Clinical trial NCT00943618
Conditions: Smoking Cessation
Keywords: Smoking Cessation Nicotine Withdrawal Smoking Reduction Varenicline Chantix Bupropion Zyban
Sponsor: M.D. Anderson Cancer Center
Start date: 2010-05-17; Completion date: 2021-09-09
Enrollment: 641 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical research study is learn if the combination of Chantix (varenicline) and Zyban (bupropion) is more effective at helping people to quit smoking than varenicline when given alone. Researchers also want to learn if this drug combination can reduce cravings and other negative symptoms of nicotine withdrawal better than varenicline does alone. The safety of this drug combination will also be tested.

Detailed description:
The Study Drugs:

Bupropion and varenicline are designed to imitate the effects that nicotine has on the body. This may reduce cigarette cravings and help patients quit smoking.

Study Groups:

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the roll of a dice) to 1 of 3 treatment groups.

* If you are in Group 1, you will receive varenicline and bupropion.
* If you are in Group 2, you will receive varenicline and a placebo. A placebo is a substance that looks like the study drug (in this case, bupropion) but that has no active ingredients.
* If you are in Group 3, you will receive a placebo that looks like varenicline and a placebo that looks like bupropion.

You will have a higher chance (5 out of 6) of receiving study drug than receiving just placebo. Equal numbers of patients will be in Groups 1 and 2. Neither you nor the study doctor will know to which group you are assigned. However, if needed for your safety, the study staff will be able to find out which study drug you are receiving.

Study Drug Administration:

You will begin taking the study drugs/placebo 1 to 10 days after the first study visit. A dose of the study drug/placebo combination will be made up of 1 tablet of varenicline or placebo and 1 tablet of bupropion or placebo. You should take each dose of study drugs/placebo with a cup (8 oz.) of water after eating a full meal.

On Days 1-3, you will take 1 dose of the study drug/placebo combination in the morning.

Beginning on Day 4, and then every day after that, you will take 1 dose in the morning and 1 dose in the evening (for a total of 2 doses of the study drug/placebo combination each day). You must return any study drug bottles as well as any unused study drug to a study staff member at each study visit.

You will be given a smoking diary to record how many cigarettes you smoke (if any) each day while you are on study. You must turn in this diary at each study visit.

Study Visits:

About 1 time each week while you are taking the study drugs/placebo, the following tests and procedures will be performed:

* Your weight and blood pressure will be measured.
* Your CO level will be measured.
* You will be asked about any other drugs you may be taking and about any side effects you may be having.
* You will answer 8 questionnaires about several topics, including depression, suicide, your smoking behavior, any effects from the study drugs, and any symptoms of attention-deficit hyperactivity disorder (ADHD). These should take about 30-45 minutes total to complete.
* You will do tasks that will measure your logic and attention. These will take about 15 -20 minutes to complete.
* You will receive counseling about quitting smoking in which you discuss possible "triggers" for smoking and strategies for dealing with quitting smoking. These sessions will take about 15 minutes each time.

During counseling at the first study visit, you will set a "quit date" for stopping smoking for about 1 week after you start taking the study drug. You should not quit smoking before the quit date. You should stay smoke-free after the quit date. Additionally, you will be given a medication instruction sheet, a card with emergency contact information, and a participant manual to help you follow along with the topics discussed during counseling.

At Week 2, saliva will be collected to check your cotinine level.

At Week 4, blood (about 2 teaspoons) will be drawn to assess liver and kidney function.

Lab Sessions:

You may be asked to take part in lab sessions during Visits 1, 2, and 6 to test your brain activity and attention span. You will be asked to watch slides and listen to a series of tones. The slides will include pictures of people, nature, and artwork. Slides showing nude people, medical procedures, and victims of car crashes will also be shown. You will be shown examples of these slides before beginning the procedure and given the opportunity to withdraw from the study.

During the lab sessions, your brain electrical activity (EEG) will be monitored. To do this, small sensors will be placed on your scalp and face. You should not drink more than 2 cups of coffee or other caffeinated drinks for at least 2.5 hours before each session. At the first lab session, you may be asked to smoke a cigarette if the doctor thinks it is needed for you to exhibit your normal smoking behavior.

Length of Study:

You will receive the study drug for up to 12 weeks. However, the entire length of the study is about 13 months (55 weeks), which includes 3, 6, and 12-month post-quit follow up visits. You will be taken off study if the doctor thinks it is in your best interest.

End-of-Study Visit:

After you have finished taking the study drugs/placebo, the following tests and procedures will be performed:

* Your weight and blood pressure will be measured.
* Your CO level will be measured.
* You will be asked about any side effects you may be having and about any other drugs you may be taking.
* Blood (about 2 teaspoons) will be drawn to assess liver and kidney function.
* You will answer the same questionnaires you completed at the regular study visits. These should take about 30-45 minutes total to complete.
* Saliva will be collected to measure your cotinine level.

Follow-Up Visits:

About 3, 6, and 12 months after you have stopped smoking, the following tests and procedures will be performed:

* Your weight, heart rate, and blood pressure will be measured.
* Your CO level will be measured.
* You will be asked about any side effects you may be having and about any other drugs you may be taking.
* You will answer the same questionnaires you completed at the regular study visits. These should take about 30-45 minutes total to complete.
* Saliva will be collected to measure your cotinine level.

You will be called by the study staff 1 day before your quit date, 3 days after your quit date, and at Weeks 14, 20, 34, 42, and 48 weeks after your quit date to check on your progress in quitting smoking. Each call should take about 10-15 minutes.

This is an investigational study. Varenicline and bupropion are both FDA approved and commercially available to help people stop smoking. The use of the drugs in combination is investigational.

Up to 385 participants will take part in this study. All will be enrolled at MD Anderson.

Arms: arm 1: Varenicline and Bupropion arm 2: Varenicline and Placebo arm 3: Placebo that looks like varenicline and a placebo that looks like bupropion.
Interventions: intervention 1: Varenicline intervention 2: Bupropion intervention 3: Placebo intervention 4: Counseling/Phone Calls
Intervention descriptions: intervention 1: On Days 1-3, .5mg tablet by mouth in the morning. Beginning on Day 4, and then every day after that, .5mg tablet by mouth in the morning and .5mg tablet by mouth in the evening (for a total of 2 doses). intervention 2: On Days 1-3, 150 mg tablet by mouth in the morning. Beginning on Day 4, and then every day after that, 150 mg tablet by mouth in the morning and 150 mg tablet by mouth in the evening (for a total of 2 doses). intervention 3: On Days 1-3, 1 tablet by mouth of placebo that looks like the study drug in the morning. Beginning on Day 4, and then every day after that, 1 tablet by mouth in the morning and 1 tablet by mouth in the evening for a total of 2 doses of the placebo each day. intervention 4: Brief-behavioral counseling sessions (10-15 minutes) provided to all participants once per week for 12 weeks. One support phone call conducted 3 days after the target quit date.

Protocol documents:
Prot_SAP_000.pdf: 
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Protocol 2008-0850 
 
 
Effectiveness of Varenicline vs. Varenicline plus Bupropion or 
Placebo for Smoking Cessation 
 
 
PI:  Paul M. Cinciripini, Ph.D. 


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Table of Contents 
 
 
 
OVERVIEW 
1 
A. SPECIFIC AIMS 
2 
B. BACKGROUND AND SIGNIFICANCE 
2 
C. PRELIMINARY STUDIES 
9 
D. RESEARCH DESIGN AND METHOD 
13 
TREATMENT INTERVENTION 
23 
DATA ANALYSIS 
27 
INTERIM ANALYSIS 
32 
E. HUMAN SUBJECTS RESEARCH - PROTECTION OF HUMAN SUBJECTS 
33 
DATA AND SAFETY MONITORING PLAN 
35 
F. VERTEBRAE ANIMALS-NA 
41 
G. LITERATURE CITED 
41 
H. CONSORTIUM/CONTRACTUAL ARRANGEMENTS - NA 
42 
I.  CONSULTANTS - NA 
42 


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Overview 
It is estimated that cigarette smoking is responsible for over 40% of premature deaths and disability in 
the US. The adverse health risks of smoking increase significantly with duration and amount smoked per day, 
and it is precisely these heavier and more nicotine dependent smokers who are most refractory to treatment 1. 
Although significant advances have occurred in smoking cessation therapy, approximately 23.4% of men and 
18.5% of women continue to smoke 2. Smoking has been characterized as a chronic relapsing disorder. Over 
40% of smokers make a serious cessation attempt each year but less than 3% of all smokers successfully quit 
3. 
 Nicotine is a ubiquitous drug with subtle effects on a smokers’ mood and cognitive performance. 
Difficulty quitting has been strongly related to affective and cognitive dysfunction following abstinence. Multiple 
biological pathways (i.e., dopaminergic, noradrenergic, cholinergic) and structures (i.e. limbic system-prefrontal 
cortex and Anterior Cingulate Cortex-ACC) are involved in mediating these effects and hence 
pharmacologically based treatments have focused on several biological targets. While current smoking 
cessation pharmacotherapies have produced several positive outcomes 4–6, no “magic bullet” has emerged, 
nor does it seem likely that will be the case. Much like the treatment of depression, the psychobiological 
complexity of the nicotine dependence disorder suggests that multiple therapies should be made available to 
account for individual differences in treatment response.  
The focus of this proposal is the evaluation of the combined effects of varenicline and bupropion, both 
in their own right FDA approved medications for smoking cessation. Both have shown effectiveness in 
randomized clinical trials for smoking cessation and the treatment of nicotine withdrawal symptoms. Bupropion 
is an atypical antidepressant whose properties include inhibition of norepinephrine re-uptake, modest 
dopamine re-uptake inhibition and noncompetitive nicotine antagonist effect 7. Vann 8 have found it to exhibit 
both NACHR agonist and antagonist-like effects. 
 Varenicline acts primarily as a strong and highly selective partial agonist of the α4β2 nicotine 
cholinergic receptor in particular at the Ventral Tegmental Area (VTA) of the mesolimbic dopamine system, 
resulting in an attenuated release of dopamine in the nucleus accumbens, relative to nicotine. The results from 
the pivotal trials of varenicline showed it to be more effective than bupropion alone. However, there are several 
lines of reasoning to suggest that the combination of these drugs might be more effective than varenicline used 
in isolation. Plausible differences in the mechanisms of action of the two drugs and differences in their intensity 
of action within the same pathways, suggest that combining these medications will affect a broader range of 
biological targets identified as important for smoking cessation. For example, one might expect enhanced 
effects on the dopaminergic pathway by combining the two drugs: reduced re-uptake of dopamine as a 
function of bupropion; and a more sustained release of dopamine in the nucleus accumbens with varenicline 
(albeit attenuated relative to nicotine). Varenicline has not been shown to have noradrenergic properties and is 
unlikely to have strong antidepressant effects (recent reports suggest it may have depressogenic effects in 
some individuals), whereas bupropion does affect the noradrenergic pathways which are believed to account in 
part for its antidepressant effects. This may offer an additional advantage of the combination therapy. At least 
one study has suggested that bupropion may improve the abstinence rates among those with a history of 
depression, relative to placebo. It may be that those with a history of depression are more likely to experience 
an exacerbation of symptoms while quitting and are possibly at greater risk for this the varenicline group. The 
addition of bupropion might reduce the likelihood of this occurring. In addition, while both medications have 
been shown to reduce nicotine withdrawal, negative affect, craving and some indices of smoking reinforcement 
(satisfaction), some of the subscales of these measures are affected by one drug and not the other and varying 
effect sizes between the two drugs are observed for the others. Moreover, the separate and combined effect of 
both drugs on noradrenergic and dopaminergic pathways involved in cognitive and attentional function might 
ameliorate deficits in these areas related to smoking cessation. This raises the possibility that additive effects 
on several psychological predictors of relapse (e.g., negative affect and craving) as well measures of smoking 
reinforcement and cognitive performance might be observed when the two drugs are combined. 
The vast majority of research in the pharmacological treatment of nicotine dependence has focused on 
the evaluation of single medications in placebo controlled trials, which by definition represents a “one-size fits 
all” approach to the application of the treatment. While this is appropriate in the initial stages of treatment 


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evaluation, the potential for combined treatments to raise the level of efficacy above individual treatments is 
often unexplored. Medication development research is almost exclusively sponsored by pharmaceutical 
companies, whose interests are not typically served by taking a combination approach (particularly when the 
other medication is generic or made by another company, although there are exceptions). It remains for 
researchers outside the pharmaceutical industry to evaluate such treatments. While it is still early in the history 
of use of varenicline, it appears to represent a significant advance over the treatments available to date. 
Nevertheless, the potential for improving treatment efficacy does exist, and combination therapies represent 
one way in which this may be realized. Increasing the diversity of available treatments for nicotine dependence 
can have a significant impact on the public health, as we attempt to understand, and in some cases reduce the 
impact of individual differences on treatment response. However, the first step in this process is to establish 
the efficacy of a treatment (combined) so that it may enter the mainstream of available therapies and that is the 
main objective of this proposal.  
 
A. Specific Aims  
 
Primary Aim: 
1. To evaluate the efficacy of varenicline plus bupropion (VB) vs. varenicline (V) or Placebo (P) alone for 
smoking cessation, 
1.1 We hypothesize that smokers treated with the combination therapy will be abstinent significantly more 
often and take a longer time to relapse at 12 months follow-up than those treated with either varenicline 
or placebo alone. 
 
Exploratory Aims: 
1. To evaluate the effects of VB vs. V and P on measures of nicotine withdrawal, negative affect, smoking 
reinforcement, sleep problems, and craving, and measures of cognitive performance. 
1.1 We hypothesize that smokers treated with the combination therapy will report significantly lower levels 
of nicotine withdrawal symptoms, negative affect, depressive symptoms, smoking reinforcement, sleep 
problems, and craving over the course of treatment, and improved cognitive performance during 
quitting, than those treated with varenicline or placebo alone. 
2. To evaluate the effects of VB vs. V and P on lapse progression  
2.1 This is an exploratory aim to evaluate possible differences between the two active treatments on time to 
an initial lapse; and time between an initial lapse and relapse. This later analysis will involve smokers 
who achieve initial abstinence but who are not continuously abstinent during treatment. This is a group 
of smokers for which little is known given the concentration of pharmaceutical research on treatment 
efficacy involving smokers who are continuously abstinent. We will test for the possibility that VB is 
more beneficial than V or P on preventing a lapse from resulting in a relapse. 
3. To evaluate the effects of VB vs. V and P on smoking reduction among those who fail to quit. 
3.1 We hypothesize that non-abstinent smokers treated with VB will smoke significantly less than smokers 
treated with V or P.  
 
B. Background and Significance 
In the following sections, we will review converging lines of evidence suggesting that VB may be an 
important combination treatment for smoking cessation pharmacotherapy. The target population for this study 
is the general population of smokers. We will review current drug treatments for smoking cessation their 
pharmacological properties, and provide a rationale for the clinical use VB in the treatment of nicotine 
dependence. 
Pharmacological Treatment used for Smoking Cessation. Until just recently, much of the focus of 
pharmacotherapy for smoking cessation has been on the use of nicotine replacement therapies (nicotine gum, 
patch, and lozenge) and antidepressants for the treatment of nicotine dependence. Several studies and meta-
analyses have established the efficacy of the nicotine replacement therapies in smoking cessation, showing 
approximately a doubling of cessation rates over placebo 9. Although numerous antidepressants have been 


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examined in clinical trials for their effectiveness to treat smoking cessation, only bupropion and nortriptyline 
have been consistently related to long term abstinence from smoking 10. 
 Bupropion (amfebutamone) is an atypical antidepressant whose mechanism of action is thought to be 
mediated through both dopaminergic (DA) and noradrenergic (NE) systems. Findings from in vitro experiments 
suggest that bupropion is a modest inhibitor of NE uptake and weaker inhibitor of DA uptake 11. Bupropion 
produces a dose-dependent increase in dopamine concentrations in the nucleus accumbens in the mesolimbic 
system of rats 12. Other research suggested that bupropion may also act as a noncompetitive nicotine 
antagonist, which might reduce the reinforcing properties of nicotine.13 In particular one of its metabolites’ 
(2S,3S) hydroxybupropion has been postulated as a better antagonist on α4β2 nicotine receptor target than 
bupropion itself 14.It is of interest that Vann 8 have found bupropion to exhibit both nACHR agonist and 
antagonist-like effects in presence of nicotine, and if confirmed this would be similar to a partial agonist effect 
seen with varenicline, which could lead to  possible potentiation when the two medications are combined. 
Studies examining bupropion’s antidepressant effects suggest it is more effective in suppressing the firing rate 
of norepinephrine than dopamine neurons at locus coeruleus (LC) in rats 15,16. A decrease in the neuronal firing 
rate in the LC is an indication of high level of synaptic norepinephrine concentrations possibly caused by a 
blockade of neurotransmitter reuptake. Thus, it is suggested that bupropion’s antidepressant effects may be 
mediated through noradrenergic rather than dopaminergic pathways. Interestingly, desensitization of α2 
adrenoreceptors 17 is also thought to play a role in the negative affect associated with cocaine withdrawal, a 
situation like that of nicotine withdrawal, that enhances relapse vulnerability, In a meta-analysis based on 31 
clinical trials of bupropion  administered to over 10,000 participants, Hughes and colleagues 10 found that 
smokers who received the drug were twice as likely as those who received placebo to have achieved long-term 
abstinence (OR= 1.94; 95% CI, 1.72 -2.19,). At least one study suggests negative affect reduction as 
measured by the PANAS (Positive and Negative Affect Scale18 may mediate bupropion’s efficacy 19.  
Nortriptyline is a tricyclic antidepressant that has highly specific effects on NE reuptake inhibition 20. It 
is10 times more potent than venlafaxine (a drug used in our previous studies) in this regard and about 7 times 
less effective at serotonin reuptake inhibition. In contrast to bupropion, it is almost 50 times more effective at 
NE reuptake inhibition but 6 times less effective at dopamine reuptake inhibition (in vitro) 20. In the most recent 
Clinical Practice Guidelines, nortriptyline has been recommended as an effective treatment for smoking 
cessation 21. While seemingly effective, nortriptyline is typically less well tolerated than bupropion and is not 
typically used in everyday treatment of nicotine dependence. Bupropion in contrast to nortriptyline is an FDA 
approved medication for smoking cessation, has far fewer side effects, and requires much less medication 
management and pretreatment screening in clinical practice. For example, prior to nortriptyline therapy 
physicians often conduct a screening ECG to rule out AV block or arrhythmias. Blood levels are also monitored 
after therapy is initiated in order to titrate the dose to a therapeutic range. Neither medical management 
procedures are routinely conducted for either bupropion or varenicline.  
Other antidepressants including doxepin, fluoxetine, imipramine, moclobemide, paroxetine, sertraline 
and tryptophan, and the anxiolytic, buspirone have also been examined in smoking cessation trials. While 
some individual studies have shown short term or limited success with these drugs, most have failed to support 
a significant effect on long-term abstinence 22. The exception is our study using venlafaxine, a norepinephrine 
and serotonin reuptake inhibitor that was found to improve the chance of abstinence among smokers who 
smoked less than a pack of cigarettes per day23. 
In the summer or 2006, a new agent, varenicline (Chantix ®) was approved by the FDA for smoking 
cessation. Varenicline is a highly selective partial agonist of the α4β2 nicotine cholinergic receptor (nACHR). It 
stimulates dopamine release in the nucleus accumbens (nAC) of animals, but to a much less extent than 
nicotine itself, and by binding at the receptor throughout its relatively long half-life (24 hrs), it displays 
antagonist properties, by preventing full stimulation of the receptor that ensues when nicotine is co-
administered24. Thus varenicline has  the potential to provide relief from withdrawal (agonist effect) and block 
the rewarding effects of nicotine (antagonist effect) 25. In addition to its effects at the α4β2 nACHR, animal 
studies have also shown that varenicline acts as a full agonist of the α7 nACHR 26. This has interesting 
implications for the drug that are not typically discussed when considering its mechanism of action. For 
example, presynaptic α7 nACHR’s enhance glutamatergic excitatory drive whereas active α4β2 nACHR’s 
directly excite DA neurons. The additive effects of presynaptic glutamate release and postsynaptic firing 


