Protocol. This trial protocol has been provided by the authors to give readers additional information about their work.

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1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: West R, Zatonski W, Cedzynska M, et al. Placebo-controlled trial of cytisine for smoking cessation. N Engl J Med 2011;365:

2 TASC trial Final protocol, protocol amendments and outcome and statistical SOP Document Page Final study protocol V Changes from Protocol V2.4 to Protocol V SOP for smoking cessation outcome and statistical analysis 17-19

3 Tabex Smoking Cessation (TASC) trial: Study Protocol V3.0 Dated 23 October 2010 Chief Investigator Professor Witold Zatonski Cancer Centre and Institute of Oncology Cancer Epidemiology and Prevention Department 5, Roentgen Street Warsaw, Poland Tel: +48 (22) Fax: +48 (22) Co-investigators Professor Robert West (Principal Applicant on the funding award) Department of Epidemiology and Public Health University College London 2-16 Torrington Place London WC1E 6BT, UK Tel: Magda Cedzynska, MA Cancer Centre and Institute of Oncology Cancer Epidemiology and Prevention Department 5, Roentgen Street Warsaw, Poland John Stapleton (trial statistician), MSc Addiction Science Building Institute of Psychiatry Kings College London 4 Windsor Walk London SE5 8AF, UK j.stapleton@iop.kcl.ac.uk Paul Aveyard, PhD Department of Primary Care & General Practice University of Birmingham Birmingham B15 2TT, UK p.n.aveyard@bham.ac.uk Sponsor contact Ms Alison Evans Joint UCLH/UCL Biomedical Research and Development (R&D) Unit 1st Floor Maple House 149 Tottenham Court Road London W1T 7NF Tel: Ext: 5696 Fax: Postal Address:- Joint UCLH/UCL Biomedical Research and Development (R&D) Unit Ground Floor, Rosenheim Wing 25 Grafton Way London WC1E 5DB 2

4 Administrator at UCL Paul Phibbs Department of Epidemiology and Public Health University College London 2-16 Torrington Place London WC1E 6BT, UK Tel: Pharmaceutical company supplying medication Head Office 16, Iliensko Shose Str., 1220 Sofia Bulgaria Representative in Poland Marek Dembowski Warszawa, ul. Szyszkowa 58 Poland Tel: (+48) Fax: (+48) Trial identifier The effect of Tabex (cytisine) on success of attempts to stop smoking 1.1 Acronym and number TASC (Tabex Smoking Cessation) trial TASC001/ Summary Promoting smoking cessation is probably the single most important goal in reducing incidence of cardiovascular disease, cancer and chronic obstructive pulmonary disease in the medium term. There are several medications that can help smokers to stop permanently, and psychological support is also effective. A medication (Tabex) that has been licensed for use in Central and Eastern Europe for several decades and currently costs approximately one tenth of current stop smoking medications. The active ingredient is cytisine which is a nicotinic receptor partial agonist. Controlled trials and a recent uncontrolled trial strongly suggest that this medication is safe and effective. This medication could be of considerable benefit to smokers across the world and especially in low income countries but its effectiveness has not been evaluated using currently accepted criteria. The aim of this study is to evaluate the effectiveness of Tabex for smoking cessation using rigorous criteria that are currently required for licensing purposes in the European Union and other western countries. The proposed study is a double-blind, placebo-controlled randomised trial comparing the standard course of 25 days of treatment with Tabex with placebo. The dosing regimen is: 1 tablet (1.5mg) every 2 hours (6 per day) for 3 days, 1 tablet every 2.5 hours (5 per day) from days 4 to 12, 1 tablet every 3 hours (5 per day) from days 13 to 16, 1 tablet every 4 hours (3 per day) from days 17-20, and 1 tablet every 6 hours (2 tablets daily) from days 21 to 25. The total regimen involves 100 tablets. The designed quit date is up to 5 th day from the start of the course. The medication is licensed for use in Poland and the treatment in this trial will be within the terms of the licence. 3

