The Smoking Cessation in Pregnancy Incentives Trial (CPIT): study protocol for a phase III randomised controlled trial

The Smoking Cessation in Pregnancy Incentives Trial (CPIT): study protocol for a phase III randomised controlled trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study protocol The Smoking Cessation in Pregnancy Incentives Trial (CPIT): study protocol for a phase III randomised controlled trial Lesley Sinclair, Margaret McFadden, Helen Tilbrook, Alex Mitchell, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.2.15197/v2 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 14 Feb, 2020 Read the published version in Trials → Version 2 posted 3 You are reading this latest preprint version Show more versions Abstract Background Eighty percent of UK women have at least one baby, making pregnancy an opportunity to help women to stop smoking before their health is irreparably compromised. Smoking cessation during pregnancy helps protect infants from miscarriage, still birth, low birth weight, asthma, attention deficit disorder and adult cardiovascular disease. UK national guidelines highlight lack of evidence for effectiveness of financial incentives to help pregnant smokers quit. This includes a research recommendation: Within a UK context, are incentives an acceptable, effective and cost-effective way to help pregnant women who smoke to quit? Methods CPIT III is a pragmatic, 39-month, multi-centre, parallel group, individually randomised controlled superiority trial of the effect on smoking status of adding to usual smoking cessation support the offer of up to £400 of financial voucher incentives, compared with usual support alone, to quit smoking during pregnancy. Participants (n = 940) are pregnant smokers (age > 16, <24 weeks pregnant, English speaking), who consent via telephone to take part and are willing to be followed-up in late pregnancy and 6 months after birth. The primary outcome is cotinine/anabasine validated abstinence from smoking in late pregnancy. Secondary outcomes include engagement with cessation services, quit rates at four weeks from agreed quit date and 6 months after birth, and birth weight. Outcomes will be analysed by intention-to-treat, and regression models will be used to compare treatment effects on outcomes. A meta-analysis will include data from the feasibility study in Glasgow. An economic evaluation will assess cost-effectiveness from a UK NHS perspective. Process evaluation using a case study approach will identify opportunities to improve recruitment and learning for future implementation. Research questions: What is the therapeutic efficacy of incentives? Are incentives cost-effective? What are the potential facilitators and barriers to implementing incentives in different parts of the UK? Discussion This phase III trial in Scotland, England and Northern Ireland, follows a successful phase II trial in Glasgow UK. The participating sites have diverse smoking cessation services, that represent most cessation services in the UK and serve demographically varied populations. If found to be acceptable and cost-effective this trial could demonstrate that financial incentives are effective and transferable to most UK cessation services for pregnant women. Internal Medicine Integrative & Complementary Medicine Translational Medicine Intervention randomised controlled trial maternal and child health outcomes pregnancy prevention smoking cessation financial incentives Figures Figure 1 Figure 2 Figure 3 Background and aims Tobacco smoking is the leading preventable cause of death in the UK [1]. Individuals who give up by age 40 (during childbearing years) avoid much of the morbidity and early mortality of continued smoking [2]; e.g. lung cancer risk is reduced to two times that of never smokers compared with 16 times for lifelong smokers. Around 80% percent of UK women have at least one baby [3] so an effective intervention will eventually reach most women who smoke. Stopping smoking during pregnancy also reduces the likelihood of the children themselves becoming smokers [4], thus reducing future cancer risk. 350 UK still births each year [5] and a third of babies born small for gestational age are attributable to smoking during pregnancy. One fifth of the 125,000 spontaneous miscarriages that occur each year in the UK [6], which cause 42,000 hospital admissions [7], are also associated with smoking during pregnancy. Compared with non-smokers the relative risk of spontaneous miscarriage is 1.2 [8]. If causality were accepted, this 20% increase in risk would mean 5000 spontaneous miscarriages and 2000 hospital admissions in the UK each year would be attributable to smoking during pregnancy. 20% of sudden unexpected deaths in infancy and 9% of premature births are attributable to maternal smoking as are 10% of admissions for bronchiolitis, one of the most common reasons infants are admitted to hospital, and 7% of admissions for respiratory infection and asthma [9]. Perhaps, surprisingly, 12% of the rare, but devastating occurrence of bacterial meningitis is attributable to maternal smoking [9] as are increases in attention deficit disorder [10] and learning difficulties [11] in children, adding substantial costs to health and social care services [12]. Prevalence and available support for stopping smoking in pregnancy UK pregnancy smoking rates remain high. One in four women smoke for part of their pregnancy and one in eight smoke throughout [13]. Stop smoking services (SSS) usually offer counselling plus free Nicotine Replacement Therapy (NRT); however, only 10% of pregnant smokers use these services and as few as 3% stop smoking [14]. Effective approaches are limited. New interventions are needed to increase engagement with SSS, encourage uptake, support quit attempts and produce better outcomes [15]. Stop smoking support Stop smoking support is freely available to pregnant women throughout the UK. Models of support differ however depending on where women live. In general, two main types of support are offered which can be described as ‘specialist’ (just for pregnant women) or ‘generic’ (for all smokers including pregnant women). Within this framework, support offered commonly includes: (1) individual/group support provided by specially trained advisers who may be nurses, or midwives, (2) support provided in hospital setting, women’s homes or other mutually acceptable venue, (3) at least one face-to-face counselling session with follow-up support, often by telephone, to 12 weeks after a quit date is set (4) advice on use of NRT utilising various models of prescribing (e.g. nurse/GP prescribing/pharmacy). The National Institute of Health and Care Excellence (NICE) - PH26 Smoking: stopping in pregnancy and after childbirth [15] published comprehensive guidance in 2010 regarding services that should be provided to pregnant smokers. Scientific premise for the trial The rationale for incentives is that they can stimulate behaviour change through providing an immediate reward for changes in health behaviours (e.g. smoking cessation), that is likely to be more motivating to people than more distal rewards such as health improvements. For smokers who quit, the saving of not buying cigarettes provides continued ‘value’ long after incentives have stopped. Despite the unborn child having no choice regarding tobacco exposure, the ‘extra’ cost of incentives is a deterrent for policymakers and planners and is linked to societal moral judgement of ‘rewarding bad habits’[16, 17]. However, public opinion towards financial incentives is mixed, and public acceptability increases with effectiveness [17, 18]. This study can justify the use of financial incentives by providing evidence to show if this upstream preventive intervention [19, 20] can be cost-effective and much cheaper than trying to cure smoking-related conditions downstream. Evidence for use of financial incentives for stopping smoking during pregnancy Published research using financial incentives for smoking cessation during pregnancy, is limited to single centre trials; however, as reported in two recent Cochrane reviews [21, 22], together they add up to a body of work indicating a beneficial effect that is likely to be cost-effective [23]. Combining data from nine trials of 2273 pregnant women, the 2019 review by Notley [21] concluded there is moderate certainty evidence that women in the incentives groups were more likely to stop smoking than those in the control groups, both at the end of the pregnancy and after the birth of the baby – the RR at longest follow-up (up to 24 weeks post-partum) was 2.38 (95% CI 1.54 to 3.69; N = 2273; I2 = 41%), in favour of incentives. The 2017 review by Chamberlain [22] reported that high quality evidence suggests incentive-based interventions are effective when compared with an alternative (non-contingent incentive) intervention (four studies; RR 2.36, 95% CI 1.36 to 4.09). Pooled effects were not calculable, however, for comparisons with usual care or less intensive interventions (substantial heterogeneity, I2 = 93%). This body of research is still not sufficient to overcome concerns put forward by policy makers regarding financial incentive payments [17] or to fully answer the first research question put forward by the NICE [15]: ‘Within a UK context, are incentives an acceptable, effective and cost-effective way to help women who smoke to quit the habit when they are pregnant or after they have recently given birth? Compared with current services, do they attract more women who smoke, do they lead to more of them completing the stop-smoking programme and do more of them quit for good? What level and type of incentive works best and are there any unintended consequences?’ To start to address these research questions in a UK context, our previous large (n=612) single centre feasibility trial in Glasgow, UK [24] added financial incentives to usual SSS care and compared outcomes with usual care alone. Smokers routinely identified at first maternity care visit were individually randomised to receive either usual SSS support only or the same support with the offer of financial voucher incentives. The first three vouchers were contingent on engagement with SSS. The last voucher (£200) could be earned by stopping without SSS support. 23% quit with the offer of usual care plus incentives (up to £400) and 9% with the offer of usual care alone (p<0.001). A novel embedded health economic evaluation indicated that the intervention was highly cost-effective [23]. Need for further trial The context within which incentives are offered is important. Socio-demographic, geographic and organisation differences may affect future transferability of the intervention and the potential to implement a sustainable intervention in the long term. [25, 26]. Adding incentives to a range of SSS models in different areas of the UK serving varied population groups needs to be tested before clear recommendations can be made. In addition, further evidence is required to inform the cost-effectiveness debate of incentive-based schemes. The economic analysis from our feasibility trial [23] indicated relapse postpartum was the biggest area of uncertainty. Six months is the recommended period to measure long-term abstinence [27] as those abstinent at this time point tend to remain smoke-free long term [28]. A pivotal Phase III multi-centre UK trial that includes cessation outcomes to six months after birth is therefore required to be able to recommend changes in policy and practice [15] and thus for SSS funders (such as the NHS or local government in the UK) to consider this approach to smoking cessation as part of mainstream services. The proposed study will assess if promising feasibility trial findings [24] can be transferred to other UK sites with different SSS configurations and population groups. If found to be effective and cost effective in this multi-site trial, the simple novel ‘bolt-on’ nature of the intervention will make the trial results generalisable to a wide range of SSS and population groups, and allow easier transfer of the intervention to other SSS within the UK and other parts of the world. Objectives This RCT will examine, within a range of usual care pathways, the effectiveness and cost-effectiveness of financial voucher incentives when offered in addition to usual SSS support, to encourage women to attend SSS and set a quit date, to quit smoking and be abstinent towards the end of pregnancy and at six months after birth. The primary objective is to determine if the offer of financial voucher incentives in addition to usual SSS support leads to a doubling of smoking cessation rate by end of pregnancy. Secondary objectives are: To compare quit rates at four weeks post quit date and six months after birth between women offered incentives and those receiving usual SSS care only. To assess, from an NHS perspective, if financial incentives are cost-effective in terms of cost per quitter (at birth and six months postpartum) and per quality adjusted life year gained. To identify the effect of differences in SSS and demographic diversity of pregnant smokers on the effectiveness, cost-effectiveness and transferability of financial voucher incentives. To explore the barriers and facilitators to trial recruitment, retention and implementation in different areas. Trial design This study is a pragmatic, 39-month, multi-centre, parallel group, single blinded, individually randomised controlled superiority trial with 1:1 allocation designed to assess if the addition of financial incentives to usual SSS helps pregnant women to stop smoking. In addition, (1) an economic evaluation from a UK NHS perspective will assess cost-effectiveness of offering financial incentives added to usual SSS, (2) a mixed methods theory-driven [29, 30] process evaluation will examine barriers and facilitators to trial enrolment and future implementation of incentives in a range of contexts, and (3) data from the feasibility trial centre in Glasgow [24], a deprived inner city, will also be analysed in an a- priori meta-analysis. An overview of the trial design is illustrated in figure 1. Figure 1: Overview of trial design and flow of participants through study Methods This protocol is reported according to the 2013 SPIRIT Guidelines [31]. Study setting Women will be recruited from SSS serving maternity hospitals in three of the four UK nations - Scotland, England and Northern Ireland. Participating sites include a deprived city, a deprived post-industrial suburban and rural area, a provincial city, two provincial towns, a deprived coastal city, and a rural area. Each of these sites have different SSS configurations offering their own care pathway within the framework of the UK NICE guidance [15]. These include NHS/Local Authority run services, generic/specialist pregnancy services, midwifery/SSS advisor led services, and opt-in/opt-out services and represent most UK usual care pathways for smoking cessation in pregnancy. Each of the sites have between 1000 and 6000 deliveries per annum. The diversity of sites thus incorporates organisational differences and facilitates recruitment of a mix of women from different geographic and socio-economic backgrounds. Eligibility criteria Eligible women for the trial are