Clinical trial NCT02856581
Conditions: Lung Carcinoma
Sponsor: Alliance for Clinical Trials in Oncology
Start date: 2017-09-29; Completion date: 2022-04-15
Enrollment: 23 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase III trial studies how well management of a tobacco treatment intervention works in reducing surgical complications in patients with newly diagnosed lung cancer who smoke cigarettes. Management of a tobacco treatment intervention compares varenicline (a drug that reduces the craving and withdrawal symptoms that occur with abstinence from nicotine) and behavioral interventions (consisting of a brief clinician-delivered intervention and tobacco quitline \[tobacco cessation service available through a toll-free telephone number\] follow-up) with placebo (a pill with no active medication) along with similar behavioral interventions. It is not yet known whether management of a tobacco treatment intervention is more effective in reducing surgical complications than placebo.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine if varenicline plus a behavioral intervention consisting of a brief clinician-delivered intervention and tobacco quitline follow-up, decreases postsurgical complications through 24 weeks after surgery when compared to placebo plus the behavioral intervention in lung cancer patients who undergo surgery and are motivated to stop smoking.

SECONDARY OBJECTIVES:

I. To compare changes from baseline to 12 and 24 weeks after surgery in the patient quality of life (Linear Analogue Self-Assessment \[LASA\]-12) domains between the intervention (varenicline) and control group (placebo).

II. To compare changes from baseline to 6, 12 and 24 weeks after surgery in the patient quality of life related domains (LASA) for the Patient Health Questionnaire (PHQ)-9 and Smoking Self Efficacy Questionnaire (SEQ)12 between the intervention and control groups.

III. To compare the proportion of patients 12 weeks and 24 weeks after surgery who endorse ("Was It Worth It") each treatment (intervention versus \[vs\] control groups).

IV. To compare post-operative care (as measured by length of hospital and high dependency unit stay) between the intervention and control groups.

V. To compare treatment adherence between the intervention and control groups. VI. To compare rates of smoking abstinence between the intervention and control groups as a covariate of the primary outcome only.

Arms: arm 1: Patients receive varenicline PO QD on days 1-3 and BID on days 4-84 for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients also complete behavioral intervention consisting of no smoking message from surgical team member and how to use NCI quitline at surgical consult. arm 2: Patients receive placebo PO QD on days 1-3 and BID on days 4-84 for 12 weeks in the absence of disease progression or unacceptable toxicity. Patients also complete behavioral intervention consisting of no smoking message from surgical team member and how to use NCI quitline at surgical consult.
Interventions: intervention 1: Varenicline intervention 2: Placebo intervention 3: Tobacco Cessation Counseling
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Complete counseling session

Protocol documents:
Prot_SAP_000.pdf: 








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Table of Contents 
 
Section 
Page 
1.0 
BACKGROUND ............................................................................................................................. 7 
1.1 
Rationale for Proposed Study ....................................................................................................... 7 
1.2 
Significance and Innovation of this Study .................................................................................. 11 
1.3  
Study Overview .......................................................................................................................... 12 
1.4 
Feasibility, Accrual Time, and Study Duration .......................................................................... 12 
2.0 
OBJECTIVES ............................................................................................................................... 13 
2.1 
Primary objective ........................................................................................................................ 13 
2.2 
Secondary objectives .................................................................................................................. 13 
2.3 
Correlative science objectives ..................................................................................................... 13 
3.0 
PATIENT SELECTION............................................................................................................... 14 
3.1 
On-Study Guidelines ................................................................................................................... 14 
3.2 
Eligibility Criteria ....................................................................................................................... 14 
4.0 
PATIENT REGISTRATION ....................................................................................................... 16 
4.1 
CTEP/DCP Registration Procedures ........................................................................................... 16 
4.2 
CTSU Site Registration Procedures ............................................................................................ 16 
4.3 
Patient Registration Requirements .............................................................................................. 18 
4.4 
Patient Registration/Randomization Procedures ......................................................................... 18 
4.5 
Registration to Correlative and Companion Studies ................................................................... 19 
4.6 
Treatment Assignments and Blinding ......................................................................................... 19 
5.0 
STUDY CALENDAR ................................................................................................................... 20 
6.0 
DATA AND SPECIMEN SUBMISSION ................................................................................... 21 
6.1 
Data Collection and Submission ................................................................................................. 21 
6.2 
Specimen collection and submission .......................................................................................... 22 
7.0 
TREATMENT PLAN/INTERVENTION ................................................................................... 25 
7.1 
Study outline ............................................................................................................................... 25 
7.2 
Behavioral Intervention (Baseline visit) ..................................................................................... 25 
7.3 
Target Quit Date ......................................................................................................................... 26 
7.4 
Pharmacologic Intervention (Varenicline) .................................................................................. 26 
8.0 
DOSE AND TREATMENT MODIFICATIONS, UNBLINDING ........................................... 26 
8.1 
Ancillary therapy, concomitant medications, and supportive care ............................................. 26 
8.2 
Dose Modifications ..................................................................................................................... 27 
8.3 
Unblinding Procedures ................................................................................................................ 29 
9.0 
ADVERSE EVENTS .................................................................................................................... 29 
9.1 
Routine adverse event reporting ................................................................................................. 30 
9.2 
CTCAE Routine Reporting Requirements .................................................................................. 31 
9.3 
Expedited Adverse Event Reporting (CTEP-AERS) .................................................................. 31 
10.0 
DRUG INFORMATION .............................................................................................................. 34 
10.1 
Varenicline Tartrate (Chantix®; Champix®) ............................................................................. 34 
10.2 
Placebo (Supplied) ...................................................................................................................... 37 
11.0 
MEASUREMENT OF EFFECT ................................................................................................. 37 
11.1 
Patient reported measures ........................................................................................................... 37 
11.2 
Biochemical confirmation using salivary cotinine ...................................................................... 38 
11.3 
Definitions of analysis variables ................................................................................................. 38 


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12.0 
END OF TREATMENT/INTERVENTION .............................................................................. 39 
12.1 
Duration of Treatment ................................................................................................................. 39 
12.2 
Definitions and Follow-up Requirements ................................................................................... 39 
12.3 
Extraordinary Medical Circumstances ........................................................................................ 39 
13.0 
STATISTICAL CONSIDERATIONS ........................................................................................ 40 
13.1 
Study Design ............................................................................................................................... 40 
13.2 
 Study Endpoints ......................................................................................................................... 40 
13.3 
Primary analysis .......................................................................................................................... 41 
13.4 
Additional Analyses .................................................................................................................... 41 
13.5 
Correlative and companion substudy analyses ........................................................................... 42 
13.6 
Power/Sample Size ..................................................................................................................... 43 
13.7 
Accrual rate and study duration .................................................................................................. 44 
13.8 
Monitoring .................................................................................................................................. 44 
13.9 
Adverse Event Stopping Rule ..................................................................................................... 44 
13.10 Interim Analysis .......................................................................................................................... 45 
13.11 Inclusion of Women and Minorities ........................................................................................... 45 
14.0 
CORRELATIVE AND COMPANION STUDIES ..................................................................... 45 
14.1 
Correlative substudy to measure saliva cotinine levels ............................................................... 45 
14.2 
Pharmacogenetics of Smoking Cessation Treatment (POST), Alliance A211401-PP1 ............. 46 
15.0 
TEACHABLE MOMENT TRAINING ...................................................................................... 47 
15.1 
Surgeons ...................................................................................................................................... 47 
15.2 
Study Staff .................................................................................................................................. 47 
16.0 
REFERENCES .............................................................................................................................. 48 
17.0 
MODEL CONSENT FORM ........................................................................................................ 54 
APPENDIX I: SURGICAL COMPLICATIONS ASSOCIATED WITH CIGARETTE SMOKING 
[104] 67 
APPENDIX II:  PATIENT INFORMATION SHEETS........................................................................ 68 
APPENDIX III: CONTEMPLATION LADDER .................................................................................. 75 
APPENDIX IV: SMOKING SELF EFFICACY QUESTIONNAIRE (SEQ12) ................................. 76 
APPENDIX V: FAGERSTRÖM TEST FOR NICOTINE DEPENDENCE ....................................... 78 
APPENDIX VI: PATIENT HEALTH QUESTIONNAIRE – 9 (PHQ-9) ............................................ 79 
APPENDIX VII: LINEAR ANALOGUE SELF-ASSESSMENT ........................................................ 81 
APPENDIX VIII: WAS IT WORTH IT (WIWI) QUESTIONNAIRE ............................................... 83 
APPENDIX IX: TOBACCO USE ASSESSMENT ................................................................................ 84 
APPENDIX X: DRUG AND BEHAVIORAL ADHERENCE LOG .................................................... 86 
APPENDIX XI: GENERAL THORACIC SURGERY DATABASE DEFINITIONS ....................... 90 
APPENDIX XII: MAYO CLINIC NICOTINE RESEARCH PROGRAM CRISIS POLICY ......... 93 
APPENDIX XIII: VARENICLINE WALLET CARD .......................................................................... 96 
 
 


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1.0 
BACKGROUND 
1.1 
Rationale for Proposed Study 
Can surgical teams capitalize on a teachable moment regarding the harmful effects of smoking 
that will reduce surgical complications among lung cancer patients who smoke? This study will 
introduce the management of a tobacco treatment intervention to health care providers who may 
not know what to do in managing lung cancer patients who smoke. By helping smoking surgical 
patients stop smoking, we are reducing harm by reducing post-operative complications. 
Therefore, this study will address both the prevention of worsening complications post 
operatively and hopefully reduction of smoking in lung cancer patients. This study will support 
the Alliance Prevention Committee’s research priority aimed at tobacco harm reduction and 
cessation and will add to the NCORP research portfolio “Cancer control studies to reduce 
incidence and co-morbidity of cancer and its treatment and enhance quality of life”. This study 
will address all four essential A’s (Advise to Quit, Assess willingness to quit, Assist with 
quitting, and Arrange follow-up) recommended by the US Guideline model for treating tobacco 
use and dependence Guidelines (http://www.rcjournal.com/ contents/09.08/09.08.1217.pdf) [1].  
1.1.1 Impact of Cigarette Smoking on Oncologic Treatment and Outcomes 
Smoking is a significant risk factor for cancer, and smoking cessation efforts have been 
widely implemented among smokers as primary prevention of cancer development. In 
addition to its effects on carcinogenesis, smoking also impacts premalignant-to-malignant 
progression [2-8] and increases the risks for perioperative morbidity and mortality. Due to 
its effect on small vessels and oxygenation, smoking may also decrease the effectiveness of 
adjunctive treatments such as radiation and chemotherapy while at the same time increasing 
symptom burden. Smoking also increases the risk of secondary cancers [2-8]. Importantly, 
there has been an increasing body of evidence indicating that smoking can be a barrier to 
successful administration and completion of multimodality oncology treatments (including 
chemotherapy, radiotherapy, and surgery), and smoking can reduce both the quality of life 
(QOL) and long-term survival. Comparison of the 5-year survival of lung cancer between 
smokers and non-smokers has shown that only 33% of smokers survive 5 years compared 
to 70% of non-smokers [3-9].  
Smoking causes temporary changes in the blood and tissue microenvironment (increased 
tissue CO2 and decreased O2 carrying capacity)[2] and in reparative cell functions, which 
can lead to delayed wound healing [2]. This can be responsible for prolonged recovery, 
which in turn, leads to an increase in the risks of hospital-acquired infections and other 
postoperative complications.[2-4] Smokers with gastrointestinal malignancies have a higher 
risk than non-smokers for surgical site infections (OR 1.25; 95% CI, 1.09–1.44), combined 
pulmonary complications (OR 1.60; 95% CI, 1.38–1.87), and reoperations (OR 1.20; 95% 
CI, 1.03–1.39)[10]. Complications of oncologic surgery (Appendix 1) can contribute to 
delays in the initiation of and lower ability to tolerate adjuvant therapy, further contributing 
to poor long-term cancer outcomes [11]. However, cigarette smokers diagnosed with cancer 
have not been a focus of smoking cessation efforts [12]. Cancer-directed treatments 
generally receive the bulk of attention after a cancer diagnosis, and smokers diagnosed with 
cancer represent a missed opportunity in smoking cessation and prevention of second 
cancers or recurrence of cancer.  
1.1.2. Benefits of Smoking Cessation in Cancer Patients 
Quitting smoking has beneficial health effects regardless of patient age.[13] Individuals who 
stop smoking significantly decrease their risk of lung cancer compared to current 
smokers.[7] For patients diagnosed with cancer, smoking cessation can improve cancer 


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treatment tolerance and effectiveness,[14, 15] overall survival,[13] prevention of second 
primary malignancy,[8, 16] and QOL.[17] Multimodal cancer therapy most often includes 
surgical procedures. Minimizing postoperative complications in oncology patients 
undergoing surgical procedures is of paramount importance both for minimizing treatment-
related morbidities and for allowing a patient to go on to other components of the 
multimodal therapy. A reduction in complications has been observed within 4 weeks of 
smoking cessation.[18] Smoking cessation is beneficial at any time point relative to lung 
cancer surgery, but “current” smoking status at the time of surgery has been associated with 
a poor postoperative QOL.[19] A recent meta-analysis of 6 studies addressing smoking and 
surgical complications found that stopping smoking can reduce the relative risk of 
postoperative complications by 41% (95% CI, 15% to 59%; P = 0.01); each week of 
cessation prior to surgery increased this effect by 19%.[20] In addition, stopping smoking 
prior to chemotherapy and radiation therapy reduces the total symptom burden (sum of 12 
symptoms scored on an 11-point Likert scale) of cancer treatment during treatment (smokers 
vs. nonsmokers: 46.3 vs. 41.2; P < 0.05) and at 6 months after treatment (27.7 vs. 21.9; P < 
0.05).[21] Fewer than 10% of smokers actively seek treatment for tobacco dependence. Over 
80% of providers in oncology practices provide brief smoking cessation counseling, but 
fewer than 30% ask about smoking in subsequent visits.[22] Barriers to smoking cessation 
among oncology patients include provider lack of confidence and patient lack of 
motivation.[22] Adjunctive use of a self-help guide for stopping smoking has been 
associated with improved motivation and has been found to be a predictor of long-term 
smoking cessation in oncology patients.[23, 24] Thus, effective methods for smoking 
cessation exist, but they have not been tested in the setting of a multicenter clinical trial 
targeting cigarette-smoking oncology patients who are scheduled for surgery. 
1.1.3  Potential for Smoking Cessation Opportunities in Surgical Cancer Patients  
Women smokers are 25.7 times more likely than women who never smoked to develop lung 
cancer. For men smokers, it’s 25 times the risk of men who never smoked.[25]  Among 
cancer patients who smoke, 85%-87% of cancer patients want to stop smoking.[26, 27] In 
one clinical trial, of the 263 cancer participants, the retention rate was approximately 84.5%. 
Teachable Moment: Smokers with cancer presenting to a surgeon present a unique 
opportunity to intervene on smoking behavior. Opportunities in which patients have 
enhanced susceptibility to interventions on unhealthy behaviors are referred to as “teachable 
moments.” Use of teachable moments can occur at office visits (associated with 2–10% 
success in smoking abstinence), notification of abnormal test results (7–21% success), 
pregnancy (10–60% success), and hospitalization and disease diagnosis (15–78% 
success).[28] Available evidence suggests that major surgery for a smoking-related cancer 
provides a significant and effective teachable moment for smoking cessation. A study of 
5498 individuals demonstrated that older individuals (≥50 years) were more likely to quit 
smoking after a major medical procedure.[29] The steps in using a teachable moment to help 
smokers quit smoking include simple physician advice to quit, brief behavioral interventions 
provided by physicians or other clinicians, and pharmacotherapy.[30, 31] A recent 
randomized controlled trial testing the clinician-delivered message versus no message has 
shown randomizing within a site can be successful.[32] 
Pharmacotherapy: Varenicline is a partial agonist/antagonist that binds with high affinity 
and selectivity at the α4β2 neuronal nicotinic acetylcholine receptors. It has been approved 
by the Food and Drug Administration (FDA) as a stop-smoking aid. Varenicline is presently 
the most efficacious pharmacotherapy for increasing smoking abstinence rates, with proven 
superiority over bupropion and suggested superiority over nicotine replacement therapy.[33, 
34] In a head to head comparison of varenicline vs. bupropion the odds ratio (OR) at end-


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of-treatment (12 weeks) were 3.85 (95% CI 2.69-5.50) for varenicline and 1.90 (95% CI of 
1.38-2.62) for bupropion. The OR at end of study (6 months) was also significant with an 
OR of 2.83 (95% CI of 1.91-4.19) for varenicline and an OR of 1.69 (95% CI 1.19-2.42) for 
bupropion.[35] A recent systematic review of interventions for pre-operative smoking 
cessation has shown that of all the interventions tested in clinical trials, varenicline given 
pre-operatively was the only intervention with long term smoking cessation.[36] Although 
the safety and acceptability of varenicline among surgical patients with thoracic cancer has 
been previously tested,[37] the efficacy of varenicline in smokers who are diagnosed with 
cancer and are undergoing surgery has yet to be proven. Recent studies among non-cancer 
patients have confirmed that varenicline has the greatest efficacy for tobacco dependence 
treatment when combined with behavioral therapy,[38, 39] and is safe as well, dispelling 
previous concerns. [40-46]  In addition, the results from an 18-study pooled analysis and a 
5-study meta-analysis have been added to the label (currently in the process of being 
published in the literature).[47] 
Behavioral Intervention (Tobacco Quitlines): According to the US guidelines, behavioral 
support is minimal intervention that all smokers should be receiving when trying to stop 
smoking. Behavioral support can be provided either as a stand alone or in conjunction with 
pharmacotherapy. Behavioral support can be provided in several different formats. 
Currently the two formats discussed in the US guidelines include face-to-face or by 
telephone. Telephone quitlines are one of the 10 key recommendations for effective tobacco 
dependence treatment.[1] The advantage of counseling via telephone quitline is that it can 
potentially provide wide-access to evidence-based cessation counseling while providing 
uniformity in the counseling approach, when utilizing a national quitline (vs. private or state 
quitline). Quitlines can include mailed materials, recorded messages, proactive and reactive 
contacts, and optional medication services.[48] A recent meta-analysis of 65 controlled 
studies, comprising of 73,000 participants, concluded that telephone quitlines provide an 
important approach in supporting smokers who are trying to stop smoking.[49]. The pooled 
odds ratio for a number of studies utilizing quitlines varies from 1.4 [50] to 1.6.[48] The US 
National Cancer Institute provided the very first telephone based quitline (early 1980’s) as 
a component of the Cancer Information Service. A national referral service to the individual 
state/private quit lines is available through the use of 1-800-QUIT-NOW. The disadvantage 
of utilizing state or private quitlines in large national studies is that each state is privately 
funded and therefore clinical services can vary from providing medication, to only one initial 
consult, depending on available funding (see http://map.naquitline.org/). Utilizing a private 
quitline for the use of a large national research study can be expensive and many quitlines 
cannot support research since it would interfere with their clinical services. The NCI quitline 
(1-877-44U-QUIT) is a national federally funded service. They provide the smoker with 
counseling support, help develop a quit plan, provide follow up calls, mail quit materials (as 
needed), and answer questions concerning medications (medications are not provided). 
Using a toll free number, smokers across the United States can call in Monday through 
Friday 8 am to 8 pm (ET). These services are at no cost and services can be provided in both 
English and Spanish.  
1.1.4  Genetics of Nicotine Addiction 
Genetic variants in nicotinic receptor genes represent the strongest known genetic risk 
factors for nicotine addiction. The genetic variant rs16969968, which causes an amino acid 
change in CHRNA5, the gene encoding the α5 nicotinic receptor subunit, strongly 
contributes to nicotine addiction and heaviness of smoking.[51, 52] This variant also 
contributes to smoking-related diseases (lung cancer and chronic obstructive pulmonary 
disease).[52-54] In a genome-wide association meta-analyses including over 73,000 