5 The trial will take place in a smoking treatment centre in Warsaw, Poland that already has extensive experience with this medication. Three hundred-and-seventy smokers of at least 10 cigarettes per day aged 18 or over not contra-indicated for Tabex, not dependent on alcohol and not diagnosed with a psychiatric disorder will be randomly allocated to active medication and a further 370 to placebo. All participants will receive a standard behavioural support programme consisting of an initial pre-treatment session, one telephone contact and an end-of-treatment session scheduled to take place 4-5 weeks after the designated date for stopping smoking (30-37 days after the start of treatment). The primary outcome measure will be obtained at a follow up taking place months after the end of treatment session. It will consist of self report of smoking not more than 5 cigarettes between the end of treatment session and that follow up, verified at the 12-month follow up by an expired air carbon monoxide (CO) concentration of less than 10 ppm. Secondary outcome measures will include: 1) self-report of smoking not more than 5 cigarettes between end of treatment session and the 6-7 month follow-up verified by an expired air CO concentration of less than 10 ppm at the 6-month follow up; 2) self-report of smoking no cigarettes for the 28 days prior to the end-of treatment session verified by expired air CO concentration of less than 10 ppm; 3) nicotine withdrawal symptoms and urges to smoke measured by the Mood and Physical Symptoms Scale (MPSS) at the one-week telephone contact in smokers who report that they have been abstinent for at least one week. It is expected that the 12-month abstinence rates will be at least 6% higher in those receiving Tabex than those receiving placebo. This study has approximately 80% statistical power to detect a difference between conditions in which the placebo abstinence rate is 6% and the active abstinence rate is 12%. This trial will be carried out according to the Good Clinical Practice guidelines and within the regulations set out in the European Union Clinical Trials directive. The sponsor is University College London. The funding agency is the National Prevention Research Initiative (NPRI). Sopharma will provide the active and matching placebo tablets free of charge. 3. Background The health benefits of smoking cessation at any age are well established. Medications that aid cessation have a clear public health benefit. Nicotine replacement therapy and bupropion have been shown to increase the 12-month continuous abstinence rates of smokers making a quit attempt by 5-14% depending on the context [1, 2]. They represent highly cost-effective lifepreserving treatments [3] and have been licensed for use in this way by the medical regulatory authorities in many countries. Other medications have also been found to aid cessation, most notably nortriptyline [2]. A new medication, varenicline, has recently been granted a licence in the US and European Union (Pfizer) [4-10]. Another, rimonabant, has been tested in Phase III trials but has not at this stage been granted a licence [11]. Nicotine vaccines are undergoing Phase II clinical trials and show promise [12]. Behavioural support, whether it be face-to-face, by telephone or through the internet can improve the chances of success of quit attempts by an estimated 2-7% [13-16]. Research continues into ways of improving the effectiveness and reach of behavioural support, for example through promotion of physical activity [17] or social support [18]. The cost of smoking cessation treatments is an important issue. Publicly funded healthcare systems have a responsibility to try to provide the best value for money they can. More importantly from a global perspective, most healthcare systems and many smokers, even in richer countries, do not feel that they can afford the current forms of treatment. If a much cheaper form of treatment exists that is as effective as, say, NRT it is important to evaluate its effectiveness using rigorous criteria. One such medication is Tabex [19]. The active ingredient is cytisine. This drug has been licensed in Central and Eastern Europe for several decades. The cost for a full course of treatment in Poland is approximately the equivalent of 6. 4

6 Tabex has been subjected to controlled and uncontrolled clinical trials. However, it has not been subjected to the kind of rigorous evaluation that would enable it to receive a licence under current criteria in the European Union and most western countries. Such evidence as exists strongly suggests that it is safe and effective [19, 20]. For more information from the manufacturer see: Cytisine has been frequently used by basic pharmacologists to unravel the complex pharmacology of the various subtypes of the nicotinic acetylcholine receptor [21]. These studies have shown that both nicotine and cytisine bind strongly and preferentially to pre-synaptic α 4 β 2 receptors that mediate the release of dopamine in the shell of the nucleus accumbens. This action is thought to be an important neuronal mechanism underlying nicotine dependence. Phase I studies show that cytisine has effects that are somewhat similar to those of nicotine. Its toxicity is broadly similar though somewhat less. Clinical studies show that Tabex is well tolerated at the doses applied. Where side effects do occur, these include: changes in both taste and appetite, dryness in the mouth, headache, irritability, nausea, constipation, tachycardia, and mild elevation of the arterial pressure. As regards efficacy, in one study reported in the documentation supporting registration in Poland, 366 smokers with chronic bronchitis were given Tabex and compared with 239 patients treated with placebo [this and the other clinical studies are described in English in 19]. Patients were smokers having a serious intention to stop smoking. At 12 weeks after the quit date, 55% of patients receiving Tabex were reported abstinent compared with 34% on the placebo (p<.05). A double-blind trial was carried out on 314 smokers, 157 on Tabex and 157 on placebo. Four weeks after the course of treatment (4 weeks) 76% of the Tabex group were reported non-smokers compared with 30.6% in the placebo group (p<.001). Another double-blind placebo-controlled trial was carried out in the Federal Republic of Germany in which 1975 smokers were allocated to receive one of 14 drugs of whom 181 were treated with Tabex. After 3-months 38% of those on Tabex were reported abstinent which was higher than all the other drugs tested, though exact figures are not available. These and other studies in the registration documentation describe the experience of more than 1000 patients using Tabex. No serious adverse effects have been reported. Lack of long-term follow-up, inadequate definitions of abstinence and absence of biochemical verification are serious limitations of the existing studies. According to the labelling Tabex is contraindicated in arterial hypertension and advanced atherosclerosis although the basis for this is not clear. It is also noted that there is insufficient clinical experience with Tabex administration to patients with ischemic heart disease, cardiac impairment, cerebrovascular diseases, occlusive arterial diseases, hyperthyroidism, diabetes mellitus, renal and hepatic insufficiency. Therefore, the labelling states that use of the drug in these categories of patients should be performed only after the potential benefit has been weighed against the possible risks. On the basis of the experimental data obtained, Tabex is recommended not to be taken by pregnant women, due to the potential risk to the fetus. It is also stated that the drug should not be administered during breast feeding. In other groups Tabex is considered safe and does not affect driving ability and machine operation. No data are available on interactions between Tabex and other pharmaceuticals. Symptoms of nicotine intoxication are observed in Tabex overdose. The toxic effects are similar to those found with nicotine and include nausea, vomiting, pupil dilation, tachycardia, general weakness, clonic convulsions, and paralysis of respiration. There has recently been an open, uncontrolled study involving 436 smokers in Warsaw. They found a CO-verified 12-month continuous abstinence rate of 14% of all those prescribed the medication even though there was only minimal behavioural support (one session in most cases). This compares with approximately 4% that has been found in untreated smokers attempting to 5

