
3.5 Dose Rationale / Medical device: Rationale for the intended purpose in study (pre-market MD) ....... 17 
3.6 Explanation for choice of comparator (or placebo) ............................................................................ 17 
3.7 Risks / Benefits ................................................................................................................................. 17 
3.8 Justification of choice of study population ......................................................................................... 17 
4. STUDY OBJECTIVES ............................................................................................................................ 18 
4.1 Overall Objective ............................................................................................................................... 18 
4.2 Primary Objective and Hypothesis .................................................................................................... 18 
4.3.1 Main Secondary Objective ........................................................................................................... 18 

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4.3.2 Further Secondary Objectives ..................................................................................................... 18 
4.4 
Safety Objectives ......................................................................................................................... 19 
5. STUDY OUTCOMES .............................................................................................................................. 19 
5.1 Primary Outcome .............................................................................................................................. 19 
5.2 Secondary Outcomes ........................................................................................................................ 19 
5.3 Safety Outcomes............................................................................................................................... 19 
6. STUDY DESIGN ..................................................................................................................................... 19 
6.1 General study design and justification of design ................................................................................ 19 
6.2 Methods of minimising bias ............................................................................................................... 20 
6.2.1 Randomisation ............................................................................................................................ 20 
6.2.2 Blinding procedures ..................................................................................................................... 20 
6.2.3 Unblinding Procedures (Code break) .......................................................................................... 20 
7. STUDY POPULATION ........................................................................................................................... 20 
7.1 Eligibility criteria ................................................................................................................................ 20 
7.2 Recruitment and screening ............................................................................................................... 21 
7.3 Assignment to study groups .............................................................................................................. 21 
7.4 Criteria for withdrawal / discontinuation of participants ...................................................................... 21 
8. STUDY INTERVENTION ........................................................................................................................ 21 
8.1 Identity of Investigational Products (treatment / medical device) ....................................................... 21 
8.1.1 Experimental Intervention (treatment / medical device) ............................................................... 21 
8.1.2 Control Intervention (standard/routine/comparator treatment / medical device) ........................... 22 
8.1.3 Packaging, Labelling and Supply (re-supply) ............................................................................... 22 
8.1.4 Storage Conditions ...................................................................................................................... 22 
8.2 Administration of experimental and control interventions ................................................................... 22 
8.2.1 Experimental Intervention ............................................................................................................ 22 
8.2.2 Control Intervention ..................................................................................................................... 22 
8.3 Dose / Device modifications .............................................................................................................. 22 
8.3.1 Dose reduction of the study drug ................................................................................................. 22 
8.3.2 Dose reduction of varenicline ...................................................................................................... 22 
8.4 Compliance with study intervention ................................................................................................... 22 
8.5 Data Collection and Follow-up for withdrawn participants .................................................................. 23 
8.6 Trial specific preventive measures .................................................................................................... 23 
8.7 Concomitant Interventions (treatments) ............................................................................................. 23 
8.8 Study Drug / Medical Device Accountability ...................................................................................... 23 
8.9 Return or Destruction of Study Drug / Medical Device ....................................................................... 23 
9. STUDY ASSESSMENTS ........................................................................................................................ 23 
9.1 Assessment of primary outcome ....................................................................................................... 23 
9.2 Assessment of main secondary outcome .......................................................................................... 23 
9.2.1 Assessment of further secondary outcomes: ............................................................................... 23 

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9.2.2 Abstinence rate during follow-up phase ....................................................................................... 23 
9.2.3 Smoking reduction....................................................................................................................... 24 
9.2.4 Craving ........................................................................................................................................ 24 
9.2.5 Body weight................................................................................................................................. 24 
9.2.6 Glucose homeostasis .................................................................................................................. 24 
9.2.7 Further explorative outcome measures ....................................................................................... 24 
9.2.8 Assessment of safety outcomes ................................................................................................ 24 
9.2.9 Assessments in participants who prematurely stop the study ...................................................... 24 
9.3 Procedures at each visit .................................................................................................................... 24 
9.3.1 Screening phase: ........................................................................................................................ 24 
9.3.2 Visit 0, Inclusion .......................................................................................................................... 24 
9.3.3 Treatment phase, visits 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 ............................................................... 25 
9.3.4 Follow-up phase, visit 24 (week 24) and Visit 52 (week 52) ......................................................... 25 
9.3.5 End of study visit for withdrawn participant .................................................................................. 25 
9.3.6 Visits within the SCS ................................................................................................................... 25 
10. SAFETY ............................................................................................................................................... 25 
10.1 Definition and assessment of (serious) adverse events and other safety related events ................. 26 
10.2 Reporting of serious adverse events (SAE) and other safety related events ................................... 26 
10.3 Follow up of (Serious) Adverse Events ............................................................................................ 27 
11. STATISTICAL METHODS .................................................................................................................... 27 
11.1 Hypothesis ...................................................................................................................................... 27 
11.2 Determination of Sample Size ......................................................................................................... 27 
11.3 Planned Analyses ........................................................................................................................... 28 
11.3.1 Datasets to be analysed ............................................................................................................ 28 
11.3.2 Primary Analysis........................................................................................................................ 28 
11.3.3 Secondary Analyses .................................................................................................................. 28 
11.4 Interim Analysis ............................................................................................................................... 28 
11.5 Safety Analysis ............................................................................................................................... 28 
11.6 Deviation(s) from the original statistical plan ................................................................................... 28 
11.7 Handling of missing data and drop-outs .......................................................................................... 28 
12. QUALITY ASSURANCE AND CONTROL ............................................................................................ 29 
12.1 Data handling and record keeping / archiving .................................................................................. 29 
12.1.1 Case Report Forms ................................................................................................................... 29 
12.1.2 Specification of source documents ............................................................................................ 29 
12.1.3 Record keeping / archiving ........................................................................................................ 29 
12.2 Data management ........................................................................................................................... 29 
12.2.1 Data Management System ........................................................................................................ 29 
12.2.2 Data security, access and back-up ............................................................................................ 29 
12.2.3 Analysis and archiving ............................................................................................................... 29 
12.2.4 Electronic and central Data validation ........................................................................................ 30 

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12.3 Monitoring ....................................................................................................................................... 30 
12.4 Audits and Inspections .................................................................................................................... 30 
12.5 Confidentiality, Data Protection ....................................................................................................... 30 
12.6 Storage of biological material and related health data ..................................................................... 30 
13. PUBLICATION AND DISSEMINATION POLICY .................................................................................. 30 
14. FUNDING AND SUPPORT ................................................................................................................... 30 
14.1 Funding ........................................................................................................................................... 30 
14.2 Other Support ................................................................................................................................. 31 
15. INSURANCE ........................................................................................................................................ 31 
16. SIGNIFICANCE OF THE STUDY ......................................................................................................... 31 
17. REFERENCES ..................................................................................................................................... 31 
APPENDICES ............................................................................................................................................ 35 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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STUDY SYNOPSIS 
Sponsor / Sponsor-Investigator 
Prof. Mirjam Christ-Crain 
Study Title: 
Smoking cessation facilitated by glucagon-like peptide-
1 (GLP-1) analogues – a randomized, double-blind, 
placebo-controlled trial 
 
Short Title / Study ID: 
Smoking cessation by GLP-1 analogues 
Protocol Version and Date: 
Version 4, 12.03.2018  
Trial registration: 
clinicaltrials.gov and kofam.ch intended 
Study category and Rationale 
Category B: Dulaglutide is approved for treatment of 
diabetes mellitus, but not studied as pharmacotherapy for 
smoking cessation.  
Clinical Phase: 
Phase 2  
Background and Rationale: 
 
 
 
 
Cigarette smoking is the leading preventable cause of 
premature death worldwide. However smoking is a very 
difficult addiction to break and despite established smoking 
cessation programs quit rates are low, especially in the 
real-life setting. The main reasons for not quitting or 
relapsing after cessation are the nicotine withdrawal 
syndrome and post-cessational weight gain. GLP-1 
analogues are well known to stimulate insulin secretion and 
to reduce energy intake and therefore body weight. Recent 
findings from animal and human studies suggest a role of 
GLP-1 in the pathophysiology of addiction. The putative role 
of GLP-1 analogues in nicotine reward regulation combined 
with its weight reducing effects might be of major interest in 
view of novel pharmatherapeutic options for smoking 
cessation.  
Objective(s): 
1. To evaluate the influence of the GLP-1 analogue 
dulaglutide combined with varenicline and 
behavioural counselling (=standard of care [SOC]) 
on point prevalence abstinence rate at 12 weeks 
compared to SOC alone. 
2. To assess the influence of the GLP-1 analogue 
dulaglutide on post-cessation weight change 
compared to SOC.  

