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A randomised trial of nicotine assisted reduction to stop in pharmacies - the redpharm studyTaskila et al. BMC Public Health 2012, 12:182http://www.biomedcentral.com/1471-2458/12/182 A Randomised trial of nicotine assisted reductionto stop in pharmacies - The RedPharm Study Taina Taskila1*, Susan MacAskill2, Tim Coleman3, Jean-Francois Etter4, Mahendra Patel5, Sarah Clarke1,Rachel Bridson1 and Paul Aveyard1 Background: Public policy and clinical treatment in tobacco addiction in the UK has focused on cessation: anabrupt attempt to stop all cigarettes. However, recent evidence suggests that allowing more gradual withdrawalfrom tobacco or even permanent partial substitution by nicotine replacement therapy (NRT) could lead to netbenefits to public health. No jurisdiction has introduced smoking reduction programmes in normal clinical careand the best methods for their implementation is uncertain. Community pharmacists offering smoking cessationservices in the UK are ideally placed to implement reduction programmes.
This pilot study aims therefore to examine the feasibility of implementing smoking reduction programme inpharmacies, and also to see if behavioural support and a longer treatment affect the success rate for cessation.
Design and methods: This is a 2 × 2 randomised factorial trial of behavioural support versus no support and shortversus standard length reduction programme. The pharmacists will recruit 16 patients per pharmacy, 160 smokersaltogether. Pharmacists will randomise each participant by sealed envelopes. In a standard supported programme, thepharmacist will give support for 34 weeks, inviting participants to set a treatment goal and providing advice on how toreduce cigarette use. Participants in the short programme will be given the same advice on how to reduce but willreduce smoking over four weeks. Participants in the no support arms will be given a leaflet that describes the reductionprogrammes in 4-week and 34-week format. All participants are encouraged to use of NRT to support the reduction.
These processes will be measured by recording the number of recruited smokers; percentage of those who reduce andsustain their consumption to at least 50% of baseline value, and the proportion of people who attain 4 weeks abstinenceand 6 months abstinence. Interviews will assess smokers' and pharmacists' views on the way the programme ran.
Discussion: This is a pilot study to assess the feasibility of offering smoking reduction programme withinpharmacies that offer naturalistic setting to show population benefit from these programmes. Findings from thistrial will inform the development of evidence-based treatment for smokers who want to reduce and bestapproaches to engage reluctant quitters onto the programme.
Trial Registration: Current Controlled Trials Keywords: Smoking, Tobacco Dependence, Controlled Clinical Trials, Randomized, Pharmacists, Harm Reduction English Smoking Toolkit study, 57% of current smokers Clinical treatment in tobacco addiction has almost reported they were cutting down, of whom 26% were exclusively focused on cessation - an abrupt attempt to using nicotine replacement therapy (NRT) to assist this stop smoking. Some smokers, however, feel that cutting The UK Department of Health (DH) new tobacco down is an appropriate way to stop smoking. In the control strategy proposes supporting smokers who feelunable to quit to reduce smoking as a precursor to quit-ting. No jurisdiction, however, has introduced reduction * Correspondence: programmes in normal clinical care.
1UK Centre for Tobacco Control Studies, Primary Care Clinical Sciences, The evidence that smoking reduction might benefit School of Health and Population Sciences, Primary Care Clinical Sciencesbuilding, University of Birmingham, Birmingham B15 2TT, UK public health is derived from clinical trials, surveys, and Full list of author information is available at the end of the article 2012 Taskila et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License ), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.
Taskila et al. BMC Public Health 2012, 12:182 other observational epidemiological data. A systematic lasting 15-30 minutes per visit over nine visits [ review of RCTs and health economic analysis [ Therefore, it is reasonable to believe that reduction pro- found that smoking reduction programmes doubled grammes work with support, but it is unclear whether long-term abstinence rates, with absolute effectiveness support enhances efficacy or whether it is necessary. One only slightly lower than comparable cessation pro- study examined the efficacy of NRT versus placebo in grammes. The cost per quality adjusted life year was smokers that wanted to quit slowly by reduction less than £2000 for most age groups, rising to less than Trial participants received no behavioural support. This £5000/QALY for the oldest.
trial showed a near trebling of long-term abstinence with The US guidance, however, recently concluded there NRT relative to placebo (OR = 2.86, 95%CI 1.93 to 2.94).
was insufficient evidence to recommend smoking reduc- These data suggest support might not be necessary.
tion programmes [The main concern is that offering However, although no behavioural support was offered, reduction alongside cessation programmes will divert this study included three visits to assess reduction and smokers from more effective and cheaper cessation pro- cessation, which might motivate adherence to the pro- grammes to ‘easier' but less effective and more expensive gramme, and hence this might not be a true study of reduction programmes. Second, trials of smoking reduc- effectiveness of medication without behavioural support.
tion offered free support and medication in countries Determining the optimum level of support and monitor- where such help for smoking cessation is neither widely ing necessary for efficacy in reduction programmes is a available nor free and so trials may have inadvertently priority for NHS implementation.
enrolled smokers keen on cessation rather than reduction One NRT industry sponsored trial enrolled partici- and that would have caused the increase in cessation seen pants who did not intend to stop smoking in the next in the intervention groups. Third, the trials took place in month and randomised them to reduce over one month specialist clinics and drew in highly motivated participants.
then stop or to reduce then stop over the typical 6-9 Consequently the best methods for implementation of months adopted in the UK Despite the lack of intui- reduction programmes outside of such contexts are uncer- tive fit between participants' intentions and the short tain and this need to be testedin naturalistic settings to programme, the four week reduction programme was show population benefit from these programmes.