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subjects, the chromosome 15 locus that includes the nicotinic receptor subunit gene cluster 
(CHRNA5, CHRNA3, and CHRNB4) had a highly significant association between 
rs16969968 and cigarettes per day (P = 5.57 × 10-72).[55-57] 
Nicotine Metabolism Genes Contribute to Heavier Smoking: Conversion of nicotine to 
cotinine accounts for 70–80% of initial nicotine metabolism and is performed by 
cytochrome P450 2A6 (CYP2A6), which is located in the cytochrome p450 gene cluster on 
chromosome 19.[58-60] Variation in CYP2A6 and nicotine metabolism efficiency is 
robustly associated with smoking phenotypes, especially cigarette consumption.[55, 61-64] 
CYP2A6 is highly polymorphic, and genome-wide association meta-analyses have identified 
variants in the CYP2A6 region associated with the number of cigarettes per day.[52, 57] 
Individuals with reduced-function alleles have significantly slower rates of nicotine 
metabolism, and several studies have reported an influence of nicotine metabolic rate upon 
cessation, with faster metabolism associated with lower abstinence and higher withdrawal 
symptoms.[65-67] 
Nicotine Addiction and Smoking Cessation: The ultimate public health significance of 
understanding the biological underpinnings of nicotine addiction comes from translating 
that knowledge into improved treatment for smoking cessation. A critical step in translation 
is to determine whether genetic variants associated with nicotine addiction influence 
smoking cessation. Until recently, genetic studies of smoking cessation have been mixed, 
finding little evidence of replicable associations.[57, 68, 69] 
We found that CHRNA5-CHRNA3-CHRNB4 variants predict age of smoking cessation, age 
of lung cancer diagnosis, and response to smoking cessation treatments. In a recent meta-
analysis, we found that the CHRNA5 variant rs16969968 is a marker of delayed smoking 
cessation and accelerated lung cancer diagnosis. The median age of smoking cessation for 
those with the high-risk variants (AA) at rs16969968 is 56 years versus 52 years for those 
with the low-risk variants (GG).  Similarly, those with the high-risk variants have a 4-year 
earlier age of lung cancer diagnosis (61 years) compared to those with the low-risk variants 
(65 years) (Chen et al, in press, JNCI). This can be clinically significant given the high 
mortality following a diagnosis of lung cancer (50% die within a year of diagnosis and a 5-
year survival rate of 16.6%). In clinical trials, those with high-risk genetic variants had more 
difficulty quitting without treatment, but this genetic risk was ameliorated by aggressive 
pharmacological treatment (Fig. 1) [70] (please also add reference Bergen et al, 2013) 
 
 


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These results revealed a statistically significant interaction between the genetic variants and 
pharmacologic treatment. The clinical impact of this genetic and treatment interaction is 
exemplified by the number needed to treat (NNT), the number of patients who must be 
treated to prevent one additional bad outcome (e.g., relapse). For example, if a drug has an 
NNT of 10, it means one would need to treat 10 people with the drug to achieve smoking 
abstinence in one person. In this smoking cessation trial,[70] the overall NNT to prevent one 
relapse was 7, supporting the established effect of pharmacotherapy. However, the NNT 
varied widely depending on haplotype: the NNT was 4 for smokers with the high-risk 
haplotype (H3) versus >1000 for smokers with the low-risk haplotype (H1). This large 
difference in NNT was the first finding that genetic variants in the chromosome 15 region 
interact with treatment for smoking cessation.  
Given the existing evidence that this CHRNA5 variant predicts accelerated risk for lung 
cancer and favorable response to cessation pharmacotherapy, these findings underscore the 
potential clinical and public health importance of rs16969968 in CHRNA5 in relation to 
smoking cessation treatments. 
1.2 
Significance and Innovation of this Study 
The adverse health consequences of smoking are profound,[71-75] and capitalizing on the 
unique teachable moment surgeons have available for smokers after cancer diagnosis may 
reduce post-operative complications. Further, if post-operative complications can be reduced or 
ameliorated, the cost of care, length of time in the hospital, and quality of life aspects of the 
cancer experience can be improved. Observational evidence indicates that smoking cessation 
prior to cancer surgery reduces complications such as pneumonia, failure to wean from 
ventilator, re-intubation, and prolonged hospital stays [10]; however, the optimal approach to 
achieving abstinence in this population is not known.  
The innovation of this study is that it directly engages the surgical team in cancer control studies 
by taking advantage of the unique teachable moment that the surgical team has with the patient 
pre-operatively. Controlling for the definition of abstinence, the duration of abstinence relative 
Figure 1: Response to Pharmacotherapy Varies by Haplotypes* 
 
 CHRNA5 haplotypes were associated with failed smoking cessation in the 
placebo group (Wald χ2 = 7.02, df = 2, P = 0.03) 
 CHRNA5 haplotypes were not associated with smoking cessation outcomes in 
the treatment group (P = 0.48) 
 The interaction of haplotypes and treatment on abstinence is significant (Wald 
χ2 = 8.97, df = 2, P = 0.01) 
* CHRNA5 haplotypes based on rs16969968 and rs680244 (N = 1073); H1 = G-C 
(21%); H2 = G-T; (44%) H3 = A-C (35%)  
From Chen et al., 2012[70] 


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to surgery, the surgical team’s message, and the smoking cessation intervention in a large 
population, will help us identify the parameters that will yield both the highest success rates for 
quitting and the best perioperative outcomes with respect to morbidity and QOL.  
The correlative genetic component of this trial may differentiate patients who are likely to 
respond strongly to pharmacologic treatment from those who receive little benefit. This will 
allow us to better target treatments and will contribute to our goal of using genetic information 
to develop personalized medicine. 
1.3  
Study Overview 
This will be a randomized clinical trial. The primary goal is to assess the effect of smoking 
cessation treatment on surgical complications. We will also report the impact of alternative 
treatments on QOL and post-operative care. According to the US Guidelines[1], although 
counseling and medication are effective when used alone, the combination of both is more 
effective than either alone. Thus clinicians should encourage smokers who want to quit, to use 
both counseling and medication in trying to quit smoking (#7 of the 10 key guideline 
recommendations). In this study, 626 cancer surgery patients will be randomized 1:1 to a 
“protocolized” smoking cessation program (varenicline plus a brief no-smoking message from 
the surgical team and behavioral support provided by a telephone smoking quitline [NCI’s 1-
877-44U-QUIT]), or to placebo plus a brief no-smoking message from the surgical team and 
behavioral support provided by the telephone smoking quitline). Surgery must occur after the 
target quit date (TQD) defined at baseline and can be performed no sooner than 10 days after 
randomization and no more than twelve weeks after randomization. The study will remain open 
to accrual until 626 patients have had surgery and are followed for 24 weeks after surgery for 
surgical complications. The primary outcome will be the rate of surgical complications, as 
identified from an investigation of the American College of Surgeons-National Surgical Quality 
Improvement Program (ACS-NSQIP). Secondary outcomes include QOL, post-operative care 
(length of hospital and high dependency unit stay), and rates of smoking abstinence. All study 
participants will have the option of enrolling in the correlative genetic study. This correlative 
study will look at important genetic variants in nicotinic receptor gene cluster (CHRNA5-
CHRNA3-CHRNB4) and nicotine metabolism (CYP2A6) that have been shown to impact 
successful smoking abstinence. This will include a blood draw at baseline, and tobacco use 
outcome will be determined by salivary cotinine at baseline and every six weeks after surgery 
for 12 weeks, with a final measurement at 24 weeks. 
1.4 
Feasibility, Accrual Time, and Study Duration 
A survey of legacy ACOSOG thoracic surgeons and the Alliance Community Oncology 
Committee members has shown that the vast majority of sites that see these patients would be 
interested in accruing patients for this study. From accrual estimates provided by sites in this 
survey, we anticipate accruing 150 evaluable patients per year. In the opinion of these surgeons, 
this study is highly feasible to accrue quickly. We conducted a follow-up survey asking surgical 
practices to describe in detail the manner in which the workflow for the study would be carried 
out. This survey provides us with example templates to guide potential participating sites. Given 
these data and our past experience with accruing patients to smoking cessation studies, we 
anticipate that our accrual estimate is conservative. In previous NCCTG trials accrual rates of 
as high as 25 patients per week were achieved, albeit in mixed treatment practices. As already 
indicated, however, we have done multiple surveys of Alliance surgical practices who indicate 
strong support for the study, with specific accrual expectations and workflow details. Hence the 
sites are unusually well prepared and aware of the needs to accrue to this study and are eagerly 
awaiting the trial opening.  That likelihood of rapid accrual, plus the involvement of surgeons 
in the prevention aim, is a major selling point for the trial. This study accrual will close when 


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626 study patients have undergone surgery; therefore, we anticipate patient accrual to be 
completed in approximately 4 years and 2 months.  
2.0 
OBJECTIVES  
Because of the considerable discussion surrounding the goals of this study, we include the 
following declarative and definitive statements:  
I. The goal of this study is to examine the impact of alternative interventions for smoking cessation 
on the reduction of surgical complications.  
II. Smoking cessation is an intermediate and concomitant secondary outcome that is not the focus 
of this study, because it already is well known that smoking cessation interventions reduce 
smoking incidence in cancer patients. 
2.1 
Primary objective 
To determine if varenicline plus a behavioral intervention consisting of a brief clinician-
delivered intervention and tobacco quitline follow-up, decreases postsurgical complications 
through 24 weeks after surgery when compared to placebo plus the behavioral intervention in 
lung cancer patients who undergo surgery and are motivated to stop smoking. 
2.2 
Secondary objectives 
2.2.1 To compare changes from baseline to 12 and 24 weeks after surgery in the patient quality 
of life (LASA-12) domains between the intervention (varenicline) and control group 
(placebo). 
2.2.2 To compare changes from baseline to 6, 12 and 24 weeks after surgery in the patient quality 
of life related domains (LASA) for the PHQ-9 and SEQ12 between the intervention and 
control groups. 
2.2.3 To compare the proportion of patients 12 weeks and 24 weeks after surgery who endorse 
(“Was It Worth It”) each treatment (intervention vs. control groups). 
2.2.4 To compare post-operative care (as measured by length of hospital and high dependency 
unit stay) between the intervention and control groups. 
2.2.5 To compare treatment adherence between the intervention and control groups. 
2.2.6 To compare rates of smoking abstinence between the intervention and control groups as a 
covariate of the primary outcome only.  
2.3 
Correlative science objectives 
2.3.1 To evaluate the predictive role of the nicotinic receptor gene cluster (CHRNA5-CHRNA3-
CHRNB4) and CYP2A6 genotypes in smoking cessation among lung cancer patients 
undergoing surgery. 
2.3.2 To evaluate the potential moderating effect of these cessation-relevant genotypes on 
smoking cessation treatment between the intervention and control groups. 
 
 


Alliance A211401 
Version Date: 04/27/18 
Update 2 
14 
3.0 
PATIENT SELECTION 
For questions regarding eligibility criteria, see the Study Resources page. Please note that the Study 
Chair cannot grant waivers to eligibility requirements.  
3.1 
On-Study Guidelines 
This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. 
All relevant medical and other considerations should be taken into account when deciding 
whether this protocol is appropriate for a particular patient. Physicians should consider the risks 
and benefits of any therapy, and therefore only enroll patients for whom this treatment is 
appropriate.  
Although they will not be considered formal eligibility (exclusion) criteria, physicians should 
recognize that the following may seriously increase the risk to the patient entering this protocol: 
• 
Psychiatric illness which would prevent the patient from giving informed consent. 
• 
Medical condition such as uncontrolled infection (including HIV), uncontrolled diabetes 
mellitus or cardiac disease which, in the opinion of the treating physician, would make this 
protocol unreasonably hazardous for the patient. 
• 
Patients with a “currently active” second malignancy other than non-melanoma skin cancers 
or cervical carcinoma in situ. Patients are not considered to have a “currently active” 
malignancy if they have completed therapy and are free of disease for ≥ 3 years. 
• 
Patients who cannot swallow oral formulations of the agent. 
In addition: 
• 
Women and men of reproductive potential should agree to use an appropriate method of 
birth control throughout their participation in this study due to the teratogenic potential of 
the therapy utilized in this trial. Appropriate methods of birth control include abstinence, 
oral contraceptives, implantable hormonal contraceptives or double barrier method 
(diaphragm plus condom). 
3.2 
Eligibility Criteria  
Use the spaces provided to confirm a patient’s eligibility by indicating Yes or No as appropriate. 
It is not required to complete or submit the following pages. 
When calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0. Therefore, if a test were done on a Monday, the Monday four weeks later 
would be considered Day 28. 
___ 
3.2.1 
Eligible patients will have either confirmed or suspected new diagnosis of lung cancer 
and have sought a surgical consult relating to this diagnosis. 
___ 
3.2.2 
Surgery must be scheduled no sooner than 10 days after randomization and no more 
than twelve weeks after randomization  
___ 
3.2.3 
Have smoked daily or nearly every day in the previous 6 months up to the date of 
surgical consult AND have smoked at least one puff in the previous 7 days. 
___ 
3.2.4 
Motivated to stop smoking, as indicated by a score of 6 or above on the Contemplation 
Ladder (see Appendix III).76 
 
 


Alliance A211401 
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15 
___ 
3.2.5 
Within the 30 days before registration, no use of: 1) any pharmacologic treatment for 
smoking cessation, including buproprion or nicotine replacement therapy; 2) any 
nicotine delivery system (i.e., e-cigarettes and vape products); or 3) be enrolled in any 
formal behavioral treatment program for tobacco dependence as determined by patient 
report. 
___ 
3.2.6 
No allergies to and not currently using varenicline. 
___ 
3.2.7 
No suicidal thoughts as indicated by a positive (1+) response to question 9 on the 
PHQ9. 
___ 
3.2.8 
No active untreated clinically significant psychiatric condition (psychosis, bipolar 
disorder, or depression). 
___ 
3.2.9 
Negative pregnancy test (serum or urine) done ≤7 days prior to registration, for women 
of childbearing potential only.  
A female of childbearing potential is a sexually mature female who: 1) has not 
undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally 
postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in 
the preceding 12 consecutive months). 
___ 
3.2.10 No unstable angina, myocardial infarction, or coronary angioplasty within the past 3 
months or an untreated cardiac dysrhythmia. 
___ 
3.2.11 No history of seizures. 
___ 
3.2.12 No unstable neurologic, hepatic, renal, cardiovascular, lymphatic, or metabolic 
disease. 
___ 
3.2.13 Not currently on renal dialysis or has a history of significant renal impairment. 
___ 
3.2.14   No recent history (≤ 90 days) of substance abuse (outside of tobacco) defined by 
NIAAA [77] as: 
• 
If male, drinking >14 alcoholic beverages per week for past 1 month. 
• 
If female, drinking >7 alcoholic beverages per week for past 1 month. 
• 
Use of cocaine, heroin, club drugs (i.e., MDMA/“ecstasy”), methamphetamine, or 
hallucinogens (e.g., LSD) at any time during the past 1 month. 
• 
Use of marijuana on a weekly basis for the past 1 month. 
___ 
3.2.15 Patients must be able to complete study questionnaires in English. 
___ 
3.2.16 ≥18 years of age 
___ 
3.2.17 No other household member or relative participating in the study. 
___ 
3.2.18 No known history of any condition or factor judged by the investigator to preclude 
participation in the study or which might hinder study adherence.   
___ 
3.2.19 Calculated creatinine clearance ≥ 30 mL/min. 
Creatinine clearance (CrCl) will be calculated using the Cockroft-Gault equation as 
follows: 
CrCI (ml/min) = 
(140-age) x actual wt (in kg) 
 
72 x serum creatinine (mg/dL) 
For females, use 85% of calculated CrCl value 
 
 




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17 
the CTSU Regulatory Support System (RSS) uses extensive data to make a determination of 
whether a site has fulfilled all regulatory criteria including but not limited to the following: 
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site. 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process. Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRB Manager to indicate their intent to open the study locally.  
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office.  In 
order for the SSW approval to be processed, the Signatory Institution must inform the CTSU 
which CIRB-approved institutions aligned with the Signatory Institution are participating in the 
study. 
4.2.1 Downloading Site Registration Documents 
Site registration forms may be downloaded from the A211401 protocol page located on the 
CTSU members’ website. Permission to view and download this protocol and its supporting 
documents is restricted and is based on person and site roster assignment housed in the 
CTSU RSS. 
• 
Go to 
 and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Either enter the protocol # in the search field at the top of the protocol tree, or 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the Alliance link to expand, then select trial protocol #A211401 
• 
Click on LPO Documents, select the Site Registration documents link, and download 
and complete the forms provided.   
4.2.2 Requirements for A211401 Site Registration 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an 
IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is 
accepted)  
4.2.3 Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal, where they will be entered and tracked in the CTSU RSS.  
Regulatory Submission Portal
  (members’ area)  Regulatory Tab  
Regulatory Submission Portal 






Alliance A211401 
Version Date: 04/27/18 
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20 
5.0 
STUDY CALENDAR 
Pre-Study Testing Intervals  
• 
To be completed ≤ 16 DAYS before registration: History and physical. 
• 
To be completed ≤ 6 months before registration: Serum creatinine. 
 
Prior to Surgery 
Day of 
Surgery** 
Post-Surgery*** 
Visit week 
Prior to 
Registration† 
Baseline* 
0 
6 
12 
18 
24 
Visit # 
1 
2 
 
3 (A) 
4 (A, B) 
5 (A, B) 
6 
Tests and observations 
 
 
 
 
 
 
 
History & physical (weight, bp, pulse) 
E 
E 
 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
Serum creatinine 
X 
 
 
 
 
 
 
Pregnancy test 
C 
 
 
 
 
 
 
Concomitant therapies 
 
X 
 
X 
X 
X 
X 
Adverse events  
 
X 
 
X 
X 
X 
X 
Surgical adverse events 
 
 
 
X(1) 
X(1) 
X(1) 
X(1) 
Suicidal ideation monitoring 
 
 
 
X (2) 
X (2) 
X (2) 
X (2) 
Tobacco use assessment (Appdx IX) 
X 
X 
X 
X 
X 
X 
X 
Surgical team message  
 
X 
 
 
 
 
 
NCI Smoking Quitline 
 
X (3) 
 
X (3) 
X (3) 
 
 
Sample submission 
 
 
 
 
 
 
 
Salivary Cotinine Measure 
 
X 
X 
X 
D 
D 
X 
Patient questionnaires 
 
 
 
 
 
 
 
Contemplation Ladder (Apdx III) 
X 
 
 
X 
X 
 
X 
SEQ-12 (Apdx IV) 
 
X 
 
X 
X 
 
X 
FTND (Apdx V) 
 
X 
 
 
 
 
 
PHQ-9 (Apdx VI) 
X (4) 
 
 
X 
X 
 
X 
LASA-12 (Apdx VII) 
 
X 
 
 
X 
 
X 
Was It Worth It Survey (Apdx VIII) 
 
 
 
 
X 
 
X 
Drug and Behavioral Support 
Adherence Logs (Apdx X) 
 
X 
 
X 
X 
 
 
Correlative study (optional) 
 
Whole blood 
To be collected at baseline, see Sections 6.2 and 14.0. 
† 
Pre-study testing may be performed on the same day as the baseline visit (see also, Section 7.1). 
* 
Baseline: After randomization and at the time the surgical message is discussed with the cancer patient. If performed within 
7 days prior to baseline, the Tobacco Use Assessment need not be repeated. 
** 
Surgery must occur after the TQD defined at baseline and can be performed no sooner than 10 days after randomization and 
no more than twelve weeks after randomization. 
*** Post surgery visits can be +/- 14 days 
A 
Patient-completed booklets for Weeks 12 and 18 should be given to patients at the Week 6 visit. Institutional staff should 
telephone patients within one week prior to Weeks 12 and 18 to remind them that they will either be completing these 
booklets by telephone at Weeks 12 and 18 or that they may bring the completed booklet to the clinic when they provide 
saliva samples for cotinine measurements (see Footnote D). 
B 
May be done by telephone or in person (see footnote D). 
C 
For women of childbearing potential. Must be done within 7 days prior to registration/randomization. 
D 
Patients will be asked to come to the treating institution to provide saliva samples for cotinine measurement.  A physician 
visit is not required. 
E 
History and Physical may take place either at pre-registration or at the baseline visit. 
1 
See Section 9.1 and Appendix I. 
2 
Per Question 9 on the PHQ-9. See Section 8.2.3. 
3 
At the baseline visit, study staff will assist the patient in making the first contact with the NCI Quitline. At the 6- and 12-
week clinic visits, patients will be asked if they utilized the Quitline since their last visit and data will be collected on its use. 
4 
Only the patient response to Question 9 is required at pre-registration in order to determine eligibility (see Section 3.2.7). 




Alliance A211401 
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22 
6.2 
Specimen collection and submission  
Salivary cotinine testing will be performed on all patients enrolled to this study. The submission 
of these samples for cotinine testing is required for all patients registered to this study. 
Rationale and methods for the scientific components of this study are described in Section 14.1. 
In addition, all participating institutions must ask patients for their consent to participate in the 
correlative substudies planned for Alliance A211401, although patient participation is 
optional. Biomarker and pharmacogenetic studies will be performed. Rationale and methods 
for the scientific components of this study is described in Section 14.2. 
REQUIRED for all patients registered to A211401: 
Visit 
Baseline 
Surgery 
At 6, 12, 18 and 24 
weeks 
Ship to: 
Saliva 
X 
X 
X 
Mayo BAP 
For patients registered to A211401 PP1,  
submit the following: 
 
Baseline 
Submit to: 
 
Number and volume of tubes to draw 
Plasma and buffy coat 
(EDTA Vacutainer) 
2 x 10 mL 
Mayo BAP 
6.2.1 Specimen submission using the Alliance Biospecimen Management System 
USE OF THE ALLIANCE BIOSPECIMEN MANAGEMENT SYSTEM (BioMS) IS 
MANDATORY AND ALL SPECIMENS MUST BE LOGGED AND SHIPPED VIA THIS 
SYSTEM.  
BioMS is a web-based system for logging and tracking all biospecimens collected on 
Alliance trials. Authorized individuals may access BioMS at the following URL:  
 using most standard web browsers 
(Safari, Firefox, Internet Explorer). For information on using the BioMS system, please refer 
to the ‘Help’ links on the BioMS webpage to access the on-line user manual, FAQs, and 
training videos.  To report technical problems, such as login issues or application errors, 
please contact: 
 For assistance in using the 
application or questions or problems related to specific specimen logging, please contact: 
 
After logging collected specimens in BioMS, the system will create a shipping manifest.  
This shipping manifest must be printed and placed in the shipment container with the 
specimens. 
All submitted specimens must be labeled with the protocol number (A211401), Alliance 
patient number, patient’s initials and date and type of specimen collected (e.g., serum, whole 
blood). 
A copy of the Shipment Packing Slip produced by BioMS must be printed and placed in the 
shipment with the specimens. 




