ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12618001792213

Ethics application status

Approved

Date submitted

22/10/2018

Date registered

2/11/2018

Date last updated

5/04/2023

Date data sharing statement initially provided

2/11/2018

Date results information initially provided

5/04/2023

Type of registration

Prospectively registered

Titles & IDs

Public title

Varenicline and nicotine replacement therapy for smokers admitted to hospitals

Scientific title

Evaluating the efficacy and safety of varenicline as a sole pharmacotherapy vs. in combination with nicotine replacement therapy (NRT) lozenges in assisting smoking cessation among hospitalised smokers: study protocol for a randomised controlled trial

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

Trial acronym

VANISH (Varenicline and nicotine replacement therapy for smokers admitted to hospitals)

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Nicotine Dependence

Condition category

Condition code

Mental Health

Addiction

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

There is one intervention arm in this study.

Participants in the intervention arm will receive varenicline plus NRT lozenges for a duration of 12 weeks. An additional 12 weeks course of varenicline and NRT lozenges will be provided (i.e. 24 weeks in total) to those who need further support (this will be determined by the Research Assistant and site coordinators in charge of delivering the intervention based on the participant’s nicotine dependence, adherence to treatment, and any adverse events).

VARENICLINE
Varenicline will be provided as oral tablets.
According to the product information sheet of varenicline, the standard dosing schedule used will be as follows:
Days 1-3 = one 0.5mg tablet once daily
Days 4-7 = one 0.5mg tablet twice daily
Day 8 onwards = one 1mg tablet twice daily

The dose of varenicline will be adjusted based on the participant's renal function. According to the product information sheet, no dose adjustments are required for mild to moderate renal impairment. For participants with CrCl <30 mL/minute dosing will begin at 0.5mg once daily for the first 3 days then increased to 1mg once daily if tolerated as is recommended by the Australian Medicines Handbook 2018.

The dose of varenicline will also be adjusted for participants who experience severe or intolerable nausea on standard dosing. A Research Assistant will check how such participants take varenicline in relation to food and water (may help if taken with or just after food) and if needed the dose will be lowered to 1mg once daily as recommended by the Australian Medicines Handbook 2018.

Participants will receive varenicline immediately after randomisation and will be advised to start the medication soon after they receive it. All participants will be asked to completely abstain from smoking if possible or at least reduce their smoking over the first seven days of the varenicline course and to aim to quit completely within one to two weeks of starting varenicline. Along with the medication, participants will be given Consumer Medicines Information (CMI) sheets highlighting key information about the dosing schedule and important adverse effects to be aware of. A trained Research Assistant will give clear verbal counselling to the participants along with a leaflet clearly stating the dosing regimen, the most common adverse events, emergency contact details and information on how to obtain a renewal of their medication.

NRT LOZENGES
The dose of NRT lozenges to be used is as follows (adopted from the product information sheet for combination NRT)
Lozenges should be taken only when there is an urge to smoke. Take a lozenge (2mg) as required when you have an urge to smoke up to every 1-2 hours as needed. You must not use more than 15 lozenges in a day.
1. Place one lozenge on the tongue and suck until the taste becomes strong
2. Rest 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)

Participants will receive NRT lozenges immediately after randomisation (i.e. at the same time as varenicline). They will be informed to start the medication (or placebo) soon after they receive it. As with varenicline, participants will receive a Consumer Medicines Information (CMI) sheet highlighting key information about the lozenges including information on how to take the lozenges and some common side effects of which to be aware. A trained Research Assistant will give clear verbal counselling to all participants along with a leaflet clearly stating the dosing regimen, the most common side effects, emergency contact details and information on how to obtain a renewal of their medication.

ADHERENCE
Adherence to study medication will be assessed at each of the follow-ups. The first of these will be one week after the initiation of treatment. A Research Assistant will contact the participants (in hospital for those that are still inpatients or over the phone for participants who have been discharged) and will ask them about their adherence to the study medicines. Adherence will also be assessed over the telephone at 3 weeks from the start of treatment, at three months and six months from treatment initiation by a Research Assistant. Research Assistants involved in the 3 and 6 month follow-up interviews/calls will be blinded to the participants treatment allocation and will be different from the Research Assistants involved in the recruitment/ randomisation phase of the study.

