Nicotine preloading for smoking cessation: the Preloading RCT

Paul Aveyard, Nicola Lindson, Sarah Tearne, Rachel Adams, Khaled Ahmed, Rhona Alekna, Miriam Banting, Mike Healy, Shahnaz Khan, Gurmail Rai, Carmen Wood, Emma C Anderson, Alia Ataya-Williams, Angela Attwood, Kayleigh Easey, Megan Fluharty, Therese Freuler, Megan Hurse, Jasmine Khouja, Lindsey Lacey & 21 others Marcus Munafò, Deborah Lycett, Andy McEwen, Tim Coleman, Anne Dickinson, Sarah Lewis, Sophie Orton, Johanna Perdue, Clare Randall, Rebecca Anderson, Natalie Bisal, Peter Hajek, Celine Homsey, Hayden J McRobbie, Katherine Myers-Smith, Anna Phillips, Dunja Przulj, Jinshuo Li, Doug Coyle, Katherine Coyle, Subhash Pokhrel

    Research output: Contribution to journalArticle

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    Abstract

    BACKGROUND: Nicotine preloading means using nicotine replacement therapy prior to a quit date while smoking normally. The aim is to reduce the drive to smoke, thereby reducing cravings for smoking after quit day, which are the main cause of early relapse. A prior systematic review showed inconclusive and heterogeneous evidence that preloading was effective and little evidence of the mechanism of action, with no cost-effectiveness data.

    OBJECTIVES: To assess (1) the effectiveness, safety and tolerability of nicotine preloading in a routine NHS setting relative to usual care, (2) the mechanisms of the action of preloading and (3) the cost-effectiveness of preloading.

    DESIGN: Open-label randomised controlled trial with examination of mediation and a cost-effectiveness analysis.

    SETTING: NHS smoking cessation clinics.

    PARTICIPANTS: People seeking help to stop smoking.

    INTERVENTIONS: Nicotine preloading comprised wearing a 21 mg/24 hour nicotine patch for 4 weeks prior to quit date. In addition, minimal behavioural support was provided to explain the intervention rationale and to support adherence. In the comparator group, participants received equivalent behavioural support. Randomisation was stratified by centre and concealed from investigators.

    MAIN OUTCOME MEASURES: The primary outcome was 6-month prolonged abstinence assessed using the Russell Standard. The secondary outcomes were 4-week and 12-month abstinence. Adverse events (AEs) were assessed from baseline to 1 week after quit day. In a planned analysis, we adjusted for the use of varenicline (Champix®; Pfizer Inc., New York, NY, USA) as post-cessation medication. Cost-effectiveness analysis took a health-service perspective. The within-trial analysis assessed health-service costs during the 13 months of trial enrolment relative to the previous 6 months comparing trial arms. The base case was based on multiple imputation for missing cost data. We modelled long-term health outcomes of smoking-related diseases using the European-study on Quantifying Utility of Investment in Protection from Tobacco (EQUIPT) model.

    RESULTS: In total, 1792 people were eligible and were enrolled in the study, with 893 randomised to the control group and 899 randomised to the intervention group. In the intervention group, 49 (5.5%) people discontinued preloading prematurely and most others used it daily. The primary outcome, biochemically validated 6-month abstinence, was achieved by 157 (17.5%) people in the intervention group and 129 (14.4%) people in the control group, a difference of 3.02 percentage points [95% confidence interval (CI) -0.37 to 6.41 percentage points; odds ratio (OR) 1.25, 95% CI 0.97 to 1.62; p = 0.081]. Adjusted for use of post-quit day varenicline, the OR was 1.34 (95% CI 1.03 to 1.73; p = 0.028). Secondary abstinence outcomes were similar. The OR for the occurrence of serious AEs was 1.12 (95% CI 0.42 to 3.03). Moderate-severity nausea occurred in an additional 4% of the preloading group compared with the control group. There was evidence that reduced urges to smoke and reduced smoke inhalation mediated the effect of preloading on abstinence. The incremental cost-effectiveness ratio at the 6-month follow-up for preloading relative to control was £710 (95% CI -£13,674 to £23,205), but preloading was dominant at 12 months and in the long term, with an 80% probability that it is cost saving.