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Outcome(s): 
The primary outcome is point prevalence abstinence rate at 
week 12 of dulaglutide treatment and SOC versus SOC 
alone, confirmed with end-expiratory exhaled carbon 
monoxide measurements of 10 ppm or less. 
The main secondary outcome is change in body weight in 
kg (and BMI [kg/m²]) relative to baseline at week 12 of 
dulaglutide treatment versus placebo. 
Further secondary outcomes are 
point prevalence abstinence rate at week 24 and 52; 
prolonged abstinence rate at week 24 and 52; 
Smoking reduction at week 12, 24, and 52; 
Change of craving at week 4 and 12 relative to baseline; 
Change of body weight in kg (and BMI [kg/m²])  at week 4, 
8, 24, and 52; 
Change in haemoglobin A1c levels at week 12, 24, 52 
relative to baseline 
Study design: 
Double-blind, placebo controlled, parallel group, superiority, single-center randomized trial 
 

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Inclusion / Exclusion criteria: 
Inclusion criteria: 
- 
Age 18 to 75 years 
- 
Daily smokers who are willing to quit and exhibit one 
of the following criteria: 
 
≥10 cigarettes per day or  
 
At least moderate nicotine dependence defined by a 
Fagerstroem Score of ≥5 points or 
 
Tobacco associated disease 
- 
Treatment with varenicline (Champix®) 
Exclusion criteria: 
- 
Pregnancy (incl. wish to become pregnant within 
next 3 months) or breast feeding 
- 
Pre-existing treatment with GLP-1 agonists  
- 
History of pancreatitis 
- 
Severe renal insufficiency (estimated glomerular 
filtration rate <30 ml/min/1,73 m2) 
- 
Instable psychiatric conditions  
Anorexia nervosa 
Measurements and procedures: 
12-week treatment phase with dulaglutide (Trulicity®) or 
placebo and SOC, followed by a 40-week non-treatment 
phase. Assessment of smoking status by end-expiratory 
exhaled carbon monoxide measurements. 
Study Product / Intervention:  
Dulaglutide (Trulicity®) 0.75 mg and 1.5 mg in 0.5 ml, via 
pen s.c. once weekly for 12 weeks. 
Control Intervention (if 
applicable): 
Placebo: 0.5 ml normal saline (0.9% sodium chloride [0.9% 
NaCl]), injection s.c. via syringe once weekly for 12 weeks. 
Number of Participants with 
Rationale: 
Power calculation was done for the primary outcome. For 
calculating sample size a simulation was carried out  . It  
was assumed that point prevalence abstinence rate in the 
control arm will be 33% and the increase of quit rate in the 
intervention arm 18% (increase from 33% to 51%) at week 
12 
For this trial a total of 256 patients should be recruited.  
Hypothesis testing to estimate efficacy of standard therapy 
plus dulaglutide is on the basis of 80% power and an α 
error threshold of 5%. 
Study Duration: 
Approximately 36 months 
Study Schedule: 
First-Participant-In (planned): 01.04.2017 
Last-Participant-Out (planned): 31.03.2020 
Investigator(s): 
Prof. Mirjam Christ-Crain 
Dr. med. Bettina Felicitas Winzeler 
Universitätsspital Basel, Petersgraben 4, 4031 Basel 
Study Centre(s): 
Single-centre: Universitätsspital Basel 

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Statistical Considerations: 
Primary analysis will assess whether point prevalence 
abstinence rate in the intervention arm after 12 weeks is 
significantly different to the control arm.  A Pearson’s ҳ2 -
test will be applied to test the hypothesis (H-Null: no 
difference H-Alternative: significant difference). 
 
Main secondary analysis will assess whether change in 
body weight in kg (and BMI [kg/m²]) relative to baseline is 
significantly different between the experimental and the 
control arm at week 12. Difference between the 2 arms will 
be assessed by ANCOVA. Weight at week 12 will be the 
outcome variable, weight at baseline and treatment arm 
both explanatory variables. 
 
Further secondary outcomes will be analysed as follows: 
- For point prevalence abstinence rate at 24 and 52 weeks 
the same methods as for the primary analysis will be 
applied. 
- For prolonged abstinence at 24 and 52 weeks, the same 
statistical methods as for the primary analysis will be 
applied except that only patients are included who were 
already abstinent at previous assessments (at week 12 for 
prolonged abstinence rate at 24 weeks and at weeks 12 
and 24 for abstinence at week 52). 
- For smoking reduction, it will be tested whether the 
difference in percentage of patients who have a reduced of 
end-expiratory exhaled CO of more than 50% at 12, 24, and 
52 weeks is significantly different between the two arms. 
The Pearson’s ҳ2 -test will be applied. 
- Whether craving  between the two arms at week 4 and 12 
relative to baseline is significantly different will be analysed 
by  ANCOVA. Craving at week 4 or 12 will be the outcome 
variable, craving at baseline and treatment arm both 
explanatory variables. 
- Change of body weight in kg (and BMI [kg/m²]) at week 4, 
8, 24 and 52 will be assessed by ANCOVA. Weight at week 
24 or 52 will be the outcome variable, weight at baseline 
and treatment arm both explanatory variables. 
- Change of haemoglobin A1c (HbA1c) concentration at 
week 12, 24, and 52, relative to baseline will be analysed 
by ANCOVA. HbA1c at 12, 24, or 52 weeks will be the 
outcome variable, HbA1c at baseline and treatment arm 
both explanatory variables. 
 
- Time trends of means or percentages of all secondary 
endpoints will be plotted including standard deviations for 
means and 95%-CI for percentages. 
 
- For hypothesis testing an alpha error threshold of 5% will 
be chosen. 
GCP Statement: 
This study will be conducted in compliance with the 
protocol, the current version of the Declaration of Helsinki, 
as well as the GCP and all national legal and regulatory 
requirements.  
 

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STUDY SUMMARY IN LOCAL LANGUAGE 
Nikotinkonsum ist mit einer deutlich erhöhten Morbidität und Mortalität vergesellschaftet. Obwohl viele 
Raucher gerne mit dieser Sucht brechen möchten, scheitern sie im Alltag an den Hindernissen, welche ein 
Rauchstopp mit sich bringt. Hier sind in erster Linie die Nikotin-Entzugserscheinungen und die 
Gewichtszunahme zu nennen. Ziel dieser Studie ist es, eine neue Behandlung zur Rauchentwöhnung zu 
untersuchen, welche genau auf diese zwei Barrieren abzielt.   
Die zur Behandlung von Zuckerkrankheit und Übergewicht eingesetzten Medikamente Glucagon-like 
Peptide 1 (GLP-1) Analoga, welche die Wirkung des körpereigenen Darmhormons GLP-1 imitieren, sind für 
ihren Appetit zügelnden Effekt bekannt. Neuste Resultate aus Tierstudien weisen darauf hin, dass GLP-1 
bei verschiedensten Suchterkrankungen (wozu letztlich auch die Adipositas gehört) eine Rolle spielt: das 
durch Suchtmittel (z.B. Alkohol, Kokain, Nikotin) aktivierte Belohnungssystem scheint durch GLP-1 
moduliert zu werden. Wir vermuten deshalb, dass eine Therapie mit GLP-1 Analoga die 
Entzugserscheinungen nach Rauchstopp zu lindern vermag.  
Des Weiteren nehmen wir an, dass bekannte gewichtsreduzierende Effekte von GLP-1 Analoga in der 
Phase der Rauchentwöhnung ebenfalls besonders vorteilhaft sein werden; damit könnte die typischerweise 
mit dem Rauchstopp vergesellschaftete Gewichtszunahme reduziert oder gänzlich verhindert werden.  
Ein dritter Aspekt macht GLP-1 Analoga zu einer vielversprechenden Behandlungsmöglichkeit: obwohl 
Rauchen an sich mit einem Risiko für die Entwicklung eines Diabetes mellitus vergesellschaftet ist, erhöht 
auch der Nikotinstopp das Risiko kurzfristig. Dies könnte durch die blutzuckersenkende Wirkung der GLP-1 
Analoga positiv beeinflusst werden. Zusammenfassend vermuten wir, dass die Therapie mit GLP-1 
Analoga zur Rauchentwöhnung sowohl die Chance auf einen erfolgreichen Rauchstopp erhöht als auch 
das kardiovaskuläre Risiko günstig beeinflusst. 
ABBREVIATIONS 
ACTH 
Adrenocorticotropic hormone 
AE  
Adverse event 
AOBPM 
Automated Office Blood Pressure Measurement 
BD 
Blood pressure 
BMI 
Body mass index  
CA 
Competent Authority (e.g. Swissmedic) 
CEC 
Competent Ethics Committee 
ClinO 
Ordinance on Clinical Trials in Human Research (in German: KlinV, in 
French: OClin) 
CO 
Carbon monoxide   
CRF 
Case Report Form  
CTCAE 
Common terminology criteria for adverse events 
CTU 
Clinical Trial Unit 
DSUR  
Development safety update report 
eCRF 
ER 
Electronic Case Report Form 
Entity-relationship modelling 
GCP 
Good Clinical Practice 
GLP-1 
glucagon-like peptide-1 
Ho 
Null hypothesis 
H1 
Alternative hypothesis 
hCG 
Human chorionic gonadotropin 
HFG 
Humanforschungsgesetz (Law on human research) 
HMG 
Heilmittelgesetz  
HPA axis 
Hypothalamic-pituitary-adrenal axis 
HR  
Heart rate  
HRA 
Federal Act on Research involving Human Beings 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
IIT  
Investigator-initiated Trial 
IMP 
Investigational Medicinal Product 

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ISO 
International Organisation for Standardisation 
ITT 
Intention to treat 
KlinV 
Verordnung über klinische Versuche in der Humanforschung (in English: 
ClinO, in French OClin) 
LPTh 
Loi sur les produits thérapeutiques 
LRH 
Loi fédérale relative à la recherche sur l’être humain 
MD 
Medical Device 
NRT  
Nicotine Replacement Therapy 
OClin 
Ordonnance sur les essais cliniques dans le cadre de la recherche sur l'être 
humain (in German : KlinV, in English : ClinO) 
PI 
Principal Investigator 
PP   
Primary polidypsia 
QoL 
Quality of life 
QSU-G 
Questionnaire of smoking urge, german version  
s.c. 
Subcutaneously 
SCS 
Smoking cessational service  
SDV  
Source Data Verification  
SOC  
Standard of Care 
SOP 
Standard Operating Procedure 
SPC 
Summary of product characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TMF 
Trial Master File  
VAS 
Visual analogue scale  
STUDY SCHEDULE 
 
Study procedure 
 
Scree
ning 
Week 
0 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Week 
7 
Week 
8 
Week 
9 
Week 
10 
Week 
11 
Week 
12 
Week 
24 
Week 
52 
 
 
End 
of 
study 
visit 
Study Visit 
 
V0 
 
 
 
V4 
 
 
 
V8 
 
 
 
V12 
V13 
V14 
 
Eligibility 
assessment 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/randomizat
ion 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VAS smoking urge  
(0-10) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
QSU-G  
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Motivation  
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Alcohol 
consumption/noxae 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Vital signs (AOBPM)  
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
Weight, height, BMI 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
Laboratory testing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
CO-measurment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
U-cotinine-
measurement 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Study drug 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Varenicline  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
New Medication  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Substudies 