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24 
6.2.3 Blood sample submission 
For patients who consent to participate, blood samples will be used for the biomarker and 
pharmacogenomics analyses described in Section 14.2. Samples may batched, but should 
be submitted at least every 3 months. 
Collect 2 x 10 mL of peripheral venous blood in EDTA vacutainer tubes at the baseline visit.  
Plasma: Centrifuge whole blood at 1,300 x g for 5 minutes at room temperature. Transfer 1 
mL of plasma into each labeled 2 mL cryovial. Typically one can get 3 x 1 mL aliquots per 
10 mL tube without disturbing the buffy coat (which will be saved for submission per the 
instructions below). Record the number of aliquots created on the Biospecimen Submission 
Form (BSF) Transfer plasma specimens to temporary storage at -80 °C until shipment. If 
there are no -80°C freezers available, keep the plasma samples on dry ice for up to 48 hours 
before shipment. Ship on dry ice to the Alliance Biorepository at Mayo clinic per Section 
6.2.1. 
Label samples with the following identification: 
1. Alliance study number (A211401-PP1) 
2. Alliance patient ID number 
3. Patient’s initials (L, F M) 
4. Date and time of specimen procurement  
5. Sample type (i.e. plasma) 
Buffy coat: After the plasma has been removed from the vacutainer tube as described above, 
remove the buffy coat layer (approximately 1 mL per 10 mL EDTA tube) and transfer into 
2 mL cryovial(s).  Snap freeze specimen in LN2 or EtOH / dry ice bath OR place in - 80°C 
if the others are not available.  Transfer specimen to temporary storage at -80°C until 
shipment.  If there are no -80°C freezers available, keep the plasma samples on dry ice for 
up to 48 hours before shipment. Ship on dry ice to the Alliance Biorepository at Mayo clinic 
per Section 6.2.1. 
Label samples with the following identification: 
1. 
Alliance study number (A211401-PP1) 
2. 
Alliance patient ID number 
3. 
Patient’s initials (L, F M) 
4. 
Date and time of specimen procurement  
5. 
Sample type (i.e. buffy coat) 
 
 


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7.0 
TREATMENT PLAN/INTERVENTION 
7.1 
Study outline 
It is understood that clinic practices may vary with respect to how patients eligible for this study 
are identified and treated. The following outline of study procedures has been provided to guide 
participating institutions with respect to the order of events for this trial. 
Screening: It is expected that at the time patients are referred to the surgical clinic (e.g., from 
pulmonary or interventional radiology service, primary care physicians), they will be screened 
for this study. Alternatively, site staff may review internal medical records to identify patients 
eligible for the study who have not yet completed the surgical consult. Time permitting, pre-
registration tests, observations, and questionnaires may be completed on the same day as 
registration/randomization and the Baseline Visit.  
Surgical Consult: The surgical consult may be done as part of the screening process.  It must 
be completed prior to registration/randomization.  PLEASE NOTE: The No-Smoking Message 
can only be delivered AFTER registration/randomization, as this is part of the study intervention 
Registration/Randomization: Patients must be registered/randomized following informed 
consent and prior to the Baseline Visit (see below). 
Baseline Visit: The Baseline Visit will include the delivery of the No-Smoking Message by the 
Surgical Team Member, collection of saliva for cotinine measurement, baseline assessments per 
Section 5.1, and the completion of the baseline questionnaires. 
7.2 
Behavioral Intervention (Baseline visit) 
Teachable Moment – No-Smoking Message from Surgical Team Member: This message will 
be given to all patients on study during the Baseline Visit, and can be delivered by the surgeon 
or by a designated surgical team member. This message contains the following key sections: 
(1) There is no better time to quit than when you are having cancer surgery;  
(2) Unique detriments of smoking in patients facing cancer surgery: a) tobacco-related 
carcinogenesis/pre-malignant to malignant progression; b) increased risks of perioperative 
morbidity or mortality; c) increased risk for surgical complications and wound healing time; 
d) possible decrease in the effectiveness of adjunctive cancer treatments and increased side 
effects of these treatments; e) increased risk of secondary cancers;  
(3) The best time to stop smoking is now;  
(4) We know it is difficult and many other health care professionals are ready to help you do 
this; and  
(5) The study team will be in contact with you periodically throughout the course of the study.  
QUITLINE: Quitlines are an approved and cost-effective smoking cessation behavioral 
intervention[76]  Quitlines are recommended by the US Smoking Cessation Guidelines[1] for 
their wide reach in large populations. The quitline selected to be used in this study can continue 
to be used by each study site long after the study is complete as it is free of charge to all. Support 
will be provided by the National Cancer Institute Telephone Smoking Quitline, 1-877-44U-
QUIT, (1-877-448-7848). This is a toll free telephone line within the United States and provides 
smoking cessation counseling Monday through Friday 8 am to 8 pm Eastern time. After 
randomization, the study staff will assist the patient in making the first contact with the quitline. 
HANDOUT: All patients will also receive a handout with reminders of why they should stop 
smoking (message from surgeon) and quitline information. 


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26 
7.3 
Target Quit Date 
Following the baseline visit, patients will receive the full 12 week supply of drug. The target 
quit date (TQD) is to be determined during the baseline visit and should occur prior to the 
planned date of surgery. It must be at least 10 days after randomization. While it is understood 
that is rare for surgery in this patient population to be delayed, in order to allow for flexibility 
in exigent circumstances, the maximum time from randomization to the TQD will be 12 weeks. 
7.4 
Pharmacologic Intervention (Varenicline) 
The initiation of the one-week dose escalation period of varenicline/placebo treatment will be 
considered Day 1 and the target quit date (one week later) will thus be Day 8 of therapy.  Patients 
will be provided with instructions on the proper use of the medication (i.e., time of day to take 
the medication).  
During Week 1, the dosing will be one of the 0.5 mg varenicline/placebo pills per day for the 
first 3 days followed by two 0.5 mg pills a day (morning and evening) for the next 4 days. 
Weeks 2-12: Day 8 is the target quit day and on this day the patient will take two 0.5 mg pills 
twice daily (morning and evening). Patients will stay on this dose for 11 weeks. 
Agent 
Dose 
Route 
Day 
 
Varenicline/Placebo 
0.5 mg 
Oral 
Days 1-3 
1 pill per day 
Varenicline/Placebo 
0.5 mg 
Oral 
Days 4-7 
1 pill twice per day –  
Minimum of 8 hours apart 
Varenicline/Placebo 
0.5 mg 
Oral 
Days 8-84 
2 pills twice per day – 
Minimum of 8 hours apart 
(4 pills per day total) 
Dosing should occur with 240 mL of water and it is recommended that patients eat prior to 
dosing to decrease gastric upset. It is recommended that there be at least 8 hours between the 
morning and evening dosing. If a dose is missed, the patient should take it as soon as s/he 
remembers.  If it is almost time for the next dose (within 6 hours), the patient should skip the 
missed dose and take the next one as scheduled. Patients should not take a double dose of 
varenicline/placebo. 
Participating institutions should have a suicide ideation monitoring and response procedures in 
place. An example of such procedures has been provided in Appendix XI. 
8.0 
DOSE AND TREATMENT MODIFICATIONS, UNBLINDING 
8.1 
Ancillary therapy, concomitant medications, and supportive care 
8.1.1 Patients should not receive any other agent which would be considered treatment for 
smoking which can impact the primary endpoint. This includes, any nicotine replacement 
products (patch, gum, nasal spray, inhaler), bupropion, naltrexone,   
8.1.2 Adjuvant chemotherapy and radiation therapy with curative intent for patients enrolled 
to this study is permitted. 
8.1.3 Patients should receive full supportive care while on this study.  This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or concurrent 
medical conditions.  All blood products and concomitant medications such as antidiarrheals, 
analgesics, and/or antiemetics received from the first day of study treatment administration 
until 30 days after the final dose will be recorded in the medical records. 


Alliance A211401 
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27 
8.1.4 Diarrhea management is per the discretion of the treating physician. Diarrhea could be 
managed conservatively with medications such as loperamide. 
8.1.5 Alliance Policy Concerning the Use of Growth Factors 
Blood products and growth factors should be utilized as clinically warranted and following 
institutional policies and recommendations.  The use of growth factors should follow 
published guidelines of the American Society of Clinical Oncology 2006 Update of 
Recommendations for the Use of White Blood Cell Growth Factors: An Evidence-Based, 
Clinical Practice Guideline.  J Clin Oncol 24(19): 3187-3205, 2006. 
8.2 
Dose Modifications 
The following general guidelines apply to all adverse events except suicidal ideation or 
personality change (see Sections 8.2.7 and 8.2.8). Addition information regarding insomnia and 
nausea is provided in Sections 8.2.5 and 8.2.6. 
• 
All missed doses should be considered as skipped and not delayed. That is, the duration of 
treatment must not continue past the original 12-week stop date. 
• 
Patients may be re-challenged only one time for grade 3 events. That is, if a particular 
adverse event recurs after a dose reduction and rechallenge, varenicline/placebo will be 
permanently discontinued. 
• 
If treatment is skipped for more than four weeks due to toxicity, permanently discontinue 
varenicline/placebo. 
8.2.1 Dose Levels 
Dose Level 0 
0.5 mg x 2 tablets twice daily 
Dose Level -1 
0.5 mg x 2 tablets once daily 
Temporary discontinuation 
8.2.2 For Grade 1 or 2 adverse events possibly related to varenicline, will be followed per 
physician’s discretion. Also, At the physician’s discretion, varenicline/placebo dose may be 
continued, reduced to Dose Level -1, or be temporarily discontinued.  
Re-challenge: 
• 
If varenicline/placebo dose is reduced or temporarily discontinued, patients may be re-
challenged at the physician’s discretion to the next higher dose level the adverse event 
remains at grade 2 or better.  
• 
If varenicline/placebo was temporarily discontinued and the patient was successfully 
rechallenged to Dose Level -1 and the adverse event remains at grade 2 or better after 
an additional week, the dose of varenicline/placebo may be resumed at Dose Level 0 at 
the discretion of the treating physician. 
8.2.3 For Grade 3 adverse events possibly related to varenicline, patients will temporarily 
discontinue varenicline/placebo and will be assessed weekly until toxicity resolves to Grade 
2 or better. Assessments may be done by telephone per institutional practices. 
Re-challenge:  
• 
If the adverse event has resolved to grade 0, the patient should restart 
varenicline/placebo at Dose Level -1.  


Alliance A211401 
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28 
• 
If the adverse event has improved to grade 1 or 2, patients may be re-challenged at the 
physician’s discretion to Dose Level -1. If the adverse event remains at grade 2 or better 
after an additional week, the dose of varenicline/placebo may be resumed at Dose Level 
0 at the discretion of the treating physician 
8.2.4 For any Grade 4 adverse events, permanently discontinue varenicline/placebo. 
8.2.5 Insomnia: If the reported adverse event is persistent sleeplessness, the patient may be 
instructed take his/her medication earlier in the day (8 hours after morning dose). If reducing 
to Dose Level -1, patients should skip the evening dose.  
8.2.6 Nausea: If the reported adverse event is persistent nausea with morning medication, patients 
should be advised to do the following: 
• 
Take varenicline/placebo on a full stomach (after eating). 
• 
Drink an 8-ounce glass of water after taking the pill. 
• 
Eat a banana. 
If reducing to Dose Level -1, patients should skip the morning dose.. 
8.2.7 Suicidal ideation: Varenicline is known to cause suicidal ideation, patients must be 
screened for suicidal ideation at Weeks 6, 12, 18, and 24.  If a patient responds with a 
positive (1+) response to question 9 on the PHQ9, s/he will be evaluated by a physician 
using the CTCAE.  
Any patient with CTCAE  grade 2 or higher suicidal ideation will immediately discontinue 
treatment with varenicline/placebo and be referred to a mental health professional in 
accordance with institutional guidelines. For reference, the CTCAE grades 1 through 4 for 
suicidal ideation are provided below: 
Grade 1: 
Increased thoughts of death but no wish to kill oneself 
Grade 2: 
Suicidal ideation with no specific plan or intent 
Grade 3: 
Specific plan to commit suicide without serious intent to die which may not 
require hospitalization 
Grade 4: Specific plan to commit suicide with serious intent to die which requires 
hospitalization 
8.2.8 Personality Change: Any patient with CTCAE grade 3 or greater personality change will 
discontinue treatment with varenicline/placebo and be referred to a mental health 
professional in accordance with institutional guidelines. For reference, the CTCAE grades 
1 through 4 for personality change are provided below: 
Grade 1: 
Mild personality change  
Grade 2: 
Moderate personality change  
Grade 3: 
Severe personality change; hospitalization not indicated 
Grade 4: 
Life-threatening consequences, threats of harm to self or others; hospitalization 
indicated 
 
 


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29 
8.2.9 Somnambulism: Any patient experiencing sleep walking will discontinue treatment with 
varenicline. 
8.2.10 Pregnancy: Varenicline/placebo will be immediately permanently discontinued for any 
patient who becomes pregnant during the treatment period of the study.  
8.3 
Unblinding Procedures 
Unblinding can be done only in cases of an emergency. Follow the directions below to unblind 
patient treatment. Please note that if a treatment assignment is unblinded, the patient must 
discontinue protocol therapy. 
Emergency Unblinding Procedures: 
Examples of emergencies include 1) a life-threatening unexpected adverse event that is at least 
possibly related to the investigational agent and for which unblinding would influence treatment 
decisions; or 2) medication error, such as accidental overdose. Expected adverse events are listed 
in the “Toxicities” section below.  
Contact the Alliance Executive Officer on call by calling 
, pressing 1 to speak 
with an operator, and then asking for pager ID 8625 to return the call.  
The institution must provide the following information to the Alliance Executive Officer: 
• 
Alliance study ID (i.e., “A211401”) 
 
• 
Alliance patient ID number (e.g., “999999”) 
• 
Patient initials (e.g., “L, FM”) 
• 
Institution name 
• 
Name and telephone number of treating physician 
• 
Name and contact information of person requesting the unblinding procedure 
• 
Name and contact information of person to inform of treatment assignment 
• 
Reason for emergency unblinding 
Please remember that an emergency unblinding request may be authorized only by an Alliance 
Executive Officer, and emergency unblinding applies only if unblinding would influence 
management of the medical situation. 
After the Executive Officer deems unblinding is warranted, the treatment assignment will be 
provided to the contact person at the treating site. 
9.0 
ADVERSE EVENTS 
The prompt reporting of adverse events is the responsibility of each investigator engaged in clinical 
research, as required by Federal Regulations. Adverse events must be described and graded using the 
terminology and grading categories defined in the NCI’s Common Terminology Criteria for Adverse 
Events 
(CTCAE), 
Version 
4.0. 
The 
CTCAE 
is 
available 
at 
 
Attribution 
to 
protocol 
treatment for each adverse event must be determined by the investigator and reported on the required 
forms. Please refer the NCI Guidelines: Adverse Event Reporting Requirements for further details 
on AE reporting procedures.  
 
 


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9.1 
Routine adverse event reporting 
Adverse event data collection and reporting, which are required as part of every clinical trial are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times according to the study calendar in Section 5.0. For this trial, Adverse Event: Baseline, 
Adverse Event: Solicited and Adverse Event: Other are used for routine AE reporting in Rave. 
Attribution of Depression: When reporting depression, the following guidelines should be used 
for determining attribution to varenicline/placebo: 
• 
If depression existed before the patient started drug, and the severity has not changed, then 
the event should not be reported as at least possibly related to varenicline/placebo. 
• 
If depression started or worsened after the patient started drug (regardless of smoking 
status), the event should be reported as at least possibly related to varenicline/placebo. 
• 
If depression starts 7 days or more following cessation of drug, then the event should not be 
reported as related to varenicline/placebo. because the half-life of the drug is less than 7 
days. 
Solicited Adverse Events: The following adverse events are considered "expected" and their 
presence/absence should be solicited, and severity graded, at baseline and at 6, 12, 18 and 24 
weeks after surgery. 
CTCAE v4.0 Term 
CTCAE v4.0 System Organ Class (SOC) 
Personality change* 
Psychiatric disorders 
Suicidal ideation* 
Psychiatric disorders 
* 
Although the black box warning in the prescribing information has been removed (in 
December, 2016), patients will be monitored for neuropsychiatric events including hostility 
or changes in behavior or thinking that are not typical for the patient, or for suicidal ideation 
or suicidal behavior. See Sections 8.2.7 and 8.2.8. 
Collection of surgical adverse events: For the purpose of determining the primary endpoint of 
the study, the following surgical adverse events must be collected at 24 weeks after surgery. 
• 30-day mortality 
• 30-day re-hospitalization 
• 1-year mortality 
• Anastomotic failure 
• Anesthesia-related respiratory 
complications 
• Bleeding (transfusions > 5 U) 
• Coma (> 24 hours) 
• Deep venous thrombosis/ 
thrombophlebitis 
• Failure to wean from the ventilator 
• ICU readmission 
• Impaired bone healing 
• Implant loss (breast reconstruction) 
• Increased postoperative pain 
• Renal insufficiency/failure 
• Return to operating room 
• Sepsis/septic shock 
• Stroke/cerebral accident 
• Surgical infection (organ space) 
• Surgical site infections 
• Urinary tract infections 
• Increased postoperative surgical 
stay 
• Increased scarring and 
asymmetry 
• Intubation (unplanned)/re-
intubation 
• Lower rates of successful digital 
replantation (microsurgery) 
• Myocardial infarction  
• Pneumonia 
• Prolonged intubation 
• Prolonged ventilator support 
• Pulmonary complications 
• Pulmonary embolism 
• Reduced skin flap survival 
• Vascular complications 
• Vein graft failure 
• Venous thromboembolism 
• Ventilator (> 48 hours) 
• Wound healing (delayed) 
• Wound infection (sternal) 
• Wound infections 
(superficial and deep) 
 
 


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9.2 
CTCAE Routine Reporting Requirements 
In addition to the solicited adverse events listed in Section 9.1, the following table outlines the 
combinations of time points, grades and attributions of AEs that require routine reporting to 
the Alliance Statistics and Data Center. Questions about routine reporting should be directed 
to the Data Manager. 
Combinations of CTCAE Grade & Attribution Required for Routine AE Data 
Submission on Case Report Forms (CRFs) 
 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
 
 
a 
a 
a 
Unlikely 
 
 
a 
a 
a 
Possible 
 
a 
a, b 
a, b 
a, b 
Probable 
 
a 
a, b 
a, b 
a, b 
Definite 
 
a 
a, b 
a, b 
a, b 
a) Adverse Events: Other CRF - Applies to AEs occurring between registration and within 
30 days of the patient’s last treatment date, or as part of the Clinical Follow-Up Phase. 
b) Adverse Events: Late CRF - Applies to AEs occurring greater than 30 days after the 
patient’s last treatment date. 
9.3 
Expedited Adverse Event Reporting (CTEP-AERS) 
Investigators are required by Federal Regulations to report serious adverse events as defined in 
the table below. Alliance investigators are required to notify the Investigational Drug Branch 
(IDB), the Alliance Central Protocol Operations Program, the Study Chair, and their Institutional 
Review Board if a patient has a reportable serious adverse event. The descriptions and grading 
scales found in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5 
will be utilized for AE reporting. The CTCAE is identified and located on the CTEP website at: 
 
All 
appropriate 
treatment areas should have access to a copy of the CTCAE. All reactions determined to be 
“reportable” in an expedited manner must be reported using the Cancer Therapy Evaluation 
Program Adverse Event Reporting System (CTEP-AERS). 
For further information on the NCI requirements for SAE reporting, please refer to the ‘NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements’ document published by 
the NCI.  
Note:  A death on study requires both routine and expedited reporting regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
 




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• 
Expedited AE reporting timelines defined: 
 “24 hours; 5 calendar days” – The investigator must initially report the AE via CTEP-AERS 
≤ 24 hours of learning of the event followed by a complete CTEP-AERS report ≤ 5 calendar 
days of the initial 24-hour report. 
 “10 calendar days” - A complete CTEP-AERS report on the AE must be submitted ≤ 10 
calendar days of the investigator learning of the event.  
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or 
prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as protocol-
specific expedited adverse event reporting exclusions (see below). 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, 
or birth defects must be reported via CTEP-AERS if the event occurs following treatment with 
an agent under a CTEP IND. 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
Additional Instructions or Exclusions to CTEP-AERS Expedited Reporting Requirements for 
Phase 2 and 3 Trials Utilizing an Agent Under a CTEP IND or non-CTEP IND: 
• 
All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also be 
forwarded to your local IRB. 
• 
Grade 3/4 hematosuppression and hospitalization resulting from such do not require CTEP-
AERS, but should be submitted as part of study results. All other grade 3, 4, or 5 adverse events 
that precipitate hospitalization or prolong an existing hospitalization must be reported via CTEP-
AERS. 
• 
All new malignancies must be reported via CTEP-AERS whether or not they are thought to be 
related to either previous or current treatment. All new malignancies should be reported, i.e. solid 
tumors 
(including 
non-melanoma 
skin 
malignancies), 
hematologic 
malignancies, 
myelodysplastic syndrome/acute myelogenous leukemia, and in situ tumors. In CTCAE version 
4.0, the new malignancies (both second and secondary) may be reported as one of the following: 
(1) Leukemia secondary to oncology chemotherapy, (2) Myelodysplastic syndrome, (3) 
Treatment-related secondary malignancy, or (4) Neoplasms benign, malignant and unspecified-
other. Whenever possible, the CTEP-AERS reports for new malignancies should include tumor 
pathology, history or prior tumors, prior treatment/current treatment including duration, any 
associated risk factors or evidence regarding how long the new malignancy may have been 
present, when and how the new malignancy was detected, molecular characterization or 
cytogenetics of the original tumor (if available) and of any new tumor, and new malignancy 
treatment and outcome, if available. 
• 
Treatment expected adverse events include those listed in Section 10.0 and in the package insert. 
• 
CTEP-AERS reports should be submitted electronically. 
• 
Pregnancy loss is defined in CTCAE as “Death in utero.” Any Pregnancy loss should be reported 
expeditiously, as Grade 4 “Pregnancy loss” under the Pregnancy, puerperium and perinatal 
conditions SOC. A Pregnancy loss should NOT be reported as a Grade 5 event under the 
Pregnancy, puerperium and perinatal conditions SOC, as currently CTEP-AERS recognizes this 
event as a patient death. 
• 
A neonatal death should be reported expeditiously as Grade 4, “Death neonatal” under the 
General disorders and administration SOC. 


