A community pharmacist-led smoking cessation intervention using a smartphone app (PharmQuit): A randomized controlled trial.

WHO supports the harnessing of mobile technologies to improve access to smoking cessation services. As such, this study evaluated the effectiveness of smoking cessation services provided by community pharmacists using PharmQuit compared with standard care. The study was a prospective, multicenter, randomized controlled trial that included 156 participants who were 18 years or older and smoked at least one cigarette daily for a month, were ready to quit, willing to participate, and had a smartphone. The study was performed at seven community pharmacies in three provinces in Thailand. Participants were allocated to the intervention (n = 78) and control groups (n = 78). Both groups received the usual smoking cessation services with pharmacotherapy and counseling from community pharmacists for 6 months. The intervention group received PharmQuit as an additional service. Both groups were scheduled for follow-up visits on days 7, 14, 30, 60, 120, and 180. The primary outcome was continuous abstinence rate on day 180. The secondary outcomes included 7-day point abstinence rate, number of cigarettes smoked per day, exhaled carbon monoxide levels, adherence rate to the program, and satisfaction with PharmQuit. An analysis using the intent-to-treat principle was performed. Smoking cessation rates and the number of cigarettes smoked per day were significantly higher during the follow-up visits in both groups (p < 0.05). However, there were no statistically significant differences between the two groups. The adherence rate to the smoking cessation program was higher in the intervention group than in the control group (74 days vs. 60 days, p > 0.05). The results showed the benefits of the contribution of community pharmacists. Although the inclusion of PharmQuit did not yield better results than pharmacists' counselling alone, it may help obtain better adherence to smoking cessation programs. Trial registration: Thai Clinical Trials Registry: TCTR20200925004 on September 25, 2020 -retrospectively registered, http://www.clinicaltrials.in.th/index.php?tp=regtrials&menu=trialsearch&smenu=fulltext&task=search&task2=view1&id=6841.

Introduction

Tobacco smoking is a major cause of premature death worldwide [1], leading to the death of up to half of its users. In 2017, smoking was the second leading risk (following hypertension) factor for premature death and disability globally, ranked by disability-adjusted life years (DALYs) [2]. The World Health Organization (WHO) has a global action plan to reduce the prevalence of tobacco use in persons aged 15 years and older by 30%, by the year 2025 [3]. In Thailand, the smoking prevalence among the general population in 2010 was 42%. With the combination of tobacco control policies and the rate of smoking cessation, the relative prevalence is predicted to be 34% in 2025, which is still higher than the WHO target [4]. Therefore, increased efforts to control tobacco use are essential for reducing the burden of non-communicable diseases in Thailand [4].

Counseling for smoking cessation is effective at helping smokers with quitting. Lancaster and Stead showed that different models of counseling provide benefits to participants [5]. Nicotine replacement therapy (NRT) increased the rate of quitting by 50‒60% for people who attempted to quit, regardless of the setting [6]. A combination of pharmacotherapy and high-intensity behavioral treatment was found to be better than high-intensity behavioral treatment alone [7], and health professionals, such as pharmacists, are in a unique position to help smokers quit. Several systematic reviews have shown that pharmacist-led interventions result in better abstinence rates in smokers [8-11] and may also be cost-effective [11, 12]. However, pharmacy counseling programs still have a high dropout rate [13].

Although various mobile apps are available to help smokers quit, studies have shown that only two out of 50 apps were accompanied with scientific and professional support [14], and most apps were not customized to the users’ needs [15]. An objective of this study was to help smokers adhere to a smoking cessation program, in which pharmacists assist and provide information and support for smokers. Developed for iOS and Android phones, PharmQuit aims to help “ready-to-quit” smokers with the assistance of community pharmacists. PharmQuit was developed using the five-user experience framework from the perspectives of smokers and pharmacists and was designed to deliver easy access to users. PharmQuit sends encouraging messages to the users’ phone every day to remind them to keep a daily record of smoking and maintain abstinence. It also provides information on cravings and adverse drug reactions from medications. Users can see clinical data screened by their pharmacists in PharmQuit, and they are also able to send messages directly to their pharmacists through the Line@ option. In addition, they can see how well they are doing based on the avatar. Participants can also share their status with others in the PharmQuit community.

Current evidence confirms the benefits of mobile phone-based smoking cessation interventions on long-term outcomes [16]. Although most app studies were designed for self-use [17, 18], one study featuring collaboration between smokers and physicians through an app and web-based system yielded positive results. However, only a few studies on smoking cessation apps have been conducted in community pharmacies and those were evaluated for short-term (8 weeks) outcomes [19, 20]. The aim of this study was to evaluate the effectiveness of the pharmacist-led smoking cessation app, PharmQuit, compared to a control group without the app. The objectives included evaluating the primary outcome of the continuous abstinence rate (CAR) at 6 months and the secondary outcomes of 7-day point abstinence rate (PAR), number of cigarettes smoked per day, exhaled carbon monoxide level at every visit, adherence to the smoking cessation program, and satisfaction with the app at 6 months.

Materials and methods

Design

This was a multi-center study using an open-label randomized trial with a control group in seven community pharmacies in three provinces in Thailand. Stratified random sampling was used for both the control and intervention groups and was based on age, sex, and nicotine dependence. The study adhered to the CONSORT guidelines [21] and includes a completed CONSORT checklist in S1 File. Cash compensation of $1.50 US dollars per visit was given to each smoker and $16.68 US dollars per smoker was given to each community pharmacist.