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fMRI 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Indirect calorimetry 
(REE) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Body 
impedance 
analysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Serum 
catecholamines 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
1. STUDY ADMINISTRATIVE STRUCTURE   
1.1 Sponsor, Sponsor-Investigator  
Prof. Mirjam Christ-Crain 
Endokrinologie, Diabetologie und Metabolismus 
Universitätsspital Basel, Petersgraben 4, 4031 Basel 
Tel: 061 328 70 80, mirjam.christ@usb.ch 
1.2 Principal Investigator 
Dr. med. Bettina Winzeler 
Endokrinologie, Diabetologie und Metabolismus 
Universitätsspital Basel, Petersgraben 4, 4031 Basel 
Tel: 061 556 50 75, bettina.winzeler@usb.ch 
1.3 Statistician ("Biostatistician")  
Dr. Tobias Erlanger 
Clinical Trial Unit (CTU) Basel 
Universitätsspital Basel 
1.4 Clinical Epidemiologists 
Dr. med. Lars G. Hemkens, MPH 
Dr. Benjamin Speich 
Basel Institute for Clinical Epidemiology and Biostatistics 
Universitätsspital Basel 
1.5 Laboratory 
Zentrallabor Universitätsspital Basel 
Universitätsspital Basel, Petersgraben 4, 4031 Basel 
1.6 Monitoring institution 
CTU Basel 
Universitätsspital Basel 
1.7 Data Safety Monitoring Committee  
Not applicable 
 
1.8 Authors’ contributions 
Authors contributions to study protocol: BW wrote the study protocol. BW and TB created the study concept 
and design. MCC, NJ, AM and FM provided input to study design and drafted the manuscript. TE drafted 
the statistical analysis section. LGH and BS critically reviewed the protocol and made important 
contributions on methodological issues. All authors were involved in the critical revision of the protocol for 
important intellectual content. MCC supervised the study protocol process. 
 
Substudy Energy: NJ and BW wrote the protocol. TB drafted the statistical section. MCC and Matthias Betz 
(MB) reviewed the protocol and made important contributions.  
 
Substudy fMRI: NJ, BW and Davide Zanchi (DZ) wrote the protocol. TB drafted the statistical section. MCC 
and Stefan Borgwardt (SB) reviewed the protocol and made important contributions.  

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2. ETHICAL AND REGULATORY ASPECTS  
Before the study will be conducted, the protocol, the proposed patient information and consent form as well 
as other study-specific documents are submitted to a properly constituted Competent Ethics Committee 
(CEC), Ethikkommission Nordwest und Zentralschweiz (EKNZ) and Swissmedic. 
The decision of the EKNZ and Swissmedic concerning the conduct of the study will be made in writing to 
the Sponsor-Investigator before commencement of this study. The clinical study can only begin once 
approval from all required authorities has been received. Any additional requirements imposed by the 
authorities shall be implemented. 
2.1 Study registration  
The study will be registered at www.clinicaltrials.gov and the Swiss National Clinical Trials Portal (SNCTP) 
on www.kofam.ch. 
2.2 Categorisation of study  
Category B: This is a placebo-controlled study. Dulaglutide is authorized in Switzerland for treatment of 
diabetes mellitus but is not used in non-diabetics. 
2.3 Competent Ethics Committee (CEC)  
The responsible investigator at each site ensures that approval from an appropriately constituted 
Competent Ethics Committee (CEC) is sought for the clinical study.  
All changes in the research activity and all unanticipated problems involving risks to humans (including in 
case of planned or premature study end and the final report) are reported within the allowed time frame to 
the CEC and no changes are made to the protocol without prior Sponsor and CEC approval, except where 
necessary to eliminate apparent immediate hazards to study participants. 
Premature study end or interruption of the study is reported within 15 days. The regular end of the study is 
reported to the CEC within 90 days, the final study report is submitted within one year after study end.  
2.4 Competent Authorities (CA)  
The Sponsor will obtain approval from the competent authority (Swissmedic) before the start of the clinical 
trial. Premature study end or interruption of the study is reported within 15 days to CA. The regular end of 
the study is reported to the CA within 90 days, the final study report is submitted within one year after study 
end. Amendments are reported according to chapter 2.10. Non-substantial amendments are reported as 
soon as possible. 
2.5 Ethical Conduct of the Study  
The study will be carried out in accordance to the protocol and with principles enunciated in the current 
version of the Declaration of Helsinki, the guidelines of Good Clinical Practice (GCP) issued by ICH, the 
Swiss Law and Swiss regulatory authority’s requirements. The CEC and regulatory authorities will receive 
annual safety and interim reports and be informed about study stop/end in agreement with local 
requirements.  
2.6 Declaration of interest  
This is an investigator driven study, there are no conflicts of interest. 
2.7 Patient Information and Informed Consent 
The investigators (or his designee) will explain to each participant the nature of the study, its purpose, the 
procedures involved, the expected duration, the potential risks and benefits and any discomfort it may entail. 
Each participant will be informed that the participation in the study is voluntary and that he/she may 
withdraw from the study at any time without giving any reasons and that withdrawal of consent will not 
affect his/her subsequent medical assistance and treatment.  
The participant is informed that his/her medical records may be examined by authorised individuals other 
than their treating physician. 
All participants for the study will be provided a participant information sheet and a consent form describing 
the study and providing sufficient information for participants to make an informed decision about their 

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participation in the study (see Appendix 1). Enough time is given to the participant to decide whether to 
participate or not.  
The patient information sheet and the consent form will be submitted to the CEC and to the competent 
authority to be reviewed and approved. The formal consent of a participant, using the approved consent 
form, must be obtained before the participant is submitted to any study procedure.   
The participant should read and consider the statement before signing and dating the informed consent 
form, and is given a copy of the signed document. The consent form is also signed and dated by the 
investigator (or his designee) and it will be retained as part of the study records. 
2.8 Participant privacy and confidentiality  
The investigator affirms and upholds the principle of the participant's right to privacy and that they shall 
comply with applicable privacy laws. Especially, anonymity of the participants is guaranteed when 
presenting the data at scientific meetings or publishing them in scientific journals.  
Individual subject medical information obtained as a result of this study is considered confidential and 
disclosure to third parties is prohibited. Subject confidentiality will be further ensured by utilising subject 
identification code numbers to correspond to treatment data in the computer files. 
For data verification purposes, authorised representatives of the Sponsor, Swissmedic or EKNZ may 
require direct access to parts of the medical records relevant to the study, including participants’ medical 
history. 
2.9 Early termination of the study  
The Sponsor-Investigator (and any competent authority) may terminate the study prematurely according to 
certain circumstances, for example: 
 
ethical concerns, 
 
insufficient participant recruitment, 
 
when the safety of the participants is doubtful or at risk, respectively, 
 
alterations in accepted clinical practice that make the continuation of a clinical trial unwise,  
 
early evidence of benefit or harm of the experimental intervention.  
2.10 Protocol amendments 
The Sponsor-Investigator and the Principal Investigators are allowed to amend the protocol or to provide 
suggestions for a protocol amendment. Substantial amendments are only implemented after approval of 
the CEC and CA respectively. 
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 sponsor and the CEC/CA. Such deviations are 
documented and reported to the sponsor and the CEC/CA as soon as possible. 
All non-substantial amendments are communicated to the CA as soon as possible and to the CEC within 
the Annual Safety Report (ASR).  
3. BACKGROUND AND RATIONALE  
3.1 Background and Rationale  
Smoking cessation needs to be a health priority as cigarette smoking is the leading preventable cause of 
premature death1. Although most of smokers say that they wish to quit, one year quit rates after an unaided 
attempt are very low (3-6 %)2,3. If smokers participate in a smoking cessation program making use of the 
most effective treatment - a combination of behavioural and pharmacotherapy - abstinence rates after one 
year are higher, but still unsatisfactory according to two systematic reviews (around 30%)4,5. 
There are several difficulties that smokers encounter when they try to quit. As nicotine is a potent 
psychoactive drug causing physical dependence6, withdrawal symptoms (e.g. craving for cigarettes, 
changes in mood) peaking in the first weeks put patients on risk for an early relapse.  
Another important barrier represents the post-cessational weight gain7. On average smoking quitters show 
an increase in mean body weight of 4-5 kg within 12 months8-10. Current pharmacotherapy for smoking 
cessation (e.g. nicotine replacement therapy (NRT), varenicline and bupropion) has not been shown to 
reduce post-cessational weight gain10,11.  
Although smoking per se is a risk factor for incident type 2 diabetes12, smoking cessation increases short 