more effective than the nine month programme assessed As recognised in Action on Smoking and Health (ASH) 12 months from the start. For confirmed prolonged guidance to the NHS specialist stop smoking services reduction, the Mantel-Haenszel relative risk (RR) (95% in the UK do not have the resources necessary to imple- CI) was 2.69 (1.08-6.68) and for confirmed prolonged ment smoking reduction programmes. NHS stop smoking abstinence it was 4.57 (1.00-20.93). Shorter and more service practitioners treat approximately only 30% of all manageable reduction programmes may be more effec- smokers. If the nicotine assisted smoking reduction pro- tive than the standard six-month programme.
grammes were to fulfill their potential, up to 5 million We propose to assess by using mixed method approach smokers might be helped by them. Specialist stop smoking whether pharmacists can be trained to implement a nico- services, however, would not have the workforce to over- tine assisted reduction programme, how well they do so, see such large numbers of smokers. Therefore the wider and how this is received by smokers and by pharmacists.
primary care workforce might need to help implement We also aim to test whether behavioural support adds to the effectiveness of reduction programmes and whether Community pharmacists are ideally placed to implement short or standard length programmes are more effective.
reduction programmes. They already provide smoking ces-sation services as part of the NHS stop smoking service, Aims and objectives treating 16% of smokers helped by the NHS in 2008/9.
They recruit patients to the service primarily by providing To examine the feasibility of introducing nicotine opportunistic brief advice to smokers and therefore they assisted reduction to stop in pharmacies.
offer a naturalistic setting to test whether reduction pro- To estimate the efficacy of: grammes can be implemented alongside cessation • more rapid versus slower reduction programmes • behavioural support relative to self-help support There are no trials investigating whether behavioural support enhances the success of reduction programmes.
There are, however, such trials for cessation programmes, which show that behavioural support increases by Primary objectives 50-100% the efficacy of abrupt cessation programmes 1) To examine whether pharmacists can be trained to Industry-sponsored trials of NRT versus placebo engage smokers who do not want to quit and enrol provided regular behavioural support and monitoring them in a smoking reduction programme.
Taskila et al. BMC Public Health 2012, 12:182 2) To compare the relative efficacy of short versus Training for professionals standard length reduction programmes on smoking Pharmacists will be trained in two evening sessions; reduction and smoking cessation.
attendance to both training sessions is required. In the 3) To examine the relative efficacy of supported versus first session, presentations will be given on principles of self-guided reduction programmes on smoking reduc- the reduction programmes and practicalities of running tion and smoking cessation.
the trial from recruitment to the final behavioural sup- Secondary objectives port visit. The second training session will give pharma- 1) To assess which strategies used in enrolment and cists the opportunity to practice what was learned in the implementation of the programmes were successful and first session by role plays. The pharmacists will be reim- bursed for their time of attending to the training. The 2) To estimate the proportion of smokers enrolled in research team will keep in regular contact with the phar- reduction programmes who reduce successfully.
macy staff and help deal with problems arising during the 3) To estimate the proportion of smokers who are referred to cessation programmes and quit successfully.
4) To obtain trial participants' and pharmacists' views Inclusion criteria on the value of reduction programmes and how such Participants must meet all of the following inclusion programmes might be improved in future.
1) aged 18 years or older.
2) daily smokers with either a CO of at least 10 parts Participant Recruitment per million (ppm) at least 15 minutes after last smoking Pharmacists who work for NHS stop smoking services will or smoke at least 10 cigarettes or 8 g of loose tobacco be recruited from areas of high smoking prevalence in Bir- as "roll up" cigarettes daily.
mingham and Yorkshire region; those treating at least four 3) do not intend to stop in the next month, but are new smokers for cessation per month will be eligible. Over prepared to reduce their consumption with any of the 60 pharmacists in Birmingham see this many patients in programmes offered.
the NHS stop smoking service and most are recruited by 4) evidence of a personally signed and dated informed brief interventions across the counter, thus providing a consent document indicating that the participant has naturalistic setting in which to test the implementation of been informed of all pertinent aspects of the study and reduction programmes and integration with other smok- consents to participate and be randomised to either arm.
ing cessation efforts.
5) have either a telephone or email for follow-up.
We plan to recruit 10 pharmacies and for each to recruit four participants into a reduction programme each month, Exclusion criteria providing a quota of 16 in four months. We plan two There are no contraindications for smokers using NRT.
waves of recruitment. Using two waves will allow us to However, there are situations where caution is required.
learn lessons from the first wave, which is consistent with This trial will be conducted with minimal clinical moni- the developmental nature of this trial.
toring using treatment regimens that have not been pro- Educational outreach visits are effective in changing ven to have a population benefit and therefore we have GP's behaviour We will make visits to local GPs to elected to exclude potential participants who have cau- inform them about the programme and encourage them tions for NRT and this represents the bulk of exclusion to refer reluctant quitters to the reduction programme.
criteria. Participants presenting any of the following GPs will be given referral cards for their local pharmacy exclusion criteria will be excluded: provider to give to patients. If the recruitment of partici- 1. currently using other NRT, bupropion, nortriptyline, pants is particularly slow during the either wave, GP's will mecamylamine, reserpine, or varenicline, or undergoing be asked to send a letter to their registered current smo- any treatment for tobacco dependence (e.g. acupunc- kers. The letter will inform them that the reduction pro- ture) that they are not willing to stop using.
gramme is available at their local pharmacy. It will also 2. unstable angina pectoris, myocardial infarction, give details of how they can take part, should they want to, acute coronary syndrome, or cerebrovascular accident along with an information leaflet about the study.
during the last 3 weeks.