Ethical approval and consent to participate

The study protocol (S2 File), consent forms, and tools (S3 File) were approved by Mahasarakham University (ID: 033/2559). The certificate of approval is in the S1 File. The participants provided written informed consent to participate in the study. This trial was registered retrospectively in the Thai Clinical Trials Registry (TCTR20200925004) on September 25, 2020. The researchers were unaware of the requirement to register the clinical trial prior to the enrolment of participants, but amendments were made to our institutional training materials to reduce the likelihood of this error occurring in the future.

Participants

The recruitment was through invitations by pharmacy students, community pharmacists, health care providers, and health care volunteers. The recruitment period was July 30, 2017, to August 28, 2018. The study was conducted in January 2019. Eligible participants were smokers who were (1) aged 18 years or older; (2) smoking at least one cigarette per day for a month or more; (3) ready to quit smoking or in the preparation stage; (4) willing to participate in the study; (5) able to complete self-recording; and (6) had a smartphone. The exclusion criteria were women who were pregnant or breastfeeding, individuals with cardiovascular disease, and individuals currently enrolled in another smoking cessation program. The sample size was estimated based on two independent proportions of equal samples [22]. The quit rate after 6 months of treatment (13.8%) and the control (1.3%) groups were based on a 2010 study by Burford et al. [23]. The minimum sample size was 69 people per group (with α = 0.05, two-tailed) with 80% power to reject the null hypothesis in the quit rate at the 6-month follow-up. A dropout rate of 15% [24] was estimated; thus, the sample size was increased to approximately 80 smokers per group.

Randomization

Stratified random allocation was used to achieve equal assignment to the two groups. Stratification was performed according to three factors: sex, nicotine dependence level as determined by the Fagerström test (FTND) score [25], and age. A computer-generated random sequence determined by a chance process and could not be predicted was used to assign participants to the intervention and control groups (1:1). A printed randomized table was delivered to each pharmacy by a researcher (S2 File). Pharmacists and participants were not blinded. The pharmacists enrolled the participants, then, using a randomized table provided by the researcher, allocated participants to either the intervention group or the control group. The main researcher (Asayut N) assessed the allocation procedure of each pharmacy by checking the registered date and entry sequence in the web system compared with the randomized table from each pharmacy.

Intervention group

Smokers assigned to the intervention group met one-on-one with a community pharmacist at the respective pharmacy. The duration of the first visit was approximately 30 min. The pharmacists asked if the participants were willing to quit smoking, if they agreed to participate in the study, and to complete a consent form. The pharmacists reassured the participants that choosing to quit was the best decision and emphasized the benefits of quitting. The pharmacists interviewed the participants for general information, intention to quit, struggles in quitting, history of attempting to quit, smoking habits, and nicotine dependence as determined by the Fagerström test. Blood pressure, weight, and exhaled carbon monoxide (CO) determined by a smokerlyzer, were measured by pharmacists. Following the treatment plans, the pharmacist checked the randomized table to see if the participant was in the intervention group and registered their name to the web system (http://www.smokefreerx.com/) to get a username for the participant login. PharmQuit was then introduced and registered on the participant’s mobile phone. At the end of the service, the pharmacist scheduled the next visit.

Nicotine gum, nortriptyline, sodium nitrate 0.5% mouth wash, Vernonia cinerea lozenges, and herbal medicine were provided as options for participants who had FTND scores of at least 4, were smoking at least 10 cigarettes per day, or had a history of failure to quit smoking. Contraindications were checked prior to dispensing. The pharmacists counseled the participants on the following: drug name, dose, regimen, administration, duration of therapy, adverse effects, and the disposal of nicotine gum. Pharmacists dispensed medications following the smoking cessation practice guidelines of Thailand [26].

Follow-up visits were scheduled for days 7, 14, 30, 60, 120, and 180. If the participants did not adhere to the schedule, follow-up was conducted by telephone, Line app, or Facebook messenger. Each follow-up visit took approximately 10‒20 minutes. The pharmacists assessed smoking status, adherence to medication, adverse drug reactions, PharmQuit use, and the participants’ overall status, to evaluate obstacles and provide encouragement. The pharmacists encouraged the participants to continue in the cessation program and did not blame them if progress had not been made. Blood pressure, weight, and exhaled CO were also recorded during follow-up sessions. At the end of the appointment, the pharmacists refilled the medications and scheduled the next visit.

Control group

Smokers assigned to the control group met one-on-one with a community pharmacist at the community pharmacy. The participants received the usual pharmacy services on smoking cessation. The procedure for the control group was as previously described for the intervention group; however, these participants did not have access to PharmQuit.

Outcomes

The pharmacists assessed outcomes at every visit. The primary outcome was the proportion of participants who remained abstinent continuously for 6 months (CAR). Secondary outcomes were the proportion of patients who remained abstinent for at least seven days before each visit (7-day PAR), the proportion who exhaled less than 7 ppm of CO, the proportion who could adhere to the follow-up schedule, the proportion of adverse events during the study, the number of cigarettes smoked per day, and the average score of satisfaction with PharmQuit, which was evaluated only in the intervention group on day 180.

