Clinical trial NCT04083144
Conditions: Tobacco Use Disorder Smoking Cessation
Keywords: smoking cessation varenicline deep rTMS insula addiction tobacco use disorder
Sponsor: Centre for Addiction and Mental Health
Start date: 2019-08-22; Completion date: 2022-12-30
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to investigate the effect of deep repetitive transcranial magnetic stimulation (rTMS) using the insula H-coil on smoking outcomes in smokers receiving varenicline. It is hypothesized that active deep rTMS will improve abstinence rates, attenuate craving and reduce cigarette consumption and dependence severity.

Detailed description:
This study will be a randomized, double-blind, sham-controlled clinical trial. Nicotine dependent participants will be recruited and randomized tor receive either active or sham rTMS intervention for 4 weeks (5 sessions/week). All participants will receive an open-label treatment of varenicline for 12 weeks and weekly counselling sessions. The aims of the study are:

1. To examine the efficacy of bilateral deep rTMS to the insula on point prevalence smoking abstinence in smokers receiving varenicline treatment.
2. To examine the efficacy of bilateral deep rTMS to the insula on other smoking outcomes such as craving, cigarette smoking and dependence severity.
3. To examine the effect of bilateral deep rTMS to the insula on abstinence at the end of rTMS treatment and at 6-month follow up.

Abstinence will be measured by point prevalence at week 4 and 12 and prolonged continuous abstinence at week 26. This will be confirmed using plasma cotinine levels. All other measures will be done using various questionnaires such as Fagerstrom Test of Nicotine Dependence (FTND), Timeline Follow-Back (TLFB), Minnesota Nicotine Withdrawal Scale (MNWS), and Tiffany Questionnaire of Smoking Urges (T-QSU).

Arms: arm 1: Participants undergoing deep rTMS (active) for 4 weeks (5 sessions/week) along with 12 weeks of varenicline. arm 2: Participants undergoing deep rTMS (sham) for 4 weeks (5 sessions/week) along with 12 weeks of varenicline.
Interventions: intervention 1: Deep Repetitive Transcranial Magnetic Stimulation (Active) intervention 2: Deep Repetitive Transcranial Magnetic Stimulation (Sham) intervention 3: Varenicline
Intervention descriptions: intervention 1: Active deep rTMS (10 Hz) using the H-coil to target the bilateral insula intervention 2: Sham deep rTMS using the H-coil. The sham coil is built into the same helmet as the active coil. It mimics the active coil with regards to acoustics and scalp sensations. intervention 3: 12 week course treatment of varenicline (0.5 mg/1 mg) using the standard dosage schedule for smoking cessation (Day 1-3: 0.5 mg daily; day 4-7: 0.5 mg twice a day; day 8-end of treatment: 1 mg twice a day).

Protocol documents:
Prot_SAP_000.pdf: 
QI: Bernard Le Foll, MD PhD 
TMS-Varenicline Study 
Version 7.0 (May 2022) 
1 
 
 
 
Deep rTMS and Varenicline for Smoking Cessation:  
A Pilot Study Exploring the Efficacy of a Combined Treatment Approach 
 
Principal and Qualified Investigator: Bernard Le Foll1,2 
Co- Investigators (CAMH): Daniel Blumberger, MD1,3 
Jeff Daskalakis, MD, PhD1,3 
Saima Malik, PhD2 
Consultant (External):           Abraham Zangen, PhD4 
 
 
1Department of Psychiatry, University of Toronto, Toronto, ON, Canada 
2Translational Addiction Research Lab, CAMH, Toronto, ON, M5S-2S1 
3Temerty Centre for Therapeutic Brain Intervention, CAMH, Toronto, ON, M6J 1H1 
4Brain Stimulation and Behavior lab, Ben Gurion University, POB 653,Beer-Sheva 84105,Israel 
 
Address of Trial Site:  
Centre for Addiction and Mental Health (CAMH), 1025 Queen Street West, Toronto, Ontario, 
M6J 1H1, and/or 100 Stokes St, Toronto, Ontario, M6J 1H4 and/or 33 Ursula Franklin Street, 
Toronto Ontario, M5S 2S1 
 
 
 
 
 


QI: Bernard Le Foll, MD PhD 
TMS-Varenicline Study 
Version 7.0 (May 2022) 
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Introduction 
While first-line pharmacotherapies for nicotine dependence (i.e. varenicline) demonstrate 
efficacy for short term smoking cessation, relapse remains a challenge in smokers. Growing 
evidence implicates the insula in cigarette craving and cue-induced relapse, with studies showing 
improved abstinence rates following deep repetitive transcranial magnetic stimulation to this 
region. The present proposal aims to optimize smoking cessation outcomes in a generalizable 
group of smokers by combining currently approved pharmacotherapy (varenicline) with deep 
repetitive transcranial magnetic stimulation (rTMS), a novel therapeutic intervention with 
recently evidenced efficacy for smoking abstinence. Such a combined approach may improve 
abstinence rates in smokers through the synergistic action of these two separate interventions, 
targeting both cessation and relapse.   
 
