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Trial registered on ANZCTR

Registration number

ACTRN12616001355460

Ethics application status

Approved

Date submitted

22/09/2016

Date registered

29/09/2016

Date last updated

24/06/2021

Date data sharing statement initially provided

24/06/2021

Type of registration

Prospectively registered

Titles & IDs

Public title

Varenicline alone or with nicotine e-cigarettes for smoking cessation in people with mental illness and drug and/or alcohol dependence.

Scientific title

A randomised controlled clinical trial to evaluate the effectiveness and safety of combining varenicline with nicotine e-cigarettes on smoking abstinence in people with co-existing mental health and drug and alcohol dependence conditions.

Secondary ID [1]

None

Universal Trial Number (UTN)

U1111-1186-7693

Trial acronym

STATUS

Linked study record

Health condition

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

Smoking

Mental illness

Drug and alcohol dependence

Condition category

Condition code

Mental Health

Addiction

Mental Health

Other mental health disorders

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

All participants will receive behavioural support phone calls of around 10 minutes duration, twice weekly, delivered by trained research assistants, for the first 6 weeks after randomisation. The calls will follow a standard format and content that includes encouragement to stay abstinent, avoid cues to relapse, tips for dealing with cravings and so on.

Varenicline tartrate 0.5 mg and 1 mg tablets (Pfizer); taken orally twice daily following a 2-week up-titration: Days 1 – 3: 0.5 mg once daily; Days 4 – 7: 0.5 mg twice daily; Day 8 –14 :1 mg twice daily. Day 15 (randomisation date) - end of Week 10: 1 mg twice daily.

PLUS
E-cigarettes with nicotine, inhaled ad libitum, 18 mg (Joyetch AOI starter kit, NZVAPOR, e-liquid from NZVAPOR) commencing on Day 1 for 10 weeks after randomisation.

Adherence will be assessed by direct enquiry by research assistants at the 6 week call and when participants return to the clinic for dispensing further supplies they will be asked to bring their medication packs for checking by the pharmacist or research assistants.

Intervention code [1]

Treatment: Drugs

Intervention code [2]

Behaviour

Comparator / control treatment

Varenicline tartrate 0.5 mg and 1 mg tablets (Pfizer); taken orally twice daily following a 1-week up-titration: Days 1 – 3: 0.5 mg once daily; Days 4 – 7: 0.5 mg twice daily; Day 8 – Day 14: 1 mg twice daily; Day 15 (randomisation day) -end of week 10: 1 mg twice daily.

Behavioural support will be offered to participants in this group>

Control group

Active

Outcomes

Primary outcome [1]

The proportion of participants that report continuous smoking abstinence verified by an exhaled breath carbon monoxide (CO) measure of <10 ppm.

Timepoint [1]

24 weeks after randomisation

Secondary outcome [1]

The proportion of participants that report 7-day point prevalence abstinence verified by an exhaled breath carbon monoxide (CO) measure of <10 ppm

Timepoint [1]

24 weeks after randomisation

Secondary outcome [2]

The proportion of participants that report 7 day point prevalence abstinence verified by an exhaled breath carbon monoxide (CO) measure of <10 ppm.

Timepoint [2]

6 weeks after randomisation

Secondary outcome [3]

The proportion of participants that report 7 day point prevalence abstinence verified by an exhaled breath carbon monoxide (CO) measure of <10 ppm.

Timepoint [3]

12 weeks after randomisation

Secondary outcome [4]

The proportion of participants that report continuous abstinence

Timepoint [4]

6 weeks after randomisation

Secondary outcome [5]

The proportion of participants that report continuous abstinence

Timepoint [5]

12 weeks after randomisation

Secondary outcome [6]

The proportion of participants that report adverse events (defined as any adverse health event whether or not it has a plausible association with the study products, such as nausea), as reported by participants when asked by research assistants, and their severity (mild, moderate or severe), frequency (single, intermittent or continuous), outcome (resolved, ongoing, death, unknown), relationship with the study medication (definitely, probably, possibly, not related)

Timepoint [6]

6 weeks after randomisation

Secondary outcome [7]