The satisfaction questionnaire for PharmQuit was specifically developed for this study using a 5-Likert scale. Each of the five items was rated as 1 (very unsatisfied), 2 (unsatisfied), 3 (neutral), 4 (satisfied), and 5 (very satisfied). The Cronbach’s alpha was 0.923. The user experience theory [27] was used as a framework for developing the questionnaire. The validity was verified by three experts in questionnaire development and research. There were 21 questions in five dimensions: objectives in quitting smoking (five questions with 25 scores), scope of application (four questions with 20 scores), format and interaction (four questions with 20 scores), design (four questions with 20 scores), and appearance (four questions with 20 scores). Online and paper-based questionnaires were administered to the participants in the intervention group at the follow-up visit on day 180.

Data analysis

Demographic data were compared between the intervention and control groups. Descriptive statistics are presented for the baseline as shown in Table 1. Categorical variables were compared using the chi-squared test, and continuous data were compared using the independent t-test for normally distributed data and the Mann-Whitney U test for data that with non-normal distribution. Intention-to-treat was applied in all analyses using the advantage of all available data points. Primary and secondary outcome variables were checked for distribution, outliers, and missing patterns. If participants missed in between visits, the information from the previous visit was assumed; for example, a participant came on day 14 with smoking then on day 30 with no smoking, day 60 would be recorded as no smoking. The missing data in the ratio scale were imputed by multivariate imputation by chained equations using R program version 4.1.1.

Table 1

Baseline characteristics of participants in the intervention and control groups.

Characteristics	Intervention group No (%) (n = 78)	Control group No (%) (n = 78)	p-value
Gender: male	71 (91.0)	72 (92.3)	0.772b
Age (years, mean ± SD)	33.5±14.2	35.0±16.4	0.532a
Weight (Kg.) (mean±SD)	69.5±14.8	70.2±15.0	0.771a
Blood pressure (mmHg)
SBP (mean±SD)	125.1±16.3	129.4±17.0	0.109a
DBP (mean±SD)	77.2±10.3	78.9±11.2	0.391a
Having underlying disease	24 (30.8)	25 (32.1)	0.908b
- Diabetes	3 (12.5)	8 (32.0)
- Hypertension and ischemic heart disease	4 (16.7)	2 (8.0)
- Asthma	3 (12.5)	5 (20.0)
- Others (allergy, GI, pain, depression, dyspepsia, GERD)	14 (58.3)	10 (40.0)
Length of time as a smoker (months) (mean±SD)	183.8±165.8	191.9±177.5	0.770a
Number of cigarettes smoked per day (mean±SD)	11.9±6.9	12.3±8.2	0.767a
FTND score (mean±SD)	3.7±2.4	3.5±2.6	0.588a
- Score 7–10: high nicotine addiction 3	13 (16.7)	11 (14.1)	0.896b
- Score 4–6: moderate nicotine addiction 2	28 (35.9)	28 (35.9)
- Score < 4: low nicotine addiction 1	37 (47.4)	39 (50.0)
Using medications for cessation	40 (51.3)	44 (56.4)	0.521b
- Nicotine gum (with lozenge)	18 (45.0)	14 (31.8)
- Lozenge	9 (22.5)	14 (31.8)
- Nortriptyline (with lozenge)	6 (15.0)	8(18.2)
- Nicotine gum and nortriptyline (with lozenge)	2 (5.0)	5 (11.3)
- others (mouth wash, lozenge with mouth)	5 (12.5)	3 (6.8)

a Independent t test

b Chi-square, FTND stands for Fagerström test nicotine dependence.

Lozenge means Vernonia cinerea lozenge, mouth wash means 0.5% sodium nitrite solution.

The primary outcome, CAR, was defined as participants who started abstinence from day 7 and remained abstinent at day 180. The 7-day point abstinence rate was defined as participants who could be abstinent for at least seven days before each visit. Differences in CAR and 7-day PAR between the groups were assessed using logistic regression. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. The number of cigarettes smoked per day was presented as means ± standard deviation (SD). Linear regression was used to compare the groups, and mixed models were used for comparisons within each group. Estimates of effect using ORs with a 95% CI and p-values, were analyzed using logistic regression. SPSS version 19 was used for the analysis. All tests were two-sided, and α was set at 5%. This study was open-label and the researcher (Olson PS) who performed the analysis was blinded to the data.

Results

We randomized a total of 156 participants to the intervention group (n = 78) or the control group (n = 78). Completion on day 180 was 30.8% (24/78) in the intervention group and 23.1% (18/78) in the control group (Fig 1). Failure to follow-up was due to participants’ unavailability, inaccessibility (after more than three attempts at contact in one week), and a loss of interest.

Fig 1

Participant flowchart.

Participant characteristics

In both groups, most of the participants were men. Participants in the control group were longer-term smokers than those in the intervention group. There was a lower proportion of high nicotine addiction in the control group than in the intervention group. Nevertheless, there were no significant differences in any of the baseline characteristics between the two groups (Table 1).

Clinical outcomes

The CAR at 180 days was similar in both groups, as shown in Table 2. At the end of the study, 25 participants stopped smoking in the intervention group; however, only 11.5% abstained for 180 days. It was discouraging to see one participant who had been abstinent from day 7 return to smoking on day 180. In the control group, there were 27 participants who stopped at the end of the study; however, only 12.8% abstained for 180 days. Most of the participants who returned to smoking could not stop smoking at the end of the study, with the exception of two participants in the control group who returned to smoking on day 30, and then abstained from day 60 to day 180, as shown in Table 3.

