Clinical trial NCT02265367
Conditions: Tobacco Use Disorder
Sponsor: University of Minnesota
Start date: 2015-01-01; Completion date: 2017-05-01
Enrollment: 56 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to provide preliminary information assessing if levomilnacipran may be effective at increasing smoking cessation rates.

Detailed description:

Arms: arm 1: In the first three week period levomilnacipran is evaluated whereas in the second three week period placebo is evaluated arm 2: In the first three week period placebo is evaluated whereas in the second three week period levomilnacipran is evaluated
Interventions: intervention 1: Levomilnacipran intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
Novel Medication as a Potential Smoking Cessation Aid 
 
 
NCT02265367 
 
02/26/2016 
 
 


The following is a summary of protocol changes approved by the IRB with the date of approval.  
The originally submitted and approved protocol follows this summary. 
 
04/06/15  
Switched from using the PRIME-MD at the screening visit to using the Patient 
Health Questionnaire (PHQ) 
 
06/15/15   Added Facebook as a recruitment method 
02/26/16 
Changed inclusion criteria to lower the required average number of cigarettes 
smoked per day from 8 to 5 cigarettes 
 
 


 
Novel Medication as a Potential Smoking Cessation Aid 
 
 
Principal Investigator 
Michael Kotlyar, PharmD 
Associate Professor 
Department of Experimental/Clinical Pharmacology 
University of Minnesota College of Pharmacy 
 
Co-Investigator: 
Dorothy K Hatsukami, PhD 
Forster Family Chair in Cancer Prevention 
Professor of Psychiatry 
Associate Director, Masonic Cancer Center 
 
Co-Investigator: 
Steven S. Fu, MD, MSCE 
Director, Center for Chronic Disease Outcomes Research 
Co-Chief, General Internal Medicine 
Minneapolis VA Health Care System 
Associate Professor of Medicine, University of Minnesota Medical School 
 
Co-Investigator and Study Physician 
John Vuchetich, MD, PhD 
Adjunct Associate Professor 
Department of Psychiatry 
University of Minnesota 
 
 
 
PI Contact Information 
Michael Kotlyar, PharmD 
Associate Professor 
Department of Experimental and Clinical Pharmacology 
College of Pharmacy 
7-153 Weaver Densford Hall 
308 Harvard St SE 
Minneapolis, MN 55455 
Phone:  612-625-1160 
Email:  kotly001@umn.edu  


 
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Table of Contents 
 
Study Abstract ............................................................................................................................... 3 
1 
Purpose and Rationale .......................................................................................................... 3 
2 
Objectives .............................................................................................................................. 4 
3 
Background ............................................................................................................................ 4 
4 
Study Design ......................................................................................................................... 5 
5 
Potential Risks of Study Participation and Protection Against Risk ....................................... 9 
6 
Statistical Considerations .................................................................................................... 10 
7 
Data and Safety Monitoring Plan (DSMP) ........................................................................... 11 
8 
References .......................................................................................................................... 12 
 
 
 


