The Efficacy and Safety of Varenicline Alone Versus in Combination With

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PEER REVIEW HISTORY

BMJ Open publishes all reviews undertaken for accepted manuscripts. Reviewers are asked to complete a checklist review form (http://bmjopen.bmj.com/site/about/resources/checklist.pdf) and are provided with free text boxes to elaborate on their assessment. These free text comments are reproduced below.

ARTICLE DETAILS

TITLE (PROVISIONAL) The efficacy and safety of varenicline alone versus in combination with nicotine lozenges for smoking cessation among hospitalised smokers (VANISH): study protocol for a randomised, placebo- controlled trial AUTHORS Gobarani, Rukshar Kaizerali; Abramson, Michael; Bonevski, Billie; Weeks, Gregory R; Dooley, Michael J; Smith, Brian J; Veale, Antony; Webb, Ashley; Kirsa, Sue; Thomas, Dennis; Miller, Alistair; Gasser, Rudi; Paul, Eldho; Parkinson, Jacqueline; Meanger, Darshana; Coward, Lisa; Kopsaftis, Zoe; Rofe, Olivia; Lee, Paula; George, Johnson

VERSION 1 – REVIEW

REVIEWER Megan Piper University of Wisconsin, Madison USA REVIEW RETURNED 07-Apr-2020

GENERAL COMMENTS This manuscript describes the protocol for a smoking cessation

clinical trial that will compare varenicline + active nicotine lozenges http://bmjopen.bmj.com/ to varenicline + placebo lozenges. This study will address a critical public health need – the need for more effective smoking cessation treatment strategies. This protocol is also innovative in the use of a prn nicotine replacement therapy (NRT) in combination with varenicline. The use of hospitalized patients and a pragmatic design will enhance the generalizeability and translation of the study findings. I found the paper to be clear and well-written. While this is a protocol and not an outcome paper, many parts of the paper contain implementation specifics that did not seem on September 26, 2021 by guest. Protected copyright. appropriate for an academic paper. There are specific implementation details (e.g., the DSMB, the criteria for withdrawing a participant from the study) that do not seem necessary. Conversely, key issues such as the timing of assessments (e.g., CO, withdrawal) were not included. There are additional concerns with the protocol.

First, the primary outcome is clearly specified as CO-validated continuous abstinence from 2 weeks to 6 months after treatment initiation. The use of a biochemically verified cessation outcome increases the rigor of the research. However, it is never stated when the CO assessments will be conducted. Because CO has such a short half-life, it is not possible to biochemically verify continuous abstinence over such a long period of time. Will the investigators take multiple CO readings?

Implementation in an in-patient setting is a strength of this research. It might be helpful to describe more of the details of how the RAs will be allowed to access providers to get permission to enroll patients.

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Also, it is unclear that certain types of hospital admissions (e.g., psychiatric, ICU) would be appropriate for this research. Finally, it is unclear whether duration of hospitalization will influence a patient’s ability to engage in the study (e.g., patients who are hospitalized only over night).

It was unclear whether this was a single-blinded study or a double- blinded study. It appears that the RA who will provide the treatment is given an envelope with information that details whether the participants will get active or placebo lozenges. The directions to the patients to reduce their smoking over the 1st 7 days of varenicline use seems odd, given that these are current inpatients who are not smoking. It was not clear why there is no attempt to maintain abstinence following release from the hospital.

The inclusion of an option for an additional 12 weeks of study medication may be pragmatic, but it definitely adds complexity to the interpretation of any outcome results, especially since the key outcome is measured 6 months post-treatment initiation, when some participants may still be using treatment. This potential additional 12 weeks of medication is not described in the Control and Intervention Arm sections of the paper where it states they will only get varenicline for 12 weeks. Further, this complexity is not addressed in the analytic plan.

There was no rationale for encouraging participants to only use the lozenge when they have an urge to smoke, rather than trying to maintain a level of nicotine to prevent emergent cravings.

The sample size section assumes a 15% difference in treatment groups in continuous abstinence, based on a single study with the largest effect size. However, the meta-analysis of the 3 varencline + patch studies revealed a 9 percentage point difference in abstinence http://bmjopen.bmj.com/ rates. Therefore, it is unclear that this study will have sufficient power to detect the likely effects of this intervention.

Minor issues: In the final paragraph of the Introduction, the text reads “The secondary objectives of this study are to compare:” with a list of outcomes rather than a list of comparators.

Should the word “compare” be replaced with something like on September 26, 2021 by guest. Protected copyright. “compare the differences between treatment groups on the following outcomes”?