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term risk of diabetes13. Besides post-cessational weight gain, several other potential causal factors are 
discussed (e.g. systemic inflammation)14,15. 
Taken together, to maximise smoking cessation, novel strategies should address both: nicotine withdrawal 
syndrome and unfavourable metabolic effects of smoking cessation especially weight gain, which is often 
reported as the main reason for not quitting or relapsing.  
The gut-brain hormone GLP-1 is released from endocrine cells from the distal gut and centrally by neurons 
in the nucleus of the solitary tract of the hindbrain in response to food entry in the gastrointestinal tract16-18 
19-21. GLP-1 receptors are expressed in several brain areas, including the hypothalamus and the reward 
nodes ventral tegmental area and nucleus accumbens20,22, implicating a role of GLP-1 in reward 
regulation23.  
Due to its well-known insulinotropic and satiation-promoting effects, GLP-1 analogues are widely used as a 
treatment of type 2 diabetes and obesity. GLP-1 might not only play a role in regulating appetite and energy 
intake (probably via food-related reward processing), but also in controlling reward induced by addictive 
drugs such as alcohol, amphetamine or nicotine24,25. A recent study found that treatment with the GLP-1 
analogue exendin-4 attenuated nicotine-induced effects on the mesolimbic dopamine system in mice23, 
which is thought to be responsible for the development of addiction and compulsive drug taking26.  
Thus, GLP-1 analogues might alleviate symptoms of the nicotine withdrawal syndrome in humans, thereby 
making it easier for smokers to stop. Furthermore, as mentioned above, both the weight reducing effect and 
the anti-diabetogenic properties of GLP-1 analogues are of particular relevance in the context of smoking 
cessation. GLP-1 analogues seem a very promising novel therapy for smoking cessation targeting 
withdrawal symptoms on the one hand and preventing weight gain and diabetes on the other.  
3.2 Investigational Product (treatment, device) and Indication  
TRULICITY contains dulaglutide, which is a human GLP-1 receptor agonist with 90% amino acid sequence 
homology to endogenous human GLP-1 (7-37). Dulaglutide activates the GLP-1 receptor, a membrane-
bound cell-surface receptor coupled to adenylyl cyclase in pancreatic beta cells. Dulaglutide increases 
intracellular cyclic AMP (cAMP) in beta cells leading to glucose-dependent insulin release. Dulaglutide also 
decreases glucagon secretion and slows gastric emptying. The overall molecular weight of dulaglutide is 
approximately 63 kilodaltons. TRULICITY is indicated as an adjunct to diet and exercise to improve 
glycemic control in adults with type 2 diabetes mellitus. 
TRULICITY is a clear, colorless, sterile solution. Each 0.5 mL of TRULICITY solution contains 1.5 mg of 
dulaglutide. Each single-dose pen contains 0.5 mL of solution and the following excipients: citric acid 
anhydrous (0.07 mg), mannitol (23.2 mg), polysorbate 80 (0.10 mg), trisodium citrate dihydrate (1.37 mg), 
in water for injection27. 
3.3 Preclinical Evidence  
There is growing literature indicating that GLP-1 is involved in the pathophysiology of addiction by 
mediating reward induced by several substances (e.g. alcohol, amphetamine, nicotine)24. Initial publications 
focused primarily on alcohol addiction and showed that the GLP-1 analogues exendin-4 and liraglutide 
attenuates the reinforcing properties of alcohol measured by locomotor stimulation and reduces alcohol 
intake in rodents28-30. Similary, exendin-4 seems to prevent as well rewarding properties of amphetamine 
and cocaine31-33.  
Results from a recent animal study are consistent with the hypothesis that GLP-1 regulates nicotine-
induced effects on the mesolimbic dopamine system in mice23, which is thought to be responsible for the 
development of addiction and compulsive drug taking26. 
3.4 Clinical Evidence to Date  
Besides preclinical data suggesting a role of GLP-1 and -analogues in reward regulation, there is growing 
indirect evidence that GLP-1 receptors may be pharmacological targets for addictive diseases in humans: 
Decreased alcohol intake in both rats and humans has been observed after gastric bypass surgery – a 
procedure well known to increase GLP-1 levels34. Furthermore, one study reported an association of 
genetic variation in GLP-1 receptors and alcohol use disorders35. So far, there is no human evidence 
available showing a role of GLP-1 in nicotine dependency. Currently, there is one ongoing experimental 
study looking at addictive behaviour under exenatide treatment assessed by functional MRI in dependent 
individuals who have recently stopped smoking or drinking alcohol (NCT02690987) and one ongoing 
randomized controlled trial evaluating the effects of the GLP-1 analogue exenatide (Bydureon®) on 
smoking cessation (NCT02975297). The study design of the latter trial differs from ours, being more 

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explorative: the experimental product (exenatide) is given for 6 weeks only on top of NRT and quit-rates are 
assessed weekly during a period of 10 weeks. The planned sample size is smaller (90 participants) and 
inclusion criteria are more restrictive focusing only on overweight or prediabetic smokers.   
3.5 Dose Rationale / Medical device: Rationale for the intended purpose in study (pre-market MD) 
Dulaglutide 1,5 mg is injected once a week according to the dosage recommended for treatment of 
diabetes mellitus. The higher of the two available treatment doses (0.75 and 1.5 mg) is chosen in order to 
achieve a higher effect. 
3.6 Explanation for choice of comparator (or placebo)  
To causally attribute the effect to dulaglutide (and not to the interventional setting) and prove that the agent 
modulates smoking cessation, we choose a placebo-controlled design for the study.   
3.7 Risks / Benefits  
The GLP-1 analogue dulaglutide is currently used as an antidiabetic treatment in type 2 diabetics at doses 
of 0.75 and 1.5 mg once weekly and has a favourable safety profile. In several phase 3a trials of the 
AWARD program (the Assessment of Weekly AdministRation of LY2189265 in Diabetes)36-39 dulaglutide 
has been evaluated in totally 4572 patients with type 2 diabetes. In these clinical trials patients were 
initiated and maintained on either 0.75 or 1.5 mg once a week, without titration algorithms. 
Predominant adverse effects were gastrointestinal symptoms with nausea (up to 20%) as the largest 
component. The gastrointestinal symptoms – peaking during the first two weeks of treatment - were usually 
mild to moderate and mostly transient. E-R modelling from pooled clinical pharmacology data found no 
significant difference in nausea events between fixed dosing (1.5 mg weekly) and a titrated regimen (0.75 
mg initial dose followed by 1.5 mg)40. In the trials of the AWARD program no severe hypoglycaemia 
occurred under monotherapy with dulaglutide, documented symptomatic hypoglycaemia in dulaglutide 
treated diabetic patients (1.5 mg/week) was rare (0.19-0,62 episodes/patient/year). Similarly, hypoglycemia 
was no relevant issue when another GLP-1 analogue (liraglutide) was evaluated in 2487 non-diabetic 
obese patients (spontaneous, not severe, hypoglycaemia reported by 1.3% versus 1.0% patients treated 
with liraglutide and placebo, respectively)41. Liraglutide is now approved for weight management in the USA 
and EU. 
Besides its glucose and weight lowering properties, GLP-1 analogues exert benefits on further 
cardiovascular risk factors such as blood pressure and dyslipidemia. There is growing literature from large-
scale clinical trials showing improved cardiovascular outcome associated with different GLP-1 analogue 
treatment42. Especially for liraglutide and semaglutide a significant cardiovascular risk reduction was shown 
in diabetic patients with high cardiovascular burden43,44.  
For dulaglutide cardiovascular outcome data are awaited from the Researching Cardiovascular Events with 
a Weekly Incretin in Diabetes (REWIND) study estimated to be completed in 2018 (NCT01394952). 
Approximately 9000 type 2 diabetic patients with established cardiovascular disease are randomized to 1.5 
mg dulaglutide or placebo in addition to standard of care during an average follow-up of 6.5 years. The 
primary end point includes time to first occurrence of a three component MACE (including CV death, 
nonfatal myocardial infarction, or nonfatal stroke). 
There are no major safety concerns with the trial product dulaglutide, thus we consider the risks of this 
study to be minor. 
During the study period possible adverse events are assessed on each study visit. In case of adverse 
events or other concerns throughout the entire study period participants can contact the study team during 
office hours or visit the emergency department of the University Hospital Basel at any time.  
3.8 Justification of choice of study population  
Adult smokers will participate in the study after thorough information and providing written informed consent. 
This study population has been chosen because the aim of the study is to offer a novel treatment to 
smokers who wish to quit.  

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4. STUDY OBJECTIVES  
4.1 Overall Objective 
The overall objective of the study is to evaluate the GLP-1 analogue dulaglutide (Trulicity®) as a new 
therapeutic drug for smoking cessation assessing abstinence rate at 3 months of dulaglutide treatment. 
4.2 Primary Objective and Hypothesis 
The primary objective is to assess the influence of dulaglutide combined with standard therapy (varenicline 
and behaviour counselling) for smoking cessation on smoking quit rates after 12 weeks compared to 
standard therapy alone. 
Question to be answered: Has dulaglutide an effect on smoking quit rates (presumably by reducing 
symptoms of the nicotine withdrawal syndrome and preventing post-cessational weight gain) when 
combined with standard therapy (i.e. SCS, daily varenicline) of smoking cessation? 
Hypothesis: The success rate of smoking cessation under standard therapy is 33 % at three months. 
Dulaglutide treatment increases smoking quit rate (week 12) by 18% compared to standard therapy alone.  
These hypotheses are based on the following data evidence and assumptions: 
 
Results of a recent smoking cessation trial evaluating the efficacy of a 3 months treatment with 
varenicline and cessation counselling in more than 2000 patients showed a continuous abstinence 
rate of 33.5% after 12 weeks45. In a retrospective analysis of all patients consulting our own 
smoking cessation service (SCS) between 2012 and 2013, the abstinence rate under standard 
therapy at 3 months was 36% (own unpublished data; counting patients with missing outcome data 
as smokers). In this analysis, smoking abstinence was self-reported and not biochemically validated 
by CO measurement. Thus, we assume that the biochemically validated abstinence rate (week 12) 
will be slightly lower (approximately 33%). 
 
The effect of varenicline on smoking cessation might be increased by adding a second component 
of medical therapy. The assumption of an additional increase by 18 % is clinically relevant. We 
presume that the effect combining varenicline with dulaglutide will be in a similar range as found in 
the largest available RCT combining varenicline with nicotine replacement therapy (NRT) that is 
included in a recent meta-analysis of the three available randomized trials46. In this trial, the 
additional increase at 3 months was 14.5%. The summary effect across the three trials in the meta-
analysis showed an increased odds of 50% (OR 1.50; 95% CI 1.14 to 1.97) to quit smoking early 
when NRT was combined with varenicline as second component of medical therapy. Given the 
potential additional weight reducing effect of GLP-1 analogues we presume a somewhat better 
effect of dulaglutide compared to NRT, supporting our assumption of an 18% absolute increase.  
 