 
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Study Abstract  
Norepinephrine reuptake inhibitors are a class of medications that may be effective at facilitating 
smoking cessation but are currently understudied.  Nortriptyline has been shown to be effective 
at increasing quit rates in several studies and is thought to work via inhibition of norepinephrine 
reuptake.  Despite its efficacy, nortriptyline use is limited due to its other pharmacological 
properties (e.g. blockade of muscarinic and histamine receptors) which are responsible for side 
effects such as dry mouth, constipation, drowsiness and in overdose situations delayed cardiac 
conduction.  Due to its adverse effect profile and lack of FDA indication for smoking cessation, 
nortriptyline is not currently recommended as a first line therapy for smoking cessation with 
none of the recommended agents acting primarily via norepinephrine reuptake inhibition.  
Levomilnacipran is a medication approved for the treatment of depression that inhibits the 
reuptake of norepinephrine more potently than the reuptake of serotonin.  The objective of this 
study is to provide preliminary information in order to determine if levomilnacipran may be 
effective at increasing smoking cessation rates.  In this cross-over study, generally healthy 
smokers will be evaluated while receiving levomilnacipran and while receiving placebo.  The 
three week evaluation periods will occur in random order (i.e. one-half of the subjects will 
receive levomilnacipran followed by placebo, whereas the other half will first receive placebo 
followed by levomilnacipran).  The first week of each three week evaluation period will be to 
obtain baseline values, the second week to titrate medication and the third week to evaluate 
efficacy.     
1 
Purpose and Rationale  
Although 70% of smokers indicate a desire to quit, the best current treatments result in less than 
30% achieving long-term abstinence.1  New treatments for tobacco dependence are introduced 
rarely with only three medications currently approved for increasing smoking cessation rates 
(i.e. medicinal nicotine, varenicline, bupropion) and one additional medication consistently 
shown to be effective but rarely used due to concerns about adverse events (i.e., nortriptyline).  
Clearly, additional therapies are needed.  
Norepinephrine reuptake inhibitors are a class of medications that are likely to be effective at 
facilitating smoking cessation but are currently understudied.  Nortriptyline has been shown to 
be effective at increasing quit rates in several placebo controlled studies and is thought to work 
via inhibition of norepinephrine reuptake.2  Despite its efficacy, nortriptyline use is limited due to 
its other pharmacological properties (e.g. blockade of muscarinic and histamine receptors) 
which are responsible for side effects such as dry mouth, constipation, drowsiness and in 
overdose situations delayed cardiac conduction.  Due to its adverse effect profile and lack of 
FDA indication for smoking cessation, nortriptyline is not currently recommended as a first line 
therapy for smoking cessation.1  None of the other approved medications act primarily via 
norepinephrine reuptake inhibition.  Therefore, in order to confirm that norepinephrine reuptake 
inhibition is an important mechanism by which smoking cessation can be facilitated, studies are 
needed with other norepinephrine reuptake inhibitors that are well tolerated.  Levomilnacipran 
(recently approved for treating major depressive disorder) fits these criteria but there is no data 
regarding its effect on smoking.   
The proposed pilot study will use novel, recently published methods to assess if levomilnacipran 
is likely to be effective at increasing smoking cessation rates.  This rapid assessment study 
design developed by Perkins et al allows for the efficacy of a smoking cessation medication to 
be assessed more quickly and at lower cost than if a full scale clinical study were to be 
conducted.3-6  Positive results would lead to studies that could more definitively assess the 
efficacy of this agent at increasing smoking cessation rates.  Conversely, negative results would 
suggest that norepinephrine reuptake inhibition is not an important mechanism by which 
medications can increase quit rates and that other mechanisms need to be explored.   


 
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2 
Objectives 
Specific Aim and Hypothesis 
The central hypothesis of this project is that norepinephrine reuptake inhibitors in general and 
levomilnacipran in particular are effective at increasing smoking cessation rates.            
We are proposing to conduct a within subject, placebo controlled, cross-over study in which 52 
subjects will complete a study in which each subject will receive 12 days of placebo and 12 days 
of levomilnacipran in random order.  During the last five days of taking medication or placebo, 
subjects will attempt to quit smoking with abstinence confirmed at daily visits.  The number of 
days smokers are successfully abstinent will be compared between levomilnacipran and 
placebo.  
The following specific aim will be pursued: 
1) Determine the importance of norepinephrine reuptake inhibition as a mechanism by 
which a medication can increase smoking cessation rates  
We hypothesize that levomilnacipran (relative to placebo) will in a laboratory study alter smoking 
behavior in a manner consistent with a medication effective at increasing smoking cessation 
rates.  
3 
Background 
The morbidity and mortality associated with cigarette smoking has been well described.7  The 
best available therapies, however, result in less than a third of smokers remaining abstinent 6 
months after cessation.1  Clearly, it is imperative that strategies are developed to increase 
smoking cessation rates.  There are currently only two non-nicotine medications that are 
approved in the United States for smoking cessation.  Two additional medications are 
recommended as second line therapies in clinical practice guidelines (i.e., nortriptyline, 
clonidine), however only one of these agents (i.e., nortriptyline) has consistent data 
demonstrating its efficacy, with the recommendation to not use it as first line largely due to its 
high rates of adverse effects rather than questions regarding efficacy (conversely, the data with 
clonidine is mixed but meta-analyses have found it to be effective).1,8  All of the currently 
available medications therefore have limited efficacy and many have questions regarding their 
safety (e.g. varenicline has been associated with neuropsychiatric adverse effects; nortriptyline 
is associated with anticholinergic and antihistaminic side effects and toxicity in overdose).  It is 
critical that new medications are identified to treat tobacco dependence.  This is particularly true 
for smokers of menthol cigarettes (who are predominantly African American) as currently 
available medications appear to be even less effective in this group.9   
Nortriptyline efficacy is based on multiple studies in which it was shown to approximately double 
smoking cessation rates relative to placebo.2  Although it is an effective antidepressant, its effect 
on smoking cessation rates are not secondary to the treatment of an underlying depressive 
disorder since individuals with depression were usually excluded from nortriptyline smoking 
cessation studies.  The pharmacology of nortriptyline is complex, resulting in a variety of both 
therapeutic and adverse effects.  Nortriptyline belongs to the tricyclic antidepressant (TCA) 
class of medications which inhibit the reuptake of both norepinephrine and serotonin.  The ratio 
of norepinephrine to serotonin reuptake differs considerably among TCAs, with nortriptyline 
being among the agents that has the greatest degree of norepinephrine reuptake inhibition 
relative to serotonin reuptake inhibition (the ratio of norepinephrine to serotonin reuptake 
inhibition being approximately 4:1).10  Nortriptyline’s effects in the treatment of depression, 
several anxiety disorders and likely in tobacco dependence are due to its ability to inhibit the 
reuptake of norepinephrine and serotonin.  TCAs generally fell out of favor in the treatment of 
psychiatric disorders due to adverse effects, which is one of the reasons that nortriptyline is 
currently recommended as a second (rather than a first) line therapy in the treatment of tobacco 


