Two-year efficacy of varenicline tartrate and counselling for inpatient smoking cessation (STOP study): A randomized controlled clinical trial.

INTRODUCTION: Varenicline tartrate is superior for smoking cessation to other tobacco cessation therapies by 52 weeks, in the outpatient setting. We aimed to evaluate the long-term (104 week) efficacy following a standard course of inpatient-initiated varenicline tartrate plus Quitline-counselling compared to Quitline-counselling alone.
METHODS: Adult patients (n = 392, 20-75 years) admitted with a smoking-related illnesses to one of three hospitals, were randomised to receive either 12-weeks of varenicline tartrate (titrated from 0.5mg daily to 1mg twice-daily) plus Quitline-counselling, (n = 196) or Quitline-counselling alone, (n = 196), with continuous abstinence from smoking assessed at 104 weeks.
RESULTS: A total of 1959 potential participants were screened for eligibility between August 2008 and December 2011. The proportion of participants who remained continuously abstinent (intention-to-treat) at 104 weeks were significantly greater in the varenicline tartrate plus counselling arm (29.2% n = 56) compared to counselling alone (18.8% n = 36; p = 0.02; odds ratio 1.78; 95%CI 1.10 to 2.86, p = 0.02). Twenty-two deaths occurred during the 104 week study (n = 10 for varenicline tartrate plus counselling and n = 12 for Quitline-counselling alone). All of these participants had known or developed underlying co-morbidities.
CONCLUSIONS: This is the first study to examine the efficacy and safety of varenicline tartrate over 104 weeks within any setting. Varenicline tartrate plus Quitline-counselling was found to be an effective opportunistic treatment when initiated for inpatient smokers who had been admitted with tobacco-related disease.

Introduction

For each death caused by cigarette smoking, 30 people remain living with serious tobacco-related illnesses [1]. On a global scale disease burden is set to increase, with approximately 6 million deaths per year growing to predictions of 8 million by 2030 [2]. Varenicline tartrate acts on the α4β2 nicotinic receptor, being the same receptor targeted by nicotine inhaled from smoke [3]. Unlike nicotine replacement therapy, varenicline has a dual action by simultaneously easing cravings whilst blunting smoking associated reward and pleasure through partial nicotinic acetylcholine receptor agonist activity. It has a longer half-life of effect compared to nicotine replacement therapy, which may be important in the inpatient hospitalised setting [4]. Indeed, targeting inpatients during a period of hospital confinement offers an opportunistic environment to initiate smoking cessation interventions, as it provides an opportunity for patients to reflect on the progression of events resulting in hospitalisation, a bedside phone to ensure initial contact with Quitline counselling and an observation period for medication related adverse events.

In 2009 the United States Food and Drug Administration (FDA) released a black box warning for varenicline following reports of psychiatric side effects including hostility, agitation, depressed mood and suicidal ideation [5]. However, in 2016 a study by Anthenelli et.al, (Evaluating Adverse Events in Global Smoking Cessation Study: EAGLES), evaluated safety and efficacy of smoking cessation pharmacotherapy among 8,000 smokers with and without history of psychiatric disorders, identifying no association between varenicline and an increased incidence of clinically significant neuropsychiatric adverse events [6]. Subsequently, the joint FDA advisory committee voted to remove the box warning pertaining to neuropsychiatric side effects [7]. The FDA has also raised concerns about a possible increased risk of cardiovascular adverse events including cardiovascular-related death, nonfatal heart attack and non-fatal stroke [8]. Another recent study by Eisenberg et.al, (Evaluation of Varenicline in Smoking Cessation for Patients Post-Acute Coronary Syndrome: EVITA), conducted in 302 patients hospitalised with acute coronary syndrome identified similar adverse event rates within 30 days of study drug discontinuation between groups [9]. These studies supports our own 52 week findings demonstrating that varenicline is effective [10], well-tolerated and can be safely administered [11] among smokers admitted to hospital with acute tobacco related illnesses. However, none of these studies examine long-term (greater than 52 week) efficacy.

Only one 1971 German placebo-controlled trial evaluated the long-term efficacy (104 week follow-up) of cytisine with statistically significant benefits (odds ratio 1.77; 95%CI 1.29 to 2.43). No other study to date has evaluated any nicotinic acetylcholine receptor agonist beyond 52 weeks. Therefore, one of the secondary objectives of this study (and main objective of this manuscript) is to report efficacy and mortality of varenicline plus counselling compared to counselling alone at 104 week follow-up for inpatients admitted to hospital following an acute smoking-related illness.