Table 2

Continuous abstinence rate at 6 months between the intervention and control groups.

Outcomes at 6 months	Intervention group (n = 78) No (%)	Control group (n = 78) No (%)	OR	95%CI	p-valuea
7 days abstinence rate	25(32.1)	27 (34.6)	0.89	0.46–1.73	0.734
30 days abstinence rate	24 (30.8)	25 (32.1)	0.94	0.48–1.85	0.863
60 days abstinence rate	24 (30.8)	25 (32.1)	0.94	0.48–1.85	0.863
120 days abstinence rate	21 (26.9)	25 (32.1)	0.78	0.39–1.56	0.483
Continuous abstinence rate	9 (11.5)	10 (12.8)	0.88	0.34–2.32	0.807

a Comparing between groups by logistic regression.

Table 3

Comparisons of 7 day-point abstinence (PAR) rates between visits between the intervention and control groups on days 7, 14, 30, 60, 120, and 180.

Visit	Intervention group (n = 78)	Status of quit attempts	p-valuea	Control group (n = 78)	Status of quit attempts	p-valuea	OR	95%CI	p-valueb
	7-day PAR No (%)			7-day PAR No (%)
Day 7	11 (14.1)	11N	0.001	12 (15.4)	12N	<0.001	0.90	0.37–2.19	0.821
Day 14	18 (23.1)	7N	0.065	21 (26.9)	9N	0.070	0.81	0.39–1.68	0.579
Day 30	20 (25.6)	3N, 1F	0.125	21 (26.9)	2N, 2F	0.070	0.94	0.46–1.91	0.856
Day 60	22 (28.2)	2N	0.375	25 (32.1)	3N, 2NF,1F	0.500	0.83	0.42–1.65	0.601
Day 120	25 (32.1)	3N	1.000	25 (32.1)	NC	0.500	1.00	0.51–1.96	1.000
Day 180	25 (32.1)	1N, 1F	ref	27 (34.6)	2N	ref	0.89	0.46–1.73	0.734

a Within group comparison using day 180 as a reference using the McNemar test.

b Comparing the point abstinence rate between groups using the logistic regression.

N stands for new cases who could stop smoking at least 7 days before the visit.

F stands for participants who returned to smoking.

NF stands for participants who returned to smoking and could be abstinent later.

NC stands for no changes.

The 7 day-point abstinence rates were not different between the groups at each follow-up visit. A comparison within the groups revealed significantly higher abstinence rates from day 7 to day 180 (p < 0.05), as shown in Table 3. The number of cigarettes smoked per day was not significantly different between the groups. However, the number of cigarettes smoked per day on day 180 decreased significantly when compared with that on days 0, 7, 14, 30, 60, and 120 in the intervention group (p < 0.05) and days 0, 7, 14, and 30 in the control group (p < 0.05), as shown in Table 4. There was no significant difference in exhaled CO between both groups at any visit, but the results showed improvement in exhaled CO from day 0 to day 180 in each group (p < 0.05), as shown in Table 5. Of the 29 participants in the intervention group who accessed PharmQuit consistently, 12 (41.3%) were successful at quitting and 17 (58.6%) failed to quit smoking.

Table 4

Comparisons of number of cigarettes smoked per day between the intervention and control groups on days 0, 7, 14, 30, 60, 120 and 180.

Visit	Intervention group (n = 78)		p-valuea	Control group (n = 78)		p-valuea	p-valueb
	Number of cigarettes smoked per day Mean±SD	95%CI		Number of cigarettes smoked per day Mean±SD	95% CI
Day 0	12.0 ± 7.0	10.40–13.57	<0.001	12.3 ± 8.4	10.46–14.24	<0.001	0.767
Day 7	8.3 ± 7.6	6.55–9.96	<0.001	6.9 ± 7.2	5.30–8.52	<0.001	0.256
Day 14	5.8 ± 5.9	4.44–7.10	<0.001	5.7 ± 6.4	4.29–7.14	<0.001	0.961
Day 30	4.3 ± 4.2	3.32–5.21	<0.001	3.0 ± 3.7	2.19–3.86	0.029	0.069
Day 60	3.4 ± 5.7	2.12–4.70	0.012	2.7 ± 4.9	1.69–3.90	0.119	0.450
Day 120	3.0 ± 4.1	2.07–3.93	0.003	2.6 ± 3.5	1.84–3.44	0.051	0.541
Day 180	1.8 ± 2.9	1.13–2.46	ref	1.9 ± 3.2	1.14–2.60	ref	0.880

a Within group comparison using mixed models (linear: Heterogeneous First-Order Autoregressive). Day 180 was a reference.

b between groups comparison using linear regression.

Table 5

Comparisons of carbon monoxide (CO) levels between the intervention and control groups on days 0, 7, 14, 30, 60, 120, and 180.

Visit	Intervention group (n = 78)	p-valuea	Control group (n = 78)	p-valuea	OR	95%CI	p-valueb
	CO <7 ppm No (%)		CO <7 ppm No (%)
Day 0	24 (30.8)	0.017	24 (30.8)	0.001	1.00	0.51–1.97	1.000
Day 7	30 (38.5)	0.210	32 (41.0)	0.057	0.90	0.47–1.71	0.744
Day 14	29 (37.2)	0.039	36 (46.2)	0.289	0.69	0.36–1.31	0.256
Day 30	33 (42.3)	0.375	38 (48.7)	0.625	0.77	0.41–1.45	0.422
Day 60	36 (46.2)	1.000	38 (48.7)	0.500	0.90	0.48–1.69	0.748
Day 120	32 (41.0)	0.125	38 (48.7)	0.500	0.73	0.39–1.38	0.335
Day 180	36 (46.2)	ref	40 (51.3)	ref	0.81	0.43–1.53	0.522

CO stands for exhaled carbon monoxide, ppm stands for part per million.

b Comparing exhaled CO between groups using the logistic regression.

a within group comparison using day 0 as a reference using the McNemar test.