 
Background and Rationale 
Although currently available pharmacotherapies for nicotine dependence have evidenced 
considerable efficacy in short term smoking outcomes, randomized trials reveal nearly three 
quarters of initial quitters relapse within a year [1, 2]. The risk for smoking relapse [3] and 
unsuccessful quit rates following pharmacotherapy treatment [4] are even higher among certain 
subgroups of smokers who are largely excluded from clinical trials (i.e., those with psychiatric 
and/or substance use co-morbidity) [5]. While varenicline demonstrates superiority over other 
first-line medications for smoking cessation [6], the probability of smoking relapse signals a 
clear need for improvement [7]. Indeed, novel multifaceted treatment approaches which in 
combination successfully address both cessation and relapse prevention are required to treat this 
complex disorder. 
 
Varenicline: a novel therapeutic approach for smokers: The nicotinic acetylcholine receptors 
(nAChRs).are ligand-gated ion channels composed of five subunits, labeled α2 to α10 and β2 to β4 
in the central nervous system. The combination of subunits determines the functionality of the 
receptor. In the brain, the most prevalent of these are the homo-oligomeric α7 and the 
heteromeric α4β2 nAChRs. A large body of evidence implicates α4β2 nAChRs in the reinforcing 
effects of nicotine [8-10]. Notably, the α4β2 nicotinic acetylcholine receptors located in the 
midbrain area are critical for nicotine’s ability to increase DA levels in the nucleus accumbens 
[11-15], an important factor linked to the motivational and reinforcing properties of drugs of 
abuse [16]. Recently, a partial agonist of the α4β2 nAChRs (varenicline), approved as a smoking 
cessation aid, has become available [17,18]. Varenicline has high affinity for α4β2 (Ki α4β2 = 0.4 
nM) and much less for other human nAChRs (Ki α7 = 125 nM; Ki α3β4 = 86 nM; Ki α6/ α3β4 = 111 
nM) [19]. The rationale to develop partial agonist for smoking cessation was to have a duality of 
effect: acting as an antagonist to block the rewarding/reinforcing effect of nicotine while 
smoking; acting as an agonist to attenuate withdrawal and cravings due to abstinence [20]. By 
correlating free human brain concentrations, estimated from therapeutic human plasma levels 
and rat brain-to-plasma ratios, with binding affinities and functional potencies at α4β2 nAChRs, 
Rollema et al. found that concentrations equal to predicted human brain concentration of 
varenicline can extensively desensitize and to a lesser extent activate α4β2 in vitro [19], but 
minimal effect at α7 nAChRs is expected [19]. Therefore, it is likely that the effects of 
varenicline in humans are mediated by α4β2 nAChRs [19]. 
 


QI: Bernard Le Foll, MD PhD 
TMS-Varenicline Study 
Version 7.0 (May 2022) 
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Repeated Transcranial Magnetic Stimulation (rTMS) as an innovative approach: rTMS is a 
technique that has been found to be useful as a potential treatment for neuropsychiatric diseases. 
rTMS is almost painless, does not require anesthesia, and is not associated with significant side 
effects. There is compelling evidence that rTMS works by affecting the function of neuronal 
circuits and inducing local changes in neural excitability. Transient inactivation of a specific 
brain structure can also be induced in humans through rTMS, through mechanisms that are likely 
associated with potentiation of GABAB receptor mediated inhibitory neurotransmission [21]. 
However, rTMS effects are complex and likely involve local modifications in the dynamic 
release patterns of various neurotransmitters, including dopamine [22-26]. The fact that there is 
in vivo evidence that rTMS of frontal brain regions has a modulatory effect on dopaminergic 
system, suggest that rTMS may be particularly useful in neuropsychiatric disorders associated 
with dopamine dysfunction, such as addiction [25, 27].  Moreover, with the recent development 
of Deep rTMS H-coils by Dr Zangen (a consultant on this protocol), it has become feasible to 
perform rTMS on deeper brain structures such as the insula [28-30]. 
 
Insula as a target structure: Several lines of research implicate the insula as a critical substrate in 
nicotine dependence following evidence that insular lesions produce a loss of self-reported 
cravings for cigarettes and immediate cessation of smoking without relapse [31,32]. As proposed 
by Naqvi et al., the insula plays a role in the recall of the interoceptive effects of drug taking, and 
through interactions with other brain regions, mediates conscious urges and decision making 
precipitating relapse [33]. This hypothesis is substantiated by growing preclinical work: results 
from studies at our own translational addiction research laboratory reveal that temporary insular 
inactivation in rats leads to reduced nicotine self-administration and seeking after exposure to 
nicotine-associated cues or a priming dose [34,35]. Neuroimaging studies further evidence 
significant associations between cue-induced activation of the insula and self-reported craving 
for a cigarette [36], with greater bilateral insular pre-quit activity also predicting relapse in 
smokers [37].  
 