Pharmacists will be asked to recruit participants oppor- 3. severe cardiac arrhythmia tunistically as well as receiving referrals from GPs. To 4. currently uncontrolled hyperthyroidism assist opportunistic recruitment, pharmacists will display 5. active phaeocromocytoma a poster in the window. Pharmacists will be compensated 6. pregnancy, lactation or intended pregnancy in the for their time with service support funding.
Taskila et al. BMC Public Health 2012, 12:182 7. a severe acute or chronic medical or psychiatric would need to use six month prolonged smoking absti- condition or previously diagnosed clinically important nence as the outcome A sample of 160 partici- renal or hepatic disease, that may increase the risk asso- pants is not large enough to provide definitive evidence of ciated with study participation or may interfere with the efficacy with such an outcome because our systematic interpretation of study results and, in the judgment of review showed that standard length programmes lead to the investigator, would make the potential participant about 7% of participants sustaining six month abstinence inappropriate for entry into this study.
[. However, we assume that shorter reduction pro-grammes are about twice as effective, as suggested by the Withdrawal criteria Haustein trial. Our most important efficacy outcome here Given the established safety profile of NRT, we do not is four week abstinence. Based on our systematic review, expect any serious adverse events (SAE) and suspected we expect about 7% of participants who follow the stan- unexpected serious adverse reactions (SUSARs) due to dard length programme with behavioural support to sus- the medication. Nevertheless, pharmacists are required to tain abstinence for six months, which equates to about report in case of any SAE or SUSARs to Principal Investi- 21% achieving 4 weeks of abstinence, our main efficacy gator. In the event of an SAE or SUSAR that is judged outcome. Based on this, we get the following table, which either possibly, probably, or definitely related to NRT, shows that this sample size will have 80% power to detect the prescription for NRT will be withdrawn and not re- a rate ratio of 1.7 or 90% power to detect a rate ratio of instituted in that person (Appendix 1).
1.8 (Table ), lower than observed in Haustein.
The following are also considerations in the sample size. If we take key process measures like attendance for This is a pilot trial designed to test the processes, exam- behavioural support sessions as 63% (observed in the ine implementation issues, and reactions to the pro- review), with 80 smokers receiving behavioural support, gramme of those involved. We estimated a sample size of we could estimate this with +/-7% precision with 80% 160 participants recruited in 10 pharmacies would be suf- confidence. Asking each pharmacy to treat 16 patients, 4 ficient to test the feasibility of the study. The outcomes in each arm, will give a reasonable range of experiences therefore include the percentage of pharmacists that for them and us to evaluate the programmes.
agree to participate, the percentage that are trained, thepercentage that actually recruit smokers into reduction Allocation to trial arms and treatment programmes. Our most important efficacy outcome (because it is linked with unequivocal health benefits) is Pharmacists will randomise smokers by sealed envelopes.
smoking cessation. We will record the weekly recruit- Block randomisation stratified by pharmacy will be used ment rate of patients into the reduction programmes and with two blocks of 4 to ensure randomisation to each into NHS stop smoking programmes, comparing the rate arm in every pharmacy that recruits at least 4 partici- of recruitment into stop smoking programmes for phar- pants. Although blocks of 4 could become predictable, macists participating in the trial with those not doing so.
no pharmacist will recruit sufficient participants to dis- This will give evidence on whether smokers are being cern the pattern. Telephonists conducting follow up will diverted by reduction. For smokers in each type of pro- be blind to treatment allocation but this is an open label gramme, we will record the number of contacts made, trial and participants and therapists will know which arm the time of the pharmacist used in delivering the pro- they are in.
grammes, the amount of NRT used in each arm, the Behavioural intervention number of people that try to quit, and the number of This is a 2 × 2 randomised factorial design trial of beha- people that attend the pharmacist for post-cessation sup- vioural support versus no support and short versus stan- port as a proportion of those that try to quit. We will dard length reduction programme (Figure It is a pilot measure the fidelity to each programme by recording study for a later definitive trial.
some consultations and analysing their content against All participants will receive NRT and be randomised to the schedule of proposed content. We will record sus- either behavioural support or no support and either stan- tained smoking reduction and abstinence, although the dard length or short reduction; approximately 80 people trial is not powered to detect worthwhile differences in in each arm.
the abstinence outcomes. Four week and six month absti-nence rates will be measured following the Russell stan- Behavioural support arms dard. We will record the proportion of people that Supported standard programme complete the webform/telephone follow up.
The behavioural support schedule will follow that used Any trial to test the role of behavioural support and in the Nicorette industry trials, providing support and shorter versus standard length reduction programmes monitoring at baseline, 2, 6, 10, 16, 22, 28, and 34 Taskila et al. BMC Public Health 2012, 12:182 Table 1 Efficacy of shorter reduction programmes versus standard length Base quit proportion Quit proportion in intervention weeks. The pharmacist giving support in a consulting be given a leaflet that describes the reduction pro- room will invite participants to set a treatment goal and grammes (unstructured, cigarettes per day, or smoking provide advice on how to reduce cigarettes using periods) and which gives brief advice on using one or unstructured or structured methods of smoking reduc- more of these approaches, and encourages use of NRT tion. Unstructured smoking reduction means that parti- to support this. Participants will be advised to reduce on cipants were not guided as to which cigarettes to a schedule that follows the standard programme, if ran- eliminate but are left to experiment themselves and domised to that arm, or the short programme, if rando- without a specific goal except 50% reduction by 6 mised to that arm. The leaflet will advise participants to weeks. Structured reduction means having specific return to the pharmacy for more NRT to support reduc- sequential goals for either reducing cigarettes per day or tion as needed. This will be dispensed on NHS prescrip- reducing smoking periods. The cigarettes per day meth- tion (following the primary care trust's patient group ods are either smoke-free periods (SFP) or lengthen the direction). The outcomes will be monitored without per- inter-cigarette interval, i.e. the timer method sonal visits to avoid the possibility that these are contri- Smoke-free periods concentrates on times when smok- buting to adherence to the programme.