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increases the likelihood of synaptic potentiation (e.g., Long Term Potentiation). In addition, α4β2 nACHR’s are 
found on the cell body of GABAergic interneurons that project to DA neurons in the VTA. Prolonged nicotine 
exposure causes some desensitization of these receptors; eventually decreasing their inhibition of VTA DA 
neurons, resulting in a complex interplay between these neural connections that acts to facilitate DA release in 
the nAC, even as α4β2 nACHR receptors on DA cell bodies are desensitized 27. While it is unknown whether or 
not varenicline may act in a similar fashion, the possibility exists that its effects on the α7 glutamatergic and 
α4β2 GABAergic nACHR receptors result in a similar pattern of DA stimulation, hence providing several routes 
of action to facilitate smoking cessation.   
Two randomized, double-blind clinical trials that compared varenicline (2 mg), bupropion (300 mg), and 
placebo showed an overall continuous abstinence rates between the end of treatment through the one year 
follow-up of 21.9%, 16.1%, and 8.4%, respectively in one study 28 and 23%, 14.6% and 10.3%, respectively in 
another6. All comparisons were significantly different although the alpha level of .057 was observed in the 
bupropion vs. varenicline comparison in the Gonzales trial. In a combined analysis of both trials28  varenicline 
resulted in significantly higher continuous abstinence rates at one year compared to either placebo or 
bupropion (all p values were <.05). In these studies, varenicline nearly tripled the odds of quitting over placebo 
during the last 4 weeks of treatment (OR, 3.09; 95% CI, 1.95-4.91; P<.001)28; (OR, 2.66; 95% CI, 1.72-4.11; 
P<.001) 6. Moreover, in a separate study, an additional 12 weeks of varenicline therapy (total of 24 weeks) has 
been shown to reduce the risk of relapse among smokers who were abstinent at the end of the first 12 
weeks29. Compared to smokers who received placebo, those who received varenicline reported significantly 
less craving and withdrawal symptoms throughout the trials 30. Side effects of varenicline may include nausea 
and abnormal dreams (see Human Subjects for listing of AE’s). 
Rationale for combining therapies. The focus of this proposal is the evaluation of the combined effects 
of varenicline and bupropion, both in their own right FDA approved medications for smoking cessation. As 
discussed above, plausible differences in the mechanisms of action of the two drugs and differences in their 
intensity of action within the same pathways, suggest that combining these medications will affect a broader 
range of the biological targets identified as important for smoking cessation. For example, considering 
bupropion’s effects on noradrenergic and dopaminergic reuptake inhibition, one might expect a synergistic 
effect with the addition of varenicline: reduced re-uptake of dopamine as a function of bupropion; a more 
sustained release of dopamine in the nucleus accumbens with varenicline; and/or a stabilization of the 
noradrenergic pathways which could lead to reduced vulnerability to negative affect while quitting. Varenicline 
has not been shown to have noradrenergic properties and is unlikely to have strong antidepressant effects, 
whereas bupropion does affect the noradrenergic pathways which are believed to account in part for its 
antidepressant affects. Relative to placebo, bupropion may improve the abstinence rates among those with a 
history of depression 31, a condition one might consider a risk factor for negative affect while quitting, placing 
such individuals at a relatively greater risk of relapse (findings are not uniform regarding the inverse 
relationship of quitting with or without bupropion to history of major depression 10). Both bupropion and 
varenicline have been shown to reduce nicotine withdrawal, negative affect, craving, and some indices of 
smoking reinforcement (satisfaction). However, relative to placebo, varenicline shows greater effect sizes for 
reducing smoking satisfaction, psychological reward, enjoyment of respiratory sensations smoking urges, 
negative affect, restlessness, and craving 4. Interestingly, varenicline actually shows an increase in appetite 
relative to placebo, a fact that is likely explained by the relatively greater proportion of abstainers in the 
varenicline group. Nevertheless, the same is not true for bupropion which is known for producing modest 
appetite suppression.  Bupropion has been shown to offset the deficits in cognitive and attentional functioning 
related to smoking cessation. This raises the possibility that additive effects on several psychological predictors 
of relapse (e.g., negative affect and craving) as well measures of smoking reinforcement and cognitive 
performance might be observed when the two drugs are combined. In addition, among those smokers for 
whom the possibility of weight gain might adversely affect their treatment success; the addition of bupropion 
could have a beneficial effect. 
Considering bupropion’s recently noted nACHR antagonistic effects it is possible that the additional 
agonistic effects of varenicline would be enhanced within such an antagonist rich environment.  Partial 
agonists are known to behave like agonists in an antagonist rich environment (bupropion in this case).  An 
example of this type of interaction also comes from studies combining mecamylamine (nicotine antagonist) 


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with the nicotine patch (agonist) 32, where favorable short term effects have been noted for smoking cessation.  
Unpublished data has not supported long term effects of this combination (E.D Glover, personal 
communication). Similarly, previous trials combining the nicotine patch with bupropion have also shown a 
significant enhancement of abstinence rates with the combination in the short term, and although not 
statistically significant, the combined approach also produced elevated abstinence rates at long term follow-up 
33. In the mecamylamine and bupropion studies, nicotine, while itself a full nACHR agonist, can be expected to 
have much more limited agonist effects when administered in patch form, given the distribution kinetics of the 
patch, relative to the targeted and longer lasting agonist properties of varenicline. From another point of view, it 
may also be noted that partial agonists (i.e., varenicline), in an agonist rich environment (i.e., smoking during a 
lapse) is expected to behave like antagonists having occupied receptor sites. Thus nACHR antagonism may 
be enhanced by the two drug combination, providing a particularly supportive environment for reducing the 
reinforcing effects of nicotine during lapse related smoking, which ultimately should reduce the probability of a 
lapse resulting in a complete return to smoking. In both scenarios (agonist/antagonist rich environment), the 
combination of both varenicline and bupropion may provide stronger and wider reaching agonist and 
antagonistic effects on effects nACHR’s, which may translate into improved rates of cessation over varenicline 
alone. 
Smoking and Psychiatric Co-morbidities. Smoking is often co-morbid with substance, mood, and 
attention disorders suggesting shared biological pathways between nicotine dependence and these psychiatric 
conditions. While a complete review of this area is beyond the scope of this proposal, suffice it say that several 
studies have demonstrated a positive relationship between alcohol, substance abuse and other psychiatric 
disorders and smoking 34–37;38–41.  For example, the lifetime prevalence rate of alcohol dependence or drug 
abuse is estimated at 23%-30% among adult smokers 42,43.  Among non-dependent and dependent current 
smokers lifetime rates of mood and anxiety disorders have been reported as 12%-26.7%, and 33.5%-46.5%, 
respectively 43. Similarly, as 
shown in Figure 1, among 
tobacco dependent 
smokers, 12-month 
prevalence of any mood or 
anxiety disorder was 21%-
22%, respectively 44. There 
is also an elevated risk of 
first onset of major 
depression, panic disorder, 
and generalized anxiety 
disorder among smokers 45–
47. In the area of cognitive 
dysfunction, odds ratios 
comparing ever to never 
smokers were positively 
related to the number of 
Attention Deficit 
Hyperactivity Disorder (ADHD) symptoms; and among those reporting regular smoking over their lifetime, an 
inverse relationship between number of (ADHD) symptoms and age of onset, and positive relationship 
between symptoms and number of cigarettes smoked, has also been observed 48.  
Although other antidepressants and anxiolytics have not generally been found efficacious for smoking 
cessation 10, bupropion’s antidepressant actions may make it a particularly attractive choice for smokers 
vulnerable to negative affect or among those with some level of affective and/or cognitive impairment. For 
example, in one study relative to placebo, bupropion was shown to be effective among smokers with a history 
of depression 31, although absolute cessation rates among depression history positive ad negative smokers 
may not differ10. Bupropion has also been used in a preliminary study to treat smokers with PTSD 49.  Apart 
from smoking, bupropion has long been indicated for the treatment of depression, and recent studies have 
shown additional benefits including prevention of the recurrence and improved efficacy for depressed patients 
Figure 1. 12 Month Prevalence of Comorbid Disorders & Nicotine Dependence  
 


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with concomitant anxiety (see Clayton 50), as well as a favorable outcome for the treatment of cocaine 
addiction when combined with behavioral treatment 51. Direct tests of bupropion with depressed smokers have 
not been carried out since those with concurrent depression are typically excluded from smoking cessation 
pharmaceutical trials. Similarly, given concerns about bupropion’s seizure potential during alcohol withdrawal, 
it has not been directly used in the treatment of smokers with alcohol use disorders (although other 
antidepressants have with similar noradrenergic properties have shown efficacy in the treatment of depressed 
alcoholics (see Torrens 52). We have noted no untoward safety concerns in an open label trial of bupropion 
with alcoholic smokers 53. Nevertheless, the potential remains for bupropion to have a favorable impact on 
smokers with some level psychiatric symptoms. The combination of these medications may have particular 
importance since recent post-marketing reports that varenicline may be associated with increased depressive 
symptoms in some individuals (i.e., those with a history of depression). Bupropion might reduce the likelihood 
of this occurring. It is plausible that in a community sample such as ours with a wide range of sub-threshold 
disorders, bupropion could exert a favorable impact on such individuals attempting to quit smoking. When 
combined with varenicline, treatment efficacy is likely to improve, since both the psychiatric symptoms as well 
as the direct agonistic effects on nACHR’s receptors are addressed,  
Bupropion’s role in the area of cognitive dysfunction represents another important area of possible 
synergy with varenicline. Difficulty concentrating is a symptom of the tobacco withdrawal syndrome 54. In 
addition, acute abstinence from tobacco generally leads to decrements on cognitive tasks55,56 including 
attention tasks 57. Studies have documented that bupropion has beneficial effects on questionnaire measures 
of attention. Gobbi and colleagues 58 administered 0 mg, 150 mg, or 300 mg bupropion to 24 healthy male 
volunteers. Participants on 300 mg bupropion reported improved self-reported attention. Wilens 59 administered 
300 mg bupropion to 36 adult ADHD and/or bipolar disorder. Participants reported reduced distractibility and 
improved concentration at 6 weeks. Some studies have reported that bupropion can improve performance on 
objective cognitive assessments. Shiffman 60 reported that 300 mg (but not 150 mg) bupropion significantly 
speeded reaction times on a logical reasoning task (vs. placebo), and marginally improved error rates. Evins 
and colleagues 61,62 administered up to 300 mg bupropion to 52 adult schizophrenics. Participants on 
bupropion exhibited reduced preservative errors on the California Verbal Learning Test, and reduced variability 
of reaction times on the Conners Continuous Performance Task (a test of sustained attention).  
Bupropion has also been shown to be effective in the treatment of adult ADHD 63. The overlap between 
symptoms of ADHD and smoking prevalence has already been discussed above. There may also be 
implications for treatment of ADHD symptoms and smoking cessation success, for which bupropion might have 
an ameliorative effect. For example the quit ratio among ever smokers is lower (29%) among smokers with a 
history of ADHD as compared to the general population (48%) 64. Similarly, a history of childhood ADHD in 
adults, has been shown to predict time to relapse in a study where only 1/47 such smokers remained abstinent 
at a one year follow-up (OR-.36 CI .28-.45) 65. However, at least one study suggests that when smokers are 
treated for ADHD, both ADHD symptoms and frequency of smoking decrease 66. Conversely, an increase in 
the number of ADHD symptoms during the early phases of a quit attempt also predicts relapse to smoking 67. 
In addition, among smokers with current ADHD symptoms of inattention, a primary reason cited for smoking is 
to control negative affect, which itself is a robust predictor of relapse 68. Adding varenicline to the mix may have 
additional benefit. For example, in laboratory settings, nicotine and nicotine agonists have been shown to 
improve attentiveness and cognitive function 69, increase memory 70, and significantly reduce other symptoms 
associated with ADHD 71,72. Taken together, these studies suggest that the combination of bupropion and 
varenicline might be particularly effective in reducing symptoms of cognitive dysfunction that might occur 
during a cessation attempt and possibly adversely affect the smoker’s chances of cessation success.   
Biological Pathways in Nicotine Dependence. Nicotine is the primary psychoactive substance in 
tobacco smoke and has diverse effects throughout the CNS. It modulates the activity of several 
neurotransmitters including, dopamine (DA), norepinephrine (NE), serotonin (5-HT), glutamate (GLUT), and γ-
aminobutyric acid (GABA), as well as endogenous opioid peptides by binding to nicotinic cholinergic receptors 
(nAChr) throughout these neuroregulatory systems. While much of the focus of previous research on nicotine 
addiction has been related to its effects on reward processes and mesolimbic dopamine neurotransmission 73–
75, and will not be reviewed here, a growing body of literature suggests that it’s noradrenergic (and 
dopaminergic) effects on attention, information processing and affective regulation, elsewhere in the limbic 


Protocol 2008-0850 
February 5, 2021  
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system, may be of considerable importance in understanding the maintenance of dependence. These effects 
are particularly relevant to understanding how varenicline and bupropion might complement each, through 
shared biological mechanisms between nicotine dependence, attentional disorders, other addictions, and 
mood and anxiety comorbidities discussed above.  
Neurological deficits common to attention and substance use disorders, such as impaired performance, 
lack of motivation, decreased working memory and impaired executive function have been well documented 76 
in both children and adults 77–81.  Current lines of investigation suggest that overlapping interrelated brain areas 
are responsible for explaining the attentional and executive impairments common to the two disorders 82,83. The 
involvement of two areas in particular, prefrontal cortex (PFC) and anterior cingulate cortex (ACC) highlight the 
commonalities between drug dependence, including nicotine and neurophysiological deficits related to 
cognitive dysfunction.  
The PFC regulates goal directed behavior, thought, and affect by using working memory to provide 
representational knowledge about past or future events and integrating this information into a plan for action or 
to exercise inhibitory control over inappropriate actions or thoughts. In attentional/cognitive disorders these 
processes are impaired and manifested in symptoms that involve poor attention, planning, impulse control, and 
monitoring of one’s behavior. Studies indicate that the right PFC in humans is particularly important in the 
inhibition of activity (i.e., Stop or Go-No Go tasks)84. The orbital and ventral PFC may also have a similar 
inhibitory effect in the affective domain, thus permitting appropriate social behaviors (e.g., Anderson et al. 
85,and  Stuss 86. In ADHD for example, the ACC has also been implicated in the regulation of the motivational 
aspects of attention as well as in the regulation of response selection and inhibition 76. Thus, researchers have 
begun to characterize ADHD as a disorder with deficits in inhibitory processes involving frontal cortical 
structures77. If a person must mentally manipulate information and make a response, the anterior cingulate 
(with its connections to the PFC) becomes active 87. This area become particularly active in tasks where 
inhibitory control or divided attention are necessary 88. 
The importance of the inhibitory role of these structures in drug dependence has also been highlighted 
by several researchers. Drug addicted individuals, including smokers, continue to use drugs even when faced 
with negative consequences and diminished reward, suggesting an apparent loss of control 89.  The failure to 
regulate (inhibit) this drive points to a dysfunction within the PFC 90 and related areas including the anterior 
cingulate and orbitofrontal corticies 91.  As shown in Figure 2, the resulting persistence of the behavior is not 
necessarily due to continued reinforcement by the drug (mesolimbic dopamine) but rather to the enhanced 
saliency of the drug and drug cues that have been firmly established (learned) in memory during the 
acquisition of dependence. During maintenance of drug dependence these “super salient” drug related cues, 
including self-administration, overcome the inhibitory control of the PFC that might normally extinguish a 
response with decreasing hedonistic properties. Preclinical studies suggest that the impairment in PFC 
function may be related to significant dendritic branching and spine density resulting from repeated drug 
administration 92, thus amplifying the signal of salient events. Moreover, abstinence, for example from smoking, 
significantly reduces the efficiency of the PFC to process information in working memory thereby interfering 
with its regulatory function93. Such effects might be mediated by the negative affect associated with nicotine 
withdrawal, and when present, reduce the probability that a smoker may exercise an appropriate coping 
response and increase the probability of relapse 94,93. There is EEG evidence supporting persistent frontal lobe 
dysfunction among smokers using tasks related to working memory (P300). Neuhaus and colleagues 95 found 
a hypoactivation of the anterior cingulate, orbitofrontal, and prefrontal cortex among both current and former 
smokers compared to never smokers, suggesting that the dysfunctional activation patterns found in smokers 
may not completely remit after quitting; a fact that may increase their vulnerability to relapse. Bupropion may 
reduce this deficit. For example, in a recent imaging study bupropion treated smokers had smaller cigarette 
cue induced increases in craving scores and less activation of perigenualyventral ACC (which projects to the 
PFC), relative to neutral cues than did untreated smokers 96.  


Protocol 2008-0850 
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Perhaps, the combination of 
varenicline with its direct effects on the 
VTA, DA release in the nAC and 
associated smoking related reward on 
the one hand, and the diverse effects of 
bupropion on central NE function with 
noted ameliorative effects on cognitive 
function, on the other, may make a 
particularly powerful drug combination for 
smoking cessation. Each drug adds to 
the diversity of biological targets which 
may play a role in the maintenance of 
smoking behavior.  
Norepinephrine and Dopamine. 
The above pathways are rich in 
catecholamines.  Cognitive symptoms 
related to ADHD for example, are 
relieved by blocking DA and NE reuptake 
into the presynaptic neuron, thereby 
increasing the concentration of these 
neurotransmitters in the extracellular 
space 97. It appears that DA dysfunction 
in the lower striatal areas reduces 
attention, focus, acquisition, and 
cognition, whereas NE dysfunction in the 
PFC is associated with distractibility, 
poor executive operations, and reduced 
behavioral and cognitive inhibition 98.  While imaging studies are required to verify the scope of varenicline’s 
anatomical targets, it is indeed plausible that varenicline acts on the DA projections from the nAC to the PFC 
and in the lower striatum in a manner consistent with that of nicotine 99, which itself has been shown to improve 
attention and memory function (see Levin et al for review 100). 
NE mechanisms have not been a major focus in drug abuse, however, NE is able to modulate midbrain 
DA function important to drug reward 101.  Nicotine also releases NE in various CNS regions 102 via nicotinic-
type acetylcholine receptors 103,104.  At least two lines of evidence point more directly to the role of NE in 
nicotine reinforcement.  First, Reboxetine, a NE reuptake inhibitor attenuates nicotine self-administration 105.  
Second, NE secretions in the paraventricular nucleus (PVN) increase during continuous nicotine self-
administration 106. NE mechanisms (desensitization of α2 adrenoreceptors) 17  are also  thought to play a role in 
the negative affect associated with cocaine withdrawal, a situation like that of nicotine withdrawal, that 
enhances relapse vulnerability, As discussed above, both bupropion and nortriptyline inhibit the reuptake of 
norepinephrine and both have been shown to be effective for smoking cessation. Taken together these studies 
suggest that a nicotine agonist like varenicline, could possibly add to the overall effects associated with 
bupropion elsewhere in the brain, to further offset cognitive deficits as well as the affective disturbances 
associated with quitting smoking that might adversely affect treatment success. The etiology of nicotine 
dependence and associated co-morbidities and the mechanism of action of shared pharmacotherapies 
suggest that regulation of NE and DA neurotransmission are involved in ameliorating affective and cognitive 
deficits associated with quitting.  
Need for current research. As indicated above, current smoking cessation pharmacotherapies using 
NRT, bupropion, nortriptyline  10, and now varenilcine28 have produced several positive outcomes.  However no 
“magic bullet” has emerged, nor does it seem likely that will be the case. Much like the treatment of 
depression, the psychobiological complexity of the nicotine dependence disorder suggests that multiple 
therapies should be made available to account for individual differences in treatment response. Continuing to 
develop new treatments for nicotine dependence will have several significant benefits. First, new treatments 
Figure 2.
 
Addiction model proposed based on imaging findings documenting 
abnormalities in brain circuits involving saliency/reward, 
motivation/drive, memory/conditioning, and control/disinhibition. These 
circuits interact with one another and change as a function of experience 
and context. During addiction, the enhanced saliency value of the drug in 
the reward, motivation, and memory circuits overcomes the inhibitory 
control exerted by the prefrontal cortex. A positive feedback loop 
initiated by consumption of the drug and perpetuated by the enhanced 
activation of the motivation/drive and memory circuits results in 
compulsive drug seeking and taking. Taken from Volkow (Volkow et al., 
2004)). 