4.3.1 Main Secondary Objective 
The main secondary objective is to assess body weight change after smoking cessation under dulaglutide 
treatment and standard therapy (varenicline and behaviour counselling) compared to standard therapy 
alone. 
Question to be answered: Can dulaglutide reduce or even avoid weight gain, which is typically seen after 
smoking cessation? 
Hypothesis: Three months treatment with dulaglutide reduces post-cessational weight gain assessed at 12 
weeks compared to standard therapy alone.  
This hypothesis is based on the following data and considerations: 
 
Mean post-cessational weight gain has been shown to be approximately 4 kg over 5 years in a 2015 
meta-analysis of observational studies47 
 
The majority of weight gain seems to occur during the first months and year48, being as high as 2.3 
kg after two months10 
 
A similar absolute weight reduction as seen in diabetic patients (-2.3 kg after 26 weeks of 
dulaglutide treatment37) is expected in participants receiving dulaglutide who do not quit smoking  
 
4.3.2 Further Secondary Objectives 
Effect of dulaglutide versus placebo on: 

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- 
Point prevalence abstinence at 24 and 52 weeks 
- 
Prolonged abstinence at 24 and 52 weeks (requires abstinence at week 12 and at week 12+24, 
respectively) 
- 
Short-term (12 weeks) and long-term (24 and 52 weeks) smoking reduction 
- 
Nicotine craving, especially in the early phase of smoking cessation (4 weeks) and at week 12 
relative to baseline 
- 
Change of body weight at 4, 8, 24 and 52 weeks 
- 
Glucose homeostasis at 12, 24 and 52 weeks 
- 
Resting Energy Expenditure (see Substudy energy Appendix 4) 
- 
Functional magnetic resonance imaging (fMRI) brain activity (see Substudy fMRI Appendix 5) 
4.4 Safety Objectives 
As dulaglutide is already in use as antidiabetic treatment, safety objectives regarding an investigational 
treatment do not apply. However the study assesses tolerability of dulaglutide in smokers who are not 
explicitly diabetic. 
 
5. STUDY OUTCOMES  
5.1 Primary Outcome 
Point prevalence abstinence rate at week 12 of dulaglutide treatment combined with standard therapy 
versus standard therapy alone, confirmed with end-expiratory exhaled carbon monoxide (CO) 
measurements of 10 ppm or less. 
Point prevalence abstinence is assessed at week 12 (within a ± 7days time window) and defined as: 
- 
Self-reported 7-days nicotine abstinence and   
- 
End-expiratory exhaled carbon monoxide (CO) measurement of 10 ppm or less  
5.2 Secondary Outcomes 
Main secondary outcome: Change of body weight in kg (and BMI [kg/m²]) at week 12 relative to baseline.  
Further outcomes:  
- 
Point prevalence abstinence at week 24 and 52 (self-reported 7 days abstinence), biochemically 
validated by end-expiratory exhaled CO (10 ppm or less) 
- 
Prolonged abstinence at week 24 and 52, defined by the condition that the patient was already 
previously abstinent (i.e. at week 12 for prolonged abstinence at week 24 and at week 12 and 24 for 
prolonged abstinence at week 52) 
- 
Smoking reduction defined as reduction of end-expiratory exhaled CO more than 50% at week 12, 
24 and 52 compared to baseline 
- 
Craving at week 4 and 12 relative to baseline assessed by the German version of the 
“Questionnaire on Smoking urges” (QSU-G) and a visual analogue scale (VAS) 
- 
Change of body weight in kg (and BMI [kg/m²]) at week 4, 8, 24 and 52 relative to baseline 
- 
Change in haemoglobin A1c (HbA1c) in percent at week 12, 24 and 52 relative to baseline 
5.3 Safety Outcomes 
During the study period possible adverse events are assessed on each visit.  
6. STUDY DESIGN  
6.1 General study design and justification of design  
This is a placebo-controlled, double-blind, parallel group, superiority, single-center randomized trial. 
- 
The estimated sample size is 256 adult smokers. 
- 
Participants are randomly allocated (1:1 ratio) to treatment with dulaglutide or placebo. 
- 
The 12-week treatment phase with dulaglutide or placebo is followed by a 40-week non-treatment 

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phase. 
- 
Participants, health-care providers and data collectors are blinded except unblinded study staff 
doing the injection of the trial drug (see below).  
- 
The primary outcome is measured after 12 weeks of treatment with dulagultide 1.5 mg weekly or 
placebo.  
- 
The experimental drug is given on top of standard of care, which include behaviour counselling and 
pharmacological treatment with varenicline. 
This is a proof of concept study evaluating GLP-1 analogues as a novel treatment option for smoking 
cessation. It focuses on mechanistic properties of this new potential indication, why the primary outcome is 
assessed at the end of the treatment phase of 12 weeks, when effects are likely to be visible. In case of a 
positive result a larger multicentre trial addressing the clinically more relevant question of long-term 
abstinence under GLP-1 analogues will be designed. 
According to national guidelines (“Nationales Rauchstopp-Programm”)49, a pharmacological treatment with 
varenicline, NRT or bupropion is recommended in smokers with moderate to severe nicotine dependency. 
As varenicline has been shown to be the most efficient pharmacological treatment5, this drug has been 
chosen as standard of care for this trial. Even though there is some randomized trial evidence suggesting 
benefit by adding NRT to varenicline46, this combination has not been adopted in current national guidelines 
and is not reimbursed by health insurers in Switzerland. Moreover, NRT lacks any of the potential additional 
benefits on body weight changes. 
6.2 Methods of minimising bias  
6.2.1 Randomisation  
After successful screening, participants are assigned to a sequentially numbered study ID. By activating the 
study ID in the electronic data capture system (secuTrial®), participants are randomized (1:1 ratio, simple 
randomization) to be given dulaglutide and placebo according to a computer generated randomisation list 
produced by the CTU Basel. 
6.2.2 Blinding procedures  
Participants, health-care providers and data collectors are blinded to treatment allocation. As injection 
devices of dulaglutide and placebo are not identical, there is unblinded study staff doing the injections. The 
unblinded study staff is otherwise not involved in the trial. During the trial drug injection, participants wear a 
blindfold and are not able to see the injection side or the injection device. This process is conducted and 
documented according to the respective SOP (trial drug application by an unblinded person) of the CTU 
Basel. 
6.2.3 Unblinding Procedures (Code break)  
In emergency situations, e.g. adverse events, and up to the decision of the investigator if medically 
important, it is allowed to break the blind of the participant and to reveal the codes in the sealed data 
system.  
7. STUDY POPULATION  
7.1 Eligibility criteria  
Inclusion criteria: 
- 
Age 18 to 75 years 
- 
Daily smokers who are willing to quit and exhibit one of the following criteria: 
 
≥10 cigarettes per day or  
 
At least moderate nicotine dependence defined by a Fagerstroem Score of ≥5 points or 
 
Tobacco associated disease 
- 
Treatment with varenicline (Champix®) 
Exclusion criteria: 
- 
Pregnancy (incl. wish to become pregnant within next 3 months) or breast feeding 
- 
Pre-existing treatment with GLP-1 agonists  
- 
History of pancreatitis 

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- 
Severe renal insufficiency (estimated glomerular filtration rate <30 ml/min/1,73 m2) 
- 
Instable psychiatric conditions  
- 
Anorexia nervosa 
 
Diabetes mellitus is not an exclusion criterion. Included patients with diabetes are treated by their private 
doctors; during the study period all kinds of anti-diabetic drugs can be used except GLP-1 analogues.  
7.2 Recruitment and screening  
At the Medical Outpatient Department of the University Hospital Basel a standardized smoking cessational 
service (SCS) was established in 2012. Under the lead of a cardiologist (TB) and a general internist (AM) 
advice and treatment is offered to all patients willing to quit smoking. Treatment consists of the combination 
of individual advice, behavioural support and pharmacotherapy according to current national guidelines for 
smoking cessation (Nationales Rauchstopp-Programm, www.frei-von-tabak.ch)49.  
The investigators will recruit potential participants primarily in this SCS. In 2016 four new smokers willing to 
quit were seen in the SCS per week. According to internal experience around 80% would meet eligibility 
criteria of this trial. We assume that 50% of currently treated patients in the SCS would be willing to 
participate (thus, we plan to recruit approximately 2 patients per week and 100 per year).  
As the SCS is still expanding and there is capacity to see more patients, potential candidates are also 
searched 
by 
advertisements 
on 
the 
homepage 
of 
the 
University 
of 
Basel 
https://markt.unibas.ch/inserate/kategorie/job-angebot-studien, on the facebook website of the University 
Hospital of Basel https://www.facebook.com/unispitalbasel/ and by announcement in different print journals. 
Interested participants contact the study investigators by email or telephone and will subsequently receive 
the ICF via mail or e-mail. Willing to participate, they contact the investigators and an appointment in the 
SCS is arranged.  
The screening requirements include a clinical evaluation with assessment of the Fagerstroem Score. In 
patients with a history of renal insufficiency a basal determination of creatinine is performed prior to 
inclusion.  
All study visits will be conducted at the study centre of the University Hospital of Basel (Ambulantes 
Studienzentrum), which is located within the hospital area and close to the SCS.   
The costs for the medical and psychosocial care (behavioural counselling) provided by the smoking 
cessational service is covered by the patient’s health insurance. The trial medication is offered from the 
study team for free. Participants completing the study according to protocol will receive CHF 150.- at the 
last visit. They receive an additional CHF 50.- compensation if both follow-up visits (after 6 and 12 months) 
are completed. 
 