Medication for cessation was used in both groups. Eleven participants (27.5%) in the intervention group and 16 participants (36.4%) in the control group reported at least one adverse event. Most of the adverse events included dry mouth and throat (47.4% in the intervention group and 50% in the control group) as shown in Table 6. All adverse events were considered mild, and no referral to a hospital was reported during the study.

Table 6

Adverse drug reactions (ADR) reported in the intervention and control groups.

Adverse events	Intervention group (n = 40) No (%)	Control group (n = 44) No (%)
Total patients who had adverse events	11 (27.5)	16 (36.4)
Total events	19 (100)	24 (100)
Dry mouth, dry throat	9 (47.4)	12 (50.0)
Drowsiness with/without dry mouth	1 (5.3)	5 (20.8)
Dizziness	0 (0.0)	1 (4.2)
Chest discomfort	1 (5.3)	0 (0.0)
Palpitation	2 (10.5)	0 (0.0)
Vomiting	2 (10.5)	0 (0.0)
Nausea with frequently urination	1 (5.3)	0 (0.0)
Flatulence	1 (5.3)	0 (0.0)
GERD	0 (0.0)	1 (4.2)
Burning throat with/without GI discomfort	1 (5.3)	2 (8.3)
Numbness at mouth	1 (5.3)	2 (8.3)
Unable to hear well	0 (0.0)	1 (4.2)

Adherence to the smoking cessation program

Adherence to the smoking cessation program in both the intervention and control groups was assessed. Table 7 shows that adherence was higher in the intervention group than in the control group for both the number of visits and days adhered to the cessation program; however, there was no significant difference between the two groups.

Table 7

Adherence rate to the smoking cessation program in the intervention and control groups.

Day	Adherence rate		p-valuea
	Intervention group (n = 78) Mean ± SD	Control group (n = 78) Mean ± SD
Number of visits	3.1±1.7	3.0±1.8	0.721
Number of days adhered to the program	74.3±76.1	60.1±70.8	0.316

a Comparing between groups by Mann-Whitney U test.

Of the 78 participants in the intervention group, 37.2% used PharmQuit in month one. After 6 months, only 2.6% were using PharmQuit, as shown in Fig 2. The number of times PharmQuit was accessed was highest during the 1st month, which decreased over time. On day 180, 24 participants completed the 6-month follow-up. Fifty-four participants were unable to make contact. Thus, only 14 out of 78 participants (response rate: 17.9%) returned the PharmQuit satisfaction questionnaire. They rated it highest for the three categories: font and size (median of 5, range 2), attractiveness and usability (median of 4.5, range 3), and the progress feature (median 4.5, range 2). Overall, satisfaction with PharmQuit was high for all questions. The convenience and ease of use of PharmQuit showed the lowest range of 1 as shown in Table 8.

Fig 2

Access rate to PharmQuit in the intervention group within the 6-month follow-up (n = 78).

Table 8

Satisfaction score (on a scale of 1–5) to PharmQuit in the intervention group at 6 months.

PharmQuit	Median (range) (n = 14)
Dimension 1: Objective to quit smoking
1. You are satisfied with PharmQuit in helping you to keep service schedules.	4.0 (2)
2. You are satisfied with the progress feature.	4.5 (2)
3. You are satisfied with the encouragement received	4.0 (2)
4. You are satisfied with question and answer section.	4.0 (2)
5. You are satisfied that PharmQuit has helped you quit or reduce the number of cigarettes smoked.	4.0 (2)
Dimension 2: Scope of application
6. You are satisfied with the number of functions.	4.0 (2)
7. You are satisfied with interactive functions between a pharmacist and other smokers.	4.0 (3)
8. You are satisfied with the ease of inputting your personal information.	4.0 (2)
9. You are satisfied with the privacy of your information.	4.0 (3)
Dimension 3: Format and interactive between PharmQuit and the user
10. You are satisfied with the daily encouraging messages and reminders.	4.0 (3)
11. You are satisfied with the response speed of the application.	4.0 (3)
12. You are satisfied with humorous and interesting features.	4.0 (3)
13. You are satisfied with the challenging and attractive interactive features.	4.0 (3)
Dimension 4: Design
14. You are satisfied with characteristics of the app.	4.0 (3)
15. You are satisfied with the amount of information on each screen.	4.0 (4)
16. You are satisfied with the sequence of each group of functions.	4.0 (3)
17. You are satisfied with the convenience and ease of use of PharmQuit.	4.0 (1)
Dimension 5: Appearance
18. You are satisfied with attractiveness and usability of the app.	4.5(3)
19. You are satisfied with the font and background color.	4.0 (3)
20. You are satisfied with the font and font size.	5.0 (4)
21. You are satisfied with beautiful and attractive pictures used.	4.0 (2)

Discussion

Participants in both groups benefited significantly from the smoking cessation program provided by community pharmacists. Although there were no significant differences between the intervention and control groups, participants in both groups showed improvement in abstinence rate, number of cigarettes smoked per day, exhaled CO, and adherence to the cessation program. Adherence to the cessation program was not different between groups. However, the number of visits and days adhered to the program were higher in the intervention group than in the control group. This may be due to the motivation provided through PharmQuit, as the participants in the intervention group were highly satisfied with the app.