Protocol 2008-0850 
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have the potential of having an immediate impact on public health and disease prevention, and in this case 
there may also be a benefit of both increased treatment efficacy and reduction in possible neuropsychiatric 
adverse effects of varenicline. Second, with an increasing diversity of available treatments, particularly 
combination therapies, future research may focus on tailoring treatments to particular characteristics of the 
individual (i.e. fitting a particular medication or treatment combination to a group of individuals based on 
genetic or other individual differences). Should this research prove successful, future proposals may focus on 
the discovering how such individual differences might map onto the complex biological response engendered 
by the combined treatment. For example, it is possible that the pharmacogenetic response of these drugs 
might be related to haplotypes of genetic polymorphisms of the NET (norepinephrine transporter gene), COMT 
(Catechol O-methyltransferase) and DRD2 -141 ins/del alleles. However, the first step in this process is to 
establish reasonable effectiveness of this combination treatment so that it may enter the mainstream of 
available therapies and that is the main objective of this proposal. 
C. Preliminary Studies 
We present a preliminary data from an open label study that was done with cancer patients who were referred 
to our tobacco treatment program. The 
Tobacco Treatment Program at the 
University of Texas M. D. Anderson 
Cancer Center is a large-scale 
comprehensive program that delivers 
tobacco-cessation counseling and 
medication to cancer patients. The 
patients present to the program with a 
wide variety of demographic, social, and 
economic backgrounds and cancer sites. 
The Tobacco Treatment Program has 
been in operation for little over 2 years. 
We do not have any exclusionary criteria 
for patients entering treatment. Patients 
in the program receive behavioral 
counseling from a clinician (Masters or 
Ph.D. level psychologist, APN) and a tobacco-cessation medication, which is managed by the program’s 
medical staff led by Maher Karam-Hage, MD (co-investigator on this application and Associate Medical 
Director of the program).  Most patients entering the program have had previous quit attempts that were 
unsuccessful.  
We present new pilot data below from an open label trial of treatment resistant smokers who are cancer 
patients/survivors referred to our clinical tobacco treatment program. This was not a randomized trial but rather 
a retrospective analysis of data from a clinical intervention program. For this analysis we first selected a group 
of smokers who had failed to quit after taking a single treatment agent (either varenicline or bupropion) for 8 
weeks. In an attempt to help them quit the alterative medication was then added, while they continued taking 
the first one. Combining these two medications for treatment resistant patients is a relatively recent clinical 
intervention used in our clinic. Thus, for comparison we selected a similar group of patients (those failing to quit 
after 8 weeks of treatment) who were treated in close proximity to the time frame of those taking the drug 
combination. In total, there were 97 smokers in the sample: 63 taking varenicline alone (the most commonly 
prescribed medication in our clinic); 16 on bupropion alone; 11 who initially began varenicline for whom 
bupropion was added; and 7 who initially 
began bupropion for whom varenicline 
was added.  The demographic 
characteristics of these groups are shown 
in Table 1. No significant difference 
between the groups was noted.  However, 
smokers in the varenicline plus bupropion 
group (varenicline given first), did have 
Table 1 Demographics for Patients Selected for Preliminary Studies Sample 
 
Table 2 Primary Cancer Type Diagnosis 
Varinicline Only
Bupropion Only
Varinicline + Bupropion
Bupropion + Varinicline
N = 63
N = 16
N = 11
N = 7
Mean (SD )
Mean (SD )
Mean (SD )
Mean (SD )
Age
54.92 (11.94)
53.56 (8.79)
60.00 (7.55)
48.00 (8.62)
PANAS-Negative
19.71 (8.85)
19.80 (7.77)
21.50 (7.75)
24.86 (12.46)
PANAS-Positive
31.05 (8.85)
31.00 (10.78)
31.42 (9.52)
26.71 (6.53)
CES-D 
14.07 (12.63)
14.13 (9.95)
14.00 (8.10)
22.29 (16.67)
PHQ Diagnoses
0.84 (1.00)
0.44 (0.63)
0.91 (0.83)
1.29 (1.38)
FTND*
4.09 (3.17)
5.44 (1.97)
6.18 (2.36)
3.83 (3.60)
Cigarettes Per Day
17.34 (15.31)
21.19 (11.37)
26.82 (11.89)
15.71 (15.25)
n (%)
n (%)
n (%)
n (%)
Male
24 (38.1%)
11 (68.8%)
4 (36.4%)
2 (28.6%)
Female
39 (61.9%)
5 (31.3%)
3 (63.6%)
5 (71.4%)
White
51 (81.0%)
12 (75.0%)
11 (100%)
4 (57.1%)
Black
7 (11.1%)
2 (12.5%)
0 (0%%)
1 (14.3%)
Other
5 (8.0%)
2 (12.5%)
0 (0%)
2 (28.6%)
* p  < .10
Varinicline Only
Bupropion Only
Varinicline + Bupropion
Bupropion + Varinicline
N = 63
N = 16
N = 11
N = 7
Breast
19 (30.2%)
3 (18.6%)
4 (36.4%)
1 (14.3%)
Gastrointestinal
16 (25.4%)
4 (25.0%)
0 (0%)
1 (14.3%)
Head & Neck/Thoracic
19 (30.2%)
5 (31.4%)
4 (36.4%)
4 (57.1%)
Other
9 (14.2%)
4 (25.0%%)
3 (27.2%)
1 (14.3%)


Protocol 2008-0850 
February 5, 2021  
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marginally higher FTND dependency scores than the other groups which could have had a deleterious effect 
on cessation from the start. The fact that we did improve abstinence rates in this group is impressive given 
their level of dependency and immediate history of lack of efficacy. 
We also show no differences in primary cancer site among groups particularly for the Varenicline vs. 
Varenicline + Bupropion groups which are most germane to this proposal (see Table 2). In addition the 
medication combinations were well tolerated as we did not find evidence of a significant increase in common 
side effects or the emergence of any serious side effects when compared with those patients administered 
varenicline or bupropion alone, in this small sample (see Table 3).  
Among those continuing on varenicline 
or bupropion alone, 7-day point 
prevalence abstinence rates at the end 
of treatment (12 weeks) was 14.3% 
(9/63) and 12.5% (2/16), respectively.  
Among those beginning on bupropion 
for whom varenicline was added and 
those beginning on varenicline for 
whom bupropion was added, 
abstinence rates 8 weeks after 
beginning the combination were 42.9% 
(3/7) and 27.3% (3/11). We chose the 8 
week mark because this allows a 
comparable amount of exposure to the combination therapy that was allowed on the monotherapy before 
initiating the combination. Among this treatment resistant group of smokers, the data suggest that adding 
bupropion to varenicline results in nearly a doubling of abstinence rates: only 14.3% of these patients quit after 
receiving a full course on varenicline, while 27.3% quit on the combination. Though not of direct import to this 
study, the substantial increase in abstinence observed when varenicline is added to bupropion (42.9%) vs. 
bupropion alone (12.5%) is likely due to the fact that these smokers are treatment failures on bupropion, a less 
effective drug than varenicline to start with. When given the more effective medication their abstinence rates 
improve to a level similar to what has been observed at the end of treatment in the original clinical trials of 
varenicline (7-day point prevalence of 50%).  
The most important comparison in this data for purposes of this proposal is the contrast between 
varenicline alone vs. varenicline plus bupropion, and our subsequent discussion is based on the possibility that 
the combination of varenicline plus bupropion is likely to result in improved efficacy over varenicline alone. The 
data shown here, while not a direct parallel of the clinical trial we propose to do, does suggest that the 
combination approach (varenicline + bupropion) may improve the efficacy rates among a group of treatment 
resistant smokers who would not have otherwise been able to quit (varenicline alone). The data do not tell us 
what the outcome would be if both medications were started in close proximity of one another (as proposed 
here); a scenario that might possibly produce stronger additive effects as discussed earlier. Starting both 
medications at the same time might result in “rescuing” more smokers, who may drop out early in the cessation 
process (prior to 8 weeks) due to lack of efficacy. Such smokers may become discouraged, and revert to 
smoking and become lost to follow-up. The favorable impact of a medication combination on these smokers 
early in the quitting process may be substantial if it brings about quitting sooner and improves the self-efficacy 
by facilitating a positive experience that would not have otherwise occurred.  
There are of course caveats to be considered in this data, including the fact that it represents a self-
selected sample of monotherapy non-responders. While the demographics and AE data may not differ across 
groups, it should be noted that the overall AE profile was lower than expected given the results of the pivotal 
studies. This sample is also comprised of cancer patients who may respond differently than our community 
sample, but it is worth noting that the 12 week abstinence rates for the over 300 patients in our program on 
varenicline is 48%, which is quite similar to the rates noted in the pivotal trials (44% continuous abstinence and 
50% point prevalence). Nevertheless, these preliminary data provide a signal that the combination of 
varenicline and bupropion may improve abstinence rates over those of varenicline alone, and that a 
randomized clinical trial may be undertaken to investigate this further. 
Table 3 AE Profile Mono vs. Combined Therapies 
 
Varinicline Only
Bupropion Only
Varinicline + Bupropion
Bupropion + Varinicline
N = 63
N = 16
N = 11
N = 7
Oral
1 (1.6%)
1 (6.3%)
1 (9.1%)
1 (14.3%)
Gastrointestinal
9 (14.3%)
3 (18.8%)
4 (36.4%)
0 (0%)
Psychiatric
11 (17.5%)
1 (6.3%)
2 (18.2%)
0 (0%)
Neurologic
5 (7.9%)
0 (0%)
1 (9.1%)
0 (0%)
Cardiovascular**
0 (0%)
2 (12.5%)
0 (0%)
0 (0%)
Dermatologic
1 (1.6%)
0 (0%)
2 (18.2%)
0 (0%)
Other
6 (9.5%)
0 (0%)
1 (9.1%)
0 (0%)
** p  < .05
Neurologic: Dizziness, headache
Oral: Dry mouth, bleeding gums
Cardiovascular: Chest pain, shortness of breath 
GI: Nausea, constipation, gas
Dermatologic: Flushing, skin irritation
Psychiatric: Depression, nervousness
Other: Ear ache, feet swelling


Protocol 2008-0850 
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Page 11 of 49 
 
 
 
Experience of the PI. Paul M. Cinciripini, Ph.D. is Professor and Deputy Chair of the Department of 
Behavioral Science, and Director of the Tobacco Treatment Program, at the University of Texas MD Anderson 
Cancer Center. He has over 20 years experience conducting basic and clinical research in the area of smoking 
cessation and nicotine psychopharmacology. Dr. Cinciripini has conducted basic laboratory studies evaluating 
psychophysiological, psychopharmacological and genetic aspects of nicotine dependence. Examples of his 
work in this area include studies of nicotine titration and compensation, psychophysiological effects of nicotine 
during stress, individual differences in the effects of nicotine on EEG and cardiovascular activity, genetic 
factors treatment outcome, pharmacogenetic effects of antidepressants during smoking cessation, and recent 
studies using startle probe methodology to examine the relationship between genetics, emotional reactivity, 
nicotine exposure and nicotine withdrawal. He has also studied the influence of treatment process measures 
and psychological characteristics of the smoker on cessation success. Examples of his work in this area 
include studies of the effects of depression, coping behavior and self-efficacy as well as genetic factors related 
to nicotine dependence. In the area of clinical trials he has led studies testing of novel approaches for the 
treatment of nicotine dependence in the form of behavioral and pharmacological therapies used alone and in 
combination.  Examples of his work in this area include:  the development of a “scheduled smoking” procedure 
and a recent application of this technology for delivery on a handheld computer; development of a smoking 
cessation video series for pregnant smokers; evaluating combination therapies using nicotine replacement, 
behavioral counseling, and other approaches; and testing novel pharmacological compounds, including 
anxiolytics, antidepressants, nicotine partial agonists, and cannabinoid antagonists.  Dr Cinciripini has been the 
recipient of several NIH, extramural and industry sponsored research grants and is the author of over 75 
articles and book chapters. 
He is currently PI on two NIH funded clinical trials. The major goal of the first project, “A Mood 
Management Intervention for Pregnant Smokers is to test the hypothesis that cessation rates during pregnancy 
and at 3 and 6 months post-partum will be significantly greater for smokers in a mood management versus the 
health education counseling conditions. The mood management condition is an adaptation of a therapy that 
has been used to treat chronic depression. The major goal of the second project, “Pharmacogenetics, 
Emotional Reactivity and Smoking”, is to assess the effects of bupropion, nortriptyline and placebo on changes 
in emotional reactivity during cessation, as measured by the human startle response, EEG asymmetry and 
dense electrode recording of Event Response Potentials (ERP), and to determine if these effects are 
moderated by genotypes involved in dopaminergic, noradrenergic and serotonergic activity. He has also been 
awarded a competitive supplement to this grant, to evaluate the pharmacogenetic response to emotional 
stimuli during cessation, using fMRI. 
Most pertinent to this application is the experience of the research team conducting smoking cessation 
clinical trials using pharmacologic agents. Our research team has considerable experience in this area. For 
example, we recently completed 3 multi-site FDA regulated trials evaluating the effectiveness of rimonabant, a 
cannabinoid antagonist, for smoking cessation, relapse prevention and reduction in selected cardiovascular 
risk factors (e.g. weight, lipids). Our site enrolled over 300 participants in these trials. Dr. Cinciripini is the 
principal investigator on one of the three trials and is responsible for conducting the data analysis and writing 
scientific publications of that trial and pooled results of all the trials with the drug. His work on the combined 
analysis of US and European rimonabant programs has been presented at an international conference 107. He 
is also the lead author on one of four manuscripts being prepared on the results of these trials. The first of 
these manuscripts have been submitted to a leading medical journal. This manuscript deals with the results of 
the first US trial and showed that the drug was safe and effective. In total, approximately 789 smokers were 
exposed to 10 weeks of rimonabant therapy or placebo (n=790). Rimonabant 20mg resulted in a significantly 
higher smoking abstinence rate compared with placebo and was also associated with significantly less post-
cessation weight gain. Dr. Cinciripini is has also been the site PI on a recently completed multi-site trial 
evaluating the effectiveness of dianicline, a partial nicotine cholinergic agonist, similar to varenicline. 
We have also completed several other investigator-initiated smoking cessation studies using other 
drugs and different types of behavioral counseling. For example we evaluated the effects of venlafaxine, a 
norepinephrine and serotonin reuptake inhibitor, on smoking cessation.  In this study, 147 smokers were 
randomly assigned to receive either venlafaxine or placebo in conjunction with behavioral counseling (9 weekly 


Protocol 2008-0850 
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sessions) and transdermal nicotine replacement therapy (22mg/day). Medication began 2 weeks prior quitting 
and continued for 18 weeks post quit, titrating the daily dose from 150-225mg. in response to symptoms of 
negative affect and relapse. The results showed no main effect of treatment on abstinence. Post-hoc analysis 
revealed that both at the end of treatment and at the one year follow up smokers consuming under a pack of 
cigarettes a day benefited from the addition of venlafaxine to the treatment regimen. Venlafaxine also reduced 
negative affect for all smokers for up to 6 weeks post cessation. The findings suggest that venlafaxine could 
have some role to play in the treatment of lighter smokers, in addition to the expected benefits of nicotine 
replacement therapy and behavioral counseling 23. Other published work in this area includes studies using the 
anxiolytic, buspirone, which was found to have a beneficial effect on smoking cessation among smokers with 
high baseline anxiety108 as well as studies combining nicotine replacement and behavioral counseling 109.  
Other published work in this area includes using the anxiolytic buspirone108 as well as studies combining 
nicotine replacement and behavioral counseling 109 and scheduled smoking110.  
The PI has also developed and tested a scheduled smoking as a technique for reducing cigarette 
consumption in a systematic way prior to cessation. This study compared the efficacy of 2 traditional methods 
of smoking cessation, gradual reduction and "cold turkey," with a new approach involving variation in the 
intercigarette interval. One hundred twenty-eight participants quit smoking on a target date, after a 3-week 
period of (a) scheduled reduced smoking (progressive increase in the intercigarette interval), (b) nonscheduled 
reduced smoking (gradual reduction, no specific change in the intercigarette interval), (c) scheduled non-
reduced smoking (fixed intercigarette interval, no reductions in frequency), or (c) nonscheduled non-reduced 
smoking (no change in intercigarette interval or smoking frequency). Participants also received cognitive-
behavioral relapse prevention training. Abstinence at 1 year averaged 44%, 18%, 32%, and 22% for the 4 
groups, respectively. Overall, the scheduled reduced group performed the best and the nonscheduled reduced 
group performed the worst. Both scheduled groups performed better than nonscheduled ones. Scheduled 
reduced smoking was associated with reduced tension, fatigue, urges to smoke, withdrawal symptoms, 
increased coping effort (ratio of coping behavior to urges), and self-efficacy, suggesting an improved 
adaptation to nonsmoking and reduced vulnerability to relapse 110. 
We have also completed a study combining scheduled smoking intervention, delivered on a hand held 
computer, with transdermal nicotine replacement. We enrolled over 800 participants in this study over a 3 year 
period. The results and analysis of this study are in preparation. 
Maher Karam-Hage, M.D., Co-Investigator, was recently appointed as Associate Professor of 
Psychiatry at MD Anderson Cancer Center in the Behavioral Science and Psychiatry departments. He brings to 
this institution and in particular to this proposal his clinical medical experience and expertise in 
psychopharmacology research as well as his knowledge of addiction in general and nicotine in particular. He 
joined our institution coming from University of Michigan where he served for six years as Medical Director and 
Director of Medical Education at the Addiction Treatment and Research Centers.  In addition to his medical 
and residency training, he had completed fellowships in addiction psychiatry and research in 
neuropsychopharmacology.  He has completed a University of Michigan Medical School and General Clinical 
Research Center (GCRC) funded study, to determine the efficacy and safety of Bupropion-SR for alcoholic-
smokers during the first six months of their abstinence from alcohol. He also participated in a trial of multi-site 
group therapy vs. nicotine patch vs. the two combined funded by NIDA-CTN (Community Trials Network) for 
smoking cessation in substance abusers.  Starting June, 2003, he had collaborated with Cynthia and Ovide 
Pomerleau at Michigan’s nicotine research program and served as project physician and participating 
investigator on three projects, including two NIDA-funded projects (R01 DA06529, Differentiation of 
phenotypes for smoking, and R01 DA14662, Effects of family smoking history in never-smokers) and a double-
blind rimonabant efficacy clinical trial funded by Sanofi-Aventis, Inc.  He most recently conducted a pilot study 
on cue induced cross reactivity between alcohol and tobacco with funds through the American Legacy 
Foundation. In his role as co-investigator in this trial he will collaborate with the PI on issues such as 
implementation, recruitment, medication prescribing and monitoring of response as well as side effects.  He will 
later take a lead role in interpreting the data collected and he will join in writing manuscripts.   
In summary, the PI and the research team he leads, has ample experience conducting smoking 
cessation research to adequately carry out the objectives of this proposal. 
 


Protocol 2008-0850 
February 5, 2021  
Page 13 of 49 
 
 
D. Research Design and Method  
Design Summary 
The main objectives of this study are to assess the efficacy of varenicline plus bupropion (VB) vs. varenicline 
(V) alone on smoking cessation and V vs. VB vs. placebo (P) on symptoms of nicotine withdrawal, negative 
affect and smoking reinforcement. The present study will use a double blind 3 group repeated measures 
design, with Group (VB/V/P) serving as the between subjects factor, and Time (Quit date, Post Cessation 
follow-ups) as the repeated measures. Following successful telephone and in-person screening sessions, 
approximately 385 eligible smokers will be randomized to receive 12 weeks of either V, VB or P, in a 3:1 ratio 
of active treatments (N=165 per V and VB) to placebo (n=55). Using an adaptive randomization approach 
(minimization)111, the sample will be balanced with the groups, for race, gender, previous history of major 
depression, history of ADHD, level of tobacco dependence (smokes first cigarette within 30 minutes of waking) 
and history of use of bupropion for smoking cessation.  Participants will receive brief in-person smoking 
cessation counseling at each of the 12 weekly visits at which time assessments of withdrawal, negative affect 
and smoking reinforcement will also be obtained. The target quit date will be set one week after beginning 
medication, consistent with the labeling of both medications. Both groups will attempt to quit smoking for the 
duration of the study if not successful on the quit date. Participants will return for follow up assessments at 3, 6, 
and 12 months post quit date. A study time line is provided in Table 5. 
 
Subject Recruitment  
Participants who want to quit smoking will 
be recruited from Houston metropolitan 
area using newspaper, radio and TV 
public service announcements, feature 
articles in the MD Anderson newsletter, 
and posted flyers. They will be offered 
modest monetary compensation for their 
time. We expect to have no difficulty 
recruiting the needed number of smokers. 
The MDACC Tobacco Treatment 
Program (TTP) is directed by the PI and 
has a high degree of community visibility. 
We have had considerable success 
recruiting participants for our clinical trials 
research. 
 
Population Description. The population of 
the Houston community from which the 
sample will be drawn (includes Harris 
county) is estimated at 3,596,086 people. 
The ethnic distribution has been reported 
as 59% Caucasian (42% of which are not 
of Hispanic origin);19% African-American; 
5% Asian; and .4% Native American, with 
33% Hispanic or Latino (of any race) 112. 
We expect to recruit minority smokers in 
proportion to the population 
demographics, and smoking prevalence.  
 