 
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dependence.  Side effects of TCAs include anticholinergic effects, antihistaminic effects and 
cardiac conduction delaying effects resulting in side effects such as dry mouth, constipation and 
drowsiness.  Furthermore, in the case of overdose, these drugs can result in potentially serious 
arrhythmias.  Nonetheless, nortriptyline offers a model for a class of medications that may 
potentially be beneficial in treating tobacco dependence (i.e., norepinephrine reuptake 
inhibitors).  
The proposed study will assess a medication with similar pharmacological therapeutic effects as 
nortriptyline but without the pharmacological effects thought to be largely responsible for 
nortriptyline’s adverse effects.  This medication, levomilnacipran (brand name Fetzima), was 
approved in 2013 by the Food and Drug Administration to treat major depressive disorder.11  
Like nortriptyline, it inhibits both norepinephrine and serotonin reuptake but with an 
approximately two fold higher potency at blocking norepinephrine reuptake relative to serotonin 
reuptake.12  Unlike nortriptyline, levomilnacipran has no significant affinity for muscarinic or 
histaminic receptors11 and therefore lacks many of the side effects that limit nortriptyline’s use.   
This study is significant in that it will assess if levomilnacipran, a medication already approved 
for the treatment of major depressive disorder, can potentially also be used to increase smoking 
cessation success rates.  Its pharmacological similarity to nortriptyline suggests that this 
medication may be effective.  Findings suggesting efficacy would likely lead to additional studies 
to further evaluate levomilnacipran’s efficacy in treating tobacco dependence.  Identifying a 
potentially effective new medication to treat tobacco dependence would be highly significant 
since currently available medications are associated with either problematic side effects and / or 
poor efficacy.     
This study will additionally assess the impact of menthol cigarette smoking on treatment 
effectiveness.  In the United States there are approximately 19.2 million menthol cigarette 
smokers and the prevalence of menthol smoking is higher among African Americans, women 
smokers across race/ethnicity and younger smokers.  Menthol cigarettes also comprise about 
20% of the tobacco industry’s sales market and advertising of these types of cigarettes are 
specifically targeted to women and racial/ethnic minorities.  Current medications appear to be 
less effective in treating menthol smokers leading to sub-optimal treatment options in menthol 
smoking populations.9  
4 
Study Design 
a) General Approach:  In order to test if levomilnacipran is a potentially effective aid for smoking 
cessation, we propose to use methods described by Perkins et al in a series of four recent 
publications.3-6  These methods have been demonstrated to be both sensitive and specific for 
screening novel smoking cessation medications but are less costly and require less time to 
conduct than a full-scale smoking cessation efficacy study, which usually involve randomizing at 
least 100 participants into each of two treatment arms (i.e. at least 200 participants total) and 
following them for a period of over 3 months.  Less costly studies have traditionally used 
laboratory methods to determine if a drug blunts abstinence-induced symptoms such as 
withdrawal symptoms or if the drug briefly attenuates positive effects of acute smoking by 
assessing reductions in ad lib cigarette smoking.  Unfortunately, these methods are not highly 
predictive of medication efficacy.3  
In developing alternative methods, the aim was to be able to combine the practical advantages 
of laboratory studies with the validity of clinical trials.  The result was the development and 
validation of a within subject cross-over design in which smokers interested in cessation are 
asked to abstain from smoking for 5 consecutive days.  The number of days that smokers can 
successfully abstain from smoking is compared between a placebo condition and a medication 
condition.  A within subject cross-over design allows a smaller number of subjects to be used 