Timepoint [7]

12 weeks after randomisation

Secondary outcome [8]

Timepoint [8]

24 weeks after randomisation

Eligibility

Key inclusion criteria

*currently live in the Auckland region
*are registered clients with Community Mental Health Services or Community Alcohol and Drug Services
*smoke cigarettes daily
*want to quit smoking
*are at least 18 years of age
*are able to provide written informed consent
*have access to a telephone (mobile and/or landline)
*are prepared to use varenicline alone or with e-cigarettes
*have tried to quit at least twice before with nicotine replacement therapy (NRT), and thus are eligible for special authority varenicline

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

*are pregnant or breastfeeding.
*are current users of other smoking cessation medications.
*are enrolled in a smoking cessation programme or another cessation research study.
*have used an e-cigarette for more than one week in the last year for smoking cessation.
*have contraindications for varenicline or nicotine e-cigarettes.
*another person in their household is already in the trial.

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)

Central computer randomisation

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

Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Parallel

Other design features

There will be run in period of two weeks as participants titrate up varenicline to full strength during which time they are expected to quit or if not, cut down smoking. Those who quit or have cut down by at least half (compared with baseline) by the end of the two weeks are not followed up further. Only those who fail to cut down by at least 50% are randomised into one of the 2 arms.

Phase

Phase 3

Type of endpoint/s

Efficacy

Statistical methods / analysis

This sample size of 338 (169 in each arm) anticipates a 30% loss-to-follow-up and will confer 80% power, 2-sided p=0.05 to detect an absolute difference of 15% between the varenicline plus e-cigarette group and varenicline alone group in 24 week carbon monoxide verified abstinence rates, with a predicted abstinence rate in the varenicline plus e-cigarette group of 30%.

All data analyses will be carried out on an intention-to-treat (ITT) basis in which participant outcome data are analysed according to the group to which they were allocated at randomisation. Simple incidence rates, relative risks, absolute risks and the 95% confidence intervals around these estimates will be obtained for all binary variables, and multiple logistic regression analysis adjusting for other variables simultaneously will also be conducted. Continuous data will be analysed using multiple linear regression modelling or non-parametric analysis. Standard sensitivity analyses will be undertaken including per protocol analysis. Cost analyses will include calculating the cost per quitter and the incremental cost effectiveness ratio and incremental cost utility ratio.

Recruitment

Recruitment status

Stopped early

Data analysis

Data analysis is complete

Reason for early stopping/withdrawal

Participant recruitment difficulties

Date of first participant enrolment

Anticipated

1/02/2017

Actual

24/07/2017

Date of last participant enrolment

Anticipated

3/08/2018

Actual

26/07/2018

Date of last data collection

Anticipated

28/02/2019

Actual

15/03/2019

Sample size

Target

338

Accrual to date

Final

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Auckland

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

Health Research Council

Address [1]

Health Research Council of New Zealand, PO Box 5541, Wellesley St, Auckland 1141,

Country [1]

New Zealand

Primary sponsor type

University

Name

The University of Auckland

Address

Private Bag 92019, Victoria Street West, Auckland 1142

Country

New Zealand

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Health and Disability Ethics Committee, Southern

Ethics committee address [1]

Ministry of Health
PO Box 5013, Wellington 6011

Ethics committee country [1]

New Zealand

Date submitted for ethics approval [1]

14/09/2016

Approval date [1]

07/11/2016

Ethics approval number [1]