Pre-Screening Telephone Assessment. All smokers will be prescreened by telephone for basic eligibility 
requirements (see Table 4). An initial description of the study design will be provided and data will be obtained 
on age, smoking history, other tobacco use, medical history, medication use, and pregnancy/lactation status. 
All subjects who remain eligible after pre-screening will be scheduled for subsequent orientation visit where the 
study requirements will be explained in more detail and the informed consent reviewed.  
Figure 3  Design Summary and Study Flow 
 
Recruitment 
Volunteers from the 
Houston Community 
Pre-screening- 
•
Telephone 
assessment 
for Incl./Excl. 
criteria 
Orientation/Screen 
•
Informed consent 
•
Medical Screening  
•
Demographics 
•
Depression 
History & Tobacco 
Dependence  
Assessments 
During Treatment Assessments  
Weekly assessments of 
abstinence, nicotine withdrawal, 
negative affect & smoking 
satisfaction, including the TQD, 1-
month post quit, and End of 
Treatment 
 
Post-Cessation Follow-up Period: 
•
3 months 
•
6 months 
•
12 months 
Experimental Groups 
•
Randomized to 
Varenicline, Varenicline + 
Bupropion (N=165 each) 
and  Placebo (N=55) 
•
Stratified by gender, race, 
depression ADHD history 
and tobacco dependence 
•
12 Weeks medication  
•
All receive brief individual 
counseling  


Protocol 2008-0850 
February 5, 2021  
Page 14 of 49 
 
 
 
Orientation Visit and Informed Consent. 
Ideally, the orientation visit will occur within 
14 days of the telephone screen but it may 
occur anytime between the phone 
assessment and the Baseline Screening 
visit. A two-stage consent procedure will be 
utilized.  During the first stage, the Primary 
Investigator or a trained senior level (e.g., 
Masters/PH.D.) staff member will present a 
thorough informational session to potential 
participants.  During this session, the study 
purpose, other study requirements, side 
effects and contraindications of the 
medications will be reviewed.  The 
information presented will be developed in 
collaboration with the Medical Doctor Co-
chair of the study (Dr. Maher Karam-Hage) 
and will be based on current studies using 
these drugs, as well as manufacturer and 
PDR information.  Participants will be given 
the opportunity to ask questions about the 
informed consent document or any aspect 
of the study.  Any medical questions that 
arise during the process, if not addressed 
in the documentation or discussion 
provided, will be referred to the medical 
staff and the information will be provided to 
the potential participant prior to consenting.  
If a subject expresses continued interest in 
participating in the study, they will be asked 
to schedule their baseline screening 
appointment at this time. 
 
Screening Overview.  At start of screening 
visit, the informed consent document will be 
reviewed with the subject and they will be 
asked to sign the informed consent 
document. Additionally, the subject will be 
assessed for interest in providing a buccal 
sample according to procedures described 
in our IRB-approved genetic banking 
protocol (Protocol # Lab 09-0099). If the 
subject agrees to provide one by signing 
the informed consent approved for that 
protocol the sample will be collected at Visit 
1.  As shown in Table 5 subjects will be 
screened to assess medical and psychiatric 
suitability for the study. Medical screening 
for potential contraindications for 
medication use will be conducted by our 
study physician and/or in conjunction with 
other qualified members of the medical 
Table 4 Inclusion Exclusion Criteria 
 
Inclusion Criteria: 
• 
Age: 25-70 years old 
• 
Smoking 5 or more cigarettes per day, on average, within the 2 months 
preceding the screening visit and expired CO ≥ 6ppm. 
• 
Able to follow verbal and written instructions in English and complete all 
aspects of the study 
• 
Provide informed consent and agree to all assessments and study 
procedures  
• 
Have an address and home telephone number where they may be 
reached 
• 
Be the only participant in their household 
 
Exclusion Criteria: 
• 
Within the month immediately preceding the screening visit, use of any 
form of tobacco products other than cigarettes on 3 or more days within a 
week if the individual refuses to refrain from such tobacco use during the 
course of the study. 
• 
Within the month immediately preceding the screening visit, use of 
marijuana in any form on 3 or more days within a week 
• 
Within the two weeks immediately preceding the screening visit, 
involvement on more than 3 days in any formal smoking cessation 
activities 
• 
Treatment on a continuous basis within 2 weeks before the screening visit: 
any contraindicated medication for Varenicline or Bupropion.  Classes of 
contraindicated medications include, but are not limited to, antiasthmatics, 
antipsychotics, some antidepressants, antihypertensives, antiarrhythmics, 
antineoplastics, some antiseizures, and MAO inhibitors (See Appendix U 
for specific list of excluded and precautionary medications). 
• 
Uncontrolled hypertension (average reading of systolic blood pressure 
greater than 150 or diastolic blood pressure greater than 95) or other major 
contraindications for Bupropion or Varenicline (See section on Screening). 
• 
Severe renal impairment (CR Clearance <30 ml/min/1.73 m2).  
• 
Laboratory evaluations outside normal limits and of potential clinical 
significance in the opinion of the investigator 
• 
Meet current criteria for psychiatric disorders or substance abuse as 
assessed by the MINI plus (major depressive episode) and the MINI for 
items B, D, I, J (Alcohol Addendum-past 6 months only), K, L, M and N 
including a past manic or hypomanic episode as well as a lifetime 
psychotic disorder. 
• 
Individuals rated as moderate (6 – 9) to high (10 or greater) on suicidality 
as assessed by Module C of the MINI. 
• 
Psychiatric hospitalization within 1 year of screening date. 
• 
A positive urine pregnancy test during the screening period.  Women who 
are two years post menopausal, or who have had a tubal ligation or a 
partial or full hysterectomy will not be subject to a urine pregnancy test. 
• 
Pregnant, breast-feeding or of childbearing potential and is not protected 
by a medically acceptable, effective method of birth control while enrolled 
in the study. Medically acceptable contraceptives include: (1) approved 
hormonal contraceptives (such as birth control pills, patches, implants or 
injections), (2) barrier methods (such as a condom or diaphragm) used 
with a spermicide, or (3) an intrauterine device (IUD). Contraceptive 
measures sold for emergency use after unprotected sex are not 
acceptable methods for routine use. 
• 
Use of Varenicline or Bupropion within two weeks before the screening 
visit. 
• 
History of hypersensitivity or allergic reaction to Varenicline, tricyclic 
antidepressant, Bupropion (Wellbutrin, Zyban) or similar chemical classes 
or any component of these formulations. 
• 
Current or previous history of a seizure disorder. 
• 
Current or previous history of anorexia. 
• 
Subject considered by the investigator as unsuitable candidate for receipt 
of an investigational drug, or unstable to be followed up throughout the 
entire duration of the study. 


Protocol 2008-0850 
February 5, 2021  
Page 15 of 49 
 
 
staff (e.g., RN, PA, or APN). These conditions include the presence of hypersensitivity to either medication; 
use of MAO inhibitors or discontinuation within the past 2 weeks, recent myocardial infarction, uncontrolled 
hypertension, tachycardia, hypotension or risk of orthostatic hypotension, clinically significant renal or hepatic 
disease, use of other psychotropic medications including some antidepressants, or drugs that inhibit the P450 
enzyme system and previous history of a seizure disorder. Based on the MINI or MINI Plus (see below) and/or 
the presence or absence of psychotropic medication, or evidence in the patients health history and/or 
interview, we will exclude serious and unstable psychiatric conditions, including schizophrenia, bipolar 
disorder, current major depression, patients at risk for suicide, as well as other disorders such as panic 
disorder, PTSD, alcohol or substance dependence. We will also exclude those with anorexia as this is a 
contraindication for bupropion. Many of these disorders are treated with medications that are contraindicated 
for the use of bupropion and given the need to accurately describe the AE profile in the combination treatment, 
concurrent medications are kept to a minimum, exclusive of those used to manage chronic systemic medical 
conditions such as hypertension, hyperlipidemia etc. Standard blood chemistries including liver and renal 
function tests will be ordered on the initial screening session and reviewed prior to the subsequent visit for 
acceptability.  
 
At the Baseline Screening (Visit 0), which will occur within 30 days of the telephone screen, study participants 
will be asked to provide medical/surgical history, smoking history and to complete other assessments as 
shown in Table 5.  They will also be asked to provide a blood sample so that liver and kidney function can be 
assessed. Participants unable to complete the Baseline screening visit within30 days of the initial telephone 
assessment will be allowed to undergo a second telephone assessment and given an additional 30 days to 
complete the Baseline screening visit. If they do not complete the Baseline by this time point, they will no 
longer be considered eligible for study participation and must undergo a 90-day waiting period to re-enroll. 
Participants will not be randomized into the study at baseline screening given that they must complete the 
medical screening and the results of the lab work must be received before final eligibility can be determined.  
Participants who remain eligible after the baseline screening visit will be scheduled to return for the second in-
clinic (medical) screening visit (Visit 1) within 7 – 21 days. If initial lab values are abnormal, blood work may be 
repeated before V1. Study physicians will use the results of the second blood draw to determine the accuracy 
of the initial values and to make a more informed decision regarding study eligibility. If a participant is eligible 
for another one of our research studies but is not enrolled in that study, the MINI, blood chemistries, and blood 
pressure collected for that study will be considered valid for 30-60 days and may be used in consideration of 
determining initial eligibility on this study. 
 
The Medical Screening (Visit 1) will occur within 21 days of the Baseline Screening visit to determine final 
eligibility.  During Visit 1, the Research Nurse (RN) will review with the participant information collected at the 
baseline screening visit (e.g., medical/surgical history, psychological history, etc), results of blood work, vital 
signs and concomitant medications to ensure the accuracy of the information reported and to make sure there 
is nothing new to add.  The RN will also conduct a Review of Systems (ROS), head, ears, lungs, heart, etc., to 
determine the participants’ current level of health. Once the medical history review and ROS are complete, the 
RN will page/call the study physician or another qualified member of the medical staff (e.g., PA or APN) for a 
consultation regarding the participants’ medical history, concomitant medications, and the results of the ROS.  
The study physician (or another qualified member of the medical staff as spelled out above) will make a 
determination as to whether a full physical examination is needed.  The following criteria will be used to make 
that determination:  (1) History of a neurological disorder (e.g., migraines, head trauma, etc), (2) History of 
chest pain or other major cardiovascular event, (3) Presence of a chronic illness (e.g., diabetes, HIV, 
hypertension), or (4) Any condition or new information that is of concern or that requires further clarification, 
based upon the professional opinion of the medical staff.  In these cases, a full physical examination will be 
conducted.  Participants will also be given the opportunity to ask questions of the medical staff during this visit. 
If it is determined that an individual is eligible for study participation, the medical staff who conducted V1 will 
sign a medication prescription that will be filled by the pharmacy at M. D. Anderson Cancer Center as per 
protocol.  The medical staff (RN, PA, APN, or study physician) will also provide written documentation (dictated 
to medical chart) that the PA, APN, or study physician cleared the potential subject to participate on the 
protocol and the subject will be randomized into treatment.  If a person is deemed ineligible, s/he will be given 


Protocol 2008-0850 
February 5, 2021  
Page 16 of 49 
 
 
a letter stating the concern(s) and referred to his/her personal physician for follow-up.  Medical personnel may 
also delay clearance until any screening issues, which are not exclusionary, have been addressed by the 
potential subject’s personal physician. 
 
On occasion, V1 randomization may be delayed beyond 21 days from the Baseline visit due to medical 
findings that may be significant but not exclusionary, participant-related events (e.g., travel, work schedules), 
or study related factors (e.g., full clinic schedule).  In these cases, participants’ pregnancy status, blood 
pressure, concomitant medications, mental health history, medical/surgical history, and smoking history will be 
reviewed before completing the randomization.  If there are no significant changes, participants will be allowed 
to continue to the V1 randomization visit as described above.  If there are significant changes, the baseline 
screening process will be conducted again as deemed appropriate by the medical team.    
 
Re-Visit Schedule and the Visit Window 
Visit 2 will occur nine days after start of medication.  Following Visit 2, in-clinic treatment visits will be 
conducted weekly for Visits 3 - 13.  Every effort will be made to have the subjects return to the clinic on the 
same day of the week for study visits, however, a +/- 3 day window will be permissible for all return treatment 
visits except Visit 2 which will only have a +3 day window.  If the end of the +/- 3 day visit window falls on a 
weekend, holiday, or other day on which the clinic is officially closed, subjects will be allowed to complete the 
visit during the next business day except for V2 which will not be scheduled beyond +3 days.  Follow-up visits 
will have expanded visit windows such that the 3-mo Follow-Up Visit has a window of +2 weeks or -13 days 
and the 6-mo Follow-Up visit has a window of +/- 1 month.  The 12-mo Follow-Up Visit has a window of -1 
month with an ending period of whenever final abstinence data is collected or the trial ends, whichever is 
sooner. For those that miss a follow up visit, staff will call them to invite them to come in as originally planned 
so that at minimum abstinence data such as the time-line follow back assessment, CO and saliva cotinine can 
be collected. For those in follow up that report current abstinence and that they will not or cannot come in to 
complete the visit, we will ask for their consent to send them an abstinence questionnaire and cotinine saliva 
collection kit which they can conduct themselves and mail back to us.  In exchange for their completed 
abstinence packet (See Appendix VV and WW), we will mail them a gift-card for $20. 
 
Start of Medication and Medication Tracking  
Subjects will begin self-administration of medication 1 to 10 days after Visit 1 and will track their medication 
dosing and cigarette consumption throughout the study using smoking diaries that will be provided to them by 
the study counselor (See Appendix Y). Ideally, subjects will take medications for a full seven days before the 
target quit date (TQD), which occurs on day eight of treatment.   
 
Early Termination of Study Drug 
If early termination of study drug is necessary and occurs before the end of the 12-week treatment period (Visit 
13), an early termination visit (ET 13) will be conducted in order to collect the end-of-treatment lab work and 
other evaluations, regardless of whether the subject continues in the study.  If a subject prematurely and 
permanently discontinues study drug, they will be encouraged to continue to be followed in accordance with 
the study protocol through the end of the study.   
 
Disposition of Study Drug 
Occasionally, research subjects may fail to take a scheduled dose of medication.  In such cases, subjects will 
be instructed to mark the missed dose(s) in their smoking diaries and return the missed dose(s) of medication 
to the study team.  Returned medications will be logged, stored in a locked file cabinet maintained by the study 
team, and will be destroyed per institutional guidelines. Unused medications (i.e., those that were never 
dispensed by Investigational Pharmacy Services) will be maintained by the pharmacy team and will be 
destroyed per institutional guidelines.   
 
Subject Withdrawal  


Protocol 2008-0850 
February 5, 2021  
Page 17 of 49 
 
 
A withdrawal occurs when an enrolled subject ceases participation in the study prior to completion of the 
protocol, regardless of the circumstances.  Subjects may withdraw from the trial at any time at their own 
request, or they may be withdrawn at any time at the discretion of the investigator for safety reasons.  All 
attempts will be made to collect medications, and to conduct the final laboratory and other evaluations required 
by the protocol at the time of withdrawal.   
 
Assessments and Questionnaires 
MINI International Neuropsychiatric Interview and the MINI Plus.  Current psychiatric disorders will be 
ruled out using version 5.0 of the MINI 113. The MINI screens for several DSM-IV Axis 1 diagnosis including 
depression, anxiety, bipolar and eating disorders, as well as substance and alcohol abuse. The MINI also 
provides a graded assessment of suicidality (low-high risk). The MINI is shorter and takes less time to 
administer than the Structured Clinical Interview for DSM-IV disorders (SCID) 114 but has been validated 
against that instrument 22,113. Module A from the MINI Plus will be used to assess current as well as past 
history of depressive episodes even though evidence of past history will not be exclusionary, it will be taken 
into consideration should participant report any psychiatric adverse events while in treatment. 
Conners Adult ADHD Rating Scale (CAARS). We will also rate current ADHD symptoms using the 
Conners’ Adult ADHD Rating Scale (CAARS) 115. This is a validated self-report instrument that has been used 
in studies of adult ADHD 116. Each of its 18 items corresponds to one of the 18 DSM-IV symptoms for ADHD 
and is rated on a 4-point scale. As shown in Table 5, the scale will be administered at several points during the 
course of treatment to track possible changes due to treatment. Several of the cognitive symptoms related to 
concentration and restlessness etc. are also evaluated as part of the nicotine withdrawal assessment. 
 
Table 5. Study Time Line and Procedures 
STUDY TIME FRAME 
SCREENING 
TREATMENT 
FOLLOW-UP* 
(3 6 &12 months Post-
Quit) 
Visit # (See ‘note’ below) 
 
-1 
0 
1a 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13b
c 
14d 
15e 
16f 
Study Day 
-28 
-14 
1g 
8 
17 
24 
31 
38 
45 
52 
59 
66 
73 
80 
87 
94 
107 
197 
382 
Days from Quit 
-42 
-28 
-14 
-7 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
91 
181 
366 
Days on Medication 
 
 
 
 
9 
16 
23 
30 
37 
44 
51 
58 
65 
72 
79 
86 
 
 
 
ASSESSMENTS  
 
Phone Screen (Basic 
Eligibility) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Orientation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical & Other Screening 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
signed 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FTND 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
        ERQ 
 
 
  X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
        CERQ 
 
 
  X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking History 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Chemistry 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
        Motivation Questions 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood Pressure/Heart 
Rt 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ROS/Physical Exam 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MINI & MINI Plus 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hx of ADHD (Kollins) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abstinence Questionnaire* 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Protocol 2008-0850 
February 5, 2021  
Page 18 of 49 
 
 
 
History Of ADHD. Smokers will be evaluated for a history of ADHD using the rating scale from the 
National Longitudinal Study of Adolescent Health, a large-scale epidemiological study of ADHD and smoking, 
and described by Kollins and colleagues 48. The scale retrospectively assesses childhood ADHD symptoms in 
adults. The 9 DSM-IV symptoms of Inattention (IN) and 8 DSM-IV symptoms of Hyperactivity/Impulsivity (HI) 
are rated for past frequency of occurrence. Symptoms rated as having occurred “often” or “very often” are 
considered to have been present. Six or more symptoms from either the IN or HI categories are needed to 
qualify for positive history of ADHD.  
The Demographic, Health and Smoking Health Questionnaires. These instruments expand on the data 
obtained during the pre-screening, providing more detailed information on demographics, health/medication 
history, alcohol, caffeine, and other drug use, for use in the medical screening. Information on smoking history 
(e.g., year’s smoked, previous quit attempts, relapse, current smoking rate, and other nicotine/tobacco use) is 
also obtained. These questionnaires have been used in our previous and current cessation studies to provide 
descriptive data for the study population (e.g., 109,110). 
The Fagerstrom Test for Nicotine Dependence (FTND). The FTND is a 6 item questionnaire that 
measures nicotine dependence by assessing various components of smoking behavior such as daily intake, 
difficulty in refraining from smoking, and time to first cigarette 117,118. In some studies, the scale has been found 
to correlate with cotinine level 119 and to predict smoking treatment outcome 120. It was modified from the most 
commonly used nicotine dependence measure, the Fagerstrom Tolerance Questionnaire 121. Time to first 
cigarette (within 30 minutes) has been noted to be the item accounting for the majority of the variance in this 
scale and the one most highly correlated with multidimensional scales of nicotine dependence 122. 
The Wisconsin Inventory of Smoking Dependence Motives. Questionnaire (WISDM) 123 yields an 
overall nicotine dependence score as well as subscale scores for other critical dimensions of tobacco 
dependence (cognitive enhancement, negative reinforcement, positive reinforcement, automaticity, affiliative 
attachment, loss of control, behavioral choice/amelioration, craving, cue exposure/associative processes, 
Conner’s (CAARS) Adult 
ADHD 
 
 
 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
WSWS 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PANAS 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CES-D 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
QSU 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
mCEQ** 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
WiSDM 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sleep Problems Scale 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Cognitive Assessment 
Tasks*** 
 
 
 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
X 
 
 
 
EEG Assessments  
 
 
 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Smoking diary 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Buccal Sample 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Saliva Cotinine 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Expired CO 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pill Count 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Adverse Events* 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Symptoms Checklist 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant Meds* 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Counseling 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Dispense Medication**** 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
a-Randomization visit; start medication the next day; bc- End of Treatment or ET 13 visit (Visit 13; Week 13);  d-3month post quit follow-up (Visit 14; Week 15); e-6 
month post quit follow-up (Visit 15; Week 28); f-12 month post quit follow-up (Visit 16; Week 54); g-within 30 days of initial phone assessment but eligible for 
rescreen and an additional 30 days if needed; * Brief telephone contacts at 1-day pre-quit, 3 days post-quit and at Weeks 14, 20, 34, 42, and 48 to provide 
counseling support (1-day pre-quit and 3-day post-quit phone calls only), and to assess adverse events (Week 14 and Week 20 phone calls only), cigarette and 
other tobacco use, as well as use of medications for smoking cessation. Note: Subjects will be given a +/- 3-day window in which to complete a visit before the 
visit is considered missed (see protocol for additional details). **Only administered to participants that indicate non-abstinence since last visit***If missed at 
designated visit (due to patient no show, error, computer malfunction, etc.) task will be conducted at subsequent visit unless task already designated for that 
visit****Medication dispensing will occur in bulk quantities at V1and then again at V4 and V8. If pt cannot come at V4 or V8, meds will be dispensed when possible. 