Are participants allowed to use other tobacco products other than combustible cigarettes? What if they are using e-cigarettes for a purpose other than smoking cessation?

It was not clear what a “cautionary condition” might be.

It is not clear what a “concession card” is.

It is not clear why the investigators selected a withdrawal assessment that has different response scales for the different withdrawal symptoms. This will make it difficult to directly compare the withdrawal symptoms.

It was unclear how the participant can disclose their treatment condition to the RA doing the follow-up assessments. If the

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participants are blinded, they are only sharing their guess as to their treatment condition.

REVIEWER Raana Zahid The Initiative, Pakistan REVIEW RETURNED 09-Apr-2020

GENERAL COMMENTS • Biochemical validation at registration in trial and a cutoff point selected for registration should be considered in my opinion for comparison with later levels recorded during followups.. • My second concern is follow ups at 3-6-12 months. I hope the team has procured enough resources for that. As many persons don’t attend phonecalls, change address, move to a different state etc. A biochemical exam means someone visiting them at home and home visits can be tricky and expensive. • Plus varenicline has side effects that can be pronounced in case of inpatients who are already hospitalized for a serious illness. This will bring down the severe adverse effects significantly. (For example In our trial we had excluded participants with history of epilepsy.. Furthermore, additional concurrent addictions should also be seriously considered like alcohol, heroin etc • The study design is not double blind? As the dispensing pharmacist knows what they are dispensing. By allocating a trial ID to a medicine pack…the trial can easily be double blind. This will strengthen the study design. • Exclusion criteria should also exclude for chewable tobacco if it is common practice in Australia. Also urinary cotinine levels should also be checked in case some participants switch from cigarettes to chewable tobacco. • The inclusion criteria should state “new hospital recruits” to automatically exclude those already on NRT as part of hospital policy.

http://bmjopen.bmj.com/ VERSION 1 – AUTHOR RESPONSE

COMMENTS BY REVIEWER ONE – MEGAN PIPER 1. This manuscript describes the protocol for a smoking cessation clinical trial that will compare varenicline + active nicotine lozenges to varenicline + placebo lozenges. This study will address a critical public health need – the need for more effective smoking cessation treatment strategies. This protocol is also innovative in the use of a prn nicotine replacement therapy (NRT) in combination with varenicline. The use of hospitalized patients and a on September 26, 2021 by guest. Protected copyright. pragmatic design will enhance the generalizability and translation of the study findings. I found the paper to be clear and well-written. While this is a protocol and not an outcome paper, many parts of the paper contain implementation specifics that did not seem appropriate for an academic paper. There are specific implementation details (e.g., the DSMB, the criteria for withdrawing a participant from the study) that do not seem necessary. Conversely, key issues such as the timing of assessments (e.g., CO, withdrawal) were not included. There are additional concerns with the protocol.

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In this study, biochemical validation of self-reports is done at the 6-month and 12-month follow-ups in those participants self-reporting both point prevalence abstinence and continuous abstinence. We agree with the reviewer that the CO test only confirms point prevalence abstinence. Our primary endpoint is line with the SRNT recommendations.1 Carbon monoxide testing was chosen because it is non-invasive and inexpensive to administer.1,2Although exhaled carbon monoxide (CO) detects only recent smoking, when smokers relapse they almost always return to daily smoking.2Six and 12-month follow-ups in this study are conducted over the telephone. Participants who self-report abstinence at these follow-ups are requested to perform a CO breath test at a time suitable to them. CO breath testing is conducted either at the participant’s home by a trained research assistant or at the hospital site. Due to the pragmatic nature of the trial, it is not always practical to perform the breath testing on the day of follow-up. All CO breath testing will be scheduled as soon as possible (within 1 week) after the self-report of point prevalence abstinence is recorded. Please see amendment on Page 18, line 17 under Primary Endpoint “All CO breath testing will be scheduled as soon as is possible (within 1 week) after self-report of abstinence has been recorded.” 2. Implementation in an in-patient setting is a strength of this research. It might be helpful to describe more of the details of how the RAs will be allowed to access providers to get permission to enrol patients. Also, it is unclear that certain types of hospital admissions (e.g., psychiatric, ICU) would be appropriate for this research. Finally, it is unclear whether duration of hospitalization will influence a patient’s ability to engage in the study (e.g., patients who are hospitalized only overnight). Nurses and pharmacists involved in their usual clinical roles screen admitted patients and refer these to a research assistant for follow up and potential recruitment. Research assistants also actively screen admission records and visit ward areas to identify inpatient smokers who fit into the inclusion criteria of the study. Clinical history records identify factors that may exclude participants from the study (e.g. pregnancy). If no exclusion factors are identified, the RA will approach potential participants and explain the study to them and invite them to participate.Medical staff may also refer potential participants for inclusion in the study.