    LIMITATIONS: The open-label design could partially account for the mediation results. Outcome assessment could not be blinded but was biochemically verified.

    CONCLUSIONS: Use of nicotine-patch preloading for 4 weeks prior to attempting to stop smoking can increase the proportion of people who stop successfully, but its benefit is undermined because it reduces the use of varenicline after preloading. If this latter effect could be overcome, then nicotine preloading appears to improve health and reduce health-service costs in the long term. Future work should determine how to ensure that people using nicotine preloading opt to use varenicline as cessation medication.

    TRIAL REGISTRATION: Current Controlled Trials ISRCTN33031001.

    FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 41. See the NIHR Journals Library website for further project information.

    Original languageEnglish
    Pages (from-to)1-84
    Number of pages84
    JournalHealth Technology Assessment
    Volume22
    Issue number41
    DOIs
    Publication statusPublished - Aug 2018

    Fingerprint

    Smoking Cessation
    Nicotine
    Cost-Benefit Analysis
    Smoking
    Confidence Intervals
    Smoke
    Tobacco Use Cessation Products
    Health Services
    Biomedical Technology Assessment
    Odds Ratio
    Health Care Costs
    Control Groups
    Costs and Cost Analysis
    Health
    Random Allocation
    Nausea
    Inhalation
    Libraries
    Tobacco
    Randomized Controlled Trials

    Bibliographical note

    Publisher: NIHR Journals Library
    All titles are open access journals

    © Queen’s Printer and Controller of HMSO 2018. This work was produced by Aveyard et al. under the terms of a commissioning contract issued by the © Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

    Copyright © and Moral Rights are retained by the author(s) and/ or other copyright owners. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This item cannot be reproduced or quoted extensively from without first obtaining permission in writing from the copyright holder(s). The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the copyright holders.

    Cite this

    Aveyard, P., Lindson, N., Tearne, S., Adams, R., Ahmed, K., Alekna, R., ... Pokhrel, S. (2018). Nicotine preloading for smoking cessation: the Preloading RCT. Health Technology Assessment, 22(41), 1-84. https://doi.org/10.3310/hta22410

    Nicotine preloading for smoking cessation : the Preloading RCT. / Aveyard, Paul; Lindson, Nicola; Tearne, Sarah; Adams, Rachel; Ahmed, Khaled; Alekna, Rhona; Banting, Miriam; Healy, Mike; Khan, Shahnaz; Rai, Gurmail; Wood, Carmen; Anderson, Emma C; Ataya-Williams, Alia; Attwood, Angela; Easey, Kayleigh; Fluharty, Megan; Freuler, Therese; Hurse, Megan; Khouja, Jasmine; Lacey, Lindsey; Munafò, Marcus; Lycett, Deborah; McEwen, Andy; Coleman, Tim; Dickinson, Anne; Lewis, Sarah; Orton, Sophie; Perdue, Johanna; Randall, Clare; Anderson, Rebecca; Bisal, Natalie; Hajek, Peter; Homsey, Celine; McRobbie, Hayden J; Myers-Smith, Katherine; Phillips, Anna; Przulj, Dunja; Li, Jinshuo; Coyle, Doug; Coyle, Katherine; Pokhrel, Subhash.

    In: Health Technology Assessment, Vol. 22, No. 41, 08.2018, p. 1-84.