Taken collectively, an intervention which directly modulates insular electrical activity such as 
deep rTMS may be promising treatment for nicotine dependence.  Indeed, a recent investigation 
revealed improved smoking outcomes following high-frequency deep rTMS non-selectively 
targeting the insula and prefrontal cortex relative to sham.  Specifically, smokers reported 
reduced cigarette consumption and greater and longer lasting abstinence rates after 2 weeks of 
treatment [38]. However, the effect of stimulation exclusively to the insula remains to be 
thoroughly explored in humans. The use of the recently developed H-coil will allow us to 
address this gap.  Although the modulation of structures adjacent to the insula cannot be 
excluded, this will unlikely be a drawback as results in human smokers suggest that extra-insular 
lesions do not implicate those areas in smoking behaviors [31]. Similarly, pilot studies from our 
lab evaluating the effect of inactivating brain areas adjacent to the insula found no significant 
effects (Le Foll et al., unpublished observations). We recently also completed a rTMS study with 
the H-coil in healthy non-dependent individuals, and our data indicate that our approach is safe 
and tolerable in humans (data not shown).  Finally, as some of varenicline’s actions involve 
down-regulation of the functional connectivity between the insula and regions pertinent to 
nicotine withdrawal in smokers [39], the combination of varenicline and deep rTMS of the insula 
is a favorable dual treatment approach. These interventions may synergistically work to yield 
more efficacious and enduring treatment effects.  


QI: Bernard Le Foll, MD PhD 
TMS-Varenicline Study 
Version 7.0 (May 2022) 
4 
 
Research Question 
Can deep rTMS to the insula using the insula H-coil improve smoking outcomes in smokers 
receiving varenicline? 
 
 
Aims and Hypotheses  
Hypotheses: 
Primary: Active deep rTMS intervention will improve point prevalence abstinence rates at the 
end of varenicline treatment (Week 12) as measured by self-report and confirmed with plasma 
cotinine levels.  
Secondary 1: Active deep rTMS intervention will significantly attenuate craving and reduce 
cigarette consumption and dependence severity. 
Secondary 2: Active deep rTMS intervention will significantly improve short-term point 
prevalence abstinence rates and long-term prolonged and continuous abstinence rates. 
 
Aims: 
Primary: To examine the efficacy of bilateral deep repeated transcranial magnetic stimulation 
(rTMS; 10 Hz) directed to the insular cortex, relative to sham stimulation, on point prevalence 
smoking abstinence in smokers who are receiving standard varenicline treatment (2 mg/day).  
Secondary 1: To examine the effect of bilateral deep rTMS directed to the insular cortex, relative 
to sham, on other smoking outcomes throughout study duration including self-reported craving, 
cigarette smoking and dependence severity.   
Secondary 2: To examine the effect of bilateral deep rTMS directed to the insular cortex, relative 
to sham, on abstinence at the end of rTMS treatment (point-prevalence abstinence at Week 4) 
and at 6-month follow-up (prolonged and continuous abstinence at Week 26). 
 
 
Study Design 
Overview: This study will be a randomized, double-blind, sham-controlled clinical trial. 
Specifically, fifty nicotine dependent participants expressing a willingness to quit smoking will 
be randomized into one of two rTMS intervention arms: Sham (n=25) or Active (10 Hz, n=25). 
All participants will receive an open-label treatment of varenicline (Week 1 to Week 12), and a 
target quit date (corresponding to the end of Week 2) will be set for each individual. Participants 
will also receive brief weekly counselling adapted from the Mayo Clinic’s ‘Smoke Free and 
Living It’ manual. The rTMS interventions will begin at Week 1 for four weeks (5 sessions a 
week for a total of 20 sessions), and will be performed with an insula-targeting H-coil. 
Moreover, follow-up visits will be scheduled weekly for the duration of the medication phase 
and on Week 26. The primary outcome of the proposed study will be plasma cotinine verified 
(<15 ng/ml) 7-day point prevalence abstinence as measured at the end of Week 12. Other 
smoking outcomes (craving, consumption patterns, and dependence) will be captured through 
standardized questionnaires throughout the study duration. Participants will also have plasma 
cotinine verified measurements of abstinence at the end of rTMS treatment (end of Week 4), and 
at the follow-up at 6 months (end of Week 26).  This trial will be conducted in compliance with 
the protocol, GCP, and Canadian Food and Drug Regulations Division 5. 
 


QI: Bernard Le Foll, MD PhD 
TMS-Varenicline Study 
Version 7.0 (May 2022) 
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Participants: Participants in the proposed study will be nicotine dependent individuals (n=50).  
We will recruit through various sources: the community, CAMH clinics, word of mouth, and/or 
through posters/fliers distributed in and around the research centers as well as on the CAMH 
website.  CAMH approved study recruitment ads will be placed primarily around, but not limited 
to, the downtown Toronto area. Ads may also be placed in various local newspapers, magazines, 
community venues (e.g., bars) as well as TTC streetcars, buses and subways. Online 
advertisement services may be employed, in accordance with CAMH guidelines. Ads and fliers 
will be approved by the REB.  Participants may also be recruited from similar protocols approved at 
CAMH provided they have agreed to being contacted about future studies.   
 
