Contemporary Clinical Trials 38 (2014) 304–313

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Contemporary Clinical Trials

journal homepage: www.elsevier.com/locate/conclintrial

Flexible and extended dosing of nicotine replacement therapy

or varenicline in comparison to fixed dose nicotine
replacement therapy for smoking cessation: Rationale,
methods and participant characteristics of the FLEX trial
Heather Tulloch a,⁎, Andrew Pipe a, Charl Els b, Debbie Aitken a, Matthew Clyde a,d,
Brigitte Corran a,c, Robert D. Reid a
a
Division of Prevention and Rehabilitation, University of Ottawa Heart Institute, Ottawa, ON, Canada
b
Department of Psychiatry, University of Alberta, Edmonton, AB, Canada
c
Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
d
School of Psychology, University of Ottawa, Ottawa, ON, Canada

a r t i c l e i n f o a b s t r a c t

Article history: Quitting smoking is the single most effective strategy to reduce morbidity and premature
Received 28 February 2014 mortality in smokers. Research has demonstrated the effectiveness of pharmacotherapy in
Received in revised form 13 May 2014 smoking cessation, but few studies have directly compared varenicline and monotherapy
Accepted 16 May 2014 nicotine replacement therapy (NRT) and none have examined varenicline and combinations
Available online 23 May 2014
of NRT products. The majority of smoking cessation trials involve carefully circumscribed
populations, making their results less generalizable to those with severe medical conditions or
Keywords: psychiatric comorbidities. This paper reports on the rationale, methodology and participant
Smoking cessation characteristics of a randomized controlled trial designed to: (1) determine which pharmaco-
RCT
therapy – NRT, long term combinations of NRT, or varenicline – is most effective in achieving
Intervention
abstinence; (2) investigate the incidence of neuropsychiatric symptoms among participants over
Psychiatric symptoms
Comorbidities the course of their quit attempt; and (3) assess whether there is a significant difference in the
incidence of neuropsychiatric symptoms in those receiving differing pharmacotherapies, and
between those with and without psychiatric illnesses. The primary outcome was carbon monoxide
confirmed abstinence from weeks 5–52 following a target quit date. Secondary outcomes included
neuropsychiatric (i.e., depression, suicidal ideation, anxiety, anger) and withdrawal symptoms.
Smokers (N = 737) were randomly assigned to one of three treatment conditions, and were
scheduled to attend 8 follow-up appointments over 12 months. All participants received
6–15 minute practical counseling sessions with nurse counselors experienced in treating tobacco
dependence. We expect that the results will lead to an enhanced understanding of the efficacy of
these pharmacotherapies, including those with a history of psychiatric illness.
© 2014 Elsevier Inc. All rights reserved.

1. Introduction

It is well established that smoking leads to multiple ad-

⁎ Corresponding author at: Division of Prevention and Rehabilitation, University
of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, ON, K1Y 4W7, Canada.
E-mail address: hetulloch@ottawaheart.ca (H. Tulloch).
verse health outcomes, and that quitting smoking dramati-
cally reduces the risk of morbidity and premature mortality.
Despite this knowledge, and given the highly addictive nature
of nicotine, smoking remains prevalent; an estimated quarter

http://dx.doi.org/10.1016/j.cct.2014.05.011
1551-7144/© 2014 Elsevier Inc. All rights reserved.