In this study, the CAR and 7-day PAR were lower in the intervention group than in the control group during most follow-up visits, but this difference was not statistically significant. Findings from other studies using different mobile apps are inconsistent. Other smoking cessation apps failed to highlight that each study uses a very different protocol, which may be the reason for the large discrepancies in outcomes. For example, in a study by Herbec et al. that included 300 community pharmacies in the UK, the results after 8 weeks showed a quit rate of 25% in the intervention group (using the NRT2Quit app) and 8% in the control group (p = 0.19) [19]. A study by Nomura et al. in Japan showed no significant difference in continuous abstinence rates between telemedicine counseling with CureApp and face-to-face clinical visits with CureApp (81.0% vs. 78.9%) [28]. Another double-blind randomized controlled trial study by Bricker et al. compared two apps (SmartQuit and QuitGuide) over two months. This study showed quit rates of 13% in SmartQuit and 8% in QuitGuide (p > 0.05) [18]. However, a study on physicians and CureApp by Masaki et al. in Japan showed a significant difference between the intervention group using CureApp and a control group using a control-app (63.9% vs. 50.5%) [29].

The magnitude of the 7-day point abstinence rate in this study was similar to that of other pharmacist-led smoking cessation programs. A study in Qatar by Hajj et al. evaluated smoking cessation rates provided by pharmacists at 6 months and found a rate of 27.0% [30]. Gong et al. conducted an RCT study with participants who received pharmacist-provided telephone counseling and medications that revealed a 42.3% 1-week point abstinence rate at week 12, which was higher than the usual care rate of 38.2% (p > 0.05) [31]. A single-arm study by Iacoviello et al. in the US using the Clickotine app for 8 weeks, showed a self-reported abstinence rate of 26.2% [20]. However, another study by Bricker et al. showed a lower quit rate (13% in SmartQuit and 8% in QuitGuide) when compared to our study [18]. Overall, this study with PharmQuit demonstrated better or similar cessation rates to those of these two previous studies.

Although most participants in the intervention group liked PharmQuit, it was accessed less frequently over time. Some participants explained that this was due to limited internet access. One participant complained that there were too many messages sent (twice per day), which may be counterproductive. In a study by Do et al., it was revealed that daily texts are less effective than weekly texts [32]. One participant uninstalled PharmQuit because of the limited memory on his phone, while another forgot to update the daily record because there was no feedback from his pharmacist. Some participants who were able to quit smoking stopped using PharmQuit after quitting. At the start of recruitment, the login feature malfunctioned, delaying recruitment by a week, which may have left a poor impression on the treatment group. These factors may explain the low rate of active users of PharmQuit, even though all participants in the intervention group were trained to use the app by their pharmacists at the start of the program. However, when considering that the aim of PharmQuit was to help participants adhere to the program with an easy-to-use app, the aim was achieved.

Another explanation for the results was the high loss to follow-up rate in both groups. Although the pharmacists reminded the participants about the appointments and made calls, most of them could not be reached by phone. This may have reduced the power of the study to show significant differences in smoking cessation rates between the two groups. One participant in the intervention group was diagnosed with cancer and decided to stop using the app. Other studies have shown that special characteristics, such as swearing to complete the study [28], much better compensation (90 US dollars per visit) [29], and effective medications (such as varenicline, bupropion, nicotine patch) [28-31] helped to increase app engagement and quit rates. Our study was performed ethically, and the participants could choose to leave the study at any time. A small compensation was provided, and any needed medications were provided free of charge. The most effective medication for smoking cessation in our study was nicotine gum, which was shown to be less effective than other medications in previous studies [33]. As only 51‒56% of participants received medications, participants who did not receive medications may have thought that follow-up was not necessary or worthwhile.

This study has some limitations. A substantial number of participants had missing data during the follow-up visits. The compensation may not have been a sufficient incentive to convince people to join and complete the study. Although participants who were engaged in other cessation programs during recruitment were excluded, no follow-up was conducted to determine if they had started another cessation program during the study. The interface of PharmQuit is in Thai, so the use of PharmQuit outside of Thailand would be limited to countries with Thai as a first or second language.

The strength of the study was that it was a multicenter study that used a randomized control design and had a long follow-up duration. Some of the community pharmacists in this study had experience serving at a university with a smoke-free campus policy [34].

Conclusions

The results showed the benefit that community pharmacists provide in helping smokers quit smoking. PharmQuit showed better or similar quit rates to those of some other studies. Although PharmQuit was not more effective than pharmacist counseling, it may help pharmacists achieve better adherence to smoking cessation programs. Thus, the use of a mobile app is one option for smokers in larger clinical trials with an aim of smoking cessation.

CONSORT 2010 checklist of information to include when reporting a randomized trial.

(PDF)

Click here for additional data file.

Research protocol as approved by the ethics committee.

(PDF)

Click here for additional data file.

English and Thai questionnaire of satisfaction with PharmQuit.

(PDF)

Click here for additional data file.