To promote adherence to study medicines participants will be sent automated text messages once a week for the first month of treatment, then once every month. Text messages will be sent by Quitline or by a Research Assistant using the ClickSend system. Text messages will reinforce the importance of adherence to the study medications, long-term abstinence and also contain emergency contact details for the participants. Participants who do not have a cell phone will be called on their land phone by the Research Assistant instead of sending text messages.

QUITLINE
Participants in both arms will be informed about and encouraged to use behavioural support from Quitline as per Quitline standard protocols. Using Quitline support is not a requirement for participation in the study. The number of Quitline calls a participant has made will be recorded during the follow-ups at three and six months from treatment initiation.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Participants in the comparator arm of the study will receive varenicline plus placebo (mint lozenges) for 12 weeks with an additional 12 weeks course of varenicline provided to those needing further support (i.e. 24 weeks in total). Additional mint lozenges will also be offered as requested.

Dosing schedules for varenicline is the same as described for the intervention arm. Participants in the comparator arm will be instructed to take the placebo lozenges in the same manner and dosing frequency as the NRT lozenges in the intervention arm.

Varenicline and placebo lozenges will be provided to participants in the comparator arm immediately after randomisation by a trained Research Assistant as is mentioned above for the intervention arm. All participants will be asked to completely abstain from smoking if possible or at least reduce their smoking over the first seven days of the varenicline course and to aim to quit completely within one to two weeks of starting varenicline. As with the intervention arm, all participants will be given Consumer Medicines Information sheets highlighting key information about the dosing schedule and important adverse effects to be aware of. A trained Research Assistant will give clear verbal counselling to the participants along with a leaflet clearly stating the dosing regimen, the most common adverse events, emergency contact details and information on how to obtain a renewal of their medication.

ADHERENCE
Adherence to study medication will be assessed at each of the follow-ups as with the intervention arm. The four follow-up points are at one and three weeks from the start of treatment and at 3 and 6 months from treatment initiation. As with the intervention arm Research Assistants involved in follow-up calls will be blinded to treatment allocation and will not have been involved in the recruitment/randomisation phase of the participant.

Participants in the comparator arm will receive reminder text messages and Quitline referral as mentioned above for the intervention arm.

Control group

Placebo

Outcomes

Primary outcome [1]

This is defined as a self-report of smoking not more than five cigarettes from the start of the abstinence period, supported by a negative biochemical test at the final follow-up.
A standard abstinence question is: ‘Have you smoked at all since (date of start of abstinence period) A: No, not a puff; B: 1–5 cigarettes; C: More than 5 cigarettes?’. Answer A or B and a negative CO breath test are required for the participant to be classified as abstinent. A participant with CO level less than 10 ppm will be considered abstinent. CO levels will be measured by a trained RA, blinded to treatment allocation, using a hand held piCO+ Smokerlyzer (Bedfont Scientific, Maidstone, Kent, UK) during a hospital or home visit.

Timepoint [1]

6 months from hospital discharge

Secondary outcome [1]

Self-reported continuous abstinence from 2 weeks to 3, 6 and 12 months from treatment initiation. A 2-week period will be allowed on treatment commencement to match the recommendation in the varenicline product information sheet. A standard abstinence question is: ‘Have you smoked at all since (date of start of abstinence period) A: No, not a puff; B: 1–5 cigarettes; C: More than 5 cigarettes?’. Answer A or B is required for the participant to be classified as abstinent.i.e. self-report of smoking abstinence over the whole follow-up period allowing up to five cigarettes.