those who: (1) are aged 16 years or over, (2) are pregnant less than 24 weeks gestation at maternity booking or if not yet had first antenatal appointment, less than 24 weeks gestation at time of consent, (3) self-report as current smokers (at least one cigarette in the last week), (4) live in the catchment area of the participating NHS site, (5) are able to understand and speak English in order to provide verbal telephone consent and follow-up smoking status. Intervention Control group women will receive the offer of usual, local SSS support. Intervention group women will receive the same offer of usual, local SSS support. In addition, they will be offered financial incentives up to £400 to engage with local SSS and set a quit date, and remain abstinent at each follow-up point throughout pregnancy. The incentives will be in the form of Love2Shop gift cards that can be redeemed in a wide variety of UK shops, none of which currently sell cigarettes. The incentive rewards structure is shown in Figure 2. Figure 2: Incentive and participation rewards structure Adherence with intervention Women allocated to the intervention group will have the opportunity to receive shopping vouchers at four key time points in the trial dependent on smoking status. Consequently, adherence will be assessed by considering distribution and receipt of shopping vouchers, which will be confirmed by Royal Mail signature. Outcomes Primary outcome The primary outcome is cotinine/anabasine verified abstinence from smoking for at least eight weeks towards the end of pregnancy at 34 to 38 weeks gestation. The proportion of abstinent women will be compared between the intervention and control group. Secondary outcomes Secondary outcomes include other key smoking cessation, child, health economic and process endpoints and focus on the difference between intervention and control group regarding: Proportion of women that engage with SSS (locally defined) and set a quit date. Proportion of women with biochemically validated (CO) self-reported abstinence from smoking for at least fourteen days at four weeks after quit date. Proportion of women with cotinine/anabasine verified self-reported point abstinence from smoking for at least eight weeks at six months post-partum. Proportion of women with cotinine/anabasine verified self-reported continuous abstinence from smoking from late pregnancy to six months post-partum. Mean difference in birth weight. Cost effectiveness: incremental cost per late pregnancy quitter and cost per quality adjusted life year (QALY) gained over the trial time horizon and lifetime. Process evaluation: barriers and facilitators to trial recruitment and future implementation of incentives in practice. Data for the primary outcome and secondary outcomes 1, 2 and 5 will be combined with data from the feasibility trial in a meta-analysis – as described in the ‘Statistical methods’ section . Sample size & recruitment The sample size for this phase III trial is 940 pregnant smokers. This was calculated on the basis of the primary outcome. 940 participants (470 in each group) will detect a clinically significant doubling of cotinine validated quit rate from 7% with usual care alone to at least 14% with usual care plus the offer of financial voucher incentives, with 90% power at the 5% significance level allowing 15% loss to follow-up. Eligible pregnant smokers will be enrolled over an 18-24 month period from January 2018 to December 2019. Recruiting for 18 months allows all participants to be followed up to the secondary outcome point six months after birth. Recruiting for 24 months, within the current funding envelope, allows an additional six months of recruitment in the event that this is slower than expected whilst allowing the first 75% of participants recruited to be followed up to the secondary outcome point six months after birth. This compromise was agreed with the funders, the ethics committee and the sponsor prior to the study start in September 2017. Allocation and blinding Enrolment and randomisation will be performed over the telephone by GCP trained call centre staff at the Database Management Company (Trial Contact Centre (TCC)) once women’s contact details and eligibility data have been submitted onto the secure online trial database by research staff. All calls will be audio recorded and information obtained during the call entered directly into the database. After obtaining informed consent and baseline data, TCC staff will then press the onscreen button to randomise women and inform them of their group allocation. TCC staff will not be able to influence or predict the random allocation which is integrated into the database. The random allocation sequence will be generated by York Trials Unit. Women will be allocated 1:1 to either intervention or control group using randomly varying permuted block sizes with no stratification factors. In addition, a random date between 34 and 38 weeks gestation for each pregnancy will be generated as the date for primary outcome data collection. This date will be concealed from both the TCC staff and the women. It will not be possible to blind women or research nurses to group allocation. The TCC staff responsible for ascertaining the primary outcome measure of self-reported smoking in late pregnancy (corroborated by saliva cotinine measurement collected by a research nurse) will however be blind to allocation. Women will be asked not to disclose group status during the follow-up telephone call with the TCC. The statistician conducting analyses will have no contact with women but will not be blind to treatment allocation. Participant timeline and data collection The trial consists of an intervention phase between six and 38 weeks gestation with five assessment points and follow up to six months post-partum. The total study period for each participant will be 42-62 weeks dependent on gestation at enrolment and timing of primary outcome assessment in late pregnancy (randomised between 34 and 38 weeks gestation). See Figure 1 for an overview of the study design and measurement time points and Figure 3 for the schedule of assessment and data collection. Figure 3: Schedule of assessment and data collection Identification and recruitment of participants Information about the trial will be displayed in appropriate clinical areas. Following antenatal assessment pregnant smokers referred to SSS will be assessed for eligibility by local SSS or trial research staff. During first routine contact with SSS, eligible women will be given information about the trial. Those who are interested in taking part will be asked to give verbal permission for further trial contact and for personal details to be passed to the TCC to allow informed telephone consent. The SSS will then continue with usual care and follow-up. If necessary (depending on trial information provided during first routine SSS contact) local research staff will phone women to further discuss the trial prior to the scheduled consent call. On receipt of personal details at the TCC a letter and a participant information sheet (PIS) will be automatically sent to women by post. Three days after this an alert will be sent to those women who agreed to text message contact to remind them of the 0800 number that the TCC will call them from to discuss the study & obtain consent. Consent and randomisation At least five days after posting the PIS the TCC will contact women to undergo formal consent procedures. Telephone contact will be attempted on a minimum of three and a maximum of eight occasions, where possible, at the time slot preferred by the client – weekday am/pm/evening or weekend am/pm - after which no further attempts at enrollment will be made. At the start of the consent call, call handlers will confirm eligibility and receipt of the PIS. Those who report not having received the PIS will be given the option of a verbal summary or to have another copy sent to them and called back in a few days. On proceeding, fifteen consent questions will follow, six of which women must answer and accept to participate in the trial. These include consenting to access to hospital records where appropriate to the trial. One of the remaining nine questions will ask women to consent to trial staff accessing ‘left-over blood’ from routine samples collected in late pregnancy. Telephone consent form is shown as an appendix. After giving informed consent women will be asked baseline questions measuring level of addiction to cigarettes (Fagerstrom Test for Cigarette Dependence [32]), partner smoking, quality of life (EQ-5D-5L), household income and use of nicotine alternatives e.g. NRT or electronic cigarettes. At the end of the telephone call women will be randomised and informed of their group allocation and an automated study pack (copy of consent form showing group allocation and PIS) will be sent to women in the post. Audio recordings of the consent process will be stored in accordance with Good Clinical Practice guidelines. Follow-up 1: SSS Engagement After women have consented and been informed of their group allocation, trial research staff will contact their local SSS to ascertain if women attended a first appointment with an SSS advisor and set a quit date. This information will be entered into the trial database for both control and intervention group women. A £50 voucher will automatically be dispatched to intervention group women who attended and set a quit date. Follow-up 2: Four weeks post quit date For those women who engaged with the SSS and set a quit date, trial research staff will contact their local SSS four weeks after this quit date to obtain smoking status in the last two weeks and CO breath test result as recorded by the SSS. Where a breath test result is not available from the SSS trial research nurses will collect this directly from the woman for the incentives group to initiate incentive payments. CO breath test results will be collected for the control group only where these are available from the SSS in line with national SSS guidelines. This information will be entered onto the trial database. If the CO result is at or below the accepted level for a non-smoker at the site a £50 voucher will automatically be dispatched to women in the incentives group. Follow-up 3: 12 weeks post quit date For those women in the intervention group who were confirmed quit at four weeks, trial research staff will contact their local SSS eight weeks later to obtain smoking status and CO breath test result as recorded by the SSS. Where this is not available from the SSS trial research nurses will collect this directly from the woman. This information will be entered into the trial database. If the CO result is at or below the accepted level for a non-smoker at the site, a £100 voucher will automatically be dispatched. Follow-up 4: Late pregnancy (34-38 weeks gestation) All women will be followed up at the primary outcome stage in late pregnancy. Follow-up telephone contact will be attempted by the TCC at a random date between 34 and 38 weeks gestation allocated at the time of initial randomisation. Trial research nurses will review womens’ notes one week prior to the telephone contact to check health status of mother and baby and alert TCC staff to any adverse events e.g. miscarriage or stillbirth, that may require particular sensitivity when conducting follow-up. TCC staff will be blind to group allocation. Three attempts will be made by the TCC to contact women. If no contact is established women will be followed up by local research staff by telephone, text, and letter. On successful contact women will be asked: ‘Have you smoked in the last 8 weeks?’ If yes ‘Have you smoked more than 5 cigarettes in that time?’ EQ-5D-5L data, and current NRT/electronic cigarette use will also be collected at this time point [33]. Self-report of not smoking will be corroborated by cotinine estimation on saliva or urine (when saliva collection cannot be tolerated). Where women are also using NRT or electronic cigarettes, anabasine assay on urine will replace cotinine. Cotinine and anabasine will be assayed by ABS Laboratories Limited. To minimise the potential for women to ‘game’ the primary outcome, incentive payments will be dependent on the CO result, which is an immediate measure, and not on the cotinine or anabasine level. An important aspect of the primary outcome for this phase III trial is the proportion of women successfully followed up in both the intervention and control group. To minimise loss to follow-up, particularly among controls, women in both groups will receive Love2Shop vouchers of £50 and £25 for providing data and saliva/urine samples where applicable at the primary (late pregnancy) and secondary (six months post-partum) outcome time points respectively (Figure 2.). Acceptable levels are around 90% of participants successfully followed up in each group. To assess if a) women lost to trial follow-up are still smoking towards the end of pregnancy, and b) the primary outcome has been ‘gamed’ (saliva cotinine below the cut-off but still smoking in late pregnancy) residual blood from routine late pregnancy samples, where available, will be tested. Follow-up 5: Six months postpartum Similar to the late pregnancy follow-up all women will be contacted at six months after their baby is born to ascertain smoking status and collect a saliva/urine sample for those women who self-report as quit. (Biological samples of saliva and urine will not be available for use by other researchers). .Quit status six months after birth will be ascertained by two sets of questions: ‘Have you smoked in the last 8 weeks?’ If yes ‘Have you smoked more than 5 cigarettes in that time?’, and ‘Have you smoked since your baby was born?’ If yes, ‘Have you smoked more than 5 cigarettes in total since your baby was born?’ Follow-up procedures (i.e. no. of contact attempts, data collection and saliva/urine sample collection and assay) will be the same as those described for the late pregnancy follow-up. Birth related data collection After the expected date of delivery, research nurses at each site will collect and input to the trial database data regarding parity, baby’s birth date and weight. Data management The data management process will be run by York Trials Unit. The protocol was built on the platform from the phase II trial [34]. This has been improved and updated by York Trials Unit in conjunction with the central trial team (DT, LS and MM) and has been used for submissions for regulatory approval. The database is a modified version of that used in CPIT II. York Trials Unit, central trial management in Glasgow and research staff at one of the recruiting sites have contributed to the design of the modified version. Data entry will be completed by trained research staff at local sites. Statistical Methods Statistical analysis will be conducted by York Trials Unit (AM, AK). All analyses will be carried out using the intention to treat principle unless stated otherwise. Treatment effect estimates will be presented along with the corresponding 95% confidence interval, and statistical tests will be two-sided at the 5% level, unless otherwise stated. Primary outcome analysis Primary outcome analysis will be by intention to treat as the intervention is the offer of a financial incentive to engage with SSS and quit smoking. Logistic regression will adjust for maternal age, years of smoking, deprivation score, level of smoking and site. Secondary outcome analysis Engagement with SSS and self-reported smoking status at four weeks will both be analysed using a logistic regression model adjusting for the same covariates as the primary analysis. Continuous and point abstinence (i.e. regardless of whether participants were abstinent in late pregnancy) outcomes obtained at six months postpartum [28] will be calculated using logistic regression also adjusting for the same covariates as the primary outcome analysis. For each of the following covariates tests for interaction with treatment group will be performed: age of mother, years of smoking, deprivation score and level of smoking. Effects on length of neonatal unit stays will be examined. Birth weight will be analysed using a linear regression model adjusting for key prognostic variables including age, site, height and weight of mother at early pregnancy. The intention to treat estimate will be severely diluted due to low smoking cessation rates and the ‘per protocol’ analysis will be biased by confounding. Consequently we will also utilise an instrumental variable approach – Complier Average Causal Effect analysis – which will estimate the true impact of incentive induced smoking cessation on birth weight [35]. Differences by subgroup (e.g. site, deprivation, age group) will be explored and reported as per the CHAMP guidelines [36]. A meta-analysis including data collected in the feasibility study in Glasgow on 612 participants [24] will be undertaken. Missing data Where there is missing data for the primary outcome (i.e. smoking status) it will be assumed that women are continuing to smoke. This assumption will be examined by testing residual blood samples (taken for other reasons in late pregnancy) for cotinine as in the feasibility trial [24]. This assumption will also apply to the six-month post-partum secondary outcome of smoking status. Other secondary outcomes, e.g. birth weight, are collected routinely and will have little missing data. Long term outcome data collection will be planned from participants and offspring to inform additional follow-up studies. Economic and process evaluations An economic evaluation to assess cost-effectiveness of offering financial incentives in addition to routine SSS will be undertaken from an NHS perspective. Details are the subject of an additional protocol paper to be published separately. A process evaluation using a mixed methods case study approach will explore recruitment and assess ‘intervention context fit’. This is essential to understand both how the trial functions within different SSS and how applicable and generalisable findings may be in terms of future implementation. Full details of the process evaluation design and methods are reported in an online supplement. Data Monitoring Data Monitoring will be coordinated by York Trials Unit (HT) and includes some self-monitoring at sites. Serious Adverse Events (SAEs) that are related to the intervention will be documented. It is not anticipated that the provision of shopping vouchers to women will be associated with any related SAEs. SAEs in the feasibility study were primarily due to miscarriages that were not related to the intervention. For this reason a separate Data Monitoring Committee will not be assembled Stopping the trial for reasons not related to safety such as ‘futility because the required sample size cannot be reached’ will be decided by the Trial Steering Committee. Data Cleaning will be conducted by York Trials Unit (AM) and the central trial management team in Glasgow (LS) Discussion At present, only 10-20% of pregnant smokers take up the offer of free SSS and only 3-8% quit during pregnancy with usual care that includes counseling and NRT. Modest incentive payments to engage with SSS and/or to quit smoking may provide a substantial benefit by decreasing pregnancy and first-infant year health care costs. If women stay smoke-free, long-term health care costs will be substantially reduced. The results of this phase III multi-centre trial will examine the costs and benefits of providing financial incentive payments for smoking cessation during pregnancy across the UK. This evidence will provide information required for NICE to consider recommending financial voucher incentive payments to support pregnant smokers to quit across the UK at the scheduled 2021 guideline PH26 [15] update. Trial status Recruitment opened in February 2018 and will be complete by the end of March 2020. On December 12th 2019, 825 of 940 participants were enrolled into the trial. Current protocol V3.1 27/09/2018 Abbreviations CI, Confidence Interval; CPIT, Cessation in Pregnancy Incentives Trial; GG&C, Greater Glasgow & Clyde; NHS, National Health Service; NICE, National Institute for Health and Clinical Excellence; NRT, Nicotine Replacement Therapy; QALY, Quality-Adjusted Life Year. Declarations Ethics approval and consent to participate Ethics approval was received from West of Scotland REC2 on the 15th August 2017. R&D approval was given to allow SSS staff to pass information to the TCC if the client gives verbal permission. Those who consent to take part in the trial will be sent a written copy of their consent form. In addition, potential participants receive an Information sheet which communicates data confidentiality procedures, the fact that participation is entirely voluntary, and the possibility of leaving the study at any time and without justification. Substantial Amendments: AM02 08/11/2017 Changes to main consent form, main PIS and protocol. REC approved 20/11/2017. AM06 10/07/2018 New procedures: Poster and summary PIS for antennal trial information. Permission for trial staff to contact participants to further explain the trial prior to consent. Process evaluation - £25 voucher to women taking part in interviews and other changes. REC approved 04/09/2018. Current protocol V3.1 27/09/2018 The annual report dated 08/08/2018 informed the ethics committee that new sites were to be involved and that one new site had agreed to take part. ‘On the 26th of July 2018 one new site confirmed that they would like to be a site and could use their own research network staff for local research nurse input required by the trial.’ Four other sites in the same area have also agreed to take part. The sponsor designated addition of these sites as minor amendments AM08 and AM09. The ethics committee has been informed regarding these new sites in the annual report dated 13/09/2019. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Funding Funding for this trial has been provided by: Cancer Research UK, the Chief Scientist Office, Scottish Government; HSC Public Health Agency NI; Chest Heart and Stroke NI, The Lullaby Trust, Public Health Agency NI and the Scottish Cot Death Trust. Authors' contributions DT and LB conceived the study. DT, LB, DTorg, FK, MU, KB, PH, FH, and JM were applicants for the funding. All authors were involved in designing the study and drafting the protocol. KB and NM designed the health economic aspects of the study. JM, PH and FH designed the qualitative aspects of the study. All authors read and approved the final protocol. Trial organisation Trial Steering Committee The overall scientific aspects of the project will be overseen by a Steering Committee. The Steering Committee includes an independent chairperson, the chief investigator, main statistician, trial management support, representatives from the major funding bodies – Cancer Research UK and the Chief Scientist Office, a patient representative and an international scientist with research interests in smoking cessation during pregnancy. The responsibility of the Steering Committee is to ensure the scientific integrity and quality of the project. To achieve this, the specific responsibilities of the Steering Committee include: maintaining adherence to the study protocol; approving changes to study protocol if required; reviewing quality assurance indicators; monitoring study recruitment and the overall study timetable; advising, as required, on specific scientific items that may arise; compliance with legislation; adherence to research governance; reporting to funders; approving publication and dissemination strategies. The Steering Committee will meet every 6 months. Trial Management Group The Trial Management Group comprises the principal investigators, trial manager and trial management support, trial administrator, senior managers from smoking cessation services, data manager, statisticians, health economists and qualitative researchers and supports the running of the trial by the Trial Management Working Group. Review meetings are being held quarterly. Trial Management Working Group The responsibilities of the Trial Management Working Group include: establishing and monitoring recruitment of participants; distributing and supplying appropriate documentation for the trial; data collection and management; data entry and cleaning; data analysis; organising and providing information for the Trial Steering Committee. Data Monitoring Committee An independent Data Monitoring Committee will not be established as adverse events related to the financial incentives intervention are not envisaged and are not being systematically collected. Database Management Company The Database Management Company and the trial team have developed the trial database which sits behind secure firewalls. The database is accessed by trial staff over a secure password protected internet portal. Data extracts are provided to York Trials Unit who manage the data output. This database serves as the data coordinating centre and is overseen by York Trials Unit in terms of data management. The Database Management Company also provide a call centre facility where trained staff conduct trial consent and perform initial data collection for both the primary and secondary outcome assessment of self-reported smoking status near the end of pregnancy and at six months after birth. The Database Management Company subcontract to a Fulfillment House for provision of a secure document fulfillment service to the trial. the Fulfillment House dispatch trial PIS’ to potential participants, paper copies of verbally obtained consent, GP letters and financial voucher incentive payments by recorded delivery. NHS Research and Development Greater Glasgow & Clyde NHS R&D Glasgow is the sponsor for the trial. NHS R&D offices provide accommodation for the main trial team in Glasgow, Scotland. York Trials Unit, University of York York Trials Unit provide trial management support and data management including data monitoring, statistical analysis and reporting for the study. Stop Smoking Services SSS staff are discussing the trial with potential participants and passing details of those who give permission to the TCC. SSS are providing cost data for the economic analysis and a sample of SSS staff will be interviewed as part of the mixed methods process evaluation. Publication policy The primary results of the trial will be published with authorship in relation to specific participation in the study, with the name order to be presented by the principal investigators for consideration by the TSC. Suggested revisions in order of authors should meet with the approval of the principal investigators. Publications in specific areas of the study or on methodological aspects can be led by co-investigators in their area of expertise subject to approval by the TSC and the principal investigators. The requirements for authorship will follow recommended practice in journal guidelines. Confidentiality Encryption defined by NHS GG&C security management is in place to pass data for potential participants from SSS to the Database Management Company managed trial database and call centre. The Database Management Company has a long history of managing government-related services and is able to demonstrate their commitment to data security and quality management through their ISO27001 and ISO9001 accreditations and recent GDPR legislation. Their ISO27001 accredited Information Security Management Systems demand that all of their systems and processes are maintained with confidentiality, integrity and availability of data at the core. In addition the Database Management Company is ISO9001 accredited, the internationally recognized standard for Quality Management Systems. Data is passed via SFTP encrypted in transit. Regular external audits ensure adherence to ISO9001 and ISO27001 standards. Data will be analysed by staff at York Trials Unit. During and after data analysis participants will be identified by their trial number to ensure confidentiality. Site confidentiality will be maintained by anonymising sites. This will allow the process evaluation to provide important insights regarding barriers and facilitators to future implementation without causing difficulties at trial sites. Acknowledgements Authors' information Lesley Sinclair (Trial Manager): Has experience of data management and the management of clinical trials including an MSc in Clinical Trials from London School of Hygiene and Tropical Medicine. She runs the trial on a day to day basis. Lesley managed the CPIT II feasibility trial in Glasgow UK. She has led on development of the trial database in conjunction with the Database Management Company. She assisted with protocol development for this trial and supported by Helen Tilbrook at York Trial Unit is managing all operational aspects of this trial. Lesley Sinclair and David Tappin wrote this paper with input from all the authors above. Margaret McFadden (Lead Trial Research Nurse) was Lead Research Nurse on CPIT II. She is a very experienced research nurse who has undertaken many trial related roles as research nurse. Margaret is acting as research nurse for one site. She is also leading the research nurses for all sites and has trained the nurses in data and sample collection for the trial. She has been closely involved in development of the trial database. Helen Tilbrook is Research Fellow at York Trials Unit, University of York. Helen has an MSc in Health Services Research and extensive experience of managing clinical trials. She is responsible for providing trial management support including data monitoring. She also supports Lesley Sinclair in her trial management role particularly regarding organisation of the Trial Steering Committee and the Trial Management Group. Helen has been closely involved in development of the trial protocol and submission to regulatory bodies as well as supporting development of the trial database. Helen is supervised by Judith Watson. Alex Mitchell is the Trial Statistician and Trainee Statistician at, York Trials Unit, University of York. Alex is responsible for providing day-to-day statistical support for the study including statistical aspects of data management and monitoring. Alex runs the statistical aspects of the trial supported by Ada Keding. Ada Keding provides supervision to Alex Mitchell at York Trials Unit and will plan and support Alex to undertake statistical analysis for the trial. Judith Watson supervises Helen Tilbrook at York Trials Unit