26 Jul 2021

PONE-D-21-17146

A community pharmacist-led smoking cessation intervention using a smartphone app (PharmQuit): A randomized controlled trial

PLOS ONE

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Reviewer #1: Partly

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: I Don't Know

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Reviewer #1: No

Reviewer #2: Yes

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Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: This is a very interesting randomised controlled studying evaluating the efficacy of an app called PharmQuit to help with smoking cessation in Thailand. Using Pharmacists to carry out the interventions.

Well done to team for carrying out such important research.

They are some comments worth mentioning for the authors attention.

1) Line 103, can the aims be clear in terms of what the primary objectives, secondary objectives are.

2) Under design, include that it was multi-centre/site since recruitment occurred in 7 community pharmacies in 3 provinces

3) The sample size calculation is incomplete, what was the quit rate (i.e the assumed quit rate together with what the ‘improvement’ was planned to be?

4) In addition if the quit rate was to be estimated at 6 months follow-up, this implies that 6 month is the primary timepoint. This needs to be clear especially when mentioning the aims.

5) Randomization allocation ratio, I assume it was 1:1, this needs to be explicitly stated.

6) Although this an open-label study, allocation concealment needs to be mentioned and explicitly stated who was not blinded.

7) For the randomization procedure of the pharmacist checking the randomisation list, what was the assurance there was no selection bias. Was an external check/validation carried out. For an example how do you know say the next group allocation was control group but then the Pharmacist then allocated the person to intervention?

8) It would benefit clarity of the manuscript if there was a separate heading “Outcomes”. That way to make it explicit that outcome is binary, misleading to use rate as this implies a count when infact it’s a logistic model that has been fitted. Its also confusing, as it looks like there were two primary outcomes i.e. quit rate and number of cigarettes smoked perday. However the sample size only shows calculations for quit rate. What about the effect size for number of cigarettes smoked per day. And whether this is a co-primary end point, this needs to elaborated in more detail.

9) Also how was the satisfaction scored? I.e. total score for each dimension? And with such small numbers of 14 people completing the questionnaire, is it best to give a median instead with range?

10) It would help if the Title for Table 6 also includes that this was restricted to intervention group only. You probably also need a ‘missing’ summary as well.

11) “We randomized a total of 156 participants to the intervention group or the control group.” Best if this also includes numbers randomised to each arm.

12) In terms of the statistical analysis, the data structure was repeated measurements of some outcomes, should this have incorporated a mixed effects model approach.

13) how was missing data handled?

14) Any statistical analysis plan written? and presumably signed off prior to any data analysis.

Items with CONSORT checklist

1) Outcomes (Item 6a)

Completely defined pre-specified primary outcome measure including how and when it was assessed

Is it clear (1) what the primary outcome is (usually the one used in the sample size calculation), (2) how it was measured (if relevant; e.g. which score used), (3) at what time point, and (4) what the analysis metric was (e.g. change from baseline, final value)?

Not adequately defined. Primary timepoint not specified as data is being collected at different timepoints.

2) Sample size (Item 7a)

How sample size was determined

Is there a clear description of how the sample size was determined, including (1) the estimated outcomes in each group; (2) the α (type I) error level; (3) the statistical power (or the β (type II) error level); and (4) for continuous outcomes, the standard deviation of the measurements?

Sample size not adequately stated as well as what the effect size is. Cannot be replicated.

3) Sequence generation (Item 8a)

Method used to generate random allocation sequence

Does the description make it clear if the "assigned intervention is determined by a chance process and cannot be predicted"?

4) Allocation concealment (Item 9)

Mechanism used to implement random allocation sequence (such as sequentially numbered containers), describing any steps taken to conceal the sequence until interventions were assigned

Is it clear how the care provider enrolling participants was made ignorant of the next assignment in the sequence (different from blinding)? Possible methods can rely on centralised or "third-party" assignment (i.e., use of a central telephone randomisation system, automated assignment system, sealed containers).

Not clearly stated in the manuscript. The method of allocation is unblinded.

5) Blinding (Item 11a)

If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes)

Is it clear if (1) healthcare providers, (2) patients, and (3) outcome assessors are blinded to the intervention? General terms such as "double-blind" without further specifications should be avoided.

Open-label, but it would be good to state if person doing the analysis was blinded to the data.

6) Outcomes and estimation (Item 17a/b)

For the primary outcome, results for each group, and the estimated effect size and its precision (such as 95% confidence intervals)

Is the estimated effect size and its precision (such as standard deviation or 95% confidence intervals) for each treatment arm reported? When the primary outcome is binary, both the relative effect (risk ratio, relative risk) or odds ratio) and the absolute effect (risk difference) should be reported with confidence intervals.

Just the odds ratio (95% CI) has been reported.

7) Harms (Items 19)

All important harms or unintended effects in each group

Is the number of affected persons in each group, the severity grade (if relevant) and the absolute risk (e.g. frequency of incidence) reported? Are the number of serious, life threatening events and deaths reported? If no adverse event occurred this should be clearly stated.

Safety outcomes not mentioned.

8) Registration (Item 23)

Registration number and name of trial registry

Is the registry and the registration number reported? If the trial was not registered, it should be explained why.

Yes,

9) Protocol (Item 24)

Where trial protocol can be accessed

Is it stated where the trial protocol can be assessed (e.g. published, supplementary file, repository, directly from author, confidential and therefore not available)?

