Open-label randomised controlled trial of nicotine replacement therapy (NRT) for preloading, lapse recovery and smoking reduction: impact on smoking in pregnancy

DESIGN: Multi-centre, parallel group, open-label RCT PARTICIPANTS: Women of 5 daily cigarettes (> 10 before pregnancy) with exhaled CO readings of > 4ppm SETTING: Hospital antenatal care INCLUSION CRITERIA: As above, agree to set a quit date, accept referral to stop smoking services and willing to use NRT. EXCLUSION: Already in a smoking cessation study, using e-cigarette, contra-indications to NRT. CONTROL: Usual care INTERVENTION: NRT used in up to three different ways: i) NRT Preloading – using NRT before a quit date (QD) whilst still smoking instead of starting NRT and attempting abstinence together from a QD onwards. ii) Standardised advice to continue NRT during brief smoking lapses occuring after a QD when women use NRT and attempt abstinence And, for women who are still smoking one month after joining the study iii) NRT to reduce smoking and induce cessation PRIMARY OUTCOME: Biochemically-validated, prolonged smoking cessation reported between a quit date and 36 weeks’ gestation with minimal smoking reported at intervening points, consistent with ‘Russell Standard’. SECONDARY OUTCOMES: Birthweight; reported abstinence at 4 weeks post-randomisation and 36 weeks’ gestation; validated 7-day abstinence & exhaled CO at 36 weeks; 50% reduction in daily cigarettes smoked (reported / CO-validated); low birth weight; premature birth; gestation at birth; other birth and neonatal outcomes and use of NHS cessation support. SAMPLE SIZE: With a 10% quit rate in the control group and a 5% significance level, a study of 1430 participants (715 per arm) will have 90% power to detect a 6% difference (odds ratio 1.7) in validated cessation rates between the treatment groups. STATISTICS: Trial analysis and reporting will be in accordance with CONSORT guidelines. The primary analysis will use the intention-to-treat population assuming those lost to follow up as smoking. Analysis will use a mixed-effect logistic regression model with a random effect for recruiting site. We will present absolute and relative measures of effect between groups with 95% confidence intervals. Secondary outcomes will be analysed using regression models appropriate to outcome variables. ECONOMICS: We will monitor key intervention costs drivers such as, amount of NRT used, time for delivery of support and use of NHS cessation support. We will use an established economic model to conduct an incremental cost-effectiveness analysis with an ‘end-of-pregnancy’ horizon generating ‘cost per quitter’ outcomes and a cost-utility analysis generating incremental costs per QALY with both maternal and infant end of pregnancy and lifetime-horizons. TIMETABLE: Months 1-6: Set-up (site selection, approvals, CRF/database/website development and app revisions); Months 4-8: Site training / initiation; Months 7-15: In-trial pilot, recruit 385 women in 26 centres; Months 16-36: Recruit 1,045 women in 26 centres; End Month 45: last follow-up; Month 44-48: analysis, reporting and dissemination. EXPERTISE: Health psychology, economics, smoking cessation, trial design & management, statistics, qualitative research, app development, lay opinion and midwifery. IMPACT: Positive findings could provide new options for using NRT effectively to stop and reduce smoking in pregnancy, protecting infants born to women who cannot stop.