Methods

Trial design

This study was an open-label randomised, multicentre controlled clinical trial, with a 12 week treatment phase. A pre-specified protocol was published online (available via clinicaltrial.gov identifier NCT01141855)), complying with the ethical principles of the Declaration of Helsinki and approved by the respective hospital ethics committees (Royal Adelaide Hospital Human Research Ethics Committee: 080520 and The Queen Elizabeth Hospital and Lyell McEwin Hospital Human Research Ethics Committee: 2008012). All participants provided written informed consent prior to commencement of pharmacotherapy or data collection. All authors were involved in some aspect of study design and/or conduct and each author contributed to writing the manuscript.

Study population

As per our previous publications [10, 11], participants were recruited between August 2008 and December 2011 from three tertiary hospitals being The Queen Elizabeth Hospital, Lyell McEwin Hospital and Royal Adelaide Hospital in South Australia. Patients presenting to hospital under disciplines of respiratory, cardiology, neurology and vascular medicine following a serious tobacco-related illness (as defined by the Centre of Disease Control [12]), were considered for recruitment. Participants were considered for inclusion if they were aged between 18 and 75 years, smoked at least 10 cigarettes on average per day over the preceding 12 months, had a plan of discharge to go home and had no contraindications to varenicline. Participants were excluded if they had cancer within the past seven years, renal impairment with creatinine clearance <30ml/min, had acute or pre-existing psychiatric illnesses including depression uncontrolled with medication, past-history psychosis or suicidal ideation, were pregnant or breastfeeding, were using other forms of nicotine replacement therapy or had used varenicline in the past 12 months. Patients with psychiatric illnesses who were stable on medication were considered for inclusion.

Randomization, allocation concealment and blinding

Following identification of participants through health professional notification of a participant meeting the inclusion/exclusion criteria and an initial screen of patient medical records they were approached for participation whilst an inpatient. Following an opportunity to consider enrolment, patients signed the consent and completed the baseline questionnaire prior to randomization. A computer-generated simple randomization sequence generation with permuted blocks of 20 was used to assign participants in a 1:1 ratio to either 12 weeks of varenicline tartrate plus Quitline counselling or Quitline counselling alone. Allocation concealment occurred with the use of consecutively numbered opaque, sealed envelopes that were opened by study investigators following completion of all baseline data collection. Randomization and allocation concealment were performed by respiratory staff independent of the study. Participants and investigators were not blinded to treatment assignment.

Interventions

All participants were provided with a quit assistance resource pack provided by the Cancer Council of South Australia including a booklet on smoking cessation entitled “Quit because you can”, smoke free stickers and fridge magnets listing tips to help manage with cravings. Initial Quitline contact was instigated by the project officer who recruited the participant at the patient’s bedside directly following recruitment and randomization, or a Quitline counsellor called the patient at a time specified by the participant. The counselling programme employed the 5A approach (Ask, Assess, Advise, Assist and Arrange), consisting of eight scheduled call backs over a 12 week period of approximately 5–10 minutes duration. Participants randomised to the intervention group received the same Quitline counselling and resource pack in addition to varenicline tartrate, administered orally at 0.5mg per day for the first three days, 0.5mg twice daily for 4 days, then 1mg twice daily thereafter for a total treatment duration of 12 weeks. Participants were permitted up to 14 days following commencement of varenicline to set their target quit date. Further details in relation to the intervention and comparator arm have been described elsewhere[10, 11].

Outcomes and data collection

The outcome of interest for this manuscript was continuous abstinence between weeks 2 and 104 (two year follow-up) with the overarching primary outcome for the trial of continuous abstinence between weeks 2 and 52 (reported elsewhere [10]). Continuous abstinence was defined as smoking ≤ five cigarettes in total by the follow-up period at 104 week (in line with recommendations for smoking cessation trials [13, 14]). Abstinence was by self-report with bio-chemical validation in a random sub-set of participants via exhaled carbon monoxide levels of ≤ 10 ppm. Secondary outcomes included adverse events during the 12-week treatment period compared to outpatient studies and all-cause mortality by 52 and 104 weeks. Other secondary outcomes related to hospital bed utilisation and health care costs, 7-day point prevalence and inpatient craving levels are reported elsewhere (cost effectiveness manuscript in production and [11]).