 
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than would be feasible using a parallel design.  The sample size needed is further reduced 
(relative to a smoking cessation clinical study) by using a continuous outcome measure (i.e. 
number of abstinence days) rather than a quit / not quit dichotomous measure.   
In a series of three papers, this method was used to test four medications.  Three of the 
medications tested are known to increase smoking cessation rates (i.e. nicotine patch, 
bupropion, varenicline) and one medication tested is known to not increase smoking cessation 
rates (i.e. modafanil).  Number of days abstinent (the primary outcome) was significantly higher 
during use of all three effective medications relative to placebo thereby demonstrating this 
method’s sensitivity.4-6  The number of days abstinent was not different between modafanil and 
placebo thereby demonstrating this method’s specificity.5  By examining motivation to quit on 
outcomes, the developers of this method found that the best results were obtained when those 
interested in cessation were recruited for studies using these methods. 
In order to determine if levomilnacipran is potentially effective at increasing smoking cessation 
rates, we will use the medication testing methods described and validated by Perkins et al.3   
b) Study Design Overview: We will utilize a cross-over, double-blind study design.  Three weeks 
of the study will be to evaluate levomilnacipran and three weeks will be to evaluate placebo with 
the two evaluation periods occurring in random order (i.e. one-half of the subjects will receive 
levomilnacipran followed by placebo, whereas the other half will first receive placebo followed 
by levomilnacipran).  The first week of each three week evaluation period will be to obtain 
baseline values, the second week to titrate medication and the third week to evaluate efficacy.  
In order to determine if effects of levomilnacipran depend on the type of cigarettes smoked (i.e. 
menthol vs. non-menthol), we will enroll an equal number of those smoking each type of 
cigarette.   
c) Subjects: Volunteers for this study will be recruited through flyers, advertisement and word of 
mouth. This study will be described in recruitment notices as an evaluation of the short-term 
effects of a medication to help smokers quit but also ‘not as a treatment study.’  This is 
consistent with how similar studies assessing medication efficacy have been advertised.5  
Approximately 19% of the population in Minnesota smokes.  There are therefore a sufficient 
number of smokers in the population to enroll the required number of study subjects.   We will 
be recruiting generally healthy smokers (smoking on average, > 8 cigarettes per day) who are 
motivated to quit smoking.  Motivation to quit will be determined by self-report.  Due to potential 
neuropsychiatric side effects of antidepressants in adolescents and young adults, we will only 
be recruiting subjects over the age of 24.  Smokers with medical or psychiatric conditions likely 
to place them at increased risk if they were to participate in the study or whose conditions might 
interfere with data interpretation will be excluded.  Similarly, smokers taking medication that 
might interfere with measures to be studied (e.g. psychiatric medications) or that would be 
expected to interact with or be unsafe to take with levomilnacipran will be excluded.   
 
Inclusion criteria are as follows: 
1) Be between > 25 years old and <55 years old   
2) Smoke, on average, at least 8 cigarettes per day for a period longer than 1 year  
3) Indicate motivation to quit smoking    
Exclusion criteria are as follows: 
1) Current serious or unstable medical or psychiatric condition (as determined by self-
reported medical history, the PRIME-MD and a physical exam)  
2) Use of medication that could interfere with measures to be studied (e.g. psychiatric 
medications) or that would be expected to interact with levomilnacipran (e.g. strong 
inhibitors of CYP3A4) 


 
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3) Substance abuse within six months of beginning the study based on self-report 
4) Regularly use any form of nicotine or tobacco other than cigarettes  
5) Are pregnant or breast feeding  (female subjects will be given a urine pregnancy test at 
the screening visit with pregnancy later in the study and breast feeding based on self-
report)  
We are planning to recruit an equal number of menthol and non-menthol cigarette smokers.  To 
qualify as a menthol smoker, greater than 80% of cigarettes smoked are menthol.   
 