Recruitment for the study may also be initiated by members of the Circle of Care who are 
treating the potential study participant. These individuals will not obtain consent but they may 
identify potential research participants and obtain verbal permission for a member of the research 
team to approach and discuss the study with them. Potential participants who provide assent to 
be contacted by a member of the research team will then be contacted by a member of the 
research team who will engage them in the informed consent process if they are agreeable to 
proceed as such.  
 
Additionally, as part of the CLEARR (Clinical Engagement and Research Recruitment) 
initiative, a delegated Research Coordinator under the supervision of a CLEARR team recruiting 
clinician and accountable to the Manager of Research Practice will identify potential participants 
and notify the research team and the client’s clinician about the potential eligibility to participate 
in the study. The clinician will then ask the client for assent to meet with a study team member to 
discuss details and participation in the study. Only clients who agree to this process will be 
approached.  
 
The delegated research Coordinator will access personal health information (PHI) in I-CARE in 
order to determine eligibility of CAMH participants to participate in the research study. No PHI 
except MRN will be collected for this purpose and this information will be kept in a secure 
locked location. 
 
The aforementioned recruitment strategies are in line with our aim to enroll a representative 
sample of smokers. This is in contrast to more traditional smoking cessation clinical trials, 
wherein the majority of smokers are often excluded, thereby jeopardizing the generalizability of 
the data [5]. Our exclusion criteria may be regarded as less restrictive for this purpose.  Nicotine 
dependence will be determined via testing/ measurements stated in the “Screening Assessment” 
section below. 
 
Interventions and Procedures: Potential participants will undergo a telephone pre-screen to 
determine initial eligibility. Participants may also complete this screening electronically, through 
REDCap (see REDCap section). They will subsequently be invited to an in-person Screening 
Assessment to confirm final eligibility to participate.  
 
Screening Assessment and Consent:  
Following the review and signing of the Informed Consent Form, the following measures and 
assessments will be administered at the screening visit: 


QI: Bernard Le Foll, MD PhD 
TMS-Varenicline Study 
Version 7.0 (May 2022) 
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1) Fagerstrom Test of Nicotine Dependence (FTND). The FTND is a measure of physical 
dependence severity [40]. 
2) Diagnostic and Statistical Manual of Mental Disorders (DSM-V/SCID-V). The DSM/SCID-V 
will be used to diagnose nicotine dependence in participants [41] and/or any other psychiatric 
issues. 
3) Timeline Follow-Back (TLFB). The TLFB is a reliable method used to detail nicotine 
(smoking), alcohol and caffeine consumption behavior over a specified period of time. 
Participants are asked to recall key anchoring events to prompt retrospective estimates of 
cigarette, alcohol or caffeine intake [42]. 
4) Expired Carbon Monoxide (CO) Measurements. Breath CO measurements provide a reliable 
indication of recent smoking status among smokers.  
5) Smoking Contemplation Ladder. This questionnaire allows for the measure of readiness to 
quit smoking in individuals. A cutoff  score of 7 is commonly used to determine individuals who 
are motivated to quit [43].  
6) Mini Mental State Examination (MMSE). The MMSE is a gross measure of cognitive status in 
individuals, with a commonly used cutoff of <24 [44]. The test will serve as indication of 
cognitive competence to provide informed consent.  
7) Medical and/or psychiatric assessment by study physician (or delegate). 
8) Blood draw for quantification of cotinine, complete blood cell count, routine blood chemistry 
and/or beta-HCG (serum pregnancy test, for females). 
9) SAFTEE: a technique for the systematic assessment of side effects in clinical trials [45]. 
10) Drug screen (urine or blood) 
11) Demographic and contact forms 
12) TASS form (TMS Adult Safety Screening Questionnaire) 
 
Total Number of Study Visits: 
In addition to the screening assessment, there will be 30 study visits.  The first visit (study start 
day) will correspond to the 1st varenicline dose and the 1st rTMS session.  There will be 4 
consecutive weeks of rTMS (20 sessions).  Weekly follow-up visits will occur for the 12 weeks 
of the trial and a final visit will occur at week 26. The TLFB, SAFTEE, concomitant medication 
log and Adverse Event log will be administered/ updated at every visit. CO measurements will 
also be taken at every visit.  Regular pregnancy testing for females will occur throughout the 
study.  Selective questionnaires (described below in Outcome Measures) will also be 
administered at study sessions.  Urine drug testing will be conducted as required. There will be a 
total of 4 blood draws (including the screening session). Cotinine blood samples will not be 
analyzed upon collection. The clinical lab will process the samples and the study stuff will pick 
up the samples and store them in a -20°C freezer. Analysis will be done in batches of 30 or more 
samples. 
 