ing is allowed and when it is not, but the number ofcigarettes is not restricted. In the timer method the Transferring to the cessation programme number of cigarettes per day is restricted and also times The aim of the reduction programme is to help people when smoking is allowed.
reduce and pharmacists will be encouraged not to pressure Supported short programme people to stop smoking, while explaining that proven Participants in the 4-week supported programme will be health benefits derive from smoking cessation rather than given the same advice and help with reduction but this reduction. However, most people who want to reduce will be provided on a different schedule. Participants will smoking want to do so as a way of stopping [ be seen weekly for four weeks with the aim of reducing though rarely with a predetermined timetable. It is for the smoking to achieve cessation by the end of four weeks. If therapist and the patient to determine whether and when this fails, reducing to induce cessation at 8 weeks will be a person is transferred to the cessation programme. Poin- the goal. Thereafter, consistent with the pragmatic nature ters towards possible cessation are: of this trial, participants in the short reduction arm will be • Increased confidence that the patient can control allowed to follow the standard reduction regime. Beha- her/his smoking.
vioural support will be provided at baseline, weekly to 4 • Cigarette consumption has fallen to five per day or weeks, 6, 8, and 16 weeks i.e. the same number of visits fewer, or the person is going most of the day without but on a different schedule.
Participants in the No-support arms will be asked about their quitting attempt when they return to the pharmacy Participants in the no support arms will not be given for more NRT. A key principle of the whole reduction advice or support by the pharmacist. Instead they will approach is that failed quit attempts do not lead to an endof the programme. If a person moves to cessation and thequit attempts fails, they can resume the reduction pro-gramme and continue to control their smoking until theyare ready to stop again.
Behavioural support (N80) No behavioural support (N80) Length of studyWe plan to recruit 10 pharmacies. If they each recruit four participants per month, they will recruit their quotaof 16 in 4 months. We plan two waves of recruitment, Figure 1 Randomised factorial design trial (2 × 2) of with final follow up of that cohort one year after the end behavioural support versus no support on smoking reduction.
of recruitment. The second wave of pharmacies will Taskila et al. BMC Public Health 2012, 12:182 begin recruiting approximately six months after the first as providing them with behavioural support or enhance wave of recruitment. In total the duration will be 30 motivation to adhere. This will be by email/Webform emailed monthly for the 12 months of a participant's The end of the trial is defined as last contact with any involvement in the trial. Monthly follow up will ensure trial participant.
that we can assess whether smokers have started theirperiod of abstinence and schedule verification visits, based on a process outlined for trials of this kind This is a pilot trial designed to test the processes, examine Web follow up has achieved > 90% follow up in a pre- implementation issues, and reactions to the programme of vious trial Based on our experience of trials in those involved i.e. whether pharmacists can be trained to smokers' clinics, most patients have email addresses and implement the reduction programme, how well they do these are useful for follow up. Text reminders will be so, and how this is received by smokers and by pharma- sent to participants registered for email follow up not cists. These processes will be measured by: responding to the email. For those not using a computer • The percentage of pharmacists that agree to partici- regularly, phone follow up by telephonists will be used pate and the percentage that are trained and pass an so that the pharmacist/therapist is not conducting fol- assessment of competence.
• The monthly recruitment rate of patients into reduc- Sustained smoking reduction will be measured as self- tion programmes and into NHS stop smoking pro- reported daily cigarette consumption at 12 month follow grammes, comparing the rate of recruitment into stop up, with a reduction being counted as self-reported con- smoking programmes for pharmacists participating in sumption lower than at baseline. Sustained reduction will the trial with those not doing so.
be counted as achieved if during the last four months (i.e.
• Recording of some consultations and analysing their reports at month 9-12) of follow up, a person is smoking content against the schedule of proposed content.
less at every follow up occasion than at baseline, measured • The proportion of people that would recommend by self-report. If a monthly report is missing, a person will the smoking reduction programme to another smoker be counted as having achieved sustained reduction if all and their views on the way that it ran, taken from the other reports show this is the case and the last report is 12 month evaluation questionnaire.
not missing. If two reports are missing, a person will be We will also examine whether behavioural support is counted as not having achieved sustained reduction. Mean more effective than no support and will investigate cigarettes per day at the end of follow up will be calculated whether shorter reduction programmes are more effective from the last follow up only. If cigarettes per day is miss- than standard length reduction programmes. This will be ing, then this will be replaced by baseline cigarettes per achieved by measuring self-reported sustained smoking day, but in sensitivity analysis, we will use last observation reduction and abstinence. Smoking cessation outcomes carried forward.
will be measured from the time of quitting and we will Participants who have maintained abstinence for 4 measure 4 week and 6 month prolonged abstinence fol- weeks will be asked to attend the pharmacy for carbon lowing the Russell standard, i.e. by intention to treat and monoxide (CO) verification if they are in the self-help biochemically confirmed . Thus abstinence will be arm or if they are in the supported arm but are not due defined as allowing a two week grace period after quit day for or have ceased to attend visits. Those who have main- in which smoking lapses do not count against abstinence tained abstinence for 6 months (defined in the same way and from day 15 onwards, no more than five cigarettes with a grace period and no more than five cigarettes have been smoked. This will be verified by a CO < 10 smoked) will be asked to return for CO verification in ppm. Smoking reduction will be assessed by the propor- the same way. Participants attending the pharmacy for a tion of people that reduce their consumption to < 50% of non-therapeutic reason i.e. to attend for abstinence verifi- baseline value, the mean cigarette consumption at the end cation will be paid £20 to compensate them for their time of the trial.
and any travel costs incurred.