Baseline data collection occurred by the project officer recruiting the participant, prior to randomization, with follow-up data collection over the phone by a different project officer/investigator than the one who recruited the participant. Data was stored electronically in a password-protected database case report forms were stored in hard copy within a lockable filing cabinet. This was an open-label study with participants assigned to the intervention arm paying the full Pharmaceutical Benefits Scheme subsidised costs or concession costs of varenicline if assigned to that treatment arm.

Statistical analyses

Sample size of 196 per arm was calculated to produce a 15% difference (45% vs. 30%) at 52 weeks, using a two group uncorrected chi-squared test with a 0.05 two-sided significance level, based on available literature [15-17]. This provided 80% power to detect the difference between the two arms, with additional adjustments for attrition and clustering (20%) with a rho of 0.02 [18]. Treatment efficacy at 104 week follow-up was not factored into statistical power calculation, as it was a secondary objective. Efficacy was defined as continuous smoking abstinence (less than five cigarettes) between week two and 104 week follow-up, calculated using a two-sided chi-squared test and Mann-Whitney U-test. Adjustments were made for differences in baseline data between medical disciplines (i.e., imbalance in people allocated to VT+C group in the vascular discipline). Analyses were based on intention to treat using statistical packages STATA version 11 and SPSS version 19. Participants lost to follow-up, withdrawn from the study or deceased during the study period were assumed to be smoking for the purpose of 104 week efficacy, regardless of smoking status at last contact period. Missing data from participant questionnaires were excluded from analyses. Data presented as mean and standard deviation (SD) unless otherwise specified.

Results

A total of 1959 patients were screened for eligibility between August 2008 and December 2011. Of the 392 participants recruited (n = 196 per arm), over 50% retention was achieved by 104 week follow-up (Fig 1). Baseline demographics were similar between groups (Table 1), with the exception of more participants randomized to varenicline tartrate plus counselling (VT+C) in the vascular discipline (n = 19) compared to counselling alone (C-alone; n = 7).

Fig 1

Participant disposition (Consort flow diagram).

Table 1

Baseline demographic characteristics and smoking history.

	VT+C	C-alone
Parameter	n = 196	n = 196
Age in years (range: 22–75)	52.8 (2.89)	53.7 (2.77)
Gender n(%)
Male	138 (70.4)	128 (65.3)
Female	58 (29.59)	68 (34.7)
Ethnicity n(%)
Caucasian	186 (94.9)	191 (97.5)
Aboriginal	9 (4.6)	4 (2.0)
Asian	1 (0.5)	1 (0.5)
Charleston Co-morbidity Index
Age unadjusted	1.67 (0.94)	1.57 (0.94)
Age adjusted	2.64 (1.15)	2.54 (1.17)
Pack years	44.8 (3.93)	45.7 (4.24)
Duration of smoking in years	37.1 (2.93)	37.7 (2.89)
Number of cigarettes per day in the past year	24.9 (2.67)	24.7 (2.89)
Fagerström score	5.8 (1.3)	5.4 (1.3)
Disciplines n(%)
Cardiology	98 (50)	97 (49.5)
Respiratory	57 (29.1)	65 (33.2)
Neurology	22 (11.2)	27 (13.8)
Vascular	19 (9.7)	7 (3.6)

Mean and (standard deviation) unless otherwise specified; as per [11]

For the primary outcome of self-reported continuous smoking abstinence between weeks 2 and 104 (intention-to-treat), a statistically and clinically significant benefit in favour of the VT+C arm was observed (VT+C 29.2% n = 56 compared to counselling alone 18.8% n = 36; odds ratio 1.78; 95%CI 1.10 to 2.86; p = 0.02). Significance in favour of VT+C over C-alone for continuous abstinence was maintained at each follow-up period from four weeks, which became more significant following adjustment for baseline differences within disciplines (Fig 2), being an imbalance in allocation to the VT+C arm for people in the vascular discipline. For continuing smokers the average number of cigarettes smoked per day reduced from baseline to 104 week follow-up in both arms (VT+C 24.9 SD2.67 to 17.1 SD11.72 and counselling alone 24.7 SD2.89 to 15.4 SD8.82 respectively).

Fig 2

Continuous smoking abstinence between weeks 4 and 104; Self-reported continuous abstinence defined as smoking ≤ 5 cigarettes between from week 2 to respective follow-up period.