Varenicline Treatment:  
All participants will receive varenicline pharmacotherapy, beginning at Week 1, for a total 
duration of 3 months (12 weeks). A target quit date for all participants will be set for Day 15. 
The varenicline dosage schedule will be that standard for smoking cessation.  It will consist of 
0.5 mg tablet once a day for the first three days (day 1 – day 3), followed by four days of 0.5 mg 
BID (i.e. twice a day: AM and PM; day 4-7). The target daily dose of 2 mg (1 mg BID, i.e. twice 


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TMS-Varenicline Study 
Version 7.0 (May 2022) 
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a day: AM and PM) will begin on Week 2 (day 8) and extend until the end of treatment. Subjects 
will be advised to orally consume the tablet with food and water.  Notably, we may use 1 mg 
daily if 2 mg daily is not well tolerated. The study medication will be dispensed weekly by the 
CAMH pharmacy. Compliance will be assessed through reported missed doses at weekly visits 
(see Follow-up Visits section below).   
 
rTMS:  
Participants will be randomized into either sham (n=25) or active (10Hz, n=25) rTMS 
intervention in a 1:1 ratio. Brainsway will provide the randomization cards and the 
randomization list, which will then be managed by an independent person outside of the study. 
The stimulation protocol will begin in Week 1, and will consist of 5 rTMS sessions per week 
over the course of 4 weeks (20 in total). Importantly, rTMS will be administered 2 weeks 
preceding and 2 weeks following the targeted quit date (Day 15), as smokers are believed to be 
most susceptible to relapse early in the abstinence phase [46].  Both active and sham stimulations 
will be administered using the insula H-Coil (Brainsway, Model 102B; Jerusalem, Israel), 
developed by Dr. Abraham Zangen (consultant on this proposal).  First, resting motor threshold 
(RMT) will be determined based on the minimum intensity to cause one of the right hand 
muscles to activate in at least 5 of 10 trials. The active simulation will comprise of 34 trains of 3 
seconds each at 10 Hz and 30 pulses per train and an inter-train interval of 26 seconds. 
Stimulation intensity will be administered at a target of 120% RMT. Titration of stimulus 
intensity may occur over the first 4 sessions to enhance tolerability.  For participants with poor 
tolerability the stimulation target will be a minimum of 110% RMT. For the sham stimulation, 
we will use the same coil placement as that used for active stimulation, matching the number of 
pulses delivered. The sham coil, which is built into the same helmet, mimics the active coil with 
respect to acoustics and scalp sensation. Notably, this coil, which allows for the bilateral 
stimulation of the insular cortex, is presently located at CAMH, and has been used by our team 
in a recently completed pilot study in healthy controls. Since rTMS sessions will occur daily for 
4 weeks, medical staff will be onsite during all procedures and standard procedures for treating 
patients with rTMS in the Temerty Centre will followed.  
 
Follow-up Visits: 
The follow-up visits scheduled on a weekly basis for the duration of the medication phase (Week 
1 through to Week 12) will serve a number of purposes. First, as counselling is clinically 
recommended to be administered alongside smoking cessation medication for increased efficacy 
[47], a trained study member will deliver brief counselling interventions. The counselling 
sessions will be adapted from the Mayo Clinic ‘Smoke Free and Living It’, a commonly used 
manual in pharmacotherapy trials for nicotine dependence, and will cover various topics aimed at 
building problem-solving skills and providing support through quitting and withdrawal [48]. 
Counselling will be provided weekly for the 12 weeks.  Second, adverse events will be recorded, 
and medication compliance will be monitored at follow-up visits. Third, questionnaires will be 
administered to assess the secondary outcome measures and suicidality of this study (details 
below).   
 
Clinical study staff may access I-CARE for research record updating as this is a treatment study. 
 
 


QI: Bernard Le Foll, MD PhD 
TMS-Varenicline Study 
Version 7.0 (May 2022) 
8 
 
Summary of Events: 
Below is a table outlining the assessments, measures, and treatments done at each visit.  
 
 
 
Week and Visit Number 
 
 
 
W1 
W2 
W3 
W4 
W5 
W 
6-8 
W
9 
W 
10-12 
W
13 
W 
26 
 
 
1* 
2 
3 
to 
6 
7 
8 
to 
11 
12 
13 
to 
16 
17 
18 
to 
21 
22 
23 
to 
25 
26 
27 
to 
29 
30 
31 
Assessments & Measures 
ICF and ICF quiz 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Contact & 
Demographic Form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical assessment, 
SCID, and ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TASS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MMSE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking 
Contemplation Ladder 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood draw 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
CO Measurement 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TLFB (Cigarettes, 
alcohol, caffeine) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medication Log 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE Log 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SAFTEE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Drug Test 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Pregnancy Test (if 
required) 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
FTND 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Counselling 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
C-SSRS 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
T-QSU 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
MNSW 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Point Prevalence 
Abstinence 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Prolonged Abstinence 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Continuous Abstinence  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
RMT for TMS 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
TMS 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Varenicline 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
*Visit 1 is the screening/baseline visit. 
During the TMS treatment (i.e., sessions 2-21) urine drug testing, pregnancy testing, counselling, 


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Version 7.0 (May 2022) 
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FTND, Columbia Suicide Severity Rating Scale (C-SSRS), T-QSU, and MNSW will be done 
once a week.  In the event that a participant misses a session during this time where these 
assessments were intended to occur, they will be conducted at the following visit. Participants 
are intended to receive 20 TMS sessions, however, any missed TMS sessions (whether due to the 
participant or to holiday closure of the Temerty centre) will not be rescheduled.   
 
