Nicotine patch preloading for smoking cessation: The Preloading Trial

ISRCTN	ISRCTN33031001
DOI	https://doi.org/10.1186/ISRCTN33031001
Protocol serial number	11918; HTA 09/110/01
Sponsor	University of Birmingham (UK)
Funder	Health Technology Assessment Programme

Submission date: 27/04/2012
Registration date: 27/04/2012
Last edited: 18/12/2019

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Mental and Behavioural Disorders

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Background and study aims
Smokers find stopping difficult because when they try they suffer urges to smoke, which compel them to smoke again. Pharmacotherapy for smoking cessation reduces the intensity and frequency of these urges to smoke, but does not abolish them entirely and consequently most quitters will be back to smoking by the end of their treatment. Better treatments are therefore necessary. One possibility is wearing a nicotine patch prior to stopping smoking (preloading), and there is promising evidence that this would enhance success rates. The mechanism is not fully clear, but the most likely explanation relates to unlearning the learned association between smoking and pharmacological reward of cigarettes, principally derived from nicotine. There is good evidence that wearing a patch while smoking is safe and well tolerated and the MHRA have removed prohibitions on doing so. Therefore we aim to establish how well nicotine patch preloading works when combined with standard NHS smoking cessation treatment, in comparison to standard NHS treatment alone.

Who can participate?
Smokers who are willing to give up smoking in four weeks time, and are 18 years of age or older. Participants will be recruited through their GP practice or through their local NHS stop smoking service clinic.

What does the study involve?
We will provide smokers in the active treatment arm with 21mg nicotine patches for 4 weeks prior to quit day. We will advise people to smoke as often as normal while wearing the patch to undermine reward from 'forced' smoked cigarettes. They will also be referred for standard NHS stop smoking service treatment (which comprises behavioural support and pharmacotherapies). Participants in the control/coping arm will be provided with a minimal behavioural intervention aimed at identifying smoking cues and ways to deal with these after quit day, and will also be referred for standard NHS stop smoking service treatment. Follow-ups will take place 1 week, 4 weeks, 6 months and 12 months after each participant's quit day. The primary outcome will be six month validated prolonged abstinence. Additional abstinence outcomes will be 4 week and 12 month prolonged abstinence, and point prevalence 4 week, 6 month and 12 month abstinence. Markers of potential mediators, such as changes in carbon monoxide and cigarettes per day, aversion, dependence, smoking reward, urges to smoke, confidence in quitting and motivation to change will also be measured. A health economic analysis will be carried out.

What are the possible benefits and risks of participating?
By utilising standard NHS support for smoking cessation smokers can increase their chances of quitting smoking by four times more than when quitting alone, therefore we hope that taking part in the trial will benefit smokers by increasing their chances of success in quitting. There are no real risks of participation, however, a minimal extra amount of time and effort may need to be put into participating in the trial in comparison to standard NHS treatment alone (due to the need to complete more questionnaires, and undertake additional clinic visits and follow-ups).

Where is the study run from?
All participants will be recruited within the UK, from one of the four research centres recruiting for the study (Birmingham, Bristol, London, Nottingham). Target recruitment is split equally between the four centres (approx 450 in each centre). Birmingham, Bristol and Nottingham will recruit through primary care practices and conduct clinic visits from these practices. London will recruit through and conduct clinics from an existing NHS smoking cessation service clinic.

When is the study starting and how long is it expected to run for?
March 2012 to August 2016

Who is funding the study?
National Institute for Health Research (NIHR) Health Technology Assessment (HTA), UK.

Who is the main contact?
Prof Paul Aveyard
paul.aveyard@phc.ox.ac.uk

Contact information

Prof Paul Aveyard
Scientific

Nuffield Department of Primary Care Health Sciences
University of Oxford
Radcliffe Primary Care Building
Radcliffe Observatory Quarter
Woodstock Road
Oxford
OX2 6GG
United Kingdom

ORCID ID	0000-0002-1802-4217
Phone	+44 (0)1865 617860
Email	paul.aveyard@phc.ox.ac.uk