c) Procedures 
c.1) Screening visit:  Initial eligibility will be assessed via a phone interview.  Those likely to 
qualify will be scheduled for a screening visit at which written informed consent will be obtained 
and eligibility confirmed.  Psychiatric exclusion will be based on the Primary Care Evaluation of 
Mental Disorders (PRIME-MD) instrument.  The PRIME-MD, designed to be administered by 
non mental health professionals, has been found to have good agreement with assessments 
made independently by mental health professionals.13  Medical history will be obtained via 
subject report and a physical exam will be performed to ensure that subjects are in generally 
good health.  A urine pregnancy test will be given to females to confirm that they are not 
pregnant.  Following the screening visit, those subjects who qualify will be scheduled for the 
remainder of their visits. 
c.2) Experimental Protocol: Subjects will participate in two evaluation periods each lasting three 
weeks. During one of the evaluation periods levomilnacipran will be evaluated whereas during 
the other evaluation period, placebo will be evaluated. Procedures for the two evaluation 
periods will be identical, with the order of which period occurs first (i.e. medication or placebo) 
assigned randomly. The procedures at each study visit are based on published methods. The 
first week of each period will consist of baseline smoking assessment. This week will also serve 
as a medication washout period when occurring as the first week of the second three week 
assessment period (with a terminal half-life of approximately 12 hours,11 this should be a 
sufficiently long washout period).  During this week subjects will be seen at the research clinic 
twice.  At the second baseline week visit subjects will  receive their initial supply of medication. 
Levomilnacipran will be dosed at 20 mg once daily for two days followed by 40 mg once daily for 
10 days. This is consistent with the recommended dose for the treatment of depression. 
During the second week of the evaluation period, subjects will begin to take their assigned 
medication (i.e. levomilnacipran or placebo) and will be seen at two visits.  At the first of these 
visits, subjects will receive a supply of the 40 mg dose of medication (or placebo).  Adverse 
events and subjective measures such as craving and withdrawal symptom severity will be 
assessed at each visit. 
During the third week of the evaluation period, subjects will attempt to abstain from smoking for 
a five day period and will be seen daily to determine smoking status. These visits will occur on 
five consecutive days with the visits in most instances occurring Monday through Friday.  
Subjects will be told to smoke normally until the evening prior to the first of the abstinence 
assessment days and then to attempt to not smoke at all during the subsequent five days. At 
each visit, smoking status will be evaluated by measuring exhaled carbon monoxide (CO) 
concentrations with a value of < 5 ppm confirming abstinence. Each visit during this week will be 
scheduled in the afternoon in order to assess mid-day CO rather than CO after just waking up.  
Subject will stop taking medication after they complete their five consecutive days of study 
visits. 


 
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The same procedures will then be repeated except that subjects will receive the alternate 
treatment. Since continued participation in the study will require subjects to resume smoking, 
subjects will be told that it is not necessary for them to resume smoking if they wish to remain 
abstinent; however they would not be able to continue participation in the study if this were the 
case. At the conclusion of the study, subjects will be given information about resources in the 
community that could assist them with the smoking cessation attempt. They will additionally be 
called by telephone approximately 1 week after completing the study in order to ensure that 
there are no adverse events and to ascertain if they have attempted to quit smoking. Those that 
have not made a cessation attempt will be encouraged to do so and will again be provided with 
information regarding community resources to assist them. 
Subjects will therefore be seen at a screening visit and at 9 visits per study period for a total of 
19 visits. 
d) Justification for Drug Dosing: Subject will initiate levomilnacipran at 20 mg daily for 2 days 
and will then increase the dose to 40 mg once daily for the next 10 days.  The recommended 
dose when used for the treatment of depression is 40 mg to 120 mg.  A review of the clinical 
studies with levomilnacipran however demonstrates that there is little difference in 
antidepressant efficacy across the dosage range.14  Furthermore, smoking cessation studies 
assessing the efficacy of nortriptyline have used doses at the lower end of the recommended 
dosage range (smoking cessation studies have evaluated daily doses of 75 to 100 mg with the 
dosage range for depression being 75 mg to 150 mg per day).  In order to minimize the risk of 
adverse events and in order to simplify the titration period (40 mg requires one dosage increase 
whereas 80 mg per day would require two dosage increases and 120 mg per day would require 
three dosage increases) we have decided to select a dose at the lower end of the therapeutic 
range but one that has clearly demonstrated efficacy when used in the treatment of depression.  
The duration of treatment is based on data demonstrating that bupropion and nortriptyline are 
successful at increasing smoking cessation rates after one week of treatment.  Active 
medication and placebo will be prepared by the University of Minnesota Investigational Drug 
Services by over-encapsulating active drug and preparing matching placebo.    
d) Subject recruitment and payment: Subjects will be recruited via the use of flyers and 
advertisements in local newspapers or on internet resources such as Craigslist.  Additional 
recruitment avenues such as radio advertising will be used if necessary.  Our research team 
has considerable experience recruiting subjects into smoking studies and has determined which 
advertisement strategies are most effective.     
Subjects will receive $20 for each visit that they complete with an additional $15 bonus for each 
day of confirmed abstinence during the abstinence assessment visits occurring at week 3 of 
each medication period.  Subjects who attend all study visits and comply with all study related 
procedures will receive a $60 bonus (regardless of how successful they are at cessation). 
Subjects can therefore receive up to $590 for completing the entire study.   
e) Outcome Measures: The primary outcome measure is the number of days of confirmed 
abstinence during the third week of each assessment period (out of a maximum of 5 days).  A 
secondary outcome is the percentage of subjects who are abstinent at all five cessation visits.   
Additionally at each visit, subjects will complete the Minnesota Nicotine Withdrawal Scale 
(MNWS), the Subjective State Scale (SSS) and the Questionnaire of Smoking Urges (QSU-
Brief).  Subjects will also be asked to report any adverse events they have experienced.  The 
Minnesota Nicotine Withdrawal Scale, is a widely used scale to assess nicotine withdrawal 
symptoms.15  The positive affect and distress subscales of the SSS, have been found to be 
reliable at assessing these mood symptoms (alphas are 0.85 and 0.82, respectively).16  The 
Brief version of the Questionnaire of Smoking Urges (QSU-Brief) is a commonly used scale to 
assess nicotine craving with a score for each of two factors (i.e. intention and desire to smoke, 


