Clinical trial NCT02151591
Conditions: Nicotine Dependence Cigarette Smoking Alcohol Consumption Heavy Drinking
Keywords: Quit smoking Quit drinking
Sponsor: Yale University
Start date: 2017-03-01; Completion date: 2018-08-01
Enrollment: 26 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to develop and test an integrated cognitive-behavioral intervention for smoking and alcohol among heavy drinking smokers. The current pre-pilot phase will be used to refine this protocol for the subsequent randomized, controlled pilot phase. The current study phase has two parts: 1) an intake session and brief physical; 2) a 12-week treatment phase in which participants receive varenicline (Chantix) and weekly, personalized counseling.

Detailed description:
The purpose of the proposed project is to develop and test a 12-week integrated cognitive-behavioral therapy (CBT) intervention for smoking and alcohol (SA) + varenicline (Chantix) among heavy drinking smokers (i.e., CBT for SA). The project involves two phases. In Phase 1, an open-label pre-pilot study of CBT for SA will be conducted with 10 heavy drinking smokers. The primary results of this phase will be used to refine the CBT for SA protocol. In Phase 2, a randomized, controlled pilot study will be conducted with 40 heavy drinking smokers comparing CBT for SA with standard smoking counseling (SC). All participants in the randomized pilot study will also receive varenicline (Chantix).

Primary and Study Completion dates were changed 6/2016 to reflect an additional year added year to the study.

Arms: arm 1: Integrated counseling for smoking and alcohol entails weekly counseling for 12-weeks targeting both behaviors. Participants in this condition will also receive 12 weeks of varenicline (Chantix). arm 2: Standard care (SC) for primary presenting concern only. For those presenting with the primary concern of tobacco, standard care will involve weekly smoking counseling alone for 12-weeks. For those presenting with the primary concern of alcohol, standard care will involve weekly alcohol counseling alone. Participants in this condition will also receive 12 weeks of varenicline (Chantix).
Interventions: intervention 1: Varenicline
Intervention descriptions: intervention 1: 12-weeks of treatment. Dose will be titrated as follows:

Days 1-3: 1 0.5mg tablet once per day Days 4-7: 1 0.5mg tablet twice per day Day 8 - Week 11: 1 1mg tablet twice per day

Protocol documents:
Prot_SAP_000.pdf: 
 
New Approaches to Smoking Cessation in Heavy Drinkers 
 
Study Protocol and Data Analysis Plan  
 
NCT # 02151591 
 
May 30, 2017 
 
 


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5 
Version 12 
APPROVED BY THE YALE UNIVERSITY IRB 7/10/2018 VALID THROUGH 7/16/2019 
 
Provide information regarding the external funding source. This information should include 
identification of the agency/sponsor, the funding mechanism (grant or contract), and whether 
the award is pending or has been awarded. Provide the M/C# and Agency name (if grant- 
funded). If the funding source associated with a protocol is “pending” at the time of the 
protocol submission to the HIC (as is the case for most NIH submissions), the PI should note 
“Pending” in the appropriate section of the protocol application, provide the M/C# and 
Agency name (if grant-funded) and further note that University (departmental) funds support 
the research (until such time that an award is made). 
 
 
PI 
Title of Grant 
Name of Funding Source 
unding 
unding Mechanism 
 
Lisa Fucito, 
PhD 
 
New Approaches to 
Smoking Cessation 
in Heavy Drinkers 
National Institute on 
Alcohol Abuse and 
Alcoholism 
 
Federal 
State 
Non Profit 
Industry 
Other For 
rofit 
Other 
 
Grant-M# 
23AA020000-01A1 
Contract# 
Contract Pending 
Investigator/Department 
nitiated 
Sponsor Initiated 
Other, Specify: 
 
 
 
 
Federal 
State 
Non Profit 
Industry 
Other For 
rofit 
Other 
 
Grant-M# 
Contract# 
Contract Pending 
Investigator/Department 
nitiated 
Sponsor Initiated 
Other, Specify: 
 
 
 
 
Federal 
State 
Non Profit 
Industry 
Other For 
rofit 
Other 
 
Grant-M# 
Contract# 
Contract Pending 
Investigator/Department 
nitiated 
Sponsor Initiated 
Other, Specify: 
 
IRB Review fees are charged for projects funded by Industry or Other For-Profit Sponsors. 
Provide the Name and Address of the Sponsor Representative to whom the invoice should be 
sent. Note: the PI’s home department will be billed if this information is not provided. 
 