Patients eligible for the trial are: adults ≥18 years, admitted to participating hospitals with a http://bmjopen.bmj.com/ history of smoking ≥10 cigarettes per day on average in the four weeks prior to their hospital admission, interested in quitting smoking, willing to use pharmacotherapy, available for a 12 months follow-up post-treatment initiation and willing/capable to provide written informed consent. Therefore, patients in ICU and those with an acute psychiatric condition will be excluded from the trial as they may not be able to provide informed consent. Furthermore, patients will be recruited in the trial if the benefits of participating in the trial outweigh the

potential risks. RAs will discuss such cases with the patient’s treating medical team and the on September 26, 2021 by guest. Protected copyright. site coordinators to ensure the benefits of participation in the study are weighed. Patients will only be included in the trial, if potential benefits of participation outweigh the potential risks and the decision is unanimous between the treating medical team and the study researchers. Please see the following change under Inclusion and Exclusion criteria on page 10, line 12 “Patients unable to provide written informed consent because of their admitting medical condition or health status at the time of recruitment (e.g. patients in the intensive care unit or patients with an acute psychiatric condition) will be excluded from the trial.” Furthermore, the length of hospitalisation does not affect the eligibility to participate in the study. Having said that, due to the pragmatic nature of the trial it may not be practical to capture short-stay inpatients (day or overnight stays) in all cases, keeping in mind the time it takes to obtain written informed consent, randomly allocate participants, have the trial medications prescribed and dispensed and provide verbal and written counselling. Moreover, the study design is such that trial medications are ideally started during hospital stay so that participants have access to direct medical help if needed and the forced abstinence created by the smoke-free hospital policy increases the likelihood of abstinence.

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3. It was unclear whether this was a single-blinded study or a double-blinded study. It appears that the RA who will provide the treatment is given an envelope with information that details whether the participants will get active or placebo lozenges.

The participants and the RAs at all the sites are unaware of the group allocation. And as stated on page 9 this is a double blinded study “A randomised, placebo-controlled, multi- centre, double blinded study”. The error in wording in the text has been corrected. Please refer to the randomisation process outlined in the manuscript and following amendment on page 13, line 2 “The clinical trials pharmacist will then dispense the study medicines as stated in the envelope ([varenicline and NRT lozenges] or [varenicline and placebo lozenges]) and hand these to the RA.” 4. The directions to the patients to reduce their smoking over the 1st 7 days of varenicline use seems odd, given that these are current inpatients who are not smoking. It was not clear why there is no attempt to maintain abstinence following release from the hospital. Although trial participants are inpatients at hospitals with a smoke-free policy which creates an environment of forced abstinence, this policy does not prevent inpatients from going outside hospital premises for a smoke. A cut down would be recommended for such patients as per the product information.3 Otherwise, if they temporarily quit smoking, the RAs will encourage them to remain abstinent. 5. The inclusion of an option for an additional 12 weeks of study medication may be pragmatic, but it definitely adds complexity to the interpretation of any outcome results, especially since the key outcome is measured 6 months post-treatment initiation, when some participants may still be using treatment. This potential additional 12 weeks of medication is not described in the Control and Intervention Arm sections of the paper where it states they will only get varenicline for 12 weeks. Further, this complexity is not addressed in the analytic plan.

The study will provide an additional 12 weeks of treatment with varenicline or NRT/placebo lozenges to participants who have ceased smoking with the initial treatment course and are undergoing counselling (e.g. Quitline) for smoking cessation. This is in line with the product http://bmjopen.bmj.com/ information sheets, therapeutic guidelines and the criteria set out in the Australian Pharmaceutical Benefits Scheme for subsidised treatment.3The additional unadjusted and adjusted analyses will be performed with analysis by medication status (additional medication given or not given) as a covariate and an interaction of the intervention with this covariate. Please see the following amendments in the manuscript: Control and Intervention arm, Page 14, line 22 “Participants who continue with an additional 12-week course of varenicline will be advised to continue with the standard maintenance dose of 1mg twice daily for this period as recommended in the Product Information Sheet for on September 26, 2021 by guest. Protected copyright. Champix.” Data Analysis, Page 21, line 19 “The additional unadjusted and adjusted analyses will be performed with analysis by medication status (additional medication given or not given) as a covariate and an interaction of the intervention with this covariate.”