As this is a preliminary trial, we will record data to allow us to assess whether the processes of the trial need improvement prior to a definitive trial. We will also examine data on adverse events and drop outs from the We will calculate descriptive statistics for the outcome programme (Appendix 1).
measures comparing these by arm where it is sensible todo so. Risk differences with 95% confidence intervals Follow up procedures will be calculated for binary outcomes such as cessation, We propose testing the feasibility of using a follow up and for continuous outcomes, such as reduction in method that is unlikely to be perceived by participants cigarettes per day, we will calculate difference in means Taskila et al. BMC Public Health 2012, 12:182 or difference in change in means. For the cessation and reduced and quit smoking, reduced only, or achieved no reduction outcomes, we will conduct an intention-to- success with the programmes will be approached for treat analysis, where all randomized subjects will be interview. We expect to enrol about 2 people per permu- included in the denominator. We will also conduct sen- tation i.e. about 26 in total. The interviewer will enquire sitivity analyses with different assumptions for missing about their motivation for using the programme, their experience of it, and what if any changes occurred to The data will be analysed by a multilevel model by their smoking and why they thought they occurred.
examining diversion of smokers from cessation into Responses to trial follow-up methods will also be reduction programmes by comparing uptake of cessation in the pharmacies prior to and during the reduction pro- The interviews will be audio-recorded and transcribed grammes with pharmacies providing a similar throughput with respondents' permission. Interviews will be con- of patients for cessation support but not selected to pro- ducted by the research fellow at a time and location con- vide reduction programmes.
venient to respondents and trial participants will be Health economic analyses are not required because offered financial compensation of £20 for their time to extensive modelling of different formats of reduction pro- acknowledge their contribution to the study. The inter- grammes showed that each of these programmes are cost- views will be systematically read and interpreted, compar- effective by NHS standards and this was robust to changes ing key features of emergent findings and concepts to in assumptions However, we will utilise our existing minimise bias in interpreting data We will use models of the cost-effectiveness of the programme by open coding to identify emergent themes, and categories updating the estimates used in modelling by including within these. We will interweave data collection and analy- these estimates derived from a naturalistic setting. The sis, conducting later interviews after initial data analysis to updated estimates will be used to set the sample size for a provide insights for refining each theme and category.
Qualitative process evaluation Participants are encouraged to use both a nicotine patch Qualitative research can contribute depth of understand- and a short-acting (acute) form of NRT and those who are ing on why programmes achieve the effects that they do eligible to pay a prescription charge on the NHS (£7.20) and we will use semi-structured interviews with will have to do so for each item dispensed. Combination pharmacists and trial participants to determine key factors patch plus acute NRT is becoming a standard dosing regi- in relation to initial engagement, ongoing participation men for cessation treatment , with manufacturers now and overall response to the programme and the trial. We packaging combined products. This is because of superior will purposively selected 4 to 6 pharmacists, some of efficacy in enhancing cessation of combination over single whom recruited none or few participants and some who form NRT There are fewer trials of NRT in smoking recruited many. Semi-structured interviews will investigate reduction, too few to assess the relative efficacy of the dif- factors that influence pharmacist recruitment to the pro- ferent NRT preparations and no trials of combination gramme and clinical trial, response to training issues, their NRT versus single form NRT. Therefore the dose regimen experiences of implementing the reduction programme is based upon limited trial evidence and extension of the and recruiting. The interviews will cover the factors that evidence from its use in cessation (reduction to zero cigar- hindered or facilitated pharmacists' ability to recruit parti- ettes). A systematic review of placebo controlled short- cipants and their perceptions of smokers' reactions to term trials of nicotine patch and acute NRT show that behavioural support and medication provided within the both reduce daily cigarette consumption in people who programmes. Delivery of the overall programme and beha- are not trying to reduce their smoking and people who are vioural support will be explored including how support [. Both patch and acute NRT appear equally effective in delivery is organised within the pharmacy and by whom.
assessing reduction. One long-term trial allowed people Pharmacists will be asked about their understanding of free choice between patch, gum, and inhaler and found tobacco addiction and its treatment and about tobacco that gum produced the greater reduction of cigarettes control in general and where smoking reduction fits in, than patch or inhaler [. The rationale for patch use is because there is evidence from studies among GPs that that smokers find regular use of the patch very easy, with these broader attitudes affect the clinical treatments doc- typically very high levels of adherence , while acute tors give their patients.
NRT dosing is often sub-optimal [. However, acute Trial participants will be approached by the research NRT provides a direct behavioural replacement of cigar- fellow who will select some who have used each of the ettes (such as ‘have a piece of gum when you would ordi- permutations of support/no support and short/standard narily smoke') and this appears important in smoking reduction programmes. Participants who drop out, reduction This population have relatively low interest Taskila et al. BMC Public Health 2012, 12:182 in cessation and might need to continue pharmacotherapy • For gum, lozenge, or sublingual tablets, participants for up to a year, so a combination approach seems most should replace each missed cigarette with one of their likely to produce optimal adherence to regimen and opti- chosen product.