including the data management and data monitoring aspects of the trial. Linda Bauld is Co-Principal Investigator for the trial and is the Bruce and John Usher Chair in Public Health, Usher Institute, University of Edinburgh. Linda has extensive experience of quantitative and particularly qualitative work related to smoking cessation. She supports the trial on a regular basis and will be involved in writing and dissemination of results. Frank Kee is Professor of Public Health at Queens University Belfast and is co-applicant. Frank administers grant funding for some staff. He has helped with protocol development and in many other aspects of support for the trial. David Torgerson is a co-applicant and is Director of York Trial Unit, University of York. He supported the study team during grant application for the trial including direction on trial design (cluster or individual randomisation). He has overseen design of data collection in relation to statistical analysis. Through York Trials Unit he has supported the running of the trial so that it is safe for the funders regarding their investment. Catherine Hewitt is co-applicant and Deputy Director of York Trials Unit. Catherine has assessed and designed the support required from York Trials Unit to reduce the risk to the funders regarding their investment. Catherine has supported the data management design for the trial. Jennifer McKell is a Research Fellow in the Institute for Social Marketing at the University of Stirling. She is a qualitative researcher with extensive experience of carrying out research in relation to tobacco use and smoking in pregnancy, including the qualitative element of the CPIT II feasibility trial. She is the main researcher working on the trial’s embedded process evaluation for this trial. Pat Hoddinott holds a Chair in Primary Care, in the Nursing Midwifery and Health Professionals Research Unit at the University of Stirling. She has clinical and trial expertise in maternal and child health, preventative medicine, behaviour change and financial incentives. She is advising on all aspects of the trial and oversees the process evaluation. Fiona Harris is an Associate Professor in Medical Anthropology and Health Services Research, Nursing, Midwifery and Allied Health Professions Research Unit at the University of Stirling. She has extensive experience of conducting mixed methods process evaluations within trials and will support the conduct, analysis and reporting of the process evaluation component of the study. Isabelle Uny is social scientist by training and a researcher at the Institute for Social Marketing (ISM), University of Stirling. Her expertise is in global policy making and policy implementation analysis. She also specialises in qualitative health research (methods/ analysis/ frameworks) and qualitative evidence synthesis (particularly meta-ethnography). Her work focuses primarily on non-communicable diseases (NCDs) and maternal health. She will support the data collection, analysis and reporting of the process evaluation. Kathleen Boyd is Senior Lecturer in Health Economics at Glasgow University with extensive experience of decision modelling and designing and analysing trial based economic evaluations, particularly in SSS. She designed and will undertake the health economic evaluation. Nicola McMeekin is a Research Assistant in health economics and has experience of designing and undertaking economic evaluations alongside clinical trials. She helped design the health economic evaluation and will carry out the analysis in conjunction with KB. Michael Ussher is Professor of Behavioural Medicine at the St George’s, University of London and at the University of Stirling. Michael has extensive experience of trials of smoking cessation in pregnancy and advises on all aspects of the study and especially on issues related to health psychology. David Tappin is Co-Principal Investigator and Senior Research Fellow at Glasgow University based at the Scottish Cot Death Trust, in Glasgow. David has experience of the management of clinical trials including an MSc in Clinical Trials from London School of Hygiene and Tropical Medicine. He wrote all the grant applications for this trial and writes all the funding reports. He co-ordinates and manages the overall running of the trial and will be closely involved in data analysis and paper writing and dissemination of results. References Parkin DM, Boyd L, Walker LC: The fraction of cancer attributable to lifestyle and environmental factors in the UK in 2010. Br J Cancer 2011, 105: S77-81. Doll R, Peto R, Boreham J, Sutherland I: Mortality in relation to smoking: 50 years’ observations on male British doctors. BMJ 2004, 328: 1519. Portanti M, Whitworth S: A comparison of the characteristics of childless women and mothers in the ONS Longitudinal Study. Office for National Statistics, Population Trends 2009, 136: 10-20. Leonardi-Bee J, Jere ML, Britton J: Exposure to parental and sibling smoking and the risk of smoking uptake in childhood and adolescence: a systematic review and metaanalysis. Thorax 2011, 66 : 847-55 . Flenady V, Koopmans L, Middleton P, Frøen JF, Smith GC, Gibbons K, Coory M, Gordon A, Ellwood D, McIntyre HD, Fretts R, Ezzati M: Major risk factors for stillbirth in high-income countries: a systematic review and meta-analysis. Lancet 2011, 377: 1331-40. Avalos LA, Galindo C, Li D: A Systematic Review to Calculate Background Miscarriage Rates using Life Table Analysis. Birth Defects Research (Part A) 2012, 94: 417–23. Jurkovic D, Overton C, Bender-Atik R. Diagnosis and management of first trimester miscarriage. BMJ , 2013; 346: f3676. Surgeon General US Department of Health and Human Services. The health consequences of smoking—50 years of progress: a report of the surgeon general. US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, Chapter 9. 2014, www. surgeongeneral.gov/library/reports/50-years-of-progress/sgr50-chap-9.pdf. Lawder R, Whyte B, Wood R, et al. Impact of maternal smoking on early childhood health: a retrospective cohort linked dataset analysis of 697 003 children born in Scotland 1997–2009. BMJ Open 2019, 9: e023213. doi:10.1136/bmjopen-2018-023213 Button TM, Maughan B, McGuffin P: The relationship of maternal smoking to psychological problems in the offspring. Early Hum Dev 2007, 83(11): 727-32. Batstra L, Hadders-Algra M, Neeleman J: Effect of antenatal exposure to maternal smoking on behavioural problems and academic achievement in childhood: prospective evidence from a Dutch birth cohort. Early Hum Dev 2003, 75(1-2): 21-33. Godfrey C, Pickett KE, Parrot S,Mdege N, Eapen D: Estimating the costs to the NHS of smoking in pregnancy for pregnant women and infants. 2010, http://phrc.lshtm.ac.uk/papers/PHRC_A3-06_Final_Report.pdf HSCIC (Health and Social Care Information Centre): Infant Feeding Survey 2010. 2011, http://www.hscic.gov.uk/catalogue/PUB00648 Tappin DM, MacAskill S, Bauld L, Eadie D, Shipton D, Galbraith L: Smoking prevalence and smoking cessation services for pregnant women in Scotland. Subst Abuse Treat Prev Policy 2010, 5: 1. NICE (National Institute for Health and Care Excellence). Smoking: stopping in pregnancy and after childbirth. Public Health Guidance 26 . 2010; https://www.nice.org.uk/guidance/ph26 Giles EL, Sniehotta FF, McColl E, Adams J: Acceptability of financial incentives and penalties for encouraging uptake of healthy behaviours: focus groups. BMC Public Health 2015, 15: 58. Hoddinott P, Morgan H, Maclennan G, Sewel K, Thomson G, Bauld L, Deokhee Y, Ludbrook A, Campbell MK: Public acceptability of financial incentives for smoking cessation in pregnancy and breastfeeding: a survey of the British Public. BMJ Open 2014, 4(7): e005524. Promberger M, Dolan P, Marteau T. ‘Pay them if it works’: discrete choice experiments on the acceptability of financial incentives to change health related behaviour. Soc Sci Med 2012; 75: 2509–14. Higgins ST, Silverman K, Sigmon SC, Naito NA: Incentives and health: An introduction . Preventive Medicine 2012, 55: S2-6. Owen L, Morgan A, Fischer A, Ellis S, Hoy A, Kelly MP : Health Economic Advisor. The cost-effectiveness of public health interventions. J Public Health 2012, 34(1): 37-45. Notley C, Gentry S, Livingstone-Banks J, Bauld L, Perera R, Hartmann-Boyce J. Incentives for smoking cessation. Cochrane Database Syst Rev 2019, 7: CD004307. DOI: 10.1002/14651858.CD004307.pub6. Chamberlain C, O'Mara-Eves A, Porter J, Coleman T, Perlen SM, Thomas J, McKenzie JE. Psychosocial interventions for supporting women to stop smoking in pregnancy. Cochrane Database Syst Rev 2017, 2: CD001055. DOI: 10.1002/14651858.CD001055.pub5 Boyd KA , Briggs AH , Bauld L , Sinclair L, Tappin D: Are financial incentives cost-effective to support smoking cessation during pregnancy? Addiction 2016, 111(2): 360-70. Tappin D, Bauld L, Purves D, Boyd K, Sinclair L, MacAskill S, McKell J, Friel B, McConnachie A, De Caestecker L, Tannahill C, Radley A, Coleman T. Financial incentives for smoking cessation in pregnancy: Randomised controlled trial. BMJ 2015, 350 : h134. Rychetnik L, Fommer M, Hawe P, Shiell A: Criteria for evaluating evidence on public health. J Epidemiol Community Health 2002, 56: 119-27. Burchett H, Umoquit M, Dobrow M: How do we know when research from one setting can be useful in another? A review of external validity, applicability and transferability frameworks. J Health Serv Res Policy 2011, 16(4): 238–44. West R, Hajek P, Stead L, Stapleton J: Outcome criteria in smoking cessation trials: proposal for a common standard. Addiction 2005, 100(3): 299-303. Gilpin EA, Pierce JP, Farkas AJ: Duration of smoking abstinence and success in quitting. J Natl Cancer Inst 1997, 89(8): 572-6. Yin RK. Enhancing the quality of case studies in health services research. Health Serv Res 1999: 34 (5 Pt 2) Stake RE. The art of case study research . 1995. Thousand Oaks, CA: Sage; Chan A-W, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin J, Dickersin K, Hróbjartsson A, Schulz KF, Parulekar WR, Krleža-Jerić K, Laupacis A, Moher D. SPIRIT 2013 Explanation and Elaboration: Guidance for protocols of clinical trials. BMJ 2013; 346: Fagerström K. Determinants of tobacco use and renaming the FTND to the Fagerstrom Test for Cigarette Dependence. Nicotine Tob Res 2012;14:75-8. Janssen MF , Pickard AS , Golicki D , Gudex C , Niewada M , Scalone L , Swinburn P , Busschbach J . Measurement properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a multi-country study. Qual Life Res 2013; 7: 1717-27. doi: 10.1007/s11136-012-0322-4. Tappin DM , Bauld L , Tannahill C , de Caestecker L , Radley A , McConnachie A , Boyd K , Briggs A , Grant L , Cameron A , Macaskill S , Sinclair L , Friel B , Coleman T . The cessation in pregnancy incentives trial (CPIT): study protocol for a randomised controlled trial. Trials 2012; 13: 113. Van Hoorn R, Tummers M, Booth A, Gerhardus A, Rehfuess E, Hind D, Bossuyt PM, Welch V, Debray TPA, Underwood M, Ciijpers P, Kraemer H, Van der Wilt GJ, Kievit W. The development of CHAMP: a checklist for the appraisal of moderators and predictors . BMC Medical Research Methodology 2017; 17: 173 DOI 10.1186/s12874-017-0451-039. Morgan H, Hoddinott P, Thomson G, Crossland N, Farrar S, Yi D, Hislop J, Hall Moran V, MacLennan G, Dombrowski SU, Rothnie K, Stewart F, Bauld L, Ludbrook A, Dykes F, Sniehotta FF, Tappin D, Campbell M. Benefits of incentives for breastfeeding and smoking cessation in pregnancy (BIBS): a mixed methods study to inform trial design. Health Technology Assessment 2015: 19; 30. Pawson R, Tilley N. Realistic Evaluation . 1997. London: Sage Ritchie J, Spencer E. Qualitative Data Analysis for Applied Policy Research. 1994 in A. Bryman and R.G. Burgess [eds.] ‘Analysing Qualitative Data’ (pp. 173-94). London: Routledge. Farmer T, Robinson K, Elliott SJ, EylesJ. Developing and Implementing a Triangulation Protocol for Qualitative Health Research Qualitative Health Research 2006; 16(3): 377-394 DOI: 10.1177/1049732305285708 Supplementary Files SPIRITChecklistTappinCPITTrialProtocol12122019.pdf Cite Share Download PDF Status: Published Journal Publication published 14 Feb, 2020 Read the published version in Trials → Version 2 posted Editorial decision: Accept 30 Dec, 2019 Editor assigned by journal 25 Dec, 2019 Submission checks completed at journal 14 Dec, 2019 You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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aims","content":"\u003cp\u003eTobacco smoking is the leading preventable cause of death in the UK [1]. Individuals who give up by age 40 (during childbearing years) avoid much of the morbidity and early mortality of continued smoking [2]; e.g. lung cancer risk is reduced to two times that of never smokers compared with 16 times for lifelong smokers. Around 80% percent of UK women have at least one baby [3] so an effective intervention will eventually reach most women who smoke. Stopping smoking during pregnancy also reduces the likelihood of the children themselves becoming smokers [4], thus reducing future cancer risk.\u003c/p\u003e\n\u003cp\u003e350 UK still births each year [5] and a third of babies born small for gestational age are attributable to smoking during pregnancy. One fifth of the 125,000 spontaneous miscarriages that occur each year in the UK [6], which cause 42,000 hospital admissions [7], are also associated with smoking during pregnancy. Compared with non-smokers the relative risk of spontaneous miscarriage is 1.2 [8]. If causality were accepted, this 20% increase in risk would mean 5000 spontaneous miscarriages and 2000 hospital admissions in the UK each year would be attributable to smoking during pregnancy.\u003c/p\u003e\n\u003cp\u003e20% of sudden unexpected deaths in infancy and 9% of premature births are attributable to maternal smoking as are 10% of admissions for bronchiolitis, one of the most common reasons infants are admitted to hospital, and 7% of admissions for respiratory infection and asthma [9]. Perhaps, surprisingly, 12% of the rare, but devastating occurrence of bacterial meningitis is attributable to maternal smoking [9] as are increases in attention deficit disorder [10] and learning difficulties [11] in children, adding substantial costs to health and social care services [12].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrevalence and available support for stopping smoking in pregnancy \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUK pregnancy smoking rates remain high. One in four women smoke for part of their pregnancy and one in eight smoke throughout [13]. Stop smoking services (SSS) usually offer counselling plus free Nicotine Replacement Therapy (NRT); however, only 10% of pregnant smokers use these services and as few as 3% stop smoking [14]. Effective approaches are limited. New interventions are needed to increase engagement with SSS, encourage uptake, support quit attempts and produce better outcomes [15]. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStop smoking support \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStop smoking support is freely available to pregnant women throughout the UK. Models of support differ however depending on where women live. In general, two main types of support are offered which can be described as \u0026lsquo;specialist\u0026rsquo; (just for pregnant women) or \u0026lsquo;generic\u0026rsquo; (for all smokers including pregnant women). Within this framework, support offered commonly includes: (1) individual/group support provided by specially trained advisers who may be nurses, or midwives, (2) support provided in hospital setting, women\u0026rsquo;s homes or other mutually acceptable venue, (3) at least one face-to-face counselling session with follow-up support, often by telephone, to 12 weeks after a quit date is set (4) advice on use of NRT utilising various models of prescribing (e.g. nurse/GP prescribing/pharmacy). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe National Institute of Health and Care Excellence (NICE) - PH26 Smoking: stopping in pregnancy and after childbirth [15] published comprehensive guidance in 2010 regarding services that should be provided to pregnant smokers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eScientific premise for the trial\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe rationale for incentives is that they can stimulate behaviour change through providing an immediate reward for changes in health behaviours (e.g. smoking cessation), that is likely to be more motivating to people than more distal rewards such as health improvements. For smokers who quit, the saving of not buying cigarettes provides continued \u0026lsquo;value\u0026rsquo; long after incentives have stopped. Despite the unborn child having no choice regarding tobacco exposure, the \u0026lsquo;extra\u0026rsquo; cost of incentives is a deterrent for policymakers and planners and is linked to societal moral judgement of \u0026lsquo;rewarding bad habits\u0026rsquo;[16, 17]. However, public opinion towards financial incentives is mixed, and public acceptability increases with effectiveness [17, 18]. This study can justify the use of financial incentives by providing evidence to show if this upstream preventive intervention [19, 20] can be cost-effective and much cheaper than trying to cure smoking-related conditions downstream.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEvidence for use of financial incentives for stopping smoking during pregnancy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePublished research using financial incentives for smoking cessation during pregnancy, is limited to single centre trials; however, as reported in two recent Cochrane reviews [21, 22], together they add up to a body of work indicating a beneficial effect that \u0026nbsp;is likely to be cost-effective [23]. Combining data from nine trials of 2273 pregnant women, the 2019 review by Notley [21] concluded there is moderate certainty evidence that women in the incentives groups were more likely to stop smoking than those in the control groups, both at the end of the pregnancy and after the birth of the baby \u0026ndash; the RR at longest follow-up (up to 24 weeks post-partum) was 2.38 (95% CI 1.54 to 3.69; N = 2273; I2 = 41%), in favour of incentives. The 2017 review by Chamberlain [22] reported that high quality evidence suggests incentive-based interventions are effective when compared with an alternative (non-contingent incentive) intervention (four studies; RR 2.36, 95% CI 1.36 to 4.09). Pooled effects were not calculable, however, for comparisons with usual care or less intensive interventions (substantial heterogeneity, I2 = 93%).\u003c/p\u003e\n\u003cp\u003eThis body of research is still not sufficient to overcome concerns put forward by policy makers regarding financial incentive payments [17] or to fully answer the first research question put forward by the NICE [15]: \u0026lsquo;Within a UK context, are incentives an acceptable, effective and cost-effective way to help women who smoke to quit the habit when they are pregnant or after they have recently given birth? Compared with current services, do they attract more women who smoke, do they lead to more of them completing the stop-smoking programme and do more of them quit for good? What level and type of incentive works best and are there any unintended consequences?\u0026rsquo;\u003c/p\u003e\n\u003cp\u003eTo start to address these research questions in a UK context, our previous large (n=612) single centre feasibility trial in Glasgow, UK [24] added financial incentives to usual SSS care and compared outcomes with usual care alone. Smokers routinely identified at first maternity care visit were individually randomised to receive either usual SSS support only or the same support with the offer of financial voucher incentives. The first three vouchers were contingent on engagement with SSS. The last voucher (\u0026pound;200) could be earned by stopping without SSS support. 23% quit with the offer of usual care plus incentives (up to \u0026pound;400) and 9% with the offer of usual care alone (p\u0026lt;0.001). A novel embedded health economic evaluation indicated that the intervention was highly cost-effective [23].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNeed for further trial\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe context within which incentives are offered is important. Socio-demographic, geographic and organisation differences may affect future transferability of the intervention and the potential to implement a sustainable intervention in the long term. [25, 26]. Adding incentives to a range of SSS models in different areas of the UK serving varied population groups needs to be tested before clear recommendations can be made.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn addition, further evidence is required to inform the cost-effectiveness debate of incentive-based schemes. The economic analysis from our feasibility trial [23] indicated relapse postpartum was the biggest area of uncertainty. Six months is the recommended period to measure long-term abstinence [27] as those abstinent at this time point tend to remain smoke-free long term [28].\u003c/p\u003e\n\u003cp\u003eA pivotal Phase III multi-centre UK trial that includes cessation outcomes to six months after birth is therefore required to be able to recommend changes in policy and practice [15] and thus for SSS funders (such as the NHS or local government in the UK) to consider this approach to smoking cessation as part of mainstream services.\u003c/p\u003e\n\u003cp\u003eThe proposed study will assess if promising feasibility trial findings [24] can be transferred to other UK sites with different SSS configurations and population groups. If found to be effective and cost effective in this multi-site trial, the simple novel \u0026lsquo;bolt-on\u0026rsquo; nature of the intervention will make the trial results generalisable to a wide range of SSS and population groups, and allow easier transfer of the intervention to other SSS within the UK and other parts of the world.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectives\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis RCT will examine, within a range of usual care pathways, the effectiveness and cost-effectiveness of financial voucher incentives when offered in addition to usual SSS support, to encourage women to attend SSS and set a quit date, to quit smoking and be abstinent towards the end of pregnancy and at six months after birth.\u003c/p\u003e\n\u003cp\u003eThe primary objective is to determine if the offer of financial voucher incentives in addition to usual SSS support leads to a doubling of smoking cessation rate by end of pregnancy.\u003c/p\u003e\n\u003cp\u003eSecondary objectives are:\u003c/p\u003e\n\u003cp\u003eTo compare quit rates at four weeks post quit date and six months after birth between women offered incentives and those receiving usual SSS care only.\u003c/p\u003e\n\u003cp\u003eTo assess, from an NHS perspective, if financial incentives are cost-effective in terms of cost per quitter (at birth and six months postpartum) and per quality adjusted life year gained.\u003c/p\u003e\n\u003cp\u003eTo identify the effect of differences in SSS and demographic diversity of pregnant smokers on the effectiveness, cost-effectiveness and transferability of financial voucher incentives.\u003c/p\u003e\n\u003cp\u003eTo explore the barriers and facilitators to trial recruitment, retention and implementation in different areas.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is a pragmatic, 39-month, multi-centre, parallel group, single blinded,\u0026nbsp; individually randomised controlled superiority trial with 1:1 allocation designed to assess if the addition of financial incentives to usual SSS helps pregnant women to stop smoking. In addition, (1) an economic evaluation from a UK NHS perspective will assess cost-effectiveness of offering financial incentives added to usual SSS, (2) a mixed methods theory-driven [29, 30] process evaluation will examine barriers and facilitators to trial enrolment and future implementation of incentives in a range of contexts, and (3) data from the feasibility trial centre in Glasgow [24], a deprived inner city, will also be analysed in an a- priori meta-analysis.\u003c/p\u003e\n\u003cp\u003eAn overview of the trial design is illustrated in figure 1.\u003c/p\u003e\n\u003cp\u003eFigure 1: Overview of trial design and flow of participants through study\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis protocol is reported according to the 2013 SPIRIT Guidelines [31].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy setting\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWomen will be recruited from SSS serving maternity hospitals in three of the four UK nations - Scotland, England and Northern Ireland. Participating sites include a deprived city, a deprived post-industrial suburban and rural area, a provincial city, two provincial towns, a deprived coastal city, and a rural area. Each of these sites have different SSS configurations offering their own care pathway within the framework of the UK NICE guidance [15]. These include NHS/Local Authority run services, generic/specialist pregnancy services, midwifery/SSS advisor led services, and opt-in/opt-out services and represent most UK usual care pathways for smoking cessation in pregnancy. Each of the sites have between 1000 and 6000 deliveries per annum. The diversity of sites thus incorporates organisational differences and facilitates recruitment of a mix of women from different geographic and socio-economic backgrounds.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEligibility criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEligible women for the trial are those who: (1) are aged 16 years or over, (2) are pregnant less than 24 weeks gestation at maternity booking or if not yet had first antenatal appointment, less than 24 weeks gestation at time of consent, (3) self-report as current smokers (at least one cigarette in the last week), (4) live in the catchment area of the participating NHS site, (5)\u0026nbsp; are able to understand and speak English in order to provide verbal telephone consent and follow-up smoking status.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntervention\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eControl group women will receive the offer of usual, local SSS support.\u003c/p\u003e\n\u003cp\u003eIntervention group women will receive the same offer of usual, local SSS support. In addition, they will be offered financial incentives up to \u0026pound;400 to engage with local SSS and set a quit date, and remain abstinent at each follow-up point throughout pregnancy. The incentives will be in the form of Love2Shop gift cards that can be redeemed in a wide variety of UK shops, none of which currently sell cigarettes. The incentive rewards structure is shown in Figure 2.\u003c/p\u003e\n\u003cp\u003eFigure 2: Incentive and participation rewards structure\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdherence with intervention\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWomen allocated to the intervention group will have the opportunity to receive shopping vouchers at four key time points in the trial dependent on smoking status. Consequently, adherence will be assessed by considering distribution and receipt of shopping vouchers, which will be confirmed by Royal Mail signature.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary outcome\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcome is cotinine/anabasine verified abstinence from smoking for at least eight weeks towards the end of pregnancy at 34 to 38 weeks gestation. The proportion of abstinent women will be compared between the intervention and control group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSecondary outcomes include other key smoking cessation, child, health economic and process endpoints and focus on the difference between intervention and control group regarding:\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003eProportion of women that engage with SSS (locally defined) \u003cu\u003eand\u003c/u\u003e set a quit date.\u003c/li\u003e\n\u003cli\u003eProportion of women with biochemically validated (CO) self-reported abstinence from smoking for at least fourteen days at four weeks after quit date.\u003c/li\u003e\n\u003cli\u003eProportion of women with cotinine/anabasine verified self-reported point abstinence from smoking for at least eight weeks at six months post-partum.\u003c/li\u003e\n\u003cli\u003eProportion of women with cotinine/anabasine verified self-reported continuous abstinence from smoking from late pregnancy to six months post-partum.\u003c/li\u003e\n\u003cli\u003eMean difference in birth weight.\u003c/li\u003e\n\u003cli\u003eCost effectiveness: incremental cost per late pregnancy quitter and cost per quality adjusted life year (QALY) gained over the trial time horizon and lifetime.\u003c/li\u003e\n\u003cli\u003eProcess evaluation: barriers and facilitators to trial recruitment and future implementation of incentives in practice.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eData for the primary outcome and secondary outcomes 1, 2 and 5 will be combined with data from the feasibility trial in a meta-analysis \u0026ndash;\u003cem\u003eas described in the \u0026lsquo;Statistical methods\u0026rsquo; section\u003c/em\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size \u0026amp; recruitment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe sample size for this phase III trial is 940 pregnant smokers. This was calculated on the basis of the primary outcome. 940 participants (470 in each group) will detect a clinically significant doubling of cotinine validated quit rate from 7% with usual care alone to at least 14% with usual care plus the offer of financial voucher incentives, with 90% power at the 5% significance level allowing 15% loss to follow-up.\u003c/p\u003e\n\u003cp\u003eEligible pregnant smokers will be enrolled over an 18-24 month period from January 2018 to December 2019. Recruiting for 18 months allows all participants to be followed up to the secondary outcome point six months after birth. Recruiting for 24 months, within the current funding envelope, allows an additional six months of recruitment in the event that this is slower than expected whilst allowing the first 75% of participants recruited to be followed up to the secondary outcome point six months after birth. This compromise was agreed with the funders, the ethics committee and the sponsor prior to the study start in September 2017.