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10.0 DRUG INFORMATION 
10.1 
Varenicline Tartrate (Chantix®; Champix®) 
Varenicline (Chantix™) is minimally metabolized by the liver, and 92% is excreted by the 
kidney unchanged.  
Varenicline tartrate (Chantix™) is a nicotinic receptor partial agonist that binds with high 
affinity and selectivity at the α4β2 neuronal nicotinic acetylcholine receptors. 
Procurement 
Varenicline and matching placebo will be provided by Pfizer Inc. and shipped by the Alliance 
Research Base Pharmacy.   
“Varenicline” and “Placebo” will be supplied as 0.5 mg tablets for oral administration. Bottles 
will be labeled as “Varenicline or Placebo” so that the local investigators will be blinded as to 
the actual contents of the bottles. 
After receiving IRB approval for this study, each participating institution will order a starter 
supply of varenicline/placebo from the Alliance Research Base Pharmacy by faxing the Alliance 
Clinical Drug Order/Return Form to: 
 
 
 
 
The A211401 Varenicline/placebo Order Form can be found on the A211401 study page of the 
Alliance and CTSU websites.  
Each bottle will be identified by a unique code number and are not to be designated for use by 
a specific patient until they have been assigned to a patient by the Alliance Registration Office 
personnel. After the treatment assignment has been ascertained in the OPEN application, the 
patient’s study medication code number will be displayed on the confirmation of registration 
screen.   
The treating institution should not have to request additional supplies after a starter supply has 
been sent.  The pharmacy and the Alliance registration office will work together to re-supply 
each location. 
Outdated or remaining drug product should be destroyed on-site per procedures in place at each 
institution.   
IND Status 
IND Exempt: Varenicline is IND exempt as used in this trial. This exemption has been 
determined by attestation that neither the investigator nor sponsor intends to seek a new 
indication for use or to support any other significant change in the labeling or product advertising 
for varenicline; this investigation will use an approved route of administration and dosage of 
varenicline and has no factors that increase the risk of the product; this investigation will be in 
compliance with 21CFR parts 56, 50, and 312.7; and neither the investigator nor sponsor will 
promote or represent that varenicline is safe or effective for the context that is under 
investigation in this study. 
Formulation 
Commercial varenicline capsular, biconvex tablets contain 0.5 mg (white to off-white, debossed 
with “Pfizer” on one side and “CHX 0.5” on the other side).  Each 0.5 mg varenicline contains 
0.85 mg of varenicline tartrate equivalent to 0.5 mg of varenicline free base.  The following 


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inactive ingredients are included in the tablets:  microcrystalline cellulose, anhydrous dibasic 
calcium phosphate, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, 
Opadry® White (for 0.5 mg), Opadry® Blue (for 1 mg) and Opadry® Clear.   
Storage and Stability 
Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) (see USP Controlled Room 
Temperature).  
Administration 
Varenicline/placebo will be administered at a dosage of 0.5 mg once daily for 3 days, increasing 
to 0.5 mg twice daily for days 4 to 7, and then to the maintenance dose of 0.5 mg 2 tablets twice 
daily for up to 12 weeks of treatment. Patients should be instructed to take medication after 
eating and with a full glass of water. 
Drug Interactions 
Varenicline is not known to interact with any medications and has no contraindications aside 
from previous allergic reactions to varenicline. 
Other smoking cessation therapies: Safety and efficacy in combination with other smoking 
cessation therapies has not been established. Coadministration of varenicline and transdermal 
nicotine resulted in a high rate of discontinuation due to adverse events. 
Effect of smoking cessation: Pharmacokinetics or pharmacodynamics of certain drugs may be 
altered due to smoking cessation with CHANTIX, necessitating dose adjustment. 
Pharmacokinetics 
a) Absorption:  Varenicline is rapidly absorbed across the gastric mucosa, reaching a peak 
plasma concentration (Cmax) in about 4 hours. After multiple oral doses, steady state is 
reached within 4 days.  Bioavailability is unaffected by food or time-of-day dosing (food 
reduces the incidence and severity of nausea, a common side effect). 
b) Distribution:  Varenicline exhibits linear pharmacokinetics after single or repeated doses.  
Plasma protein binding is low (< 20%). 
c) Metabolism:  Varenicline undergoes minimal metabolism. 
d) Excretion:  Elimination half-life of varenicline is approximately 24 hours.  Ninety-two 
percent of varenicline is excreted unchanged in the urine. Renal elimination of varenicline 
is primarily through glomerular filtration along with active tubular secretion possibly via 
the organic cation transporter, OCT2. 
Adverse Events 
The most commonly reported adverse effects (>5% and twice the rate seen in placebo-treated 
patients) of varenicline are nausea (29.4% vs. 10% placebo), insomnia (14.3% vs. 12.4% 
placebo), abnormal dreams (13.1% vs. 3.5% placebo), headache (12.8% vs. 12.6% placebo), and 
constipation (9% vs. 1.5% placebo). Nausea is generally mild (72%) to moderate (23%) in 
intensity, becomes less severe with continued drug use, and causes 2.3% of the subjects to 
discontinue treatment. 
Drug Warnings: The FDA previously required a boxed warning on the varenicline label to alert 
physicians and subjects to behavior change risks. The labeling warned of the risk of behavioral 
changes such as: depression, hostility, aggression, suicidal thoughts, suicide, and vehicular 
crashes. Subjects and family members will be given clear instructions on discontinuing 
varenicline and alerting study staff in the event such behavior changes occur. This is detailed in 
the DSMP. 


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As a result of the black box warning for varenicline, a number of studies have recently (2010-
2015) focused on the safety of varenicline in various populations.  Studies have included both 
individual studies with hospitalized smokers and meta-analysis of past randomized clinical 
trials.  The common result in all these studies/reviews is that varenicline is safe and no significant 
increase in psychiatric conditions was observed in any of these cases.  These studies include:  
• 
In 2010, Tonstad reviewed 10 clinical trials comparing varenicline to placebo in over 3091 
smokers.  Psychiatric disorders (excluding sleep disorders or disturbances) was 10.7% in 
varenicline and 9.7% in placebo (RR=-1.02 – ns).  No cases of suicidal ideation or behavior 
in the varenicline arms in all 10 trials;[99]  
• 
In 2011, Park et al., conducted a study with 49 smokers who had lung cancer who met with 
a thoracic surgeon and were given varenicline and counseling or just counseling.  The OR 
was 3.14 (not significant).  This study did demonstrate that varenicline is safe (only nausea 
and abnormal dreams were higher in varenicline arm), and feasible (smokers with lung 
cancer did adhere to varenicline treatment);[37]  
• 
In 2012, Wong et al., conducted a study with 286 patients who were randomized to 
varenicline or placebo perioperatively.  Relative Risk (RR) was 1.45 for varenicline to help 
smokers stop smoking.  The only significant event was nausea (13.3 vs 3.7, p=0.004);[100]   
• 
In 2013, Nayan et al., reviewed 10 randomized clinical trials and 3 prospective clinical 
studies of smoking intervention in oncology patients.  The interventions included NRT, 
bupropion and varenicline.  The odds ratio (OR) of all interventions was 1.31 to 1.54 (not 
significant) depending on follow up period.  But when the interventions were delivered 
perioperatively, the OR was significant at 2.31, thereby demonstrating that surgery does 
present the teachable moment in oncology patients;[101]  
• 
In 2014, Carson et al., conducted a study with 392 hospitalized smokers who were 
randomized to varenicline vs. placebo for 12 weeks.  No increase in psychiatric events were 
noted, the only increase was nausea (16.3% in varenicline patients vs. 1.5% in counseling 
alone);[102] 
• 
In 2015 two studies took place, both with very large number of smokers: 
Thomas et al. – meta-analysis of 39 randomized trials (10,761 pts.) using varenicline vs. 
placebo to evaluate the incidence of neuropsychiatric events.  No increase of suicide, 
attempted suicide, suicidal ideation, depression, irritability, aggression, or death.  There was 
evidence of reduced anxiety and increase in sleep disorders, insomnia and abnormal dreams 
and fatigue.[103]  
Kotz et al. – A review of 753 general practices in England which identified 164,766 smokers 
who received prescription to stop smoking (106,759 NRT; 6557 bupropion; 51,450 
varenicline). Neither bupropion nor varenicline showed any increase in cardiovascular or 
neuropsychiatric events (including depression and self-harm) compared to NRT (Hazard 
Ratio (HR)= 0.80), cerebral infarction (HR=0.62), heart failure (HR=0.61), arrhythmia 
(HR=0.73) or self-harm (HR=0.56).[104] 
Weight Gain: Varenicline does not attenuate weight gain after stopping smoking. 
Abuse Potential: The manufacturer’s data, available in the package insert, suggests that 
varenicline is not likely to be abused. The FDA did not classify varenicline as a controlled 
substance. 
 
 


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Pregnancy Risk: Varenicline is FDA Pregnancy Class “C” drug defined as “Either studies in 
animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and 
there are no controlled studies in women or studies in women and animals are not available. 
Drugs should be given only if the potential benefit justifies the potential risk to the fetus.” Since 
we do not know the potential benefits, we cannot determine the risk-benefit ratio and will, 
therefore, exclude pregnant individuals at the beginning and during the study. Not enough 
medical information exists to know what the risks might be to a breast-fed infant so we will 
exclude individuals who are breast-feeding. 
Nursing Guidelines 
1. Be aware of black box warning regarding behavior changes, including depression, hostility, 
aggression, suicidal thoughts, and vehicular crashes. Warn patients of this risk and instruct 
patients to report any changes in mood or behavior to the study team. 
2. Patients may experience nausea. Nausea may improve with time. Treat symptomatically and 
monitor for effectiveness. 
3. Warn of difficulty sleeping and/or unusual dreams.  
4. Headache may occur. Treat symptomatically and monitor for effectiveness. 
5. Patients may experience mild constipation, encourage increased fluid intake and treat 
symptomatically as necessary. 
10.2 
Placebo (Supplied)  
Investigators ordering and/or dispensing supplied agents at any time for study treatment must 
be currently registered with PMB, DCTD, NCI. A registered investigator must co-sign for other 
non-registered personnel prescribing the supplied agents 
A matching placebo will be provided.  It will be identical in appearance to the varenicline.   
11.0 MEASUREMENT OF EFFECT 
All of the following measures relate to the secondary endpoints.  
The primary endpoint of surgical complication incidence rates at 24 weeks after surgery will 
be measured as described in Appendix X. 
11.1 
Patient reported measures 
For the purposes of this study, patients should be reevaluated every 6 weeks.  In total, the time 
for the patient to complete these forms is approximately 16 minutes at Baseline, 10 minutes at 
Week 6, 10 minutes at Week 12, and 13 minutes at Week 24. 
11.1.1 Tobacco Use Assessment (Appendix IX): We will record the patient’s self-reported 
smoking status including current use, use during the past 7 days, use since time of last self-
report, and use since Target Quit Date (TQD) as appropriate. This form will collect vitals, 
smoking status, contact made with the tobacco quitline. This will take approximately 3 
minutes to complete. 
11.1.2 Contemplation Ladder (Appendix III)[77]: The Contemplation Ladder is a visual analog 
comprised of 11 rungs and 5 anchor statements (item 0, 2, 5, 8, 10), representing stages of 
change. The response options (0) to (3) correspond with pre-contemplation, (4) to (6) 
represent contemplation, (7) and (8) refer to preparation, (9) and (10) represent action and 
maintenance, respectively. It is a brief measure of motivation or readiness to change, where 
(0) is the least motivated and (10) is the most motivated. This measure will be used to screen 
out those who are not motivated to change (scoring a 5 or below) and therefore lower 
likelihood of responding to the intervention and completing the study. Two recent studies 


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of smokers with co-morbid conditions showed the average hospitalized smoker enrolled 
scored a 6 and above and they found that 70-80% of the enrolled subjects scored an “8” or 
above.[78, 79] This will take approximately 1 minute to complete. 
11.1.3 Smoking Self-Efficacy Questionnaire (SEQ-12; Appendix IV)[80]: Two six-item 
subscales measuring confidence of smokers in their ability to remain tobacco abstinent in 
the face of internal stimuli (e.g., feeling depressed) and external stimuli (e.g., in company 
of smokers). This will take approximately 5 minutes to complete. 
11.1.4 Fagerström Test for Nicotine Dependence (FTND; Appendix V)[81]: Predicts smoking 
abstinence and is correlated with biochemical measures of tobacco dependence. This will 
take approximately 3 minutes to complete. 
11.1.5 Patient Health Questionnaire-9 (PHQ-9; Appendix VI)[82]: A valid diagnostic and 
severity measure for depression, with scores ≥10 indicating moderately severe depression. 
The PHQ9 is used to help guide the investigator during the study enrollment process and to 
help the investigator monitor the patient with respect to depression after randomization. The 
study investigator will determine if the person is still eligible for study enrollment. This will 
take approximately 2 minutes to complete. 
11.1.6 Linear Analogue Self-Assessment (LASA; Appendix VII)[83]: Single-item LASA items 
have become the most widely-used assessment in all NCI-sponsored cancer control 
studies.[84] Normative data have been obtained from various clinical populations enrolled 
in NCCTG clinical trials and from healthy participants.[85, 86] This will take approximately 
3 minutes to complete. 
11.1.7 “Was it Worth It?” Survey (Appendix VIII)[87]: This is an end-of-study survey to ask 
the patient if the entire experience was worth it for them. This will take approximately 2 
minutes to complete. 
11.1.8 Drug and Behavioral Support Adherence Logs (Appendix X): Each patient will be 
provided with an adherence log which is specific to his/her treatment phase. In this log, they 
will provide details of their daily pharmacotherapy intake, contacts made to/from the 
telephone quitline, amount of cigarettes smoked (if any), and any other comments the patient 
feels is pertinent.  This will take approximately 5 minutes to complete. 
11.2 
Biochemical confirmation using salivary cotinine 
Biochemical confirmation will be used in the cotinine analysis in saliva. Cotinine analyses are 
two of five validated methods to analyze and verify smoking in patients during smoking 
cessation.[93-95] Salivary cotinine will be analyzed using the commercially available 
quantitative enzyme linked immunosorbent assay (ELISA),[96] which we have used in several 
prior studies.[97, 98]  Using salivary cotinine will allow for testing of clinically useful measures.  
All saliva will be shipped to the Medical University of South Carolina, Charleston, SC per 
Section 6.2.2. The correlative analyses will be performed in the laboratory of Dr. G. Warren at 
MUSC. 
11.3 
Definitions of analysis variables 
Formal definitions of variables used in analyses can be found in the Statistical Considerations 
section of the protocol. 
 
 


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12.0 END OF TREATMENT/INTERVENTION 
12.1 
Duration of Treatment  
Patients should be treated with varenicline/placebo for 12 weeks. 
If the patient discontinues varenicline/placebo before completing 12 weeks of therapy, patients 
should be followed for the duration of the study period (6 months). 
12.2 
Definitions and Follow-up Requirements 
Definition of ineligible patients: A study participant who is registered to the trial but does not 
meet all of the eligibility criteria is deemed to be ineligible. Patients who are deemed ineligible 
may continue protocol treatment, provided the treating physician, study chair, and executive 
officer agree there are no safety concerns if the patient were to continue protocol treatment. 
Notification of the local IRB may be necessary per local IRB policies. 
Definition of clinical follow-up: The follow-up period where the study participant is no longer 
receiving treatment, but is still following the study calendar for tests, exams, and correlative 
endpoints (e.g., specimen collection, quality of life, disease assessments as required by the 
study). 
Baseline data must be submitted per Section 5.0 for patients deemed ineligible or canceled. See 
also the Forms Packet for full details of data submission requirements 
12.2.1 Follow-up for Ineligible Patients 
Study participants who are registered to the trial but deemed ineligible must complete 
follow-up requirements.  
Baseline, on-study, endpoint (e.g., relapse or progression), off treatment, and survival data 
submission required.  
12.2.2 Follow-up for Patients Never Receiving Protocol Intervention 
Study participants who receive the study intervention (varenicline/placebo and behavioral 
module), but never go on to have the surgery, can complete study intervention if they wish.  
Data on outcome and complications (adverse events) will continue to be collected, but these 
patients will not be included in the analysis of the primary endpoint.  
Study participants initiate the study intervention (varenicline/placebo and behavioral 
module), go on to receive surgery, but wish to stop study intervention thereafter, will 
continue to have data on outcome and complications (adverse events) collected. These data 
will be used in the analysis of the primary endpoint. 
Study participants who were registered/randomized but never received varenicline/placebo 
will be considered “canceled” and baseline data must be submitted per Section 5.0.. 
12.3 
Extraordinary Medical Circumstances 
If, at any time the constraints of this protocol are detrimental to the patient's health and/or the 
patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In 
this event: 
• 
Document the reason(s) for discontinuation of therapy on data forms. 
• 
Follow the patient for protocol endpoints as required by the Study Calendar. 
 
 


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13.0 STATISTICAL CONSIDERATIONS 
13.1 
Study Design  
This is a randomized, double-blind, placebo-controlled, phase III trial evaluating varenicline vs. 
placebo for reduction in post-surgical complications through 24 weeks after surgery in lung 
cancer patients who undergo surgery and are motivated to stop smoking. A parallel group design 
will be utilized for this two-arm study: varenicline vs. placebo. Both arms will also include a 
brief no smoking message from the surgical team and the NCI Quitline.   
13.1.1 Study Populations 
Intent-to-Treat (ITT) Population: Consists of all randomized patients who had surgery. 
The ITT population will be used for the efficacy evaluation at each of the planned analyses.  
Following the intent-to-treat principle, patients will be analyzed according to the treatment 
they were assigned at randomization. Patient with missing values will be considered to have 
complications. 
Safety Population: Consists of all patients who were randomized, had surgery, and who 
have at least one post-baseline safety assessment.  The safety population will be used in the 
safety data summaries   Note that a patient who had no adverse events (on the Adverse Event 
CRF) constitutes a safety assessment.  Patients who have received at least one dose of study 
drug but have no post-treatment safety data of any kind would be excluded. 
13.2 
 Study Endpoints 
13.2.1 Primary Endpoint 
The primary endpoint will be the incidence for any of the following complications from 
surgery within 24 weeks after surgery: 30-day mortality, 30-day re-hospitalization, 
pulmonary complications, ICU readmission (an upgrade from any inpatient status [floor or 
intermediate care status] to full intensive care nursing acuity because of a serious 
deterioration in physical condition that warrants closer physician monitoring or nursing 
care), wound infection (NOS), anastomotic failure. These complications were identified as 
being sufficiently numerous from an investigation of the national surgical database (ACS-
NSQIP). They will be defined using the General Thoracic Surgery Database (GTSD) for 
study purposes. These complications will be considered equally important in determining 
complication rates. Patients who have any of these individual morbidities will be considered 
to have a perioperative complication. Patients without any of these individual morbidities 
will be considered to not have a perioperative complication. 
Formal definitions for all complications of the primary and secondary endpoints are found 
in Appendix X. We have reviewed the elements of the primary endpoint with the 
Community Oncology Committee and the Alliance lung cancer surgeon working group and 
surveyed potential participating sites for a description of the workflow for treatment 
administration and data collection to ensure that all the elements can be recorded across the 
Alliance sites. 
13.2.2 Secondary Endpoints 
• 
QOL-related domains as measured by the LASA-12, PHQ-9, SEQ-12, and Was It Worth It 
assessments. 
• 
Post-operative care as measured by length of hospital and high dependency unit stay. Length 
of stay will include only the time from surgery until the patient is released from the hospital. 