Send IRB Review Fee Invoice To: N/A 
Name: 
Company: 
Address: 


6 
Version 12 
APPROVED BY THE YALE UNIVERSITY IRB 7/10/2018 VALID THROUGH 7/16/2019 
 
2. Research Team: List all members of the research team. Indicate under the affiliation column whether 
the investigators or study personnel are part of the Yale faculty or staff, or part of the faculty or staff 
from a collaborating institution, or are not formally affiliated with any institution. ALL members of 
the research team MUST complete Human Subject Protection Training (HSPT) and Health 
Insurance Portability and Accountability Act (HIPAA) Training before they may be listed on the 
protocol. See NOTE below. 
 
NOTE: The HIC will remove from the protocol any personnel who have not completed required training. 
 
 
Name 
Affiliation: Yale/Other 
Institution (Identify) 
NetID 
Principal Investigator 
Lisa Fucito, PhD 
Yale Faculty 
lmf35 
Role: Consultant 
Stephanie O’Malley 
Yale Faculty 
sss02 
Role: Consultant 
Kathleen Carroll, PhD 
Yale Faculty 
ernieb 
Role: Consultant 
Nancy Redeker, PhD, RN, FAHA, 
FAAN 
Yale Faculty 
nsr24 
Role: Consultant 
Ralitza Gueorguieva, PhD 
Yale Faculty 
rg268 
Role: Study Personnel 
Srinivas Muvvala, MD 
Yale Faculty 
sm826 
 
 
 
 
Role: Study Personnel 
Denise Romano, APRN, FNP 
Yale Staff 
dmr35 
Role: Study Personnel 
Elaine LaVelle, MS 
Yale Staff 
etl7 
Role: Study Personnel 
Susan Neveu 
Yale Staff 
sn227 
 
 
 
 
Role: Study Personnel 
Tess Hanrahan, MRes 
Yale Staff 
th473 
Role: Study Personnel 
Ran Wu, MS 
Yale Staff 
rw74 
Role: Study Personnel 
Ann Agro, MPH 
Yale Staff 
ada22 
Role: Study Personnel 
Phyllis Hunt 
YNHH 
 
Role: Study Personnel 
Victoria Ogbejesi 
YNHH 
 
Role: Study Personnel 
Steve Baldassarri 
Yale Fellow 
 
Role: Study Personnel 
Steve Bernstein 
Yale Faculty 
 
Role: Study Personnel 
Abedalrazaq Alkukhun 
Yale Postgraduate Student 
 
Role: Study Personnel 
Kelly DeMartini, PhD 
Yale Faculty 
 
Role: Study Personnel 
Hochang Ben Lee 
Yale Faculty 
 
Role: Study Personnel 
Maura D’Andrea 
YNHH 
 
Role: Study Personnel 
Christina Heffern 
Quinnipiac University 
Study Intern 
 
Role: Study Personnel 
Helen Sackler, PhD 
Yale Casual Employee 
 
Role: Study Personnel 
Lisa Blumenthal, LCSW 
CMHC/Yale Casual 
Employee 
 
Role: Study Personnel 
Krysten Bold, PhD 
Yale Staff 
 
A personnel protocol amendment will need to be submitted when training is completed. 


APPROVED BY THE YALE UNIVERSITY IRB 7/10/2018 VALID THROUGH 7/16/2019 
7 
Version 11 
 
SECTION IV: 
PRINCIPAL INVESTIGATOR/FACULTY ADVISOR/ DEPARTMENT CHAIR 
AGREEMENT 
As the principal investigator of this research project, I certify that: 
▪ The information provided in this application is complete and accurate. 
▪ I assume full responsibility for the protection of human subjects and the proper conduct of the 
research. 
▪ Subject safety will be of paramount concern, and every effort will be made to protect subjects’ 
rights and welfare. 
▪ The research will be performed according to ethical principles and in compliance with all federal, 
state and local laws, as well as institutional regulations and policies regarding the protection of 
human subjects. 
▪ All members of the research team will be kept apprised of research goals. 
▪ I will obtain approval for this research study and any subsequent revisions prior to my initiating the 
study or any change and I will obtain continuing approval of this study prior to the expiration date 
of any approval period. 
▪ I will report to the HIC any serious injuries and/or other unanticipated problems involving risk to 
participants. 
▪ I am in compliance with the requirements set by the University and qualify to serve as the 
principal investigator of this project or have acquired the appropriate approval from the 
Dean’s Office or Office of the Provost, or the Human Subject Protection Administrator at 
Yale-New Haven Hospital, or have a faculty advisor. 
▪ I will identify a qualified successor should I cease my role as principal investigator and facilitate a 
smooth transfer of investigator responsibilities. 
_
 