7 stop in countries such as the US and UK and 15-20% in clinical trials of nicotine replacement therapy with intensive behaviour support [1] [22]. There may be many reasons for the high success rate in the Polish study other than treatment using Tabex, but the absolute percentage figure, together with clinical data used to register the product, give strong a priori grounds for believing that the drug is effective and possibly as effective as nicotine replacement therapy. 4. Trial objectives, design and statistics 4.1 Trial objectives The trial seeks to answer the question: Does taking the standard course of Tabex (cytisine) as licensed in Poland improve the success of attempts to stop smoking compared with placebo? A secondary objective is to answer the question: Does Tabex reduce nicotine withdrawal symptoms and urges to smoke compared with placebo in the first week of abstinence? 4.2 Trial design This is a double blind RCT with two arms: active drug and placebo. Assessment will be performed at baseline (approximately one week prior to the quit date), then 7-10 days and 4-5 weeks after the designated quit date (end of treatment session) and 6-7 months and months after the end of treatment. Table 1 shows the schedule of procedures and assessments. Recruitment is expected to start in January 2007 and continue for up to 12 months. 4.3 Trial medication The medication will be Tabex or a matching placebo. The pharmacologically active ingredient of Tabex is cytisine. It is derived from the plant Cytisus laborinum L. (Golden Rain) which is widespread in southern areas of Central Europe and Italy. It is an alkaloid with the formula: C 11 H 14 ON 2. The medication and placebo will be supplied, labelled for the trial, by Sopharma (Bulgaria) free of charge. The dosage will be as currently licensed in Poland: 1 tablet (1.5mg) every 2 hours (6 per day) for 3 days, 1 tablet every 2.5 hours (5 per day) from days 4 to 12, 1 tablet every 3 hours (5 per day) from days 13 to 16, 1 tablet every 4 hours (3 per day) from days 17-20, and 1 tablet every 6 hours (2 tablets daily) from days 21 to 25. The total regimen involves 100 tablets. Smokers reduce their smoking over the first 5 days of treatment so that they are not smoking at all by the fifth day which is the designated quit date. For the purposes of this trial smokers are retained in treatment and followed up even if they do not manage complete abstinence immediately. 4.4 Adjunctive treatment All participants will receive psychological counselling at the baseline visit. This will focus on 1) enhancement and maintenance of resolve to remain abstinent through support from the counsellor and engagement with other forms of social support, 2) preparation for and management of urges to smoke and difficult situations and 3) appropriate use of the medication. The counselling in the initial session will last approximately minutes. The counselling will be given by a doctor and a psychologist. Participants will also receive a session of telephone support from a psychologist or counsellor scheduled for the time of the designated quit date and one week after the quit date. They will receive further support from a doctor during a visit to the clinic 4-5 weeks after the designated quit date. There will be a telephone helpline available for participants to call if they need further assistance. 4.6 Allocation of participants to trial groups Randomisation into study conditions will be individually by computer generated random numbers. Each package of medication will have a label with a subject number. The random number 6

8 generation will assign each of these numbers to active or placebo treatment using block randomisation to ensure that there is a balance between active and placebo in every block of 50 numbers. The randomisation and labelling will be supervised by a Qualified Pharmacist in accordance with the European Union Clinical Trials Directive. All trial medication (ie for Days 1-25) will be dispensed to the participant at session 2. Accountability logs will be kept of all medication dispensed. The study team will possess a sealed envelope containing the random number codes. This will remain sealed until the last 12-month assessment has been performed, all data entered into the trial database and all data checks completed. The code will then be broken by the Data Monitoring and Ethics Committee (see below). The 12-month follow-up will be undertaken blind to the group assignment. In the event of emergency unblinding, for example in the event of a SUSAR, the DMEC will be contacted to break the code for an individual participant. 4.7 Inclusion/exclusion criteria The sample will be smokers of 10 or more cigarettes per day willing to attempt to stop smoking permanently, not diagnosed with a psychiatric disorder or suffering from any medical condition that contraindicates cytisine as listed on the data sheet, not pregnant or breastfeeding, not planning on becoming pregnant, willing to attend all the sessions, able to read and write Polish and provide informed consent and able to be contacted by telephone. Participants must agree not to use any other smoking cessation medications or tobacco products during the study, at least until the point where they have relapsed (more than 5 cigarettes) and are therefore regarded as a treatment failure. 4.8 Withdrawal of participants Participants will be informed that they may withdraw from the study at any time without giving a reason. Unless they withdraw consent they will be followed-up irrespective of smoking outcome or protocol violation. Participants that cannot be followed up will be regarded as having resumed smoking unless they have died or are known to have moved to an untraceable address, in which case they will be withdrawn from the analysis. 4.9 Participant compliance Compliance with the medication regimen and non-use of nicotine products will be assessed by self-report at relevant assessment points Timing of assessments and procedures (see Table 1) After expressing an interest in the trial, smokers will be contacted by the clinic by telephone. They will be informed about the trial at this stage to give them time to consider whether or not they wish to take part. They will be formally invited to take part once they attend the first clinic session. This session is largely the same whether or not they are taking part in the trial. If they are eligible and consent to taking part in the trial they will receive study medication. Otherwise they will receive treatment as is routinely provided by the clinic. A quit date will be set approximately one week hence and they will start taking the study medication 5 days prior to that. Subsequent assessments will take place 1 week and 4 weeks after the quit date and 6, and 12 months after the end of treatment Efficacy parameters Primary: The primary outcome assessment will follow the Russell Standard 12-months criteria (RS12) [23]. This will involve a self-report of abstinence from the end of treatment session (session 5, 4 weeks) with no more than 5 cigarettes in total from that date, confirmed by an 7