Intention-to-treat analysis used (n = 196 per arm) with data above bar representing % abstinence. P-values are unadjusted and adjusted for baseline differences observed between disciplines.

The most common adverse event reported by participants during the 12-week treatment phase was nausea with 16.3% in the VT+C group compared with 1.5% in C- alone. This was less than the prevalence of nausea reported by Pfizer (27%) among outpatient studies with healthy volunteers. Indeed, all adverse events reported among STOP trial participants was less than those observed by Pfizer reports (Table 2). The one exception was mortality. However, the STOP population all presented to hospital with acute illnesses and substantial co-morbidities. At both 52 and 104 week follow-up all-cause mortality was observed to be similar between groups (Table 3; not statistically significant).

Table 2

Mortality and self-reported adverse events within 12 week treatment phase.

	STOP trial (inpatients with smoking related illness)		Pfizer [19] (Outpatient ‘healthy’ volunteers)
	VT+C (n = 196)	C-alone (n = 196)	Varenicline (n = 5072)	Placebo (n = 3449)
Mortality	5 (2.55)	2 (1.02)	6 (1.7) [20]	1 (0.3) [20]
Nausea	32 (16.33)	3 (1.53)	1430 (28.2)	335 (9.7)
Abnormal dreams	12 (6.12)	2 (1.02)	543 (10.7)	145 (4.2)
Headache	12 (6.12)	3 (1.53)	751 (14.8)	410 (11.9)
Insomnia	10 (5.10)	4 (2.04)	715 (14.1)	300 (8.7)
Vomiting	8 (4.08)	1 (0.51)	228 (4.5)	66 (1.9)
Dizziness	4 (2.04)	1 (0.51)	249 (4.9)	197 (5.7)

Reported as n and (%); Pfizer data from outpatient health volunteers [19]; Mortality data from Pfizer using a different cohort of participants (n = 353 in varenicline arm and n = 350 in placebo arm) [20]

Table 3

All-cause mortality during the 52 and 104 week follow-up periods.

	VT+C	C-alone
Arrhythmic event	1	0
Bradycardia	1	0
Lung cancer	0	2
Non ST segment Myocardial Infarction	2	4
Respiratory failure/COPD	2	0
Stroke	0	1
Total deaths ≤ 12 months	6	7
Charleston: age unadjusted (mean ± SD)	3.29 ± 2.43	2.43 ± 1.62
Charleston: age adjusted (mean ± SD)	5.14 + 2.61	3.86 ± 2.12
Lung cancer	1	2
Respiratory failure/COPD	1	2
Peripheral vascular disease	2	1
Total deaths between >12 and ≤ 24 months	4	5
Charleston: age unadjusted (mean ± SD)	4.25 ± 3.20	4.40 ± 4.28
Charleston: age adjusted (mean ± SD)	5.50 + 3.70	5.80 ± 4.44

Number of events per arm; total sample size in each arm n = 196

Discussion

This study showed superior treatment efficacy of varenicline plus counselling compared to counselling alone for self-reported continuous smoking abstinence at 104 week follow-up. Adverse events during the treatment period were lower in the STOP trial among the acute illness setting than side effects reported among outpatient ‘healthy’ volunteers. Mortality within 52 and 104 weeks were also reported to be similar between groups.

The STOP trial is the first study world-wide to examine the efficacy and safety of varenicline tartrate over 104 weeks within any setting as well as being the first study to examine administration of varenicline within the inpatient setting among acute smokers with tobacco related illnesses. It is also the first appropriately powered study of varenicline not sponsored by the manufacturer, Pfizer. Subsequently, these results provide a real-world evaluation of varenicline for the inpatient setting, particularly given that patients randomized to the varenicline plus counselling arm were required to pay for the study drug themselves as this was not supplied as part of the trial.

Long-term efficacy of smoking cessation pharmacotherapy has been debated, with very few appropriately powered studies examining prolonged treatment effectiveness (beyond 52 weeks). One prospective cohort study conducted in 787 recent quitters over five years found no difference in the odds of relapse between patients who used nicotine replacement therapy for more than six weeks and those without pharmacotherapeutic assistance [21]. A placebo controlled trial published in 1971 evaluating cytisine, a drug similar to varenicline in that it acts on the nicotinic acetylcholine receptor pathway, also examined treatment efficacy at 104 week follow-up [22] producing similar results to those observed in this study (odds ratio of cytisine study 1.77; 95%CI 1.29 to 2.43; odds ratio of STOP study 1.78; 95%CI 1.10 to 2.86). There is insufficient information on the various smoking cessation products available to determine prolonged treatment efficacy, though products which substitute nicotine from cigarettes (such as transdermal nicotine patches) may be less effective than those facilitating complete removal of nicotine from the body.