    Research output: Contribution to journalArticle

    Aveyard, P, Lindson, N, Tearne, S, Adams, R, Ahmed, K, Alekna, R, Banting, M, Healy, M, Khan, S, Rai, G, Wood, C, Anderson, EC, Ataya-Williams, A, Attwood, A, Easey, K, Fluharty, M, Freuler, T, Hurse, M, Khouja, J, Lacey, L, Munafò, M, Lycett, D, McEwen, A, Coleman, T, Dickinson, A, Lewis, S, Orton, S, Perdue, J, Randall, C, Anderson, R, Bisal, N, Hajek, P, Homsey, C, McRobbie, HJ, Myers-Smith, K, Phillips, A, Przulj, D, Li, J, Coyle, D, Coyle, K & Pokhrel, S 2018, 'Nicotine preloading for smoking cessation: the Preloading RCT' Health Technology Assessment, vol. 22, no. 41, pp. 1-84. https://doi.org/10.3310/hta22410
    Aveyard P, Lindson N, Tearne S, Adams R, Ahmed K, Alekna R et al. Nicotine preloading for smoking cessation: the Preloading RCT. Health Technology Assessment. 2018 Aug;22(41):1-84. https://doi.org/10.3310/hta22410
    Aveyard, Paul ; Lindson, Nicola ; Tearne, Sarah ; Adams, Rachel ; Ahmed, Khaled ; Alekna, Rhona ; Banting, Miriam ; Healy, Mike ; Khan, Shahnaz ; Rai, Gurmail ; Wood, Carmen ; Anderson, Emma C ; Ataya-Williams, Alia ; Attwood, Angela ; Easey, Kayleigh ; Fluharty, Megan ; Freuler, Therese ; Hurse, Megan ; Khouja, Jasmine ; Lacey, Lindsey ; Munafò, Marcus ; Lycett, Deborah ; McEwen, Andy ; Coleman, Tim ; Dickinson, Anne ; Lewis, Sarah ; Orton, Sophie ; Perdue, Johanna ; Randall, Clare ; Anderson, Rebecca ; Bisal, Natalie ; Hajek, Peter ; Homsey, Celine ; McRobbie, Hayden J ; Myers-Smith, Katherine ; Phillips, Anna ; Przulj, Dunja ; Li, Jinshuo ; Coyle, Doug ; Coyle, Katherine ; Pokhrel, Subhash. / Nicotine preloading for smoking cessation : the Preloading RCT. In: Health Technology Assessment. 2018 ; Vol. 22, No. 41. pp. 1-84.
    @article{a8c16272566e4e13bcde962d025d0804,
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    abstract = "BACKGROUND: Nicotine preloading means using nicotine replacement therapy prior to a quit date while smoking normally. The aim is to reduce the drive to smoke, thereby reducing cravings for smoking after quit day, which are the main cause of early relapse. A prior systematic review showed inconclusive and heterogeneous evidence that preloading was effective and little evidence of the mechanism of action, with no cost-effectiveness data.OBJECTIVES: To assess (1) the effectiveness, safety and tolerability of nicotine preloading in a routine NHS setting relative to usual care, (2) the mechanisms of the action of preloading and (3) the cost-effectiveness of preloading.DESIGN: Open-label randomised controlled trial with examination of mediation and a cost-effectiveness analysis.SETTING: NHS smoking cessation clinics.PARTICIPANTS: People seeking help to stop smoking.INTERVENTIONS: Nicotine preloading comprised wearing a 21 mg/24 hour nicotine patch for 4 weeks prior to quit date. In addition, minimal behavioural support was provided to explain the intervention rationale and to support adherence. In the comparator group, participants received equivalent behavioural support. Randomisation was stratified by centre and concealed from investigators.MAIN OUTCOME MEASURES: The primary outcome was 6-month prolonged abstinence assessed using the Russell Standard. The secondary outcomes were 4-week and 12-month abstinence. Adverse events (AEs) were assessed from baseline to 1 week after quit day. In a planned analysis, we adjusted for the use of varenicline (Champix{\circledR}; Pfizer Inc., New York, NY, USA) as post-cessation medication. Cost-effectiveness analysis took a health-service perspective. The within-trial analysis assessed health-service costs during the 13 months of trial enrolment relative to the previous 6 months comparing trial arms. The base case was based on multiple imputation for missing cost data. We modelled long-term health outcomes of smoking-related diseases using the European-study on Quantifying Utility of Investment in Protection from Tobacco (EQUIPT) model.RESULTS: In total, 1792 people were eligible and were enrolled in the study, with 893 randomised to the control group and 899 randomised to the intervention group. In the intervention group, 49 (5.5{\%}) people discontinued preloading prematurely and most others used it daily. The primary outcome, biochemically validated 6-month abstinence, was achieved by 157 (17.5{\%}) people in the intervention group and 129 (14.4{\%}) people in the control group, a difference of 3.02 percentage points [95{\%} confidence interval (CI) -0.37 to 6.41 percentage points; odds ratio (OR) 1.25, 95{\%} CI 0.97 to 1.62; p = 0.081]. Adjusted for use of post-quit day varenicline, the OR was 1.34 (95{\%} CI 1.03 to 1.73; p = 0.028). Secondary abstinence outcomes were similar. The OR for the occurrence of serious AEs was 1.12 (95{\%} CI 0.42 to 3.03). Moderate-severity nausea occurred in an additional 4{\%} of the preloading group compared with the control group. There was evidence that reduced urges to smoke and reduced smoke inhalation mediated the effect of preloading on abstinence. The incremental cost-effectiveness ratio at the 6-month follow-up for preloading relative to control was £710 (95{\%} CI -£13,674 to £23,205), but preloading was dominant at 12 months and in the long term, with an 80{\%} probability that it is cost saving.LIMITATIONS: The open-label design could partially account for the mediation results. Outcome assessment could not be blinded but was biochemically verified.CONCLUSIONS: Use of nicotine-patch preloading for 4 weeks prior to attempting to stop smoking can increase the proportion of people who stop successfully, but its benefit is undermined because it reduces the use of varenicline after preloading. If this latter effect could be overcome, then nicotine preloading appears to improve health and reduce health-service costs in the long term. Future work should determine how to ensure that people using nicotine preloading opt to use varenicline as cessation medication.TRIAL REGISTRATION: Current Controlled Trials ISRCTN33031001.FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 41. See the NIHR Journals Library website for further project information.",
    author = "Paul Aveyard and Nicola Lindson and Sarah Tearne and Rachel Adams and Khaled Ahmed and Rhona Alekna and Miriam Banting and Mike Healy and Shahnaz Khan and Gurmail Rai and Carmen Wood and Anderson, {Emma C} and Alia Ataya-Williams and Angela Attwood and Kayleigh Easey and Megan Fluharty and Therese Freuler and Megan Hurse and Jasmine Khouja and Lindsey Lacey and Marcus Munaf{\`o} and Deborah Lycett and Andy McEwen and Tim Coleman and Anne Dickinson and Sarah Lewis and Sophie Orton and Johanna Perdue and Clare Randall and Rebecca Anderson and Natalie Bisal and Peter Hajek and Celine Homsey and McRobbie, {Hayden J} and Katherine Myers-Smith and Anna Phillips and Dunja Przulj and Jinshuo Li and Doug Coyle and Katherine Coyle and Subhash Pokhrel",
    note = "Publisher: NIHR Journals Library All titles are open access journals {\circledC} Queen’s Printer and Controller of HMSO 2018. This work was produced by Aveyard et al. under the terms of a commissioning contract issued by the {\circledC} Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. Copyright {\circledC} and Moral Rights are retained by the author(s) and/ or other copyright owners. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This item cannot be reproduced or quoted extensively from without first obtaining permission in writing from the copyright holder(s). The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the copyright holders.",
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    TY - JOUR