\u003c/p\u003e\n\u003cp\u003eAllocation and blinding\u003c/p\u003e\n\u003cp\u003eEnrolment and randomisation will be performed over the telephone by GCP trained call centre staff at the Database Management Company (Trial Contact Centre (TCC)) once women\u0026rsquo;s contact details and eligibility data have been submitted onto the secure online trial database by research staff. All calls will be audio recorded and information obtained during the call entered directly into the database. After obtaining informed consent and baseline data, TCC staff will then press the onscreen button to randomise women and inform them of their group allocation. TCC staff will not be able to influence or predict the random allocation which is integrated into the database.\u003c/p\u003e\n\u003cp\u003eThe random allocation sequence will be generated by York Trials Unit. Women will be allocated 1:1 to either intervention or control group using randomly varying permuted block sizes with no stratification factors. In addition, a random date between 34 and 38 weeks gestation for each pregnancy will be generated as the date for primary outcome data collection. This date will be concealed from both the TCC staff and the women.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;It will not be possible to blind women or research nurses to group allocation. The TCC staff responsible for ascertaining the primary outcome measure of self-reported smoking in late pregnancy (corroborated by saliva cotinine measurement collected by a research nurse) will however be blind to allocation. Women will be asked not to disclose group status during the follow-up telephone call with the TCC. The statistician conducting analyses will have no contact with women but will not be blind to treatment allocation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipant timeline and data collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial consists of an intervention phase between six and 38 weeks gestation with five assessment points and follow up to six months post-partum. The total study period for each participant will be 42-62 weeks dependent on gestation at enrolment and timing of primary outcome assessment in late pregnancy (randomised between 34 and 38 weeks gestation). See Figure 1 for an overview of the study design and measurement time points and Figure 3 for the schedule of assessment and data collection.\u003c/p\u003e\n\u003cp\u003eFigure 3: Schedule of assessment and data collection\u003c/p\u003e\n\u003cp\u003eIdentification and recruitment of participants\u003c/p\u003e\n\u003cp\u003eInformation about the trial will be displayed in appropriate clinical areas. Following antenatal assessment pregnant smokers referred to SSS will be assessed for eligibility by local SSS or trial research staff. During first routine contact with SSS, eligible women will be given information about the trial. Those who are interested in taking part will be asked to give verbal permission for further trial contact and for personal details to be passed to the TCC to allow informed telephone consent. The SSS will then continue with usual care and follow-up. If necessary (depending on trial information provided during first routine SSS contact) local research staff will phone women to further discuss the trial prior to the scheduled consent call. On receipt of personal details at the TCC a letter and a participant information sheet (PIS) will be automatically sent to women by post. Three days after this an alert will be sent to those women who agreed to text message contact to remind them of the 0800 number that the TCC will call them from to discuss the study \u0026amp; obtain consent.\u003c/p\u003e\n\u003cp\u003eConsent and randomisation\u003c/p\u003e\n\u003cp\u003eAt least five days after posting the PIS the TCC will contact women to undergo formal consent procedures. Telephone contact will be attempted on a minimum of three and a maximum of eight occasions, where possible, at the time slot preferred by the client \u0026ndash; weekday am/pm/evening or weekend am/pm - after which no further attempts at enrollment will be made. At the start of the consent call, call handlers will confirm eligibility and receipt of the PIS. Those who report not having received the PIS will be given the option of a verbal summary or to have another copy sent to them and called back in a few days. On proceeding, fifteen consent questions will follow, six of which women must answer and accept to participate in the trial. These include consenting to access to hospital records where appropriate to the trial. One of the remaining nine questions will ask women to consent to trial staff accessing \u0026lsquo;left-over blood\u0026rsquo; from routine samples collected in late pregnancy. Telephone consent form is shown as an appendix. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAfter giving informed consent women will be asked baseline questions measuring level of addiction to cigarettes (Fagerstrom Test for Cigarette Dependence [32]), partner smoking, quality of life (EQ-5D-5L), household income and use of nicotine alternatives e.g. NRT or electronic cigarettes. At the end of the telephone call women will be randomised and informed of their group allocation and an automated study pack (copy of consent form showing group allocation and PIS) will be sent to women in the post. Audio recordings of the consent process will be stored in accordance with Good Clinical Practice guidelines.\u003c/p\u003e\n\u003cp\u003eFollow-up 1: SSS Engagement\u003c/p\u003e\n\u003cp\u003eAfter women have consented and been informed of their group allocation, trial research staff will contact their local SSS to ascertain if women attended a first appointment with an SSS advisor and set a quit date. This information will be entered into the trial database for both control and intervention group women. A \u0026pound;50 voucher will automatically be dispatched to intervention group women who attended and set a quit date.\u003c/p\u003e\n\u003cp\u003eFollow-up 2: Four weeks post quit date\u003c/p\u003e\n\u003cp\u003eFor those women who engaged with the SSS and set a quit date, trial research staff will contact their local SSS four weeks after this quit date to obtain smoking status in the last two weeks and CO breath test result as recorded by the SSS. Where a breath test result is not available from the SSS trial research nurses will collect this directly from the woman for the incentives group to initiate incentive payments. CO breath test results will be collected for the control group only where these are available from the SSS in line with national SSS guidelines. This information will be entered onto the trial database. If the CO result is at or below the accepted level for a non-smoker at the site a \u0026pound;50 voucher will automatically be dispatched to women in the incentives group.\u003c/p\u003e\n\u003cp\u003eFollow-up 3: 12 weeks post quit date\u003c/p\u003e\n\u003cp\u003eFor those women in the intervention group who were confirmed quit at four weeks, trial research staff will contact their local SSS eight weeks later to obtain smoking status and CO breath test result as recorded by the SSS. Where this is not available from the SSS trial research nurses will collect this directly from the woman. This information will be entered into the trial database. If the CO result is at or below the accepted level for a non-smoker at the site, a \u0026pound;100 voucher will automatically be dispatched.\u003c/p\u003e\n\u003cp\u003eFollow-up 4: Late pregnancy (34-38 weeks gestation)\u003c/p\u003e\n\u003cp\u003eAll women will be followed up at the primary outcome stage in late pregnancy. Follow-up telephone contact will be attempted by the TCC at a random date between 34 and 38 weeks gestation allocated at the time of initial randomisation. Trial research nurses will review womens\u0026rsquo; notes one week prior to the telephone contact to check health status of mother and baby and alert TCC staff to any adverse events e.g. miscarriage or stillbirth, that may require particular sensitivity when conducting follow-up. TCC staff will be blind to group allocation.\u003c/p\u003e\n\u003cp\u003eThree attempts will be made by the TCC to contact women. If no contact is established women will be followed up by local research staff by telephone, text, and letter. On successful contact women will be asked: \u0026lsquo;Have you smoked in the last 8 weeks?\u0026rsquo; If yes \u0026lsquo;Have you smoked more than 5 cigarettes in that time?\u0026rsquo; EQ-5D-5L data, and current NRT/electronic cigarette use will also be collected at this time point [33].\u003c/p\u003e\n\u003cp\u003eSelf-report of not smoking will be corroborated by cotinine estimation on saliva or urine (when saliva collection cannot be tolerated). Where women are also using NRT or electronic cigarettes, anabasine assay on urine will replace cotinine. Cotinine and anabasine will be assayed by ABS Laboratories Limited. To minimise the potential for women to \u0026lsquo;game\u0026rsquo; the primary outcome, incentive payments will be dependent on the CO result, which is an immediate measure, and not on the cotinine or anabasine level.\u003c/p\u003e\n\u003cp\u003eAn important aspect of the primary outcome for this phase III trial is the proportion of women successfully followed up in both the intervention and control group. To minimise loss to follow-up, particularly among controls, women in both groups will receive Love2Shop vouchers of \u0026pound;50 and \u0026pound;25 for providing data and saliva/urine samples where applicable at the primary (late pregnancy) and secondary (six months post-partum) outcome time points respectively (Figure 2.). Acceptable levels are around 90% of participants successfully followed up in each group.\u003c/p\u003e\n\u003cp\u003eTo assess if a) women lost to trial follow-up are still smoking towards the end of pregnancy, and b) the primary outcome has been \u0026lsquo;gamed\u0026rsquo; (saliva cotinine below the cut-off but still smoking in late pregnancy) residual blood from routine late pregnancy samples, where available, will be tested.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-up 5: Six months postpartum\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSimilar to the late pregnancy follow-up all women will be contacted at six months after their baby is born to ascertain smoking status and collect a saliva/urine sample for those women who self-report as quit. (Biological samples of saliva and urine will not be available for use by other researchers). .Quit status six months after birth will be ascertained by two sets of questions:\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003e\u0026lsquo;Have you smoked in the last 8 weeks?\u0026rsquo; If yes \u0026lsquo;Have you smoked more than 5 cigarettes in that time?\u0026rsquo;, and\u003c/li\u003e\n\u003cli\u003e\u0026lsquo;Have you smoked since your baby was born?\u0026rsquo; If yes, \u0026lsquo;Have you smoked more than 5 cigarettes in total since your baby was born?\u0026rsquo;\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eFollow-up procedures (i.e. no. of contact attempts, data collection and saliva/urine sample collection and assay) will be the same as those described for the late pregnancy follow-up.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBirth related data collection\u003c/p\u003e\n\u003cp\u003eAfter the expected date of delivery, research nurses at each site will collect and input to the trial database data regarding parity, baby\u0026rsquo;s birth date and weight.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData management\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data management process will be run by York Trials Unit. The protocol was built on the platform from the phase II trial [34]. This has been improved and updated by York Trials Unit in conjunction with the central trial team (DT, LS and MM) and has been used for submissions for regulatory approval.\u003c/p\u003e\n\u003cp\u003eThe database is a modified version of that used in CPIT II. York Trials Unit, central trial management in Glasgow and research staff at one of the recruiting sites have contributed to the design of the modified version.\u003c/p\u003e\n\u003cp\u003eData entry will be completed by trained research staff at local sites.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analysis will be conducted by York Trials Unit (AM, AK). All analyses will be carried out using the intention to treat principle unless stated otherwise. Treatment effect estimates will be presented along with the corresponding 95% confidence interval, and statistical tests will be two-sided at the 5% level, unless otherwise stated.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary outcome analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrimary outcome analysis will be by intention to treat as the intervention is the offer of a financial incentive to engage with SSS and quit smoking. Logistic regression will adjust for maternal age, years of smoking, deprivation score, level of smoking and site.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary outcome analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEngagement with SSS and self-reported smoking status at four weeks will both be analysed using a logistic regression model adjusting for the same covariates as the primary analysis. Continuous and point abstinence (i.e. regardless of whether participants were abstinent in late pregnancy) outcomes obtained at six months postpartum [28] will be calculated using logistic regression also adjusting for the same covariates as the primary outcome analysis. For each of the following covariates tests for interaction with treatment group will be performed: age of mother, years of smoking, deprivation score and level of smoking. Effects on length of neonatal unit stays will be examined.\u003c/p\u003e\n\u003cp\u003eBirth weight will be analysed using a linear regression model adjusting for key prognostic variables including age, site, height and weight of mother at early pregnancy. The intention to treat estimate will be severely diluted due to low smoking cessation rates and the \u0026lsquo;per protocol\u0026rsquo; analysis will be biased by confounding. Consequently we will also utilise an instrumental variable approach \u0026ndash; Complier Average Causal Effect analysis \u0026ndash; which will estimate the true impact of incentive induced smoking cessation on birth weight [35].\u003c/p\u003e\n\u003cp\u003eDifferences by subgroup (e.g. site, deprivation, age group) will be explored and reported as per the CHAMP guidelines [36].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA meta-analysis including data collected in the feasibility study in Glasgow on 612 participants [24] will be undertaken.