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 H. Tulloch et al. / Contemporary Clinical Trials 38 (2014) 304–313
to a third of the world's population aged 15 years and older
consumes tobacco on a daily basis [1,2]. Prevalence rates in
the United States and Canada have decreased since the 1990's,
but continue to hover just under 20% [3].
Without intervention, most smokers are unsuccessful in
their quit attempts; only 3–5% of smokers quitting “cold-turkey”
remain abstinent [4]. To enhance the likelihood of cessation
and to prevent relapse, smokers need help in the control
and management of withdrawal symptoms. Currently available
first-line pharmacological treatments include various formula-
tions of nicotine replacement therapy (NRT), sustained-release
buproprion, and varenicline. Reviews of research have shown
that these treatments are effective in assisting smokers in
their cessation attempts [5,6], and indirect comparisons from
meta-analyses have favored a combination of NRT products and
varenicline [5–7]. Yet, conclusions from meta-analyses may
conflict with large trials with direct comparisons due to hetero-
geneity across studies [8,9]. Of late, many studies have directly
compared NRT and varenicline to placebo; few studies have
compared monotherapy NRT to combined NRT [5–7,9] or
varenicline to monotherapy NRT [10,11], and no head-to-head
comparisons of varenicline and a combination of NRT products
have been reported to date. Without more direct evidence of the
relative effectiveness of these pharmacotherapies, clinicians and
smokers are unable to select the most appropriate treatment.
Previous efficacy investigations have been conducted with
restricted populations, often excluding those with severe health
conditions and/or psychiatric comorbidities. These restrictions
substantially limit the generalizability of the findings to popu-
lations living with these comorbidities who might benefit most
from cessation efforts. For example, cardiac patients who may
gain immediate benefits from quitting are often deemed
ineligible for participation in smoking cessation research due
to concerns of potential adverse events. In fact, only 2 RCTs
investigating varenicline prescribed to patients with active
cardiovascular disease have been published [12,13]. Similarly,
only one study exists that evaluates the effect of varenicline in
COPD patients [14]. More research assessing the applicability
and effectiveness of pharmacological treatments for smoking
cessation among patients with chronic conditions is warranted.
When RCTs do include psychiatric patients, certain limita-
tions have been evident. These studies often have small samples
sizes drawn from specific psychiatric populations, tend to
employ cross-sectional rather than longitudinal designs, and
typically use symptom checklists rather than an assessment
of psychiatric diagnoses. A lack of data is especially evident
for trials with varenicline: Only 6 RCTs have been published,
3 of which included less than 50 smokers [15–20]. Our trial
is the first to concurrently assess and compare the efficacy of
varenicline and NRT in participants with and without psychi-
atric illness.
As noted above, concerns regarding the safety and tolerance
of pharmacotherapy for smoking cessation have arisen in
the past. Population-based studies and clinical databases have
provided initial reassurance that these medications do not
lead to a worsening in neuropsychiatric symptoms including
depression, suicidal ideation, or psychiatric hospital admissions
[21–23]. In addition, a recent review of 17 placebo-controlled
RCTs of varenicline conducted by Pfizer concluded that the
rate of suicidal events, depression and aggression/agitation did
not increase with the use of varenicline at 30–60 days follow
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305
up [24]. Yet, to date, no study has measured the presence
or accentuation of neuropsychiatric symptoms at multiple
time points from baseline to long-term follow-up (i.e., 1 year)
during a treated quit attempt. Given the importance of smoking
cessation for overall health, further investigations are required
to improve our knowledge of the efficacy, safety and reach of
smoking cessation treatments.
The primary objective of our trial was to determine which
pharmacotherapy is most effective in achieving cessation: NRT,
long-term combination of NRT or varenicline. The secondary
objectives were to determine the incidence of neuropsychiatric
symptoms among participants during their cessation attempt,
and to assess whether there is a significant difference in the
prevalence of these symptoms in participants receiving differing
pharmacotherapies and in those with and without psychiatric
illnesses. In this paper, we describe the study design, method-
ology, and the baseline characteristics of the sample.
2. Methods
2.1. Design
This study used a parallel, three-group, pre- and post-test
experimental design conducted at a single site. Participants
were randomly assigned to one of three treatment conditions:
1) transdermal NRT (NRT), 2) long-term transdermal NRT and
other NRT formulations (NRT+), and 3) varenicline (VR). All
groups received smoking cessation medication at no cost and
six 15-minute counseling sessions from a nurse-counselor
experienced in tobacco dependence treatment. All sessions
occurred at the University of Ottawa Heart Institute (UOHI), a
cardiac care hospital, and coincided with medication distri-
bution and questionnaire completion. The CONSORT diagram
including the study flow is shown in Fig. 1.
2.2. Selection of participants
Recruitment began in June 2010 and was completed in
March 2013. The primary sources of recruitment included media
announcements (i.e. radio, local newspaper, and posters), the
Quit Smoking Program at the UOHI, local physicians, and word
of mouth referrals. Individuals interested in participating in the
study contacted the research coordinator for more information
and were screened for eligibility by phone (Table 1). If eligible,
a baseline visit was scheduled, at which time the research
coordinator further explained the study protocol and ob-
tained informed consent. This study received approval from
the Ottawa Health Sciences Network Research Ethics Board and
was registered on Clinical Trials.gov (identifier # NCT01623505).
2.3. Protocol
2.3.1. Baseline assessment and randomization
After informed consent was obtained, participants com-
pleted questionnaires that assessed demographic informa-
tion, smoking status and history, nicotine dependence,
and withdrawal and neuropsychiatric symptoms. The study
nurses reviewed the participants' medical history and ob-
tained their physician and/or psychiatrist's (if applicable)
contact information. An assessment of previous and current
psychiatric diagnoses was performed by graduate students
306 H. Tulloch et al. / Contemporary Clinical Trials 38 (2014) 304–313
Fig. 1. CONSORT diagram: RWT screening, enrollment, and follow-up.
Table 1
Inclusion and exclusion criteria.
Inclusion criteria
1. Be a current smoker (≥10 cigarettes smoked per day over the
preceding 6 months).
2. Participant is willing to make a quit attempt within 2–4 weeks after
initial screening.
3. Participant is 18 years of age and older.
4. Participant is willing and able to provide informed consent.
Exclusion criteria
1. Participant is currently using or has used any intervention medication
(i.e. varenicline, nicotine replacement therapy (patch, gum, inhaler,
lozenge) in the previous month for more than 72 consecutive hours.
2. Participant has contraindication(s) to any of the following cessation
medications:
• NRT – allergic reaction to adhesive; serious cardiac arrhythmias (e.g.
tachycardia); participant is within the immediate post-myocardial
infarction period (i.e. incident has occurred within last 10 days);
severe or worsening angina pectoris; participant has had a recent
cerebral vascular accident;
• Varenicline – end-stage renal disease; use of cimetidine (by participants
with severe renal impairment); previous allergic reaction to varenicline.
3. Pregnant or breastfeeding women or those intending to become
pregnant within the next year.
4. Current or previous (past 3 months) substance abuse.
5. Unable to provide informed consent due to unstable psychiatric
symptoms (e.g. active, untreated psychosis or suicidality).
6. Participant is unable to read/write and understand English or French
7. In order to prevent contamination, only one person per household