 5.31.17  
 
PI Name (PRINT) and Signature 
Date 
As the faculty advisor of this research project, I certify that: 
▪ The information provided in this application is complete and accurate. 
▪ This project has scientific value and merit and that the student or trainee investigator has the 
necessary resources to complete the project and achieve the aims. 
▪ I will train the student investigator in matters of appropriate research compliance, protection of 
human subjects and proper conduct of research. 
▪ The research will be performed according to ethical principles and in compliance with all federal, 
state and local laws, as well as institutional regulations and policies regarding the protection of 
human subjects. 
▪ The student investigator will obtain approval for this research study and any subsequent revisions 
Prior to initiating the study or revision and will obtain continuing approval prior to the expiration 
of any approval period. 
▪ The student investigator will report to the HIC any serious injuries and/or other unanticipated 
problems involving risk to participants. 
▪ I am in compliance with the requirements set forth by the University and qualify to serve as 
the faculty advisor of this project. 
Advisor Name (PRINT) and Signature 
Date 
 


8 
Version 12 
APPROVED BY THE YALE UNIVERSITY IRB 7/10/2018 VALID THROUGH 7/16/2019 
 
Department Chair’s Assurance Statement 
Do you know of any real or apparent institutional conflict of interest (e.g., Yale ownership of a 
sponsoring company, patents, licensure) associated with this research project? 
Yes (provide a description of that interest in a separate letter addressed to the HIC.) 
No 
 
As Chair, do you have any real or apparent protocol-specific conflict of interest between yourself and 
the sponsor of the research project, or its competitor or any interest in any intervention and/or method 
tested in the project that might compromise this research project? 
Yes (provide a description of that interest in a separate letter addressed to the HIC) 
No 
 
I assure the HIC that the principal investigator and all members of the research team are qualified by 
education, training, licensure and/or experience to assume participation in the conduct of this research 
trial. I also assure that the principal investigator has departmental support and sufficient resources to 
conduct this trial appropriately. 
 
 
Chair Name (PRINT) and Signature 
Date 
Department 
YNHH Human Subjects Protection Administrator Assurance Statement 
Required when the study is conducted solely at YNHH by YNHH health care providers. 
 
 
 
 
Date 
YNHH HSPA Name (PRINT) and Signature 
As Human Subject Protection Administrator (HSPA) for YNHH, I certify that: 
I have read a copy of the protocol and approve it being conducted at YNHH. 
I agree to notify the IRB if I am aware of any real or apparent institutional conflict of interest. 
The principal investigator of this study is qualified to serve as P.I. and has the support of the hospital 
for this research project. 
This protocol is valid through   
 
Human Investigation Committee Signature 
Date Approved 
For HIC Use Only 


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1. Statement of Purpose: State the scientific aim(s) of the study, or the hypotheses to be tested. 
 
The purpose of the proposed project is to develop and test an integrated cognitive-behavioral 
intervention for smoking and alcohol (CBT for SA) among heavy drinking smokers presenting for 
smoking cessation treatment. The project involves three phases. In Phase 1, focus group interviews 
will be conducted with 30 heavy drinking smokers to identify intervention components that are 
feasible and acceptable to this population. In Phase 2, an open-label pre-pilot study of CBT for SA 
will be conducted with 10 heavy drinking smokers. The primary results of this phase will be used 
to refine the CBT for SA protocol. In Phase 3, a randomized, controlled pilot study will be 
conducted with 40 heavy drinking smokers comparing CBT for SA with standard smoking 
counseling (SC) and standard alcohol counseling (AC). The specific aims are as follows: 
Primary Aim 1.1: In an iterative process based on detailed review of audiotaped focus group and 
treatment sessions, develop and refine CBT for SA manual, participant materials, therapist training 
materials, and treatment fidelity documents. 
 
Primary Aim 1.2: Conduct pre-pilot study of CBT for SA (N=10) with heavy drinking smokers to 
evaluate the feasibility and acceptability of the intervention. 
 
Primary Aim 2.1: Conduct RCT pilot study of CBT for SA versus SC and AC (N=40) with heavy 
drinking smokers to obtain effect size estimate data for the two primary outcomes of: 
1. Point prevalence smoking abstinence over the last 7 days at 6 months post 
treatment completion. 
2. Percentage of heavy drinking days at 6 months post treatment completion. 
 
2. Background: Describe the background information that led to the plan for this project. 
Provide references to support the expectation of obtaining useful scientific data. 
 