Limitations of the study

Limitations relating to the lack of blinding (resulting in both a placebo and demoralization effect) and issues pertaining to generalizability (due to predominant non-Caucasian population who are highly motivated to quit), have been described previously [11]. The lack of placebo in the control arm, as discussed previously [11], further limits the reliability of efficacy at 104-week follow-up. However, inclusion of real-world intervention arms allows for true representation of how the package of VT+C compared to C-alone will perform in the acute hospital setting, which will be of more use to policy makers and clinicians. In addition, there is the economic principal of loss aversion [23], that could be influencing the superior quit attempts observed among the VT+C arm due to the financial commitment made by these participants when purchasing the quit medication. People experience loss about twice as strongly compared to benefits from a gain of equal magnitude [24], e.g., paying $5 for the medication would be equivalent to earning $10 from a successful quit attempt. Therefore, the financial commitment made by VT+C participants has likely impacted quit efficacy in favour of the VT+C group. Of note, participants were aware of the need to purchase medication if randomised to the VT+C group.

There is an additional limitation of self-reporting treatment efficacy at 104 weeks follow-up that may overestimate the efficacy in favour of VT+C. Self-reporting of cessation among both cardiac patients [25] and those with chronic obstructive pulmonary disease [26] have suggested underreporting of true smoking status. Therefore, results need to be interpreted with caution. Of note the sample size was calculated based on the primary outcome of 52 weeks follow-up, rather than 104 weeks. Low statistical power reduces the likelihood that statistically significant results reflect the true effect of the intervention leading to potential overestimate of the effect size and low reproducibility of results [27]. However, given the large effect size observed at 104 week follow-up the reliability of findings can be considered true and accurate.

In conclusion, the STOP trial has provided a real-world evaluation of varenicline tartrate plus counselling compared to counselling alone for administration within the inpatient setting. It has demonstrated clinically and statistically significant prolonged smoking abstinence that is well tolerated by inpatients with no increased risk of adverse events despite presentation with an acute illness episode. We suggest varenicline tartrate plus counselling be considered for standard practice among hospitalized smokers.

28 Nov 2019

PONE-D-19-25086

Two year efficacy of varenicline tartrate and counselling for inpatient smoking cessation (STOP study): A Randomized Controlled Clinical Trial

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Reviewer #1: The document sent by the authors is of good quality apart from some typing errors to correct, including in the summary. The methodology is clearly described and the limits are well covered in the appropriate chapter. This article is original and meets the ethical criteria of the journal.My main criticism is that varenicline placebo has not been placed in the arm with only the advice to help with weaning by phone.The second reservation, identified by the authors, is that weaning is mainly declarative. The expired CO measurement could have been done at each stage of the study and in all participants.This independent study of the laboratory that markets Varenicline shows the benefit of this molecule in long-term withdrawal and its side effects to a lesser extent than in previous studies. As such, it seems to me that this study can be published.

Reviewer #2: Comments

This study proposes to evaluate the long-term efficacy (primary objective at 2 years) and the tolerance (secondary objective) of the addition of varenicline to management by advice without medication (advice and telephone support without medication)

This is a long-term evaluation of a previous study whose effects were published in 2013 and 2014 (ref 10 and 11) after 12 months of treatment.

Usually, varenicline appears to be even more effective than nicotine substitutes for smoking cessation assistance. Alerts concerning possible neuropsychological and vascular undesirable effects, subsequently invalidated, have led to underutilization and mistrust on the part of some health professionals with regard to this molecule.

This study, which suggests a long-term efficacy of varenicline and an acceptable tolerance without excess mortality in patients with tobacco-related diseases delivers an interesting message

Another highlight of this study concerns its evaluation in patients hospitalized for a pathology secondary to smoking.

Initial inclusion: a large number of patients were excluded or not included at the beginning of the study. It would be interesting to know the main causes of non-inclusion, especially for neuropsychic diseases. This element is important since these side effects under varenicline were the subject of a debate. The good tolerance in this area under varenicline in the study may be related in part to a strict selection of patients with neuropsychological antecedents.