6. There was no rationale for encouraging participants to only use the lozenge when they have an urge to smoke, rather than trying to maintain a level of nicotine to prevent emergent cravings. This recommendation is based on the product information sheet for nicotine lozenges.4The aim of this study is to compare the efficacy and safety of varenicline in combination with an acute dosing form of nicotine replacement therapy (NRT) versus varenicline alone for smoking cessation. Maintaining high level of nicotine in heavy smokers by regular dosing (instead of prn) would have been safe if the patient was not receiving varenicline treatment. In addition to this, acute dosing nicotine products (e.g. nicotine lozenges) provide relief from nicotine craving as they provide an immediate release of nicotine in the body.4,5 They are not

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designed to be used to maintain a constant level of nicotine in the body to prevent cravings.4,5 This is the place reserved for nicotine transdermal patches which release nicotine more gradually over a period of time to maintain a constant level of nicotine in the body.5 Furthermore, the rationale for the use of ad lib nicotine product is discussed in the introduction page 7, paragraphs 1, 2 and 3. 7. The sample size section assumes a 15% difference in treatment groups in continuous abstinence, based on a single study with the largest effect size. However, the meta-analysis of the 3 varenicline + patch studies revealed a 9-percentage point difference in abstinence rates. Therefore, it is unclear that this study will have sufficient power to detect the likely effects of this intervention.

A reasonably large study (n=446)6 that compared the efficacy and safety of varenicline in combination with nicotine patches versus varenicline alone reported continuous abstinence rates at 24 weeks of 49% for the intervention group and 32.6% for the control group.6 Our study assumed a conservative 45% quit rate in the intervention group and 30% in the control group based on the results of this study. The sample size required using this approach is 320 participants (80% power and 5% level of significance) to show a 15% difference using an uncorrected chi-square test. Since the primary analysis is Intention to treat (ITT), the drop- outs are not considered in the sample size calculation. We acknowledge that other small studies have demonstrated smaller differences in abstinence rates, but the funding restrictions did not allow for a larger trial.

8. Minor issues: In the final paragraph of the Introduction, the text reads “The secondary objectives of this study are to compare:” with a list of outcomes rather than a list of comparators. Should the word “compare” be replaced with something like “compare the differences between treatment groups on the following outcomes”? This change has been made. Please see final paragraph of the introduction, page 9 “The secondary objectives of this study

are to compare the differences between treatment groups on the following outcomes:” http://bmjopen.bmj.com/ 9. Are participants allowed to use other tobacco products other than combustible cigarettes? What if they are using e-cigarettes for a purpose other than smoking cessation?

Abstinence in this study refers to abstinence from all tobacco products, including alternative products (e-cigarettes). Please refer to Secondary endpoints page 19, bullet point 8 “Self- reported utilisation of other smoking cessation therapies and alternative products e.g. electronic cigarettes”. However, we acknowledge that CO testing is not able to detect the use of smoke-less tobacco products. CO was chosen as the method for the biochemical on September 26, 2021 by guest. Protected copyright. verification of abstinence in this study because it is non-invasive and relatively inexpensive to administer. Furthermore, the use of chewing tobacco is uncommon in Australia compared to some parts of Asia. The results of the 2016 National Drug Strategy Household Survey showed that only 0.4% of Australians aged 14 years and over reported the use of chewing tobacco in the 12 months prior to completing the questionnaire.7

Please also see question 5 by reviewer two.

10. It was not clear what a “cautionary condition” might be. This sentence has been amended. Please see page 12, line 4 “Participants who do not meet any of the exclusion criteria, but who have a specified precaution for the use of the trial medications, will be referred to an in-house clinician for further assessment.” The precautions for the use of varenicline, as mentioned in the product information sheet3are: seizures, hypersensitivity reactions, somnambulism, new or worsening cardiovascular events,

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psychiatric symptoms and the use of other medications metabolised by CYP1A2 (examples include warfarin and insulin). The precautions for the use of nicotine lozenges (as mentioned in the Product Information Sheet)4 are: patients who are haemodynamically unstable, diabetes, allergic reactions, phaeochromocytoma and uncontrolled hyperthyroidism, gastrointestinal disease, phenylketonuria and patients on a low sodium diet. 11. It is not clear what a “concession card” is.

