Comparing the Effectiveness of Nicotine Patch With Gum Versus Nicotine Patch Alone in Smoking Cessation in Hong Kong Primary Care Clinics
Phase: NA
Conditions: Smoking Cessation
Sponsor: Hospital Authority, Hong Kong

Research document number: SCCP_2012_v2_12_Dec_2012 
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Research Proposal  
 
Comparing the effectiveness of nicotine patch with gum 
versus nicotine patch alone in smoking cessation in Hong 
Kong primary care clinics 
 
Introduction 
Cigarette smoking is the leading preventable cause of mortality, responsible for nearly 
six million deaths worldwide (WHO, 2011). Smoking related-diseases kill 1 in 10 
adults globally. By 2030, if current trends continue, smoking will kill 1 in 6 people. In 
Hong Kong, smoking kills 5700 persons per year. Smoking is related to cardiovascular 
diseases, stroke, chronic obstructive pulmonary disease and many kinds of cancers. 
Thus, smoking cessation is associated with substantial health benefits for all smokers 
(Rigotti, 2002). 
 
Pharmacotherapy in smoking cessation plays an important role in reducing the 
withdrawal symptoms, thus, facilitating clients to stop the habit of smoking. First line 
pharmacotherapies for smoking cessation include varenicline, bupropion and NRT. In 
a recent meta-analysis (Mills et at, 2012), Varenicline was the only treatment 
demonstrating effects over the other options including high dose nicotine patch, 
combined NRT and bupropion. However, according to FDA report 2008, there is a 
possible association between suicidal events and the use of varenicline. According to 
our local pilot study in 2011 presented in Hospital Authority Convention (Chan et al, 
2011), the smoking cessation rate after a 12-weeks course of Varenicline can be as 
high as 43%. However, 20% of smokers experienced side effects such as 
gastrointestinal upset, dizziness and headache. As a result, these patients could not 
complete the course of therapy. 
 
Nicotine replacement therapy (NRT) aims to provide nicotine to smokers without them 
smoking tobacco, thus, helping them to break the smoking habit. It is a safe and 
effective intervention. Currently, different preparations are available for smokers: 
transdermal patch, gum, and lozenge as well as combination therapy.  
 
The efficacy of any monotherapy is limited (Ebbert et al, 2010) especially in heavy 
smokers due to significant withdrawal symptoms. Combination NRT provides a stable 
baseline nicotine level by means of nicotine patch plus intermittent usage of short 
acting NRT e.g. gums, lozenges or inhalers for withdrawal symptoms. Combined NRT 
is associated with higher salivary continine concentrations and lower withdrawal 

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scores (Fagerstrom et al, 1993). Randomized controlled trials (Smith et al, 2009; 
Piper et al, 2009) have also shown that the 6-month post quit cessation rate of 
combination therapy of nicotine patch and lozenge was 26.9%. Megan et al (2009) 
also showed that combination nicotine therapies were superior to nicotine 
monotherapies. Trials of combining various NRTs (Stead et al, 2008) did not report 
that combination treatment produced increased adverse events.  
 
Yet, data on benefits of combined NRT in smoking cessation are lacking in Hong Kong 
primary care clinics. Thus, this study serves as the first territory wide study across all 
seven clusters in Hospital Authority to compare the effectiveness of combined NRT 
with single NRT in primary care smoking cessation clinics. The results of this study 
can help enhance the workflow in our smoking cessation framework, which in turn, 
can further enhance smoking cessation. Such improvement can greatly help reduce 
the total costs on healthcare in a long run. 
 

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Literature Review 
 
Pharmacotherapy in smoking cessation plays an important role in reducing the 
withdrawal symptoms, thus, facilitating clients to stop the habit of smoking. First line 
pharmacotherapies for smoking cessation include varenicline, bupropion and nicotine 
replacement therapy. 
 
Varenicline 
Varenicline is a partial agonist at the alpha-4 beta-2 subunit of the nicotinic 
acetylcholine receptor, the receptor that appears to produce the reinforcing effects of 
nicotine and leads to nicotine dependence (Coe et al, 2005; Hays et al 2008; 
Henningfield et al, 2005). A meta-analysis (Fiore et al, 2008) done for the US 
Preventive Health Service practice guidelines found that varenicline increased the 
odds of quitting three-fold compared to placebo (OR 3.1, 95% CI 2.5-3.8) and 
produced a quit rate of 33 percent at six month follow-up. 
 