7.3 Assignment to study groups  
Participants are assigned to a sequentially numbered study ID. By activating the study ID in the electronic 
data capture system (secuTrial®), participants are assigned to a treatment arm (dulaglutide and placebo) 
according to a computer generated randomization list produced by the CTU Basel. Investigators and 
involved study staff are informed by email if a new participant is enrolled. However only members of the 
unblinded study staff have access to the study group assignment of enrolled participants. 
7.4 Criteria for withdrawal / discontinuation of participants  
Participants can at any time and without reasons withdraw their informed consent to the study. 
8. STUDY INTERVENTION  
8.1 Identity of Investigational Products (treatment / medical device)  
8.1.1 Experimental Intervention (treatment / medical device) 
 
Dulaglutide  injection 0.75 mg in 0.5 ml via Pen (only first injection) 
Dulaglutide, injection 1.5 mg in 0.5 ml, via Pen (second to twelfth injection) 

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8.1.2 Control Intervention (standard/routine/comparator treatment / medical device)  
0.5 ml normal saline (0.9% sodium chloride [0.9% NaCl]), injection via syringe. 
8.1.3 Packaging, Labelling and Supply (re-supply)  
Prior to the initiation of the study the drugs are labelled by an unblinded study person (CTU Basel). 
8.1.4 Storage Conditions  
Investigational products are kept in a secure, limited access storage area under the recommended storage 
conditions. 
8.2 Administration of experimental and control interventions  
The study drug (experimental or control) is injected s.c. once weekly by unblinded study staff at the study 
centre of the University Hospital Basel.  
8.2.1 Experimental Intervention  
Dulaglutide weekly s.c. injection of 0.75 mg/0.5 mL (first injection) and 1.5 mg/0.5 mL (second to twelfth 
injection) in the abdomen or thigh (total treatment duration: 12 weeks).  
8.2.2 Control Intervention 
Placebo weekly s.c. injection of 0.5 mL in the abdomen or thigh (total treatment duration: 12 weeks).  
8.3 Dose / Device modifications  
During the study period all participants are on a concomitant treatment with varenicline (=SOC). As 
varenicline may also produce gastrointestinal (GI) side effects (nausea [≥1/10], other GI symptoms [≥1/100, 
<1/10]), all patients in the smoking cessational service are generally instructed to ingest varenicline 
together with a meal and to use a PPI if needed – in order to obtain an optimal tolerability.  
If a study participant complains gastrointestinal side effects at any time, investigators proceed as follows: 
1. Remind participant to ingest varenicline together with a meal 
2. Prescription of a proton pump inhibitor (PPI) 
3. Dose reduction of the study drug 
4. Dose reduction of varenicline 
8.3.1 Dose reduction of the study drug 
Given the transient nature of gastrointestinal side effects of dulaglutide, the standard dose of 1,5 mg is 
given after the first injection – whenever possible. In case of persisting gastrointestinal side effects, the 
investigator may decide at any time whether treatment dosage should be reduced to 0.75 mg/0.5 ml 
dulaglutide (or 0.5 ml of 0.9% NaCl). The unblinded study person is instructed to conduct a dose reduction 
if possible (=patient on verum) while the involved study team and the patient remain blinded. If intolerable 
side effects persist after dose reduction, investigators decide whether the dose of varenicline should be 
reduced. If side effects resolve, investigators decide whether the dose should again be increased during 
the remaining study period.  
8.3.2 Dose reduction of varenicline 
If gastrointestinal symptoms persist after reduction of the study drug, investigators may consider at any 
time a dose reduction of varenicline (standard dose: 1 mg twice daily, reduction to 0.5 mg twice daily or 0,5 
mg once daily). If side effects resolve, investigators decide whether the varenicline dose should again be 
increased during the remaining study period. If intolerable side effects persist after dose reduction of the 
study drug and varenicline the participant will not continue with the allocated intervention but remains under 
follow-up. 
8.4 Compliance with study intervention  
Participants not presenting to the planned study visits are contacted by phone and a new appointment is 
arranged. The study drug is usually injected once weekly on a fixed weekday, but a time span of ±3 days is 
allowed (=one injection/week, independent of the day). If participants do not present within this time span, 

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the investigator decides if the visit is postponed by maximally one week or skipped. On reciprocal 
agreement smoking status incl. CO measurement and urinary cotinine can be assessed at a home visit.  
8.5 Data Collection and Follow-up for withdrawn participants  
For withdrawn patients an End of Study Visit is arranged in order to complete clinical data and assess 
possible AEs. Already collected data and biological material of withdrawn participants will be analysed and 
afterwards made anonymous. Patients have the right to let delete their data after study exclusion. If 
participants agree, they are contacted at week 12, 24 and 52 and smoking status is assessed. Whenever 
possible, self-reported smoking abstinence is biochemically validated by CO-measurement and urinary 
cotinine measurement. These tests can be assessed during a home visit.  
8.6 Trial specific preventive measures 
During the whole study period, use of other GLP-1 analogues (e.g. liraglutide) is not allowed. 
8.7 Concomitant Interventions (treatments)  
Whenever possible, any additional treatment during study period should be avoided. If concomitant 
medication is strongly recommended, the investigator decides whether the study can be continued. During 
the whole study period NRT are not allowed. 
8.8 Study Drug / Medical Device Accountability  
From shipment to the site until return or disposal study drugs are accurately and adequately monitored. 
Dates of receipt/expiry/use/return are recorded.  
8.9 Return or Destruction of Study Drug / Medical Device  
During the whole study period and at the end of the study the product is kept by the Sponsor. 
9. STUDY ASSESSMENTS  
See Study Schedule 
9.1 Assessment of primary outcome  
The primary outcome point-prevalence abstinence rate for week 12 is assessed by questionnaire (self-
reported 7-days abstinence) and end-expiratory exhaled carbon monoxide measurements of 10 ppm or 
less at visit 12. The patient is considered smoker if one of these two tests is positive. 
9.2 Assessment of main secondary outcome 
Body weight in kg (and BMI [kg/m²]) is assessed at baseline and week 12 
9.2.1 Assessment of further secondary outcomes:  
9.2.2 Abstinence rate during follow-up phase 
Abstinence rate is assessed at week 24 and 52 by: 
 
Questionnaire (7-days abstinence) 
 
End-expiratory exhaled carbon monoxide measurements of 10 ppm or less   
 
Qualitative testing for urinary cotinine (negative result=abstinent, positive result=smoker) 
Abstinence is defined as follows: 
 
Point prevalence abstinence: self-reported 7-days abstinence biochemically confirmed by a CO 
measurement of 10 ppm or less 
 
Prolonged abstinence:  
 
-> at week 24: biochemically confirmed self-reported abstinence at week 12 and 24  
 
-> at week 52: biochemically confirmed self-reported abstinence at week 12, 24 and 52 

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9.2.3 Smoking reduction 
Smoking reduction is assessed at week 12, 24, 52 by: 
 
Questionnaire (number of cigarettes per day during the last week) 
 
End-expiratory exhaled carbon monoxide measurements at week 12, 24 and 52 compared to 
baseline (a reduction of more than 50% is required) 
9.2.4 Craving 
Craving is assessed: 
 
at baseline and week 4 and 12 by the german version of the “Questionnaire of smoking urge” (QSU-
G)50 (see Appendix 2) 
 
at baseline and week 4 and 12 by a visual analogue scale (VAS), ranging from 0-10 points (no to 
maximal craving), compromising the last 24 hours (see Appendix 3) 
9.2.5 Body weight 
 
Body weight in kg (and BMI [kg/m²]) is assessed at week 4, 8, 24 and 52 
9.2.6 Glucose homeostasis 
 
Glucose homeostasis is assessed at baseline, week 12, 24 and 52 by measurement of HbA1c  
9.2.7 Further explorative outcome measures 
 
Abstinence assessed by urinary cotinine (qualitative testing) at week 12, 24, 52 
 
Smoking status and habits incl. end-expiratory exhaled carbon monoxide on every visit 
 
Smoking Cessation: Motivation and confidence assessed by a self-constructed questionnaire of the 
SCS at week 0, 12, 24, 52  
 
Craving assessed by VAS (range 0-10) on every visit 
 
AOBPM at baseline, week 4, 8 and 12 
 
Alcohol consumption and other substance abuse assessed by a self-constructed questionnaire at 
week 0,12, 24, 52 
9.2.8 Assessment of safety outcomes 
On all study visits while participants receive a dose of dulaglutide/placebo, tolerability of the drug and 
symptoms (abdominal pain, nausea, vomitus, diarrhoea, local irritation or pain, allergic reaction) are 
assessed.  
9.2.9 Assessments in participants who prematurely stop the study 
Withdrawn patients will be asked to complete the following assessments at the end of study (End of Study 
Visit): 
Smoking status incl. biochemical validation 
Smoking urge (VAS) 
Alcohol and substance abuse by questionnaire 
Vital signs (incl. weight and AOBPM) 
Blood withdrawal for routine (HbA1c) and specific laboratory measurements 
9.3 Procedures at each visit 
9.3.1 Screening phase:  
The following tests/actions are performed within 8 weeks before or on Visit 0 (see source doc):  
Information about the study 
Fagerstroem Score 
Eligibility Criteria 
Blood withdrawal (creatinine) if history of renal insufficiency present 
9.3.2 Visit 0, Inclusion 
Informed Consent 
Demographics 
Medical history questionnaire 

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Blood pressure, heart rate (AOBPM) 
Weight, Height, BMI 
CO-measurement  
Questionnaire for smoking urge (QSU-G) 
VAS smoking urge during the last 24 hours 
Blood withdrawal 
Urinary analysis 
Pregnancy test in premenopausal females 
Randomization 
Scheduling of all other study visits  
The first dose of trial medication is injected by an unblinded study person 
The medication with varenicline is started the same as visit 0 
9.3.3 Treatment phase, visits 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 
- 
The weekly dose of the trial medication is injected 
- 
Tolerability of the drug, adverse events and new medications are assessed 
- 
Dose of the trial drug and varenicline are documented 
- 
Assessment of smoking status by questionnaire and CO measurement 
- 
Assessment of smoking urge by VAS 
Additionally: 
- 
Body weight on visits 4,8,12 
- 
AOBPM on visits 4,8,12 
- 
Questionnaire for smoking urge on visits 4,12 
- 
Blood withdrawal on visit 12 
- 
Urinary analysis on visit 12  
9.3.4 Follow-up phase, visit 24 (week 24) and Visit 52 (week 52) 
- 
Assessment of adverse events 
- 
Assessment of smoking status 
- 
Assessment of smoking urge by VAS  
- 
Co-measurement 
- 
AOBPM 
- 
Weight 
- 
Blood withdrawal 
- 
Urinary analysis 
 9.3.5 End of study visit for withdrawn participant 
- 
Assessment of adverse events 
- 
Assessment of smoking status 
- 
Assessment of smoking urge by VAS  
- 
Co-measurement 
- 
AOBPM 
- 
Weight 
- 
Blood withdrawal 
- 
Urinary analysis 
9.3.6 Visits within the SCS 
The program of the SCS generally includes 4 follow-up visits (e.g. week 2,4,8,12), or more on an individual 
basis if needed. Treatment consists of a combination of individual advice and behavioural support.  
10. SAFETY  
During the entire duration of the study, all adverse events (AE) and all serious adverse events (SAEs) are 
collected, fully investigated and documented in source documents and case report forms (CRF).  