• For nasal spray, participants should take one spray in There is no foolproof way to give a person exactly the each nostril to replace each missed cigarette.
right dose of nicotine. However, serious problems from • For inhalator, patients should puff as often as is too much nicotine replacement are uncommon in smo- needed. As a rough guide, 40-80 puffs on the inhalator kers. All smokers have had episodes of rapid smoking and replace one cigarette.
can easily identify symptoms resulting from too much Participants will be strongly encouraged to use both a nicotine and can cut back. Furthermore, nicotine replace- patch and a short-acting form of NRT concurrently. How- ment, particularly in the form of patches, delivers nicotine ever, participation in the study depends upon willingness in a very slow form. Experience of using high dose nico- to use NRT in general, so individuals prepared to use only tine patches (up to 63 mg daily) shows that side-effects one form of NRT will be allowed to participate. Partici- from ‘overdose' are unusual when nicotine is given slowly pants will choose the preferred product together with to smokers ]. On the other hand, there is good evidence pharmacists. Participants are allowed to change their NRT that the smoking reduction without NRT or with an at anytime during the trial.
inadequate dose of NRT is much less effective Bearingthese considerations in mind, we propose the following Dose alteration procedure dosing algorithm.
Overdose of nicotine is unlikely in clinical practice usingthe above products. There is still a common perception Initial patch dose that it is inadvisable to use NRT and smoke, although • < 10 cigs/day - 7 mg/24 hour patch or 5 mg/16 hour the data suggest that this is not true [This belief is reinforced by the old labelling that advised people not • 10-19 cigs/day - 14 mg/24 hour patch or 10 mg/16 to smoke while using NRT. The Medicines and Health- care Regulatory Authority (MRHA) has removed this • 20+ cigs/day - 21 mg/24 hour patch or 15 mg/16 from all products, but the perception is slower to change, so we will advise pharmacists to reassure This dosing guideline should be modified according to exhaled carbon monoxide (CO) reading and patient Although nausea or indigestion can be symptoms of overdose, they are common adverse events to oral or nasal • < 10 ppm - 7 mg/24 hour patch or 5 mg/16 hour NRT and are an unreliable guide to overdose. Likewise, some symptoms such as agitation or restlessness are both • 10-19 ppm - 14 mg/24 hour patch or 10 mg/16 hour symptoms of nicotine withdrawal suggesting under-dosing and of overdose. Pharmacists will therefore be advised to • ≥20 ppm - 21 mg/24 hour patch or 15 mg/16 hour look for definite symptoms of: • Muscular twitching The patch dose from cigarettes per day will be esti- mated by exhaled CO. If there is a conflict, the pharma- cist should generally use the higher suggested dose.
• Rapid pounding heart Pharmacists are emphasised that CO levels are typically • High blood pressure lower in the morning rising steadily through the day; therefore the dosing guidelines are only approximate Participants will be advised to remove the patch at night Assuming overdose symptoms are not present, then the and replace with a new patch each morning i.e. use under option for dose alteration will be either to continue with 16 hours only, even if the product is a 24 hour patch. One the present patch dose, or to increase the patch dose to of the most frequent side-effects of patch is vivid dreams the next step i.e. from 7 mg to 14 mg or 14 mg to 21 mg or insomnia and using over 16 hours prevents this, with no decrement in efficacy Reducing adverse reactions 25 mg. Criteria for suggesting an increased dose of patch is a key aim of treatment that might last for nine months.
• The patient wants to reduce smoking further Initial short-acting NRT dose • The patient is finding smoking reduction difficult Participants can have free choice of nicotine inhalator, 2 because s/he is feeling irritable, edgy, and urges to mg gum, 2 mg sublingual tablets, 2 mg lozenges, or smoke in periods when smoking is ‘not allowed' by the nasal spray.
programme they are following.
Taskila et al. BMC Public Health 2012, 12:182 The short-acting forms of NRT have no upper limit of patch, advice will be given on the use of over the counter dose for all practical purposes because practical consid- emollients and 1% hydrocortisone cream, as is standard.
erations (such as the need to eat), or local irritation from Data on all concomitant medication will be recorded.
the products, and the sensation of having used too muchnicotine within a short time of using the product, natu- rally limit the dose consumed. The patient will be advised The findings from the proposed trial are timely and to replace each additional missed cigarette with a short- highly relevant in public health as there is a recognized acting form of NRT as described in the initial dosing.
need to support smokers who feel unable to quit to Should a person find that going without cigarettes is diffi- reduce their smoking instead. The Department of cult; the dose of short-acting NRT should be increased in Health (DH) proposed a new tobacco control strategy the following way: that envisaged ‘tailored quit plans' meaning smoking • For gum or lozenge, increase the dose from 2 mg reduction as an intermediate goal without necessarily lozenge to 4 mg lozenge.
committing to abstinence. Although the DH has com- • For sublingual tablets, participants should use two mitted to harm reduction, there is no trial showing that microtabs at a time.
allowing reduction alongside cessation leads to greater • For nasal spray, participants should administer two health benefits than offering abrupt cessation only. This sprays in each nostril to replace each missed cigarette.
is a pilot study to assess the feasibility of offering smok- • For inhalator, patients should puff as often as is ing reduction programme within pharmacies that offer naturalistic setting to show population benefit from • Modification of medication regime these programmes. In addition, findings from this trial Participants who have problems with insomnia or diffi- will inform the development of evidence-based treat- culties with vivid dreams will use the patch for 16 hours ment for smokers who want to reduce and best daily, not 24 hours. Participants who have skin reactions approaches to engage reluctant quitters onto the to the patch that are not controlled by switching prepara- tions, emollient and hydrocortisone cream will switch toshort-acting NRT only.
Procedures for handling the data • Participants who become pregnant may have their dose adjusted in line with NICE guidance(8) and in The trial will run as part of the portfolio of trials in the accord with the wishes of the participant.
Primary Care Clinical Research and Trials Unit • Participants who show symptoms of overdose will (PCCRTU), an NIHR recognised trials unit in Primary have the dose reduced.
Care Clinical Sciences at the University of Birmingham.