During the follow up visits (i.e., sessions 22-31), in the event a subject misses a session; they 
will be able to reschedule the session within the same week. If they are not able to attend within 
the same scheduled week, the session will be considered as a missed session. The following 
visits will proceed as scheduled.   
 
COVID-19:  
All participants will be screened for COVID-19 symptoms and COVID-19 contacts. If a 
participant screens positive, they will not continue treatment at that time and the case will be 
reviewed with Infection Prevention and Control Canada (IPAC) around if, and when, treatment 
can resume. IPAC recommendations include that all patients and staff wear surgical masks while 
at CAMH (including waiting areas). 
 
Subject Eligibility Criteria 
Inclusion criteria:  
1) Age 18-65;  
2) Nicotine dependent as assessed by DSM-V;  
3) Reported daily cigarette consumption ≥ 10 and expired carbon monoxide (CO) measurement 
of ≥ 10 ppm;  
4) Fagerstrom Test of Nicotine Dependence (FTND) ≥ 4;  
5) Reported motivation to quit within 30 days as assessed using the Contemplation Ladder score 
of ≥ 7.  
 
Exclusion criteria:  
1) Reported smoking abstinence in the 3 months preceding screening visit;  
2) Current use of other smoking cessation aids;  
3) Allergy and/or contraindication to varenicline or rTMS;  
4) Pregnancy, trying to become pregnant or breastfeeding;  
5) Current or recent history of cardiovascular or cerebrovascular disease and/or current 
hypertension;  
6) Current or historical evidence of suicidal behavior;  
7) Serious current or personal history of medical condition/disease (neurological disorders, brain 
lesions, multiple sclerosis, head trauma, loss of consciousness, hearing loss, etc.);  
8) Current, personal history or family history of seizures;  
9) Cognitive impairment as defined as a Mini Mental State Examination (MMSE) score <24;  
10) Concomitant use of medication that lowers seizure threshold. 
                                                   


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Version 7.0 (May 2022) 
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Consent 
All subjects will provide written informed consent prior to study enrolment.  i.e. before 
undergoing any study-related procedures. 
 
Sample Size and Power Calculation 
Based on the results of a recently completed multi-centre trial [4] and results from our previous 
trial investigating varenicline’s efficacy in patients in a residential drug program, we anticipate a 
12 week abstinence point prevalence rate of approximately 40% following treatment with 
varenicline. To detect a clinically relevant 30% difference in the proportion of abstinence 
between active deep rTMS and sham rTMS treatments with a power of 0.80 (α = 0.05), we 
would need n=42 participants per study arm. However, in light of the pilot nature of this 
proposed study and the allotted time frame for study completion, we will recruit n=25 
participants per study arm (power = 0.66). However, we anticipate attrition with this study 
sample and as such, we will recruit n=30 per arm to obtain 50 completers in total.  
 
Data Analysis 
Descriptive statistics will be used to compare groups (Sham, rTMS) at baseline on main clinical 
and demographic variables. Fisher’s Exact and Mann-Whitney U test will be used for categorical 
and continuous variables, respectively. Subjects with missing values in the primary outcome 
(abstinence at 4, 12 or 26 weeks) will be compared with completers on baseline characteristics, 
to help in the understanding of the reasons for missing values, if at least 10 subjects (20%) are 
found to be missing. Mixed effect logistic regression that using abstinence at 4, 12 and 26 weeks 
as dependent variables will be adjusted to the data, with groups and categorical time (4, 12 and 
26 weeks) specified as fixed effect, and subject intercepts as random effects. Baseline variables 
correlated with missingness and/or known to be associated with the outcome will be added as 
covariates with focus on model parsimony (not to include many covariates) due to small sample 
size. The primary hypothesis will be tested using a contrast that compares abstinence at week 12 
in the logit scale. Similarly, abstinence will also be compared at weeks 4 and 26 as part of our 
secondary objectives. Mixed effect models that uses maximum likelihood estimation accounts 
for missingness in the dependent variable by using all available information in the estimation, 
under the MAR assumption (Missing At Random – the values of a data points are not associated 
with the missing status of the data point after accounting for relevant covariates) [49]. Other 
measures related to our secondary objectives (e.g., FTND, CO, TLFB, etc.)  will also be 
analyzed using linear mixed or generalized mixed models, depending on the nature of the 
outcome of interest. Graphs will be used to explore the data, the models assumptions (for 
example, residual plots), as well as model results (for example, estimated means plot). Due to 
small sample, effect sizes with 95% confidence intervals as well as standardized effect sizes will 
be reported.  
 