9 expired air CO reading at the month follow-up of less than 10ppm. A self-report of smoking no more than 5 cigarettes in total will also be required at the 6 month follow-up. When taken, a CO reading of less than 10ppm will be required at the 6 month follow-up. Subjects who smoke and start a new successful treatment session, possibly with another medication, will be counted as smokers. Inclusion will be by intent to treat and all subjects whose smoking status cannot be determined but who are not known to have moved to an untraceable address or died will be counted as smokers. Secondary: The intervention and treatment groups will also be compared on a number of secondary measures including: 1) self-report of smoking no more than 5 cigarettes between end of treatment session and 6 month follow up confirmed by an expired air CO reading at the 6-7 month follow-up session of less than 10ppm (Russell Standard, RS6). By definition, those classified as abstinent on the primary outcome (RS12) will also be classified as abstinent on RS6 2) self-report of not smoking any cigarettes for 4 weeks leading up to the end-of-treatment assessment supported by CO verification at the end-of-treatment session 3) the severity of withdrawal symptoms and urges to smoke one week after the designated quit date in participants who have been abstinent since the quit date. The withdrawal symptom measure has been validated [24]. The one-week time point is chosen because it is the time when most withdrawal symptoms are at their peak and it is also the point before which there will have been significant attrition because of a return to smoking [25]. Only abstinent smokers will be assessed for withdrawal symptoms because those who have smoked will not experience these in the same way and this would be expected to lead to bias [25] 4) Minor and Serious Adverse events reported throughout the trial. 5) Depression, mood and physical symptoms reported throughout the trial Safety assessments and concomitant medication Medical history and concomitant medication will be assessed at the first visit. All adverse events and changes in concomitant medication will be recorded in the CRF at subsequent visits up to Session 5 (the post-treatment session at about 3 10 days after the last dose of IMP). Collection, recording and reporting of adverse events (including serious and non-serious events and reactions) to the sponsor will be done according to the sponsor s SOP on AE/SAE reporting. All serious adverse events will be reported to the sponsor within 24 h of the investigator becoming aware of them, by the CI or delegate. All deaths will be reported to the sponsor, by the CI or delegate, within 24 h, irrespective of whether the death is related to disease progression, the IMP, or an unrelated event. Any SUSAR related to the IMP will need to be reported to the Sponsor irrespective of how long after IMP administration the event occurred. The SAE Reporting Form should be faxed to the sponsor on or ed to the sponsor trial co-ordinator. Subject confidentiality must be maintained on all reports in relation to recording and reporting of AEs. The CI in Poland (or appropriate delegate) will be responsible for sending SAE reports (and follow-up reports), as applicable, in an expedited fashion to the Polish regulatory authority and to the ethics committee, as per Polish regulatory requirements. The CI in Poland will also be responsible for preparing and submitting annual safety reports to the Polish regulatory authority and to the ethics committee, and also for preparing and submitting annual progress reports to the ethics committee. When prepared, the annual safety reports and annual progress reports will be sent to the sponsor. 8

10 4.13 Baseline measurements The following variables will be assessed at the fist visit: age, gender, occupational group, educational level, marital status, Fagerstrom Test for Nicotine Dependence (FTND) [26], daily cigarette consumption, other tobacco use, number of previous quit attempts, longest duration of quit attempt, motivation to stop smoking, depression (using the Beck depression inventory [27] and a baseline measure for later determination of nicotine withdrawal symptoms using the Mood and Physical Symptoms Scale (MPSS) [24] Outcomes to be measured at follow-up Initial follow up screening for the 6-7 months and months assessments will be by telephone. Smokers who report that they have been abstinent for the past 7 days will be asked to attend the clinic for biochemical verification by expired-air carbon monoxide test. They will receive a high-street voucher worth approximately 5 to reimburse them for their time. If necessary, home visits may be made at the participants convenience. The MPSS and Beck Depression Inventory will also be administered at follow ups: see Table Sample size We aimed to achieve 80% power to detect at the 5% significance level a difference between groups of 6% on the primary outcome measure (i.e. 6% vs 12%). Using the Chi-square distribution with continuity correction indicates that 389 subjects per group would be required (778 in total). However, given the large sample size and the fact that all expected cell counts will be greater than 10, the continuity correction will over-correct in our study [29]. Without the continuity correction, the required sample size is 355 subjects per group (710 in total). A sample size of 740 would give 82% without the continuity correction (78% power with the correction). We can therefore be fairly confident that with this sample size the true power will be close to, if not greater than, 80% 4.16 Recruitment rate Subjects will be recruited through the smoking treatment service being operated at the clinic in Warsaw. This treatment service has a throughput of approximately 100 smokers per month. On the basis of the experience with the uncontrolled study, it is estimated that recruitment could be completed within 12 months. If necessary, the recruitment rate will be boosted through the use of advertisements for the clinic Likely rate of loss to follow-up In smoking cessation trials, participants are frequently lost to follow-up if they resume smoking. This is addressed in the commonly used outcome criteria in which smokers lost to follow-up are counted as smokers. We propose to use the Russell Standard criteria [23]. Based on other studies, it is estimated that the figure in this study will be 20%. Withdrawals or drop-outs will not be replaced Number of centres involved One centre will be used (Warsaw) Statistical analyses and data management The assessments involving abstinence rates will involve a logistic regression to calculate the odds ratio comparing the odds of abstinence in the two groups; 95% confidence intervals will be calculated for odds ratios. 9