In 2008, the FDA reported "a possible association between suicidal events and the 
use of varenicline” based upon review of post-marketing reports (FDA newsletter, 
2009). Patients should be monitored for neuropsychiatric symptoms including 
changes in behavior, hostility, agitation, depressed mood, suicidal ideation, and 
suicide attempts. 
 
Nicotine replacement therapy (NRT) 
NRT aims to provide nicotine to smokers without them smoking tobacco, thus, helping 
them to break the smoking habit. Currently, different preparations are available for 
smokers: transdermal patch, gum, and lozenge as well as combination therapy.  
 
Combination nicotine replacement therapy 
Nicotine combination therapy involves a nicotine patch plus a short-acting nicotine 
replacement therapy such as gum, inhaler or lozenge. The nicotine patch is the 
primary NRT product to control baseline nicotine withdrawal symptoms. A short-acting 
form of NRT helps to control cravings and withdrawal symptoms during the day on an 
as needed basis. The choice of a short-acting agent depends on patient preference. 
Randomized controlled trials (Smith et al, 2009; Piper et al, 2009) have shown that the 
6-month after quitting cessation rate of combination therapy of nicotine patch and 
lozenge was 26.9%. A meta-analysis done by Fiore et at (2008) (see Table 1) showed 
that 6-month after quitting cessation rate of a combination therapy with patch with 

Research document number: SCCP_2012_v2_12_Dec_2012 
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gum/spray was 36.9%. Both rates are higher than single nicotine replacement 
therapy. 
 
Table 1. 
Preparation 
No of arms 
Estimated abstinence rates at 6 months post 
quit 
Placebo 
80 
13.8 
Nicotine patch (6-14 weeks) 
32 
23.4 (21.3-25.8) 
Nicotine gum (6-14 weeks) 
15 
19.0 (16.5 – 21.9) 
Nicotine patch + ad lib 
gum/spray 
3 
36.5 (28.6 – 45.3) 
 
With the current evidence from overseas studies, both varenicline and combined 
nicotine replacement therapy are the two most effective smoking cessation therapies. 
However, there is not without limitations when using varenicline. There is a possible 
association of varenicline with neuropsychiatric symptoms and should be best 
avoided in these patients. In addition, a certain proportion of patients report side 
effects from varenicline (Chan et al, 2011). On the other hand, not much side effects 
have been reported with combined nicotine replacement therapy and this regimen can 
also be used in patients with psychiatric illnesses. If combined nicotine replacement 
therapy is shown to be more effective than single NRT in our locality, it could be widely 
used to help further improve the smoking cessation rates. 
 
Research questions: 
1. 
How effective is combination nicotine replacement therapy compared to single 
nicotine replacement therapy in Chinese population? 

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Hypothesis: 
Nicotine patch with gum is more effective than nicotine patch alone in smoking 
cessation.  
 
Objective: 
To compare the effectiveness of nicotine patch with gum and nicotine patch alone in 
Hong Kong primary care smoking cessation clinics  
 
Methods: 
This is an interventional, non-blinded randomized controlled trial. 
 
Participants: 
Inclusion criteria: 
Current smokers, who smoke 10 or more cigarettes a day, will be recruited from 
general outpatient clinics.   
 