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• 
Expanded complication rate defined as any of the complications listed in Appendix I that 
are not being examined as part of the primary endpoint. This is included to account for the 
possibility that other complications, which do not occur with high frequency in the ACS-
NSQIP data base, actually occur in our study. 
• 
Treatment adherence rates related to visits, medication compliance, quitline usage, and 
surgeon teachable moment delivery.  
• 
Smoking abstinence rates as measured by self-report and salivary cotinine testing. 
13.3 
Primary analysis 
Surgical complication incidence rates at 24 weeks after surgery will be compared between the 
intervention vs. control groups using a Fisher’s exact test.  
Logistic regression models will supplement the univariate analysis, using complication 
incidence as the dependent variable and will include smoking status at the time of surgery as an 
independent variable and also adjust for age, gender, FTND, time between randomization and 
surgery, and presence of adjuvant chemotherapy and/or radiation therapy. A separate logistic 
model will be created including treatment arm instead of smoking status. We will also explore 
the collinear relationship between arm and smoking status to see whether they can be included 
together in the logistic models. 
13.4 
Additional Analyses 
We will compare changes from baseline in patient quality of life related domains (LASA-12, 
PHQ-9, SEQ12) between the intervention and control groups using analysis of covariance and 
linear mixed model repeated measures analysis for each assessment domain. Specifically, we 
will analyze each LASA domain with a separate ANCOVA model using the change from 
baseline to 12 weeks post-surgery as the dependent variable, followed by a similar analysis using 
the change from baseline to 24 weeks post-surgery. Each LASA question corresponds to a 
separate domain. For the PHQ-9 and SEQ12, we will use the scale scores in a repeated measures 
analysis involving data from all time points (baseline, 6, 12, and 24 weeks). For the PHQ-9 there 
is one overall score and for the SEQ12 there are two scales (internal stimuli and external stimuli).  
The WIWI survey will be analyzed by comparing the proportion of patients at the end of the 
treatment period (i.e., 12 weeks after surgery) and at 24 weeks after surgery who endorse each 
treatment (intervention versus control) via Fisher’s exact testing.  
These QOL-related domain variables will be included in the modeling process of the primary 
and other secondary analyses as potentially concomitant confounding covariates so as to produce 
more efficient estimates from the models. Sensitivity analysis for potential differences between 
groups demonstrated via the ANCOVA and repeated measures models will be assessed using 
Generalized Estimating Equations models to account for the correlation of repeated measures 
on the same patient. 
We will compare post-operative care (length of hospital and high dependency unit stay) between 
the intervention vs. control groups using separate logrank testing of Kaplan-Meier estimates for 
length of hospital stay and length of high dependency unit stay and supplemented by Cox models 
to control for concomitant covariates. The assumptions underlying the Cox model will be tested 
for veracity.  
For the expanded complication rate, we will utilize the same analysis approach as the primary 
endpoint analysis for all complications listed in Appendix I. We will also compare the incidence 
rates of each specific type of complication between arms. 
We will also measure treatment adherence. The number of study visits completed by each patient 
during the treatment phase will be summarized and compared between groups using the rank 


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sum test. Patient self-report will be used to collect adherence data on the use of the quitline and 
the medication adherence for the patients receiving the multi-faceted smoking cessation 
intervention. To assess medication compliance, patients will report to the study staff at each visit 
the amount of study medication used each day. In addition, patients will return unused 
medication at each study visit and study staff will maintain drug accountability logs to account 
for dispensed and returned medication. The amount of study medication taken by each patient 
will be calculated weekly. Adherence data on teachable moment delivery from the surgical team 
will be collected by the study staff at the time of the message delivery. These data will be 
summarized using simple descriptive statistics to indicate the degree of treatment adherence that 
is achieved for the multi-faceted smoking cessation intervention. 
Rates of smoking abstinence will be compared between arms using Fisher’s exact test and 
logistic regression models. Abstinence definitions are based upon the Society for Research on 
Nicotine and Tobacco (SRNT) Working Group recommendations.[88] The major advantage of 
point prevalence estimates is that they are widely reported in the literature and can be verified 
biochemically. However, point prevalence abstinence does not account for slips/lapses that 
might occur between follow-up periods. Prolonged abstinence is defined as smoking abstinence 
sustained after an initial 2-week grace period[88] and accounts for initial lapses. However, 
prolonged abstinence cannot be verified biochemically short of daily biochemical confirmations 
and, ultimately, must rely on self-report. Research suggests that self-reports among smokers in 
general tend to be accurate, and misreporting rates are generally very low.[89]  We allow for a 
2-week grace period after TQD based upon the SRNT Working Group recommendations.[88]  
Prolonged smoking abstinence will be adjudicated if the following criteria are met: 1) Self-
reported smoking abstinence since 2 weeks after the TQD. This will be identified by a negative 
response to the question, “Since xx/xx/xxxx, which was 2 weeks after your TQD, have you 
smoked any tobacco, even a puff, for 7 consecutive days or at least once each week on 2 
consecutive weeks?” and 2) No failed biochemical confirmation of self-reported smoking 
abstinence at any previous outcome assessment. Point prevalence smoking abstinence will be 
adjudicated if both of these criteria are met: 1) Self-reported smoking abstinence for the last 7 
days. This will be identified by a negative response to the question, “Have you smoked any 
tobacco, even a puff, in the past 7 days?”, and 2) Salivary cotinine less than 15 ng/mL. Relapse 
will be defined as smoking on 7 consecutive days or smoking at least once each week on 2 
consecutive weeks.[88] 
13.5 
Correlative and companion substudy analyses 
13.5.1 Correlative substudy analysis (A211401) 
Salivary cotinine is an evidence-based biochemical method to confirm tobacco use that 
significantly increases the accurate identification of current smoking.  Data demonstrate that 
30-40% of cancer patients who smoke do not accurately report smoking status even using 
structured assessments (97-98).  As a result, quantitative cotinine analyses (96) will be used 
to increase the accuracy of identifying current smoking, which will in parallel be used to 
evaluate changes in study outcomes using a more accurate methodology.  For this study, a 
cutoff of 15 ng/mL will be used to define biochemically confirmed current smoking (>15) 
according to recommendations from the Society for Nicotine and Tobacco Research (95). 
13.5.2 Pharmacogenetic companion substudy analysis (A211401-PP1) 
For the correlative analysis, we will examine whether cigarette smokers undergoing surgery 
for cancer who have the high-risk variants of CHRNA5-CHRNA3-CHRNB4 will have higher 
abstinence rates, as determined by the tobacco use assessment and continine levels, than 
those with the low-risk variants of CHRNA5-CHRNA3-CHRNB4. We will examine this 
genetic effect in the overall group and in each treatment arm. We will also examine whether 


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intervention effect varies with CHRNA5-CHRNA3-CHRNB4 (i.e. a genotype X intervention 
interaction). A series of logistic regression models will be used to examine main effects of 
genotype and intervention before testing genotype x intervention interactions, with age, sex, 
and intervention arm as covariates. Similarly, we will examine whether smokers with 
CYP2A6-defined fast nicotine metabolism will have lower abstinence and higher withdrawal 
symptoms at 12 weeks after surgery and at 24 weeks after surgery (end of study) , compared 
with smokers with slow metabolism. We will examine whether the effect of varenicline 
varies with participant’s CYP2A6-defined nicotine metabolism status. Fisher exact tests will 
be used, supplemented by logistic regression models similar to what is described for the 
primary analysis. We will examine if these cessation-relevant genotypes (CHRNA5-
CHRNA3-CHRNB5, CYP2A6) modify the effect of the intervention vs. control groups. 
These correlative analyses will not be adjusted for multiple comparisons, since the 
magnitude of the associations is of more interest than the statistical significance for whether 
or not there is any association. 
13.6 
Power/Sample Size 
The primary statistical endpoint for this study is the incidence of surgical complications as 
described in Sections 13.1 and 13.3. Patients that have any of these individual morbidities will 
be considered to have a perioperative complication. Patients without any of these individual 
morbidities will be considered to not have a perioperative complication.  
In a study of 635,265 non-cardiac surgical cases treated in 200 centers throughout the United 
States, the incidence rate of the perioperative complications listed above from the National 
Surgical Quality Improvement Program (NSQIP) data was in the range of 25–30%. They further 
found that smokers undergoing non-cardiac surgery had an estimated 40% increased odds of 
developing major morbidity and mortality within 30 days of surgery over never smokers, 
representing a modest difference of between 10%-12% in the actual percentage of patients with 
major morbidity.[90] One report focused on the limitations of NSQIP in identifying adverse 
events following major cancer surgery. NSQIP does not abstract the complications considered 
most important by many surgical subspecialists (e.g., anastomotic leak).[91] Therefore, the true 
impact of smoking on adverse surgical events may be greater in this trial.  
For the purposes of this power calculation then, we will assume a 30% perioperative 
complication incidence rate in the control group.104 The study design is a randomized clinical 
trial intended to estimate the incidence rate of perioperative complications in patients who are 
smoking at the time of enrollment. The primary statistical analysis will be a comparison of the 
perioperative complication incidence rates from the time of surgery to 24 weeks after surgery 
between the intervention and control groups. We will hence power the study to detect a 10% 
difference in perioperative complication rates between the intervention and control groups. 
With a sample size of 626 patients (313 patients per arm), a Fisher exact test can detect a 
difference in the perioperative complication rate between the two treatment groups of 10% (20% 
versus 30% in the intervention arm and control arm, respectively) with 80% power using a Type 
I error rate of 5% and a two-sided alternative.  
The prevalence of smoking among lung cancer surgical patients is roughly 42%.[91] We 
estimate that 90% of these patients will be motivated to quit and enroll on the study, given the 
relaxed eligibility requirements requiring only a desire to quit and teachable moment delivery 
by the surgeons. Hence we can expect to screen roughly three patients to enroll one. An 
adjustment is also needed for patients that enter the smoking cessation part of the study, but drop 
out before surgery. We expect that at most 20% of the patients entering the study will drop out 
after registering and before having surgery. To obtain a sample size of 626 smoking patients 
with a new diagnosis of lung cancer for which surgery is indicated, we will need to screen 


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approximately 1878 oncology patients undergoing surgery to enroll 783 smoking patients. Of 
these 783 patients, we expect 626 to undergo surgery. The study will remain open to accrual 
until 783 patients have been enrolled. If we take into consideration patient refusal, we would 
need to approach 2000 smoking oncology patients undergoing surgery to have 626 patients 
enroll in the study and undergo surgery. 
13.7 
Accrual rate and study duration 
From accrual estimates provided by sites in this survey, we anticipate accruing 150 evaluable 
patients per year. Multiple surveys have been conducted to obtain realistic accrual expectations 
as well as detailed descriptions as to how patients will be accrued, treated, and assessed at each 
site. This study accrual will close when 783 study patients have been enrolled; therefore, we 
anticipate patient accrual to be completed in approximately 4 years and 2 months.  If, after 400 
patients have been enrolled to the study, the proportion of patients who fail to undergo surgery 
is ≤ 10%; then accrual to the study will be stopped when 700 patients have been enrolled, as this 
would produce the required 626 patients for the primary analysis. 
13.8 
Monitoring 
This study will be monitored by the Alliance Data and Safety Monitoring Board (DSMB), an 
NCI-approved functioning body.  Reports containing efficacy, adverse event, and administrative 
information will be provided to the DSMB every six months as per NCI guidelines. 
This study will be monitored by the Clinical Data Update System (CDUS) version 2.0.  An 
abbreviated report containing cumulative CDUS data will be submitted quarterly to CTEP by 
electronic means.  Reports are due January 31, April 30, July 31, and October 31. 
13.9 
Adverse Event Stopping Rule 
The stopping rule specified below is based on the knowledge available at study development. 
We note that the Adverse Event Stopping Rule may be adjusted in the event of either (1) the 
study re-opening to accrual or (2) at any time during the conduct of the trial and in consideration 
of newly acquired information regarding the adverse event profile of the treatment(s) under 
investigation.  The study team may choose to suspend accrual because of unexpected adverse 
event profiles that have not crossed the specified rule below.  CTCAE v4.0 will be used to 
determine grading for these stopping rules. 
Accrual will be temporarily suspended to this study if at any time we observe events considered 
at least possibly related to study treatment (varenicline) (i.e., an adverse event with attribute 
specified as  “possible”, “probable”, or “definite”) that satisfies the following: 
• 
If 3 or more patients in the first 15 treated patients or, if at any time after the first 15 patients 
are enrolled, 20% or more patients develop ≥ grade 4 non-hematologic adverse events felt 
to be at least possibly related to treatment, the study team will review the data to determine 
the proper course of action. These actions may include further adverse event monitoring, 
suspension of accrual, dose modification, or closure of the trial. 
We note that we will review grade 4 and 5 adverse events deemed “unrelated” or “unlikely to 
be related”, to verify their attribution and to monitor the emergence of a previously unrecognized 
treatment-related adverse event. 
 
 


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13.10 Interim Analysis 
Although the final analyses will utilize a 5% Type I error rate, we will use a more conservative 
interim bound of 0.001 for the P value for all interim analyses. Freidlin’s[92] simulation studies 
have demonstrated that such a bound trivially impacts both the interim bounds and the final 
significance level. Interim analyses will be done in concert with the semi-annual Data Safety 
Monitoring Board (DSMB) reports. These interim analyses will report on the primary endpoint 
using all patients that have been on study for at least 3 months.  
13.11 Inclusion of Women and Minorities 
This study will be available to all eligible patients, regardless of race or ethnic origin. There is 
no information currently available regarding differential effects in subsets defined by race or 
ethnicity, and there is no reason to expect such differences to exist. Based on prior smoking 
cessation studies, we expect about 15% of patients will be classified as minorities by race and 
about 40% of patients will be male. 
 
 
Racial Categories 
Ethnic Categories 
Not Hispanic or Latino 
Hispanic or Latino 
 
Total 
Female 
Male 
Female 
Male 
American Indian/Alaska Native 
9 
6 
0 
0 
15 
Asian 
5 
2 
1 
0 
8 
Native Hawaiian or Other Pacific Islander 
5 
2 
0 
0 
7 
Black or African American 
37 
25 
0 
1 
63 
White 
391 
262 
7 
5 
665 
More Than One Race 
15 
10 
0 
0 
25 
Total 
462 
307 
8 
6 
783 
14.0 CORRELATIVE AND COMPANION STUDIES  
There are two substudies within Alliance A211401. Measurement of saliva cotinine levels is a 
correlative substudy, which is mandatory for all patients registered to A211401.  There is one 
pharmacogenetics companion substudy, which must be offered to all patients enrolled on Alliance 
A211401 (although patients may opt to not participate). The companion substudy included within 
Alliance A211401 is: 
• 
Pharmacogenetics of Smoking Cessation Treatment (POST), Alliance A211401-PP1  
14.1 
Correlative substudy to measure saliva cotinine levels  
14.1.1 Background 
For patients enrolled on study, saliva samples will be obtained to analyze for cotinine.  
Salivary cotinine is an evidence-based biochemical method to confirm tobacco use that 
significantly increases the accurate identification of current smoking.  In cancer patients 
who are asked about tobacco use in person, approximately 30-40% of current smokers 
misrepresent smoking status (97-98, Khuri et al.).  In cancer patients who participate in 
phone based assessments, recent data demonstrate that 48% of adult smokers (REF) and up 
to 80% of childhood cancer survivors (REF) misrepresent smoking status.  For this study, a 
cutoff of 15 ng/mL will be used to define biochemically confirmed current smoking (>15) 
according to recommendations from the Society for Nicotine and Tobacco Research (95). 


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14.1.2 Hypothesis/objective 
This biomarker will be used to increase the accuracy of tobacco assessment as compared 
with self-reported tobacco use.  The hypothesis is that biochemically confirmed tobacco use 
will increase the magnitude of difference in study outcomes as compared with self-reported 
tobacco use.  This biomarker will be used for the following objectives: 
Primary objective: To evaluate the effect of biochemically confirmed tobacco use on study 
outcomes 
Secondary objectives: 
To evaluate the accuracy of self-reported tobacco use among study participants 
To evaluate if biochemically confirmed tobacco use correlates with a larger magnitude of 
difference in study outcomes as compared with self-reported tobacco use 
To evaluate longitudinal accuracy of self-reporting among study participants at baseline and 
throughout the study 
14.1.3 Methodology 
Saliva will be collected in patients as described in 6.2 and patients will be identified as 
current smokers using a salivary cotinine cutoff of >15 ng/mL (95-96) analyzed by G. 
Warren at the Medical University of South Carolina.  Parallel evaluations of study outcomes, 
behavior, and genetic linkages will be performed using self-reported tobacco use 
assessments and biochemically confirmed tobacco use assessments.   
14.2 
Pharmacogenetics of Smoking Cessation Treatment (POST), Alliance A211401-PP1 
14.2.1 Background 
Alliance 211401-PP1 will evaluate genetic effects on cessation outcomes and treatment 
response. Dr. Laura Bierut and Dr. Li-Shiun Chen will identify genetic predictors for 
cessation outcomes and treatment response.  (See section 1.1.4 for more background 
information).  
14.2.2 Hypothesis/objective 
To evaluate if biochemically confirmation strengthens associations between genetic 
markers, behaviors, and study outcomes 
To evaluate the predictive role of the nicotinic receptor gene cluster (CHRNA5-CHRNA3-
CHRNB4) and CYP2A6 genotypes in smoking cessation among lung cancer patients 
undergoing surgery. 
To evaluate the potential moderating effect of these cessation-relevant genotypes on 
smoking cessation treatment between the intervention and control groups. 
14.2.3 Methodology 
Participants will provide a blood sample of 10ml (EDTA Vacutainer) for assessment of 
genotyping and nicotine metabolism by Washington University.  Multiple genes have been 
shown to predict abstinence and response to cessation pharmacotherapy. The blood sample 
will be used to extract DNA and the plasma will be used for the biomarker, NMR (ratio of 
3’hydroxycotinine/cotinine) which reflect CYP2A6 activity and nicotine clearance in 
smokers, and may predict smoking cessation. All blood samples will be collected, stored, 
and shipped to the Alliance biorepository and will subsequently be shipped to Dr. Laura 
Bierut at Washington University in St. Louis for genotyping and nicotine metabolism 
essays.  


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15.0 TEACHABLE MOMENT TRAINING 
Surgeons and designated members of the surgeon’s team will be trained and educated in the basics 
of smoking cessation counseling and delivery of the No-Smoking message to the surgical oncology 
patient. The training will be based upon a validated approach to clinician-delivered tobacco use 
intervention (Warner et al, Anesthesiology 114:847-855, 2011).  Two different training modules will 
be required:  One for the surgeon and one for the site staff (study coordinator/nurse).  Modules will 
be on-line and asynchronous, and available on the Alliance Web site via a link on the study-specific 
web page.  Sites will certify that the training was completed by notifying the study chair or co-chair 
via email.  To supplement this training, there will also be a training exercise at the Fall Alliance 
meeting. 
15.1 
Surgeons 
The module will emphasize the importance of brief surgeon advice to quit and the compelling 
rationale for smoking cessation to reduce perioperative complications. 
The surgeon module will require approximately 5 minutes to complete 
15.2 
Study Staff 
The module will demonstrate the brief behavioral intervention to be delivered by the study 
coordinator/nurse, including the elements addressed in Section 7.1. 
The study staff module will require approximately 30 minutes to complete.   


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16.0 REFERENCES 
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Sorensen, L.T., Wound healing and infection in surgery: the pathophysiological impact of smoking, 
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Eur J Cardiothorac Surg, 2011. 40(6): p. 1432-7; discussion 1437-8. 


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20. 
Mills, E., et al., Smoking cessation reduces postoperative complications: a systematic review and 
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35. 
Jorenby, D.E., et al., Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor 
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Hays, J.T., Varenicline may reduce negative effect while aiding smoking cessation. Evidence-based 
medicine, 2014. 19(1): p. 23. 