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10.1 Definition and assessment of (serious) adverse events and other safety related events 
An Adverse Event (AE) is any untoward medical occurrence in a patient or a clinical investigation 
participant administered a pharmaceutical product and which does not necessarily have a causal 
relationship with the study procedure. An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) product. 
ICH 
E6 1.2  
A Serious Adverse Event (SAE) is classified as any untoward medical occurrence that: 
 
results in death, 
 
is life-threatening, 
 
requires in-patient hospitalization or prolongation of existing hospitalisation, 
 
results in persistent or significant disability/incapacity, or 
 
is a congenital anomaly/birth defect. 
Assessment of Causality 
Both Investigator and Sponsor-investigator make a causality assessment of the event to the study drug, 
based on the criteria listed in the ICH E2A guidelines: 
 
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 fulfil the above 
conditions 
Not related 
Causal relationship can be ruled out 
*Improvement after dechallenge only taken into consideration, if applicable to reaction 
 
Unexpected Adverse Drug Reaction 
An “unexpected” adverse drug reaction is an adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (e.g. Investigator’s Brochure for drugs that are not yet 
approved and Product Information for approved drugs, respectively). ICH E2A  
 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
The Sponsor-Investigator evaluates any SAE that has been reported regarding seriousness, causality and 
expectedness. If the event is related to the investigational product and is both serious and unexpected, it is 
classified as a SUSAR.  
 
Assessment of Severity 
For this study the severity grading scale “Common Terminology Criteria for Adverse Events CTCAE 
Version 4.0” is used.  
10.2 Reporting of serious adverse events (SAE) and other safety related events  
All SAEs are reported immediately and within a maximum of 24 hours to the Sponsor-Investigator of the 
study. The Sponsor-Investigator will re-evaluate the SAE and return the form to the site. 
SAEs resulting in death are reported to the local Ethics Committee (via local Investigator) within 7 days. 
 
Reporting of SUSARs 
SUSAR’s are reported to the local Ethics Committee and to Swissmedic (via Sponsor-Investigator) within 7 
days, if the event is fatal, or within 15 days (all other events). 
 

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Reporting of Safety Signals 
All suspected new risks and relevant new aspects of known adverse reactions that require safety-related 
measures, are reported to the Sponsor-Investigator within 24 hours. The Sponsor-Investigator reports the 
safety signals within 7 days to the local Ethics Committee and to Swissmedic. 
Reporting and Handling of Pregnancies 
Participants have to be willing to use contraceptive measures adequate to prevent becoming pregnant. 
Adequate contraceptive measures include hormonal methods used (e.g., oral contraceptive pills, 
contraceptive patch, or contraceptive vaginal ring), double barrier methods (e.g. diaphragm used together 
with contraceptive foam or jelly, and condom used combined with contraceptive foam or jelly), intrauterine 
methods (IUD) and sterilization (e.g., tubal ligation or a monogamous relationship with a vasectomized 
partner).  
Pregnant participants are immediately withdrawn from the clinical study. Any pregnancy during the 
treatment phase of the study and within 20 days after discontinuation of study medication will be reported to 
the Sponsor-Investigator within 24 hours. The course and outcome of the pregnancy is followed up 
carefully, and any abnormal outcome regarding the mother or the child is documented and reported. 
 
Periodic reporting of safety 
An annual safety report is submitted once a year to the local Ethics Committee via local Investigator and to 
Swissmedic. 
 
10.3 Follow up of (Serious) Adverse Events 
Following a comprehensive baseline evaluation, each subject’s safety will be monitored with periodic 
recording and evaluation of all treatment-emergent AEs. 
Once evidence of a clinical abnormality is noticed, the condition will be treated while trying to determine its 
cause. The subject will then be followed until the condition resolves or becomes chronic or stable. Patients 
will be instructed about possible acute AEs. If adverse events are observed, the patients are promptly 
treated according to standard of care. 
11. STATISTICAL METHODS  
11.1 Hypothesis 
The Null Hypothesis (H0 ) is as follows: point prevalence abstinence rate in smokers treated with 
dulaglutide in addition to standard of care (varenicline and behavioural counselling) for 12 weeks, is not 
different from point prevalence abstinence rate when treated with placebo in addition to standard of care. 
H0 will be rejected when point prevalence abstinence rate between dulaglutide in addition to standard of 
care and placebo in addition to standard of care is significantly different. 
For hypothesis testing, an alpha error threshold of 5% will be used. 
11.2 Determination of Sample Size 
Sample size was estimated using a simulation approach. Each sample size, ni=1,...,201 = 100, ..., 500, was 
evaluated by simulating R = 999 times ni outcomes as differences in point prevalence abstinence rates in %. 
The difference between point prevalence abstinence rates of intervention and control arm follows, 
presumably, a χ2 -distribution. To assess the significance between the two point prevalence abstinence 
rates, a Pearson’s χ2 -test was applied. 
It is assumed that efficacy (point prevalence abstinence rates) for the control group is 33% and the 
increase of effect size under experimental treatment is 18%, i.e. point prevalence abstinence rate increases 
from 33% to 51%. 
For this study, 256 patients should be recruited for both arms. This sample size allows in at least 80% of 
999 hypothetical repetitions of the study to show a difference in point prevalence abstinence rates between 
the two study arms at a significance level, α, of 5%. 

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11.3 Planned Analyses  
11.3.1 Datasets to be analysed 
The full analysis dataset (FAS) consists of all patients who are randomised. Following ITT 
recommendations, they are analysed according to their group of randomisation. 
The per protocol dataset (PP) consists of patients in the FAS data set without any major protocol deviations. 
Major protocol deviations occur if patients receive less than 80% of the trial medication, i.e. less than 10 of 
12 possible doses. 
11.3.2 Primary Analysis 
Primary analysis will assess whether point prevalence abstinence rates between experimental and control 
arms are significantly different. Since the difference follows a ҳ2 distribution, a Pearson’s ҳ2_test will be 
applied.  
11.3.3 Secondary Analyses 
Difference of change of body weight (kg) between the 2 arms will be assessed by ANCOVA. Body weight in 
kg at week 4, 8, 12, 24, and 52 will be the outcome variable, baseline weight and treatment arm both 
explanatory variables. 
Difference of change of BMI (kg/m2) between the 2 arms will be assessed by ANCOVA. BMI at week 4, 8, 
12, 24, and 52 will be the outcome variable, baseline BMI and treatment arm both explanatory variables. 
Differences between arms regarding point prevalence abstinence rates at week 24 and 52 will be 
calculated like the primary analysis. 
Differences between arms regarding prolonged abstinence at week 24 and 52 will be calculated like the 
primary analysis, except that only patients are considered being abstinent who were so at previous 
assessments (week 12 for abstinence at week 24 and weeks 12+24 for abstinence at week 52). 
Smoking reduction at week 12, 24, and 52 relative to baseline will be analysed as a binomial outcome. 
Percentage of people who reduced smoking by at least 50% will be compared between arms. A Pearson’s 
χ2 -test will be applied to assess whether there are significant differences between arms. 
Differences of craving between the 2 arms assessed by QSU-G and VAS at week 4 and 12 relative to 
baseline will both be analysed by ANCOVA. Scores at week 4 or 12 will be the outcome variable, baseline 
BMI and treatment arm explanatory variables. 
Change of haemoglobin A1c (HbA1c) concentration at week 12, 24, and 52, relative to baseline will be 
analysed by ANCOVA. HbA1c at week 12, 24, and 52 will be the outcome variable, HbA1c at baseline and 
treatment arm explanatory variables. 
Time trends of means or percentages of all secondary endpoints will be plotted including standard 
deviations for means and 95%-CI for percentages. 
Sensitivity analysis for primary and secondary outcomes will be done using the PP dataset. 
For hypothesis testing an alpha error threshold of 5% will be chosen. 
11.4 Interim Analysis  
No interim analysis is planned. 
11.5 Safety Analysis 
The proportion of participants with an adverse or serious adverse event will be estimated by trial arm, and 
reported together with 95%-CIs. Safety analyses will be performed on the FAS. 
11.6 Deviation(s) from the original statistical plan 
If substantial deviations of the analysis as outlined in these sections are needed for whatever reason, the 
protocol will be amended. 
All deviations of the analysis from the protocol or from the detailed analysis plan will be listed and justified 
in a separate section of the final statistical report and described in the study publication. 
11.7 Handling of missing data and drop-outs 
Careful trial planning and conducting will minimise the occurrence of missing data as far as possible. 
Results will be summarised using all available data. Multiple attempts will be made to obtain missing data. 
If participants are not able to present at the study center, the CO measurement and urinary test (cotinine) 

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can be obtained at a home visit.  
Considerable efforts will be made to minimize attrition due to technical or logistical reasons and minimize 
outcome measurements missing completely at random. We assume that the remaining missing 
measurements for the primary outcome are missing for reasons closely linked to the smoking status, and 
we assume that such patients are smokers. We will describe a detailed algorithm for handling of missing 
data in the statistical analysis plan, including sensitivity analyses addressing this issue.  
This includes that for patients with missing values at-random, missing values at random will be imputed by 
linear interpolation of the preceding and subsequent measure, using a numeric time scale. 
For patients with missing values with informative character, the method of inverse probability of censoring 
weights will be applied.  
Criteria to decide whether missing values are at random or informative, will be described in the statistical 
analysis plan. 
 