As noted by the authors, the strength of this study was not identified for a 2-year efficacy demonstration and a large number of patients are not assessable by that date.

Another limiting factor of the study concerns the absence of placebo versus varenicline (non-blind study) which may be negatively perceived by patients included in the group without varenicline and for health professionals. This limit is for efficacy compared to 1 and 2 years, but less alters tolerance and mortality data at 2 years (which is one of the important data in this publication).

Was there specific monitoring of varenicline patients during the first 12 weeks of follow-up?

A number of patients in the varenicline-free group eventually received varenicline and / or nicotine replacement therapy, probably during follow-up. Was this element contraindicated a priori in the context of the study?

Was treatment with varenicline systematically interrupted at 12 weeks or were some patients able to continue treatment for longer?

Deaths reported in table 2 to 12 weeks appear numerically larger under varenicline (5 versus 2). Is this element significant?

How many patients did they have a CO test to validate their self-reporting?

Patients in the varenicline group paid for their medication. This treatment is reimbursed in other countries. Can this element be an additional motivation factor for motivation and therefore effectiveness in this group?

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1 Jan 2020

Response to editor and reviewer comments have been provided in the attachment titled 'response to reviewers' using a table format. We have provided a response to each point below as well.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

The manuscript has been reformatted to meet the PLOS ONE’s style requirements, including those for file naming.

2. We noticed you have some minor occurrence(s) of overlapping text with the following previous publication(s), which needs to be addressed: In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the Methods section. Further consideration is dependent on these concerns being addressed.

We put the manuscript through the plagiarism detection software (Turnitin), identifying some overlap with our previous 12-month efficacy publication and our published abstracts submitted to scientific conferences. Where appropriate, we have referenced the 12-month efficacy manuscript and rephrased duplicated text outside of the methods section. In particular, we have revised the introduction opening paragraph to reduce overlap with our previous 12-month efficacy publication, added the reference to our publication for methodology, and referenced table 1 for baseline demographics. For table 2 and table 3, we have not referenced this, as there is overlapping text related to some of the 12-week/baseline variables (not all of them as we are also presenting new variables) with the comparisons at 2-year follow-up all being completely new to this manuscript. We have not referenced our own abstracts, which is where much of the duplication outside of our safety (Carson 2014 et.al.) and 12-month efficacy (Smith 2012) references are coming from.

3. Thank you for stating the following in the Acknowledgments Section of your manuscript: 'The Department of Respiratory Medicine, The Queen Elizabeth Hospital, Adelaide, Australia' We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: 'The authors received no specific funding for this work.'

We have removed funding from the manuscript. The statement of ‘no specific funding’ would be correct for the publication, as we never received any specific funding, rather the department of respiratory medicine supported the research through personnel time as part of usual practice.

Reviewer 1: typing errors to correct, including in the summary

Amended

My main criticism is that varenicline placebo has not been placed in the arm with only the advice to help with weaning by phone

We have previously mentioned the lack of placebo as a limitation of this study design, and briefly touched on it again in the limitations on page 13. To reiterate this point, we have more information about the lack of placebo in the limitations section, highlighting the reason for this specific design is to provide a real-world study for use by policy makers and clinicians.

The second reservation, identified by the authors, is that weaning is mainly declarative. The expired CO measurement could have been done at each stage of the study and in all participants. This independent study of the laboratory that markets Varenicline shows the benefit of this molecule in long-term withdrawal and its side effects to a lesser extent than in previous studies.

Agree, this is an important limitation of this study, which has been highlighted in the discussion under limitation. We have not made any further changes at this point, however, happy to amend further if required.

Reviewer 2: Initial inclusion: a large number of patients were excluded or not included at the beginning of the study. It would be interesting to know the main causes of non-inclusion, especially for neuropsychic diseases. This element is important since these side effects under varenicline were the subject of a debate. The good tolerance in this area under varenicline in the study may be related in part to a strict selection of patients with neuropsychological antecedents.

Unfortunately, we were not given ethics approval to capture that level of detailed information from participants.

Another limiting factor of the study concerns the absence of placebo versus varenicline (non-blind study) which may be negatively perceived by patients included in the group without varenicline and for health professionals. This limit is for efficacy compared to 1 and 2 years, but less alters tolerance and mortality data at 2 years (which is one of the important data in this publication).