Protocol 2008-0850 
February 5, 2021  
Page 19 of 49 
 
 
social/environmental goals, taste/sensory processes, weight control, and tolerance). The scale was developed 
using samples of daily smokers and validated on both clinical and non-clinical samples. As such it is highly 
sensitive to predictors of daily smoking level, “heaviness of smoking” expired CO, as well as abstinence 
following treatment. 
As shown in Table 5, participants will be asked to complete additional assessments throughout the 
course of the study. Brief descriptions of these assessments are provided below. 
The Wisconsin Smoking Withdrawal Scale (WSWS). The WSWS 124 will be used to assess withdrawal 
symptoms. We will use the Anger, Anxiety, Concentration, and Sadness subscales of WSWS, and the Craving 
subscale to ascertain the effects of quitting on mood and urges to smoke, respectively.  The WSWS has scale 
coefficient alphas between 0.75 and 0.93 and the mood and craving scales demonstrate increases as a 
function of nicotine abstinence as well as prediction of treatment outcome. Items from the Minnesota 
Withdrawal 125 are included in the scale for comparability to earlier studies using that measure. 
The Positive and Negative Affect Scale (PANAS). The PANAS 18 is comprised of two 10-item mood 
scales: Positive Affect (PA) and Negative Affect (NA). Participants rate different feelings and emotions on a 
scale of 1-5.  Various time instructions (e.g., today, past few days, past week, general, etc.) have been used 
with acceptably high alpha reliability ranging from .86 to .90 for PA and .84 to .87 for NA. Post-cessation 
PANAS negative affect is a robust predictor of relapse23,68 
The Center for Epidemiologic Studies Depression Scale (CES-D). The CES-D is a 20-item self-report 
measure developed to assess depressive symptoms in community (nonclinical) populations 126 and in recent 
studies of smoking cessation 127. This scale consists of four factors: depressed affect, enervation, lack of 
positive affect and interpersonal problems. 
Questionnaire on Smoking Urges -- Brief Version (QSU). The QSU Brief Form is a 10 item validated  
questionnaire measuring desire and intention to smoke; and anticipation of relief from negative affect 
and desire to smoke. The QSU has been found to be predictive of craving in laboratory studies 128 and lower 
scores on each of the subscales have been noted for smokers treated with varenicline or bupropion in the 
original clinical trials of varenicline 4,6.  
Modified Cigarette Evaluation Questionnaire (mCEQ). The mCEQ is a 12 item self-administered 
instrument  providing ratings of a smokers most recent smoking experience on multi-item domains of Smoking 
Satisfaction (satisfying, taste good, smoking, enjoyment), Psychological Reward (calm down, more awake, less 
irritable, help concentrate, reduce hunger), and Aversion (dizziness, nauseous), as well as a single-item 
assessment on Enjoyment of Respiratory Tract Sensations and on Craving Reduction, using a scale of 1 (not 
at all) to 7 (extremely). The original version contained 11 has been shown to be sensitive to interventions that 
purportedly reduce the pleasure associated with smoking (i.e., the nicotine antagonist mecamylamine and 
denicotinzed cigarettes 129,130. A factor analysis of the mCEQ in which a 12th item (enjoyment) was added to the 
satisfaction subscale was carried out using data from the 3 pivotal varenicline trials 131 , This analysis 
demonstrated the validity and, in general, the reliability of the multidimensional framework of the mCEQ. 
Cronbach's alpha for internal consistency exceeded 0.70 for all scales except Aversion domain. Test–retest 
reliability exceeded 0.70 on the three multi-item domains and two single items.  Moreover, varenicline (and 
bupropion) has been shown to reduce smoking satisfaction and reward, relative to placebo, although the effect 
sizes were somewhat larger for varenicline.4,6 
Motivation Scale. This is a 10-item assessment created specifically for smoking cessation research to 
measure a participant’s motivation to quit smoking.  
CERQ-short. The CERQ-short is an 18 item validated questionnaire that assesses an array of cognitive 
emotional regulation strategies and consists of 9 subscales: self-blame, acceptance, rumination, positive 
refocus, refocus on planning, positive reappraisal, putting into perspective, catastrophizing, and other-blame. 
These regulation strategies have been related to a variety of affective outcomes and may be related to 
cessation rates in this study. 
ERQ. The ERQ is a 10-item validated questionnaire that assesses individual differences in two 
emotional regulation strategies: cognitive reappraisal and emotional suppression. These strategies have been 
related to negative affect, which may be related to cessation rates in this study. 


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Sleep Problems Scale.  This 4-item scale, designed to assess symptoms of sleep disturbance as a 
function of treatment and nicotine withdrawal, will be administered at baseline and again at 4 weeks, 8 weeks, 
and 12 weeks after treatment begins. 
Cognitive Assessments. Cognitive performance will be assessed using the Attention Network Test 
(ANT), and the Rapid Visual Information Processing Task (RVIP-CED). The tasks are programmed using E-
Prime, Version 1.1 143and take about 15 minutes to complete (in total).  
The Attention Network Test (ANT) has been implemented following the procedure used by Fan et al. 
{Fan, 2005 8027 /id}. The task lasts for approximately 20 minutes and it is divided into four blocks with resting 
pauses in between blocks. The first block is a practice block. The task has been implemented using Eprime 
software. In each trial, a fixation cross appears in the center of the screen all the time. Depending on the cue 
condition, a cue (none, center, or spatial cue) appears for 200 ms. After a variable duration (300– 11800 ms), 
the target (the center arrow) and flankers of left and right two arrows (congruent or incongruent flankers) are 
presented until the participant responds with a button press, but for no longer than 2000 ms. After the 
participant makes a response, the target and flankers disappear immediately and a post-target fixation period 
lasts for a variable duration (from the onset of the target and the start time of the next trial is between 3000 and 
15000 ms). 
The Rapid Visual Information Processing Task (RVIP-CED). proposed in this trial consists of numeric 
digits (1-9) which will be presented every 600 ms (100/min) at the center of the computer monitor interspersed 
with slide distracters (pleasant, unpleasant, neutral and cigarette pictures that last 600 ms each. The 
participant will be instructed to push a response button if either three consecutive even or odd digits are 
shown. The task will last approximately 15 minutes. 
Slide Distracter Stimuli. The distracter slides are presented immediately prior to some of the RVIP digits 
in order to evaluate their impact on smokers' attention to the RVIP task {Gilbert, 2005 6717 /id}. The distracter 
slides will be composed of four types, including smoking, pleasant, unpleasant, and neutral content. The 
pleasant, unpleasant, and neutral slides will be drawn from the International Affective Picture System (IAPS 
{Center for the Study of Emotion and Attention, 1999 4947 /id}). Additional cognitive assessments are provided 
by the CAARS as indicated in Table 5. 
Laboratory Assessment of Cognitive Response.  Electroencephalography (EEGs) assessments will 
supplement the ANT, RVIP-CED and CAARS as an additional measure of cognition. The protocol for the 
individual EEG assessments will be similar for all sessions.  Each session will begin at approximately the same 
time of day for each participant. Participants who are selected to participate in this part of the protocol will be 
asked to limit their intake of coffee (or equivalent) to no more than 1 cup prior to 8:00 am on the day of each 
laboratory session. Smoking for all groups will be unrestricted prior to the first (baseline) EEG assessment 
session (V1). The first session will be used to assess normal EEG responses to affective stimuli prior to any 
nicotine deprivation or pharmacological treatment.  Subsequent sessions will be used to assess the effects of 
treatment modality (Varenicline, Varenicline plus Bupropion, placebo) on EEG responses to affective stimuli. 
The target days for these laboratory assessments are one week pre-quit (V1), one-day post-quit (V2), and one-
month post-quit (V6).  At the beginning of each EEG session, participants will be asked to complete the 
session questionnaires.  After completing the questionnaires, sensors will be placed on the scalp to measure 
electroencephalography (EEG).  Participants will be asked to rest quietly, while seated in a comfortable 
recliner, so that baseline data can be measured – with eyes open and with eyes closed. The subject will be told 
that a series of slides will be presented and that each slide should be viewed the entire time it is on the screen. 
Participants will sit approximately six feet from the viewing screen and will see a variety of pictures.  Each slide 
will be presented for approximately 6s, followed by a randomly determined interslide interval, 1.5 to 20 seconds 
in duration.  The images will be selected from the International Affective Picture System (IAPS) (Center for the 
Study of Emotion and Attention, 1995) and are the same as used in our preliminary studies.  These slides have 
been standardized for valence and arousal (e.g., ).  The smoking cue slides (lit cigarette, ash tray, people 
smoking, etc.) were developed in our laboratory for our preliminary study  and will also be used here. The 
slides will be equally divided among the valence categories and the smoking cues. Different slide sets will used 
in each session with the order of set presentation counterbalanced across subjects. Within each set, each 
subject will see pictures from each category equally often in each position. Counterbalancing for slide order 
within a set will be arranged. After the final block, participants will view an additional set of slides and will be 


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asked to rate the valence of the pictures. EEG physiological recordings from this task will be scored offline for 
early and late components of the ERP. These components are sensitive to cognitive and emotional processing 
of visual stimuli. EEG assessments will not be done until funding becomes available and will only be conducted 
in up to 120 subjects.   
Upon completion of each questionnaire set, participants will be asked to sign an acknowledgement 
form in which they will indicate and acknowledge the assessments they just completed. (See Appendix HH). 
EEG Data acquisition and reduction. During the execution of the task, the electroencephalogram (EEG) 
will be recorded using a 129-channel Geodesic Sensor Net and amplified with an AC coupled high input 
impedance (200 MΩ) amplifier (Geodesic EEG System 250; Electrical Geodesics Inc., Eugene, OR) vertex 
referenced to Cz. Sampling rate will be 250 Hz and data will be filtered online using a 0.1 Hz high pass filter. 
After data collection, a 100 Hz low pass filter will be applied to the recording and an artifact detection 
procedure will be used following the method proposed by Junghöfer and colleagues 132. This procedure detects 
artifacts by performing two passes on the data. The first pass uses the original reference (i.e., Cz), to avoid 
contamination of all channels by the artifacts when transforming EEG data to the average reference. The 
second pass uses the re-referenced data. At the end of the first pass, sensors consistently contaminated by 
artifacts will be interpolated using the information contained in the uncontaminated sensors. After this first 
pass, the average reference (necessary for accurate topographic mapping and topographic waveform plots) 
will be calculated and the second pass will be performed to identify contaminated sensors within specific trials. 
If, within each trial, more than 5% of the sensors are artifact contaminated, the trial will be rejected; otherwise 
the contaminated channels will be interpolated. After these steps individual epochs, time-locked to the stimulus 
onset, will be extracted from the continuous EEG. Event-Related Potentials (ERPs) will be computed 
individually for each participant according to the experimental condition. ERP components (e.g., P1/N1, P300, 
late positive potential) will be identified and average voltage within specific time windows will be computed and 
used in the statistical analyses. 
Abstinence Questionnaire & Expired CO. The Abstinence Questionnaire is a 16-item interview 
administered questionnaire that will be used to assess smoking behavior and abstinence throughout the 
course of the study. Abstinence will be verified by an expired CO reading of < 10ppm at each in-person 
measurement occasion. This questionnaire has been used in our previous studies and is administered using a 
computer. The program utilizes subject specific events (birthdays, anniversaries etc.) and general milestones 
(holidays) which allows the interviewer to conduct a time-line follow back procedure to assess all smoking in 
between visits. All measures of abstinence as described can be assessed using this procedure. 
Cotinine. Cotinine is the first metabolite of nicotine and has a half-life of about 20 hrs134. Saliva cotinine 
will be obtained at the time of randomization and at selected follow-up points shown in Table 5. Cotinine values 
will provide information regarding the participant’s tobacco exposure within the previous 24-36 hours. Baseline 
cotinine values will be used in the descriptive analyses of smoker characteristics, along with other variables 
from the smoking history questionnaire. Cotinine values (<25ng/ml) from subsequent assessments will be used 
as a crosscheck on abstinence requirements during follow-ups. Cotinine assays will be performed by 
Salimetrics in State College Pa. This is a reliable lab affiliated with Penn State and one which we have 
successfully used in several previously studies. We anticipate no problems in transporting samples or 
obtaining valid results. 
 Adverse Event Monitoring & Concomitant Medication  
Participants will be assessed for side effects and concomitant medications using standard FDA guidelines 
recommended for these two procedures. Additionally, from V1 through V14, a symptoms checklist will be 
administered to quickly assess for certain symptoms a participant may be currently experiencing or have 
experienced since the last visit that may require immediate follow-up by someone from the study medical team 
before the study visit is concluded (see Appendix II). Blood pressure, heart rate, and weight will be monitored 
weekly during treatment and at follow-up. We consider a sustained blood pressure (BP) > 150/95 the stopping 
criterion where this measure is concerned. That is, if a subject has an average BP> 150/95 for three 
consecutive study visits, the study physician will be contacted to evaluate whether the study medication should 
be discontinued, a change in dose ordered and/or whether the subject should be referred to his/her personal 
physician for follow-up.  The subject would not be discontinued from the study (see Appendix BB for details). If 


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there are clear reasons for the elevation, such as the patient failing to take their antihypertensive medication, 
they may be re-challenged with the study drug, at the study physician’s discretion once their BP is controlled. 
Additionally, if a subject has a sustained (for three consecutive study visits) average reading of systolic BP of 
140 – 149 and/or a sustained diastolic BP of 90 – 94, the study physician will be contacted to evaluate whether 
the medication should be discontinued, a change in dose ordered and/or whether the subject should be 
referred to his/her personal physician for follow-up.  The subject will not be taken off study drug unless the 
study physician or his/her personal physician recommends that we do so.  Liver (LFT’s) and renal function 
renal function (creatinine clearance) will be evaluated at baseline, after 3 weeks on the medication(s) and at 
the end of treatment. Blood chemistries will be repeated as needed accordingly when clinically warranted.  
Adverse events will be reviewed by our medical personnel or the PI and the physician along with the PI 
may adjust medication doses to manage subject complaints of intolerable or untoward side effects.  Medication 
doses may also be adjusted if subjects’ reports of side effects cause concern even if there are no specific 
subject complaints.  Dose adjustment strategies will follow good clinical practice guidelines as recommended 
for management of side-effects for these two medications. This may include reduction to once per day dosing 
on the maintenance dose(s), twice per day dosing at a lower dose(s), stopping medications altogether, or any 
other approach the medical team deems most appropriate to manage the side effect profile.  For example, in 
the VB group one or both medications may be dose adjusted or medications may be stopped altogether if the 
side effect profile and/or subject complaints warrant it.  Adverse event monitoring will continue up to 90 days 
after medication is completed, which corresponds to the 6-month post-quit visit (V 15). If an AE is 
spontaneously reported after the AE reporting period is over, the AE will be recorded.  Those AEs that are 
probably, possibly or definitely related to treatment will be followed until resolution or end of study, whichever 
comes first. In the case of reports of suicidal ideation, depression or anxiety which we believe may be related 
to treatment, if possible, we will engage in our normal psychological assessments (see Appendix S). This may 
not always be possible if reported by phone. In any case, procedures for Good Clinical Practice will be followed 
with respect to medical management of the symptoms. A specific plan for monitoring increased depression and 
suicidality is presented in the appendix (see Appendix S).  Details regarding the monitoring/management of 
treatment-emergent anxiety are also included in Appendix S. The clinical assessment tool we use is the HAD 
(the Hospital Depression and Anxiety Scale) and the procedures outlined in Appendix S apply to both 
symptoms of anxiety and depression. Moreover, because aggression and irritability are intimately associated 
with anxiety, these symptoms are also captured in our monitoring and management procedures. Treatment-
emergent psychosis is extremely rare in smoking cessation trials. If it does occur, it will be captured by our 
weekly assessment of adverse events. These cases will be referred for further evaluation by a Ph.D. licensed 
Clinical Psychologist and/or the Addiction Psychiatrist, who is a co-investigator on this protocol.  The Addiction 
Psychiatrist will determine the course of clinical management according to methods of good clinical practice. 
The PI or physician is responsible for determining the attribution of adverse events to study medication.  
For this trial, AEs will be recorded according 
to the Recommended Adverse Event 
Recording Guidelines for Phase III 
protocols (see shaded areas of Table 6). 
Concomitant use of varenicline & 
Bupropion. Bupropion is hydroylated into 
hydroxybupropion, its active form via the 
enzyme CYP2B6, and bupropion is a 
cytochrome p450 2D6 inhibitor. Nicotine 
was first found to be an inducer of CYP2B6 
in rat brains and a 2003 study suggests that 
the same affect is seen in human brains. 
These data are interesting in that higher 
levels of CYP2B6 can be thought to 
increase the levels of active form of 
bupropion that would be seen in a normal 
brain.  This could lead to an elevated effect 


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of the drug and thus increased efficacy135. However, pharmacokinetic studies of varenicline show that it is 
metabolized extensively and that 92% of drug-related material is excreted unchanged in the urine. The 
straightforward dispositional profile of varenicline simplifies adding bupropion to it without any foreseeable 
complications or competitive metabolism 136. The concomitant use of varenicline and bupropion has been 
tested among 46 smokers in a pre-marketing study conducted by Pfizer (see www.chantix.com). These 
subjects were not instructed to quit smoking and began both varenicline and bupropion SR using the same 
dosing schedule for the first two weeks as described in this protocol. The results showed that varenicline did 
not alter the pharmacokinetics of bupropion nor were there any clinically significant adverse reactions observed 
during the period of co-administration. The primary AE’s for either drug (nausea for varenicline and insomnia 
for bupropion) were as expected for either drug alone. There are also post-marketing reports of an increase in 
depression, anxiety and suicidal thoughts while on varenicline. As discussed above a proper plan for 
monitoring and responding to such symptoms has been established. 
Assessment Protocol and Participant Burden. All assessments will be conducted by non-counselor 
research staff (e.g., research assistants, nursing and medical staff, etc), who like other staff are blind to 
medication assignment. This procedure eliminates the likelihood of counselor bias on the outcome 
assessments. Self-report measures are administered on a computer-based program. To reduce the potential 
frequency of missing data, we follow a standardized procedure for contacting the participant with appointment 
reminders by telephone and letter and in the event a session is missed every attempt is made to reschedule 
the visit within a 3 day window.  As a last resort, telephone visits will be conducted but no compensation will be 
earned for these phone visits. In these cases Adverse Events, Concomitant Medications, Abstinence 
Questionnaire, Symptoms Checklist and counseling will be assessed/administered. The entire assessment 
protocol should take no longer than 45 minutes. We have conducted numerous trials using these and many 
other psychological and cognitive assessments with little problems in participant compliance. Past experience 
has shown us that the longer a participant is enrolled, the greater the chance that they will fail to complete a 
visit.  So, although we strive to ensure patients complete each visit, we expect that some will not and as such, 
we will not require every visit be completed in order to participate in the study. 
Treatment Intervention 
Counseling Component   Behavioral counseling is a recommended standard of care to be used in 
conjunction with pharmacotherapy 137.  At visit 1, the counselor will provide the participant with a card with 
emergency contact information, study medication instructions and a participant manual which they will refer to 
throughout treatment. As shown in Table 5, individual brief-behavioral counseling sessions (10-15 minutes) will 
be provided to all participants once per week for 12 weeks. One support phone call will also be conducted 3 
days after the target quit date. The counseling intervention is modeled after programs that have been used in 
several smoking cessation medication studies, including bupropion 128,138, nortriptyline 139, venlafaxine 23, 
rimonabant 107 and varenicline4,6. Our individual counseling sessions are comparable in duration and scope to 
that used in the pivotal trial contrasting varenicline and bupropion4,6, although in those trials counseling was 
more frequent than that used in the original trial of bupropion (7 weekly individual counseling sessions, 1 call, 
10-15 minutes each) 138, since a longer duration of medication was used (12 weeks). This is meant as an 
example and will be modified accordingly to reflect appropriate time line, number of visits phone support and 
drug information.  In addition to the 3-day post quit support call, there will also be one pre-quit day phone call 
and five follow-up assessment phone calls during the course of the study. If unable to reach participant during 
first call attempt, the visit will be considered missed and no further attempts will be made for the 1 day pre-quit 
and the 3 days post-quit calls as the visit window is only 1 day.  For the remaining five follow-up assessment 
phone calls, the first two phone calls will observe an additional 1-2 call attempts within the 3-day window 
before the visit is considered missed. The last three phone calls will observe an additional 2-3 call attempts 
within the +1 month window before the visit is considered missed. Although we strive to ensure patients 
complete each visit, we expect that some will not and as such, we will not require every phone visit be 
completed in order to participate in the study. 
Varenicline/Varenicline plus Bupropion/Placebo   Smokers will receive a 12-week regimen of V, VB or P 
beginning the day after they complete the second screening visit (Visit 1). During the first week of medication 
the dose will be titrated, as recommended in the dosing guidelines for both drugs. Smokers in both groups V 
and VB will take 0.5mg varenicline once per day (am) for the first 3 days and 0.5mg bid (am and pm) for the 