A concession card is a Services Australia or Department of Veteran’s Affairs Healthcare card which allows eligible individuals access to subsidised health services and medications. This has been clarified. Please see page 17, paragraph 2, line 2 “General demographics including age, gender, ethnicity, highest level of education, employment status and possession of any healthcare card(allowing subsidised health services and medications for the cardholders) will be collected at baseline”

12. It is not clear why the investigators selected a withdrawal assessment that has different response scales for the different withdrawal symptoms. This will make it difficult to directly compare the withdrawal symptoms.

The Mood and Physical Symptoms Scale (MPSS) is a validated questionnaire used to assess withdrawal symptoms and the strength and frequency of their urges to smoke.8 West et al evaluated the internal structure and responsiveness to abstinence of the core items of the scale and concluded that the MPSS met the key requirements of a cigarette withdrawal scale.8 Furthermore, they reported that the MPSS was sensitive to change in mood and physical symptoms resulting from 24 hours of abstinence, despite only using one rating per construct.8 West et al also concluded that the MPSS bore the closest resemblance to the Minnesota Withdrawal Scale.8 The purpose of including the MPSS in the study is so that we can compare withdrawal symptoms and urges to smoke within the 2 treatment groups (varenicline + placebo lozenges

vs. varenicline + nicotine lozenges). http://bmjopen.bmj.com/ 13. It was unclear how the participant can disclose their treatment condition to the RA doing the follow-up assessments. If the participants are blinded, they are only sharing their guess as to their treatment condition. Participants are blinded and should not know their treatment allocation. Hence, we have deleted that sentence. Please see Blinding, Page 18, line 11 COMMENTS BY REVIEWER TWO – Raana Zahid on September 26, 2021 by guest. Protected copyright. 1. Biochemical validation at registration in trial and a cut-off point selected for registration should be considered in my opinion for comparison with later levels recorded during follow-ups Self-report of recent smoking by participants was accepted as confirmation of their smoking status. The Russell Standard does not recommend using baseline CO testing in trials.2The methodology for thistrial has been developed in line with recent clinical trials in the same area of research.9-11 Given the trial has been approved by the ethics committees of the participating hospitals and is actively recruiting participants, it is not feasible to make this change at this stage. 2. My second concern is follow-ups at 3-6-12 months. I hope the team has procured enough resources for that. As many persons don’t attend phonecalls, change address, move to a different state etc. A biochemical exam means someone visiting them at home and home visits can be tricky and expensive. We agree with the reviewer regarding the challenges in conducting follow-ups. However, this study was awarded a grant by the Global Awards for Nicotine Dependence. The study budget, developed prior to the implementation of the trial has considered such expenses.

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Sufficient funds have been allocated to the conduct of the follow-ups and carbon monoxide breath testing at 6 and 12 months to verify self-reported abstinence. 3. Plus, varenicline has side effects that can be pronounced in case of inpatients who are already hospitalized for a serious illness. This will bring down the severe adverse effects significantly. (For example,in our trial we had excluded participants with history of epilepsy. Furthermore, additional concurrent addictions should also be seriously considered like alcohol, heroin etc One of the main strengths of this trial is the pragmatic design and greater generalisability of its findings as it is designed to recruit a study population that is representative of the inpatient smokers at Australian public hospitals. The exclusion criteria for the trial have been formulated with reference to the product information sheet of varenicline and nicotine lozenges.3,4 Although the trial does not explicitly exclude patients with epilepsy or substance use disorders from participating, the decision on whether to include such patients in the trial will be discussed with the patient’s treating medical team, the research assistant at the site and other research coordinators on a case by case basis. Such participants will only be recruited in the trial, if the benefits of participating outweigh the potential risks. 4. The study design is not double blind? As the dispensing pharmacist knows what they are dispensing. By allocating a trial ID to a medicine pack…the trial can easily be double blind. This will strengthen the study design. This is a double-blind study. Please see page 9, Study design section “A randomised, placebo-controlled, multi-centre, double blinded study” Please also see response to question 4 fromReviewer One above. The clinical trials pharmacist involved in the dispensing of trial medication is not involved in other aspects of the trial such as outcome assessments. All outcome assessments including carbon monoxide breath testing are performed by research assistants blinded to treatment allocation, hence making this a double blinded trial. Furthermore, the sealed envelopes used for randomisation each have their own participant study ID on the top and the group allocation (intervention or control) inside. When a participant is recruited the clinical trial pharmacist opens an envelope in a sequential manner to reveal the group allocation. The group