Exclusion criteria: 
The following smokers will be excluded:  
⚫ 
unstable angina, 
⚫ 
severe cardiac arrhythmia, 
⚫ 
recent acute myocardial infarction or cerebrovascular accident in preceding 3 
months (McRobbie and Hajek, 2001), 
⚫ 
below 18 years old, 
⚫ 
being pregnant or on breast-feeding,  
⚫ 
unable to use gum, 
⚫ 
with a previous history of failure to NRT  
⚫ 
hypersensitivity to nicotine 
 
Recruitment procedure: 
The study will be carried out in the smoking cessation clinics located in the 5 clusters 
(Table 2): Hong Kong East, Kowloon East, Kowloon Central, New Territories East and 
New Territories West Clusters. Doctors and nurses from the involved clinics will refer 
motivated patients to smoking cessation counselors at the sites. In the initial 
assessment, smoking cessation counselor will assess their smoking history. When 
these patients meet the inclusion criteria, smoking cessation counselors will explain 
the research to these patients and recruit them. Written consent will be obtained from 
these patients. A statistician who is not involved in any part of the study independently 

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randomized participants by using a predetermined random table generated by 
Microsoft Excel 2002. The randomization number generated will be assigned to one of 
the two treatments: combined nicotine replacement therapy or single nicotine 
replacement therapy. Patients will then be followed up at 1 week, 4 weeks, 12 weeks, 
26 weeks and 52 weeks after quit day (Diagram 1). 
 
Table 2. A List of involved clinics for this study 
Clusters 
Clinics 
Hong Kong East 
1. Anne Black GOPC 
2. Chai Wan GOPC 
3. Sai Wan Ho GOPC 
4. Shau Kei Wan JC GOPC 
5. Wan Tsui GOPC1 
Kowloon East 
1. Tseung Kwan O JC GOPC 
2. Ngau Tau Kok JC GOPC 
Kowloon Central 
1. Queen Elisabeth SCCC 
2. Central Kowloon Heatlh Centre 
3. Yau Ma Tei General Outpatient clinic 
New Territories East 
1. Fanling family medicine centre, 
2. Wong Siu Ching family medicine centre 
3. Tai Po Jockey Club GOPC 
4. Ma On Shan family medicine centre 
5. Lek Yuen GOPC 
New Territories West 
1. Tuen Muen CCC/Yan Oi GOPC 
2. Tin Shui Wai Health Centre 
3. Tin Shui Wai CHC 
4. Yuen Long JC GOPC 
 

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Diagram 1. Details of workflow and study timeline 
 
Visit 1: 
Doctors and nurses refer suitable subjects to SCCC 
(smokes  10 cigs/day) 
Visit 2 
SCCC counselor carries out initial assessment 
Fulfill inclusion criteria and 
explain research 
Does not fulfill inclusion criteria 
Will not recruit into study and  
FU SCCC for usual care 
Disagree to join 
Agree to join 
Obtain written consent, discuss quit date and dispense pre-assigned randomized treatment 
Nicotine patch 
Follow up: 1 week post quit 
Follow up & refill drug treatment: 4 weeks post quit 
Follow up: 12 weeks post quit 
Follow up & refill drug treatment: 4 weeks post quit 
Follow up: 1 week post quit 
Follow up: 12 weeks post quit 
Follow up: 26 weeks post quit 
Follow up: 52 weeks post quit 
Follow up: 26 weeks post quit 
Follow up: 52 weeks post quit 
Nicotine patch with gum 
Start treatment on target quit date 
Start treatment on target quit date 

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Intervention: 
Participants receive open labeled medications. NRT will be given by counselors for 8 
weeks.  
 
Control group: 
In this study, control group receives usual counseling and single NRT i.e. nicotine 
patch 
 
Intervention group: 
The intervention group receives usual counseling and combined NRT consisting of 
nicotine patch and gum. 
 
Table 3. Treatment arms 
1 
Combined nicotine therapy 
i.e. nicotine patch + gum 
Long acting nicotine patch + short acting 
nicotine gum (appendix 1 on prescription 
guideline on NRT) 
2 
Single nicotine therapy i.e. 
nicotine patch 
Nicotine patch (appendix 1 on prescription 
guideline on NRT) 
 
Potential side effects from interventions (Please see Appendix 1 for details) 
 
Intervention 
Potential side effects 
Nicotine gum 
⚫ 
If the gum is chewed continuously and quickly, side 
effects such as throat and stomach irritation, indigestion 
or hiccups may occur 
Nicotine patch 
⚫ 
May cause redness, burning or stinging feeling or skin 
rash 
Combined nicotine 
gum and patch 
⚫ 
Same as above 
 
 
Trials of combining various NRTs (Stead et al, 2008) did not report that combination 
treatment produced increased adverse events. Any adverse effects from treatment 
will be reported to the investigators and patients will be advised to stop the 
intervention.