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39. 
Cinciripini, P.M., et al., Effects of varenicline and bupropion sustained-release use plus intensive 
smoking cessation counseling on prolonged abstinence from smoking and on depression, negative 
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Meyer, T.E., et al., Neuropsychiatric events in varenicline and nicotine replacement patch users in 
the Military Health System. Addiction, 2013. 108(1): p. 203-10. 
42. 
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psychiatric adverse events. Addiction, 2013. 108(7): p. 1336-43. 
43. 
Thomas, K.H., et al., Smoking cessation treatment and risk of depression, suicide, and self harm in 
the Clinical Practice Research Datalink: prospective cohort study. BMJ, 2013. 347: p. f5704. 
44. 
Anthenelli, R.M., et al., Effects of varenicline on smoking cessation in adults with stably treated 
current or past major depression: a randomized trial. Annals of Internal Medicine, 2013. 159(6): 
p. 390-400. 
45. 
Gonzales, D., et al., Retreatment with varenicline for smoking cessation in smokers who have 
previously taken varenicline: a randomized, placebo-controlled trial. Clinical Pharmacology and 
Therapeutics, 2014. 96(3): p. 390-6. 
46. 
Cinciripini, P.M. and M. Karam-Hage, Study suggests varenicline safe and effective among adults 
with stable depression. Evidence-based medicine, 2014. 19(3): p. 92. 
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Lichtenstein, E., S.H. Zhu, and G.J. Tedeschi, Smoking cessation quitlines: an underrecognized 
intervention success story. The American psychologist, 2010. 65(4): p. 252-61. 
49. 
Stead, L.F., R. Perera, and T. Lancaster, Telephone counselling for smoking cessation. Cochrane 
database of systematic reviews, 2006(3): p. CD002850. 
50. 
Stead, L.F., R. Perera, and T. Lancaster, A systematic review of interventions for smokers who 
contact quitlines. Tob Control, 2007. 16 Suppl 1: p. i3-8. 
51. 
Saccone, S.F., et al., Cholinergic nicotinic receptor genes implicated in a nicotine dependence 
association study targeting 348 candidate genes with 3713 SNPs. Human Molecular Genetics, 
2007. 16(1): p. 36-49. 
52. 
Thorgeirsson, T.E., et al., A variant associated with nicotine dependence, lung cancer and 
peripheral arterial disease. Nature, 2008. 452(7187): p. 638-42. 
53. 
Amos, C.I., et al., Genome-wide association scan of tag SNPs identifies a susceptibility locus for 
lung cancer at 15q25.1. Nature Genetics, 2008. 40(5): p. 616-22. 
54. 
Pillai, S.G., et al., A genome-wide association study in chronic obstructive pulmonary disease 
(COPD): identification of two major susceptibility loci. PLoS genetics, 2009. 5(3): p. e1000421. 
55. 
Thorgeirsson, T.E., et al., Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking 
behavior. Nature Genetics, 2010. 42(5): p. 448-53. 
56. 
Liu, J.Z., et al., Meta-analysis and imputation refines the association of 15q25 with smoking 
quantity. Nature Genetics, 2010. 42(5): p. 436-40. 
57. 
Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nature 
Genetics, 2010. 42(5): p. 441-7. 
58. 
Yamazaki, H., et al., Roles of CYP2A6 and CYP2B6 in nicotine C-oxidation by human liver 
microsomes. Archives of Toxicology, 1999. 73(2): p. 65-70. 


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59. 
Su, T., et al., Human cytochrome P450 CYP2A13: predominant expression in the respiratory tract 
and its high efficiency metabolic activation of a tobacco-specific carcinogen, 4-
(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Cancer Research, 2000. 60(18): p. 5074-9. 
60. 
Malaiyandi, V., et al., CYP2A6 genotype, phenotype, and the use of nicotine metabolites as 
biomarkers during ad libitum smoking. Cancer Epidemiol Biomarkers Prev, 2006. 15(10): p. 1812-
9. 
61. 
Audrain-McGovern, J., et al., The role of CYP2A6 in the emergence of nicotine dependence in 
adolescents. Pediatrics, 2007. 119(1): p. e264-74. 
62. 
Bloom, A.J., et al., Use of a predictive model derived from in vivo endophenotype measurements 
to demonstrate associations with a complex locus, CYP2A6. Human Molecular Genetics, 2012. 
21(13): p. 3050-62. 
63. 
Fujieda, M., et al., Evaluation of CYP2A6 genetic polymorphisms as determinants of smoking 
behavior and tobacco-related lung cancer risk in male Japanese smokers. Carcinogenesis, 2004. 
25(12): p. 2451-8. 
64. 
Schoedel, K.A., et al., Ethnic variation in CYP2A6 and association of genetically slow nicotine 
metabolism and smoking in adult Caucasians. Pharmacogenetics, 2004. 14(9): p. 615-26. 
65. 
Lerman, C., et al., Genetic variation in nicotine metabolism predicts the efficacy of extended-
duration transdermal nicotine therapy. Clinical Pharmacology and Therapeutics, 2010. 87(5): p. 
553-7. 
66. 
Patterson, F., et al., Toward personalized therapy for smoking cessation: a randomized placebo-
controlled trial of bupropion. Clinical Pharmacology and Therapeutics, 2008. 84(3): p. 320-5. 
67. 
Schnoll, R.A., et al., Nicotine metabolic rate predicts successful smoking cessation with 
transdermal nicotine: a validation study. Pharmacol Biochem Behav, 2009. 92(1): p. 6-11. 
68. 
Breitling, L.P., et al., Prospective association of dopamine-related polymorphisms with smoking 
cessation in general care. Pharmacogenomics, 2010. 11(4): p. 527-36. 
69. 
Bousman, C.A., et al., Alpha-5 and -3 nicotinic receptor gene variants predict nicotine dependence 
but not cessation: findings from the COMMIT cohort. American journal of medical genetics. Part 
B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric 
Genetics, 2012. 159B(2): p. 227-35. 
70. 
Chen, L.S., et al., Interplay of genetic risk factors (CHRNA5-CHRNA3-CHRNB4) and cessation 
treatments in smoking cessation success. Am J Psychiatry, 2012. 169(7): p. 735-42. 
71. 
Centers for Disease Control and Prevention, Vital signs: current cigarette smoking among adults 
aged >/=18 years--United States, 2005-2010. MMWR. Morbidity and Mortality Weekly Report, 
2011. 60(35): p. 1207-12. 
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Peto R., et al. Mortality from smoking in developed countries 1950-2000, second edition. [Web 
Site] 2006 June 2006 10 February 2012]; Available from: http://www.deathsfromsmoking.net. 
73. 
McGinness, J. and W. Foege, Actual causes of death in the United States. Journal of the American 
Medical Association, 1993. 270: p. 2207-2212. 
74. 
Martin, T. Cancer Statistics:  Smoking and Cancer - Statitstics for the U.S. About.com 10 August 
2005 
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75. 
Peto, R., Smoking and death: the past 40 years and the next 40. BMJ, 1994. 309(6959): p. 937-9. 
76. 
CDC. Best Practices for Comprehensive Tobacco Control Programs:  III.  Cessation Interventions.  
17 
December 
2014]; 
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from: 
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77. 
Biener, L. and D.B. Abrams, The Contemplation Ladder: validation of a measure of readiness to 
consider smoking cessation. Health Psychol, 1991. 10(5): p. 360-5. 
78. 
Shah, L.M., et al., Effect of clinician advice and patient preparedness to quit on subsequent quit 
attempts in hospitalized smokers. Journal of hospital medicine : an official publication of the 
Society of Hospital Medicine, 2010. 5(1): p. 26-32. 
79. 
Unrod, M., et al., Smoking behavior and motivation to quit among chronic pain patients initiating 
multidisciplinary pain treatment: a prospective study. Pain medicine, 2014. 15(8): p. 1294-303. 
80. 
Etter, J.F., et al., Development and validation of a scale measuring self-efficacy of current and 
former smokers. Addiction, 2000. 95(6): p. 901-13. 
81. 
Heatherton, T.F., et al., The Fagerström Test for Nicotine Dependence: a revision of the 
Fagerström Tolerance Questionnaire. British Journal of Addiction, 1991. 86(9): p. 1119-27. 
82. 
Kroenke, K., R.L. Spitzer, and J.B. Williams, The PHQ-9: validity of a brief depression severity 
measure. Journal of General Internal Medicine, 2001. 16(9): p. 606-13. 
83. 
Buchanan, D., et al., Quality-of-life assessment in the symptom management trials of the National 
Cancer Institute-supported Community Clinical Oncology Program. Journal of Clinical Oncology, 
2005. 23(3): p. 591-598. 
84. 
Locke, D.E., et al., Validation of single-item linear analog scale assessment of quality of life in 
neuro-oncology patients. Journal of Pain and Symptom Management, 2007. 34(6): p. 628-38. 
85. 
Sloan, J., et al., Validation of and normative data for simple single-item numerical analogue self-
assessments for quality of life J. Pain Symptom Mgmt, 2014(submitted). 
86. 
Singh, J.A., et al., Normative data and clinically significant effect sizes for single-item numerical 
linear analogue self-assessment (LASA) scales. Health and quality of life outcomes, 2014. 12(1): 
p. 187. 
87. 
Chauhan, C. and P.J. Atherton, Patient satisfaction with participation in phase II/III NCCTG 
clinical trials: Was it worth it? (N0392). . J Clin Oncology, 2012a. 30(15_Supplement): p. 6133. 
88. 
Hughes, J.R., et al., Measures of abstinence in clinical trials: issues and recommendations. 
Nicotine Tob Res, 2003. 5(1): p. 13-25. 
89. 
Velicer, W.F., et al., Assessing outcome in smoking cessation studies. Psychological Bulletin, 1992. 
111(1): p. 23-41. 
90. 
Turan, A., et al., Smoking and perioperative outcomes. Anesthesiology, 2011. 114(4): p. 837-46. 
91. 
Borja-Cacho, D., et al., Assessment of ACS NSQIP's predictive ability for adverse events after 
major cancer surgery. Annals of Surgical Oncology, 2010. 17(9): p. 2274-82. 
92. 
Freidlin, B., E.L. Korn, and S.L. George, Data Monitoring Committees and Interim Monitorying 
Guidelines. Controlled Clinical Trials, 1999. 20: p. 395-407. 
93. 
SRNT Subcommittee on Biochemical Verification, Biochemical verification of tobacco use and 
cessation. Nicotine & Tobacco Research, 2002. 4(2): p. 149-59. 
94. 
Jatlow, P., et al., Comparison of expired carbon monoxide and plasma cotinine as markers of 
cigarette abstinence. Drug and Alcohol Dependence, 2008. 98(3): p. 203-9. 
95. 
Cooke, F., et al., Diagnostic accuracy of NicAlert cotinine test strips in saliva for verifying smoking 
status. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and 
Tobacco, 2008. 10(4): p. 607-12. 
96. 
Cotinine Elisa Test: summary and explanation. 2013 18 December 2014]; Available from: 
http://www.calbiotech.com/products/elisa-kits/human-elisa-kits/drugs-of-abuse-elisa-
kits/cotinine-elisa-detail. 


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97. 
Morales, N.A., et al., Accuracy of self-reported tobacco use in newly diagnosed cancer patients. 
Cancer causes & control : CCC, 2013. 24(6): p. 1223-30. 
98. 
Warren, G.W., et al., Accuracy of self-reported tobacco assessments in a head and neck cancer 
treatment population. Radiotherapy and oncology : journal of the European Society for Therapeutic 
Radiology and Oncology, 2012. 103(1): p. 45-8. 
99. 
Tonstad S, Davies S, Flammer M, Russ C, Hughes J. Psychiatric adverse events in randomized, 
double-blind, placebo-controlled clinical trials of varenicline: a pooled analysis. Drug Saf. Apr 1 
2010;33(4):289-301. 
100. 
Park ER, Japuntich S, Temel J, et al. A smoking cessation intervention for thoracic surgery and 
oncology clinics: a pilot trial. J Thorac Oncol. Jun 2011;6(6):1059-1065. 
101. 
Wong J, Abrishami A, Yang Y, et al. A perioperative smoking cessation intervention with 
varenicline: a double-blind, randomized, placebo-controlled trial. Anesthesiology. Oct 
2012;117(4):755-764. 
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Nayan S, Gupta MK, Strychowsky JE, Sommer DD. Smoking cessation interventions and cessation 
rates in the oncology population: an updated systematic review and meta-analysis. Otolaryngology-
-head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck 
Surgery. Aug 2013;149(2):200-211. 
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Carson KV, Smith BJ, Brinn MP, et al. Safety of varenicline tartrate and counseling versus 
counseling alone for smoking cessation: a randomized controlled trial for inpatients (STOP study). 
Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco. 
Nov 2014;16(11):1495-1502 
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Thomas KH, Martin RM, Knipe DW, Higgins JP, Gunnell D. Risk of neuropsychiatric adverse 
events associated with varenicline: systematic review and meta-analysis. BMJ. 2015;350:h1109. 
105 
Kotz D, Viechtbauer W, Simpson C, van Schayck OC, West R, Sheikh A. Cardiovascular and 
neuropsychiatric risks of varenicline: a retrospective cohort study. Lancet Respir Med. Oct 
2015;3(10):761-768. 
 
 
 
 


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17.0 MODEL CONSENT FORM 
Study Title for Study Participants: 
Smoking Cessation Prior to Surgery to Reduce Surgical Complications 
 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov: 
Reducing Surgical Complications in Newly Diagnosed Lung Cancer Patients 
Who Smoke Cigarettes 
 
This study is conducted by the Alliance for Clinical Trials in Oncology, a national clinical 
research group supported by the National Cancer Institute. The Alliance is made up of cancer 
doctors, health professionals, and laboratory researchers, whose goal is to develop better 
treatments for cancer, to prevent cancer, to reduce side effects from cancer, and to improve the 
quality of life of cancer patients. 
 
 
What is the usual approach to quitting smoking before having lung cancer 
surgery?  
You are being asked to take part in this research study because you are a smoker who is 
scheduled to have surgery for your lung cancer. Many surgeons encourage patients to stop 
smoking before surgery in order to reduce the chance of having medical complications after the 
surgery.   
 
 
What are my other choices if I do not take part in this study? 
There are many way to stop smoking.  You do not have to be in this study to receive treatment 
for smoking cessation.  You may attempt other methods to quit smoking in addition to the 
methods used in this study.  Your other choices may include: 
• Nicotine replacement (for example, nicotine patches, gums, lozenges, nicotine nasal 
spray, or nicotine inhalers) 
• Taking varenicline not on this study 
• Taking a drug called bupropion 
You should talk to your doctor about each of your choices before you decide if you will take part 
in this study. 
 
 
 
 




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You should take varenicline with at least 8 ounces of water and after eating a meal. 
 
Days 1-3 
Days 4-7 
Weeks 2-12 
1 tablet 
Any time of day 
1 tablet in the Morning and  
1 tablet in the Evening 
2 tablets in the Morning and  
2 tablets in the Evening 
 
 
How long will I be in this study? 
You will take varenicline/placebo plus have access to the quitline for 12 weeks. You will be in 
this study until 24 weeks after your surgery. You will continue to have access to the NCI 
Tobacco Quitline after you have finished your participation in this study. 
 
 
What extra tests and procedures will I have if I take part in this study? 
Most of the exams, tests, and procedures you will have are part of the usual approach for your 
cancer. However, there are some extra tests and procedures that you will need to have if you take 
part in this study. 
 
Before you begin the study: 
You will need to have the following extra to find out if you can be in the study: 
• 
Physical exam and medical history 
• 
Vitals (height, weight, blood pressure and pulse) 
• 
Blood test to measure kidney function, if you have not had one recently 
• 
You will be asked to complete a short questionnaire about your motivation to quit 
smoking 
• 
If you are a female of child bearing potential, you will be asked to have a pregnancy test. 
 
On the first day of the study (“Baseline Visit”): 
On the first day of the study, you will meet with your surgeon or member of the surgical team to 
discuss quitting smoking and to learn about the NCI Tobacco Quitline.  
You will be asked to set a target quit date to quit smoking. You should start taking 
varenicline/placebo one week before the target quit date that you set. Your surgery will be 
scheduled to take place after that quit date, and must be at least ten days and no more than 12 
weeks after the visit with your surgeon.  
You will also be asked to complete questionnaires about your tobacco use history, your ability to 
stay smoke free, your mood/depression level and your quality of life. This should take about 10 to 
15 minutes to complete. 
On the day of your surgery:  You will be asked to complete a brief (3 minutes) questionnaire 
about your tobacco use and provide a sample of your saliva to measure amount of cotinine in 
your body. Cotinine is produced by nicotine, which is found in tobacco. 
 
6 weeks after your surgery: You will be asked to come to the clinic for a doctor’s visit to see how 
you are doing physically and with your tobacco cessation efforts. You will be asked to complete 


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questionnaires at this visit. These should take about 15 minutes to complete. Finally, you will be 
asked to provide some of your saliva to measure the amount of cotinine in your body. 
 
12 and 18 weeks after your surgery: You will be asked to complete a questionnaire either by 
telephone or in person to see how you are doing physically (week 12 only) and with your 
tobacco cessation efforts (on both weeks 12 and 18). You will be asked to come to the clinic (not 
a doctor’s visit) to provide some of your saliva to measure the amount of cotinine in your body.  
 
24 weeks after your surgery:  You will be asked to come to the clinic for a doctor’s visit to see 
how you are doing physically and with your tobacco cessation efforts. You will be asked to 
complete questionnaires at this visit and to provide some of your saliva to measure the amount of 
cotinine in your body. 
 
The following table summarizes your visit schedule for this study: 
 
 
Before Surgery 
Day of 
Surgery 
Weeks after surgery 
 
Before 
randomiza
tion 
On the day of 
the Baseline 
Visit 
 
6* 
12*  
18* 
24* 
Visit # 
1 
2 
 
3 
4** 
5** 
6 
Pregnancy test 
X*** 
 
 
 
 
 
 
History & physical  
X 
X 
 
X 
 
 
X 
Saliva measurement 
 
X 
X 
X 
X 
X 
X 
Monitoring 
 
 
 
X 
X 
X 
X 
Tobacco use 
questionnaire 
X 
X 
X 
X 
X 
X 
X 
Other questionnaires 
X 
X 
 
X 
X 
 
X 
Drug diary 
 
X 
 
X 
X 
 
 
 
* 
These visits may be up to 2 weeks before or after the scheduled day of the visit on the calendar. 
** 
You will be asked to come to the clinic to provide saliva samples for cotinine measurement.  A 
doctor visit is not required and the questionnaires may be completed either in the clinic or by 
telephone. 
*** 
If you are a female of child bearing potential. 
 
 
 
 


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What possible risks can I expect from taking part in this study? 
If you choose to take part in this study, there is a risk that: 
• 
You may be asked sensitive or private questions which you normally do not discuss 
  
Here are important points about side effects: 
• 
The study doctors do not know who will or will not have side effects. 
• 
Some side effects may go away soon, some may last a long time, or some may never go 
away. 
• 
Some side effects may interfere with your ability to have children. 
• 
Some side effects may be serious and may even result in death. 
 
Here are important points about how you and the study doctor can make side effects less of a 
problem: 
• 
Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 
• 
The study doctor may be able to treat some side effects. 
• 
The study doctor may adjust the study drugs to try to reduce side effects. 
 
The tables below show the most common and the most serious side effects that researchers know 
about. There might be other side effects that researchers do not yet know about. If important new 
side effects are found, the study doctor will discuss these with you. 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving varenicline, more than 20 and up to 100 may have: 
• 
Nausea  
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving varenicline, from 4 to 20 may have: 
• 
Trouble getting to sleep or staying asleep (insomnia) 
• 
Having vivid, unusual, or strange dreams, nightmares 
• 
Headache 
• 
Constipation 
• 
Stomach pain, swelling, belching, passing gas 
• 
Vomiting 
• 
Upper respiratory problems such as bronchitis, coughing, sinus congestion 
• 
Dry mouth 
• 
Anxiety 
• 
Depression 
• 
New or worse heart or blood vessel (cardiovascular) problems 
 


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RARE, AND SERIOUS 
In 100 people receiving varenicline, 3 or fewer may have: 
• 
Nervousness, agitation, anger, suicidal or thoughts of hurting someone else—If you, 
your family, or your caregivers notice agitation, hostility, depression, suicidal 
thoughts or changes in your behavior or thinking that are not typical for you, you 
should call your doctor right away. 
• 
Sleepwalking—If you or your family notice that this has happened you should call 
your doctor. 
• 
Heart attack 
• 
Stroke 
• 
Severe allergic reaction 
• 
Very bad skin reaction (Stevens-Johnson syndrome – red, swollen, blistered or 
peeling skin with or without fever) 
• 
Seizures–(this is most likely to occur in first month of treatment) 
 
Alcohol consumption: You should decrease the amount of alcoholic beverages that you drink during 
treatment with varenicline until you know if the drug affects your ability to tolerate alcohol. 
 
You should use caution when driving or operating machinery until you know how varenicline affects 
you. Varenicline may make you fell sleepy, dizzy, or have trouble concentrating, making it hard to drive 
or perform other activities safely.  
 
If you successfully stop smoking, you may experience nicotine withdrawal.  Effects of nicotine 
withdrawal include:  
• 
Feeling angry, irritable, anxious,  
• 
Having difficulty concentrating, sleep problems (insomnia or abnormal dreams) 
• 
Feeling agitated or depressed, sometimes with thoughts of suicide. 
 