allocation is noted along with the participant study ID and the respective trial medications are http://bmjopen.bmj.com/ dispensed. Please also refer to page 18, Blinding “Three-, six- and twelve- month follow-ups will be conducted by a RA blinded to treatment allocation. All possible measures will be taken to prevent participant disclosure of treatment allocation to the RA. Any accidental unblinding will be documented and reported.” 5. Exclusion criteria should also exclude for chewable tobacco if it is common practice in Australia. Also, urinary cotinine levels should also be checked in case some participants on September 26, 2021 by guest. Protected copyright. switch from cigarettes to chewable tobacco. The trial does not exclude users of chewable tobacco, which is relatively uncommon in Australia, compared to some parts of Asia.7 However, we acknowledge that CO is unable to detect the use of smoke-less tobacco products.1 Despite this, given that the trial is actively recruiting participants and that some participants have performed their carbon monoxide breath testing it would not be feasible to make this change. Please also see response to question 9 fromreviewer one. 6. The inclusion criteria should state “new hospital recruits” to automatically exclude those already on NRT as part of hospital policy. Recruitment is not limited to new hospital admissions. Inpatient smokers at the hospitals who fit the inclusion criteria of the study are eligible to participate in the trial. However, upon recruitment to the trial, all participants are encouraged to cease the use of other smoking cessation pharmacotherapies including NRT received during hospital stay. The use of NRT after hospital admission will be documented and adjusted for in the analysis. Please refer to page 25, line 11 “Use of NRT after admission to the hospital will be captured and adjusted for in analysis.”

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References 1. Biochemical verification of tobacco use and cessation. Nicotine Tob Res. 2002;4(2):149-159. 2. West R, Hajek P, Stead L, Stapleton J. Outcome criteria in smoking cessation trials: proposal for a common standard. Addiction. 2005;100(3):299-303. 3. Pfizer. Australian product information - Champix (varenicline as tartrate). 2015. 4. Perrigo Australia. Australian product information - Nicotinell (Nicotine) 2mg and 4mg lozenges. 2016. 5. Wadgave U, Nagesh L. Nicotine Replacement Therapy: An Overview. Int J Health Sci (Qassim). 2016;10(3):425-435. 6. Koegelenberg CF, Noor F, Bateman ED, et al. Efficacy of varenicline combined with nicotine replacement therapy vs varenicline alone for smoking cessation: a randomized clinical trial. Jama. 2014;312(2):155-161. 7. Australian Institute of Health and Welfare. National Drug Strategy Household Survey 2016: detailed findings. Canberra: AIHW;2017. 8. West R, Hajek P. Evaluation of the mood and physical symptoms scale (MPSS) to assess cigarette withdrawal. Psychopharmacology (Berl). 2004;177(1-2):195-199. 9. Thomas D, Farrell M, McRobbie H, et al. The effectiveness, safety and cost- effectiveness of cytisine versus varenicline for smoking cessation in an Australian population: a study protocol for a randomized controlled non-inferiority trial. Addiction. 2019;114(5):923- 933. 10. Smith BJ, Carson KV, Brinn MP, et al. Smoking Termination Opportunity for inPatients (STOP): superiority of a course of varenicline tartrate plus counselling over counselling alone for smoking cessation: a 12-month randomised controlled trial for inpatients. Thorax. 2013;68(5):485-486. 11. Chang P-H, Chiang C-H, Ho W-C, Wu P-Z, Tsai J-S, Guo F-R. Combination therapy of varenicline with nicotine replacement therapy is better than varenicline alone: a systematic review and meta-analysis of randomized controlled trials. BMC Public Health. 2015;15(1):689.

http://bmjopen.bmj.com/ VERSION 2 – REVIEW

REVIEWER Megan Piper University of Wisconsin, Madison USA REVIEW RETURNED 21-May-2020

on September 26, 2021 by guest. Protected copyright. GENERAL COMMENTS The authors provided clear responses to the reviewers’ earlier concerns. However, it would be helpful for readers to have some of those responses included in the manuscript. Specifically, the discussion of the fact that hospitalized smokers can go out and smoke and that this is why investigators are recommending reduced smoking over the first 7 days of varenicline use and the details regarding the power analysis (e.g., the proposed base rate for the control group) would be helpful for readers.