 
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anticipation of relief from negative affect) calculated in order to examine several aspects of the 
urge to smoke.17   
5 
Potential Risks of Study Participation and Protection Against Risk 
a.  Risks to subjects: Levomilnacipran is generally well tolerated with the most common side 
effects reported being nausea / vomiting, constipation, excessive sweating, increased heart 
rate, urinary hesitation, palpitations and erectile dysfunction.  Although occurring rarely other 
side effects including but not limited to mania, rash and allergic reaction, mydriasis, increases in 
blood pressure and abnormal bleeding have been occasionally reported.  There is the possibility 
that when discontinuing levomilnacipran, subjects may experience a withdrawal syndrome that 
includes symptoms of dizziness, nausea and paresthesias.   Questionnaires will be used to 
assess a variety of measures to ensure eligibility for the study and to measure outcomes of 
interest such as cigarette craving and withdrawal symptoms.  Some of these questionnaires 
may ask questions that subjects would consider personal. 
As with any medication, there is a risk that unanticipated side effects may occur.  
b. Adequacy of protection against risk: This study will be submitted for approval by the 
University of Minnesota Institutional Review Board.  The study will be explained to subjects by 
an investigator or a study coordinator trained in the protection of human subjects (per university 
guidelines) and subjects will have an opportunity to ask any questions prior to signing an 
informed consent form.   
Levomilnacipran, like all antidepressants, has a warning regarding increased risk of suicidal 
thinking and behavior in children, adolescents and young adults.  For this reason, we are 
limiting enrollment to those over the age of 24.  Additionally, we are limiting enrollment to 
generally healthy individuals ages 55 and under.  Individuals with medical or psychiatric 
conditions likely to place them at increased risk of being in the study will be excluded.  Medical 
and psychiatric history will be obtained via subject report and a physical exam will be performed 
to ensure that subjects are in generally good health.  Similarly, smokers taking medication that 
might interfere with measures to be studied (e.g. psychiatric medications) or that would be 
expected to interact with or be unsafe to take with levomilnacipran (e.g. strong CYP3A4 
inhibitors) will be excluded.  Additionally, we are using a relatively low dose of medication (the 
dose being used is the lowest recommended dose when used for the treatment of depression).  
Although many side effects are not reported to be dose related, side effects such as erectile 
dysfunction and urinary hesitancy appear to be.11  The risk of these side effects should be 
decreased due to the low dose being used as should the risk of withdrawal symptoms after 
discontinuation of the medication.  
Subjects will be informed that they are free to not answer any questions that they are 
uncomfortable with, however by doing so they may be excluded from the study if eligibility 
cannot be assessed or dropped from the study if measures of interest cannot be ascertained.  
To ensure confidentiality, all subjects enrolled in the study will be assigned a study identification 
code.  These codes will be used on all study related data collection forms except for those on 
which the use of personal identifiers is mandatory (e.g. informed consent form).  Forms that link 
the name of the participant and the subject identification code will be kept in a locked cabinet or 
office or in an electronic file stored on password protected computer servers meeting University 
guidelines.  Access to subject identifiable information will be limited to those that require this 
information such as study investigators or others who have direct contact with study subjects 
(e.g. study coordinator). 
 