    T1 - Nicotine preloading for smoking cessation

    T2 - the Preloading RCT

    AU - Aveyard, Paul

    AU - Lindson, Nicola

    AU - Tearne, Sarah

    AU - Adams, Rachel

    AU - Ahmed, Khaled

    AU - Alekna, Rhona

    AU - Banting, Miriam

    AU - Healy, Mike

    AU - Khan, Shahnaz

    AU - Rai, Gurmail

    AU - Wood, Carmen

    AU - Anderson, Emma C

    AU - Ataya-Williams, Alia

    AU - Attwood, Angela

    AU - Easey, Kayleigh

    AU - Fluharty, Megan

    AU - Freuler, Therese

    AU - Hurse, Megan

    AU - Khouja, Jasmine

    AU - Lacey, Lindsey

    AU - Munafò, Marcus

    AU - Lycett, Deborah

    AU - McEwen, Andy

    AU - Coleman, Tim

    AU - Dickinson, Anne

    AU - Lewis, Sarah

    AU - Orton, Sophie

    AU - Perdue, Johanna

    AU - Randall, Clare

    AU - Anderson, Rebecca

    AU - Bisal, Natalie

    AU - Hajek, Peter

    AU - Homsey, Celine

    AU - McRobbie, Hayden J

    AU - Myers-Smith, Katherine

    AU - Phillips, Anna

    AU - Przulj, Dunja

    AU - Li, Jinshuo

    AU - Coyle, Doug

    AU - Coyle, Katherine

    AU - Pokhrel, Subhash

    N1 - Publisher: NIHR Journals Library All titles are open access journals © Queen’s Printer and Controller of HMSO 2018. This work was produced by Aveyard et al. under the terms of a commissioning contract issued by the © Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. Copyright © and Moral Rights are retained by the author(s) and/ or other copyright owners. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This item cannot be reproduced or quoted extensively from without first obtaining permission in writing from the copyright holder(s). The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the copyright holders.