The SRNT workgroup has recently updated the recommendations regarding the assessment and biochemical verification of abstinence. It appears that the primary outcome for this study would be considered to be prolonged abstinence with lapses, rather than continuous abstinence. Updating the language in the paper to be consistent with the SRNT recommendations would help the readers. Further, the recommended CO cut-off for abstinence has been updated. • Piper ME, Bullen C, Krishnan-Sarin S, et al. Defining and

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measuring abstinence in clinical trials of smoking cessation interventions: An updated review [published online ahead of print, 2019 Jul 4]. Nicotine Tob Res. 2019;ntz110. doi:10.1093/ntr/ntz110 • Benowitz NL, Bernert JT, Foulds J, et al. Biochemical Verification of Tobacco Use and Abstinence: 2019 Update [published online ahead of print, 2019 Oct 1]. Nicotine Tob Res. 2019;ntz132. doi:10.1093/ntr/ntz132

The 3rd bullet of outcomes on p. 9 is unclear – it describes 7-day point-prevalence abstinence from 2 weeks to 6 or 12 months rather than no smoking in the last 7 days at 6 and 12 months.

The discussion of the control and intervention arm treatment is somewhat confusing as it is currently organized. It appears that there is no lozenge treatment for the control arm. It might be better to just combine the discussion of interventions and note that the only difference will be the type of lozenge participants receive.

It is unclear what assessments are used for the secondary endpoints. Is psychological distress the PHQ-9? How will lozenges be reported – for the last 7 days, for the duration of the study? Will the Time Line Follow Back method be used or some other self-report measure?

VERSION 2 – AUTHOR RESPONSE

COMMENTS BY REVIEWER ONE – MEGAN PIPER 1. The authors provided clear responses to the reviewers’ earlier concerns. However, it would be helpful for readers to have some of those responses included in the manuscript. Specifically, the discussion of the fact that hospitalized smokers can go out and smoke and that this is why investigators are recommending reduced smoking over the first 7 days of varenicline use and the details regarding the power analysis (e.g., the proposed base rate for the control group) would be helpful for readers. http://bmjopen.bmj.com/ This has been amended. Please see section titled “Study arms and medicines, paragraph 5, page 14, line 16. “Participants will be advised to commence the trial medication(s) during their hospital stay. The smoke-free policies of Australian hospitals create an environment conducive for abstinence. However, this does not prevent inpatient smokers from going outside hospital premises for a smoke. Therefore, all participants will be asked to reduce their smoking over the first seven days of varenicline treatment

and aim to quit completely within two weeks. Patients will be asked to stop smoking in line with the on September 26, 2021 by guest. Protected copyright. varenicline Product Information Sheet (1).” A reasonably large study (n=446) that compared the efficacy and safety of varenicline in combination with nicotine patches versus varenicline alone reported continuous abstinence rates at 24 weeks of 49% for the intervention group and 32.6% for the control group(2). Our study assumed a conservative 45% quit rate in the intervention group and 30% in the control group based on the results of this study. The sample size required using this approach is 320 participants (80% power and 5% level of significance) to show a 15% difference using an uncorrected chi-square test. As suggested by the reviewer the base proposed base rates have been added under the section titled “Sample size” on page 22, line 1. “Our study assumed a conservative 45% quit rate in the intervention group and 30% in the control group based on previous work (2). To show an absolute difference of 15% in prolonged abstinence rate between study arms (estimate based on prolonged abstinence rates in varenicline-NRT trials) (3) at the 5% level of significance with 80% power, we will need 160 subjects per arm.”

2. The SRNT workgroup has recently updated the recommendations regarding the assessment and biochemical verification of abstinence. It appears that the primary outcome for this study

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would be considered to be prolonged abstinence with lapses, rather than continuous abstinence. Updating the language in the paper to be consistent with the SRNT recommendations would help the readers. Further, the recommended CO cut-off for abstinence has been updated. As suggested by the reviewer, continuous abstinence has been amended to prolonged abstinence with lapses (4, 5). Therefore, the word “continuous abstinence” has been replaced by “prolonged abstinence” throughout the manuscript document.

The exhaled carbon monoxide (CO) cut-off used in this study has been amended from <10ppm to <6ppm based on the updated recommendations by the SRNT subcommittee(6). Please see amendment made under section titled “Primary endpoints” on page 19, line 23 “Participants with a CO level <6 ppm will be considered abstinent” And amendment made under section titled “Data analysis” on page 23, line 3. “Primary analysis will be performed using a cut-off CO of <6ppm”

As a result of this amendment we have changed the sensitivity analysis on page 23, line 4, as below: "Primary analysis will be performed using a cut-off CO of <6ppm10ppm and additional sensitivity analysis will be conducted using a higher cut-off of <10ppm” And under “Primary endpoints” on page 19, line 24 as: “Sensitivity analysis will be performed using a higher CO cut-off of <10ppm.”