may participate.
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in clinical psychology supervised by the study psychologist
(HT) using the Mini International Neuropsychiatric Interview
6.0.0 (M.I.N.I. 6.0.0). Participants with previous or current
psychiatric diagnoses were categorized as Psychiatric “yes”
(PY), while those with no psychiatric history were catego-
rized as Psychiatric “no” (PN). Female participants provided
a urine sample to determine pregnancy status. Participants
were then randomized to one of the three treatment
conditions: NRT, NRT +, or VR. Randomization was stratified
by psychiatric illness (PY/PN); block sizes varied from 6 to 12.
The randomization sequence was generated using a com-
puter generated algorithm in Statistical Analysis Software
(SAS program) by a researcher not involved in the study
and blinded to the identity of participants. Randomization
numbers were placed in opaque, sealed, and consecutively
numbered envelopes and opened following the completion of
the baseline data collection. To easily identify the appropriate
envelop for stratification purposes, envelopes were color
coded (white/brown for PY/PN, respectively). All participants
then received a 15-minute counseling session from a nurse-
counselor trained in tobacco dependence treatment. This
session focused on information regarding the smoking cessa-
tion medication, setting a target quit date (within 2 weeks of
baseline assessment), and identifying and problem solving
around triggers to smoke. Medications were then dispensed
and all follow-up appointments were scheduled. Details re-
garding the pharmacotherapy and behavioral interventions are
described in detail below.
 H. Tulloch et al. / Contemporary Clinical Trials 38 (2014) 304–313
After baseline assessment, a letter was sent to each
participant's family physician and/or psychiatrist advising
them of their patient's involvement in the study, the group to
which they were allocated and the prescribed medication
dosage, as well as any current psychiatric diagnoses based
on the results of their M.I.N.I. 6.0.0. Participants who did not
have a family physician were provided with a referral list of
family physicians in their community. Medical oversight of
the study was provided by the qualified medical investigator
(AP). Throughout participants' involvement in the study,
physicians were also alerted to any elevated scores (≥20)
obtained on the Beck Depression Inventory-2 [25].
2.3.2. Smoking cessation interventions
2.3.2.1. Behavioural counselling interventions. All participants
received six 15-minute counseling sessions from experienced
nurse-counselors in accordance with current Clinical Practice
Guidelines [26]. A description of the nurses' training is
presented below. Counseling sessions focused on practical
counseling and strategic advice (e.g., problem solving, skills
training, behavioral activities to cope with urges), motiva-
tional interviewing, social support, and relapse prevention.
Important key success indicators (e.g., motivation, confi-
dence, withdrawal symptoms) were assessed to support the
counseling sessions. The number and length of sessions were
based on the recommendations from the most recent Clinical
Practice Guidelines [26] which concluded that 4–8 sessions
are most advantageous, and that optimal total contact time is
31–90 minutes. We felt it necessary to structure the interven-
tion so as to be feasible in primary care and other clinical
settings; therefore, six 15-minutes sessions were decided upon
(90 minutes total). Counseling sessions were completed at
the baseline assessment (2 weeks pre-target quit date), and 1,
3, 5, 8, and 10 weeks post-target quit date. Participants also
received self-help materials, including information about the
pharmacotherapy they had been prescribed, a booklet for
smoking cessation [27], information on the benefits of quitting,
tips to prepare for a quit date, things to expect when quitting
(e.g., sensitivity to caffeine), strategies to manage cravings (e.g.,
4-D's – delay, drink water, distract, deep breaths), a “coping
with stress” booklet [28] and the phone number of the local
mental health distress line.
2.3.2.2. Nurse training. All RWT nurses were employed with
the UOHI Quit Smoking Program, and were required to
possess a Bachelor of Nursing Degree, to be a member of the
College of Nurses of Ontario, and demonstrate knowledge
in health education, health promotion, and behavior change
strategies. The nurses received training in tobacco dependence
treatment from the Clinical Nurse Manager of the UOHI Quit
Smoking Program (DA), leaders of the Ottawa Model for
Smoking Cessation (OMSC; www.ottawamodel.ca) [29] and
the Training Enhancement in Applied Counselling and Health
(TEACH; www.nicotinedependenceclinic.com) training offered
at the Centre for Addiction and Mental Health. Nurse training
also included a review of the product monographs and medical
directives, motivational interviewing, and relevant readings
[30]. Nurses initially shadowed the Clinical Manager or senior
staff during interventions with smokers, and were directly
observed and received corrective feedback when providing the
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307
smoking cessation counseling. The eight nurses involved in the
study received specific protocol training from the RWT principal
investigator (HT), qualified medical investigator (AP), and
research coordinator. Mandatory institutional research ethics
training was also completed. During the intervention period,
regular nursing meetings were held to ensure adherence to the
protocol and for discussions of patient-related issues.
2.3.2.3. Pharmacological interventions. All medications were
prescribed open label, however, the research coordinator
who gathered the 6 and 12-month follow-up data was blind
to treatment condition.
2.3.2.3.1. NRT group. The NRT group received a 10-week
supply of NRT transdermal patches (Nicoderm®). Participants
applied the first patch on their target quit date. The initial dosage
was determined from the average number of cigarettes smoked
each day. Participants smoking ≥20 cigarettes per day were
prescribed 21 mg/24 hours for 6 weeks, 14 mg/24 hours for
2 weeks, and 7 mg/24 hours for 2 weeks. Participants smoking
10–19 cigarettes per day were prescribed 14 mg/24 hours for
6 weeks, and 7 mg/24 hours for 4 weeks.
2.3.2.3.2. NRT + group. Participants in the NRT + group
followed the same regimen as the NRT group, but were not
limited to a fixed dosing strategy, nor limited to a 10-week
treatment duration. They were advised about the putative
advantages of titrating NRT to ensure the elimination of
withdrawal symptoms, with a maximum dosage from patches
of 35 mg/day for up to 22 weeks. Participants were also
provided with NRT gum or inhaler to help manage cravings.
If patients scored in the moderate to severe range on items
of the Minnesota Withdrawal Scale (i.e., N2), or if they
expressed significant cravings to the nurse, they were
advised to increase the dosage of NRT, either with patches
or gum/inhaler.
2.3.2.3.3. VR group. Participants started varenicline on the
day of their baseline assessment and set a target quit date any
time within the 8–14 day period after baseline. Participants
were prescribed 0.5 mg once daily for 3 days, 0.5 mg twice
daily for 4 days, and 1 mg twice daily for 11 weeks. Partic-
ipants in the VR group received a 12-week supply of this
medication. In consultation with the study nurse at the week
10 counseling session (i.e., 12 weeks of varenicline usage),
participants were given the option of extending their treat-
ment to a maximum of 24 weeks.
2.3.3. Treatment-phase assessments and follow-ups
At weeks 1, 3, 5, 8, 10, 22, and 52 post-target quit date,
all participants completed questionnaires measuring with-
drawal and neuropsychiatric symptoms, had their smoking
status assessed (self-reported continuous abstinence con-
firmed by CO monitoring), and adverse events and the use of
cessation resources not offered by the study (e.g., smokers quit
lines) were recorded. Participants who were unable to return
on-site for their follow-up visits were sent the questionnaires
by mail and, for non-smokers, validation of smoking status was
obtained at an off-site appointment (i.e., home or community).
3. Measurements
The timeline of all measurements is displayed in Table 2.
308 H. Tulloch et al. / Contemporary Clinical Trials 38 (2014) 304–313