    PY - 2018/8

    Y1 - 2018/8

    N2 - BACKGROUND: Nicotine preloading means using nicotine replacement therapy prior to a quit date while smoking normally. The aim is to reduce the drive to smoke, thereby reducing cravings for smoking after quit day, which are the main cause of early relapse. A prior systematic review showed inconclusive and heterogeneous evidence that preloading was effective and little evidence of the mechanism of action, with no cost-effectiveness data.OBJECTIVES: To assess (1) the effectiveness, safety and tolerability of nicotine preloading in a routine NHS setting relative to usual care, (2) the mechanisms of the action of preloading and (3) the cost-effectiveness of preloading.DESIGN: Open-label randomised controlled trial with examination of mediation and a cost-effectiveness analysis.SETTING: NHS smoking cessation clinics.PARTICIPANTS: People seeking help to stop smoking.INTERVENTIONS: Nicotine preloading comprised wearing a 21 mg/24 hour nicotine patch for 4 weeks prior to quit date. In addition, minimal behavioural support was provided to explain the intervention rationale and to support adherence. In the comparator group, participants received equivalent behavioural support. Randomisation was stratified by centre and concealed from investigators.MAIN OUTCOME MEASURES: The primary outcome was 6-month prolonged abstinence assessed using the Russell Standard. The secondary outcomes were 4-week and 12-month abstinence. Adverse events (AEs) were assessed from baseline to 1 week after quit day. In a planned analysis, we adjusted for the use of varenicline (Champix®; Pfizer Inc., New York, NY, USA) as post-cessation medication. Cost-effectiveness analysis took a health-service perspective. The within-trial analysis assessed health-service costs during the 13 months of trial enrolment relative to the previous 6 months comparing trial arms. The base case was based on multiple imputation for missing cost data. We modelled long-term health outcomes of smoking-related diseases using the European-study on Quantifying Utility of Investment in Protection from Tobacco (EQUIPT) model.RESULTS: In total, 1792 people were eligible and were enrolled in the study, with 893 randomised to the control group and 899 randomised to the intervention group. In the intervention group, 49 (5.5%) people discontinued preloading prematurely and most others used it daily. The primary outcome, biochemically validated 6-month abstinence, was achieved by 157 (17.5%) people in the intervention group and 129 (14.4%) people in the control group, a difference of 3.02 percentage points [95% confidence interval (CI) -0.37 to 6.41 percentage points; odds ratio (OR) 1.25, 95% CI 0.97 to 1.62; p = 0.081]. Adjusted for use of post-quit day varenicline, the OR was 1.34 (95% CI 1.03 to 1.73; p = 0.028). Secondary abstinence outcomes were similar. The OR for the occurrence of serious AEs was 1.12 (95% CI 0.42 to 3.03). Moderate-severity nausea occurred in an additional 4% of the preloading group compared with the control group. There was evidence that reduced urges to smoke and reduced smoke inhalation mediated the effect of preloading on abstinence. The incremental cost-effectiveness ratio at the 6-month follow-up for preloading relative to control was £710 (95% CI -£13,674 to £23,205), but preloading was dominant at 12 months and in the long term, with an 80% probability that it is cost saving.LIMITATIONS: The open-label design could partially account for the mediation results. Outcome assessment could not be blinded but was biochemically verified.CONCLUSIONS: Use of nicotine-patch preloading for 4 weeks prior to attempting to stop smoking can increase the proportion of people who stop successfully, but its benefit is undermined because it reduces the use of varenicline after preloading. If this latter effect could be overcome, then nicotine preloading appears to improve health and reduce health-service costs in the long term. Future work should determine how to ensure that people using nicotine preloading opt to use varenicline as cessation medication.TRIAL REGISTRATION: Current Controlled Trials ISRCTN33031001.FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 41. See the NIHR Journals Library website for further project information.