3. The 3rd bullet of outcomes on p. 9 is unclear – it describes 7-day point-prevalence abstinence from 2 weeks to 6 or 12 months rather than no smoking in the last 7 days at 6 and 12 months. This has been amended. Please see “Objectives”, page 9, bullet points2 and 3:

 Self-reported 7-day point prevalence abstinence (smoking not even a puff in the past 7 days on the day of follow-up)at 3, 6, and 12 months after treatment initiation  Self-reported prolonged abstinence measured from 2 weeks to 3, 6 and 12 months after

treatment initiation http://bmjopen.bmj.com/

4. The discussion of the control and intervention arm treatment is somewhat confusing as it is currently organized. It appears that there is no lozenge treatment for the control arm. It might be better to just combine the discussion of interventions and note that the only difference will be the type of lozenge participants receive.

Please see amendments made under the section titled “Study arms and medicines” on page 13, on September 26, 2021 by guest. Protected copyright. paragraph 1.

“Participants randomised to the control group will receive varenicline plus placebo (mint) lozenges while Participants randomised to the intervention arm will receive varenicline plus NRT lozenges.” “Varenicline in both treatment arms will be used at the standard dose as follows: 0.5mg once daily on days 1-3, 0.5mg twice daily on days 4-7 and 1mg twice daily from day 8 onwards for 11 weeks. Participants who continue with an additional 12-week course of varenicline will be advised to continue with the standard maintenance dose of 1mg twice daily for this period as recommended in the Product Information Sheet for Champix™ (35).” “NRT/Placebo lozenge dosing schedule (36) Lozenges will be used by participants only when there is an urge to smoke. Participants will be advised to use a lozenge (2mg) as required when they have an urge to smoke (up to every 1-2 hours initially) and not to use more than 15 lozenges in a day. Participants will also be advised on how to use the lozenges as per the points below: 1. Place one lozenge on the tongue and suck until the taste becomes strong

BMJ Open: first published as 10.1136/bmjopen-2020-038184 on 6 October 2020. Downloaded from

2. Park the lozenge between the gum and cheek 3. When the taste fades start sucking the lozenge again 4. Repeat this process until the lozenge completely dissolves (it takes about 30 minutes)”

5. It is unclear what assessments are used for the secondary endpoints. Is psychological distress the PHQ-9? How will lozenges be reported – for the last 7 days, for the duration of the study? Will the Time Line Follow Back method be used or some other self-report measure? This has been mentioned on page 12 under “Baseline data collection” paragraph 2, line 13. “The baseline interview will also involve an assessment of the presence of psychological distress using the Patient Health Questionnaire (PHQ-9).” As per the reviewer’s suggestion the following amendments have been made under the section titled “Secondary endpoints” on page 20, bullet points 4 and 5.  Self-reports of the average number of lozenges consumed per day (NRT or placebo)at 3- weeks from treatment initiation.  Change in psychological distress measured using the PHQ-9 scale References: 1. Pfizer Australia Pty Ltd. Product information. Champix (as varenicline tartrate). . 2. Koegelenberg CF, Noor F, Bateman ED, van Zyl-Smit RN, Bruning A, O'Brien JA, et al. Efficacy of varenicline combined with nicotine replacement therapy vs varenicline alone for smoking cessation: a randomized clinical trial. Jama. 2014;312(2):155-61. 3. Koegelenberg CF, Noor F, Bateman ED, van Zyl-Smit RN, Bruning A, O'Brien JA, et al. Efficacy of varenicline combined with nicotine replacement therapy vs varenicline alone for smoking cessation: a randomized clinical trial. JAMA. 2014;312(2):155-61. 4. Hughes JR, Keely JP, Niaura RS, Ossip-Klein DJ, Richmond RL, Swan GE. Measures of abstinence in clinical trials: issues and recommendations. Nicotine Tob Res. 2003;5(1):13-25. 5. Piper ME, Bullen C, Krishnan-Sarin S, Rigotti NA, Steinberg ML, Streck JM, et al. Defining and Measuring Abstinence in Clinical Trials of Smoking Cessation Interventions: An Updated Review. Nicotine & Tobacco Research. 2019. 6. Benowitz NL, Bernert JT, Foulds J, Hecht SS, Jacob P, Jarvis MJ, et al. Biochemical Verification of Tobacco Use and Abstinence: 2019 Update. Nicotine Tob Res. 2020;22(7):1086-97. http://bmjopen.bmj.com/