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMissing data\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWhere there is missing data for the primary outcome (i.e. smoking status) it will be assumed that women are continuing to smoke. This assumption will be examined by testing residual blood samples (taken for other reasons in late pregnancy) for cotinine as in the feasibility trial [24]. This assumption will also apply to the six-month post-partum secondary outcome of smoking status. Other secondary outcomes, e.g. birth weight, are collected routinely and will have little missing data. Long term outcome data collection will be planned from participants and offspring to inform additional follow-up studies.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEconomic and process evaluations \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAn economic evaluation to assess cost-effectiveness of offering financial incentives in addition to routine SSS will be undertaken from an NHS perspective. Details are the subject of an additional protocol paper to be published separately.\u003c/p\u003e\n\u003cp\u003eA process evaluation using a mixed methods case study approach will explore recruitment and assess \u0026lsquo;intervention context fit\u0026rsquo;. This is essential to understand both how the trial functions within different SSS and how applicable and generalisable findings may be in terms of future implementation. Full details of the process evaluation design and methods are reported in an online supplement.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Monitoring\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData Monitoring will be coordinated by York Trials Unit (HT) and includes some self-monitoring at sites.\u003c/p\u003e\n\u003cp\u003eSerious Adverse Events (SAEs) that are related to the intervention will be documented. It is not anticipated that the provision of shopping vouchers to women will be associated with any related SAEs. SAEs in the feasibility study were primarily due to miscarriages that were not related to the intervention. For this reason a separate Data Monitoring Committee will not be assembled\u003c/p\u003e\n\u003cp\u003eStopping the trial for reasons not related to safety such as \u0026lsquo;futility because the required sample size cannot be reached\u0026rsquo; will be decided by the Trial Steering Committee.\u003c/p\u003e\n\u003cp\u003eData Cleaning will be conducted by York Trials Unit (AM) and the central trial management team in Glasgow (LS)\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAt present, only 10-20% of pregnant smokers take up the offer of free SSS and only 3-8% quit during pregnancy with usual care that includes counseling and NRT. Modest incentive payments to engage with SSS and/or to quit smoking may provide a substantial benefit by decreasing pregnancy and first-infant year health care costs. If women stay smoke-free, long-term health care costs will be substantially reduced. The results of this phase III multi-centre trial will examine the costs and benefits of providing financial incentive payments for smoking cessation during pregnancy across the UK. This evidence will provide information required for NICE\u0026nbsp; to consider recommending financial voucher incentive payments to support pregnant smokers to quit across the UK at the scheduled 2021 guideline PH26 [15] update.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRecruitment opened in February 2018 and will be complete by the end of March 2020. On December 12th 2019, 825 of 940 participants were enrolled into the trial.\u003c/p\u003e\n\u003cp\u003eCurrent protocol V3.1 27/09/2018\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCI, Confidence Interval; CPIT, Cessation in Pregnancy Incentives Trial; GG\u0026C, Greater Glasgow \u0026 Clyde; NHS, National Health Service; NICE, National Institute for Health and Clinical Excellence; NRT, Nicotine Replacement Therapy; QALY, Quality-Adjusted Life Year.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthics approval was received from West of Scotland REC2 on the 15th August 2017.\u003c/p\u003e\n\u003cp\u003eR\u0026amp;D \u0026nbsp;approval was given to allow SSS staff to pass information to the TCC if the client gives verbal permission. Those who consent to take part in the trial will be sent a written copy of their consent form. In addition, potential participants receive an Information sheet which communicates data confidentiality procedures, the fact that participation is entirely voluntary, and the possibility of leaving the study at any time and without justification.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSubstantial Amendments:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAM02 08/11/2017 Changes to main consent form, main PIS and protocol. REC approved 20/11/2017.\u003c/p\u003e\n\u003cp\u003eAM06 10/07/2018 New procedures: Poster and summary PIS for antennal trial information. Permission for trial staff to contact participants to further explain the trial prior to consent.\u003c/p\u003e\n\u003cp\u003eProcess evaluation - \u0026pound;25 voucher to women taking part in interviews and other changes. REC approved 04/09/2018.\u003c/p\u003e\n\u003cp\u003eCurrent protocol V3.1 27/09/2018\u003c/p\u003e\n\u003cp\u003eThe annual report dated 08/08/2018 informed the ethics committee that new sites were to be involved and that one new site had agreed to take part. \u0026lsquo;On the 26th of July 2018 one new site confirmed that they would like to be a site and could use their own research network staff for local research nurse input required by the trial.\u0026rsquo; Four other sites in the same area have also agreed to take part. The sponsor designated addition of these sites as minor amendments AM08 and AM09. The ethics committee has been informed regarding these new sites in the annual report dated 13/09/2019.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFunding for this trial has been provided by: Cancer Research UK, the Chief Scientist Office, Scottish Government; HSC Public Health Agency NI; Chest Heart and Stroke NI, The Lullaby Trust, Public Health Agency NI and the Scottish Cot Death Trust.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDT and LB conceived the study. DT, LB, DTorg, FK, MU, KB, PH, FH, and JM were applicants for the funding. All authors were involved in designing the study and drafting the protocol. KB and NM designed the health economic aspects of the study. JM, PH and FH designed the qualitative aspects of the study. All authors read and approved the final protocol.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial organisation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial Steering Committee\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe overall scientific aspects of the project will be overseen by a Steering Committee. The Steering Committee includes an independent chairperson, the chief investigator, main statistician, trial management support, representatives from the major funding bodies \u0026ndash; Cancer Research UK and the Chief Scientist Office, a patient representative and an international scientist with research interests in smoking cessation during pregnancy.\u003c/p\u003e\n\u003cp\u003eThe responsibility of the Steering Committee is to ensure the scientific integrity and quality of the project. To achieve this, the specific responsibilities of the Steering Committee include: maintaining adherence to the study protocol; approving changes to study protocol if required; reviewing quality assurance indicators; monitoring study recruitment and the overall study timetable; advising, as required, on specific scientific items that may arise; compliance with legislation; adherence to research governance; reporting to funders; approving publication and dissemination strategies.\u003c/p\u003e\n\u003cp\u003eThe Steering Committee will meet every 6 months.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial Management Group\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Trial Management Group comprises the principal investigators, trial manager and trial management support, trial administrator, senior managers from smoking cessation services, data manager, statisticians, health economists and qualitative researchers and supports the running of the trial by the Trial Management Working Group. Review meetings are being held quarterly.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial Management Working Group\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe responsibilities of the Trial Management Working Group include: establishing and monitoring recruitment of participants; distributing and supplying appropriate documentation for the trial; data collection and management; data entry and cleaning; data analysis; organising and providing information for the Trial Steering Committee.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Monitoring Committee\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAn independent Data Monitoring Committee will not be established as adverse events related to the financial incentives intervention are not envisaged and are not being systematically collected.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDatabase Management Company\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Database Management Company and the trial team have developed the trial database which sits behind secure firewalls. The database is accessed by trial staff over a secure password protected internet portal. Data extracts are provided to York Trials Unit who manage the data output. This database serves as the data coordinating centre and is overseen by York Trials Unit in terms of data management.\u003c/p\u003e\n\u003cp\u003eThe Database Management Company also provide a call centre facility where trained staff conduct trial consent and perform initial data collection for both the \u0026nbsp;primary and secondary outcome assessment of self-reported \u0026nbsp;smoking status \u0026nbsp;near the end of pregnancy and at six months after birth.\u003c/p\u003e\n\u003cp\u003eThe Database Management Company subcontract to a Fulfillment House for provision of a secure document fulfillment service to the trial. the Fulfillment House dispatch trial PIS\u0026rsquo; to potential participants, paper copies of verbally obtained consent, GP letters and financial voucher incentive payments by recorded delivery.\u003c/p\u003e\n\u003cp\u003eNHS Research and Development Greater Glasgow \u0026amp; Clyde\u003c/p\u003e\n\u003cp\u003eNHS R\u0026amp;D Glasgow is the sponsor for the trial. NHS R\u0026amp;D offices provide accommodation for the main trial team in Glasgow, Scotland.\u003c/p\u003e\n\u003cp\u003eYork Trials Unit, University of York\u003c/p\u003e\n\u003cp\u003eYork Trials Unit provide trial management support and data management including data monitoring, statistical analysis and reporting for the study.\u003c/p\u003e\n\u003cp\u003eStop Smoking Services\u003c/p\u003e\n\u003cp\u003eSSS staff are discussing the trial with potential participants and passing details of those who give permission to the TCC. SSS are providing cost data for the economic analysis and a sample of SSS staff will be interviewed as part of the mixed methods process evaluation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePublication policy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary results of the trial will be published with authorship in relation to specific participation in the study, with the name order to be presented by the principal investigators for consideration by the TSC. Suggested revisions in order of authors should meet with the approval of the principal investigators. Publications in specific areas of the study or on methodological aspects can be led by co-investigators in their area of expertise subject to approval by the TSC and the principal investigators. The requirements for authorship will follow recommended practice in journal guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConfidentiality\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEncryption defined by NHS GG\u0026amp;C security management is in place to pass data for potential participants from SSS to the Database Management Company managed trial database and call centre. The Database Management Company has a long history of managing government-related services and is able to demonstrate their commitment to data security and quality management through their ISO27001 and ISO9001 accreditations and recent GDPR legislation. Their ISO27001 accredited Information Security Management Systems demand that all of their systems and processes are maintained with confidentiality, integrity and availability of data at the core. In addition the Database Management Company is ISO9001 accredited, the internationally recognized standard for Quality Management Systems. Data is passed via SFTP encrypted in transit. Regular external audits ensure adherence to ISO9001 and ISO27001 standards.\u003c/p\u003e\n\u003cp\u003eData will be analysed by staff at York Trials Unit. During and after data analysis participants will be identified by their trial number to ensure confidentiality.\u003c/p\u003e\n\u003cp\u003eSite confidentiality will be maintained by anonymising sites. This will allow the process evaluation to provide important insights regarding barriers and facilitators to future implementation without causing difficulties at trial sites.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eLesley Sinclair\u003c/em\u003e (Trial Manager): Has experience of data management and the management of clinical trials including an MSc in Clinical Trials from London School of Hygiene and Tropical Medicine. She runs the trial on a day to day basis. Lesley managed the CPIT II feasibility trial in Glasgow UK. She has led on development of the trial database in conjunction with the Database Management Company. She assisted with protocol development for this trial and supported by Helen Tilbrook at York Trial Unit is managing all operational aspects of this trial. Lesley Sinclair and David Tappin wrote this paper with input from all the authors above.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMargaret McFadden \u003c/em\u003e(Lead Trial Research Nurse) was Lead Research Nurse on CPIT II. She is a very experienced research nurse who has undertaken many trial related roles as research nurse. Margaret is acting as research nurse for one site. She is also leading the research nurses for all sites and has trained the nurses in data and sample collection for the trial. She has been closely involved in development of the trial database.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eHelen Tilbrook\u003c/em\u003e is Research Fellow at York Trials Unit, University of York.\u0026nbsp; Helen has an MSc in Health Services Research and extensive experience of managing clinical trials. She is responsible for providing trial management support including data monitoring. She also supports Lesley Sinclair in her trial management role particularly regarding organisation of the Trial Steering Committee and the Trial Management Group. Helen has been closely involved in development of the trial protocol and submission to regulatory bodies as well as supporting development of the trial database. Helen is supervised by Judith Watson.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAlex Mitchell\u003c/em\u003e is the Trial Statistician and Trainee Statistician at, York Trials Unit, University of York. Alex is responsible for providing day-to-day statistical support for the study including statistical aspects of data management and monitoring. Alex runs the statistical aspects of the trial supported by Ada Keding.