1. Effects of a combination of varenicline and nicotine patch on post-quitting urges to smoke Katie Myers Smith BSc MSc CPsychol Research Fellow Wolfson Institute of Preventive Medicine Queen Mary University of London

2. Disclosures The study was supported by an investigator- initiated grant from Pfizer, who also supplied varenicline. Nicotine and placebo patches were supplied by McNeil. The two pharmaceutical companies had no involvement in the design and conduct of the study, analysis and interpretation of the data, or preparation of the manuscript.

3. Current pharmacotherapy for smoking cessation Nicotine Replacement Therapy (NRT) Patch, gum, lozenge, inhaler, nasal spray, minis, mouth spray Bupropion Varenicline Evidence that patch + a rapid delivery form of NRT more effective than single NRT use 1 Combination of NRT recommended by The National Institute for Health and Clinical Excellence (NICE) 2 Evidence that patch + a rapid delivery form of NRT more effective than single NRT use 1 Combination of NRT recommended by The National Institute for Health and Clinical Excellence (NICE) 2 Insufficient evidence that bupropion + NRT increases long term abstinence 3 Combination not recommended by NICE 2 Insufficient evidence that bupropion + NRT increases long term abstinence 3 Combination not recommended by NICE 2 ? ? 1.Stead LF, Perera R, Bullen C, Mant D, Lancaster T. Nicotine replacement therapy for smoking cessation. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD000146. DOI: 10.1002/14651858.C D000146.pub3 2. www.nice.org.uk/nicemedia/pdf/PH010guidance.pdf 3. Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation. Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD000031. DOI: 10.1002/14651858.CD000031.pub3.

4. Combining NRT & varenicline: does it make sense? Both act on nAChRs (full and partial agonist) Both medications seem to achieve their effect on abstinence by alleviating the discomfort of nicotine withdrawal [1,2]. It is not clear if the central effects of the two medications are sufficiently different to allow synergy, but if they do differ, their combination could have some beneficial effects. 1. Stead LF, Perera R, Bullen C, Mant D, Lancaster T: Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev 2008, 1, CD000146. 2. Cahill K, Stead LF, Lancaster T: Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev 2011, 2, CD006103.

5. Ebbert et al (2009) Observational cohort study Setting – inpatient smoking cessation facility Medications – NRT with/without varenicline, NRT with/without bupropion Results – no difference in outcome, no safety issues reported with combination treatment Currently no RCTs looking at varenicline+ NRT

6. Why it is important to do this research Increased number of dependent smokers Anecdotal clinical experience of benefit but needs to be experimentally investigated.

7. Study Aims To examine if there are differences between varenicline + nicotine patches varenicline + placebo patches In reduction of urges to smoke and withdrawal relief at 24hr and 1 week after quitting (primary endpoint) In short term abstinence rates (secondary endpoint)

8. Flow of participants Potential participants responding to adverts (n=514) Not invited to screening (n=234) - Not meeting inclusion criteria (n=72) - Did not want to participate (n=162) Not invited to screening (n=234) - Not meeting inclusion criteria (n=72) - Did not want to participate (n=162) Invited to screening/consent session (n=280) Attended screening/consent session (n=144) Not eligible (n=10) Randomised at TQD (n=117) Did not attend randomisation session (n=17) Allocated to placebo patch (n=59) Completed follow-up at 12-weeks post TQD (n=31) Allocated to nicotine patch (n=58) Completed follow up at 12-weeks post TQD (n=33) Measures Rating of urges to smoke and tobacco withdrawal symptoms (MPSS) Smoking status CO in expired breath(Lost to follow up = SMOKER) AEs recorded Measures Rating of urges to smoke and tobacco withdrawal symptoms (MPSS) Smoking status CO in expired breath(Lost to follow up = SMOKER) AEs recorded Abstinence endpoints Self reported abstinence at 24 hour phone call Continuous, validated abstinence at 1 week Russell Standard (up to 5 lapses allowed since TQD with validated report of no smoking at week 4) at 4 weeks post TQD Self reported abstinence at 12 weeks Abstinence endpoints Self reported abstinence at 24 hour phone call Continuous, validated abstinence at 1 week Russell Standard (up to 5 lapses allowed since TQD with validated report of no smoking at week 4) at 4 weeks post TQD Self reported abstinence at 12 weeks Patch use for 4 weeks Varenicline use for 12 weeks

9. Effect of combination on withdrawal No significant effect of combination treatment on urge to smoke or other withdrawal symptoms at 24 hour & 1 week post TQD

10. Abstinence *Self reported outcome Period after TQDPlacebo Patch (n=59) Nicotine patch (n=58) Pearson Chi- square; p value 24 hours80% (n=47)79% (n=46)0.00; p = 0.96 1 week N (%)59% (n=35)69% (n=40)1.18; p = 0.28 4 weeks N (%)59% (n=35)60% (n=35)0.01; p = 0.91 12 week* N (%)29% (n=31)36% (n=33)0.73; p = 0.39

11. Adherence to medications There was no difference in adherence to medication between the two study arms at any time point. Adherence to the combination treatment during the crucial first week post TQD was high.

12. Adverse events No sig differences in ratings of nausea or any other AEs reported between the two groups at any time point AEs reported by more that 5% of participants included; - Abnormal dreams -Headache -Insomnia

13. Comments Adding nicotine patches to varenicline had no beneficial or detrimental effect on urges to smoke, withdrawal discomfort, abstinence rates, or adverse effects profile. Limitations; short-term follow up, small sample size

14. Patch use vs oral NRT use –short acting NRT (e.g. nasal spray) could be more effective. These products are typically under used as they require more effort from users, which would in theory reduce any benefit of combination treatment. Results from this study should be generalised to short acting NRT with caution.

15. No increase in nausea or any other AE was seen. Results suggest that this combination is well tolerated

16. Conclusion There is a widespread interest in combining NRT and varenicline in the hope of improving treatment outcomes. The results of this study suggest that such practice may not be productive or economical.

17. Publication Hajek, P., Myers Smith, K., Dhani, A., & McRobbie, H. (2013) Is a combination of varenicline more effective in helping smokers quit than varenicline alone? A randomised controlled trial. BMC Medicine. 11; 140 http://www.biomedcentral.com/1741- 7015/11/140

18. Acknowledgments The study randomisation was conducted by Mark Simmonds.

19. THANK YOU Katie.smith@qmul.ac.uk