11 The assessment of withdrawal symptoms and urges to smoke will involve a set of analyses of covariance of MPSS individual ratings comparing the two groups at one week post-quit date controlling for baseline ratings in each case. Additionally, we will test for differences between intervention and placebo arms for the frequency of occurrence of specific adverse events at 1 and 4 weeks by chi-square tests. Case Report forms (CRF) will be prepared in English and then translated into Polish. They will be completed in Polish. All data will be entered directly into the CRF; there will be no other source documents. Data entry will be undertaken by the Polish investigators. Data entry will be into a pre-specified Microsoft Access database. On completion, data will be analysed using the SPSS statistical package. The database will be prepared with English labels and variable names. Data analysis will be undertaken by the Trial Statistician in conjunction with the Principal Applicant and other members of the study team as appropriate. The contract research organization, Quantum Satis Sp. will monitor the conduct of the trial and data integrity. CRFs and data entry to the database will be checked during routine monitoring visits. Errors will be corrected and logged and monthly reports sent to the investigators Subgroup analyses The study is not powered for subgroup analyses but it will be possible to examine differential effects of baseline demographics, mood and smoking characteristics. This will be done by logistic regression focusing on the interaction between active versus placebo treatment group and the baseline variable of interest Proposed frequency of analyses Data will be analysed at the discretion of the DMEC, but the investigators will remain blind to treatment allocation until the end of the trial. Should early results be requested by organisations such as NICE, these will only be released following agreement by the TSC and DMEC Economic issues An economic analysis will be conducted based on current costs of the medication and the cost of treatment delivery [28]. This will use standard health-economic methods in this field to calculate the marginal cost per life year gained, as recently adopted for the NICE review of nicotine replacement therapies Risks to patient safety The pharmacological treatment in this trial will be prescribed in accordance with its Polish licence and subject to the contraindications listed in the Summary of Product Characteristics. The medication has been in use in a number of countries in former Eastern Europe and Russia for several decades and is currently in use in the clinic where the trial will be taking place. No serious adverse events from use of the medication have yet been detected but this trial will undertake close monitoring in accordance with Good Clinical Practice and the EU Directive on Clinical Trials. Any patient who becomes pregnant during the trial will be taken off medication but not removed from the trial. They will be followed up within the treatment condition that they were originally entered. 5. Governance and ethics The trial will conform to the requirements of MRC clinical trials which involves a Trial Steering Committee (TSC) and a Data Management and Ethics Committee (DMEC). It will also conform to the EU Clinical Trials Directive and guidance on Good Clinical Practice. 10

12 The Trial Steering Committee will be: Dr Michael Ussher (St George s, London University: Chair), Lindsay Stead (Cochrane and the University of Oxford), a lay representative, a representative from the funding body, Elspeth Lee (Cancer Research UK), a representative of the sponsor (University College London), Prof Robert West (University College London: Principal Grant Holder). The DMEC will be: Prof Peter Hajek (Royal London and Barts: Chair), Prof Ann McNeill (Nottingham University), Dr Lesley Owen (NICE). The study protocol and other documentation is being submitted to the UCL ethics committee and the ethics committee of the Cancer Centre in Warsaw. The trial is being submitted for regulatory approval and registration in Poland. The trial has been registered with the MRC register of clinical trials. 6. References 1. Silagy, C., et al., Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev, 2004(4): p. CD Hughes, J.R., L.F. Stead, and T. Lancaster, Antidepressants for smoking cessation. Cochrane Database Syst Rev, 2003(2): p. CD NICE, National Institute for Clinical Excellence Technology Appraisal Guidance No. 38 Nicotine replacement therapy (NRT) and bupropion for smoking cessation. 2002, London: NICE. 4. Coe, J.W., et al., Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation. J Med Chem, (10): p Oncken, C., et al., Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist, varenicline, for smoking cessation. Arch Intern Med, (15): p Nides, M., et al., Smoking cessation with varenicline, a selective alpha4beta2 nicotinic receptor partial agonist: results from a 7-week, randomized, placebo- and bupropion-controlled trial with 1-year follow-up. Arch Intern Med, (15): p Tonstad, S., et al., Effect of maintenance therapy with varenicline on smoking cessation: a randomized controlled trial. Jama, (1): p Jorenby, D.E., et al., Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. Jama, (1): p Gonzales, D., et al., Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustainedrelease bupropion and placebo for smoking cessation: a randomized controlled trial. Jama, (1): p Burstein, A.H., et al., Pharmacokinetics, safety, and tolerability after single and multiple oral doses of varenicline in elderly smokers. J Clin Pharmacol, (11): p Cinciripini, P., et al. Pooled analysis of three short-term, randomised, double-blind, placebo-controlled trials with rimonabant 20mg/d in smoking cessation. in SRNT Europe, Kusadasi, Turkey. 12. Cerny, T., Anti-nicotine vaccination: where are we? Recent Results Cancer Res, : p Stead, L.F., T. Lancaster, and R. Perera, Telephone counselling for smoking cessation. Cochrane Database Syst Rev, 2003(1): p. CD Stead, L.F. and T. Lancaster, Group behaviour therapy programmes for smoking cessation. Cochrane Database Syst Rev, 2002(3): p. CD Lancaster, T. and L.F. Stead, Individual behavioural counselling for smoking cessation. Cochrane Database Syst Rev, 2002(3): p. CD Strecher, V.J., S. Shiffman, and R. West, Randomized controlled trial of a web-based computer-tailored smoking cessation program as a supplement to nicotine patch therapy. Addiction, (5): p Ussher, M.H., et al., Exercise interventions for smoking cessation. Cochrane Database Syst Rev, 2005(3): p. CD May, S. and R. West, Do social support interventions ("buddy systems") aid smoking cessation? A review. Tob Control, (4): p Sopharma, Tabex: Documentation for Registation. 2002: Bulgaria. 20. Etter, J.F., Cytisine for smoking cessation: a literature review and a meta-analysis. Arch Intern Med, (15): p Gopalakrishnan, M., et al., Stable expression, pharmacologic properties and regulation of the human neuronal nicotinic acetylcholine alpha 4 beta 2 receptor. J Pharmacol Exp Ther, (1): p