Table 2
Overview of the study schedule.

Procedure Initial Screen Week-2 BL Week 0 TQD Week 1 Week 3 Week 5 Week 8 Week 10 Week 22 Week 52

Eligibility criteria ✓ ✓
Informed consent ✓
Demographics ✓
Medical history ✓
Smoking status ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓
Smoking history ✓
CO monitoring ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓
Fagerström Test for Nicotine Dependence ✓
MINI Plus (past & current psychiatric ✓
diagnoses)
Beck Depression Inventory (BDI-II) ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓
State-Trait Anxiety Inventory (STAI) ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓
State-Trait Anger Expression Inventory ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓
(STAXI)
Withdrawal symptoms (MNWS) ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓
Randomization ✓
Dispense medications ✓ ✓ ✓ ✓ ✓
Counselling session ✓ ✓ ✓ ✓ ✓ ✓
VR group starts medication ✓
NRT groups start medication ✓
Use of cessation resources ✓ ✓ ✓ ✓ ✓ ✓ ✓

BL = Baseline assessment; TQD = Target quit date.

3.1. Demographic information and medical history 3.2.3. Nicotine dependence

Participants reported their age, gender, ethnicity, marital
and employment status, education level and income. The
study nurse obtained participants' self-reported medical history
(e.g., cardiovascular, respiratory, endocrine, cancer, chronic
pain) and current medications.
3.2. Smoking-related variables
3.2.1. Smoking status
The primary outcome of the study was carbon monoxide
(CO) confirmed continuous abstinence from weeks 5 to
52 following the target quit date. Continuous abstinence from
5 to 10 and 5 to 22 weeks post-target quit date was also
collected. Based on the Russell Standard [31], participants
were defined as non-smokers if they smoked 5 cigarettes or
less over the designated period. For non-smokers, abstinence
was confirmed by an expired CO reading of ≤ 9 ppm at 5, 10,
22, and 52 weeks [31]. For a participant to be considered
a non-smoker for the 5–52 week period, s/he would have
smoked a maximum of 5 cigarettes from week 5 to 52, and had a
CO reading of ≤9 ppm at the 52-week follow-up appointment.
CO readings at previous assessments were not considered.
Drop-outs and participants lost to follow up were considered
smokers for the purpose of outcome analyses. At each follow-up
visit, participants reported if they had smoked any cigarettes
(even a puff) in the last 7 days to obtain their 7-day point
prevalence rate.
3.2.2. Smoking history
Smoking history assessed at baseline included: the age of
onset of smoking, number of years as a daily smoker, number
of previous quit attempts, and number of cigarettes smoked
per day.
The participant's level of nicotine dependence was mea-
sured at baseline using the Fagerström Test for Nicotine
Dependence [32]. Scores for this 6-item questionnaire range
from 0 to 10. Scores ≥6 indicate a high degree of nicotine
dependence. The test–retest coefficient is N0.80 and the
validity of the scale has been well established using cotinine,
number of years smoked, and the “addictive” factor on the
Classification of Smoking by Motives questionnaire as criterion
variables [33].
3.3. Neuropsychiatric symptoms
Incidence of neuropsychiatric symptoms was assessed
with the measures below.
3.3.1. Depression/suicidal ideation
The Beck Depression Inventory-II (BDI-II) assessed the
intensity of depressive symptoms, including suicidal ideation,
over the preceding 2 weeks. This 21-item scale is a widely
used, psychometrically sound self-administered questionnaire
[25]. Internal consistency is high (α = .92) and content validity
has been established with the Diagnostic and Statistical Manual
of Mental Disorders (DSM-IV). A total score was calculated by
summing the participant's responses to all items. Scores from
0–13 indicate minimal depression, 14–19 indicate mild depres-
sion, 20–28 indicate moderate depression, and 29–63 indicate
severe depression.
3.3.2. Anxiety
The State-Trait Anxiety Inventory (STAI) was used to
measure participants' severity of anxiety. This self-report
scale measures state and trait anxiety on a 4 point scale.
Participants indicated their level of anxiety “right now”, “at
this moment” and “generally”. Raw scores were converted
into percentiles and normalized t-scores with a mean of