 
12. QUALITY ASSURANCE AND CONTROL 
12.1 Data handling and record keeping / archiving  
 
12.1.1 Case Report Forms  
Study data will be recorded in Case Report Forms (CRF) in an encrypted fashion, i.e. by their individual 
study participant number.  
 
12.1.2 Specification of source documents  
- Written informed consent forms  
- Demographic data of the patients  
- Study number  
- Visit dates  
- Results of laboratory analysis 
 
The source data will be stored in the department of Endocrinology, Diabetes and Metabolism, University 
Hospital Basel.  
 
12.1.3 Record keeping / archiving  
Records and documents pertaining the conduct of this study, including CRFs, consent forms, laboratory 
test results and clinical notes will be retained for 10 years.  
12.2 Data management  
12.2.1 Data Management System 
The clinical data will be collected in an electronic data capture (EDC) system, named secuTrial®. The EDC 
system runs on a server maintained by the IT-department of the University Hospital Basel. The electronic 
CRF (eCRF) is implemented (set-up and adjusted) by the data management group at the Clinical Trial Unit 
(CTU) at the University Hospital Basel.  
12.2.2 Data security, access and back-up  
The EDC system is accessible via a standard browser on a WWW-connected device. 
Password protection ensures that only authorized persons can enter the system to view, add or edit data 
according to their permissions. User administration and user training is performed by the CTU according to 
predefined processes. Back-up of secuTrial® study data is performed according to the processes of the IT-
department of the University Hospital Basel. 
12.2.3 Analysis and archiving  
The EDC will be locked after all data has been monitored and all raised queries have been resolved. Data 
is exported and transferred to the investigator by the CTU according to internally defined processes. Data 
will be archived by the investigator. 

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12.2.4 Electronic and central Data validation  
Data is entered into the eCRF and can be validated for completeness and discrepancies automatically. An 
audit trail system maintains a record of initial entries and changes (reasons for changes, time and date of 
changes, user identification of entry and changes). 
12.3 Monitoring  
The monitoring of the study is performed by the Clinical Trial Unit of the University Hospital Basel.  
12.4 Audits and Inspections  
Authorized representatives of the national or local authorities will be permitted to inspect or audit the 
facilities and records relevant to this study. 
12.5 Confidentiality, Data Protection  
All personal and medical information obtained for this study is confidential and disclosure to third parties 
other than those noted below is prohibited. Patients’ data will be identified by study and subject ID number.  
Confidentiality of the patients will be maintained by assigning patients a study number, keeping identifiers 
separate from the data and storing data in a locked file in the department of Endocrinology, Diabetes and 
Metabolism. The sponsor investigator, the principle investigator, co-investigators  and the study nurses will 
have access to the encryption list.  
Scientific reports generated from the study will not contain information that would identify the patients. After 
termination of the study records will be archived for ten years and then destroyed.  
Upon the participant’s permission, medical information may be given to his or her personal physician or 
other appropriate medical personnel responsible for her or his welfare. 
12.6 Storage of biological material and related health data  
Biological material, i.e. blood samples, will be handled according to good clinical practice and good 
laboratory practice. Samples will be collected in secure containers (Sarstedt Monovette®) and will be 
centrifuged to collect serum. Serum will be stored at – 80 C in a thermo-controlled ultra-deep freezer.  
Blood samples are stored for eventual future research aims (Biobank Departement Endokrinologie). 
Records and documents pertaining the conduct of this study, including CRFs, consent forms, laboratory 
test results and clinical notes will be retained for at least 10 years. 
13. PUBLICATION AND DISSEMINATION POLICY  
The results of this study shall be published in a peer-reviewed journal and presented at scientific 
conferences. No use of professional writers is intended. 
Criteria for authorship will be based on the rules of the International Committee of Medical Journal Editors 
and will include participation in the planning phase of the study, raising of funds, completion of assigned 
duties and promptness of response, number of patients recruited and completed into the trial and the level 
of involvement in data analysis and in the drafting of the manuscript. Individual contributions will be 
specified at the end of the text and upon submission of the manuscript, authors will declare that they 
participated in the trial and will have to revise forwarded versions and approve the final version within 5 
working days. Potential conflicts of interest will be listed and specified. 
The principal investigator decides whether abstracts are to be submitted to conferences, and how the 
results are distributed if more than one manuscript is to be drafted.  
14. FUNDING AND SUPPORT  
14.1 Funding  
This is an investigator-initiated trial. The study is supported by funds of the University of Basel and the 
Clinic for Endocrinology, University Hospital Basel. We are currently applying for further funding to cover 
the study costs (e.g. Swiss National Science Foundation, propatient Foundation, Bangerter-Rhyner 
Foundation).  

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14.2 Other Support  
The University Hospital Basel, will provide the location and infrastructure.  
This is collaborative work of the Department of Endocrinology and the Medical Outpatient Department of 
the University Hospital of Basel, where recently (2012) a smoking cessation service was set up. The 
service is under the lead of a cardiologist and a general internist. Treatment consists of a combination of 
individual advice, behavioural support and pharmacotherapy according to current guidelines for smoking 
cessation. In average four new patients are seen each week (220 new patients per year), such that enough 
patients are available for recruitment.  
By this interdisciplinary approach, which brings different disciplines of the University Hospital Basel 
together (endocrinology, internal medicine, cardiology, smoking cessation counsellors), the professional 
competence is assured. 
Moreover the project is integrated in the Clinical Trail Unit (CTU) of the University of Basel, where 
necessary working space and infrastructure are available. Onsite-management activities by study-nurses, 
the set-up of quality assurance and control measures are taken over by the CTU. 
15. INSURANCE  
The Insurance will be provided by the Sponsor.  
 
16. SIGNIFICANCE OF THE STUDY 
Cigarette smoking associated morbidity and mortality is preventable. Efficient smoking cessation strategies 
are therefore of high interest. In clinical practice many patients struggle with obstacles associated with 
smoking cessation such as nicotine withdrawal syndrome and weight gain.  
As outlined above GLP-1 analogues are thought to influence exactly these two main barriers and are 
therefore a very promising novel treatment option for patients, who wish to quit smoking.  
So far, there are no published or on-going human studies addressing this question. This project is of high 
relevance as it opens new therapeutic possibilities in a field of health priority with immediate benefits for 
patients by potentially preventing the disastrous consequences of nicotine abuse and obesity.  
17. REFERENCES  
1. 
Jha P, Ramasundarahettige C, Landsman V, et al. 21st-century hazards of smoking and benefits of 
cessation in the United States. N Engl J Med 2013; 368(4): 341-50. 
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Rigotti NA. Strategies to help a smoker who is struggling to quit. JAMA 2012; 308(15): 1573-80. 
3. 
Centers for Disease C, Prevention. Quitting smoking among adults--United States, 2001-2010. 
MMWR Morb Mortal Wkly Rep 2011; 60(44): 1513-9. 
4. 
Stead LF, Koilpillai P, Fanshawe TR, Lancaster T. Combined pharmacotherapy and behavioural 
interventions for smoking cessation. Cochrane Database Syst Rev 2016; 3: CD008286. 
5. 
Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: 
an overview and network meta-analysis. Cochrane Database Syst Rev 2013; (5): CD009329. 
6. 
Henningfield JE, Miyasato K, Jasinski DR. Abuse liability and pharmacodynamic characteristics of 
intravenous and inhaled nicotine. J Pharmacol Exp Ther 1985; 234(1): 1-12. 

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7. 
Siahpush M, Singh GK, Tibbits M, Pinard CA, Shaikh RA, Yaroch A. It is better to be a fat ex-
smoker than a thin smoker: findings from the 1997-2004 National Health Interview Survey-National 
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8. 
Chinn S, Jarvis D, Melotti R, et al. Smoking cessation, lung function, and weight gain: a follow-up 
study. Lancet 2005; 365(9471): 1629-35; discussion 00-1. 
9. 
Flegal KM, Troiano RP, Pamuk ER, Kuczmarski RJ, Campbell SM. The influence of smoking 
cessation on the prevalence of overweight in the United States. N Engl J Med 1995; 333(18): 1165-70. 
10. 
Aubin HJ, Farley A, Lycett D, Lahmek P, Aveyard P. Weight gain in smokers after quitting 
cigarettes: meta-analysis. BMJ 2012; 345: e4439. 
11. 
Parsons AC, Shraim M, Inglis J, Aveyard P, Hajek P. Interventions for preventing weight gain after 
smoking cessation. Cochrane Database Syst Rev 2009; (1): CD006219. 
12. 
Willi C, Bodenmann P, Ghali WA, Faris PD, Cornuz J. Active smoking and the risk of type 2 
diabetes: a systematic review and meta-analysis. JAMA 2007; 298(22): 2654-64. 
13. 
Duncan AE, Lessov-Schlaggar CN, Nelson EC, Pergadia ML, Madden PA, Heath AC. Body mass 
index and regular smoking in young adult women. Addict Behav 2010; 35(11): 983-8. 
14. 
Yeh HC, Duncan BB, Schmidt MI, Wang NY, Brancati FL. Smoking, smoking cessation, and risk for 
type 2 diabetes mellitus: a cohort study. Ann Intern Med 2010; 152(1): 10-7. 
15. 
Harris KK, Zopey M, Friedman TC. Metabolic effects of smoking cessation. Nat Rev Endocrinol 
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APPENDICES  
Appendix 1: Informed Consent Form, V2, 03.05.2017 
Appendix 2: QSU-G 
Appendix 3: VAS smoking urge 
Appendix 4: Substudy Energy 
Appendix 5: Substudy fMRI