Yes, in supplementary

10) Funding (Item 25)

Sources of funding and other support (such as supply of drugs) and role of funders

Are (1) the funding sources, and (2) the role of the funder(s) described?

Yes.

Reviewer #2: The authors should be commended for running an overall well designed study, and writing a generally high quality paper.

Unfortunately I do have one major concern about how the ITT protocol was followed - the authors state an ITT protocol was developed, but the results are a bit unclear and seem to indicate that this was perhaps not the case? Clarification is urgently needed.

Apart from this one issue I am more than happy to recommend publication, but this issue must be adequately addressed as a matter of urgency, as it brings the major part of the results/conclusion of the paper into question. More details provided below.

Major comments:

208: "There were a total of 7 participants who relapsed after quitting". This is a completely incorrect statement. You said you used an intention to treat methodology. Therefore every participant who dropped out of the study (the vast majority!) is assumed to have resumed smoking! This must be qualified very clearly! This mistake makes me wonder if your other results are genuinely calculated on an intention to treat basis? i.e. in Table 3, you say n=78 in each group but then your quit rate goes up over time - I suspect you have not included the drop-outs (as relapsers) in this data. This same comment can potentially be made for others of the reported results.

Minor comments:

Design: please include the $ symbol and report to 2 decimal places the currency information at lines 111 and 112

Ethical approval: failure to register the clinical trial prior to enrolment is a fairly big mistake under the current clinical trials rules, however, it is only very recently that a trial like this would have been considered a clinical trial at all. The excuse about the requirement not being mentioned "in the graduate program" is a bit confusing though (the reader doesn't know anything about your "graduate program" or how it relates to this mistake). I suggest replacing this statement with something like "The researchers were unaware of the requirement to register the clinical trial prior to the enrolment of participants, but amendments have been made to our institutional training materials to reduce the likelihood of this error occurring in the future." If possible, it may also be valuable to state that the HREC was made aware of this mistake and judged it to be low risk, or something to that effect.

Lines 130-131: Is there a reference to support the estimated drop-out rate of 15%?

Line 134: Fagerstorm => Fagerström

Line 148: The whole URL should be hyperlinked, not just the inner part.

Line 166: "usual pharmacy services on smoking cessation and medications" => It is important to state explicitly what these usual services are, since practice in various regions differs significantly. Most important is the conditions under which participants would gain access to NRT, and the frequency of counselling/assessments - I assume that this is the same as in the intervention group, but this must be made explicitly clear. It may be beneficial to instead report the common characteristics of treatments in both groups, then state how the intervention and control groups differed (presumably the only difference was access to PharmQuit). As it is currently written, it seems like the intervention group gets WAY more care than the control group but I do not think this is correct (and it would be a major design flaw if true).

Line 172-173: "Quit rate was determined by counting the number of visits with the pharmacist since quitting" this doesn't make sense.

Line 177 "User’s experience theory ": a reference should be included.

Line 186: " using the logistic regression" => "using logistic regression"

Line 186-187: "Data for participants with missing data were assumed to be the same as their last visit information." -> this must be justified. Was it the policy of the recording pharmacists to leave fields blank if they were unchanged? Missing data is not normally treated this way.

Line 187: " SPSS version 19" It's a little unusual to use such an ancient version of SPSS, but probably not of an importance given the statistical analyses are quite straightforward.

Results

Line 190-191: your completion rate makes me think your estimated drop-out rate of 15% was extremely naive? Unless you meant 15% drop-out per visit? Some follow-up with participants who were "unable to be contacted" might be useful to figure out what their reasons for dropping out were (presumably they relapsed and were no longer interested in quitting, but it would be nice to get some data).

196: "More medications were used by participants in the control group than in the intervention group" - this is clearly false when looking at the table. There is no significant difference, and there doesn't seem to be a huge clinical difference between 51% and 56%.

196-197: "FTND in the control group was lower in the high nicotine addiction group than in the intervention group" - This sentence is difficult to understand, as we have not been introduced to the concept of "high nicotine dependence" groups before now. Upon examination of the table it makes sense, but it is a clumsy sentence.

Discussion:

287: "this good" => "this could"

Discussion re: other quit smoking apps fails to highlight that each study is using a very different protocol and this is likely the largest reason for the large discrepancies in outcomes. i.e. if you don't have face to face interviews drop out rates are higher etc.

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Reviewer #1: No

Reviewer #2: No

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20 Oct 2021

Thank you very much for all comments to help us improve our manuscript. We clarified and changed the outcome measures and analysis as recommended. We made all other suggested changes as well.

Submitted filename: Response to reviewers.docx

Click here for additional data file.

3 Mar 2022

A community pharmacist-led smoking cessation intervention using a smartphone app (PharmQuit): A randomized controlled trial

PONE-D-21-17146R1

Dear Dr. Olson,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Shahrad Taheri

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

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Comments to the Author

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Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

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Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

**********

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PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

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Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: Thanks for submitting your revision. The paper is significantly improved.

I would note that a limitation of the design is that your satisfaction survey was only given to participants who completed the whole program - this may introduce a selection bias (presumably participants who were unsatisfied would drop out, and participants who were satisfied would remain).

**********

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Reviewer #1: No

Reviewer #2: Yes: Dr Ivan Karl Bindoff

8 Mar 2022

PONE-D-21-17146R1

A community pharmacist-led smoking cessation intervention using a smartphone app (PharmQuit): A randomized controlled trial

Dear Dr. Olson:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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