Timepoint [1]

3, 6 and 12 months from treatment initiation

Secondary outcome [2]

Participant self-reports of withdrawal symptoms and cravings using the Mood and Physical Symptoms Scale (MPSS)

Timepoint [2]

3, 6 and 12 months from treatment initiation

Secondary outcome [3]

Self-report of treatment adherence using the 8-item Tool for Adherence Behaviour Screening (TABS)

Timepoint [3]

3 and 6 months from hospital discharge

Secondary outcome [4]

Adverse events from treatment medications

Below is a list of the possible adverse events caused by varenicline and NRT lozenges (information derived from product information sheets)

VARENICLINE
Common (rate greater than or equal to 1%)
- nausea
- vomiting
- weight gain
- insomnia

Uncommon (greater than or equal to 1/1,000, <1/100)
- mood swings
- restlessness

Rare but serious (greater than or equal to 1/10,000 to <1/1,000))
- thoughts of self-harm
- changes in mood or behaviour

For some people stopping smoking with or without the aid of treatment has been linked to changes in behaviour, mood or thinking e.g. developing suicidal thoughts or anxiety. Some people had these symptoms when they began taking varenicline (Champix), and others developed them after several weeks of treatment or after stopping. It is not known whether these changes are related to Champix, as mood changes can also occur as a result of stopping smoking.

Drinking alcohol while taking varenicline can increase the effects of alcohol. It may also increase the risk of experiencing changes to behaviour, thinking or mood and there have also been reports of increased feelings of being drunk while taking varenicline. Participants will be recommended to avoid drinking alcohol or be careful if drinking alcohol while taking this medicine and consult the Research Assistant or GP if they notice any changes in behaviour, mood or thinking.

NRT LOZENGES
Very Common (>1/10)
- nausea
- hiccups

Common (>1/100; <1/10)
- heartburn
- indigestion
- dry mouth

Uncommon (>1/1000; <1/100)
- excessive thirst
- sore lips

Timepoint [4]

Participants will be encouraged to report adverse events experienced throughout the duration of the trial however, they will be asked to report adverse events directly at the four follow-up time points (at one and three weeks from the start of treatment, three and six months from treatment initiation).

Secondary outcome [5]

Assessment of psychological distress compared to baseline using the Patient Health Questionnaire (PHQ-9)

Timepoint [5]

3, 6 and 12 months from treatment initiation

Secondary outcome [6]

Number of Quitline sessions attended/received
Recorded through Quitline records as well as through the use of data collection forms at each of the follow-ups

Timepoint [6]

3, 6 and 12 months from treatment initiation

Secondary outcome [7]

Other health resources used (e.g. emergency department visits and new medicines tried)
This data will be collected through review of medical records and participant/next of kin self-report with the use of data collection forms

Timepoint [7]

3, 6 and 12 months from treatment initiation

Secondary outcome [8]

Self-reported 7-day point prevalence abstinence - self-report of smoking not even a puff in the past 7 days from the day of follow-up

Timepoint [8]

3, 6 and 12 months from treatment initiation

Secondary outcome [9]

CO verified 7-day point prevalence abstinence for participants who self-report 7-day point prevalence abstinence

Timepoint [9]

6 and 12 months from treatment initiation

Secondary outcome [10]

CO verified continuous abstinence from 2 weeks to 12 months post-treatment initiation for participants who self-report continuous abstinence at this follow-up

Timepoint [10]

12 months from treatment initiation

Eligibility

Key inclusion criteria

Adults aged 18 years or over, admitted to participating hospitals with a history of smoking 10 or more cigarettes per day on average in the four weeks prior to their hospital admission, interested in quitting smoking, willing to use pharmacotherapy and available for 12 months follow-up post-discharge and willing/capable to provide signed informed consent will be eligible for the study. This study will not recruit any outpatient smokers.

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

Patients who do not meet all of the above inclusion criteria, those who have a terminal illness with an anticipated survival of of less than 6 months, those who have an unstable cardiovascular status or a current major psychiatric illness as well as those admitted to outpatient clinics will be excluded from the study. Patients unable to communicate in English and provide written consent will also be excluded due to the potential need to regularly communicate with the investigators during the entire trial period and the lack of funding available for interpreters. Further exclusion criteria for this study are women who are pregnant, breastfeeding or planning to become pregnant in the next 6 months, patients who are current (on the day of hospital admission) users of smoking cessation medications or approaches (i.e. NRT, varenicline, bupropion [Zyban™], clonidine, nortriptyline, electronic nicotine cigarettes), those currently participating in other smoking cessation programs or study, patients who have completed a 12 weeks or longer course of varenicline in the 12 months prior to their hospitalisation, those who have had intolerable adverse reactions from the use of varenicline or NRTs in the past as well as people who have contraindications for their use (including those using medications known to have major interactions with either varenicline or NRT).