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next 4 days. Smokers in the VB group will also take 150mg bupropion (SR) once per day (am) for the first 3 
days followed by150mg bid for the next 4 days. Smokers in the V group will also take a matching bupropion 
placebo on the same schedule as those in the VB group. For safety reasons, if a participant misses any dose 
of medication during a ramp-up phase, the PI and/or Study Physician may re-evaluate whether the start or 
change of medications and/or the Quit Date should be delayed. From week 2-12, smokers in the V group will 
take 1mg of varenicline and one bupropion matching placebo twice per day. Smokers in the VB group will take 
1mg of varenicline and one active 150 mg bupropion tablet twice per day. Smokers in the P group will take a 
matching varenicline and bupropion placebos on the same schedule as the V group takes varenicline and the 
B group takes bupropion, respectively. Bupropion and matching placebo will be made by over-coating the 
active medication and matching placebo so that they appear identical. Varenicline and matching placebo will 
appear identical in size, color, and shape to maintain blinding.  Varenicline and matching placebos will be 
provided by Pfizer pharmaceuticals and will be encapsulated by a compounding pharmacy. We currently use a 
similar procedure in our on-going R01 using pharmacogenetic trial of bupropion, varenicline and placebo, and 
have an established relationship with a pharmaceutical compounding company to provide this service. 
Bupropion (SR) is now in generic form and no matching placebo is available directly from the generic 
manufacturers. Varenicline will be purchased and prepared by the compounding pharmacy and delivered to 
Investigational Pharmacy Services, which will manage the inventory for dispensing by the Outpatient 
Pharmacy. The MD Anderson pharmacy will implement the randomization schedule as developed by the study 
data manager. Our pharmacists have considerable experience preparing multiple medication regimens such as 
this and are currently doing just that for our on-going trial using bupropion and varenicline. Patients in that trial 
receive 1 of 2 active medications and a matching placebo of the opposite drug. Thus we have logistical 
support, expertise and experience to carry out a study using multiple medications and anticipate no problem in 
successfully conducting these procedures.  
Smokers will be instructed to quit smoking the day before Visit 2. We chose the quit date to be 
consistent with previous trials using these drugs. Current guidelines note that both drugs may be discontinued 
without tapering. All medication will be stopped at the end of week 12.  Subjects’ thoughts about their treatment 
assignment will be assessed by querying participants at the end of treatment, using a brief questionnaire we 
developed for our current medication trials. While not a valid measure of blinding success, this assessment 
provides valuable insight regarding the subjects’ perception of their medication assignment and the associated 
side effects (see Appendix X).  Medication dispensation, pill counts and assessment of adverse events will be 
carried out by medical and other research staff members who have been trained on these procedures. 
As described above, given the data from Pfizer and the AE profile of both of these drugs, we do not 
anticipate any significant increase in adverse events as a result of combining these medications. However we 
will closely monitor AE’s during an initial pilot of 5-6 smokers (as well as throughout the study) paying particular 
attention to the first cohort of patients (approximately 20) to complete the full 12 weeks of combined 
medication. If the frequency of AE’s exceed that which is expected for either drug, we will consider a change in 
the titration schedule, for example, delaying the onset of bupropion for 1-2 weeks after the start of varenicline, 
to allow for some adaptation to take place prior to the first drug, before introducing the second medication. The 
quit date would also be adjusted accordingly. It should also be noted that consistent with the principals of good 
clinical practice, individual adjustments in medication dose might be occasionally recommended by our study 
physician at any time, in response to an emergent medical concern. All medication adjustments are recorded in 
the database and used in the analyses model that includes dose as a covariate (see Data Analysis section 
below). 
Breaking the Blind. Un-blinding of single cases by the investigator will only be performed if relevant for 
the safety of the participant. The PI along with the Program Director (PD) will be responsible for implementing 
procedures for maintaining the blind and for breaking the blind when necessary.  In emergency situations, the 
Principal Investigator (PI) would consult with the Program Director (PD) and/or the research team’s Data 
Management Supervisor (DMS) to obtain immediate blinding information for the participant. The PD/DMS 
would then pass this information on to the PI to enable the participant to be treated. In non-emergency 
situations, the same procedures would apply, however the PI and PD will discuss and evaluate the request, 
then, the PI after consulting with the study physician would be responsible for making the decision of whether 


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or not to un-blind. When the blinding code is broken, the reason will be fully documented and included on the 
appropriate data collection forms.  The MDACC IND office will also be notified. 
Un-blinding of all participants will occur at the end of study, whereby the PI will be provided with a list 
containing data regarding the arms to which each of his patients were randomized. Also, at the end of study, 
subjects will also be told which medication(s) they were taking if requested. 
Counselor Training and Supervision. In order to ensure consistency in the counseling portion of the 
intervention, all study counselors will be required to attend training sessions with Ph.D. or Master’s - level 
certified smoking cessation clinicians from Dr. Cinciripini team. Dr. Cinciripini and his team are more than 
qualified to train the study counselors.  In addition, many of the clinicians on his team are licensed professional 
counselors in the state of Texas and have been certified for smoking cessation counseling by a recognized 
national program at the ACT Center at the University of Mississippi Medical Center which meets the guidelines 
set forth by the Association for the Treatment of Tobacco Use and Dependence (ATTUD). 
Training components include: 1) an overview and rationale for the use of behavioral therapy in smoking 
cessation treatment; 2) an overview and rationale for the use of the pharmacological treatments used in the 
study; 3) a comprehensive review of the therapist and patient manuals; 4) watching videos of experienced 
smoking cessation counselors delivering the counseling intervention, with a follow-up discussion of the 
techniques used; 5) role play practice of counseling sessions with follow-up discussions; and 6) conducting a 
counseling session under supervision, again with post-session discussions.  All counselors will go through 
each of these training components at least once and will go through refresher training as often as deemed 
necessary by the counselor supervisor.  In addition, all study counselors meet with the counselor supervisor on 
a weekly basis (or more frequently if initiated by the counselor) to discuss any patient issues and to get brief 
training or refreshing in a number of areas relevant to the individual needs/circumstances of the counselor. 
Intervention Fidelity. In the proposed study, intervention fidelity will be maintained through several 
means: manual-driven approaches; on-going training; completion of post-counseling inventory of topic 
discussed; individual and team supervision; and independent ratings of tape-recorded intervention sessions.  
Follow-up Assessments. In person follow-up assessments will be conducted at 3, 6, and 12 months 
after the target quit date. Similar to the pivotal trials of varenicline, brief telephone contacts at weeks 14, 20, 
34, 42 and 48 will be conducted to assess cigarette (abstinence) and other tobacco use as well as use of 
medications for smoking cessation (See Table 5 for additional details). 
Abstinence Assessments. Abstinence outcome assessments will conform to the recently developed 
guidelines from the Society of Research on Nicotine and Tobacco (SRNT) committee on measurement of 
abstinence 140, as well guidelines established by the FDA for proof of concept trials of a new smoking cessation 
medication.  The SRNT guidelines recommend measuring and reporting abstinence in several ways, including, 
point prevalence abstinence, prolonged abstinence, continuous abstinence, and time to relapse. In addition, it 
is recommended that measures of smoking exposure be obtained to assess reduction among participants who 
fail to quit.  Our analyses will include an evaluation of each of these measures of abstinence as well as 
smoking reduction.  
 Seven-day point prevalence abstinence is the most commonly used measure in smoking cessation 
studies and is defined as a self-report of no smoking, not even a puff, in the 7 days prior to the assessment 
plus a confirmatory CO <10ppm. Prolonged abstinence refers to abstinence beginning with the end of the post-
quit date grace period and extending to a subsequent follow-up point.  The grace period is usually 2 weeks but 
can be any time frame in which the treatment is expected to have produced an effect. For this study, the grace 
period will be 2 weeks from the quit date. Relapse after the grace period is defined by any smoking (or other 
tobacco use) over 7 consecutive days or smoking less than 7 consecutive days but over 2 consecutive weeks. 
Prolonged abstinence will be reported at each time point following the grace period.  Continuous abstinence is 
defined as no smoking, not even a puff, beginning on the quit day through the end of follow-up. Finally, the 
FDA proof of concept measure is defined as no smoking, not even a puff, for four consecutive weeks during 
the last 4 weeks of treatment. 
 Our primary outcome measure for this trial will be prolonged abstinence as that is the recommended 
SRNT guideline standard. However, to provide comparability to older studies as well as more recent 
medication trials, we will also report repeated point prevalence, continuous and the FDA proof of concept 


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measure of abstinence. In addition, our abstinence interview will enable us to capture days to relapse and 
number of cigarettes smoked at each time point. Days to relapse will be used to conduct a survival analysis, 
also recommended in the SRNT guidelines. Cotinine will also be assessed at follow-up to provide a measure of 
tobacco exposure among those who fail to quit. Cotinine levels and self-reported cigarettes per day data 
obtained through the time line follow-back procedure will be used to evaluate drug related smoking reduction 
among those who fail to quit. 
Participant Compensation Following randomization, participants will be remunerated approximately $20 
per weekly clinic visit and $50 for each of the in-person follow-ups for expenses associated with study 
participation. If a subject completes an EEG assessment, an additional $25 will be offered as compensation.  
Free parking and/or bus passes (if available) will also be provided. 
Design Considerations There are several design issues that were considered in choosing the present 
methodology.  Although the combination of these two drugs has not been extensively evaluated we chose to 
begin each medication simultaneously based on the fact that a previous short term study of co-administration 
of both medications (www.chantix.com) showed no significant alteration in the pharmacokinetics of either drug 
and no significant elevation in side effects. Moreover, although not started together, our preliminary data shows 
no increase in side effects associated with combined use of these medications. We chose to use the same 
dose escalation procedure recommended for either drug by itself in order to maximize potential efficacy of the 
combination. However, it is possible that dose adjustment of either drug in some smokers may be required to 
medically manage adverse events. This would be consistent with good clinical practice guidelines established 
for either drug and will be recorded as they occur in the present study.  
Similarly, at this stage of evaluation of the combination of these two medications, it seemed 
inappropriate to include a bupropion alone arm. Two independent studies have already established that 
varenicline is more effective than bupropion 4,28,6 alone and there are numerous independent trials showing the 
bupropion out performs placebo5. Little seemed to be gained by including a bupropion alone conditions in the 
current trial since the scientific question at hand is determining whether the combination treatment out 
performs the solo treatment of varenicline, and to what extent such effects if observed may be mediated by our 
affective and cognitive measures, relative to placebo. Moreover, given the animal data showing no effect on 
nAC DA release when nicotine and varenicline are co-administered there appears to be little benefit of 
including a treatment arm combining NRT and varenicline 24.  
We also chose to use a 12 month follow-up period for determining prolonged abstinence (our primary 
dependent measure) and long term drug effectiveness as we feel this represents an appropriate balance 
between the definition of abstinence used to establish FDA proof of concept (continuous abstinence over the 
last 4 weeks of treatment), and the one year continuous outcome milestone most often used as the standard in 
smoking cessation clinical research. This study, while clearly looking for an off-label application for the 
combination of both drugs, is not a traditional industry sponsored medication trial. We reasoned that the 4-
week proof of concept measure while acceptable for purposes of meeting FDA requirements for moving from a 
phase 2 to phase 3 medication trials and phase 3 to approval, would not meet the traditional standards for 
determining abstinence of the research community. The additional cost of extending follow-up to 12  months, in 
our view, are outweighed by the beneficial contribution of the study to the research literature that would accrue 
as a function of using a longer follow-up period. 
Time Line and Pilot. As shown in Figure 4, we 
anticipate conducting a logistical pilot as is our practice 
prior to full randomization. We will use this time to test 
the database, assessment procedures, and to complete 
the real-time training of any new hires. We will run 
approximately 5-10 smokers through the entire 12 week 
medication protocol and make any adjustments as 
necessary in our procedures to facilitate ease of patient 
flow compliance, and management of side effects. We 
already have a strong infrastructure in place for 
conducting clinical trials, including established relationships with medication vendors, our pharmacy and other 
suppliers, trained medical and support staff, and adequate space and supportive resources to conduct the trial 
Figure 4 
 
Study Event
Duration
Start
End
Set-up/Hiring and
1
0
1
Database Programming
2
1
3
Staff Training /Pilot
3
3
6
Randomize, Treat, Follow
54
6
60
Complete Follow up & Data Analysisis
6
60
66


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(see Resources and Environment). Thus we anticipate few problems in getting this study underway. In the time 
line, we allow for the possibility that completion of the post-treatment phone assessments and 6 and 12 month 
follow-ups may reach into the 6 month period following the official end date of the grant. We have budgeted our 
resources from this project to allow for the needed staff to complete these follow-ups in a no-cost extension 
period should that be necessary. 
Data Analytic Plan 
 Prior to inferential procedures, extensive descriptive analyses will be conducted on the 
screening/baseline data and repeated measures data from study questionnaires, medical assessments 
(including laboratory tests, dosage levels, pill counts, etc.) and adverse event reports (see Table 5).  For 
continuous measures standard descriptive statistics, including means, standard deviations, ranges, etc., will be 
computed together with ninety-five percent confidence intervals.  Graphical methods, including box plots and 
histograms, will also be employed to closely examine the distributions of the questionnaire scores.  If required, 
potential normalizing transformations will be explored.  Vicariate associations between the scores and selected 
demographic variables including age, ethnicity, gender, initial cotinine, FTND score, depression and ADHD  
history, baseline smoking level and other initial assessments will be evaluated using Pearson’s product 
moment correlation coefficients and ANOVA.  Cross-tabulations and chi-square analyses will be used to 
examine questionnaire categorical data and relations with study group.  
General Statistical Approach.  
Logistic regression will be used to evaluate the prolonged abstinence at 12 months (primary outcome) 
as well as exploratory abstinence outcomes, including EOT and 6 months abstinence and all other abstinence 
definitions at each time-point. The primary contrast of interest compared the Combo and Var groups. Missing 
abstinence observations will be imputed as smoking, Moreover, our analytic strategy will involvethe use of a 
mixed model regression to examine the effects of the dependent variables (e.g., abstinence, PANAS, WSWS, 
mCEQ, CAARS, cognitive assessment tasks, etc.) across assessments. The mixed model approach provides 
a generalization to the classic linear regression model, using likelihood functions instead of least squares to 
estimate effects 141. The mixed model approach is ideally suited for analysis of repeated measures data in that 
it allows for more specific estimation of the correlation structure of the residuals, and more efficiently handles 
unbalanced designs and is very robust to missing data, without excluding participants or imputing values 142,143. 
Fit statistics (e.g., Akanke’s Information Criterion) will be evaluated for all models to ascertain the best fit of the 
correlation structure of the dataset. We will use a computer program, PROC MIXED (SAS v9.1 SAS Institute 
Inc, Cary, NC) to estimate and to test the models with continuous dependent measures. In the case of 
abstinence data where the value is binary, we will use SAS PROC GLMIMX, which provides an adaptation to 
the mixed model approach for categorical data.  Post hoc comparisons within multilevel main effects and 
between interaction terms will be conducted using tests of simple main effects 144. We have considerable 
experience with these procedures and have employed them in our previously published studies 145,23,146. Post 
hoc comparisons within multilevel main effects and between interaction terms will be conducted using tests of 
simple main effects 144. We have considerable experience with these procedures and have employed them in 
our previously published studies 145,23,146. 
EEG Statistical Approach. To test our exploratory hypotheses involving EEG, the information from the 
whole topographies will be used. To avoid setting arbitrary regions of interests and to take advantage of the 
better spatial resolution provided by the dense-sensor array, we will perform the statistical analyses using 
randomization tests to control for the increase of the family-wise error rate due to multiple comparisons 133. The 
randomization procedure involves two steps: (a) computing a statistic (e.g., an F-statistic) for each sensor and 
(b) evaluating its p value under the randomization distribution. The randomization distribution is built by first 
randomly assigning to different data vectors the data matrix obtained for each participant within each 
experimental condition. The statistic of interest is then calculated for each sensor. These are the F-values 
obtained when the data are randomly assigned to the experimental conditions and the highest value is stored. 
This process is repeated 10000 times to form a distribution for the F-statistic associated with the hypothesis of 
interest. After the construction of these randomly generated data vectors, the F-statistic is computed at each 
sensor using the actual data as obtained from the experiment. If the value of the F-statistic obtained during 
actual hypothesis testing exceeds the F-value marking the upper 5% of the distribution obtained from the 
random iterations, then it is considered significant at the .05 level. To test each hypothesis a new 


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randomization distribution will be generated. This will ensure the independence of each statistical test and will 
keep the probability of a Type I error within the 5 % threshold for each comparison. An example of our work 
and approach in this area can be found in Appendix T. 
Power Analysis. Our primary hypothesis is that abstinence rates will be significantly greater in VB vs. 
the V group at the end of treatment and through the follow-up assessments. Based on our previous experience 
using monetary compensation for completion of assessments, we expect the follow-up completion rate to be 
approximately 80%. Intention-to-treat will be used as the standard for all analyses, classifying participants 
whom we are unable to contact at follow-up as smokers, thus no abstinence data is regarded as missing once 
a participant has been randomized. Because of the binary form of the primary outcome measure, the multiple 
follow-up visits and the potential for non-homogeneous correlations among the measures over time, we have 
estimated power across the time points (EOT-through 1 year follow-up) using power calculations for 
longitudinal data with binary responses 147, assuming that we will have an equal number of study participants in 
each treatment group from the intent to treat analysis, and that the impact of the effect of the other covariates 
will be equal across treatment groups. 
As the combination of varenicline and bupropion has not been used in a smoking cessation trial, there 
are no data from which to directly estimate effect sizes of the combined treatment. However, data from the 
pivotal trials with varenicline provide a basis from which we can estimate needed power in order to detect 
reasonable and meaningful differences in abstinence between varenicline alone and the combined treatment. 
In these trials both 7-day point prevalence and continuous abstinence are reported for the end of treatment 
(week 12) and both 6 and 12 month follow-up points. Estimates of prolonged abstinence using the SRNT 
guidelines, which will serve as the primary dependent measure in this study, were not provided. It is expected 
that prolonged abstinence rates could be somewhat higher than continuous abstinence rates given the more 
liberal definition of relapse. Nevertheless, for purposes of calculating power we chose to use continuous 
abstinence at the selected time points, as this may provide the more conservative estimate and is preferred 
over 7-day point prevalence for reporting abstinence in clinical trials. In the two pivotal varenicline trials 
continuous abstinence at the end of treatment, and the 6 and 12 month follow-up were, 44%, 30% and 23% 4 
and 44%, 30% and 22%6 for the two respective trials. Our analysis will involve one additional time point, 3 
months post quit, which lies between the EOT and 6 month follow-up in the pivotal studies. For purposes of 
power calculations we took the average abstinence between the end of treatment and the 6 month follow-up 
point to provide one additional point to be used in the calculations. In order to calculate power for our study, we 
estimated the average varenicline abstinence rate across these time points to be 33%. 
Power curves for abstinence are depicted in Figure 5 for several possible intra-class correlations (rho), 
assuming at least 150 subjects per treatment group and a Type I error rate of 0.05. Even assuming a 
conservative intra-class correlation of 0.8, our power analysis indicates that our sample size provides 80% 
power to detect about a 12% increase in abstinence or an odds ratio of 1.67 or greater, for the combined 
treatment.  
Our preliminary data may also provide an estimate of expected abstinence rates in the combined group 
of those who would otherwise remain as treatment failures if not treated with the combination therapy. Based 
on an observed 7 day point prevalence rate of abstinence of 50.3% at the end of treatment in the pivotal trials 
and a 27.3% abstinence rate among those who received combination therapy in our preliminary study (after 
initially failing to quit), we calculate an expected effect size as follows: .503 + (1- .503)*.273= .64; .64-.503=.14 
or 14% improvement in abstinence rates among nonabstainers. In this case, given that the 7 day point 
prevalence abstinence rates for varenicline alone at the end of treatment was 50.3% that could mean the 
overall success rate in the combined group could reach 64%. We cannot determine from our data how this 
difference will hold up over time but most smoking cessation data (our own included from multiple trials) 
suggest that the percentage differences between treatment and controls tend to remain constant from the end 
of treatment through follow-up, although the absolute cessation rates decrease. The average effect from the 
end of treatment through follow-up could be 10-18%, allowing a 4% difference on either side. This is likely at 
the very low end of such estimates given the fact that it is based on a difficult to treat population and due to the 
fact that the combined intervention was instituted later (after 8 weeks of monotherapy) rather than earlier in our 
pilot. These figures could underestimate of the number of early treatment failures we might have captured had 
we intervened sooner. For example, smokers who fail to quit may become discouraged, stop trying and 