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 H. Tulloch et al. / Contemporary Clinical Trials 38 (2014) 304–313
50 and a SD of 10 (N60 is considered clinically elevated). This
questionnaire has strong psychometric properties [34].
3.3.3. Anger/aggression
The State-Trait Anger Expression Inventory-2 (STAXI-2)
assessed the participants' intensity (1–4 Likert scale) of angry
feelings and actions “in general”, “right now”, as well as how
they react or behave when angry. This questionnaire has strong
psychometric properties [35]. Raw scores were converted into
percentiles and normalized T-scores with a mean of 50 and
SD of 10.
3.3.4. Withdrawal symptoms
The Minnesota Nicotine Withdrawal Scale [36] assessed
withdrawal symptoms within the previous 24 hours (e.g., urge
to smoke, psychological distress, concentration, restlessness,
increased appetite, insomnia). Participants indicated on a
5-point scale (0 = none, 4 = severe) the severity of symp-
toms experienced. Evidence of the validity and reliability of the
MNWS has been obtained [37].
3.4. Past and/or current psychiatric diagnoses
Previous and current psychiatric illnesses were assessed
at baseline with the Mini International Neuropsychiatric
Interview 6.0.0 (M.I.N.I.) [38]. The M.I.N.I. 6.0.0 is a structured
diagnostic interview designed to evaluate psychiatric disor-
ders from the DSM-IV and International Classification of
Diseases (ICD-10). The M.I.N.I. 6.0.0 has been shown to have
high validation and reliability scores when compared to other
structured interviews assessing DSM diagnoses [39].
3.5. Use of cessation resources
Participants reported if they have used various forms
of pharmacotherapies, smoking cessation aids, or counseling
(e.g., individual, group, helpline) for smoking cessation since
their last visit.
3.6. Medication usage
On a daily basis during the treatment phase, participants
completed study medication log sheets, including the date, dose
and number of pills/patches taken. At each visit, the medication
logs were collected by the nurse counselor, who also inquired
about use of the prescribed medication, the number of missed
doses and, if medication was discontinued, the reason and
date for discontinuation. Participants also returned with their
medication at each visit (used, empty or unused packages). The
amount of medication used was calculated by subtracting the
amount unused from that dispensed.
3.7. Adverse events and Data Safety and Monitoring Committee
(DSMC)
Adverse events were defined as any untoward medical
occurrence in a research participant who was administered
an investigational product; adverse events do not necessarily
have a causal relationship with the product. Any adverse
event that was life-threatening (including death), persistent or
caused significant disability, or that required hospitalization
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309
was recorded as a serious adverse event. Adverse events were
tracked from baseline to study completion. Adverse events
were both unsolicited and solicited. Unsolicited adverse events
were reported by participants without any prompting from
study staff. Staff solicited adverse events at each time point by
asking participants about any changes to their medical health,
medications, and if they had been admitted to hospital since
their last visit. Study staff could also be alerted to adverse
events when reviewing the withdrawal and neuropsychiatric
symptom questionnaires (e.g., depression or anxiety scales)
with the participant. The qualified investigator (AP) classified
the adverse event as to its severity, seriousness, expectedness
and causality, and depending on its classification, a report
was submitted to the institutional ethics review board, Health
Canada, and the DSMC.
Our independent DSMC's primary role was to ensure the
overall safety of patients enrolled in the trial. The three
committee members, a statistician, a physician specializing in
addictions and smoking cessation, and a psychiatrist, were
selected on the basis of their experience in clinical trials and
knowledge of approaches to smoking cessation. The DSMC
met on a semi-annual basis to review unexpected adverse
events and serious adverse events. However, all unexpected
and serious adverse events reported were submitted to the
chair of the committee within one week of occurrence, and a
full meeting could be requested at any time. The meetings
included an open session with study staff and DMSC members
to review the adverse events and their classification, followed
by a closed session with DSMC members only. The DSMC chair
communicated the outcome of the meeting and any sug-
gested changes to the conduct of the study to be implemented
by study staff.
4. Biostatistical considerations
4.1. Sample size calculation
The primary endpoint used to determine sample size was
the CO-confirmed continuous abstinence rate measured from
weeks 5 to 52. The sample size was calculated based on the
assumption that the proportion in the NRT group will be 0.20
compared to 0.30 in the VR group and .35 in the NRT+ group.
These assumptions were based on a meta-analysis of previous
smoking cessation studies reported in the recent Clinical
Practice Guidelines [6]. The sample size required to detect this
difference in abstinence rates between the NRT and NRT+, and
the NRT and VR group was N = 1068 (alpha level = 0.025;
80% power). We used an alpha level of 0.025 to adjust for
multiple comparisons (i.e., 0.05 divided by 2).
4.2. Primary analysis
Analyses will be intention-to-treat: Drop-outs and partic-
ipants lost to follow-up will be considered smokers for the
purpose of outcome analyses. A logistic regression model
will be fit to the smoking status (abstinent or not abstinent)
from 5 to 52 weeks and will include treatment group as the
independent variable. The analysis of the primary outcome
will also be conducted with psychiatric illness as a factor. The
same analysis will be repeated using continuous abstinence
310 H. Tulloch et al. / Contemporary Clinical Trials 38 (2014) 304–313