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Sample size Calculation: 
 
According to a meta-analysis in 2008, smoking cessation rates (26 weeks post quit) 
for combined nicotine therapy is about 36.5% and that of nicotine patch is 23.4%. 
Based on the sample size calculator provided from Chinese university, the sample 
size could be calculated as below: 
 
Suppose it is of interest to test for equality of the smoking cessation rates of combined 
NRT as compared to single NRT. Considering that the true mean 26 weeks post quit 
cessation rate of combined NRT and single NRT are given as θ1=36.5% and 
θ2=23.4%, respectively. Then, the required sample size with equal allocation (r=1) to 
achieve a 90% power (β=0.1) at α=0.05 will be n1=n2=252. 
 
However, it is important to take into account the response rate, eligible rate, and the 
prevalence. Hence, the sample size has to be adjusted according to these. Assuming 
only 90% of these patients are eligible to join according to the exclusion criteria, then 
the actual sample size should be 252/0.9 = 280. Then to get the effective sample size 
(n=56), each cluster should be expected to enroll 40 smokers per arm over a period of 
nine months. A total of 280 smokers per arm would be required. 
 
This means the sample size for each clinic site will be: 
Cluster 
Nicotine patch + gum 
(n1=280) 
Nicotine patch  
(n2=280) 
Hong Kong East 
56 
56 
Kowloon East 
56 
56 
Kowloon Central 
56 
56 
New Territories East 
56 
56 
New Territories West 
56 
56 
Total 
280 
280 
 

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Smoking status 
In this study, carbon monoxide (CO) level would be obtained to confirm smoking 
status. It is simple to measure and is relatively inexpensive. It can be measured in 
expired air by CO meter in the clinics. With reference from SRNT (2002), a CO level of 
<8pp in expired air will be used as a cut off concentration to distinguish non-smokers 
from smokers.  
 
Primary Outcome:  
7-day point-prevalence abstinence assessed at 1 week, 4 weeks, 12 weeks, 26 
weeks and 52 weeks after the quit date. In the study, the date of recruitment i.e. date 
of initial assessment will be used as quit date. 
 
Secondary Outcome: 
Demographic factors and co-existing medical conditions will be collected for analyzing 
association with cessation rates. Adverse events related to the intervention will be 
recorded and analysed. 
 
Statistical analysis: 
All analyses will be carried out on an intent-to-treat basis. Data will be extracted from 
notes from Smoking Cessation Programme. Statistical analyses will be done using the 
Statistical Package for Social Sciences (SPSS). All statistical significance tests are 
two-tailed, and the level of significance will be taken as p < 0.05. Longitudinal analysis 
will be conducted to compare the effectiveness between the two drugs over time 
(Wiley, 2011). 
 
Data collection and patient confidentiality: 
In order to safeguard patient confidentiality, patients’ data will be collected by 
counselors and will be stored in Clinical Management System (CMS) which can only 
be accessed by the doctors and smoking cessation counselors who have access 
rights to CMS in the centre.  
 
Written informed consent: 
Potential benefits and risks of the study will be explained to participants by counselors. 
Written consent will be obtained from participants in written form. Participants would 
be allowed to withdraw from the study at any time with no consequences to their usual 
treatment. 
 

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Primary responsibility 
Investigators from Hospital Authority will be solely responsible for the primary 
responsibilities of the research as listed in the Clinical Research handbook (Hospital 
Authority, 2010). 
 
Application for Certification of Clinical Trial 
For the purpose of regulatory compliance, a Certificate for Clinical Trial (“CTC”) shall 
be obtained before initiation of any clinical study of any pharmaceutical product. An 
application for a CTC shall be submitted to the Pharmaceutical Registration Section of 
the Hong Kong Department of Health (“DOH”). It could take up to 3 months for 
approval and should be done at the same time as application for ethics committee 
approval. 
 
Application for Ethics Committee approval 
Application for approval from Ethics Committee will be done separately by individual 
cluster. 
 