 


 
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6 Statistical Analysis 
a. Statistical Methods of Data Analysis 
a.1) Statistical Design: A within-subject cross-over design will be used for the study in which 
smokers will receive levomilnacipran and placebo (double-blind) with the order of treatment 
being randomly assigned. The primary aim is to compare the number of abstinent days between 
levomilnacipran and placebo by type of cigarette smoked (menthol cigarette and non-menthol 
cigarette). A secondary aim is to compare levomilnacipran responses between menthol 
cigarette smokers and non-menthol cigarette smokers. 
a.2) Outcome Variables and Measurements: The primary outcome is the number of days 
abstinent during the third week of each assessment period as assessed by self-report of no 
smoking that day and verified by an exhaled carbon monoxide (CO) concentration of <5 parts 
per million.  A secondary outcome is the percentage of subjects who are abstinent at all five 
cessation visits. The other outcomes include ratings on the Minnesota Nicotine Withdrawal 
Scale (MNWS), the Subjective State Scale (SSS), the Questionnaire of Smoking Urges (QSU-
Brief) and frequency of reported adverse events.   
a.3) Hypotheses: The following hypothesis will be tested: 1) Levomilnacipran increases the 
number of abstinent days vs. placebo.  This hypothesis will then be tested separately for 
smokers of menthol cigarettes and for smokers of non-menthol cigarettes.  2) A secondary 
hypothesis is that the increase in number of abstinent days will be lower in smokers of menthol 
cigarettes than in smokers of non-menthol cigarettes (i.e. levomilnacipran will be less effective 
in smokers of menthol vs. non-menthol cigarettes).   
a.4) Data analysis: A paired t-test will be used to test treatment effect based on days of 
abstinence per quit assessment week (range 0-5, not necessarily consecutive) between 
levomilnacipran and placebo.  Additional separate analyses for menthol and non-menthol 
cigarette smokers will be conducted.  A two-sample t-test will be used to compare the difference 
in days of abstinence per quit assessment week for menthol cigarette smokers compared to 
non-menthol cigarette smokers.  
Repeated measures Analysis of Variance (ANOVA) will be used for days of abstinence per quit 
assessment week, assuming mixed effects three-factor ANOVA model (“Order of phases” with 
two levels, “Treatment” with two levels, “Menthol cigarettes smoker” with two levels, subject 
effects are random); then use contrasts to compare treatment with placebo for all participants 
and for menthol cigarette smokers and non-menthol cigarette smokers separately. This 
approach allows us to investigate primary and secondary aims simultaneously, therefore, to 
potentially achieve higher statistical power. The use of paired t-tests, on the other hand, 
provides a proper tool for sample size determination as seen in the following section.  
Generalized estimating equation (GEE) model will be used to analyze the longitudinal data, with 
the number of subjects able to maintain continuous abstinence on all 5 days throughout the quit 
week as the secondary outcome. Treatment effect (levomilnacipran vs. placebo) and cigarette 
type effect (menthol vs. non-menthol) will be estimated.  
Secondary variables such as scores on the MNWS, SSS and QSU-Brief will be summarized by 
the mean, standard deviation, median and range.  The change in these measures occurring 
between baseline (i.e. the first week of treatment) and the last day of the third week will be 
compared between drug and placebo.  Similar two-factor ANOVAs will be used to analyze each 
of the calculated differences as the primary endpoint.  Additionally, frequency of subject 
reported adverse events will be compared between treatments via the use of paired t-tests.    
a.5) Power Consideration: The adequacy of planned sample sizes are assessed using two-
sided paired t-test.  We tested the “minimum detectable difference”, expressed as the number of 
standard deviations (i.e. “effect size”) for several sample sizes where the two-sided paired t-test 
is pre-set at a 5% significance level and 80% power. The variability is based on estimates found 