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withdraw from treatment. 
Combination therapy from the starts 
may reduce the likelihood of this 
happening. Our choice to power our 
study for an average 12% difference 
seems reasonable in this regard and 
provides for a meaningful difference 
between V and VB groups. 
Data from our own smoking 
cessation studies on nearly 1000 
smokers 148,23 suggest that the intra-
class correlation coefficient for point 
prevalence and continuous 
abstinence across multiple post quit 
assessment points may be 
considerably lower than .8 (range .4-
.6), which would favorably impact 
power, and afford detection of 
smaller differences in abstinence 
between the two groups, given the 
same sample size. Thus, we expect 
power to be adequate for detecting 
differences of at least 12% which would represent a meaningful increment in efficacy of the combined 
treatment. Although not our primary outcome measure, we also estimated power for detecting differences in 
continuous abstinence during the last 4 weeks of treatment (FDA proof of concept measure) and at the one 
year follow-up. Given the data for these time points in the studies cited above, we will have 80% power to 
detect differences of 16% at the end of treatment; and 12.5% at the one year follow-up, for a comparison 
between the V and VB groups. All comparisons with placebo, while not part of our primary predictions are 
adequately powered since the difference between P and either active treatment is likely to be substantially 
larger than the 12% between the two active groups (i.e., based on data from the pivotal trials the difference 
between P and V at the end of treatment was approximately 27%). 
We also estimated power to detect differences between the groups in measures of negative affect and 
smoking reinforcement (we used the satisfaction scale from the mCEQ for this purpose) as these are among 
our primary measures secondary to abstinence. Means and standard deviations of negative affect and 
smoking satisfaction scores for varenicline were taken from the Gonzales study (means were not reported in 
the Jorenby study, just difference scores). These trials used the Minnesota Withdrawal scale to measure 
negative affect and the mCEQ to measure smoking satisfaction. We are using the WSWS and the PANAS as 
primary measures of negative affect. These scales have superior psychometric properties in relation to the 
MNWS and were conceptualized and developed for research specifically evaluating the role of negative affect 
in smoking withdrawal in the case of the WSWS; and the circumplex theory of emotion in the case of the 
PANAS. Although scored for other subscales, the WSWS has within it, the identical items that comprise the 
MNWS so a comparison can be made to MSWS scores from other studies. For purposes of calculating power, 
we used data from the Gonzales study to estimate mean MNWS negative affect and mCEQ scores for 
varenicline; and data from our own clinical trials to estimate PANAS and WSWS scores, since these scales  
were not given in that study. With a sample size of at least 150 per group, we would have 80% power to detect 
differences effect size of 0.21-0.26 standard deviations for the MNWS/PANAS/WSWS/mCEQ, across 
subscales, assuming a value of rho ranging from .4-.8 among four repeated measures. The power calculation 
is based on the method provided by Diggle and colleagues 147. Thus we should have enough power to detect 
small to moderate effect size differences between groups given the current sample size.  
Adjustment of Sample Size Addendum on 2/1/2013. We are requesting approval to increase the total 
number of subjects in this protocol from 350 to 385, an increase of 35 overall participants. Our original estimate 
for a sample size of 350 was based on a 20% attrition rate. We recently examined the blinded data and noted 
Figure 5 Power Curves for Abstinence Assessments 
 


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the attrition rates (combined lost to follow-up and withdrawal) averaged 30%. This should not affect our primary 
analysis for abstinence since we will be carrying out an intent to treat analysis for smoking abstinence, in which 
missing data is assumed to be smoking. However, the accuracy of our estimates for our continuous secondary 
measures, such as nicotine withdrawal, might be reduced. Based on the original sample of 350, about 70 
subjects might be expected to have missing data at one or more of the time points for the analysis of 
withdrawal. Using the attrition rate of 30% noted above this could rise to 105, a difference of 35 participants. 
Our randomization is based on a 3:3:1 ratio for varenicline, varenicline plus bupropion, and placebo (adding an 
additional 15:15:5 subjects).  We have also taken other steps noted elsewhere in the protocol to enhance our 
follow-up rates, and to capture the missing data on current participants. 
Our original calculations on ITT analysis allowed us to detect a 12% difference.  We originally estimated 
based on our preliminary data that the treatment difference could range between 10% and 18%.  With the 
increase in subjects, we still expect the treatment difference to be in this range.  With this increase in subjects, 
our power to detect treatment difference will remain above 80%. We also expect that the increase in sample 
size will compensate for the higher than expected attrition rate and will improve the accuracy of our estimates 
for our continuous secondary measures to the level that we had expected originally. 
Statistical Analyses of Primary and Exploratory Aims 
Primary Aim & Hypotheses  
1. To evaluate the efficacy of varenicline plus bupropion (VB) vs. varenicline (V) or Placebo (P) alone for 
smoking cessation, 
1.1. We hypothesize that smokers treated with the combination therapy will be abstinent significantly more 
often and take a longer time to relapse at 12 months follow-up than those treated with varenicline 
alone. 
1.1.1. Logistic regression analysis will be used to evaluate this hypothesis, regressing prolonged 
abstinence at 12 months follow-up on Group (Varenicline/Varenicline plus 
Bupropion/Placebo). Prolonged abstinence is defined as no smoking from the quit date to 
the 12-month follow-up, verified by expired CO < 4 ppm. As part of the exploratory analyses, 
we will also evaluate 7-day repeated point prevalence abstinence, continuous abstinence 
(single value-no repeated measure) from the quit date through the 6 and 12 month follow-
ups as well as 4-week continuous abstinence from the end of treatment (FDA proof of 
concept measure). These measures are described in the “Abstinence Assessment” section 
in methods. 
 
Exploratory Aim & Hypotheses  
1. To evaluate the effects of VB vs. V and P on measures of nicotine withdrawal, negative affect, depression, 
smoking reinforcement, sleep problems, and craving, and measures of cognitive performance. 
1.1. We hypothesize that smokers treated with the combination therapy will report significantly lower levels 
of nicotine withdrawal symptoms, negative affect, smoking reinforcement, sleep problems, and craving 
over the course of treatment, and improved cognitive performance during quitting, than those treated 
with varenicline alone. 
1.1.1. Mixed model repeated measure regression analyses will be used to evaluate this 
hypothesis, regressing scores from the negative and positive affect scales of the PANAS, 
total depression from the CES-D, total score from the Sleep Problems Scale, subscales of 
the WSWS (Anger, Anxiety, Concentration, Sadness and Craving ), QSU, and mCEQ 
(Smoking Satisfaction, Psychological Reward, Enjoyment of Respiratory Tract Sensations, 
Craving Reduction and Aversion), scores on the Conners Adult ADHD rating scale(CAARS), 
and each of the cognitive assessments (ANT, RVIP-CED), on Group (VB/V) with Time as the 
repeated measures factor. The main effect of treatment Group is of primary interest in this 
model and will be evaluated first, followed by Time, and the Group X Time interaction.  In 
this model, the pre-medication/pre-cessation value of the dependent measure from Visit 1 
will serve as the covariate. In addition, we will also test models that include abstinence 
status at each time point as a covariate to control for the effects of smoking (among 
relapsers) on negative affect and withdrawal. 


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1.1.2. We will also evaluate the extent to which changes in these process variables (e.g., affect, 
cognitive function, smoking satisfaction, etc.) on each of the process measures described 
above in 2.1.1may mediate the effect of treatment group on abstinence. For this analysis we 
will use end of treatment abstinence rates as they are the most proximal to the time the 
process measures are obtained. Our group has the requisite experience conducting 
meditational analyses and has published two papers in this area: one using the procedures 
of Baron and Kenny 149, examining mediators of the effects of depression history on 
abstinence 150; and those of MacKinnon 151 estimating meditational effects of psychological 
process variables in cognitive behavior therapy 152. We will use the later approach to 
examine the extent to which our major process variables may account for differences in 
treatment outcome. MacKinnon’s approach is very straight forward and involves using a 
series of regression analyses to determine the effect of the independent variable (treatment) 
on outcome (abstinence-as we propose to do to test our main hypotheses), and to use this 
same approach to determine the effect of the independent variable on the hypothesized 
mediator (e.g., PANAS negative affect scores; CES-D scores). Mediation is determined by 
examining the extent to which including the hypothesized mediator in the regression model 
predicting outcome along with the independent variable, changes that relationship. This can 
be calculated by dividing the mediated effect by its standard error resulting in a z-score 
which can be evaluated for significance 153. Guidelines we have followed in our previous 
work can be found on Dr. MacKinnon’s website (see 
http://www.public.asu.edu/~davidpm/ripl/mediate.htm#whatis). For our initial analysis we 
would examine the mean of the hypothesized mediators in the first and second week post-
quit, since this time frame for examining withdrawal and affective states has been shown to 
be predictive of relapse in earlier studies 94,68,154. We would also evaluate longitudinal models 
where the repeated assessments of the mediator allow us to determine whether or not 
changes in the mediator occur prior to the subsequent measure of outcome (i.e., is a 
reduction in withdrawal from baseline for example, on the quit date or at subsequent times 
associated with end of treatment abstinence between the groups. We will use a series of 
regression analyses as outlined by MacKinnon 155.  
2. To evaluate the effects of VB vs. V on lapse progression  
2.1. This is an exploratory aim to evaluate possible differences between the two treatments on time to an 
initial lapse; and time between an initial lapse and relapse. This later analysis will involve smokers who 
achieve initial abstinence but who are not continuously abstinent during treatment.-Little is known 
about this group of smokers given the concentration of pharmaceutical research on treatment efficacy 
involving smokers who are continuously abstinent. We will test for the possibility that VB is more 
beneficial than V on preventing a lapse from resulting in a relapse. 
2.1.1. For this analysis we will follow the procedures outline by Shiffman and colleagues 156 who 
evaluated the effects of NRT on lapse progression. We will use several treatment milestones 
and construct survival curves using Cox proportional hazard, for the percent of individuals 
within each group that achieve that milestone as a function of time. The milestones are as 
follows: 1) time to achieve initial abstinence (abstain for 24 hours) beginning on the target 
quit date; 2) Days to lapse (first smoking event after achieving initial abstinence); 3) Days to 
relapse after the first lapse. For this analysis we will construct models using 2 SRNT 
definitions of relapse (i.e., 7 consecutive days of smoking or smoking over 2 consecutive 
weeks.  
2.1.2. As recommended by the SRNT guidelines, a survival analysis will also be carried on days 
to relapse using Cox proportional hazards regression. 
3. To evaluate the effects of VB vs. V and P on smoking reduction among those who fail to quit. 
3.1. We hypothesize that non-abstinent smokers treated with VB will smoke significantly less than smokers 
treated with V. 
3.1.1. Mixed model repeated measure regression analyses will be used to evaluate this 
hypothesis, regressing average daily cigarette consumption (from the abstinence interview) 
and cotinine values on Group (VB/V/P) with Time (e.g., Visits 2-16 for cigarettes and 2, and 


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13-16 for cotinine) as the repeated measures factor. The main effect of treatment Group is of 
primary interest in this model and will be evaluated first, followed by Time, and the Group X 
Time interaction.  In this model, the pre-medication/pre-cessation value of the dependent 
measure from Visit 1 will serve as the covariate. 
  
Each of the models described above will be run with and without covariates and we will report on any 
differences in models with and without covariates. Given our careful balancing strategy in group assignment 
we do not expect major differences in factors previously associated with difference in treatment out come (e.g., 
FTND, depression history) For the mixed models, the likelihood ratio test procedure will be utilized to compare 
two models where one (without covariates) is a special case (with covariates) of the other. The covariates to be 
used include ethnicity, age, gender, smoking history, and depression history.  Interactions between ethnicity or 
gender and treatment will be explored.  If we find statistically significant interactions, separate models for each 
will also be tested.  We will also test models that include medication levels, average dose, and visit compliance 
and dose covariates based on biological assays, pill count, and sessions attended, respectively. Although the 
results of the analyses with these covariates are secondary to our main intent to treat models described above, 
they will provide information regarding the relationship between compliance with pharmacological and 
behavioral treatment recommendations and overall treatment outcome. 
 
Interim Analysis 
In this trial, the focus of the interim analysis is toxicity. The efficacy of Varenicline and Bupropion in 
improving smoking cessation has been very established7,8 and both of these medications have been FDA 
approved for smoking cessation.  We do not expect the early stopping due to futility.  The side effect profiles of 
Varenicline and Bupropion have been well characterized. From a clinical standpoint the most potentially 
significant side effect profile would involve neuropsychiatric symptoms, such as depression, anxiety, suicidal 
ideation. This protocol includes a specific plan to monitor neuropsychiatric events and intervene as required. 
Risks for these events are also reduced by the exclusion of participants with a current psychiatric disorder as 
defined by out standardized screening instruments (i.e., MINI). Nevertheless we consider the occurrence of 
these symptoms at a Grade III level as the basis for developing a stopping rule for this study.  
Ongoing assessment of these symptoms will 
be accomplished initially through the collection of 
adverse events at each visit. Participants will be 
asked open-ended questions regarding any 
changes to their physical or mental health since the 
previous visit. This is our standard practice. In the 
event that a patient reports any severe psychiatric 
symptom, an in-depth clinical assessment will be 
initiated. Patients will be evaluated for severe 
mood, anxiety and psychotic symptoms 
(encompassing symptoms such as irritability and 
agitation) using version 5.0 of the MINI International 
Neuropsychiatric Interview. Any patient who meets 
criteria for a severe psychiatric disorder on the MINI 
will be considered as a case to be included in the 
stopping rule for that disorder. Severe in this 
context is defined as marked limitation in activity 
that interrupts the subject’s usual daily activity and 
requires medical intervention/therapy and/or hospitalization. All individuals who meet criteria for a severe 
psychiatric disorder will be referred to the Clinical Psychologist and/or Addiction Psychiatrist for further 
assessment and clinical management. 
If 5 serious neuropsychiatric events occur at anytime during the trial we will take steps to halt 
recruitment and examine the un-blinded data to determine if the rate of these events in the combination arm 
(varenicline plus bupropion) differ significantly from what is observed in the placebo group. A serious 
Figure 6. Adverse Events for Varenicline and Bupropion 


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neuropsychiatric event will be defined as those which meet the regulatory definition of serious adverse event 
as well as those defined by a marked limitation in activity that interrupts the subject’s usual daily activity and 
requires medical intervention/therapy and/or hospitalization. After an examination of the unblinded data by the 
PI, medical staff and study statistician a determination will be made to continue if the rates of these events in 
the combination arm do not significantly exceed that observed in the placebo group. 
  
 
E. Human Subjects Research - Protection of Human Subjects 
     Risks to the Subjects 
Human Subjects Involvement and Characteristics:  Subjects recruited for this study (N=385) will be 
current smokers from the Houston metropolitan community. Based upon our past experiences recruiting 
from this population, we estimate that we will need to screen up to 1100 people in order to attain the 
targeted 385 eligible participants who will actually be enrolled in the study. Inclusion criteria are presented 
in Table 4. All smokers meeting these qualifications will be accepted into the study. Given the nature of the 
study design it will be necessary to eliminate subjects who do not speak English or have a telephone.  
 
Sources of Materials: Participants will be providing physiological data in the form of blood pressure, 
weight, blood chemistry, and saliva cotinine.  Questionnaire data will be obtained that assess previous 
smoking, smoking cessation history (including Rx medications and NRT’s) and health history (including 
depression and ADHD), mood, nicotine withdrawal, craving, and cigarettes smoked. All data will be 
collected specifically for research purposes and will be coded to maintain confidentiality. Screening 
laboratory data will be shared with the participant and appropriate referral for follow-up medical care will be 
provided as needed.  
 
Potential Risks: As reported in Micromedex (Thompson Healthcare) the frequency of adverse events 
reported for varenicline are as follows: Abdominal pain (5% to 7% ), Constipation (5% to 8% ), Flatulence 
(6% to 9% ), Nausea (16% to 40% ), Vomiting (1% to 5% ); Neurologic: Dream disorder (9% to 13% ), 
Headache (15% to 19% ), Insomnia (18% to 19%). The typical side effects are not usually serious in nature 
and often abate within a few days to weeks after starting medication or once the medication is withdrawn. 
The most common, nausea, was rated by the majority of patients who experienced it as mild to moderate 
and resolved after 10-12 days. Less than 3% of smokers in the pivotal trials withdrew due to nausea. 
 
The frequency of adverse events reported for bupropion are as follows: Hypertension (2% to 4% ), 
Tachyarrhythmia (11% ); Pruritus (2% to 4% ), Rash (3% to 5% ), Urticaria (1% to 2% ); Weight change 
(3% to 23% ); Constipation (5% to 10% ), Disorder of taste (2% to 4% ), Nausea (13% to 24% ), 
Pharyngitis (3% to 11% ), Xerostomia (17% to 26% ); Arthralgia (1% to 4% ), Myalgia (2% to 6%); 
Confusion (8% ), Dizziness (6% to 11% ), Headache (25% to 34% ), Insomnia (11% to 20% ), Tremor (3% 
to 6% ); Tinnitus (3% ) Psychiatric: Agitation (2% to 9% ), Anxiety (5% to 7% ), Hostile behavior (6% ); 
Disorder of menstruation (5% ); Cardiac dysrhythmia (5% ); Stevens-Johnson syndrome (rare); 
Anaphylaxis; Seizure (0.1% to 0.4% ); Depression, exacerbation, Mania, Psychotic disorder, Suicidal 
thoughts. 
 
Because bupropion is also used as an antidepressant with smokers and non-smokers and often used far 
longer than proposed here it is informative to assess the specific adverse events profile on a population of 
smokers trying to quit. Data from the pivotal trials using varenicline provide an AE frequency table for both 
bupropion and varenicline 6, as shown in Figure 6 
 
Post-Marketing Experience: The following adverse events have been reported during post-approval use of 
varenicline. Because these events are reported voluntarily from a population of uncertain size, it is not 
always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.  
There have been reports of depressed mood, agitation, changes in behavior, suicidal ideation and suicide 
in patients attempting to quit smoking while taking varenicline. Smoking cessation with or without treatment 


Protocol 2008-0850 
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is associated with nicotine withdrawal symptoms and the exacerbation of underlying psychiatric illness. Not 
all patients had known pre-existing psychiatric illness and not all had discontinued smoking. The role of 
varenicline in these reports is not known. Participants are informed of these issues in the informed consent 
form. In addition, they are told that should they experience any of these symptoms, to stop taking the 
medication and call our study physician immediately. We have also developed a comprehensive plan to 
monitor and evaluate any emergent psychiatric symptoms, including depression, anxiety and suicidal 
ideation. 
Participants may also experience minor bruising, pain or infection following phlebotomy, skin irritation 
due to electrode adhesive for an ECG assessment (if required), and tobacco withdrawal effects (e.g., 
increased irritability, difficulty concentrating, etc.) during smoking cessation.  None of these effects typically 
result in serious adverse health consequences. It is unlikely that completing questionnaires would lead to 
any potential risks for participants.  In sum, it is highly unlikely that any legal, social, or psychological 
problems will result from this research. 
 
Adequacy of Protection Against Risks 
Recruitment and Informed Consent: Participants will be recruited from the Houston community sample 
using: (1) mail, public service announcements, media interviews, MD Anderson Internet access, 
newspaper advertisements, MD Anderson Conquest Magazine; (2) through the MDACC community liaison 
and outreach offices, sending advertisements and mailers to all affiliated providers on the mailing list. 
Consent will be obtained at the onset of the orientation/baseline interview. Participants will be provided with 
a detailed description of the study, information on risks, and on their right to withdraw from the study.  
 