Conflicts of interests 
Nil 
 
Schedule of the research 
 
0 - 4 weeks 
Sep 2013 
Liaison with counsellor and doctor in charge from each 
cluster, recruitment of research assistant 
5 - 39 weeks 
Oct 2013 – Jun 2014 
Patient recruitment 
40 – 92 weeks 
Jul 2014 - Jun 2015 
Ongoing study with patients being followed up according 
to protocol 
92-104 weeks 
Jul 2015 – Sep 2015 
Data analysis and report preparation 
 
This study complies with Declaration of Helsinki and ICH-CGP.

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References: 
1. 
Casegrande, Pike and Smith (1978), Biometrics 34:483-486. 
2. 
Coe JW, Brooks PR, Vetelino MG, et al. Varenicline: an alpha4beta2 nicotinic 
receptor partial agonist for smoking cessation. J Med Chem 2005; 48:3474. 
3. 
Chow, Shao and Wang, Sample Size Calculations In Clinical Research, Taylor & 
Francis, NY. (2003) Pages 88-89 
4. 
Chan LP, Leung KW, Wong PH, Cheung KW, Lam TA, Li KTP. Efficacy of 
Varenicline in enhancing smoking cessation in primary care clinic. HA 
Convention 2011. 
5. 
Clinical Research. Management and compliance at study sites. A practical 
handbook for investigators, clinical research personnel and administrators of the 
Hong Kong Hospital Authority, 2010. 
6. 
Ebbert JO, Hays T, Hurt RD. Combination Pharmacotherapy for stopping 
smoking: what advantages does it offer? Drugs. 2010; 70:643-50. 
7. 
Fagerstrom KO, Schneider NG, Lunell E. Effectiveness of nicotine patch and 
nicotine gum as individual versus combined treatments for tobacco withdrawal 
symptoms. Psychopharmacology (Berl) 1993; 111(3): 271-7. 
8. 
Fiore, MC, Jaen CR, Baker TB, et al. Clinical Practice Guideline. Treating 
Tobacco Use and Dependence: 2008 update. US Department of Health and 
Human Services, May 2008.  
9. 
Fitzmaurice Garrett M. Applied Longitudinal Analysis (2nd edition). Wiley Series in 
Probability and Statistics 2011 (ISBN-10:0470380276, 
ISBN-13:9780470380277). 
10. Flesis J.L., Statistical Methods for Rates and Proportions (2nd edition). Wiley: New 
York, 1981 
11. Hays JT, Ebbert JO. Varenicline for tobacco dependence. N Engl J Med 2008; 
359:2018. 
12. Henningfield JE, Fant RV, Buchhalter AR, Stitzer ML. Pharmacotherapy for 
nicotine dependence. CA Cancer J Clin 2005; 55:281. 
13. Hong Kong Thematic Household Survey report 48 
14. Leung M; Chan LP; Wong CL; Lam A; Li KTP. Smoking cessation - are we 
targeting at the right group of patients. Poster presentation, Hospital Authority 
Convention, 2011. 
15. McRobbie H; Hajek P. Nicotine therapy in patients with cardiovascular disease: 
guideline for health professionals. Advice. 2001; 96: 1547-1551. 
16. Mills EJ, Wu P, Lockhart I, Thorlund K, Puhan M, Ebbert JO. Comparsions of 
high dose and combination NRT, varenicline, and bupropion for smoking 

