Tobacco smoking is a leading cause of preventable disease and death. Smoking rates are higher among disadvantaged Australians and facilitating smoking cessation in this group is a national health priority. A number of strategies can increase cessation success, but relatively few smokers use proven effective strategies on any given quit attempt. New strategies that have a greater population wide health benefit are needed, yet there are few effective evidence-based interventions.
Worldwide scant data exists on cytisine's efficacy compared to frontline marketed smoking cessation medications; at the exception of one RCT that demonstrated superiority with nicotine patch.
Given that no trials have compared cytisine to varenicline, the aim of this study is to conduct a world-first CONSORT-adherent, pragmatic, single-blind, noninferiority randomised controlled trial (RCT).
A/Prof Natalie Walker
University of Auckland
Dr Hayden McRobbie
Queen Mary University London
Dr Coral Gartner
University of Queensland
Prof Mohammad Siahpush
University of Nebraska Medical Center
Dr Dennis Petrie
University of Melbourne
A/Prof Christine Paul
University of Newcastle
Prof Robyn Richmond
University of New South Wales
A/Prof Stuart Ferguson
University of Tasmania
Prof Piotr Tutka
University of Rzeszow
Prof Christopher Doran
Central Queensland University
Dr Colin Mendelsohn
University of New South Wales
Prof Nicholas Zwar
University of New South Wales
Prof Robert West
University College London
Prof Wayne Hall
University of Queensland
Cytisine may offer an efficacious, affordable, cost-effective smoking cessation treatment. Two members of our study team (CI Walker and CI McRobbie) recently published a RCT of cytisine against NRT (NEJM) which showed cytisine is superior to standard nicotine patch (see below web link). Yet, cytisine has not been compared with the most effective pharmacotherapy – varenicline – an important comparison for health policy because cytisine is considerably cheaper than varenicline and the Pharmaceutical Benefits Scheme (PBS) spent $44 million in 2014 subsiding varenicline.
Our aim. Evaluate the cost-effectiveness of cytisine compared to varenicline to inform Australian and international health agencies.
This research is of high significance and international importance. Modelled evidence from a placebo-controlled trial and a recent (2014) UK systematic review (see below web link) suggests that health care systems globally could make substantial savings by offering cytisine instead of nicotine replacement products, bupropion and varenicline. However, a direct comparison between varenicline and cytisine was identified as a significant gap in the literature. Our proposed evaluation will determine if cytisine offers equivalent effectiveness to varenicline at much lower cost. This research will be the first of its kind worldwide, in terms of originality, significance, and potential to cost-effectively improve smoking cessation rates.
To conduct a CONSORT-adherent, rigorous, pragmatic, single-blind, non-inferiority RCT,
(1) smoking abstinence rates in two groups of 621 smokers (overall N = 1242) receiving either:
Group 1: cytisine (and standard Quitline behavioural support); or
Group 2: varenicline (and standard Quitline behavioural support);
(2) the cost-effectiveness of cytisine compared with varenicline.
We hypothesise that:
H1 (Effectiveness): cytisine will yield a 12-month continuous-abstinence rate that is at least as good as varenicline.
H2 (Cost-effectiveness): cytisine will be more cost-effective than varenicline.
Design. We will conduct a large-scale, CONSORT-adherent, single-blind, pragmatic non-inferiority randomised controlled trial (RCT) that compares abstinence rates in two groups of 621 smokers (overall N = 1242), receiving standard Quitline support with either:
(1) varenicline; or (2) cytisine.
Inclusion criteria. Current daily smoker; willing to quit using either varenicline or cytisine; willing to have medications supplied and delivered by mail; own a mobile phone; speak English; more than 18 years old.
Exclusion criteria. In accordance with consumer medicines information (CMI) contraindications include: pregnancy or planned pregnancy in the next six months; breastfeeding; and hypersensitivity to varenicline or to any of the excipients. Additional contraindications for cytisine include: arterial hypertension and advanced atherosclerosis.
Recruitment. State/territory Quitline staff will inform callers of a study “providing free support to help smokers quit”, and with callers permission pass on phone numbers of interested smokers to the researchers. All of the Quitline Co-ordinators nationally has followed this approach in our current RCT (APP1021862), and we will continue this successful arrangement for this new RCT.
Randomisation and allocation concealment. Participants will be randomised using a pre-determined, computer-generated list, with unequal block sizes of 12 and 16, stratified by referral source. This list will be securely held by the University of Sydney NHMRC Clinical Trials Centre.
Baseline and follow-up assessments. PSPs will complete baseline, three, six, and 12-month assessments, blind to intervention allocation (see Measures below) via computer assisted telephone interview (CATI).
Treatments.There are two conditions cytisine and varenicline, that will be equally matched in access to treatment, namely the medications will be free and will be sent by mail.
Varenicline treatment. A 12-week course of tablets will be mailed to participants. In accordance with the CMI statement, participants will be asked to choose one of two ways to use varenicline: (1) participants can set a predetermined quit date 1-2 weeks after the commencement of varenicline and stop smoking on that date; or (2) alternatively, participants can begin varenicline dosing and then quit smoking between days 8 and 35 of treatment. We will record during check-in calls which option participants had chosen. Dosage will be in accordance with the CMI statement for a 12-week period.
Cytisine treatment. A 25-day course of tablets will be mailed to participants who will be asked to reduce their smoking at their own pace for the first four days of treatment and ensure that they are not smoking by the fifth day (i.e. their quit date). Dosage regime will be in accordance with the manufacturer’s recommendation.
Primary outcome. The primary outcome will be biochemically-verified 12-month continuous abstinence at final follow-up. Continuous 12-month cessation will be defined as reporting having remained quit, for entire 12-months (taking into account an initial grace period of one-month), with the additional criterion of no slip-ups (not even a puff) in the last week, and return of a negative biochemical test. Only participants self-reporting continuous abstinence at 12-month follow-up will be biochemically verified.
Project to commence in 2016.
Cost-effective smoking cessation medications are needed and highly important. Currently subsidised smoking cessation medications on the PBS are costly. Since 2008 the Australian government has spent AUD$342 million on varenicline alone and AUD$44 million was spent in 2014. Policy makers need effective and lower-cost methods to reduce smoking. The proposed study is novel, and internationally relevant.
The expected outputs/outcomes include several significant public health gains and breakthroughs:
- First, if cytisine is at least as effective as varenicline (i.e. the non-inferiority hypothesis is met) we will conduct a cost-effectiveness analysis. This study would be the first of its kind worldwide to assess cytisine’s cost-effectiveness compared to varenicline.
- Second, if cytisine (as hypothesised) is at least as effective as varenicline, it will have substantial ramifications for future treatment approaches in Australia and internationally, as cytisine may be a cheaper, more cost-effective treatment than treatments currently on the PBS (varenicline, bupropion and NRT). This would produce huge potential health care system savings to health care systems and to consumers.
- Third, the results from the cost-effectiveness analyses may lead to a cheaper, more affordable and effective cessation treatments for smokers. It has the potential to inform policy decisions on a drug treatment that could annually save millions of lives worldwide, particularly in underdeveloped countries where smoking rates are rising and smoking cessation treatments are too expensive.
The results from this study are internationally important and further evidence on cytisine's effectiveness in smoking cessation is needed. The data (cost effectiveness and safety) from this trial is imperative and if cytisine presents as an affordable and cost-effective smoking cessation aid, it has great potential to reduce health care costs, improve smoking cessation rates and save millions of lives globally.