 
Page 11 of 12 
  
in the literature by others using these methods.5  With a total of 52 subjects completing the 
study (26 menthol smokers and 26 non-menthol smokers), we are able to detect an effect size 
of 0.57 standard deviations for the comparisons between levomilnacipran and placebo which is 
considerably smaller than the effect size of approximately 1.65 reported by Perkins et al for 
bupropion.5  Since we anticipate a 20% attrition rate, we are planning on enrolling 64 smokers in 
total (32 smokers of menthol cigarettes and 32 smokers of non-menthol cigarettes).       
7 
Data and Safety Monitoring Plan (DSMP) 
The principal investigator in conjunction with the study physician will be responsible for 
monitoring adverse effects.  At the conclusion of each visit subjects will be asked whether they 
have had any side effects.  Any positive response will be followed up with questions regarding 
details of what the adverse effect was and the severity.  To the extent possible, each adverse 
event will be evaluated to determine 1) its severity (mild, moderate, severe), 2) its relationship to 
the study medication; 3) its duration and 4) whether it constitutes a serious adverse event.      
The participation of any subject will be discontinues if they develop a side effects of greater than 
moderate severity (as determined by the investigators) or develops any symptoms that in the 
opinion of the investigators would warrant discontinuation from the study.  Participation in the 
study would also be discontinued if during the course of the study the subject develops a 
significant medical condition (regardless of whether it can be attributed to the study drug) or is 
initiated on medication that can be expected to interact with the measures being assessed or 
increase the risk of being on the study medication.  The subject has the option of discontinuing 
their participation at any time for any reason.  Adverse events will be reported to the IRB as 
required per IRB guidelines.   
 


 
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8 
References 
1. 
Fiore MC, et al. Treating tobacco use and dependence: 2008 Update. Clinical 
Practice Guidelines. U.S. Department of Health and Human Services. Public 
Health Service. Rockville, MD2008. 
2. 
Hughes JR, et al. Antidepressants for smoking cessation. Cochrane Database 
Syst Rev. 2014;1:CD000031. 
3. 
Perkins KA, et al. An efficient early phase 2 procedure to screen medications for 
efficacy in smoking cessation. Psychopharmacology (Berl). 2014;231:1. 
4. 
Perkins KA, et al. Cross-validation of a new procedure for early screening of 
smoking cessation medications in humans. Clin Pharmacol Ther. 2010;88:109. 
5. 
Perkins KA, et al. Sensitivity and specificity of a procedure for early human 
screening of novel smoking cessation medications. Addiction. 2013;108:1962. 
6. 
Perkins KA, et al. Development of procedures for early screening of smoking 
cessation medications in humans. Clin Pharmacol Ther. 2008;84:216. 
7. 
USDHHS. The Health Consequences of Smoking - 50 Years of Progress. 
Washington, D.C.: Office of the Surgeon General; 2014. 
8. 
Kotlyar M, et al. Effect of nonnicotine pharmacotherapy on smoking behavior. 
Pharmacotherapy. 2001;21:1530. 
9. 
TPSAC. Tobacco Products Scientific Advisory Tobacco.  Menthol Cigarette and 
Public Health: Review of the Scientific Evidence and Recommendations. 2012. 
2012; 
http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/TobaccoP
roductsScientificAdvisoryCommittee/ucm247605.htm. 
10. 
O'Donnell JM, et al. Drug Therapy of Depression and Anxiety Disorders. In: 
Goodman LS, Gilman A, Brunton LL, Lazo JS, Parker KL, eds. Goodman & 
Gilman's The Pharmacological Basis of Therapeutics. 12th ed. New York: 
McGraw-Hill, Medical Publishing Division;  2011. 
11. 
Product Information. Fetzima (levomilnacipran hydrochloride) extended-release 
capsules. Forest Laboratories 2013. 
12. 
Auclair AL, et al. Levomilnacipran (F2695), a norepinephrine-preferring SNRI: 
profile in vitro and in models of depression and anxiety. Neuropharmacology. 
2013;70:338. 
13. 
Spitzer RL, et al. Utility of a new procedure for diagnosing mental disorders in 
primary care. The PRIME-MD 1000 study. Jama. 1994;272:1749. 
14. 
Citrome L. Levomilnacipran for major depressive disorder: a systematic review of 
the efficacy and safety profile for this newly approved antidepressant--what is the 
number needed to treat, number needed to harm and likelihood to be helped or 
harmed? Int J Clin Pract. 2013;67:1089. 
15. 
Hughes JR, et al. Signs and symptoms of tobacco withdrawal. Arch Gen 
Psychiatry. 1986;43:289. 
16. 
al'Absi M, et al. Attenuated adrenocortical and blood pressure responses to 
psychological stress in ad libitum and abstinent smokers. Pharmacol Biochem 
Behav. 2003;74:401. 
17. 
Cox LS, et al. Evaluation of the brief questionnaire of smoking urges (QSU-brief) 
in laboratory and clinical settings. Nicotine Tob Res. 2001;3:7.