    AB - BACKGROUND: Nicotine preloading means using nicotine replacement therapy prior to a quit date while smoking normally. The aim is to reduce the drive to smoke, thereby reducing cravings for smoking after quit day, which are the main cause of early relapse. A prior systematic review showed inconclusive and heterogeneous evidence that preloading was effective and little evidence of the mechanism of action, with no cost-effectiveness data.OBJECTIVES: To assess (1) the effectiveness, safety and tolerability of nicotine preloading in a routine NHS setting relative to usual care, (2) the mechanisms of the action of preloading and (3) the cost-effectiveness of preloading.DESIGN: Open-label randomised controlled trial with examination of mediation and a cost-effectiveness analysis.SETTING: NHS smoking cessation clinics.PARTICIPANTS: People seeking help to stop smoking.INTERVENTIONS: Nicotine preloading comprised wearing a 21 mg/24 hour nicotine patch for 4 weeks prior to quit date. In addition, minimal behavioural support was provided to explain the intervention rationale and to support adherence. In the comparator group, participants received equivalent behavioural support. Randomisation was stratified by centre and concealed from investigators.MAIN OUTCOME MEASURES: The primary outcome was 6-month prolonged abstinence assessed using the Russell Standard. The secondary outcomes were 4-week and 12-month abstinence. Adverse events (AEs) were assessed from baseline to 1 week after quit day. In a planned analysis, we adjusted for the use of varenicline (Champix®; Pfizer Inc., New York, NY, USA) as post-cessation medication. Cost-effectiveness analysis took a health-service perspective. The within-trial analysis assessed health-service costs during the 13 months of trial enrolment relative to the previous 6 months comparing trial arms. The base case was based on multiple imputation for missing cost data. We modelled long-term health outcomes of smoking-related diseases using the European-study on Quantifying Utility of Investment in Protection from Tobacco (EQUIPT) model.RESULTS: In total, 1792 people were eligible and were enrolled in the study, with 893 randomised to the control group and 899 randomised to the intervention group. In the intervention group, 49 (5.5%) people discontinued preloading prematurely and most others used it daily. The primary outcome, biochemically validated 6-month abstinence, was achieved by 157 (17.5%) people in the intervention group and 129 (14.4%) people in the control group, a difference of 3.02 percentage points [95% confidence interval (CI) -0.37 to 6.41 percentage points; odds ratio (OR) 1.25, 95% CI 0.97 to 1.62; p = 0.081]. Adjusted for use of post-quit day varenicline, the OR was 1.34 (95% CI 1.03 to 1.73; p = 0.028). Secondary abstinence outcomes were similar. The OR for the occurrence of serious AEs was 1.12 (95% CI 0.42 to 3.03). Moderate-severity nausea occurred in an additional 4% of the preloading group compared with the control group. There was evidence that reduced urges to smoke and reduced smoke inhalation mediated the effect of preloading on abstinence. The incremental cost-effectiveness ratio at the 6-month follow-up for preloading relative to control was £710 (95% CI -£13,674 to £23,205), but preloading was dominant at 12 months and in the long term, with an 80% probability that it is cost saving.LIMITATIONS: The open-label design could partially account for the mediation results. Outcome assessment could not be blinded but was biochemically verified.CONCLUSIONS: Use of nicotine-patch preloading for 4 weeks prior to attempting to stop smoking can increase the proportion of people who stop successfully, but its benefit is undermined because it reduces the use of varenicline after preloading. If this latter effect could be overcome, then nicotine preloading appears to improve health and reduce health-service costs in the long term. Future work should determine how to ensure that people using nicotine preloading opt to use varenicline as cessation medication.TRIAL REGISTRATION: Current Controlled Trials ISRCTN33031001.FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 41. See the NIHR Journals Library website for further project information.

    U2 - 10.3310/hta22410

    DO - 10.3310/hta22410

    M3 - Article

    VL - 22

    SP - 1

    EP - 84

    JO - Health Technology Assessment

    JF - Health Technology Assessment

    SN - 1366-5278

    IS - 41

    ER -