The topics discussed in interviews or in questionnaires may cause you to feel embarrassed or 
uncomfortable. If this happens to you, please let your study doctor, nurse or other study staff 
know about your discomfort. 
 
Let your study doctor know of any questions you have about possible side effects. You can ask 
the study doctor questions about side effects at any time. 
 
Reproductive risks: You should not get pregnant, breastfeed, or father a baby while in this 
study. The varenicline used in this study could be damaging to an unborn baby. Check with the 
study doctor about what types of birth control, or pregnancy prevention, to use while in this 
study. 
 
 
What possible benefits can I expect from taking part in this study? 
The usual approach to performing surgery on people who smoke is to recommend that they quit 
prior to surgery.  Quitting smoking has been shown to decrease surgical complications in other 
types of surgery. Although it is not possible to know if participation in this study will result in 
less surgical complications, it may help you quit smoking. Quitting smoking at any time has 


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numerous health benefits.  This study will also help researchers learn things that will help people 
in the future with lung cancer who smoke or quit smoking. 
 
Can I stop taking part in this study? 
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let 
the study doctor know as soon as possible so you can stop safely. If you stop, you can decide 
whether or not to let the study doctor continue to provide your medical information to the 
organization running the study. 
 
The study doctor will tell you about new information or changes in the study that may affect 
your health or your willingness to continue in the study. 
 
The study doctor may take you out of the study: 
• If your health changes and the study is no longer in your best interest 
• If new information becomes available 
• If you do not follow the study rules 
• If the study is stopped by the sponsor, IRB or FDA. 
 
 
What are my rights in this study? 
Taking part in this study is your choice. No matter what decision you make, and even if your 
decision changes, there will be no penalty to you. You will not lose medical care or any legal 
rights. 
 
For questions about your rights while in this study, call the ________________________ (insert 
name of center) Institutional Review Board at __________________ (insert telephone number). 
(Note to Local Investigator: Contact information for patient representatives or other individuals 
at a local institution who are not on the IRB or research team but take calls regarding clinical 
trial questions can also be listed here.) 
 
 
What are the costs of taking part in this study? 
Varenicline/placebo will be supplied at no charge while you take part in this study. The cost of 
getting varenicline/placebo ready and giving it to you is not paid by the study, so you or your 
insurance company may have to pay for this.. It is possible that the varenicline/placebo may not 
continue to be supplied while you are on the study. Although not likely, if this occurs, your study 
doctor will talk to you about your options. 
 
You and/or your health plan/insurance company will need to pay for all of the other costs of 
treating your cancer while in this study, including the cost of tests, procedures, or medicines to 
manage any side effects, unless you are told that certain tests are supplied at no charge. Before 
you decide to be in the study, you should check with your health plan or insurance company to 
find out exactly what they will pay for. 
 


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You will not be paid for taking part in this study. 
 
 
What happens if I am injured or hurt because I took part in this study? 
If you are injured or hurt as a result of taking part in this study and need medical treatment, 
please tell your study doctor. The study sponsors will not offer to pay for medical treatment for 
injury. Your insurance company may not be willing to pay for study-related injury. If you have 
no insurance, you would be responsible for any costs. 
 
If you feel this injury was a result of medical error, you keep all your legal rights to receive 
payment for this even though you are in a study. 
 
 
Who will see my medical information? 
Your privacy is very important to us and the researchers will make every effort to protect it. 
Your information may be given out if required by law. For example, certain states require 
doctors to report to health boards if they find a disease like tuberculosis. However, the 
researchers will do their best to make sure that any information that is released will not identify 
you. Some of your health information, and/or information about your specimen, from this study 
will be kept in a central database for research. Your name or contact information will not be put 
in the database. 
 
There are organizations that may inspect your records. These organizations are required to make 
sure your information is kept private, unless required by law to provide information. Some of 
these organizations are: 
• The Alliance for Clinical Trials in Oncology 
• Pfizer™, the pharmaceutical company supplying varenicline/placebo 
• The Institutional Review Board, IRB, is a group of people who review the research with 
the goal of protecting the people who take part in the study. 
• The Food and Drug Administration and the National Cancer Institute in the U.S., and 
similar ones if other countries are involved in the study. 
 
The Alliance has received a Certificate of Confidentiality from the federal government, which 
will help us to protect your privacy. The Certificate protects against the involuntary release of 
information about you collected during the course of the study. The researchers involved in this 
project may not be forced to identify you in any legal proceedings (criminal, civil, 
administrative, or legislative) at the federal, state or local level. However, some information may 
be required by the Federal Food, Drug, and Cosmetic Act, the U.S. Department of Health and 
Human Services, or for purposes of program review or audit. Also, you may choose to 
voluntarily disclose the protected information under certain circumstances. For example, if you 
or your guardian requests the release of information about you in writing (through, for example, 
a written request to release medical records to an insurance company), the Certificate does not 
protect against that voluntary disclosure. 
 
 


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Where can I get more information? 
You may visit the NCI Web site at http://cancer.gov/ for more information about studies or 
general information about cancer. You may also call the NCI Cancer Information Service to get 
the same information at: 1-800-4-CANCER (1-800-422-6237). 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 
 
Who can answer my questions about this study? 
You can talk to the study doctor about any questions or concerns you have about this study or to 
report side effects or injuries. Contact the study doctor __________________ (insert name of 
study doctor[s]) at __________________ (insert telephone number). 
 
 
 
 


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ADDITIONAL STUDIES SECTION: 
This section is about optional studies you can choose to take part in 
This part of the consent form is about optional studies that you can choose to take part in. You 
will not get health benefits from any of these studies. The researchers leading this optional study 
hope the results will help other people with cancer in the future. 
 
The results will not be added to your medical records and you or your study doctor will not know 
the results. 
 
You will not be billed for these optional studies. You can still take part in the main study even if 
you say “no” to any or all of these studies. If you sign up for but cannot complete any of the 
studies for any reason, you can still take part in the main study. 
 
Circle your choice of “yes” or “no” for each of the following studies. 
 
Optional Sample Collections for Laboratory Studies and Biobanking for 
Possible Future Studies 
Researchers are trying to learn more about cancer, diabetes, and other health problems. Much of 
this research is done using samples from your tissue, blood, urine, or other fluids. Through these 
studies, researchers hope to find new ways to prevent, detect, treat, or cure health problems. 
 
Some of these studies may be about genes. Genes carry information about features that are found 
in you and in people who are related to you. Researchers are interested in the way that genes 
affect how your body responds to treatment. 
 
If you choose to take part in this study, the study doctor for the main study would like to collect 
blood for research on determining who will react better to the intervention in helping them stop 
smoking. 
 
In addition, the researchers ask your permission to store and use your samples and related health 
information (for example, your response to cancer treatment, results of study tests and medicines 
you are given) for medical research. The additional research that may be done is unknown at this 
time. Storing samples for future studies is called “biobanking”. The Biobank is being run by the 
Alliance and supported by the National Cancer Institute. 
 
WHAT IS INVOLVED? 
If you agree to take part, here is what will happen next: 
1) About 2 tablespoons of blood will be collected from a vein in your arm at the baseline 
visit.  
2) Your baseline blood sample and some related health information will be sent to a 
researcher for use in the study described above. Remaining baseline blood samples may 
be stored in the Biobank, along with samples from other people who take part. The 
samples will be kept until they are used up. 


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3) Qualified researchers can submit a request to use the materials stored in the Biobanks. A 
science committee at the Alliance, and/or the National Cancer Institute, will review each 
request. There will also be an ethics review to ensure that the request is necessary and 
proper. Researchers will not be given your name or any other information that could 
directly identify you.  
4) Neither you nor your study doctor will be notified when research will be conducted or 
given reports or other information about any research that is done using your baseline 
blood samples.  
5) Some of your genetic and health information may be placed in central databases that may 
be public, along with information from many other people. Information that could 
directly identify you will not be included. 
 
WHAT ARE THE POSSIBLE RISKS? 
1) The most common risks related to drawing blood from your arm are brief pain and 
possibly a bruise.  
2) There is a risk that someone could get access to the personal information in your medical 
records or other information researchers have stored about you. 
3) There is a risk that someone could trace the information in a central database back to you. 
Even without your name or other identifiers, your genetic information is unique to you. 
The researchers believe the chance that someone will identify you is very small, but the 
risk may change in the future as people come up with new ways of tracing information. 
4) In some cases, this information could be used to make it harder for you to get or keep a 
job or insurance. There are laws against the misuse of genetic information, but they may 
not give full protection. There can also be a risk in knowing genetic information. New 
health information about inherited traits that might affect you or your blood relatives 
could be found during a study. The researchers believe the chance these things will 
happen is very small, but cannot promise that they will not occur. 
 
 
HOW WILL INFORMATION ABOUT ME BE KEPT PRIVATE? 
Your privacy is very important to the researchers and they will make every effort to protect it. 
Here are just a few of the steps they will take: 
1) When your samples are sent to the researchers, no information identifying you (such as 
your name) will be sent. Samples will be identified by a unique code only. 
2) The list that links the unique code to your name will be kept separate from your sample 
and health information. Any Biobank and Alliance staff with access to the list must sign 
an agreement to keep your identity confidential. 
3) Researchers to whom the Alliance sends your sample and information will not know who 
you are. They must also sign an agreement that they will not try to find out who you are. 
4) Information that identifies you will not be given to anyone, unless required by law. 
5) If research results are published, your name and other personal information will not be 
used. 
 
 


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WHAT ARE THE POSSIBLE BENEFITS? 
You will not benefit from taking part. The researchers, using the samples from you and others, 
might make discoveries that could help people in the future. 
 
 
ARE THERE ANY COSTS OR PAYMENTS? 
There are no costs to you or your insurance. You will not be paid for taking part. If any of the 
research leads to new tests, drugs, or other commercial products, you will not share in any 
profits. 
 
 
WHAT IF I CHANGE MY MIND? 
If you decide you no longer want your samples to be used, you can call the study doctor, 
_________________, (insert name of study doctor for main trial) at 
________________________ (insert telephone number of study doctor for main trial) who will 
let the researchers know. Then, any sample that remains in the bank will no longer be used and 
related health information will no longer be collected. Samples or related information that have 
already been given to or used by researchers will not be returned. 
 
 
WHAT IF I HAVE MORE QUESTIONS? 
If you have questions about the use of your samples for research, contact the study doctor, 
________________, (insert name of study doctor for main trial), at _____________________ 
(insert telephone number of study doctor for main trial). 
 
Please circle your answer to show whether or not you would like to take part in each option: 
 
SAMPLES FOR THE LABORATORY STUDIES: 
1. 
I agree to have my specimen collected and I agree that my specimen samples and related 
information may be used for the laboratory study described above. 
 
 
YES 
 
NO 
 
SAMPLES FOR FUTURE RESEARCH STUDIES: 
2. 
My samples and related information may be kept in a Biobank for use in future health 
research. 
 
 
YES 
 
NO 
 
3. 
I agree that my study doctor, or their representative, may contact me or my physician to 
see if I wish to participate in other research in the future. 
 
 
YES 
 
NO 
 
This is the end of the section about optional studies. 
 


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My Signature Agreeing to Take Part in the Main Study 
I have read this consent form or had it read to me. I have discussed it with the study doctor and 
my questions have been answered. I will be given a signed copy of this form. I agree to take part 
in the main study and any additional studies where I circled ‘yes’.  
 
Participant’s signature________________________________ 
 
Date of signature_____________________________________ 
 
 
 
Signature of person(s) conducting the informed consent 
discussion___________________________________ 
 
Date of signature_____________________________________ 
 
 
 
 
 


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APPENDIX I: SURGICAL COMPLICATIONS ASSOCIATED WITH CIGARETTE SMOKING [104] 
30-day mortality 
30-day re-hospitalization 
1-year mortality 
Anastomotic failure 
Anesthesia-related respiratory 
complications 
Bleeding (transfusions >5 U) 
Coma (>24 hours)  
Deep venous thrombosis/thrombophlebitis 
Failure to wean from the ventilator 
ICU readmission 
Impaired bone healing 
Implant loss (breast reconstruction) 
Increased postoperative pain 
Renal insufficiency/failure 
Return to operating room 
Sepsis/septic shock 
Stroke/cerebral accident 
Surgical infection (organ space) 
Surgical site infections 
Urinary tract infections 
Increased postoperative surgical stay 
Increased scarring and asymmetry 
Intubation (unplanned)/re-intubation 
Lower rates of successful digital replantation 
(microsurgery) 
Myocardial infarction 
Pneumonia 
Prolonged intubation 
Prolonged ventilator support 
Pulmonary complications 
Pulmonary embolism 
Reduced skin flap survival 
Vascular complications 
Vein graft failure 
Venous thromboembolism 
Ventilator (>48 hours) 
Wound healing (delayed) 
Wound infection (sternal) 
Wound infections (superficial and deep) 
 
 


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APPENDIX II:  PATIENT INFORMATION SHEETS 
 
Patient Information Sheet 
(Prior to registration) 
 
You have been given a booklet to complete for this study.  The booklet contains some 
questions about your ‘quality of life’ as a patient receiving treatment for cancer.  Your 
answers will help us to better understand how the treatment you are receiving is affecting 
the way you feel. 
 
 
1. This booklet contains: 
a. Tobacco Use Assessment 
b. Contemplation Ladder 
c. Patient Health Questionnaire PHQ-9 
 
2. Directions on how to complete each set of questions are written on the top of each set. 
 
3. You will be given the nurse’s name and telephone number.  You can call any time 
with any concerns or questions. 
 
4. It is very important that you return the booklet to us, whether you finish the study or 
not. 
 
 
 
 
Thank you for taking the time to help us. 
 
 


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Patient Information Sheet 
(Baseline) 
 
You have been given a booklet to complete for this study.  The booklet contains some 
questions about your ‘quality of life’ as a patient receiving treatment for cancer.  Your 
answers will help us to better understand how the treatment you are receiving is affecting 
the way you feel. 
 
 
1. This booklet contains: 
a. Tobacco Use Assessment 
b. Smoking Self Efficacy Questionnaire (SEQ-12) 
c. Fagerström Test for Nicotine Dependence (FTND) 
d. Linear Analogue Self-Assessment (LASA-12) 
 
2. Directions on how to complete each set of questions are written on the top of each set. 
 
3. You will be given the nurse’s name and telephone number.  You can call any time 
with any concerns or questions. 
 
4. It is very important that you return the booklet to us, whether you finish the study or 
not. 
 
 
 
 
 
Thank you for taking the time to help us. 
 
 


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Patient Information Sheet 
(Day of surgery) 
 
You have been given a booklet to complete for this study.  The booklet contains some 
questions about your ‘quality of life’ as a patient receiving treatment for cancer.  Your 
answers will help us to better understand how the treatment you are receiving is affecting 
the way you feel. 
 
 
1. This booklet contains the Tobacco Use Assessment. 
 
2. Directions on how to complete each set of questions are written on the top of each set. 
 
3. You will be given the nurse’s name and telephone number.  You can call any time 
with any concerns or questions. 
 
4. It is very important that you return the booklet to us, whether you finish the study or 
not. 
 
 
 
 
 
Thank you for taking the time to help us. 
 
 


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Patient Information Sheet 
(Week 6) 
 
You have been given a booklet to complete for this study.  The booklet contains some 
questions about your ‘quality of life’ as a patient receiving treatment for cancer.  Your 
answers will help us to better understand how the treatment you are receiving is affecting 
the way you feel. 
 
 
1. This booklet contains: 
a. Tobacco Use Assessment 
b. Contemplation Ladder 
c. Smoking Self Efficacy Questionnaire (SEQ12) 
d. Patient Health Questionnaire (PHQ-9) 
 
2. Directions on how to complete each set of questions are written on the top of each set. 
 
3. You will be given the nurse’s name and telephone number.  You can call any time 
with any concerns or questions. 
 
4. It is very important that you return the booklet to us, whether you finish the study or 
not. 
 
 
 
 
 
Thank you for taking the time to help us. 
 
 


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Patient Information Sheet 
(Week 12) 
 
You have been given a booklet to complete for this study.  The booklet contains some 
questions about your ‘quality of life’ as a patient receiving treatment for cancer.  Your 
answers will help us to better understand how the treatment you are receiving is affecting 
the way you feel. 
 
 
1. This booklet contains: 
a. Tobacco Use Assessment 
b. Contemplation Ladder 
c. Smoking Self Efficacy Questionnaire (SEQ12) 
d. Patient Health Questionnaire (PHQ-9) 
e. Linear Analogue Self-Assessment (LASA) 
f. Was It Worth It (WIWI) 
 
2. Directions on how to complete each set of questions are written on the top of each set. 
 
3. You will be given the nurse’s name and telephone number.  You can call any time 
with any concerns or questions. 
 
4. It is very important that you return the booklet to us, whether you finish the study or 
not. 
 
5. You will be asked to either complete the questionnaires by telephone or to bring the 
booklet with you to your next clinical visit. 
 
 
 
Thank you for taking the time to help us. 
 
 


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Patient Information Sheet 
(Week 18) 
 
You have been given a booklet to complete for this study.  The booklet contains some 
questions about your ‘quality of life’ as a patient receiving treatment for cancer.  Your 
answers will help us to better understand how the treatment you are receiving is affecting 
the way you feel. 
 
 
1. This booklet contains the Tobacco Use Assessment. 
 
2. Directions on how to complete each set of questions are written on the top of each set. 
 
3. You will be given the nurse’s name and telephone number.  You can call any time 
with any concerns or questions. 
 
4. It is very important that you return the booklet to us, whether you finish the study or 
not. 
 
5. You will be asked to either complete the questionnaires by telephone or to bring the 
booklet with you to your next clinical visit.. 
 
 
 
Thank you for taking the time to help us. 
 
 


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Patient Information Sheet 
(Week 24) 
 
You have been given a booklet to complete for this study.  The booklet contains some 
questions about your ‘quality of life’ as a patient receiving treatment for cancer.  Your 
answers will help us to better understand how the treatment you are receiving is affecting 
the way you feel. 
 
 
1. This booklet contains: 
a. Tobacco Use Assessment 
b. Contemplation Ladder 
c. Smoking Self Efficacy Questionnaire (SEQ12) 
d. Patient Health Questionnaire (PHQ-9) 
e. Linear Analogue Self-Assessment (LASA) 
f. Was It Worth It (WIWI) 
 
2. Directions on how to complete each set of questions are written on the top of each set. 
 
3. You will be given the nurse’s name and telephone number.  You can call any time 
with any concerns or questions. 
 
4. It is very important that you return the booklet to us, whether you finish the study or 
not. 
 
 
 
 
 
Thank you for taking the time to help us. 
 
 
 


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APPENDIX III: CONTEMPLATION LADDER 
 
 
Directions:  Please complete the following concerning you readiness to quit smoking. 
 
Each number below represents where various tobacco-users are in their thinking about quitting. Circle the 
number that indicates where you are now. 
  
 
 
10 
I am ready to quit now. 
 
9 
 
 
8 
I have cut down or am seriously thinking of 
quitting. 
 
7 
 
 
6 
I am thinking about cutting down or quitting. 
 
5 
 
 
4 
I think I should quit but I’m not quite ready. 
 
3 
 
 
2 
I think I need to consider quitting some day. 
 
1 
 
 
0 
I am not ready to quit. 
 
 
 
 


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APPENDIX IV: SMOKING SELF EFFICACY QUESTIONNAIRE (SEQ12) 
 
The following are some situations in which certain people might be tempted to smoke. 
 
Directions:  Please indicate whether you are sure that you could refrain from smoking in each situation by 
placing an “X” in the appropriate box. 
 
1.  When I feel nervous (check one) 
 
Not at all sure     
Not very sure     
More or less sure     
Fairly sure     
Absolutely sure 
 
2.  When I feel depressed (check one) 
 
Not at all sure     
Not very sure     
More or less sure     
Fairly sure     
Absolutely sure 
 
3.  When I am angry (check one) 
 
Not at all sure     
Not very sure     
More or less sure     
Fairly sure     
Absolutely sure 
 
4.  When I feel very anxious (check one) 
 
Not at all sure     
Not very sure     
More or less sure     
Fairly sure     
Absolutely sure 
 
5.  When I want to think about a difficult problem (check one) 
 
Not at all sure     
Not very sure     
More or less sure     
Fairly sure     
Absolutely sure 
 
6.  When I feel the urge to smoke (check one)  
 
Not at all sure     
Not very sure     
More or less sure     
Fairly sure     
Absolutely sure 
 
7.  When having a drink with friends (check one) 
 
Not at all sure     
Not very sure     
More or less sure     
Fairly sure     
Absolutely sure 
 
8.  When celebrating something (check one) 
 
Not at all sure     
Not very sure     
More or less sure     
Fairly sure     
Absolutely sure 
 
9.  When drinking beer, wine or other spirits (check one) 
 
Not at all sure     
Not very sure     
More or less sure     
Fairly sure     
Absolutely sure 
 
10.  When I am with smokers (check one) 
 
Not at all sure     
Not very sure     
More or less sure     
Fairly sure     
Absolutely sure 
 
 


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11.  After a meal (check one) 
 
Not at all sure     
Not very sure     
More or less sure     
Fairly sure     
Absolutely 
sure 
 
12.  When having coffee or tea (check one) 
 
Not at all sure     
Not very sure     
More or less sure     
Fairly sure     
Absolutely 
sure 
 
 


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APPENDIX V: FAGERSTRÖM TEST FOR NICOTINE DEPENDENCE  
Directions:  Please read each question below.  
Check only one  box for each question that best describes your response. 
 