We have previously mentioned the lack of placebo as a limitation of this study design, and briefly touched on it again in the limitations on page 13. To reiterate this point, we have more information about the lack of placebo in the limitations section, highlighting the reason for this specific design is to provide a real-world study for use by policy makers and clinicians.

Was there specific monitoring of varenicline patients during the first 12 weeks of follow-up?

Yes, monitoring occurred at day 3, day 5, week 1, 2, 3, 4 and 12. This has been reported in the 12-month efficacy manuscript by Smith et.al. 2012.

A number of patients in the varenicline-free group eventually received varenicline and / or nicotine replacement therapy, probably during follow-up. Was this element contraindicated a priori in the context of the study?

Yes, it was contraindicated. Participants were asked to only use the treatment assigned to them through randomisation. However, deviations from the protocol did occur and were monitored. This has been reported in the safety manuscript by Carson et.al. 2014.

Was treatment with varenicline systematically interrupted at 12 weeks or were some patients able to continue treatment for longer?

For this study, all participants reported discontinuation of treatment after 12-weeks.

Deaths reported in table 2 to 12 weeks appear numerically larger under varenicline (5 versus 2). Is this element significant?

No, it is not significant. ‘not statistically significant’ has been added to the text of the manuscript on page 10.

How many patients did they have a CO test to validate their self-reporting?

CO testing occurred in 28 VT+C participants and 23 C-alone participants. This has been reported in the Carson et.al. 2014 publication.

Patients in the varenicline group paid for their medication. This treatment is reimbursed in other countries. Can this element be an additional motivation factor for motivation and therefore effectiveness in this group?

Yes, we agree the addition of payment could be a motivating factor. We have now mentioned this in the limitations with supporting references relating to the economic principle of loss aversion.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

28 Jan 2020

PONE-D-19-25086R1

Two year efficacy of varenicline tartrate and counselling for inpatient smoking cessation (STOP study): A Randomized Controlled Clinical Trial

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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Reviewer #3: All comments have been addressed

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Reviewer #3: Yes

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Reviewer #3: No

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Reviewer #3: Yes

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Reviewer #3: Yes

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Reviewer #3: Major;

Methods

1) Was this a registered trial on clinical trials.gov if so, should be stated in methods section.

2) Reference of protocol should be given, not just saying published in NEJM?

3) More detail required on the randomisation process, i.e was it simple randomisation, any block sizes?

Statistical analysis

1) Sample size calculation, says clustering effect was adjusted for in the sample size, the rho needs to be reported to be able to replicate the sample size?

2) If the sample size was based on the 52 weeks, then the primary analysis should based on 52 weeks with results at 104 also presented as part of the primary outcome analysis. Otherwise this needs to be mentioned if the hypothesis is that the treatment effect would be maintained at 2 years?

3) Needs more information about how the dependant variable is defined.

4) Analysis population, needs to be clearly defined, i.e. ITT population?

5) It looks like logistic regression analysis was carried out, but no mention of this in the statistical analysis section. Also based some reported results it looks like repeated measures were taken in which case, perharps more appropriate analysis is suitable to take into account the nature of the data. Also if multiple tests were done and multiple timepoints the adjustments of the p-values need to be done for these.

6) More detail on what baseline adjustment were made by discipline?

Outcome and data collection;

1) The authors state the primary outcome was continuous outcome between weeks 2 and week 104 defined smoking at ≤ 5 cigarettes in total during the follow-up periods – was this a one-off questionnaire or question asked during the phone call to participants? Also from looking at Figure 2, this implies primary outcome was collected repeatedly at various time-points? And starting from 4 weeks instead of the mentioned from 2 weeks, please clarify.

Minor;

1) Abstract in results section: “odds ratio odds ratio” repeated twice.

Introduction

1) At the end, it would be worthwhile mentioning/distinguishing primary and secondary objectives.

Results

1) It would be good add the range for age.

2) If adjustments were baseline characteristics within disciplines, then it would be helpful to present (as supplementary) a baseline table stratified by discipline to the factors adjusted for are transparent.

Outcome and data collection;

2) The sentence relating to participants assigned to intervention paying the full PBS subsided costs- does this mean they had to pay for their medication, would this have influenced/biased the primary outcome, in that motivation to stop smoking because they spent money themselves? I know it is acknowledged as a limitation, were the participants asked or aware during the consent process?