13 22. Hughes, J.R., J. Keely, and S. Naud, Shape of the relapse curve and long-term abstinence among untreated smokers. Addiction, (1): p West, R., et al., Outcome criteria in smoking cessation trials: proposal for a common standard. Addiction, (3): p West, R. and P. Hajek, Evaluation of the mood and physical symptoms scale (MPSS) to assess cigarette withdrawal. Psychopharmacology (Berl), Shiffman, S., R. West, and D. Gilbert, Recommendation for the assessment of tobacco craving and withdrawal in smoking cessation trials. Nicotine Tob Res, (4): p Heatherton, T.F., et al., The Fagerstrom Test for Nicotine Dependence: a revision of the Fagerstrom Tolerance Questionnaire. Br J Addict, (9): p Beck, A.T. and A. Beamesderfer, Assessment of depression: the depression inventory. Mod Probl Pharmacopsychiatry, (0): p Stapleton, J.A., A. Lowin, and M.A. Russell, Prescription of transdermal nicotine patches for smoking cessation in general practice: evaluation of cost-effectiveness. Lancet, (9174): p Sokal RR, Rohlf FJ. The Principals and Practice of Statistics in Biologiacl Research. Oxford: W.H. Freeman (1981), ISBN

14 Table 1: Study Schedule/Flow Chart of Procedures Procedure/assessment S1: Initial contact S2: Pre-quit session S3: Post-quit telephone contact S4: Optional additional support S5: End-oftreatment session S6: 6-month follow up (tel) S7: 6-month follow-up (clinic) S8: 12-month follow up (tel) Procedure Telephone contact x x x x x Send Patient Info Sheet x Clinic visit x x x x Clinic appointment booked x Study described to patient x x Assessment/screening x Consent/randomisation x Counselling x x x Medication dispensed x Assessment Patient contact details x x Demographic information x Blood pressure x x x x Lung function x x x x Heart rate x x x x Expired air CO x x x x Smoking history x Dependence (FTND) x Weight x x x x Beck depression inventory x x x x Mood and physical symptoms x x x x x Medical history x Smoking abstinence x x x x x x x Medication compliance x x x Adverse events x x x Concomitant medication x x x x Note: For more details of procedures see TASC Sequence of Events S9: 12-month follow up (clinic) 13

15 TASC Trial Details of changes from Protocol V2.4 to Protocol V3.0 primarily to change the primary outcome from 6-months to 12-months smoking cessation. V3.0 and V2.4 amended sections listed below with changes in bold typeface: 2. Summary V3.0 The primary outcome measure will be obtained at a follow up taking place months after the end of treatment session. It will consist of self report of smoking not more than 5 cigarettes between the end of treatment session and that follow up, verified at the 12-month follow up by an expired air carbon monoxide (CO) concentration of less than 10 ppm. Secondary outcome measures will include: 1) self-report of smoking not more than 5 cigarettes between end of treatment session and the 6-7 month follow-up verified by an expired air CO concentration of less than 10 ppm at the 6-month follow up; 2) self-report of smoking no cigarettes for the 28 days prior to the end-of treatment session verified by expired air CO concentration of less than 10 ppm; 3) nicotine withdrawal symptoms and urges to smoke measured by the Mood and Physical Symptoms Scale (MPSS) at the one-week telephone contact in smokers who report that they have been abstinent for at least one week. It is expected that the 12-month abstinence rates will be at least 6% higher in those receiving Tabex than those receiving placebo. This study has approximately 80% statistical power to detect a difference between conditions in which the placebo abstinence rate is 6% and the active abstinence rate is 12%. V2.4 The primary outcome measure will be obtained at a follow up taking place 6-7 months after the end of treatment. It will consist of self report of smoking not more than 5 cigarettes between the end of treatment session and that follow up, verified at the 6-month follow up by an expired air carbon monoxide (CO) concentration of less than 10 ppm. Secondary outcome measures will be: 1) self-report of smoking not more than 5 cigarettes between end of treatment and month follow-up verified by an expired air CO concentration of less than 10 ppm at the 12-month follow up; 2) self-report of smoking no cigarettes for the 28 days prior to the end-of treatment session verified by expired air CO concentration of less than 10 ppm; 3) nicotine withdrawal symptoms and urges to smoke measured by the Mood and Physical Symptoms Scale (MPSS) at the one-week telephone contact in smokers who report that they have been abstinent for at least one week. It is expected that the 6-month continuous abstinence rates will be at least 7% higher in those receiving Tabex than those receiving placebo. This study has more than 80% statistical power to detect a difference between conditions in which the placebo abstinence rate is 8% and the active abstinence rate is 15%. 4.6 Allocation of participants to trial groups V3.0 The study team will possess a sealed envelope containing the random number codes. This will remain sealed until the last 12-month assessment has been performed, all data entered into the trial database and all data checks completed. The code will then be broken by the Data Monitoring and Ethics Committee (see below). The 12-month follow-up will be undertaken blind to the group assignment. 14

