The effectiveness, safety and cost-effectiveness of cytisine versus varenicline for smoking cessation in an Australian population: a study protocol for a randomized controlled non-inferiority trial.

BACKGROUND AND AIMS Smoking cessation medications are effective, but often underutilized because of costs and side effects. Cytisine is a plant-based smoking cessation medication with more than 50 years of use in central and eastern Europe. While cytisine has been found to be well-tolerated and more effective than nicotine replacement therapy, direct comparisons with varenicline have not been conducted. This study evaluates the effectiveness, safety and cost-effectiveness of cytisine compared with varenicline. DESIGN Two-arm, parallel group, randomized, non-inferiority trial, with allocation concealment and blinded outcome assessment. SETTING Australian population-based study. PARTICIPANTS Adult daily smokers (n = 1266) interested in quitting will be recruited through advertisements and Quitline telephone-based cessation support services. INTERVENTION AND COMPARATOR Eligible participants will be randomized (1 : 1 ratio) to receive either cytisine capsules (25-day supply) or varenicline tablets (12-week supply), prescribed in accordance with the manufacturer's recommended dosing regimen. The medication will be mailed to each participant's nominated residential address. All participants will also be offered standard Quitline behavioural support (up to six 10-12-minute sessions). MEASUREMENTS Assessments will be undertaken by telephone at baseline, 4 and 7 months post-randomization. Participants will also be contacted twice (2 and 4 weeks post-randomization) to ascertain adverse events, treatment adherence and smoking status. The primary outcome will be self-reported 6-month continuous abstinence from smoking, verified by carbon monoxide at 7-month follow-up. We will also evaluate the relative safety and cost-effectiveness of cytisine compared with varenicline. Secondary outcomes will include self-reported continuous and 7-day point prevalence abstinence and cigarette consumption at each follow-up interview. COMMENTS If cytisine is as effective as varenicline, its lower cost and natural plant-based composition may make it an acceptable and affordable smoking cessation medication that could save millions of lives world-wide.

[1]  Universities Australia Australian code for the responsible conduct of research , 2018 .

[2]  A. Ferrari,et al.  Global statistics on alcohol, tobacco and illicit drug use: 2017 status report , 2018, Addiction.

[3]  R. West,et al.  Predictors of retention in a randomised trial of smoking cessation in low-socioeconomic status Australian smokers. , 2017, Addictive behaviors.

[4]  S. Michie,et al.  New Pharmacological Agents to Aid Smoking Cessation and Tobacco Harm Reduction: What Has Been Investigated, and What Is in the Pipeline? , 2016, CNS Drugs.

[5]  N. Benowitz,et al.  Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial , 2016, The Lancet.

[6]  T. Lancaster,et al.  Nicotine receptor partial agonists for smoking cessation. , 2016, The Cochrane database of systematic reviews.

[7]  R. West,et al.  Health‐care interventions to promote and assist tobacco cessation: a review of efficacy, effectiveness and affordability for use in national guideline development , 2015, Addiction.

[8]  Hayden McRobbie,et al.  Cytisine versus nicotine for smoking cessation. , 2014, The New England journal of medicine.

[9]  N. Rigotti Cytisine--a tobacco treatment hiding in plain sight. , 2014, The New England journal of medicine.

[10]  M. Stevenson,et al.  What is the clinical effectiveness and cost-effectiveness of cytisine compared with varenicline for smoking cessation? A systematic review and economic evaluation. , 2014, Health technology assessment.

[11]  J. Prochaska,et al.  Cytisine, the world’s oldest smoking cessation aid , 2013, BMJ.

[12]  R. West,et al.  Cytisine and the failure to market and regulate for human health , 2013, Thorax.

[13]  R. Perera,et al.  Pharmacological interventions for smoking cessation: an overview and network meta-analysis. , 2013, The Cochrane database of systematic reviews.

[14]  L. Brose,et al.  Comparison of the effectiveness of varenicline and combination nicotine replacement therapy for smoking cessation in clinical practice. , 2013, Mayo Clinic proceedings.

[15]  H. McRobbie,et al.  Efficacy of cytisine in helping smokers quit: systematic review and meta-analysis , 2013, Thorax.

[16]  Robert West,et al.  Placebo-Controlled Trial of Cytisine for Smoking Cessation , 2012 .

[17]  R. West,et al.  A direct method and ICER tables for the estimation of the cost-effectiveness of smoking cessation interventions in general populations: application to a new cytisine trial and other examples. , 2012, Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco.

[18]  R. West,et al.  Placebo-controlled trial of cytisine for smoking cessation. , 2011, The New England journal of medicine.

[19]  N. Walker,et al.  Cytisine's potential to be used as a traditional healing method to help indigenous people stop smoking: a qualitative study with Māori. , 2011, Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco.

[20]  G. Bonsel,et al.  Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L) , 2011, Quality of Life Research.

[21]  Ian R White,et al.  Strategy for intention to treat analysis in randomised trials with missing outcome data , 2011, BMJ : British Medical Journal.

[22]  A Hyland,et al.  The reliability and predictive validity of the Heaviness of Smoking Index and its two components: findings from the International Tobacco Control Four Country study. , 2010, Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco.

[23]  S. Helgerson,et al.  Characteristics and abstinence outcomes among tobacco quitline enrollees using varenicline or nicotine replacement therapy. , 2010, Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco.

[24]  R. West,et al.  An uncontrolled trial of cytisine (Tabex) for smoking cessation , 2006, Tobacco Control.

[25]  W. Zatónski,et al.  Cytisine for the treatment of nicotine addiction: from a molecule to therapeutic efficacy. , 2006, Pharmacological reports : PR.

[26]  J. Etter Cytisine for smoking cessation: a literature review and a meta-analysis. , 2006, Archives of internal medicine.

[27]  J. Carlin,et al.  Financial stress, smoking cessation and relapse: results from a prospective study of an Australian national sample. , 2006, Addiction.

[28]  Robert West,et al.  Outcome criteria in smoking cessation trials: proposal for a common standard. , 2005, Addiction.

[29]  R. West,et al.  Evaluation of the mood and physical symptoms scale (MPSS) to assess cigarette withdrawal , 2004, Psychopharmacology.

[30]  R. Kessler,et al.  Screening for serious mental illness in the general population with the K6 screening scale: results from the WHO World Mental Health (WMH) survey initiative , 2003, Archives of general psychiatry.

[31]  W. Velicer,et al.  Biochemical verification of tobacco use and cessation. , 2002, Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco.

[32]  Kenneth F Schulz,et al.  For Personal Use. Only Reproduce with Permission from the Lancet Publishing Group. Trialists Rely on the Security of Unpredictability. in the Forcing Cosmetic Credibility Unequal Group Sizes in Randomised Trials: Guarding against Guessing , 2022 .

[33]  I. Merican Good clinical practice. , 2000, The Medical journal of Malaysia.

[34]  D. Kivlahan,et al.  The AUDIT alcohol consumption questions (AUDIT-C): an effective brief screening test for problem drinking. Ambulatory Care Quality Improvement Project (ACQUIP). Alcohol Use Disorders Identification Test. , 1998, Archives of internal medicine.

[35]  P. J. van der Maas,et al.  The health care costs of smoking. , 1997, The New England journal of medicine.

[36]  P. Lovibond,et al.  Manual for the Depression Anxiety Stress Scales. 2 , 1995 .