from 5 to 10 weeks and 5 to 22 weeks as the dependent
variable.
4.3. Secondary analyses
Descriptive statistics will be used to analyze the incidence
of neuropsychiatric symptoms. Linear mixed-effects modeling
for repeated measures over time will be used to compare the
severity of neuropsychiatric symptoms (as measured by the
BDI-II, STAI, STAXI-2) between the experimental groups, as well
as between those with and without a psychiatric diagnosis. Of
note, linear mixed modeling uses all available data, and only
available data, so there is no need to impute missing data.
5. Results
5.1. Recruitment flow
Of the 1700 participants who expressed interest in the
study, 596 were deemed ineligible, 327 were eligible but
refused to participate, and 40 failed baseline assessment
screening, leaving a final sample of 737 participants. Thus,
43% screened were randomized: 245 to NRT, 245 NRT +,
and 247 to VR. With 244 participants per group and the
assumption that the proportion quit in the NRT group would be
0.20, 0.30 in the VR group and 0.35 in the NRT+ group [26], we
had 72% power to detect a 0.10 improvement in quit rates and
96% power to detect a 0.15 improvement in quite rates with VR
and NRT+, respectively. Those refusing to participate in our
study preferred to participate in other programs at our center
(e.g., smoking cessation studies or Quit Smoking Program),
did not attend or could not be reached for their scheduled
baseline assessment, or were simply not interested in partic-
ipating. Many expressed disappointment at the prospect of
randomization and the possibility that they would not receive
a ‘new’ (to them) medication. No significant differences were
detected between participants and those who refused on
age, education, and employment; men were more likely than
women to refuse participation at the time of screening (33% vs.
27%, respectively; p = .028). The CONSORT diagram is shown
in Fig. 1.
5.2. Baseline sociodemographic, medical and smoking profiles
Missing data were minimal at the baseline assessment
(≤3%), and no changes in the variable means were observed
when a comparison was conducted between raw and imputed
scores. The baseline characteristics of the randomized sample
are displayed in Tables 3 and 4.
Study participants were, on average, 48.6 (SD = 10.8)
years old and had received, on average, 14 (SD = 3.0) years
of formal education. The sample was fairly equally distrib-
uted across the sexes (53.6% male), and about half (46%) of
participants were in a relationship (i.e., married or living
common law). Although 52% of participants were working
full-time, 25% were on disability or unemployed. A bimodal
pattern was observed regarding income: 23% earned less
than $20 000 annually while 26% reported incomes of $70,000

Table 3
Baseline demographic information.

N (%) Overall NRT NRT+ VR

Age (mean, SD) 48.61 (10.83) 48.13 (11.14) 48.57 (10.52) 49.11 (10.83)
Gender
Male 395 (53.6) 137 (55.9) 131 (53.5) 127 (51.4)
Female 342 (46.6) 108 (44.1) 114 (46.5) 120 (48.6)
Marital status
Married 250 (34.1) 85 (34.7) 81 (33.2) 84 (34.4)
Living common law 90 (12.3) 35 (14.3) 26 (10.7) 29 (11.9)
Divorced 136 (18.6) 40 (16.3) 45 (18.4) 51 (20.9)
Separated 63 (8.6) 17 (6.9) 22 (9.0) 24 (9.8)
Widowed 33 (4.5) 12 (4.9) 12 (4.9) 9 (3.7)
Single/never married 161 (22.0) 56 (22.9) 58 (23.8) 47 (29.2)
Years of education (M, SD) 14.13 (2.95) 13.97 (2.65) 14.19 (3.01) 14.21 (3.18)
Employment status
Full time 381 (52.0) 131 (53.7) 129 (52.9) 121 (49.4)
Part time 68 (9.3) 26 (10.7) 16 (6.6) 26 (10.6)
Homemaker 14 (1.9) 4 (1.6) 4 (1.6) 6 (2.4)
Retired 92 (12.6) 33 (13.5) 29 (11.9) 30 (12.2)
Disability leave 126 (17.2) 38 (15.6) 48 (19.7) 40 (16.3)
Unemployed 52 (7.1) 12 (4.9) 18 (7.4) 22 (9.0)
Annual household income
19 999 K or less 162 (22.7) 50 (20.7) 61 (25.8) 51 (21.6)
20 K–29 999 K 63 (8.8) 17 (7.1) 22 (9.3) 21 (8.9)
30 K–39 999 K 84 (11.8) 34 (14.1) 22 (9.3) 28 (11.9)
40 K–49 999 K 75 (10.5) 24 (10.0) 30 (12.7) 21 (8.9)
50 K–50 999 K 85 (11.9) 31 (12.9) 22 (9.3) 32 (13.6)
60 K–60 999 K 188 (26.4) 21 (8.7) 15 (6.4) 20 (8.5)
70 K or greater 188 (26.4) 64 (26.6) 61 (26.8) 63 (26.7)
Smoking characteristics (mean, SD)
Cigarettes smoked per day (CPD) 23.2 (10.8) 22.4 (11.3) 24.0 (10.9) 23.3 (10.1)
Cumulative years smoked 31.04 (11.67) 30.47 (12.18) 30.98 (11.34) 31.66 (11.51)
Fagerström Test for Nicotine Dependence 6.14 (2.22) 6.01 (2.20) 6.31 (2.20) 6.09 (2.25)
Number of previous quit attempts 4.58 (5.43) 4.30 (4.49) 4.22 (4.47) 5.21 (6.72)