16 V2.4 The study team will possess a sealed envelope containing the random number codes. This will remain sealed until the last 6-month assessment has been performed. The code will then be broken by the Data Monitoring and Ethics Committee (see below). The 12-month follow-up will be undertaken blind to the group assignment Efficacy parameters V3.0 Primary: The primary outcome assessment will follow the Russell Standard 12 months criteria (RS12) [23]. This will involve a self-report of abstinence from the end of treatment session (session 5, 4 weeks) with no more than 5 cigarettes in total from that date, confirmed by an expired air CO reading at the month follow-up of less than 10ppm. A self-report of smoking no more than 5 cigarettes in total will also be required at the 6 month follow-up. When taken, a CO reading of less than 10ppm will be required at the 6 month follow-up. Subjects who smoke and start a new successful treatment session, possibly with another medication, will be counted as smokers. Inclusion will be by intent to treat and all subjects whose smoking status cannot be determined but who are not known to have moved to an untraceable address or died will be counted as smokers. Secondary: The intervention and treatment groups will also be compared on a number of secondary measures including: 1) self-report of smoking no more than 5 cigarettes between end of treatment session and 6 month follow up confirmed by an expired air CO reading at the 6-7 month follow-up session of less than 10ppm (Russell Standard, RS6). By definition, those classified as abstinent on the primary outcome (RS12) will also be classified as abstinent on RS6 2) self-report of not smoking any cigarettes for 4 weeks leading up to the end-of-treatment assessment supported by CO verification at the endof-treatment session. 3) the severity of withdrawal symptoms and urges to smoke one week after the designated quit date in participants who have been abstinent since the quit date. The withdrawal symptom measure has been validated [24]. The one-week time point is chosen because it is the time when most withdrawal symptoms are at their peak and it is also the point before which there will have been significant attrition because of a return to smoking [25]. Only abstinent smokers will be assessed for withdrawal symptoms because those who have smoked will not experience these in the same way and this would be expected to lead to bias [25]. 4) Minor and Serious Adverse events reported throughout the trial. 5) Depression, mood and physical symptoms reported throughout the trial. V2.4 Primary: The primary outcome assessment will follow the Russell Standard (RS) at 6-7 months [23]. This will involve a self-report of abstinence from two weeks after the quit date with no more than 5 cigarettes in total from that date, confirmed by an expired air CO reading at the 6-7 month follow-up of less than 10ppm. Inclusion will be by intent to treat and all subjects whose smoking status cannot be determined but who are not known to have moved to an untraceable address or died will be counted as smokers. Secondary: The intervention and treatment groups will also be compared on: 1) self-report of smoking no more than 5 cigarettes between end of treatment and month follow up; 2) self-report of not smoking any cigarettes for 4 weeks leading up to the end-of-treatment assessment supported by CO verification at the end-of-treatment session; 3) the severity of withdrawal symptoms and urges to smoke one week after the designated quit date in participants who have been abstinent since the quit date. The withdrawal symptom measure has been validated [24]. The one-week time point is chosen because it is the time when most 15

17 withdrawal symptoms are at their peak and it is also the point before which there will have been significant attrition because of a return to smoking [25]. Only abstinent smokers will be assessed for withdrawal symptoms because those who have smoked will not experience these in the same way and this would be expected to lead to bias [25] Sample size V3.0 We aimed to achieve 80% power to detect at the 5% significance level a difference between groups of 6% on the primary outcome measure (i.e. 6% vs 12%). Using the Chi-square distribution with continuity correction indicates that 389 subjects per group would be required (778 in total). However, given the large sample size and the fact that all expected cell counts will be greater than 10, the continuity correction will over-correct in our study [29]. Without the continuity correction, the required sample size is 355 subjects per group (710 in total). A sample size of 740 would give 82% without the continuity correction (78% power with the correction). We can therefore be fairly confident that with this sample size the true power will be close to, if not greater than, 80% V2.4 A sample size of 740 will give more than 80% power to detect an improvement of 7% in the active medication condition over a 8% success rate in the placebo condition (using the primary outcome measure) Subgroup analyses V3.0 The study is not powered for subgroup analyses but it will be possible to examine differential effects of baseline demographics, mood and smoking characteristics. This will be done by logistic regression focusing on the interaction between active versus placebo treatment group and the baseline variable of interest. V2.4 The study is not powered for subgroup analyses but it will be possible to examine differential effects of the intervention by gender, occupational group, educational level and level of nicotine dependence. This will be done by logistic regression focusing on the interaction between active versus placebo treatment group and the demographic/smoking variable of interest. 16