• Participants who give up on their reduction attempt The data management will be run in accord with the will cease using NRT.
standard operating procedures (SOPs), which are fully • Participants who experience adverse reactions or compliant with the Data Protection Act and Interna- adverse events will stop using NRT products, definitively tional Conference on Harmonisation (ICH) and Good or temporarily, when deemed necessary by the study Clinical Practice (GCP). The source documents for the trial will be the case report forms (CRFs) which will be • Participants who stop the treatment early will not be stored in the pharmacies in a locked cabinet in a locked replaced, and they will be followed-up like the other office. The trial database will be securely held and main- tained by the PCCRTU. Data cleaning will take place by Pharmacists are advised to apply same guidelines for a series of logical checks on the electronic data. (For patients who come to them with any above issues if example, a person cannot be recorded as prolonged they are in the arm of the study which does not give abstinent smoker at 6 months if they were not in such a state at 8 weeks). Discrepant records will be checkedwith the source documents and the database amended if Concomitant medication necessary. On completion of the trial and data checking, All medications will be permitted for use concurrently, the CRFs will be transferred to Modern Records, a except those that are proven to help smoking cessation secure archiving facility at the University of Birming- (bupropion, nortriptyline, mecamylamine, reserpine, vare- ham, where they will be held for 15 years and then nicline), or medications that are unlicensed and for which destroyed. The database will be anonymised and a no interaction data with NRT are available. The NRT itself secure compact disc containing the link between identi- is aimed at the relief of symptoms of nicotine withdrawal.
fication number and patient identifiable information will Should adverse skin reactions occur with the use of the be stored in modern records.
Taskila et al. BMC Public Health 2012, 12:182 Data Protection and Confidentiality • abnormal test findings, Data will be kept in accordance with the Data Protection • clinically significant symptoms and signs, Act and the trial registered with the Data Protection Act • changes in physical examination findings, website at the University of Birmingham. The SOPs of the • hypersensitivity, and trials unit will be followed, which are designed to protect • progression/worsening of underlying disease.
patient confidentiality. Patient identifiable data will be Additionally, they may include the signs or symptoms shared only within the clinical team on a need-to-know basis to provide clinical care and ensure good and appro- • drug overdose, priate follow up. Patient identifiable data will also be • drug withdrawal, shared with the GP and approved auditors from the Research Ethics committee (REC), NHS Research and Development, or the MHRA will also be able to see • drug interactions, patient identifiable information. Otherwise, confidentiality • drug dependency, will be maintained and no one outside the trial team will • exposure in utero.
have access to either the CRFs or the database. No data Failure of expected pharmacological action or thera- relating to individuals will be identified in publications.
peutic benefit alone (i.e. lack of efficacy) is not necessa-rily an AE.
B.2. Definition of serious adverse event The trial will be conducted in compliance with the princi- A serious adverse event or serious adverse drug reaction ples of the Declaration of Helsinki (1996), the principles of is any untoward medical occurrence at any dose that: ICH-GCP and run in accord with EU Clinical Trials results in death, is life-threatening (immediate risk of Directive and all of the applicable regulatory requirements.
death), requires inpatient hospitalisation or prolongation The study protocol and other documentation have been of existing hospitalisation, results in persistent or signifi- approved by the Birmingham East, North and Solihull cant disability/incapacity, and/or results in congenital Research Ethics Committee, 14th of June 2010 (REC refer- anomaly/birth defect. An important medical event may ence number: 10/H1206/22) and amendment on 21 not be immediately life-threatening and/or result in November 2011 (Amendment number: AM01). Any sub- death or hospitalisation. However, if it is determined that sequent protocol amendments will be submitted to the the event may jeopardize the participant and may require REC for approval and the other bodies if necessary. We intervention to prevent one of the other outcomes listed will comply with ICH-GCP Guidelines over the reporting in the definition above, the important medical event of adverse events, serious adverse events, and suspected should be reported as serious. Examples of such events serious adverse reactions (SUSARS). In addition we will are intensive treatment in an accident and emergency provide the REC with progress reports as well as a copy of department or at home for bronchospasm; blood dyscra- the Final Study Report.
sias or convulsions that do not result in hospitalisation;or development of drug dependency or drug abuse. Ser- Dissemination of the results ious adverse events will be those that occur during the The trial results will be written up for submission to peer period of medication use or within 7 or more days of reviewed scientific journals and presented in national and ceasing medication use.
international conferences. No data relating to individuals B.3. Definition of suspected serious adverse reaction (SSAR) will be identified.
Means an adverse reaction that is classed as serious andwhich is consistent with the information about the med- icinal product in question set out (in the case of a The study is funded by the award of a grant from the licensed product, in the summary of product character- Prevention Research Advisory Board of the National istics for that product.) Prevention Research Initiative (NPRI) B.4. Definition of suspected unexpected serious adversereaction (SUSAR) Appendix 1 Adverse Event Reporting Means an adverse reaction that is classed as serious and which is not consistent with the information about the B.1. Adverse event medicinal product in question set out (in the case of a An AE is any untoward medical occurrence in a clinical licensed product, in the summary of product character- investigation participant administered a product or med- istics for that product) ical device; the event need not necessarily have a causal B.5. Monitoring and reporting adverse events relationship with the treatment or usage. Examples of NRT is a well tried and tested medication and there are AEs include but are not limited to: minor common and well known side-effects that it will Taskila et al. BMC Public Health 2012, 12:182 not be practical or useful to record. For example, oral know whether or not investigational product caused the NRT almost universally causes burning in the mouth event, then the event will be handled as "related to investi- that most people find initially unpleasant but become gational product" for reporting purposes. If the investiga- used to in due time. Where adverse events are listed in tor's causality assessment is "unknown but not related to SPC as expected and are classified as mild, pharmacists investigational product", this should be clearly documen- will not be required to record these on the adverse ted in the CRF. In addition, if the investigator determines a serious adverse event is associated with trial procedures, For all other adverse events (i.e. moderate or severe or the investigator must record this causal relationship, as possibly serious), the investigator will pursue and obtain appropriate, and report such an assessment in accordance information adequate both to determine the outcome of with the serious adverse event reporting requirements, if the adverse event and to assess whether it meets the cri- teria for classification as a serious adverse event requiring B.9. Evaluation of AEs for causality immediate notification to the sponsor, the NHS R&D • Not Related. Onset of the event as relative to adminis- office, and the research ethics committee. The investiga- tration of the product, is not reasonable; or, another tor will assess causality. For adverse events follow-up by cause itself can explain the occurrence of the event the investigator is required until the event or its sequela • Unlikely to be related. Onset of the event as relative resolve or stabilise.