Outcome Measures 
Main Outcome Measure: 7-day point prevalence abstinence at the end of 12 weeks.  This 
outcome will be measured by self-report of abstinence for the past 7 days, and confirmed using a 
plasma cotinine measurement of <15 ng/ml 
 
Secondary Outcome Measures: 
1) Fagerstrom Test of Nicotine Dependence (FTND). The FTND will be used to assess physical 


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dependence severity in participants [40].  
2) Expired Carbon Monoxide (CO) Measurements. Expired CO measurements will be regularly 
taken as a biological confirmation of recent smoking.  
3) Cigarettes per day. The Timeline Follow-Back (TLFB) will be used to determine daily self-
reported cigarette consumption [42].  
4) Minnesota Nicotine Withdrawal Scale (MNWS). The MNWS will be used to assess tobacco 
withdrawal symptoms [50].  
5) Tiffany Questionnaire of Smoking Urges (T-QSU). The T-QSU will be used to assess 
symptoms of craving/urges for tobacco [51].  
6) Point prevalence abstinence at end of 4 weeks:  This outcome will be measured by self-report 
of abstinence for the past 7 days and confirmed using a plasma cotinine measurement of <15 
ng/ml. 
7) Prolonged abstinence from end of treatment (Week 12) to end of follow up (Week 26). This 
outcome will be measured by self-report of continuous abstinence since the last visit (at Week 
12) and confirmed using a plasma measurement of <15 ng/ml. 
8) Prolonged abstinence with 2-week grace period at end of follow up (Week 26). This outcome 
will be measured by self-report of continuous abstinence since Week 4 and confirmed using a 
plasma measurement of <15 ng/ml. 
9) Continuous abstinence at 6 months: This outcome will be measured by self-report of 
continuous abstinence since the target quit day (Week 2) and confirmed using a plasma 
measurement of <15 ng/ml.  
 
The FTND, T-QSU and MNWS will be administered weekly for the first month (i.e. 4 weeks) 
and subsequently at 8, 12 and 26 weeks. 
 
In the case that a participant declines blood draws, urine will be collected instead for the 
quantification of cotinine levels.  
 
Study Monitoring and Access to Study Documents  
The PI/ QI will permit trial-related monitoring, audits, REB review, and/or regulatory 
inspections, by providing direct access to source data/documents. This will be mentioned in the 
Informed Consent Form.  Monitoring will be conducted according to the study monitoring plan. 
 
Ethical Considerations 
This study is approved by CAMH REB. 
 
Risks and Inconveniences 
Blood Collection: Blood collection may cause some bruising and discomfort at the site of needle 
stick, and rarely, a small infection at the skin puncture site. These risks are minimized by using 
proper techniques. 
 
Varenicline: Current prescribing practice recommends varenicline be administered at 0.5mg once 
daily for 3 days, 0.5mg twice daily for 4-7 days followed by 1mg twice daily for the remainder 
of treatment. According to the varenicline product monograph, the most common side effect of 
varenicline is nausea, which is dependant on dose. Approximately 30% of subjects treated with 
1mg varenicline reported nausea while 16% of subjects reported these symptoms at a 0.5mg 


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dose. However, this symptom was typically described as being mild to moderate in severity and 
transient causing only 3% of subjects to discontinued treatment prematurely because of this 
adverse effect.  Other common adverse effects associated with varenicline treatment include 
sleep disturbances, constipation, and vomiting. There are reassuring data concerning the mental 
health side effects of varenicline [4]. However, we will monitor suicidality by the Columbia-
Suicide Severity Rating Scale.  Should any subject begin experiencing significant changes in 
their mood or behavior, we will ask them to discontinue the medication and contact the study 
physician or if they cannot contact the study physician, to attend their local emergency room for 
treatment.  
 
rTMS: When the stimulation is applied to the head, the machine yields a sound.  To minimize 
any inconvenience, ear plugs will be offered to subjects to mute the sound.  At certain positions 
on the head, the stimulation may cause eyes to blink or a brief contraction of the scalp, neck, 
trunk or upper arm muscles. While these contractions may be annoying, they should not be 
painful. Some people may experience a mild headache or shoulder stiffness after testing but 
these symptoms will usually go away in 24 hours. Typically, 1-2 doses (325 mg) of 
acetaminophen (i.e. “Tylenol”) should help to rid these symptoms.  
 
Very rarely, rTMS has been reported to cause seizures. For example, there have approximately 
been a total of 10 reported seizures when safety guidelines are followed out of thousands of 
treated patients. However, patients with epilepsy and/or patients with stroke may be more 
vulnerable to potential seizures. Safety guidelines that minimize seizure risk will be followed. 
We intend to follow these guidelines and control stimulation so it is well below the maximum 
limits of the safety guidelines. To our knowledge, no seizures have been reported when 
stimulation is kept within these safety guidelines. Magnetic brain stimulation (rTMS) has been 
used on thousands of individuals in the United States, Canada and Europe over several years 
without any serious problems.  That said, the study investigator (or delegate) will be available 
during rTMS sessions, and will immediately assess and treat any emerging side effects.   
 
Questionnaires:  There are no risks associated with the questionnaires, except possibly fatigue.  
Breaks will be provided as required.    
 
Benefit to participants: Should the dual treatment approach for nicotine dependence be 
successful, subjects will directly benefit from participation in the study.   
 
Study Documentation 
Investigators will retain a participant identification code list if they need to contact participants 
after the study. This list will contain the complete name, identification number, address, phone 
number and email of all participants and will be held confidentially at the investigator’s site after 
completion of the study. 
 