16/STH/153

Summary

Brief summary

People with mental illnesses or alcohol and/or other drug addictions are a group that needs to quit smoking: smoking prevalence is high among this population. They also have a high burden of tobacco-related illness. Current cessation treatments adopt a ‘one size fits all’ approach, overlooking considerable between-person variation in response to medication: the one third of smokers who reduce the amount they smoke by at least 50% (‘responders’) during the first two weeks after starting varenicline or nicotine replacement treatment (NRT) are 2.5 times more likely to quit smoking than those who do not (‘non-responders’). Trials (total N=557) showed NRT non-responders without a dual diagnosis can experience quit rates at 6 months identical to NRT responders by switching to varenicline or adding bupropion to NRT. Combining varenicline with either bupropion or NRT increased quit rates over varenicline alone, whilst the efficacy of nicotine e-cigarettes may be enhanced when used in addition to varenicline. These approaches to treatment have neither been integrated nor trialed among people with a dual diagnosis who are varenicline non-responders (a group with great opportunity to benefit should such simple changes to the use of available treatments lead to improved cessation efficacy).
Aims : To determine whether adding a nicotine e-cigarette to varenicline plus behavioural support improves 6 month smoking cessation outcomes, relative to remaining on varenicline alone plus behavioural support, in people with a dual diagnosis who are varenicline non-responders.
Design: An open label, pragmatic 3 arm, randomised controlled trial with the study population adult (18 years and older) outpatients currently receiving treatment who want to stop smoking. Exclusion criteria: contra-indications to trial medications and uncontrolled dual diagnosis symptoms (assessed by case doctor). Interventions: Participants will be prescribed varenicline by their case doctor, and receive telephone behavioural support from smoking cessation specialists for 2 weeks; those reporting a reduction in baseline cigarettes smoked per day of >50% by day 14 will continue on varenicline with referral to local cessation services. Varenicline non-responders will be randomised to one of 2 treatment arms for 12 weeks: 1) varenicline + nicotine e-cigarette; 2) varenicline only. All participants will set a target quit date for 2 weeks later and receive 6 more support calls over the next 6 weeks; the primary outcome will be measured at 24 weeks after randomisation.

Trial website

www.https://status.nihi.auckland.ac.nz

Trial related presentations / publications

Bullen et al. The effectiveness and safety of combining
varenicline with nicotine e-cigarettes for
smoking cessation in people with mental
illnesses and addictions: study protocol for
a randomised-controlled trial. BMC Public Health (2018) 18:596
https://doi.org/10.1186/s12889-018-5351-7

Public notes

Contacts

Principal investigator

Name

Prof Chris Bullen

Address

National Institute for Health Innovation
School of Population Health
The University of Auckland
Private Bag 92019
Auckland Mail Centre
Auckland 1142
New Zealand

Country

New Zealand

Phone

+6493737599

Fax

+6493731710

[email protected]

Contact person for public queries

Name

Chris Bullen

Address

National Institute for Health Innovation
School of Population Health
The University of Auckland
Private Bag 92019
Auckland Mail Centre
Auckland 1142
New Zealand

Country

New Zealand

Phone

+64937373599

Fax

+6493731710

[email protected]

Contact person for scientific queries

Name

Chris Bullen

Address

National Institute for Health Innovation
School of Population Health
The University of Auckland
Private Bag 92019
Auckland Mail Centre
Auckland 1142
New Zealand

Country

New Zealand

Phone

+64937373599

Fax

+6493731710

[email protected]

Data sharing statement

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

No/undecided IPD sharing reason/comment

Consent for this was not specifically obtained from participants. A special request would have to be made to the Ethics Committee. However, the datasets analysed during the current study are available from the corresponding PI on reasonable request.

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
12247	Study protocol	Bullen C, Verbiest M, Galea-Singer S, Kurdziel T, Laking G, Newcombe D, Parag V, Walker N. The effectiveness and safety of combining varenicline with nicotine e-cigarettes for smoking cessation in people with mental illnesses and addictions: study protocol for a randomised-controlled trial. BMC Public Health. 2018 May 4;18(1):596. doi: 10.1186/s12889-018-5351-7. PMID: 29728074; PMCID: PMC5935940.			The Consent form is available as an additional fil... [More Details]
12248	Informed consent form	Bullen C, Verbiest M, Galea-Singer S, Kurdziel T, Laking G, Newcombe D, Parag V, Walker N. The effectiveness and safety of combining varenicline with nicotine e-cigarettes for smoking cessation in people with mental illnesses and addictions: study protocol for a randomised-controlled trial. BMC Public Health. 2018 May 4;18(1):596. doi: 10.1186/s12889-018-5351-7. PMID: 29728074; PMCID: PMC5935940.

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