Protection against Risks: Varenicline and bupropion are both FDA approved medications for smoking 
cessation. We will follow the medication dosing procedures used for both drugs in the original clinical trials 
comparing varenicline and bupropion to placebo. Moreover, we will also provide smoking cessation 
counseling consistent with the Clinical Practice Guidelines for Smoking Cessation.  Our procedures closely 
follow those used in previous clinical trials involving several medications for smoking cessation. Our study 
physician will identify participants who have contraindications for use of either drug and we will monitor 
participants for adverse reactions while they are on medication.  The risks of blood sampling will be 
minimized by use of trained phlebotomists and the provision for on-site medical assistance should any 
untoward complications result.  The Tobacco Research & Treatment Program (TRTP) clinic is located 
adjacent to the Department of Clinical Cancer Prevention, which has trained medical personnel on staff 
that will be available to assist the study physician and other personnel in managing medically related study 
issues.  Confidentiality will be protected by identifying all subjects by ID numbers in all data used outside 
the institution (e.g., laboratory assessments). Analyses of such data are provided by sample number coded 
on each collection container and cannot be connected to individual participant names by the laboratory 
conducting the assays.  Only the PI and his staff will have access to the master file linking laboratory and 
other data to participant names. All study data files are server maintained with limited access using 
password entry and log in restrictions to study staff. All information will be reported in aggregate form and 
individual participants will not be identified in any public reports or documents.  We expect these 
procedures to be highly effective for protecting participant confidentiality.  See Data and Safety Monitoring 
section for further details concerning protection against risks. 
 
Potential Benefits of the Proposed Research to the Subjects and Others 
A primary benefit to participants in the proposed study is smoking cessation.  All participants will receive an 
empirically validated treatment for smoking cessation (smoking cessation counseling) and two groups will 
receive active medication. We anticipate that many of them will continue to be non-smokers after the 
completion of the study.  Smoking cessation is important in cancer prevention, cardiovascular events and 
emphysema rate reduction therefore reducing medical costs, and increasing well-being for both the 
participants and society in general. Smoking cessation is cost effective and results in a substantial 
reduction in healthcare costs for both the individual and society.  
 


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Importance of the Knowledge to be Gained 
The potential to add a new medication to the treatment armamentarium allows for expanded future 
research on the assessment of individual differences in patient characteristics that may predict drug 
response, including genetic factors related to dependence, metabolism and psychiatric risk factors. The 
ultimate goal of such studies will be to eventually develop tailored treatments that maximize an individual’s 
chances at success by pairing treating them with the correct compound(s). Given the significant benefits 
that would accrue with increased effectiveness in smoking cessation, these potential benefits far outweigh 
the risks associated with the proposed research. 
 
Inclusion of Women   
Women participants will be included in this research and will comprise approximately 50% of the population 
sample.  In our previous research we have encountered no difficulty in the recruitment of women 
participants. 
 
Inclusion of Minorities 
The population of the Houston community from which the sample will be drawn (includes Harris county) is 
estimated at 3,596,086 people. The ethnic distribution has been reported as 59% Caucasian (42% of which 
are not of Hispanic origin) ;19% African-American; 5% Asian; and .4% Native American, with 33% Hispanic 
or Latino (of any race) 112. We expect to recruit minority smokers in proportion to the population 
demographics.  We have had good success recruiting from ethnic minority populations, especially African 
Americans across all of our studies. Our success with Hispanic smokers has been more modest although it 
must be noted that smoking rates are lower in the Hispanic and Latino community in comparison to the 
non-Hispanic community. We expect to attract minority smokers to the proposed study using direct public 
service advertisements targeted for minority smokers on Houston radio stations and newspapers 
supporting a large minority audience. Houston has two television stations, and several radio stations and 
newspapers that serve the Hispanic Community. The office of Public Affairs at MD Anderson has also 
agreed to assist us by arranging for our participation in institution wide Cancer Prevention outreach 
programs directed at the Hispanic Community. Such events are sponsored several times a year in areas of 
the community with high concentrations proportions of minority Houstonians. We will focus additional 
recruitment effort on these venues to increase our recruitment of Hispanic smokers. Such efforts will be in 
addition to the normal interviews, advertisements, and news releases conducted on our behalf by the 
Office of Public Affairs at MDACC.  Recruitment and enrollment for the proposed study is scheduled to 
begin as soon as (Institutional Review Board) IRB approval is obtained (within 3-5 months of funding). 
 
 
 
Inclusion of Children 
We will exclude smokers under the age of 25 because the focus of our intervention is on adult smokers.  
Additionally, individuals 24 years of age and younger have a higher risk of suicidal tendencies with some of 
the study drugs.  The characteristics of smokers seeking treatment in smoking cessation trials have been 
very consistent in our recruitment as well as national samples. The average age of these smokers is over 
40; they consume about a pack of cigarettes or less per day, have made numerous quit attempts, and have 
smoked for over 15 years (23. There are also likely to be significant differences between adults and 
adolescent in numerous domains including physiological (e.g., physiological responses to nicotine may be 
different in adolescents), and psychological (e.g., developmental processes may affect mood self-reports). 
Therefore, the study of the cessation and emotional processes related to smoking behavior among 
adolescent smokers requires a separate focus on those factors that are relevant for this population.  
 
DATA AND SAFETY MONITORING PLAN 
The IRB of the University of Texas M. D. Anderson Cancer Center (MDACC) reviews and approves the 
Data and Safety Monitoring Plan for all clinical trials This study will be monitored by the institutional DMC 
as determined by the IRB during their review of the protocol. Plans and procedures for maintaining data 


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integrity, defining and reporting adverse events/experiences, and IRB oversight and monitoring of this 
project are described below. These procedures include monitoring of participant eligibility and accrual, 
adverse events, interim data analyses, etc. The procedures for monitoring by the IRB, PI and DMC are 
described in separate sections below, followed by a section defining and further describing procedures for 
reporting adverse experiences as well as procedures for ensuring data quality and integrity. 
 
IRB Monitoring 
During the protocol review and approval process, the IRB determines the level of safety monitoring required 
for each protocol. The minimum monitoring requirements include investigator monitoring of participant 
safety, adverse event (AE) reporting in compliance with IRB, NIH, and FDA guidelines, and participation in 
the Continuing Review process with the IRB. Clinical trials may also be monitored by the Data Monitoring 
Committee (DMC). The outcomes of IRB and DMC reviews are conveyed to the PI via the administrative 
support staff in the Office of Protocol Research (OPR). As a medication related clinical trial this study will be 
monitored by the institutional DMC. 
 
For all protocols conducted at the MDACC, the PI is responsible for submitting Adverse Events AE's to the 
IRB. The MDACC’s policy for AE submission has been defined and approved by the IRB and must be 
included as an appendix to all protocols. AE’s are submitted to OPR and forwarded to the designated IRB 
vice chairperson for review. Attached to each AE, is a listing of all prior AE’s submitted for that protocol. Any 
comments, questions or changes the IRB requests to the protocol as a result of this review are conveyed to 
the PI. The PI response and protocol modification process is monitored by the IRB vice chairperson and 
OPR support staff. The vice chairperson presents the report on AE review to the full committee at the next 
IRB meeting. 
 
All protocol participants will be registered in the Protocol Data Management System/Clinical Oncology 
Research System (PDMS/CORe) according to institutional guidelines.  All other study-related data, 
including adverse events, will be entered into a database designed and maintained by the PI and his data 
management team.  Representatives from The Office of Protocol Research will have unrestricted access to 
the database for auditing and other regulatory purposes.    
 


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Table 7. Targeted/Planned Enrollment Table 
Study Title: Effects of Varenicline and Bupropion on Smoking Cessation and Nicotine Withdrawal 
Total Planned Enrollment: 385 
TARGETED/PLANNED ENROLLMENT: Number of Subjects 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
31
46
77
Not Hispanic or Latino 
154
154
308
Ethnic Category Total of All Subjects* 
185
200
385
Racial Categories 
  
American Indian/Alaska Native 
0
0
0
Asian 
3
6
9
Native Hawaiian or Other Pacific Islander  
0
0
0
Black or African American  
46
58
104
White 
136
136
272
Racial Categories: Total of All Subjects * 
185
200
385
 
 
Monitoring by the Data and Safety Monitoring Board 
If required by the IRB the protocol will receive monitoring by the (Data Monitoring Committee) DMC. The 
DMC is an officially constituted committee of MDACC designed to oversee the data and safety monitoring 
of clinical trials. The primary objectives of the DMC are to: 
 
• 
ensure that participants in a trial are protected; 
• 
ensure that participants’ interests are not made secondary to the interests of the scientific 
investigation; and 
• 
monitor all clinical trials that originate at MDACC or that are coordinated or analyzed by the MDACC. 
 
The DMC has the following responsibilities to accomplish the above objectives: 
 
• 
to review interim analyses of outcome data (prepared by the study Statistician or other responsible 
person at the time points defined in the protocols approved by the IRB), and to recommend, if 
necessary, whether the study needs to be changed or terminated based on these analyses; 
 
• 
to determine whether and to whom outcome results should be released prior to the reporting of study 
results from this trial at the time specified in the protocol; 


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• 
to review interim toxicity data and efficacy of treatment; 
 
• 
to review major modifications to the study proposed by the PI prior to implementation (e.g., 
termination, dropping an arm based on toxicity results from this trial or results of other trials, increasing 
target sample size); 
 
• 
to communicate information and recommendations to appropriate persons at MDACC regarding the 
assessment of issues or problems and effective resolutions for educational purposes and improved 
participant care and risk prevention. 
 
The Committee consists of not more than 15 members (including the Chairman). A majority of members 
attending meetings of the DMC constitute a quorum. Appointments are made based on the breadth of 
backgrounds and experience. The committee includes scientists and statisticians from within and outside 
the institution selected based on their experience, reputation for objectivity, absence of conflicts of interest, 
and knowledge of good clinical trial methodology. At least fifty one percent of the voting members are not 
affiliated with MDACC. DMC members represent participant interests, and not that of the institution.  
 
The DMC meets at least once a year and more often if necessary. Each randomized clinical trial protocol 
has specified interim analyses times. Information provided to the DMC include: title of study, PI, date start 
of study, expected termination date, expected total number of participants, number of participants entered 
currently, data from interim analyses, date of interim analyses, toxicity concerns, and the next formal 
monitoring date as specified in the protocol. The PI may prepare a report addressing specific toxicity 
concerns or other concerns about the conduct of the study during the open session. A copy of the 
statistician’s report may be sent to the DMC Chair for presentation during the closed portion, but not to any 
other individuals not on the DMC. The report may contain recommendations on whether to close the 
study, whether to report the results, whether to continue accrual or follow-up and whether DMC discussion 
is needed. 
 
The review of each trial may include two parts. The first part will be an open session in which members of 
the study team may be present at the request of the DMC to answer questions. In this part, the focus is on 
accrual, compliance and toxicity issues. Following this open session, there will be a closed, executive 
session in which the DMC discusses interim outcome results by treatment arm, what action needs to be 
taken, and then votes. At the executive session, those present are limited, to DMC members, alternates, 
and ex officio members. If a decision is made by the DMC to modify or discontinue a trial - 
recommendations will be made as to whether and how participants are to be informed and by whom and 
communicated to the PI in writing. Copies of such communication will be preserved in the official 
Committee Minutes. 
 
DMC recommendations are based upon results for the current study being monitored as well as upon data 
available to the DMC from other related studies. The PI will assure that the DMC is advised about relevant 
non-confidential results from other related studies that become available. It will be the responsibility of the 
DMC to determine the extent to which this information is relevant to decisions to continue or modify the 
current study. The DMC will provide recommendations in writing to the PI to change or stop a study, or 
part thereof (e.g., one arm), or to continue a study unchanged. Special consideration will be given to 
participants already in treatment. 
 
In the event that a study change is recommended for participant safety reasons (including early stopping 
of inferior therapy), the PI acts to implement the change as expeditiously as possible to ensure safety of all 
participants on the study. In the unlikely situation that the PI does not concur with the DMC 
recommendation, then the Vice President for Research Administration must be informed of the 
recommendation of the DMC and of the PI’s reason for disagreeing with the recommendation. The Vice 
President for Research Administration and the PI, in consultation with the DMC Chair, are responsible for 


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reaching a mutually acceptable decision about the study. Confidentiality is maintained during these 
discussions. In the event that a change in a study is recommended for reasons other than participant 
safety (e.g., to extend accrual because of a lower than expected accrual rate), the DMC provides to the PI 
as much rationale for the proposed change as can be made without jeopardizing the conduct of the study. 
The PI is responsible for having an amendment prepared and submitted to the IRB the recommendations 
of the DMC and providing the rationale for the changes. The IND Sponsor – MDACC and IRB approval of 
the amendment will be required prior to implementation of the change, although a decision to override the 
DMC’s recommendation is made only in the most exceptional circumstances. 
 
All documents, investigative reports or information and conversations relating to this committee’s work are 
strictly confidential and are not shared with anyone other than other committee members. Although 
committee documents are subject to legal privileges as set forth in statutory and case law and are not 
subject to discovery during a litigation process, the privilege may be lost if committee documents are given 
to, shown to or discussed with non-committee members without an official DMC request to do so. 
 
No communication of the deliberations or recommendations of the committee, either written or oral is 
made outside of the committee except as provided for in these policies and procedures. Statements of 
confidentiality will be signed by all DMC members or alternates at the beginning of an appointment period. 
Outcome (efficacy) results are strictly confidential and are not divulged to non-members (excepting the PI 
and Associate Vice President for Clinical Investigations) until the recommendation to report the results are 
accepted and implemented. 
 
Individuals invited to serve on the DMC disclose to the Group Chair any potential, real or perceived, 
conflicts of interest. These include professional interest, proprietary interest and miscellaneous interest 
considerations. Potential conflicts that develop during the conduct of a trial should also be disclosed to the 
PI. 
 
Guidelines for Filling Reports of Adverse Experiences at MDACC 
Given the non-invasive, minimal risk nature of the proposed research, we anticipate that the types of adverse 
experiences that may occur, if any, will focus on concerns about medication side effects, phlebotomy, and the 
discomfort of nicotine withdrawal, possible distress associated and with sensitive issues arising during data 
collection. We have taken several steps to minimize these risks, as described below. 
 
Adverse Experiences Associated with Nicotine Abstinence/Withdrawal 
Participants may experience nicotine abstinence/withdrawal effects. These effects may include irritability, 
difficulty concentrating, insomnia, anxiety, dysphoria, and increased hunger. None of these effects result in 
serious adverse health consequences.  
 
Adverse Experiences Associated with Medication Use 
Comprehensive screening will be conducted to ensure that all participants with contraindications for either 
varenicline or bupropion use would get excluded from participation. For bupropion, these conditions include the 
presence of hypersensitivity to bupropion; use of MAO inhibitors or discontinuation within the past 2 weeks, 
history of seizures, prior head trauma, recent abrupt discontinuation of alcohol or sedatives (including 
benzodiazepines), current diagnosis of bulimia or anorexia, recent myocardial infarction, uncontrolled 
hypertension, tachycardia, hypotension or risk of orthostatic hypotension, unstable heart disease, 
history/current renal or hepatic disease, use of other psychotropic medications including antidepressants, or 
drugs that inhibit the CYP2B6 enzyme system, Suicidal ideation and behavior or worsening depression; 
addiction to opiates, cocaine, or stimulants; diabetes treated with oral hypoglycemics or insulin; excessive 
alcohol or sedative use insomnia medications or treatments that lower seizure threshold, CNS tumor psychosis 
and/or mania and use of over-the-counter stimulants and anorectics. For varenicline these conditions include, 
severe renal impairment and intolerable nausea. In addition, smoking cessation alone may alter the 
pharmacokinetics or pharmacodynamics of some drugs including theophylline, warfarin and insulin, in which 
case a dose reduction of such drugs should be considered. 


Protocol 2008-0850 
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Standard blood chemistries including liver and renal function tests will be ordered on the first screening session 
and reviewed prior to the subsequent screening visit for acceptability.  
 
The typical side effects are not usually serious in nature and often abate within a few days to weeks after 
starting medication or once the medication is withdrawn. Adverse effects and concomitant medications will be 
assessed at each of the post-baseline in-clinic, phone, and counseling sessions.  Participants’ vital signs, 
including blood pressure, heart rate, and weight will also be measured at each in-clinic visit.  The study 
physician will monitor participants’ complaints of adverse events and, when necessary, adjust the dosage or 
discontinue medication, order additional lab tests, etc.  Adverse experiences and medication assessments will 
continue until 90 days following completion of the drug regimen. 
 
Adverse Experiences Associated with Blood Collection 
Syncope, hematoma, and infection are among the common adverse experiences associated with phlebotomy.  
To minimize participants’ exposure to these adverse effects, trained phlebotomists will be employed to handle 
all blood collection procedures. 
 
Serious Adverse Event Reporting (SAE) 
A serious adverse event is any adverse drug experience occurring at any dose that results in any of the 
following outcomes:  
 
• 
Death 
• 
A life-threatening adverse drug experience – any adverse experience that places the patient, in the 
view of the initial reporter, at immediate risk of death from the adverse experience as it occurred. It 
does not include an adverse experience that, had it occurred in a more severe form, might have caused 
death. 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant disability/incapacity – a substantial disruption of a person’s ability to conduct 
normal life functions. 
• 
A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require hospitalization may be 
considered a serious adverse drug experience when, based upon appropriate medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse (21 CFR 312.32). 
 
Important medical events, as defined above, may also be considered serious adverse events. Any 
important medical event can and should be reported as an SAE if deemed appropriate by the Principal 
Investigator or the IND Sponsor, Office of Research Education and Regulatory Management (ORERM). 
 
• 
All events occurring during the conduct of a protocol and meeting the definition of a SAE must be 
reported to the IRB in accordance with the timeframes and procedures outlined in “University of Texas 
M. D. Anderson Cancer Center Institutional Review Board Policy on Reporting Serious Adverse 
Events”.  Unless stated otherwise in the protocol, all SAEs, expected or unexpected, must be reported 
to ORERM, regardless of attribution (within 5 working days of knowledge of the event). 
 
• 
All life-threatening or fatal events, expected or unexpected, and regardless of attribution to the study 
drug, must have a written report submitted within 24 hours (next working day) of knowledge of the 
event to the Safety Project Manager in ORERM.   
 


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The MDACC “Internal SAE Report Form for Prompt Reporting” will be used for reporting to ORERM.  
Serious adverse events will be captured from the time the patient signs consent until 90 days after the 
last dose of drug.  This 90-day time frame may be extended if the PI and/or the study’s medical team deem it 
necessary. Serious adverse events must be followed until clinical recovery is complete and laboratory tests 
have returned to baseline, progression of the event has stabilized, or there has been acceptable resolution of 
the event. 
Additionally, any serious adverse events that occur after 30-days post treatment that are related to the 
study treatment must be reported to ORERM. This may include the development of a secondary malignancy. 
 
Reporting to FDA: 
 
• 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project Manager 
ORERM) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse events are reported 
according to the Code of Federal Regulations, Good Clinical Practices, the protocol guidelines, the 
sponsor’s guidelines, and Institutional Review Board policy. 
 
Reporting to Pfizer Pharmaceutical Company: 
Serious adverse events will be reported to Pfizer according to the company’s most recent Safety Reference 
Manual.  Currently, Pfizer’s Safety Reference Manual requires that all SAEs be reported to Pfizer from the time 
the subject signs the informed consent document through 28 calendar days after last administration.  If the 
SAE is fatal or life-threatening, it will be reported to Pfizer immediately after the study team becomes aware.  
All other cases will be reported within 24 hours of knowledge.  All SAE’s will be reported to Pfizer regardless of 
attribution (relatedness).      
 
Data Quality and Integrity 
Because of the ongoing monitoring of the project, study investigators and staff are responsible for ensuring that 
data quality assurance procedures are developed and maintained. Several procedures will be used to maintain 
the integrity of the data. All databases will be stored in a centralized location on one of the departmental 
servers, which is backed up daily, with access limited to specific users at the discretion of the PI. The PI will 
assure that audits of selected subsets of data are performed and that appropriate safeguards of participant 
privacy are maintained. Privacy safeguards will include appropriate password protection and physical security 
for all computer systems. 
 
Additional quality assurance procedures include a data collection protocol documented in a protocol manual; a 
two-stage editing procedure for survey data collection consisting of the initial review of the data collection form 
by a project member immediately following data collection, and a second review by a project member who will 
record any significant deviations from the protocol; and regular meetings between the study statistician, the PI, 
data managers, and other project staff to review problems and solutions, and discuss concerns. Data entry 
systems, whether via a CATI, or QDS, system, scannable forms, or hand entry with verification, specifically 
provide field checks, range checks for continuous variables and valid value checks for categorical variables; 
checks for legitimate dates and times and logical consistency. During data collection, we will issue reports 
weekly, or even following any new data entry, depending on the needs of the project. Queries and reports will 
be provided to the PI. Preliminary review will be initiated shortly after data collection begins to allow monitoring 
of data quality. 
 
F. Vertebrae Animals-NA 
 
G. Literature Cited 
 


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H. Consortium/Contractual Arrangements - NA 
   
I.  Consultants - NA     
 
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