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAda Keding \u003c/em\u003eprovides supervision to Alex Mitchell at York Trials Unit and will plan and support Alex to undertake statistical analysis for the trial.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eJudith Watson \u003c/em\u003esupervises Helen Tilbrook at York Trials Unit including the data management and data monitoring aspects of the trial.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eLinda Bauld\u003c/em\u003e is Co-Principal Investigator for the trial and is the Bruce and John Usher Chair in Public Health, Usher Institute, University of Edinburgh. Linda has extensive experience of quantitative and particularly qualitative work related to smoking cessation. She supports the trial on a regular basis and will be involved in writing and dissemination of results.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFrank Kee \u003c/em\u003eis Professor of Public Health at Queens University Belfast and is co-applicant. Frank administers grant funding for some staff. He has helped with protocol development and in many other aspects of support for the trial.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDavid Torgerson \u003c/em\u003eis a co-applicant and is Director of York Trial Unit, University of York. He supported the study team during grant application for the trial including direction on trial design (cluster or individual randomisation). He has overseen design of data collection in relation to statistical analysis. Through York Trials Unit he has supported the running of the trial so that it is safe for the funders regarding their investment.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCatherine Hewitt \u003c/em\u003eis co-applicant and Deputy Director of York Trials Unit. Catherine has assessed and designed the support required from York Trials Unit to reduce the risk to the funders regarding their investment. Catherine has supported the data management design for the trial.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eJennifer McKell\u003c/em\u003e is a Research Fellow in the Institute for Social Marketing at the University of Stirling. She is a qualitative researcher with extensive experience of carrying out research in relation to tobacco use and smoking in pregnancy, including the qualitative element of the CPIT II feasibility trial. She is the main researcher working on the trial\u0026rsquo;s embedded process evaluation for this trial.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePat Hoddinott\u003c/em\u003e holds a Chair in Primary Care, in the Nursing Midwifery and Health Professionals Research Unit at the University of Stirling. She has clinical and trial expertise in maternal and child health, preventative medicine, behaviour change and financial incentives. She is advising on all aspects of the trial and oversees the process evaluation.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFiona Harris \u003c/em\u003eis an Associate Professor in Medical Anthropology and Health Services Research, Nursing, Midwifery and Allied Health Professions Research Unit at the University of Stirling. She has extensive experience of conducting mixed methods process evaluations within trials and will support the conduct, analysis and reporting of the process evaluation component of the study.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eIsabelle Uny\u003c/em\u003e is social scientist by training and a researcher at the Institute for Social Marketing (ISM), University of Stirling. Her expertise is in global policy making and policy implementation analysis. She also specialises in qualitative health research (methods/ analysis/ frameworks) and qualitative evidence synthesis (particularly meta-ethnography). Her work focuses primarily on non-communicable diseases (NCDs) and maternal health. She will support the data collection, analysis and reporting of the process evaluation.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eKathleen Boyd \u003c/em\u003eis Senior Lecturer in Health Economics at Glasgow University with extensive experience of decision modelling and designing and analysing trial based economic evaluations, particularly in SSS. She designed and will undertake the health economic evaluation.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eNicola McMeekin\u003c/em\u003e is a Research Assistant in health economics and has experience of designing and undertaking economic evaluations alongside clinical trials.\u0026nbsp; She helped design the health economic evaluation and will carry out the analysis in conjunction with KB.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMichael Ussher\u003c/em\u003e is Professor of Behavioural Medicine at the St George\u0026rsquo;s, University of London and at the University of Stirling. Michael has extensive experience of trials of smoking cessation in pregnancy and advises on all aspects of the study and especially on issues related to health psychology.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDavid Tappin\u003c/em\u003e is Co-Principal Investigator and Senior Research Fellow at Glasgow University based at the Scottish Cot Death Trust, in Glasgow. David has experience of the management of clinical trials including an MSc in Clinical Trials from London School of Hygiene and Tropical Medicine. He wrote all the grant applications for this trial and writes all the funding reports. He co-ordinates and manages the overall running of the trial and will be closely involved in data analysis and paper writing and dissemination of results.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eParkin DM, Boyd L, Walker LC: \u003cstrong\u003eThe fraction of cancer attributable to lifestyle and environmental factors in the UK in 2010.\u003c/strong\u003e \u003cem\u003eBr J Cancer\u003c/em\u003e 2011, \u003cstrong\u003e105:\u003c/strong\u003eS77-81.\u003c/li\u003e\n\u003cli\u003eDoll R, Peto R, Boreham J, Sutherland I: \u003cstrong\u003eMortality in relation to smoking: 50 years\u0026rsquo; observations on male British doctors.\u003c/strong\u003e \u003cem\u003eBMJ\u003c/em\u003e 2004, \u003cstrong\u003e328:\u003c/strong\u003e1519.\u003c/li\u003e\n\u003cli\u003ePortanti M, Whitworth S: \u003cstrong\u003eA comparison of the characteristics of childless women and mothers in the ONS Longitudinal Study.\u003c/strong\u003e \u003cem\u003eOffice for 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London: Routledge.\u003c/li\u003e\n\u003cli\u003eFarmer T, Robinson K, Elliott SJ, EylesJ.\u003cstrong\u003eDeveloping and Implementing a Triangulation Protocol for Qualitative Health Research \u003c/strong\u003eQualitative Health Research 2006;\u003cstrong\u003e16(3):\u003c/strong\u003e377-394 DOI: 10.1177/1049732305285708\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Intervention, randomised controlled trial, maternal and child health, outcomes, pregnancy, prevention, smoking cessation, financial incentives","lastPublishedDoi":"10.21203/rs.2.15197/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.2.15197/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Background\nEighty percent of UK women have at least one baby, making pregnancy an opportunity to help women to stop smoking before their health is irreparably compromised. Smoking cessation during pregnancy helps protect infants from miscarriage, still birth, low birth weight, asthma, attention deficit disorder and adult cardiovascular disease. UK national guidelines highlight lack of evidence for effectiveness of financial incentives to help pregnant smokers quit. This includes a research recommendation: Within a UK context, are incentives an acceptable, effective and cost-effective way to help pregnant women who smoke to quit?\nMethods\nCPIT III is a pragmatic, 39-month, multi-centre, parallel group, individually randomised controlled superiority trial of the effect on smoking status of adding to usual smoking cessation support the offer of up to £400 of financial voucher incentives, compared with usual support alone, to quit smoking during pregnancy.\nParticipants (n = 940) are pregnant smokers (age \u003e 16, \u003c24 weeks pregnant, English speaking), who consent via telephone to take part and are willing to be followed-up in late pregnancy and 6 months after birth.\nThe primary outcome is cotinine/anabasine validated abstinence from smoking in late pregnancy. Secondary outcomes include engagement with cessation services, quit rates at four weeks from agreed quit date and 6 months after birth, and birth weight. Outcomes will be analysed by intention-to-treat, and regression models will be used to compare treatment effects on outcomes. A meta-analysis will include data from the feasibility study in Glasgow. An economic evaluation will assess cost-effectiveness from a UK NHS perspective. Process evaluation using a case study approach will identify opportunities to improve recruitment and learning for future implementation.\nResearch questions: What is the therapeutic efficacy of incentives? Are incentives cost-effective? What are the potential facilitators and barriers to implementing incentives in different parts of the UK?\nDiscussion\nThis phase III trial in Scotland, England and Northern Ireland, follows a successful phase II trial in Glasgow UK. The participating sites have diverse smoking cessation services, that represent most cessation services in the UK and serve demographically varied populations. If found to be acceptable and cost-effective this trial could demonstrate that financial incentives are effective and transferable to most UK cessation services for pregnant women.","manuscriptTitle":"The Smoking Cessation in Pregnancy Incentives Trial (CPIT): study protocol for a phase III randomised controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2019-12-16 18:30:02","doi":"10.21203/rs.2.15197/v2","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accept","date":"2019-12-30T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2019-12-25T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2019-12-14T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2019-09-26 13:07:00","doi":"10.21203/rs.2.15197/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2019-11-27T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2019-11-27T12:00:00+00:00","index":1,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2019-11-27T12:00:00+00:00","index":1,"fulltext":"Recommendation: Minor Revision\nForm responses:\n---\n* Level of interest: **An article of importance in its field**\n* Quality of written English: **Acceptable**\n* Quality of figures: **Acceptable**\n* Statistical review: **No, the manuscript does not need to be seen by a statistician**\n* Declaration of competing interests: **I declare that I have no competing interests.**\n\nComments to Author:\n---\nThis is the editorial comment.\n\nThis is a well written, comprehensive protocol to evaluate the use of incentives to stop smoking during pregnancy. I had a few comments based on the SPIRIT checklist framework.\n\n* SPIRIT checklist - It is not acceptable for Trials journal for the authors leave any items blank or with N/A in the SPIRIT checklist. Further information is required. Please either edit the protocol and insert page numbers in the checklist or insert relevant information in the SPIRIT checklist.\n\nItem 11b: Could state, if applicable, \"There will be no special criteria for discontinuing or modifying allocated interventions\".\nItem 17b: N/A is not acceptable please answer the question regarding unblinding. Perhaps write in the SPIRIT checklist \"the design is open label with only outcome assessors being blinded so unblinding will not occur\".\n\nItem 26b: Please state why N/A and check your consent form for wording, this was not included in an appendix (Item 32 SPIRIT checklist) so I could not check! Can suggest something like this: \"On the consent form, participants will be asked if they agree to use of their data should they choose to withdraw from the trial. Participants will also be asked for permission for the research team to share relevant data with people from the Universities taking part in the research or from regulatory authorities, where relevant. On page 23, 6 month post-partum follow up you state that biological samples of saliva and urine are collected - will these be used in ancillary studies? Please state in protocol if yes or no and SPIRIT checklist.\n\nItem 29: Could state \"Any data required to support the protocol can be supplied on request.\"\n\nItem 30: Provisions for post-trial care - you could state \"There is no anticipated harm and compensation for trial participation\" and it would be helpful to know if there will be any provision for post-trial care.\n\nItem 31b: This has been stated on page 30 and comprehensively on page 22-37 so please insert page numbers into SPIRIT checklist or you could also state \"All named authors adhere to the authorship guidelines of Trials. All authors have agreed to publication.\" Or \"All authors have contributed to writing the manuscript as detailed p33-37\"\n\nItem 31c: Access to data cannot be left blank - it is really important so complete information. Consider stating \"The datasets analysed during the current study are available from the corresponding author on reasonable request.\"\n\nItem 33: See above 26b suggest if not in appendix, give page number for protocol information on collection, lab evaluation, and storage of biological samples of saliva and urine in the current trial, stating no plans for use in ancillary studies, if applicable.\n\n* References: There were 8 articles that could not be checked, please check format for websites, include date checked and ensure sufficient information as in guidelines below. Two articles were not validated (https://trialsjournal.biomedcentral.com/submission-guidelines/preparing-your-manuscript/study-protocol/#references).\n"},{"type":"decision","content":"Minor revision","date":"2019-11-27T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2019-11-22T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2019-09-21T12:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2019-09-15T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0e3aa227-6ef0-486d-af8d-b5a9e66141ed","owner":[],"postedDate":"December 16th, 2019","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":28503,"name":"Internal Medicine"},{"id":28504,"name":"Integrative \u0026 Complementary Medicine"},{"id":28505,"name":"Translational Medicine"}],"tags":[],"updatedAt":"","versionOfRecord":{"articleIdentity":"rs-5867","link":"https://doi.org/10.1186/s13063-019-4042-8","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2020-02-14 12:00:00","publishedOnDateReadable":"February 14th, 2020"},"versionCreatedAt":"2019-12-16 18:30:02","video":"","vorDoi":"10.1186/s13063-019-4042-8","vorDoiUrl":"https://doi.org/10.1186/s13063-019-4042-8","workflowStages":[]},"version":"v2","identity":"rs-5867","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"identity":"rs-5867","version":["v2"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}