Study protocol for a non-inferiority trial of cytisine versus nicotine replacement therapy in people motivated to stop smoking

BMC Public Health Study protocol for a non-inferiority trial of cytisine versus nicotine replacement therapy in people motivated to stop smoking Natalie Walker 0 Colin Howe 0 Chris Bullen 0 Hayden McRobbie 2 Marewa Glover 1 Varsha Parag 0 Jonathan Williman 0 Reon Veale 5 Vili Nosa 4 Joanne Barnes 3 0 Clinical Trials Research Unit, School of Population Health, The University of Auckland , Private Bag 92019, Auckland 1142 , New Zealand 1 Centre for Tobacco Control Research, Social and Community Health, School of Population Health, The University of Auckland , Private Bag 92019, Auckland 1142 , New Zealand 2 UK Centre for Tobacco Control Studies, Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine and Dentistry, Queen Mary University of London , UK 3 School of Pharmacy, The University of Auckland , Private Bag 92019, Auckland 1142 , New Zealand 4 Pacific Health, School of Population Health, The University of Auckland , Private Bag 92019, Auckland 1142 , New Zealand 5 The Quit Group , PO Box 12605, Wellington , New Zealand Background: Smokers need effective support to maximise the chances of successful quit attempts. Current smoking cessation medications, such as nicotine replacement therapy (NRT), bupropion, nortriptyline or varenicline, have been shown to be effective in clinical trials but are underused by smokers attempting to quit due to adverse effects, contraindications, low acceptability and/or high cost. Cytisine is a low-cost, plant-based alkaloid that has been sold as a smoking cessation aid in Eastern Europe for 50 years. A systematic review of trial evidence suggests that cytisine has a positive impact on both short- and long-term abstinence rates compared to placebo. However, the quality of the evidence is poor and insufficient for licensing purposes in many Western countries. A large, wellconducted placebo-controlled trial (n = 740) of cytisine for smoking cessation has recently been published and confirms the findings of earlier studies, with 12-month continuous abstinence rates of 8.4% in the cytisine group compared to 2.4% in the placebo group (Relative risk = 3.4, 95% confidence intervals 1.7-7.1). No research has yet been undertaken to determine the effectiveness of cytisine relative to that of NRT. Methods/design: A single-blind, randomised controlled, non-inferiority trial has been designed to determine whether cytisine is at least as effective as NRT in assisting smokers to remain abstinent for at least one month. Participants (n = 1,310) will be recruited through the national telephone-based Quitline service in New Zealand and randomised to receive a standard 25-day course of cytisine tablets (Tabex) or usual care (eight weeks of NRT patch and/or gum or lozenge). Participants in both study arms will also receive a behavioural support programme comprising an average of three follow-up telephone calls delivered over an eight-week period by Quitline. The primary outcome is continuous abstinence from smoking at one month, defined as not smoking more than five cigarettes since quit date. Outcome data will also be collected at one week, two months and six months post-quit date. Discussion: Cytisine appears to be effective compared with placebo, and given its (current) relative low cost may be an acceptable smoking cessation treatment for smokers, particularly those in low- and middle-income countries. Cytisine's 'natural' product status may also increase its acceptability and use among certain groups of smokers, such as indigenous people, smokers in countries where the use of natural medicines is widespread (e.g. China, India), and in those people who do not want to use NRT or anti-depressants to help them quit smoking. However it is important to ascertain the effectiveness of cytisine compared with that of existing cessation treatments. Trial registration: Australian New Zealand Clinical Trials Registry (ACTRN12610000590066) - Background One in two smokers will die of a smoking-related disease, and half of those who die as a direct consequence of smoking will die in middle age [1]. Smoking (combining active and passive smoking) is responsible for approximately 18% of all deaths in New Zealand [2], an island nation (population 4.3 million) in the Southwest Pacific. Smoking contributes substantially to the life expectancy differential between Mori (indigenous New Zealanders who comprise 15% of the national population) and non-Mori [3]. Stopping smoking at any age reduces smoking related risks and increases life expectancy [4]. Effective treatments to aid smoking cessation have clear individual and public health benefits and provide the most efficient use of health care resources at a population level [5]. Use of pharmacological treatments such as nicotine replacement therapy (NRT), bupropion and nortriptyline approximately doubles a smokers chance of long-term abstinence [6,7]. Varenicline appears superior to bupropion and at least doubles the long-term chances of quitting compared to placebo [8]. The success of a smoking cessation product depends on its availability and acceptability to smokers as well as its efficacy. In 2009 in New Zealand, among smokers aged 15-64 years who had made a recent quit attempt, 22% had used NRT and 4.6% had used a prescription medicine (e.g. varenicline) to support their quit attempts [9]. Many smokers are misinformed about the risks of nicotine and are therefore hesitant to use NRT [10,11]. Bupropion and nortriptyline have a number of adverse effects and contraindications [7], which may contribute to their relatively poor uptake among smokers trying to quit. Given these issues new pharmacological treatments to help people quit smoking need to be identified - one such product is cytisine. Cytisine is an alkaloid found in plants such as the Golden Rain tree (Cytisus laburnum) [12] and the New Zealand Kowhai tree (Sophora tetraptera) [13]. Such plants are considered to be poisonous to humans, with the alkaloids they contain (including cytisine) considered to be the toxic components. However, an oral tablet form of cytisine, Tabex, has been marketed by Sopharma (Bulgaria) as a smoking cessation aid since the 1960s. When used at its therapeutic dose (1.5-9 mg of cytisine per day) trial data indicates that Tabex is well tolerated with few adverse effects, similar to those seen with NRT use [14-17]. Furthermore, West et al. (2011) report that a recent Periodic Safety Update provided to European authorities, did not identify any safety signals for cytisine (based on a sample of more than 7 million exposed persons) [17]. Cytisine overdose has been reported and is likened to nicotine intoxication, with symptoms including nausea, vomiting, pupil dilation, tachycardia, general weakness, clonic convulsions, and respiratory paralysis [18]. Cytisine is offpatent and currently relatively inexpensive compared with most other pharmacological cessation products on the market. Cytisine may also be attracti (...truncated)