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Allocation is concealed

Participants will be randomised (1:1) using a randomisation scheme generated using an independent web-based randomisation system. Random block sizes of two and four will be used to reduce the predictability of treatment allocation. Each site will be provided with 64 opaque envelopes containing the group allocation information. The clinical trials pharmacist will open the envelopes in a sequential manner when a participant is recruited. The 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 along with the envelope. The RA will then hand the medicine to the participant and provide detailed counselling. Participants will not be told whether they are receiving NRT or placebo lozenges.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Permuted block randomisation - Participants will be randomised (1:1) using an independent web-based randomisation system. Random block sizes of two and four will be used to reduce the predictability of treatment allocation. The numbers that are generated through the web-based system will be enclosed in separate envelopes. 64 envelopes will be prepared and distributed to each of the five hospitals. The clinical trials pharmacist will open the envelopes in a sequential manner when a participant is recruited

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data

Intervention assignment

Parallel

Other design features

Phase

Phase 4

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

SAMPLE SIZE
To show a difference of 15% in continuous abstinence between study arms (based on continuous abstinence rate of 23% in varenicline trials) at the 5% level of significance with 80% power, we will need 160 subjects per arm. i.e. 320 participants in total from the five hospitals, 64 subjects from each hospital, 32 in each of the VANISH and varenicline monotherapy arms. The primary analysis will be intention to treat (ITT) and lost to follow-up participants will be regarded as smokers according to the Russel Standard.

DATA ANALYSIS
Data will be stored in a suitable database (e.g. REDCap™, ACCESS™) and exported for analysis in Statistical Package for Social Sciences (SPSS) (version 23.0; IBM, Armonk, NY) and Stata (ver 15, StataCorp, College Station, TX). As recommended by the Russell Standard, all randomised patients will be accounted for in the intention to treat (ITT) analysis. Participants with missing outcomes at follow-up or whose self-reported abstinence was not biochemically validated will be considered as smokers. Sensitivity analyses using multiple imputation methods will also be carried out. Deceased participants will be excluded from analyses. In a supportive analysis of the primary efficacy endpoint, an analysis will also be conducted on the per protocol set, which excludes patients with any major protocol deviations.

Logistic regression analyses will be used to examine the efficacy of intervention on the primary outcome, after testing homogeneity between hospitals using a random effects meta-analysis. In the event of heterogeneity, a more robust model incorporating clustering by hospital will be fitted. The effect of intervention on continuous abstinence at 6 months will be tested in pre-specified subgroups (per hospital, nicotine dependence, highly motivated versus moderately motivated smokers and men versus women) using models fitted for each subgroup containing main effects for intervention and subgroup and an interaction between them. Statistical significance will be considered at a two-sided p value of 0.05.

All randomised participants who take at least one dose of the treatment medications will be included in the safety analysis. A chi-squared test will be done to compare the frequency of treatment withdrawal between the treatment and comparator arms. The number of participants discontinuing treatment prematurely for any reason will be summarised by treatment group and by reasons for discontinuation.

The incidence of all suspected adverse events will be summarised by treatment group under the following categories: type, severity, action taken and outcome. Severity of adverse events will be reported using the CTEAE grading scale (v5.0). The causality of the adverse events will be determined using the Noranjo algorithm.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

1/12/2018

Actual

10/05/2019

Date of last participant enrolment

Anticipated

31/03/2020

Actual

31/05/2021

Date of last data collection

Anticipated

31/03/2021

Actual

8/07/2022

Sample size

Target

320

Accrual to date

Final

320

Recruitment in Australia

Recruitment state(s)

SA,VIC

Recruitment hospital [1]

Barwon Health - Geelong Hospital campus - Geelong

Recruitment hospital [2]

The Queen Elizabeth Hospital - Woodville

Recruitment hospital [3]

Monash Medical Centre - Clayton campus - Clayton

Recruitment hospital [4]

Frankston Hospital - Frankston

Recruitment hospital [5]

Box Hill Hospital - Box Hill

Recruitment postcode(s) [1]

3220 - Geelong

Recruitment postcode(s) [2]