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 H. Tulloch et al. / Contemporary Clinical Trials 38 (2014) 304–313 311

Table 4
Medical and psychiatric history.

Positive – N (%) Overall NRT NRT+ VR

Medical illness
Cardiovascular disease 142 (19.3) 51 (20.8) 46 (18.9) 45 (18.2)
Dyslipidemia 191 (26.1) 68 (27.9) 59 (24.3) 64 (26.0)
Hypertension 172 (23.5) 57 (23.4) 58 (23.9) 57 (23.2)
Respiratory illnesses 255 (34.7) 79 (32.2) 85 (35.1) 91 (36.8)
Gastrointestinal 203 (27.7) 68 (28.1) 72 (29.5) 63 (25.5)
Genitourinary 38 (5.2) 15 (6.2) 14 (5.8) 9 (3.6)
Endocrine 110 (15.0) 36 (14.9) 35 (14.4) 39 (15.8)
Dermatologic 111 (15.1) 43 (17.6) 29 (26.1) 39 (15.9)
History of cancer 48 (6.5) 18 (7.3) 14 (5.8) 16 (6.5)
Arthritis 229 (31.2) 75 (30.6) 66 (27.2) 88 (35.9)
Chronic pain / injury 286 (39.1) 98 (40.0) 97 (40.2) 91 (37.1)
Psychiatric illness (lifetime)
None 302 (41.0) 101 (41.2) 102 (41.6) 99 (40.1)
Major depressive disorder 281 (38.1) 84 (34.3) 90 (36.7) 107 (43.3)
Bipolar disorders 38 (5.2) 14 (5.7) 14 (5.7) 10 (4.0)
Anxiety disorders 93 (12.6) 36 (14.7) 31 (12.7) 26 (10.5)
Psychotic disorders 18 (2.4) 8 (3.3) 7 (2.9) 3 (1.2)
Substance/alcohol dependence (past year) 5 (0.7) 2 (0.8) 1 (0.4) 2 (0.8)

or greater. Most participants were Caucasian (91.9%). Partic-
ipants reported a wide range of medical comorbidities, with
the most common being chronic pain or injury (39.1%) and
respiratory illnesses (35%; Table 4). Based on the results of
the M.I.N.I., 59% of participants had a lifetime psychiatric
diagnosis (past or current); 24% of the sample met current
diagnostic criteria. Of those diagnosed, major depressive
disorder and anxiety disorders were most prevalent; 65%
and 21%, respectively. Participants tended to start smoking
during adolescence (mean age = 14.5, SD = 4.0 years), and
were daily smokers for a mean of 31 (SD = 11.7) years. At
baseline, participants smoked on average of 23.2 (SD = 10.8)
cigarettes per day, and reported high nicotine dependence
(FTND = 6.1, SD = 2.2; Table 3). No statistically significant
differences were found between treatment conditions on all
variables.
6. Discussion
The present study is one of a small number of randomized
controlled trials evaluating the relative effectiveness of
varenicline and NRT for smoking cessation; it is the first
to report a head-to-head comparison of varenicline and
various combinations of NRT. No trials are registered in
ClinicalTrials.gov at present despite calls for such comparisons
[7,9]. These direct comparisons, most notably of varenicline
and combinations of NRT, are warranted to determine which
pharmacotherapy is most effective. The results of our primary
analyses are expected to inform smokers and clinicians of
the most efficacious cessation treatment, enhance professional
practice and, thereby, increase cessation rates and improve
health outcomes. At the time of writing, follow-up data collec-
tion are in progress; emerging results of our study will be
presented in subsequent publications.
Smoking cessation interventions have traditionally em-
ployed a ‘fixed-dose paradigm’ in which established doses
of medication are provided, often in a declining-dose format,
for a specified period of time. Increasingly practitioners are
employing ‘titrated’ doses, particularly of NRT, for varying
periods of time. This study will permit an analysis of the
effectiveness of titrating NRT in response to symptoms and
smoking history and add to our understanding of how best to
employ smoking cessation pharmacotherapy.
Our study extends previous research by including a large
sample of treatment-seeking smokers, including those with or
without medical and/or psychiatric comorbidities. Results from
our baseline analyses illustrate the varied sociodemographic
and medical profile of current smokers and reflect, in our
view, a population in contrast to those typically participating
in smoking cessation studies. Similar to population-level data
[40,41], a significant portion of our participants would be
classified as “underserved smokers” — defined as those who
have disproportionate tobacco-related health disparities and
yet are underrepresented in studies involving prospective,
longitudinal treatments [42]. Approximately one quarter of our
sample were receiving disability benefits or were unemployed;
they had an annual household income below $20 000. The
use of tobacco appears to reinforce poverty [43]. Our partici-
pants are also chronic smokers with high nicotine dependence,
illustrating the “hardening” of the smoking population over the
last two decades [44,45]. Finally, participants with medical and
psychiatric diagnoses were prevalent in our sample: 82% re-
ported at least one medical condition and 59% were diagnosed
with a lifetime or current psychiatric illness. Clinicians need
to be aware of this smoking profile in order to ensure appro-
priate coordination of care such that medical, psychiatric and
smoking cessation needs are met.
The public, and a great many clinicians, are unaware of
the distinct relationship that exists between certain psychi-
atric conditions and smoking. Those with a history of or
propensity for depression have much higher rates of smoking
than the general public [46]. Patients living with schizophre-
nia frequently have prodigiously high rates of smoking [46].
In both clinical conditions components of tobacco smoke
provide a partial relief of symptoms [47]. Those with chronic
psychiatric diagnoses have life expectancies almost 25 years
less than the general population – a shocking discrepancy
to which high rates of tobacco-caused disease are a large
contributor [48]. Smoking cessation is a priority in this
patient population; it is ironic that most smoking cessation

