Wagena 2005.

Methods	Design Randomised controlled trial Setting Outpatients
Participants	Inclusion criteria The study population consisted of current daily smokers at risk for COPD or with COPD (GOLD criteria). All participants were aged between 30 and 70 years, had to have a smoking history of at least 5 years, smoked on average at least 10 cigarettes per day during the last year, and were motivated to stop smoking. Exclusion criteria We excluded people who reported having used or who were still using bupropion SR or nortriptyline, people who were using nicotine therapy or psychoactive medication at the time of assessment, and people who had any serious or unstable medical disorders that might affect lung function or for which bupropion SR or nortriptyline was contraindicated. Number randomised Total 255, bupropion 86, nortriptyline 80, placebo 89, people with COPD 155 (following data accounts for all randomised participants and is not stratified for participants with COPD) Number followed up Total 220 Age mean (SD): bupropion 51.1 (8.3), nortriptyline 51.2 (9.1), placebo 51.3 (8.4) Sex n (%) male: bupropion 34 (40), nortriptyline 44 (55), placebo 46 (52) Cigarettes/day mean (SD): bupropion 24.2 (9.4), nortriptyline 22.2 (7.6), placebo 23.6 (8.8) FTND mean (SD): bupropion 6.2 (2.1), nortriptyline 6.0 (2.2), placebo 5.9 (2.1) Severity COPD FEV1 post‐bronchodilator % predicted, mean (SD): bupropion 86.3 (21.0), nortriptyline 83.1 (21.7), placebo 87.4 (23.0) FEV1/FVC ratio, x 100, mean (SD): bupropion 66.7 (13.4), nortriptyline 65.5 (13.6), placebo 65.1 (15.3)
Interventions	Behavioural treatment For all groups at the baseline visit, the target quit date (TQD) was set for the second week, usually day 11 from the start of the medication. Individual face‐to‐face counselling by trained counsellor (baseline and 1 and 3 weeks after the TQD; 10 to 20 minutes per session). Supportive telephone calls by trained counsellor (TQD and at 2, 4, 6, 8, and 11 weeks after the TQD). Pharmacological treatment A. Bupropion group Bupropion 1 x 150 mg (day 1 to 6); 2 x 150 mg (day 7 to 84) AND placebo nortriptyline 1 x 25 mg (day 1 to 3); 1 x 50 mg (day 3 to 7); 1 x 75 mg (day 8 to 84) B. Nortriptyline group Nortriptyline 1 x 25 mg (day 1 to 3); 1 x 50 mg (day 3 to 7); 1 x 75 mg (day 8 to 84) AND placebo bupropion 1 x 150 mg (day 1 to 6); 2 x 150 mg (day 7 to 84) C. Placebo group Placebo bupropion 1 x 150 mg (day 1 to 6); 2 x 150 mg (day 7 to 84) AND placebo nortriptyline 1 x 25 mg (day 1 to 3); 1 x 50 mg (day 3 to 7); 1 x 75 mg (day 8 to 84)
Outcomes	Abstinence Prolonged abstinence from week 4 to 26 after the TQD and point prevalence at 6 months Validation Urinary cotinine values ≤ 60 ng/mL at weeks 4, 12, and 26 after TQD
Notes	Funding This study was funded by grant 3.2.00.21 from the Asthma Foundation Netherlands, Leusden; and by grant 2200.0111 from the The Netherlands Organisation for Health Research and Development, The Hague. Lundbeck BV, Amsterdam, the Netherlands, provided the nortriptyline for free. Conflicts of interest Not reported Correspondence No additional information received after correspondence
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randomization was done according to a computer‐generated randomisation list provided by the pharmacist of Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands, stratified for COPD severity, using blocks of 33."
Allocation concealment (selection bias)	Low risk	"Randomization was done according to a computer‐generated randomisation list provided by the pharmacist." This is central allocation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"No participant, research nurse, counsellor, investigator, or any other staff member was aware of the treatment assignments for the duration of the study. Blinding of participants was checked 1 week after the TQD and at the end of treatment."
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not described
Incomplete outcome data (attrition bias) All outcomes	Low risk	High follow‐up rates (> 80%) in all groups, no differential attrition
Selective reporting (reporting bias)	Unclear risk	All prespecified outcomes were reported, however for smokers with COPD only prolonged abstinence at week 26 was reported, while this was not a prespecified outcome
Other bias	High risk	Participants' and personnel's adherence to the intervention protocol was poor. "Medication compliance was assessed by counting number of pills allotted minus those returned." "55% of participants using 80% or fewer of the pills that they were asked to take. Poor compliance may have resulted in lower overall abstinence rates in our study population." "Forty participants (16%) discontinued medication because of adverse events: 8 (9%) in the placebo group, 12 (15%) in the bupropion SR‐treated group, and 19 (24%) in the nortriptyline treated group. The rate of discontinuation of treatment was statistically significantly higher among the participants receiving nortriptyline (P 0.01) compared with the participants receiving placebo."