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cessation: A systemic review and multiple treatment meta-analysis. Annals of 
Med, 2012: early online: 1-10. 
17. Piper ME; Smith SS; Tanya R. Schlam; Michael C. Fiore; Douglas E. Jorenby; 
David Fraser; Timothy B. Baker. A Randomized Placebo-Controlled Clinical Trial 
of 5 Smoking Cessation Pharmacotherapies. Arch Gen Psychiatry. 2009; 66 (11): 
1253-1262. 
18. Rigotti NA. Clinical practice. Treatment of tobacco use and dependence. N Engl 
J Med 2002; 346:506. 
19. Sample size calculator. Chinese Univeristy. Available at : 
http://www.cct.cuhk.edu.hk/stat/Proportions.htm (Accessed on 14 Aug 2012) 
20. SRNT Subcommittee on Biochemical Verification. Biochemical verification of 
tobacco use and cessation. Nicotine Tob Res. 2002; 4(2):149-159. 
21. Stead LF, Perera R, Bullen C, Mant D, Lancaster T. Nicotine replacement 
therapy for smoking cessation. Cochrane Database of Systematic Reviews 2008, 
Issue 1. Art. No.: CD000146. DOI: 10.1002/14651858.CD000146.pub3.  
22. Smith SS; Danielle E. McCarthy; Sandra J. Japuntich; Bruce Christiansen; 
Megan E. Piper; Douglas E. Jorenby; David L. Fraser; Michael C. Fiore; Timothy 
B. Baker; Thomas C. Jackson. Comparative Effectiveness of 5 Smoking 
Cessation Pharmacotherapies in Primary Care Clinics. Arch Intern Med. 2009; 
169(22): 2148-2155. 
23. The smoking cessation aids varenicline (marketed as Chantix) and bupropion 
(marketed as Zyban and generics): suicidal ideation and behavior. FDA Drug 
Safety Newsletter 2009; 2:1. Available at: 
http://www.fda.gov/downloads/Drugs/DrugSafety/DrugSafetyNewsletter/ucm107
318.pdf (Accessed on 11 Aug 2012). 
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Warning about the dangers of tobacco. World Health Organization, Geneva 2011. 
http://whqlibdoc.who.int/publications/2011/9789240687813_eng.pdf (Accessed 
on 11 Aug 2012). 
 

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Appendix 1. Prescription guideline on Nicotine Replacement Therapy 
Item 
Pros and cons 
Preparations 
Dosing Recommendations 
Nicotine Patch 
Pros: 
⚫ Easy to use 
⚫ Long acting 
Cons: 
⚫ Slower onset 
⚫ May cause redness, burning or 
stinging feeling or skin rash 
⚫ 
24 hours: 7, 14, 
21 mg 
24 hours patch: 
⚫ 
40 cpd = 42mg/day 
⚫ 
21-39 cpd = 28-35mg/day 
⚫ 
10-20 cpd = 14-21mg/day 
⚫ 
<10 cpd = 14mg/day 
Maximum dosage: 42mg/day 
Adjust dosage according to withdrawal symptoms, cravings and 
discomfort. 
Initial dose for 4-6 weeks, then taper every 2-4 weeks in 7-14mg 
steps. 
If patient develops irritative symptoms at night, can take off the 
patch during sleep. 
Nicotine Gum 
Pros: 
⚫ Easy to use 
⚫ Faster delivery, for short acting use 
Cons: 
⚫ Should not eat or drink 15 mins 
before use 
⚫ Frequent to ease off cravings 
⚫ If the gum is chewed continuously 
⚫ 
2mg, 4mg 
⚫ 
In original/mint 
flavours 
Based on time to first cigarette of the day: 
⚫ 
If <30mins = 4mg 
⚫ 
If >30mins = 2mg 
Based on cigarettes/day 
⚫ 
20 cpd = 4mg  
⚫ 
<20 cpd = 2mg 
Initial dosing is 1-2 pieces every 1-2 hrs (10 to 12 pieces/day) 
 

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and quickly, side effects such as 
throat and stomach irritation, 
indigestion or hiccups may occur 
Item 
Pros and Cons 
Preparations 
Dosing Recommendations 
Combination 
Patch + gum 
Pros: 
⚫ More effective than monotherapy 
Cons: 
⚫ Including the side effects from 
nicotine gum and patch 
As above 
⚫ 
Prescribe patch dosage according to number of cigs/day and 
add 2mg gum every 1-2 hours as needed when withdrawal 
symptoms occur. 
⚫ 
Step up dose of patch if frequent use of gum is needed. 
References: 1) Mayo Clinic NDC tobacco dependence treatment medication summary; 2) Department of Health; 3) Mils et al , Adverse events associated with nicotine replacement therapy 
(NRT) for smoking cessation. A systematic review and meta-analysis of one hundred and twenty studies involving 177.390 individuals, Tobacco Induced Diseases 2010, 8:8