Study information

Primary study design	Interventional
Study design	Randomised controlled trial
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	An open label pragmatic randomised controlled trial of nicotine patch preloading for smoking cessation
Study acronym	The Preloading Trial
Study objectives	The evidence for the efficacy of preloading using nicotine replacement therapy is inconclusive. Therefore a hypothesis is not specified, however our research question is: Is four weeks of nicotine patch treatment before quitting smoking alongside standard NHS stop smoking service treatment more effective than standard NHS stop smoking service treatment alone?
Ethics approval(s)	ref: 12/EM/0014
Health condition(s) or problem(s) studied	Tobacco smoking; smoking cessation; nicotine addiction
Intervention	Active treatment arm: daily 24hr use of 21mg nicotine transdermal patches over a four week period prior to participants quitting smoking. Control arm: no pharmacotherapy. Minimal behavioural intervention encouraging participants to explore their cues to smoke and ways to counter these following their quit day. Both arms will also receive the same standard NHS Stop Smoking Service treatment to help them quit smoking (comprising behavioural support and pharmacotherapy as standard)
Intervention type	Other
Primary outcome measure(s)	Current secondary outcome measure (as of 24/01/2018): Six month prolonged abstinence, measured by the Russell standard criteria i.e. a grace period of 2 weeks, followed by smoking fewer than 5 cigarettes thereafter to six months and biochemically confirmed by an exhaled CO of <10ppm or a salivary cotinine <14ng/ml. This is assessed in the same way as all smoking-related outcomes, namely by participant self-report confirmed biochemically. Previous primary outcome measure Six month prolonged abstinence, measured according to the Russell standard criteria, i.e. a grace period of 2 weeks, followed by smoking fewer than 5 cigarettes thereafter and biochemically confirmed by an exhaled CO of <10ppm
Key secondary outcome measure(s)	Current secondary outcome measures (as of 24/01/2018): 1. Russell standard abstinence at 4 weeks and 12 months, measured and defined analogously. They also comprise seven-day point prevalence, meaning total abstinence by self-report for the seven preceding days confirmed biochemically, as in the Russell standard measures. 2. Adverse events (adverse health states reported by the participant that occurred for the first time between baseline and the second assessment ) are self-reported in response to enquiry by the trial staff at one week after baseline and one week after quit day (approximately 5 weeks after baseline). We will also assess some adverse events that may indicate an excess dose of nicotine by a self-completion questionnaire one week after baseline. 3. Costs of behavioural support and NRT, in order to calculate cost/lifetime quitter, the cost/life year gained and the cost/quality adjusted life year, and health service use. 4. Potential mediators of the preloading effect will be measured at baseline, one week later in the pre-quit period, and one week after quit day by self-completion questionnaire: 4.1 Positive reinforcement: modified Cigarette Evaluation Questionnaire (mCEQ) satisfaction subscale and noticing whether cigarettes were more or less enjoyable than previously. 4.2 Negative reinforcement: mCEQ reward subscale. 4.3 Drive to smoke: self-reported change in urge strength and frequency of urges to smoke combined assessed using the Mood and Physical Symptoms Scale Craving subscale (MPSS-C), smoking stereotypy taken from the Nicotine Dependence Syndrome Scale, the mCEQ craving question, and a question used by Hajek and colleagues in a similar trial that asked participants to rate their urge to smoke compared with usual. 4.4 Cigarette consumption: cigarettes per day, and exhaled carbon monoxide. 4.5 Symptoms of addiction: modified score on the Fagerstrom Test for Cigarette Dependence- modified by removing cigarette consumption from the scale to ensure it was distinct from cigarette consumption. 4.6 Medication adherence: days of use of post-quit day medication measured at the +1week visit. 4.7 Confidence ‘How high would you rate your chances of giving up smoking for good at this attempt?’ on a 5-point scale (not at all, to extremely). 4.8 Nausea and aversion: we assessed nausea using the mean of two questions derived from themes from our participant interviews in a previous trial. These were ‘over the past week how nauseous have you felt when you have seen cigarettes or lighters’ and ‘Over the past week how nauseous have you felt when you have smelt cigarette smoke?’ on 5-point scales from not at all to extremely. Aversion was measured using the aversion subscale of the mCEQ. Previous secondary outcome measures 1. Efficacy - abstinence measured according to Russell standard at four weeks and 12 months post-quit, and 7-day point prevalence, biochemically confirmed abstinence at 4 weeks, 6 and 12 months post-quit. 2. Side-effects of NRT patch use and symptoms of nicotine overdose (such as nausea, watering mouth) at each contact. 3. Costs of behavioural support and NRT, in order to calculate cost/lifetime quitter, the cost/life year gained and the cost/quality adjusted life year, and health service use.
Completion date	30/08/2016

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	All
Target sample size at registration	1786
Total final enrolment	1792
Key inclusion criteria	1. Smokers (defined as regular smokers of cigarettes, cigars, and tobacco cigarettes combined with marijuana) 2. Aged ≥18 years of age 3. Smokers who, in the judgement of the trial researcher, would be suitable for preloading 4. Seeking NHS support to stop smoking and willing to quit in 4 weeks 5. Able to understand and consent to, and willing to comply with, study procedures
Key exclusion criteria	1. Pregnant or breastfeeding 2. Extensive dermatitis/other skin disorder that precludes patch use 3. Acute coronary syndrome or stroke within the past three weeks 4. Active phaeocromocytoma 5. Uncontrolled hyperthyroidism
Date of first enrolment	13/08/2012
Date of final enrolment	01/03/2014

Locations

Countries of recruitment

United Kingdom
England

Study participating centre

University of Birmingham

Birmingham
B15 2TT
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results	13/06/2018		Yes	No
Results article	results	01/08/2018		Yes	No
Protocol article	protocol	22/07/2014		Yes	No
HRA research summary			28/06/2023	No	No
Other publications	analysis of pre-loading	01/12/2018	18/12/2019	Yes	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes

Editorial Notes

18/12/2019: The following changes have been made:
1. Publication reference added.
2. The total final enrolment number has been added from the reference.
01/03/2019: Publication reference added.
07/08/2018: Publication reference added.
24/01/2018: The following changes were made:
1. Recruitment start date was changed from 01/03/2012 to 13/08/2012.
2. Overall trial end date was changed from 01/09/2015 to 30/08/2016.
3. Professor Paul Aveyard replaced Dr Nicola Lindsen as primary contact.
4. Primary and secondary outcome measures were updated.
5. Publication plan was added.