Co-occurring Heavy Alcohol Use and Cigarette Smoking: An Important Co-Morbidity. 
More than 50% of heavy drinkers (defined as >14 drinks per week/5 per day for men and >7 drinks 
per week/4 per day for women) smoke cigarettes compared with 23-39% of individuals who either 
abstain from alcohol or drink only moderately(1, 2). This figure increases to nearly 80% in clinical 
samples of alcohol dependent individuals. Cigarette smoking is the leading preventable cause of 
morbidity and mortality in the United States(3) and when combined with heavy alcohol has a 
synergistic effect on health including increased risk of liver, head, and neck cancers, liver cirrhosis, 
and pancreatitis(4-7), and greater abnormalities in brain structure and function(8). Combined heavy 
alcohol use and cigarette smoking is also associated with poor treatment outcomes. Heavy drinking 
smokers are less likely to initiate a smoking quit attempt(9, 10), achieve and maintain smoking 
abstinence (1, 11-25), and successfully moderate or abstain from alcohol use(26, 27). Thus, more 
effective treatments for concurrently reducing smoking and heavy drinking are warranted. 
 
Why Integrate Treatment for Heavy Alcohol Use and Cigarette Smoking? 
Several factors may limit treatment response in heavy drinking smokers. Through conditioning 
processes, heavy alcohol use may enhance smoking motivation and smoking may promote 
SECTION V: RESEARCH PLAN 


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motivation to drink(28-33). Heavy drinking may disinhibit individuals to smoke(33) or potentiate 
the rewarding effects of nicotine(34). Similarly, cigarette smoking may enhance alcohol 
reinforcement by reducing the sedating effects and cognitive deficits associated with alcohol use 
thereby enabling drinkers to consume heavier amounts of alcohol(33). Thus, treating one behavior 
in isolation of the other may render heavy drinking smokers’ efforts to change either behavior less 
successful. Despite these risks, heavy alcohol use and smoking are not typically treated 
concurrently largely due to concerns that quitting smoking will negatively affect drinking 
outcomes(35) and misperceptions that smoking is less harmful. On the contrary, more heavy 
drinkers will die from smoking-related causes than alcohol-related causes(33, 36), quitting 
smoking does not jeopardize and may even promote drinking changes(37), and many heavy 
drinkers are motivated to quit smoking(35). 
 
Current Combination Treatments for Heavy Drinking and Smoking of Limited Efficacy. 
Prior research has primarily focused on smoking interventions provided during or shortly 
following outpatient or inpatient alcohol treatment (37, 38). Most interventions were brief (i.e., a 
few sessions), not integrated into alcohol treatment, and associated with low smoking quit rates 
(37, 38). Adding smoking pharmacotherapy to these interventions yields higher smoking quit rates, 
but these effects are not sustained beyond treatment (37, 38). Only 1 study examined a brief alcohol 
intervention integrated into smoking cessation treatment for heavy drinkers seeking to quit 
smoking(39). Heavy drinkers, not currently alcohol dependent, received 8 weeks of nicotine patch 
therapy starting on the quit day and either 4 weeks of standard smoking counseling or standard 
smoking counseling plus brief alcohol advice starting 2 weeks before quitting. The integrated 
treatment resulted in greater smoking abstinence and alcohol use reductions but these effects were 
modest; smoking changes also did not persist beyond treatment and were greatest among only 
moderately heavy drinkers. Moreover, through personal communication with Dr. Kahler, many 
participants were unmotivated to discuss drinking after the first session. Despite these limitations, 
this protocol is a promising model for integrating smoking and alcohol treatment and highlights 
how smoking treatment can provide an opportunity to identify and intervene with heavy drinkers. 
Providing more health information to motivate them to also reduce their drinking before and after 
quitting smoking and incorporating skill development relevant for changing alcohol use might 
promote sustained smoking abstinence and greater drinking reductions in this population. 
 