1.  How soon after you wake up do you smoke you first cigarette? (check one) 
 
 Within 5 minutes 
 
 6-30 minutes 
 
 31-60 minutes 
 
 After 60 minutes 
 
2.  Do you find it difficult to refrain from smoking in places where it is forbidden, e.g. in 
church, at the library, in cinema, etc.? (check one) 
 
 Yes 
 
 No 
 
3.  Which cigarette would you hate most to give up? (check one) 
 
 The first one in the morning 
 
 Any other 
 
4.  How many cigarettes per day do you smoke? (check one) 
 
 10 or less 
 
 11-20 
 
 21-30 
 
 31 or more 
 
5.  Do you smoke more frequently during the first hours after awakening than during the 
rest of the day? (check one) 
 
 Yes 
 
 No 
 
6.  Do you smoke even when you are so ill that you are in bed most of the day? (check one) 
 
 Yes 
 
 No 
 
 


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APPENDIX VI: PATIENT HEALTH QUESTIONNAIRE – 9 (PHQ-9) 
Over the last 2 weeks, how often have you been bothered by any of the following problems? 
 
1.  Little interest or pleasure in doing things  
 
 0 – Not at all  
 1- Several days  
 2 – More than half the days 
 3- Nearly every day 
 
2.  Feeling down, depressed, or hopeless  
 
 0 – Not at all  
 1- Several days  
 2 – More than half the days 
 3- Nearly every day 
 
3.  Trouble falling or staying asleep, or sleeping too much  
 
 0 – Not at all  
 1- Several days  
 2 – More than half the days 
 3- Nearly every day 
 
4.  Feeling tired or having little energy  
 
 0 – Not at all  
 1- Several days  
 2 – More than half the days 
 3- Nearly every day 
 
5.  Poor appetite or overeating  
 
 0 – Not at all  
 1- Several days  
 2 – More than half the days 
 3- Nearly every day 
 
6.  Feeling bad about yourself – or that you are a failure or have let yourself or your  family down  
 
 0 – Not at all  
 1- Several days  
 2 – More than half the days 
 3- Nearly every day 
 


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7.  Trouble concentrating on things, such as reading the newspaper or watching television  
 
 0 – Not at all  
 1- Several days  
 2 – More than half the days 
 3- Nearly every day 
 
8.  Moving or speaking so slowly that other people could have noticed? Or the opposite – being 
 
so fidgety or restless that you have been moving around a lot more than usual. 
 0 – Not at all  
 1- Several days  
 2 – More than half the days 
 3- Nearly every day 
 
9.  Thoughts that you would be better off dead or of hurting yourself in some way 
 0 – Not at all  
 1- Several days  
 2 – More than half the days 
 3- Nearly every day 
_________________________________________________________________________ 
 
 
 
 
 
For office coding    _____+_____+_____+_____ 
 
 
 
 
 
 
 
 
 
 
 
= ________ 
_________________________________________________________________________ 
 
If you checked off any problems, how difficult have these problems made if for you to do you work, 
take care of things at home, or get along with other people? (check one) 
 
 Not difficult at all     
 Somewhat difficult     
Very difficult     
 Extremely difficult 
 
 
 


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APPENDIX VII: LINEAR ANALOGUE SELF-ASSESSMENT 
Directions:  Please circle the number (0-10) best reflecting your response to the following that describes 
your feelings during the past week, including today 
 
How would you describe:  
 
1.  your overall Quality of Life?  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
 it can be 
 
 
 
 
 
 
 
As good as  
it can be 
 
2.  your overall mental (intellectual) well being?  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
 it can be 
 
 
 
 
 
 
 
As good as  
it can be 
 
3.  your overall physical well being?  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
 it can be 
 
 
 
 
 
 
 
As good as  
it can be 
 
4.  your overall emotional well being?  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
 it can be 
 
 
 
 
 
 
 
As good as  
it can be 
 
5.  your level of social activity?  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
 it can be 
 
 
 
 
 
 
 
As good as  
it can be 
 
6.  your overall spiritual well being?  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as 
 it can be 
 
 
 
 
 
 
 
As good as  
it can be 
 
7.  the frequency of your pain?  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No pain 
 
 
 
 
 
 
 
Constant 
pain 
 
8.  the severity of your pain, on the average?  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No pain 
 
 
 
 
 
 
 
Pain as bad  
as you can 
imagine 
 
 
 


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9.  your level of fatigue, on the average?  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No fatigue 
 
 
 
 
 
 
 
Constant  
tiredness 
 
10.  your level of support from friends and family?  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No support 
 
 
 
 
 
 
 
Highest level  
of support 
 
11.  your financial concerns?  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Constant 
concerns 
 
 
 
 
 
 
 
No concerns 
 
12.  your legal concerns (will, advanced directives, etc.)?  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Constant 
concerns 
 
 
 
 
 
 
 
No concerns 
 
 
 


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APPENDIX VIII: WAS IT WORTH IT (WIWI) QUESTIONNAIRE  
 
Participating in a clinical trial / research study is a personal choice and an individual experience.  
We would like to get your feedback on your experience in this research study.  Please respond to 
the following questions as indicated. 
 
 
Directions:  Please answer each question by circling Y (for yes), N (for no), or U (for uncertain). 
 
Was it worthwhile for you to participate in this research study?     Y     N     U 
 
If you had to do it over, would you participate in this research study again?     Y     N     U 
 
Would you recommend participating in this research study to others?     Y     N     U 
 
 
Directions:  In the next two questions, please answer each question by circling one response. 
 
Overall, did your quality of life change by participating in this research study? 
 
 
It improved          It stayed the same          It got worse 
 
 
 
Overall, how was your experience of participating in this research study?  
 
 
Better than I expected          The same as I expected          Worse than I expected 
 
 
 
If there was one thing that could have been done to improve your experience in this research study, what 
would it be? 
______________________________________________________________________________ 
______________________________________________________________________________ 
 
Would you like to talk to someone about your concerns (circle one response)?     Yes     No 
 
 
 






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APPENDIX X: DRUG AND BEHAVIORAL ADHERENCE LOG 
Date of Baseline Visit: _______________________ 
This log applies to: 
(circle one) 
Weeks 1-6 
Weeks 7-12 
 
Day 
Varenicline/ 
placebo dose 
taken 
Circle One) 
Did you 
contact the 
tobacco 
Quitline on 
this day? 
(Circle One) 
Number of 
Cigarettes 
Smoked 
 
Comment 
Date:_______________ 
1 
AM 
Yes    No 
Yes    No 
 
 
Date:_______________ 
2 
AM 
Yes    No 
Yes    No 
  
  
Date:_______________ 
3 
AM 
Yes    No 
Yes    No 
  
  
Date:_______________ 
4 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
5 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
6 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
7 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
8 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
9 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
10 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  


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Day 
Varenicline/ 
placebo dose 
taken 
Circle One) 
Did you 
contact the 
tobacco 
Quitline on 
this day? 
(Circle One) 
Number of 
Cigarettes 
Smoked 
 
Comment 
Date:_______________ 
11 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
12 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
13 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
14 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
15 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
16 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
17 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
18 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
19 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
20 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
21 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  


Alliance A211401 
Version Date: 04/27/18 
Update 2 
88 
Day 
Varenicline/ 
placebo dose 
taken 
Circle One) 
Did you 
contact the 
tobacco 
Quitline on 
this day? 
(Circle One) 
Number of 
Cigarettes 
Smoked 
 
Comment 
Date:_______________ 
22 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
23 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
24 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
25 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
26 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
27 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
28 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
29 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
30 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
31 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
32 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  


Alliance A211401 
Version Date: 04/27/18 
Update 2 
89 
Day 
Varenicline/ 
placebo dose 
taken 
Circle One) 
Did you 
contact the 
tobacco 
Quitline on 
this day? 
(Circle One) 
Number of 
Cigarettes 
Smoked 
 
Comment 
Date:_______________ 
33 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
34 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
35 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
36 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
37 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
38 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
39 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
40 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
41 
AM 
Yes    No 
Yes    No 
  
  
  
 
PM 
Yes    No 
 
  
Date:_______________ 
42 
AM 
Yes    No 
Yes    No 
  
  
 
 
PM 
Yes    No 
 
 
 
 


Alliance A211401 
Version Date: 04/27/18 
Update 2 
90 
APPENDIX XI: GENERAL THORACIC SURGERY DATABASE DEFINITIONS 
 
Complication 
Definition 
Air leak 
Patient experienced a postoperative air leak for >5 days 
Bronchoscopy for 
atelectasis 
Postoperative atelectasis documented clinically or radiographically that needed 
bronchoscopy 
Pneumonia 
Defined according to the last CDC criteria: two or more serial chest radiographs 
with at least one of the following: 
• 
New or progressive and persistent infiltrate 
• 
Consolidation 
• 
Cavitation 
and at least one of the following: 
• 
Fever (>38°C or >100.4°F) with no other recognized cause 
• 
Leukopenia (<4000 WBC/mm3) or leukocytosis (≥12,000 WBC/mm3) 
• 
For adults ≥70 years old, altered mental status with no other recognized 
cause 
and at least two of the following: 
• 
New onset of purulent sputum, or change in character of sputum, or 
increased respiratory secretions, or increased functioning requirements 
• 
New onset or worsening cough, or dyspnea, or tachypnea 
• 
Rales or bronchial breath sounds 
Worsening gas exchange (e.g. O2 desaturations [eg, PaO2/FiO2 ≤240], increased 
oxygen requirements, or increased ventilator demand) 
ARDS 
Adult respiratory distress syndrome defined according to the American-
European consensus conference; all of the following criteria should be met: 
• 
Acute onset 
• 
Arterial hypoxemia with PaO2/FIO2 ratio <200 (regardless of PEEP 
level) 
• 
Bilateral infiltrates at chest radiograph or CT scan 
• 
No clinical evidence of left atrial hypertension or pulmonary artery 
occlusive pressure <18 mm Hg 
• 
Compatible risk factors 
Bronchopleural fistula 
Patient experienced a complete or partial dehiscence of the bronchial stump 
documented in the postoperative period (such as bronchoscopy or other 
operative intervention) 


Alliance A211401 
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Pulmonary embolism 
Patient experienced a pulmonary embolus in the postoperative period as 
documented by a V/Q scan, angiogram, or spiral CT 
Initial ventilator support 
Patient initially was ventilated >48 hours in the postoperative period; ventilator 
support ends with removal of endotracheal tube or, if the patient has a 
tracheostomy tube, until no longer ventilator dependent 
Reintubation 
Patient was reintubated during the initial hospital stay after the initial extubation; 
this may include patients who have been extubated in the operating room and 
require intubation in the postoperative period 
Tracheostomy 
Patient required a tracheostomy in the postoperative period whether performed 
in the ICU or the OR; prophylactic minitracheostomy on the day of operation 
should not be considered a complication 
Atrial arrhythmia 
New onset of atrial fibrillation/flutter (AF) requiring medical treatment or 
cardioversion; does not include recurrence of AF that was present preoperatively 
Ventricular arrhythmia 
Sustained ventricular tachycardia or ventricular fibrillation that has been 
clinically documented and treated by ablation therapy, implantable cardioverter 
defibrillator, permanent pacemaker, pharmacologic treatment. or cardioversion 
Myocardial infarction 
Evidenced by one of the following criteria: 
• 
Transmural infarction diagnosed by the appearance of a new Q wave in 
two or more contiguous leads on ECG 
• 
Subendocardial infarction (non Q wave) evidenced by clinical, 
angiographic, electrocardiographic signs 
• 
Laboratory isoenzyme evidence of myocardial necrosis 
Empyema 
Patient experienced an empyema requiring treatment in the postoperative period; 
diagnosis of empyema should be confirmed by thoracentesis; frank pus or 
merely cloudy fluid may be aspirated from the pleural space; the pleural fluid 
typically has leukocytosis, low pH (<7.20), low glucose (<60 mg/dL), high 
lactate dehydrogenase, and elevated protein and may contain infectious 
organisms 
Wound infection 
Patient experienced a wound infection in the postoperative period as evidenced 
by meeting two of the following criteria: 
• 
Wound opened with excision of tissue (I&D) 
• 
Positive culture 
• 
Treatment with antibiotics 
 
 


Alliance A211401 
Version Date: 04/27/18 
Update 2 
92 
Cerebrovascular 
complications 
Occurrence of one of the following central neurologic postoperative events not 
present preoperatively: 
• 
A central neurologic deficit persisting postoperatively for more than 
72 hours 
• 
A transient neurologic deficit (transient ischemic attack or reversible 
ischemic neurologic deficit) with recovery within 72 hours. 
• 
A new postoperative coma persisting at least 24 hours and caused by 
anoxic/ischemic and/or metabolic encephalopathy, thromboembolic 
event, or cerebral bleed 
Recurrent nerve palsy 
Patient experienced in the postoperative period a recurrent laryngeal nerve 
paresis or paralysis that was not identified during the preoperative evaluation 
Delirium 
Patient experienced a new onset of symptoms like illusions, confusion, cerebral 
excitement in the postoperative period 
Renal failure 
Defined as the onset of new renal failure in the postoperative period according to 
one of the following criteria: 
• 
Increase of serum creatinine to >2.0 mg/dL 
• 
Two times the preoperative creatinine level 
• 
A new requirement for dialysis postoperatively 
Chylothorax 
Patient experienced a chylothorax in the postoperative period that required 
persistent or new drainage and medical intervention (e.g. NPO, TPN) or 
reoperation. 
 
Chylothorax is defined by the clinical appearance of the pleural fluid or the 
presence of pleural fluid triglyceride levels >110 mg/dL with a cholesterol level 
<200 mg/dL 
Unexpected admission 
to the ICU 
An unplanned transfer of the patient to the ICU owing to deterioration in the 
condition of the patient requiring active life support treatment 
 
 
 


Alliance A211401 
Version Date: 04/27/18 
Update 2 
93 
APPENDIX XII: MAYO CLINIC NICOTINE RESEARCH PROGRAM CRISIS POLICY 
This policy is provided as an example of suicide ideation monitoring and response procedures sites 
should have in place. For dose modification instructions for patients participating in this study, refer 
to Section 8.2 of the protocol. 
 
Psychiatric Symptom Management 
1. Suicidal Ideation  
Assessment: Any study participant reporting suicidal ideation to a study coordinator or nurse 
will be psychiatrically evaluated immediately thereafter by either the site principal investigator 
or the on-call clinical investigator.  
Procedures in place to deal with suicidal ideation: If the participant is unwilling to seek help, 
the individual will be advised that the Site Research Team is required to report that the subject 
is threatening to harm him/herself and the patient will be escorted to the Emergency Department 
of the local hospital by ambulance for an evaluation by the psychiatrist on call.  
How and when study medication might be discontinued: At that time, the study medication will 
be stopped until further notice from the treating physician. If the medication is stopped 
permanently, the subject will be given the option of continuing in the study without the 
medication. 
2. Depression 
Assessment: To diagnose depression, most of the following signs and symptoms must be present 
most of the day, nearly every day, for at least two weeks: sleep disturbances, impaired thinking 
or concentration, significant weight loss or gain, agitation or slowing of body movements, 
fatigue, low self-esteem, less interest in sex, thoughts of death (suicidal ideation – see above). 
Accordingly, any study participant reporting depression or severe change in mood to a study 
coordinator or nurse will be psychiatrically evaluated immediately thereafter by either the 
principal investigator or the on-call clinical investigator.  
Procedures in place to deal with depression: 
• 
If it is determined that the current level of depression is likely to lead to self-harm or harm 
to others, the individual will be advised that the Site Research Team is required to report 
that the subject is threatening to harm him/herself and the patient will be escorted to the 
Emergency Department of the local hospital by ambulance for an evaluation by the 
psychiatrist on call.  
• 
If it is determined that the emerging depression requires treatment, the subject will be 
referred to one of the following: 
- 
Primary provider (the physician will call the provider) 
- 
Local mental health facility 
- 
Community psychiatric services 
How and when the study medication would be discontinued: If the site investigator notes new 
depression or an exacerbation of existing depression, the subject may be advised to modify the 
dose of the study drug. Based on the clinical assessment by the site investigator or one of the 
co-investigators the study medication may be stopped temporarily and then re-challenged at the 
target dose, reduced permanently, or discontinued permanently. If the study drug is permanently 
discontinued, the subject would still receive follow-up counseling according to the study 
protocol.  


Alliance A211401 
Version Date: 04/27/18 
Update 2 
94 
3. Less Common Psychiatric Symptoms 
Assessment: In the case of emergency, diagnoses will be made immediately by the site 
investigator and/or the on-call clinical investigator.  
Procedures in place to deal with anxiety:  
• 
If it is determined that the current psychiatric symptom is likely to lead to self-harm or harm 
to others, the individual will be advised that the Site Research Team is required to report 
that the subject is threatening to harm him/herself and the patient will be escorted to the 
Emergency Department of the local Hospital by ambulance for an evaluation by the 
psychiatrist on call.  
• 
If it is determined that the emerging psychiatric condition requires treatment, the subject 
will be referred to one of the following: 
- 
Primary provider (the physician will call the provider) 
- 
Local mental health facility 
- 
Community psychiatric services 
How and when the study medication would be discontinued: If the site investigator notes a new 
psychiatric illness or syndrome or an exacerbation of an existing mental health condition, the 
subject may be advised to modify the dose of the study drug. Based on the clinical assessment 
by the site investigator or one of the co-investigators the study medication may be stopped 
temporarily and then re-challenged at the target dose, reduced permanently, or discontinued 
permanently. If the study drug is permanently discontinued, the subject would still receive 
follow-up counseling according to the study protocol. 
4. Crisis Management of Maltreatment, Neglect, Violence:  
In the event that the subject expresses thoughts or actively performs behaviors related to the 
mistreatment of vulnerable adults, domestic violence, workplace violence, child abuse, or 
neglect, the event(s) will be referred immediately by the nursing staff to the physician on duty. 
All events will be documented by nursing staff. 
5. Homicidal Threat:  
Hospital Security will be immediately called to report that the participant has threatened to harm 
another person or staff member. 
• 
Staff who are threatened by a participant should take immediate precautions to protect 
themselves and others. 
• 
The participant expressing homicidal ideation should be advised that we are required to take 
action to protect all individuals(s) being threatened.  
• 
Participants who threaten to harm another individual will be assessed by study nursing staff 
who will then consult with the principal investigator or the on-call clinical investigator to 
determine the seriousness of the situation. 
• 
Staff should attempt to locate a telephone number for the person being threatened. The 
person will be contacted as soon as possible and warned that such a threat has been made. 
 
 


Alliance A211401 
Version Date: 04/27/18 
Update 2 
95 
Contact Resources: 
If a patient has expressed current symptoms of depression, active suicidal ideation, maltreatment, 
neglect, violence, and drug/alcohol issues signs and symptoms of severe depression, the following 
resources should be contacted in the order listed: 
1. Principal Investigator for the study  
2. Study Call Schedule (this includes physicians overseeing the residential treatment program and 
the outpatient clinical program). 
3. Local Site Security, at any point they are needed for support. 
Important facts to remember: 
• 
If a participant will not cooperate or you have any concern for their safety or your own safety,  
• 
Call Local Site Security.  
• 
Please remember to document all events in the participant study record. 
• 
The on-call clinical psychiatrist at local Hospital Emergency Room is an available resource. 
 
 


Alliance A211401 
Version Date: 04/27/18 
Update 2 
96 
APPENDIX XIII: VARENICLINE WALLET CARD 
[Note to investigators:  This convenient wallet-sized information card is to be completed and then 
provided for the patient to clip out and retain at all times.] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial to help you stop smoking.  
This clinical trial is sponsored by the NCI.  Quitting smoking 
may change how your body interacts with certain drugs that 
are processed by your liver.  Because of this, it is very 
important to: 
 Tell your doctors if you stop taking regular medicine or if 
you start taking a new medicine. 
 Tell all of your prescribers (doctor, physicians’ assistant, 
nurse practitioner, pharmacist) that you are taking part in a 
clinical trial. 
 Check with your doctor or pharmacist whenever you need 
to use an over-the-counter medicine or herbal supplement. 
Quitting smoking may change levels of a specific liver enzyme 
called CYP1A2, and may change how certain medications are 
metabolized by your body.  
 After you stop smoking, your study doctor will work with 
your regular prescriber to adjust medicines that are 
considered “substrates” of CYP1A2 such as the blood 
thinner warfarin. 
 Before prescribing new medicines, your regular 
prescribers should go to 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx for 
a list of drugs to avoid, or contact your study doctor.   
 Your study doctor’s name is ____________________________ and 
can be contacted at ______________________________.