REDCap 
REDCap will be used as an electronic data capture tool for some questionnaires. If used for this 
purpose, data collected in REDCap will be considered as source.  
 


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REDCap may also be used as a survey for recruitment purposes. For recruitment, the survey will 
be a stand alone site where participants will answer preliminary questions to determine 
eligibility. To gain access to the survey, participants will respond to our advertisement by email 
or telephone. Staff will reply to them with a unique Study ID that the participant will use to gain 
access to the survey.  No PHI will be stored in the same Project as the Survey. At the end of the 
survey participants will give consent to be contacted and they will be directed to a stand-alone 
Project with their telephone number and name. The only link between the Survey and Telephone 
number Project will be a unique Screening ID. 
 
Archiving of Study Documentation 
Study data and other essential documents will be retained in a secure setting by the investigators for 
a period of 15 years as required by current regulations. 
 
Confidentiality 
All personal study participant data collected and processed for the purposes of this study will be 
managed by the investigators and their research staff with adequate precautions to ensure the 
confidentiality of this data, and in accordance with applicable national and local laws and 
regulations on personal data protection. The Ethics Committees approving this research, 
monitors and Health Canada will be granted direct access to all source documents for verification 
of clinical trial procedures and/or data, without violating the confidentiality of the participants, to 
the extent permitted by the law and regulations. In any presentation of study results (at meetings 
or in publications), participant identity will remain confidential. 
 
Participant Safety and Adverse Events 
The occurrence of adverse events resulting from varenicline treatment and/or rTMS intervention 
is a possibility, particularly as we are not excluding various co-morbid disorders. However, in a 
previous trial completed by our team, we demonstrated the safe use of varenicline in smokers 
presenting with co-morbid alcohol dependence. Similarly, large recent meta-analyses also reveal 
the safety of varenicline in smokers with various psychiatric diagnoses [41].  Regardless, 
possible side effects will be monitored on a regular basis (weekly) during the medication phase. 
Moreover, we will follow current guidelines for the safe use of both varenicline and deep rTMS, 
including the exclusion of individuals with any known absolute contraindications to either of 
these treatments. 
 
The Qualified Investigator (QI) will ensure patient safety.  Potential safety concerns and 
associated solutions will be discussed at regular study meetings.  Since this study involves both a 
pharmacological (varenicline) and device (rTMS with H-coil) intervention, the QI (along with 
any medical professionals delegated by the QI) will monitor, treat and follow-up on any 
emerging side/adverse effects.  In the event of AEs, the QI will determine severity of the event 
along with any causal association to the study interventions.   
 
Additional Safety Procedures: 
1. Participants will be provided with the QI contact information with an available pager 
number for 24-hr contact, in case of any unexpected side effects.  
2. If necessary, the participants will be transferred home via taxi. 
 


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Adverse Events Reporting 
Every adverse event and observed device deficiency will be recorded.  AEs will be assessed at 
each study visit.  Study staff will question the subject directly asking: how they are feeling and 
how have they been feeling since last visit.  All AEs, whether reported by the subject or observed 
by study staff/investigators, will be recorded on the AE log along with a brief description, start 
date/resolution date and any action taken. Symptoms related to smoking cessation will not be 
recorded as AEs. The AE log will be initialed by the QI, who will make the determination on 
relationship of the AE to the investigational device/study procedures.  
 
Serious adverse events and device deficiencies meeting Health Canada’s mandatory problem 
reporting requirements (Part 3, Medical Devices for Investigational Testing Involving Human 
Subjects) will be reported to Health Canada within the reporting time periods required by Health 
Canada and/or to REB in accordance with REB’s local reporting requirements and timelines.  
  
Termination of the Study 
Reasons for withdrawing individual subjects from the study may include one or more of the 
following: 
1) Failure to continue to meet inclusion criteria; 
2) Severe rTMS side effects; 
3) Major protocol violation; 
4) Subject lost to follow-up; 
5) Withdrawal of consent; 
6) Pregnancy 
7) The subject missed more than 3 days of TMS treatment during the treatment trial period (not     
 
including holiday closures or due to COVID) 
 
Notably, any subject may be discontinued from the study at the discretion of the Qualified 
Investigator if it is deemed to be in the best interest of the subject.   
 
When participants are prematurely withdrawn they will be replaced by a new participant until the 
total recruitment aims are met or until the trial is stopped.  Replacement will be according to the 
inclusion and exclusion criteria above and will follow the same procedure as for the original 
participants.  Data collected until the time of withdrawal may be used in analyses.   
 
Criteria for the Termination of the Trial 
The study will be terminated upon completion of the recruitment targets.  The study may also be 
terminated due to adverse events or at the discretion of the QI/Sponsor. 
 
Funding 
This study is funded by Pfizer Global Research Award for Nicotine Dependence (GRAND) 2016 
(Reference # WI218848).   
 
 Participant Compensation 
Assessment visit: $20 
rTMS visits (20 total): $400 ($20/ visit) 
9 follow-up visit: $15 per visit (total=$135) 


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Final follow-up visit: $30 
TOTAL: $585 
 (Taxi vouchers will be provided, if needed). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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