5011 - Woodville

Recruitment postcode(s) [3]

3168 - Clayton

Recruitment postcode(s) [4]

3199 - Frankston

Recruitment postcode(s) [5]

3128 - Box Hill

Funding & Sponsors

Funding source category [1]

Other Collaborative groups

Name [1]

Global Research Awards for Nicotine Dependence

Address [1]

Engage Scientific
Part of the Envision Pharma Group
Envision House, 5 North Street
Horsham, West Sussex RH12 1XQ UK

Country [1]

United States of America

Primary sponsor type

University

Name

Monash University, Faculty of Pharmacy and Pharmaceutical Sciences, Centre for Medicine Use and Safety

Address

Centre for Medicine Use and Safety
381 Royal Parade
Parkville
Victoria 3022

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Barwon Health Human Research Ethics Committee (HREC)

Ethics committee address [1]

Research Ethics, Governance and Integrity (REGI) Unit, Barwon Health
PO Box 281
Geelong VIC 3220

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

31/08/2018

Approval date [1]

15/10/2018

Ethics approval number [1]

18/163

Ethics committee name [2]

Monash Health Human Research Ethics Committee (HREC)

Ethics committee address [2]

Research Support Services
Monash Health
Level 2, I Block
Monash Medical Centre
246 Clayton Road
Clayton, Victoria 3168

Ethics committee country [2]

Australia

Date submitted for ethics approval [2]

16/11/2018

Approval date [2]

15/03/2019

Ethics approval number [2]

RES-18-0000-713A

Summary

Brief summary

Cigarette smoking is one of the leading causes of preventable deaths worldwide. In Australia, in the year 2016 alone, 14,900 Australians died from smoking related illnesses. Various pharmaceutical agents are currently available to assist those trying to quit. Nicotine replacement therapies (NRTs) and varenicline are two such agents. To date, several studies have evaluated the efficacy and safety of NRTs and varenicline for smoking cessation. Evidence surrounding their use in combination is limited to the use of NRT patches with varenicline. The efficacy and safety of varenicline in combination with short-acting forms of NRT (such as lozenges) is yet to be known. This research project, therefore, aims to evaluate the efficacy and safety of this combination treatment.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Johnson George

Address

Monash University (Parkville campus)
Faculty of Pharmacy and Pharmaceutical Sciences
Centre for Medicine Use and Safety
381 Royal Parade
Parkville
Victoria 3022

Country

Australia

Phone

+61 3 9903 9178

Fax

+61 3 9903 9629

[email protected]

Contact person for public queries

Name

Miss Rukshar Gobarani

Address

Monash University (Parkville campus)
Faculty of Pharmacy and Pharmaceutical Sciences
Centre for Medicine Use and Safety
381 Royal Parade
Parkville
Victoria 3022

Country

Australia

Phone

+61 403 477 524

Fax

[email protected]

Contact person for scientific queries

Name

Dr Johnson George

Address

Monash University (Parkville campus)
Faculty of Pharmacy and Pharmaceutical Sciences
Centre for Medicine Use and Safety
381 Royal Parade
Parkville
Victoria 3022

Country

Australia

Phone

+61 3 9903 9178

Fax

+61 3 9903 9629

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

Yes

What data in particular will be shared?

The type of data that will be made available will be at the discretion of the chief investigator and will be in a de-identifiable form

When will data be available (start and end dates)?

The dates/ proposed time frames have not been determined

Available to whom?

IPD will be available on a case-by-case basis at the discretion of the chief investigator of the trial and based on an appropriate research question/proposal that has received ethics approval

Available for what types of analyses?

The types of analyses for which IPD will be available will be on a case-by-case basis and at the discretion of the Chief investigator of the study

How or where can data be obtained?

Access will be subject to approval by Chief investigator of the study Dr. Johnson George. Dr. George can be contacted by email: [email protected]

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
32	Study protocol					375941-(Uploaded-28-01-2020-22-55-44)-Study-related document.docx

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Source	Title	Year of Publication	DOI
Embase	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.	2020	https://dx.doi.org/10.1136/bmjopen-2020-038184

N.B. These documents automatically identified may not have been verified by the study sponsor.

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