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Reviewer #3: No

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6 Mar 2020

Major

Methods:

1) Was this a registered trial on clinical trials.gov if so, should be stated in methods section. Yes, it was registered with clinicaltrial.gov; Now added to methods.

2) Reference of protocol should be given, not just saying published in NEJM? Amended protocol to be the clinicaltrial.gov protocol, as this is the protocol that was being referred to (though in retrospect very ambiguously).

3) More detail required on the randomisation process, i.e was it simple randomisation, any block sizes? Simple randomisation with permuted blocks of 20, now amended in the manuscript

Statistical analysis

1) Sample size calculation, says clustering effect was adjusted for in the sample size, the rho needs to be reported to be able to replicate the sample size? Rho of 0.02 as per Campbell 2000 used; Now included with reference added.

2) If the sample size was based on the 52 weeks, then the primary analysis should based on 52 weeks with results at 104 also presented as part of the primary outcome analysis. Otherwise this needs to be mentioned if the hypothesis is that the treatment effect would be maintained at 2 years? The sample size calculation was only based on 52 week follow-up. This was published separately. The sample size was not powered to evaluate efficacy at 104-week follow-up. This has been reported in the manuscript.

3) Needs more information about how the dependant variable is defined. Now provided for treatment efficacy as the dependant variable.

4) Analysis population, needs to be clearly defined, i.e. ITT population? This is already reported on page 8 as being ‘intention to treat’.

5) It looks like logistic regression analysis was carried out, but no mention of this in the statistical analysis section. Also based some reported results it looks like repeated measures were taken in which case, perharps more appropriate analysis is suitable to take into account the nature of the data. Also if multiple tests were done and multiple timepoints the adjustments of the p-values need to be done for these. There were no logistic regression or repeated measure analyses undertaken.

6) More detail on what baseline adjustment were made by discipline? Amended in text to specify adjustment was for imbalance in people assigned to VT+C arm of the study from the vascular discipline.

Outcome and data collection

1) The authors state the primary outcome was continuous outcome between weeks 2 and week 104 defined smoking at ≤ 5 cigarettes in total during the follow-up periods – was this a one-off questionnaire or question asked during the phone call to participants? Also from looking at Figure 2, this implies primary outcome was collected repeatedly at various time-points? And starting from 4 weeks instead of the mentioned from 2 weeks, please clarify. A one-off questionnaire at 104-weeks determined the outcome of continuous abstinence for this manuscript. Re-worded in text to be clearer.

The outcome measure of 104-week continuous abstinence was not repeated at each time point, but only at 104-weeks.

Minor

Abstract:

1) Abstract in results section: “odds ratio odds ratio” repeated twice. Amended

Introduction:

1) At the end, it would be worthwhile mentioning/distinguishing primary and secondary objectives. This has been amended to better reflect that 104 week follow-up was a secondary objective for the study, but evaluation of this outcome was the result presented in this manuscript.

Results:

1) It would be good add the range for age. Added to table 1

2) If adjustments were baseline characteristics within disciplines, then it would be helpful to present (as supplementary) a baseline table stratified by discipline to the factors adjusted for are transparent. A break-down by disciplines are already presented at the end of table 1. At this stage we don’t feel that an additional breakdown of demographic characteristics will add anything further across each of the four disciplines, above what is presented in table 1.

Outcome and data collection:

2) [sic.] The sentence relating to participants assigned to intervention paying the full PBS subsided costs- does this mean they had to pay for their medication, would this have influenced/biased the primary outcome, in that motivation to stop smoking because they spent money themselves? I know it is acknowledged as a limitation, were the participants asked or aware during the consent process? Yes, participants did pay for their medication, which we do acknowledge in the limitations as a potential factor influencing their quit attempts. They were aware during the consent procedure and this has been added as a sentence to study limitations.

Submitted filename: Response to Reviewers - statistical review.docx

Click here for additional data file.

17 Mar 2020

Two-year efficacy of varenicline tartrate and counselling for inpatient smoking cessation (STOP study): A Randomized Controlled Clinical Trial

PONE-D-19-25086R2

Dear Dr. % Carson-Chahhoud,

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Academic Editor

PLOS ONE

16 Apr 2020

PONE-D-19-25086R2

Two-year efficacy of varenicline tartrate and counselling for inpatient smoking cessation (STOP study): A randomized controlled clinical trial

Dear Dr. Carson-Chahhoud:

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PLOS ONE