Smoking Cessation Facilitated by Glucagon-like Peptide-1 (GLP-1) Analogues (SKIP)

Smoking Cessation Facilitated by Glucagon-like Peptide-1 (GLP-1) Analogues - a Randomized, Double-blind, Placebo-controlled Trial

Cigarette smoking is the leading preventable cause of premature death worldwide. However smoking is a very difficult addiction to break whereby 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 pharmacotherapeutic options for smoking cessation. Substudy "fMRI": This substudy is to evaluate effects of Dulaglutide treatment on functional neuronal changes in smokers who want to quit smoking. Substudy "Energy": This substudy is to investigate the effect of Dulaglutide (Trulicity®) on REE and further parameters associated with energy metabolism (bodycomposition, haemodynamic parameters and catecholamine action) in a subset of patients recruited for the main trial.

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 pharmacotherapeutic options for smoking cessation. Substudy "fMRI" (60 patients): Supposing that GLP-1 and analogues modulates nicotine induces reward system this substudy is to analyze if treatment with Dulaglutide (Trulicity®) attenuates craving and therefore functional brain activation. It is to evaluate effects of Dulaglutide treatment on functional neuronal changes in smokers who want to quit smoking. Substudy "Energy" (60 patients): The aim of the substudy "Energy" is to investigate the effect of Dulaglutide (Trulicity®) on REE and further parameters associated with energy metabolism (bodycomposition, haemodynamic parameters and catecholamine action) in a subset of patients recruited for the main trial.

0.5 ml normal saline (0.9% sodium chloride (NaCl)), injection s.c. via syringe once weekly for 12 weeks.

Point prevalence abstinence rate at week 12 of dulaglutide treatment and Standard of care (SOC) versus SOC alone, confirmed with end-expiratory exhaled carbon monoxide measurements of 10 ppm or less

Change in body weight in kg (and BMI [kg/m²]) relative to baseline at week 12 of dulaglutide treatment versus placebo.

Point prevalence abstinence rate at weeks 24 and 52 of dulaglutide treatment and SOC versus SOC alone, confirmed with end-expiratory exhaled carbon monoxide measurements of 10 ppm or less

Behavioural endpoint of the substudy fMRI. The VAS rating scale includes seven steps from no craving to high craving.

Behavioural endpoint of the substudy fMRI. During the N-back task, all subjects see series of letters with an interstimulus interval of 2 s. Each stimulus is presented for 1 s. During a baseline (0-back) condition, subjects are required to press the button with the right hand when the letter "X" appears. During 1-back and 2-back conditions, participants are instructed to press the button if the currently presented letter is the same as that presented 1 (1-back condition) or 2 trials beforehand (2-back condition). The three conditions will be presented in ten alternating 30 s blocks (2 × 1-back, 3 × 2-back and 5 × 0-back) matched for the number of target letters per block (i.e., 2 or 3), in a pseudo-random order.

Functional neuronal changes are assessed through the surrogate of blood oxygenated level dependent (BOLD) signal, an indirect measure of neural activity.

Change in structural plasticity of grey and white matter in regions parts of the reward pathway (i.e. anterior cingulate cortex, insula, striatum) and in subcortical regions. One T1 sequence and one DTI sequence will be performed to investigate changes in grey and white matter.

Kcal per 24 hours. It is assessed by indirect calorimetry measuring volume of oxygen uptake (VO2) and expelled volume of carbon dioxide (VO2) in ml/min and calculated by the Weir Equation REE = [3.9 * (VO2) + 1.1 (VCO2)] * 1.44. The respiratory quotient (RQ) is calculated by dividing VCO2 by VO2.

Body composition is assessed by bioelectrical impedance analysis. Measures are muscle and fat mass as a proportion (%) of total body weight.

Blood pressure (mmHg), heart rate (beats per minute), cardiac index (l/min/m2), and peripheral vascular resistance (Pa*[s/m3]) assessed by non-invasive thoracic bioimpedance (HOTMAN®)

Plasma catecholamine (epinephrine and norepinephrine) and neuropeptide Y (NPY)* levels measured in pg/ml. NPY is a 36 aminoacid peptide well known to potentiate the action of catecholamine postsynaptically through the Y1 receptor and inhibit presynaptically the catecholamine secretion through the Y2 receptor

Inclusion Criteria for the main study: 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®) Additional Inclusion Criteria for the "substudy fMRI": Only patients aged 18-50 years are eligible Additional Inclusion Criteria for the "substudy Energy": BMI of 18-30 kg/m2 Exclusion Criteria for the main study: 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 smaller than 30 ml/min/1.73 m2) Instable psychiatric conditions Anorexia nervosa Additional Exclusion Criteria for the "substudy fMRI": Medical conditions that affect brain function (e.g. stroke, epilepsy, space occupying lesions, multiple sclerosis, Parkinson's disease, dementia, transient ischemic attack), Current use of medications that alter brain function Current illicit drug abuse including marijuana (alcohol ≤ 1 drink per day allowed) Claustrophobia, cardiac pacemaker, electronic device or ferromagnetic metal foreign bodies