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312 H. Tulloch et al. / Contemporary Clinical Trials 38 (2014) 304–313
studies have purposefully excluded those with psychiatric
conditions.
As noted, a large numbers of individuals with current
or previous psychiatric diagnoses participated in our study.
Another recent study examined smoking cessation in a similar
population (i.e., 75% with lifetime psychiatric diagnoses [9]).
Although the question of smoking cessation in those with
psychiatric illness is now the subject of much academic interest,
clinical practice among this patient population still reflects
concepts and attitudes that are outdated. As a consequence,
smoking cessation among persons with psychiatric disorders
is an area of research priority that continues to be largely
unaddressed [49,50]. The current literature describes small
samples, typically restricted to specific psychiatric populations,
and rarely assesses or reports formal diagnoses. Such investi-
gations frequently employ cross-sectional rather than longitu-
dinal designs. Data on the effects of varenicline in smokers with
psychiatric illnesses are even scarcer [27,50]. Only 6 RCTs have
been published to date [15–20]. As noted above, many of these
studies had limitations in sample size (e.g., N = 5 [20]; N = 8
[18]) and lacked a formal assessment of psychiatric diagnoses
[15]. The present trial is the first RCT to test the efficacy of
varenicline in persons with and without mental illness. Due to
the design and measurement rigor of the trial, we are able to
directly compare the treatment effects by psychiatric illness
(yes/no). Our secondary analyses will also explore the safety
and tolerance of varenicline using psychometrically-sound
instruments to track the presence or accentuation of neuro-
psychiatric symptoms from baseline to long-term follow-up
during a treated quit attempt. Initial reports of the side-effects
of varenicline led to the suggestion that this medication has
contributed to the emergence or accentuation of psychiatric
symptoms. Such concerns are receding as the results of larger
studies emerge [21–24]. Nevertheless this study will permit a
further understanding of the effects, if any, of these medications
in a population attempting cessation with established, well-
documented psychiatric diagnoses.
Quitting smoking has immediate health benefits, but often
individuals with chronic medical conditions are not included
in smoking cessation trials due to misplaced concerns re-
garding medication side-effects. Just as those with psychiatric
conditions have been excluded from clinical trials assessing
the efficacy and effectiveness of smoking cessation pharma-
cotherapies, so it is typical that cardiac patients have been
deemed ineligible to participate. As noted in a recent review
of the use of varenicline and cardiac events [51], only 2 RCTs
have included patients with active cardiovascular disease
(CVD) and only 11 enrolled patients with a history of CVD.
Only one RCT has examined the use of varenicline in COPD
patients [14]. Our study includes participants with tobacco-
related illnesses, including those with established CVD (19%),
respiratory illnesses such as COPD and asthma (35%), and
gastrointestinal conditions (28%). Our study will allow for the
evaluation of treatment efficacy when smokers with chronic
medication conditions are included.
It is important to note that we employed conservative
estimates for sample size calculations. In contrast to the
guidelines which summarized 6-month abstinence rates, we
are evaluating 12-month abstinence rates; we expect to see
greater differences between the NRT group and the VR and
NRT + groups at 12-months than was observed at 6-months.
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As such, we may require fewer participants to reach statistical
significance than initially calculated. Nonetheless, it remains
possible that clinically important differences in quit rates
between the treatment groups will not be detected statisti-
cally due to a reduced sample size.
Finally, this trial was designed to assess interventions
that could be easily translated into clinical practice. Intensive
counseling interventions such as the weekly contact used
in most RCTs have shown positive effects on smoking
cessation, however, today's health care providers typically
have 5–15 minutes to spend with each patient and hence
such intensive programs may not be realistic or practical to
implement in most primary care or other clinical settings.
Our design will facilitate the translation of research findings
into practice and may contribute to improving smoking ces-
sation interventions in the general population, including
those with medical and psychiatric comorbidities. In fact,
our colleagues are engaged in training medical staff and
implementing similar interventions with success in a large
number of primary care settings.
Acknowledgments
This project is supported by the Heart and Stroke founda-
tion of Ontario – Grant in Aid.
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