to administration of the product is possible but another B.6. Severity Assessment cause itself can explain the occurrence of the event or The treating clinician or investigator will use the adjec- there are no reasonable grounds for suspecting that the tives mild, moderate, or severe to describe the maximum product could have caused the event.
intensity of the adverse event. For purposes of consis- • Possibly related. Onset of the event as relative to tency, these intensity grades are defined as follows: administration of the product is reasonable; however the • Mild- Does not interfere with participant's usual event could have been due to another, equally likely, • Moderate- Interferes to some extent with partici- • Probably related. Onset of the event as relative to pant's usual function.
administration of the product is reasonable and is more • Severe- Interferes significantly with participant's likely explained by the drug than by any other cause.
• Definitely related. Onset of the event as relative to Note the distinction between the severity and the ser- administration of the product is reasonable and there is iousness of an adverse event. A severe event is not neces- no other cause to explain the event; or a re-challenge (if sarily a serious event. For example, a headache may be feasible) is positive.
severe (interferes significantly with participant's usual AE is classified as "not related" or "unlikely to be function) but would not be classified as serious unless it related" in case the patient has stopped using NRT met one of the criteria for serious adverse events, listed seven days or longer at occurrence of the event.
The pharmacists/clinicians' responsibilities and pro- B.7. Exposure In Utero cesses for evaluating AEs The license for NRT does not exclude use in pregnancy The participant will be encouraged to report AEs to the and NICE guidelines allow such use. We will exclude pharmacist, who will manage these in the normal manner pregnant or breast feeding women because the dose for reported AEs. The pharmacist completes a form and format of NRT advised for pregnant women is dif- called: "Undiagnosed health problem or hospitalisation/ ferent from that used in our protocol. Consequently, death/disability log" in the CRF. In the case of SUSARs we will adjust the dose of NRT should a woman or SAEs, the pharmacist will report to the PI or other become pregnant during treatment. As NRT use in member of the investigating team within 24 hours of pregnancy is routine in NHS practice, we will not fol- becoming aware of such a possible occurrence. In case low up such women to determine the outcome of preg- the research team becomes aware of the occurrence first, nancy in such cases.
the Principal Investigator will inform the pharmacist and B.8. Causality Assessment fill in the log in the online CRF. It is pharmacist's respon- The pharmacist's or investigator's assessment of causality sibility to ensure that both versions of the CRF log must be provided for all adverse events (serious and non- (online and paper version) are accurate.
serious). An investigator's causality assessment is the B.10. The CI/PI's responsibilities and processes for determination of whether there exists a reasonable possibi- lity that the investigational product caused or contributed Each AE reported to the PI will be evaluated for serious- to an adverse event. If the investigator's final determina- ness, causality, expectedness and severity. The responsi- tion of causality is unknown and the investigator does not bility for this will lie with Dr Paul Aveyard, the PI.
Taskila et al. BMC Public Health 2012, 12:182 Reporting to the sponsor will be required where the AE has a possible causal relationship to the trial inter- 2009, 338:b1024.
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Fiore MC, Jaen CR, Baker TB, Bailey WC, Benowitz NL, Curry SJ: Treating made but will be followed promptly with a detailed writ- tobacco use and dependence: update. U S Department of Health and ten report on the trial SAE form The copy of the form Human Services 2008, 2008:1-256.
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Aveyard P, Wang D, Connock M, Fry-Smith A, Barton P, Moore D: Authors' contributions TT participated in the design of the study and drafted the manuscript. PA Nicotine Tob Res 2009, 11(5):475-80.
conceived of the study, participated in its design and helped to draft the manuscript. TC, JFE, SM, RB, MP, SC and DW all participated in the design of Patient Educ Couns 2007, 66(2):188-191.
the study and reviewed the manuscript. All authors read and approved the final manuscript.
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Competing interests Campbell M, Fitzpatrick R, Haines A, Kinmonth AL, Sandercock P, TT has no competing interests. PA has done consultancy work for Pfizer, Spiegelhalter D: McNeil, and Xenova/Celtic. TC has done consultancy work for Johnson and BMJ 2000, 321:694-696.
Johnson and Pierre Fabre Laboratories, MP has no competing interests. SM Creswell JW: Qualitative inquiry and research design: choosing among five has no competing interests, RB has worked with Pfizer on unrelated research traditions Sage Publications: California; 1998.
projects. JFE has no competing interests. SC has no competing interests.
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Pre-publication historyThe pre-publication history for this paper can be accessed here: doi:10.1186/1471-2458-12-182Cite this article as: Taskila et al.: A Randomised trial of nicotine assistedreduction to stop in pharmacies - The RedPharm Study. BMC PublicHealth 2012 12:182.
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