18 TASC Trial SOP for smoking cessation outcome and statistical analysis (A) A detailed description of the smoking cessation outcome criteria The primary outcome of 12-months smoking cessation (RS12) is based on the Russell Standard criteria 1. The essential features are that subjects should record a CO level of less that 10ppm at the endpoint (12 months after the end of treatment) and should self-report not smoking in the last week and not more than 4 cigarettes in each of the 6 month periods prior to the end point. Additionally, because those who fail to stop by the end of drug treatment (EOT) frequently return to the clinic for a new treatment course, those who report smoking or fail CO verification at EOT will also be classified as having failed RS12. The secondary outcome of 6-months smoking cessation is also based on the Russell Standard criteria and is similar to RS12. Those who fulfil RS6 but not RS12 are classified as having relapsed to smoking between 6 and 12 moths. Relevant data are collected at Session 5 (S5), Session 6(S6), Session 7 (S7), Session 8 (S8) and Session 9(S9). S5 is an optional visit to the clinic at the end of drug treatment (EOT), approximately 1 month after quit day. A self-report of smoking status and a CO reading are taken for those who attend. S6 is the 6-month follow-up for self-reported smoking status. If necessary, several telephone calls are made by the clinic staff aiming to contact all subjects. Smoking behaviour since the EOT is recorded and those abstinent from smoking (not smoking in the last week) are invited to attend the clinic for CO verification at S7. S7 is the 6-month clinic visit for those reporting abstinence at S6. A CO reading to verify smoking abstinence and a self-report of smoking behaviour are recorded. S8 is the 12-month follow-up for self-reported smoking status. If necessary, several telephone calls are made by the clinic staff aiming to contact all subjects. Smoking behaviour in the last 6 months is recorded and those abstinent from smoking (not smoking in last week) are invited to attend the clinic for CO verification at S9. S9 is the 12-month clinic visit for those reporting abstinence at S8. A CO reading to verify smoking abstinence and self-report of smoking behaviour are recorded. Note: in the below description variables names (e.g. S5ltw) are those printed on the paper CRFs against each item and used in the trial database. Primary Outcome - 12 months of smoking cessation (RS12). To be classified as successfully stopped smoking for 12 months, the following 3 criteria need to be met: (1) If the subject attends the optional end of treatment session (S5) there must not be evidence of smoking in the last 2 weeks (i.e. neither S5ltw=1 nor S5co>9ppm). (2) At the 6 months follow-up (S6) a subject must either: (a) Report not smoking since the end of treatment (S6smo=2). or (b) If they report smoking since the end of treatment (S6smo=1), must report not smoking 5 or more cigarettes (S6cig=1) and not smoking in the last 7 days (S6ltw=2). or (c) If the S6 follow-up is missed, the subject must attend the 6-month clinic visit (S7) and report not smoking since the end of treatment (S7smo=2) or, if they report smoking (S7smo=1), must report not smoking 5 or more cigarettes (S7cig=1) and not smoking in the last 7 days (S7ltw=2). Additionally, all subjects who attend the clinic at 6 months (S7) must record a CO level of < 10 17

19 ppm (S7co<10). (3) At the 12 month follow-up (S8) a subject must either: (a) Report not smoking in the last 6 months (S8smo=2) or (b) If they report smoking in the last 6 months (S8smo=1), must report not smoking 5 or more cigarettes (S8cig=1) and not smoking in the last 7 days (S8ltw=2). or (c) If the S8 follow-up is missed, the subject must attend the 12-month clinic visit (S9) and report not smoking in the last 6 months (S9smo=2) or, if they report smoking (S9smo=1), must report not smoking 5 or more cigarettes (S9cig=1) and not smoking in the last 7 days (S9ltw=2). Additionally, to be classified as RS12 abstinent a subject MUST attend the clinic at 12 months (S9) and must record a CO level of < 10 ppm (S9co<10). NOTE: Any subject not fulfilling the above will be classified as having failed to stop smoking according to RS12. Secondary Outcome - 6 months of smoking cessation (RS6). A subject classified as not smoking for 12 months according to the primary outcome criteria (RS12) will also be classified as successful according to the secondary outcome i.e. by definition any subject classified as abstinent for the whole 12 months is abstinent for the first 6 months. Alternatively, if a subject is not classified as abstinent according to RS12, the following two criteria need to be met: (1) If the subject attends the optional end of treatment session (S5) there must not be evidence of smoking in the last 2 weeks (i.e. neither S5ltw=1 nor S5co>9ppm). (2) At the 6 months follow-up (S6) a subject must either: (a) Report not smoking since the end of treatment (S6smo=2). or (b) If they report smoking since the end of treatment (S6smo=1), must report not smoking 5 or more cigarettes (S6cig=1) and not smoking in the last 7 days (S6ltw=2). or (c) If the S6 follow-up is missed, the subject must attend the 6-month clinic visit (S7) and report not smoking since the end of treatment (S7smo=2) or, if they report smoking since the end of treatment (S7smo=1), must report not smoking 5 or more cigarettes (S7cig=1) and not smoking in the last 7 days (S7ltw=2). Additionally, if a subject is not classified as abstinent according to RS12, they MUST attend the clinic at 6 months (S7) and record a CO level of < 10 ppm (S7co<10). NOTE: Any subject not fulfilling the above will be classified as having failed to stop smoking for 6 months according to RS6. Secondary Outcome point prevalence at 12 months (PP12) To be classified as successful according to the 12-month point-prevalence outcome a subject must either: (a) Report not smoking during the last week at the 12-month follow-up (S8ltw=2). or (c) If the S8 follow-up is missed, the subject must attend the 12-month clinic visit (S9) and report not smoking in the last week (S9ltw=2). Additionally, to be classified as PP12 abstinent the subject MUST attend the clinic at 12 months and record a CO level of < 10 ppm (S9co<10). 18