Proposed Integrated CBT Intervention for Heavy Drinking Smokers: CBT for SA. We will 
develop a manual that integrates smoking and alcohol treatment and incorporates empirically 
supported CBT techniques to support reductions in both smoking and alcohol use. Treatment will 
address obstacles and teach skills relevant for both issues and will be organized around two major 
areas of development: (1) stimulus control and (2) mood/stress management strategies. Treatment 
will be focused so that participants acquire high competence in two major skills in rather than poor 
to moderate competence in many skills. This content was selected based on data analyses and focus 
group interviews conducted by Dr. Fucito on the factors that predict poor smoking cessation 
outcomes among heavy drinkers. Stimulus control involves setting up environmental constraints 
to avoid exposure to cues that trigger problematic behaviors and feelings(73, 74). For smoking and 
drinking, stimulus control emphasizes avoiding people, places, and things that trigger urges to use 
(73, 74). Relative to moderate and non-drinkers, the smoking behavior of heavy drinkers appears 
to be more environmentally and socially cued. For these reasons, skill development will focus on 
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or managing social situations without using. Mood/stress management strategies will emphasize 
behavioral activation - engaging in pleasant activities that do not involve smoking and drinking to 
reduce negative mood (i.e. stress, anxiety, boredom), specific relaxation techniques (e.g., deep 
breathing, progressive muscle relaxation), and anger management techniques. Behavioral 
activation is an empirically-supported intervention for the treatment of mood problems. 
Counseling will information about moderate drinking guidelines for men and women and will 
include specific strategies to reduce drinking (e.g., slowing the pace of drinking, substituting a 
non-alcoholic drink in between alcoholic drinks, counting drinks). 
 
In initial sessions and reinforced throughout treatment, participants will be taught how problematic 
behaviors and feelings are the result of a learning process. By conducting a functional analysis in 
session (a core component of CBT), participants will understand the factors that maintain the 
problematic behavior or feeling and what they can do to break the cycle(79). Discussions will focus 
on situations, thoughts, and feelings that maintain smoking and drinking and other problems that 
could affect efforts to change them (i.e., mood, social networks). They will learn general stimulus 
control skills (i.e., how to create an environment that supports adaptive behaviors) and how to 
apply them to these specific problems as well as how to identify and implement pleasant activities 
that do not involve smoking and drinking. 
 
In addition to CBT skills, the intervention will incorporate motivational components to encourage 
participants to make changes to both behaviors. This will be provided through personalized health 
feedback and general feedback about smoking and drinking behaviors that will be provided at the 
first session and then monitored during treatment. We will first provide a number of different types 
of health profile information in the pre-pilot study in order to identify which components are the 
most motivating and helpful for participants. The highest rated health profile components among 
these will then be provided in the final RCT pilot study. The final components will include: (1) 
liver function tests using blood samples, (2) inflammation markers using blood samples, (3) blood 
pressure, (4) metabolic function (i.e., glucose, lipid profile) from blood samples, (6) lung function 
based on spirometry tests, which involve having participants exhale into a tube for 6 seconds as 
hard as they can, and (7) breath carbon monoxide (CO) levels, and (8) hemoglobin, hematocrit, 
MCV. We will also provide personalized feedback to participants about the money they are 
spending on cigarettes and alcohol, the extra calories they are consuming from alcohol use, typical 
cues that trigger smoking and alcohol use. Consistent with Dr. Kahler’s intervention for heavy 
drinking smokers, sessions will also involve open-ended, personalized discussions of current 
drinking and smoking patterns, pros and cons of smoking and drinking, how drinking and smoking 
are associated, history of prior quit attempts for both, the role of alcohol in smoking relapse, 
normative feedback on current drinking, and preliminary drinking goal setting. 
 
We will recruit heavy drinkers interested in quitting smoking or interested in changing drinking; 
we will not require an interest in changing both. Unlike Dr. Kahler’s study(39), participants with 
current alcohol dependence will be eligible to participate since the aim is to evaluate smoking 
treatments that could be applicable to a broader heavy drinking population, though severe alcohol 
dependent participants who require additional alcohol treatment will be excluded (see exclusion 
criteria). The intention is to improve smoking and drinking outcomes among heavy- drinking 
smokers. Thus, participants’ motivation to change their behaviors will vary. In addition to the CBT 
skills above, motivational strategies will be utilized to support participants who are interested in 


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changing and encourage those who may be more ambivalent. These strategies include eliciting and 
reinforcing participants’ self-motivational drinking statements, using reflective listening, and 
expressing acceptance and affirmation(80). 
 
Participants will be advised to consider abstaining from drinking for the first 2 weeks of quitting 
smoking and ideally for the duration of treatment, regardless of their long-term drinking goals. 
They will be provided with specific strategies for moderating their alcohol use in addition to the 
general skills mentioned above. Likewise, participants will be advised that reducing their smoking, 
and ideally quitting smoking, is helpful for promoting better long-term drinking outcomes. 
 
We will also provide varenicline to all participants in the pre-pilot and RCT pilot studies, instead 
of the nicotine patch as initially planned, for several reasons. Varenicline is a highly efficacious 
smoking cessation pharmacotherapy that yields higher smoking quit rates than bupropion and 
placebo (127, 128). 
 
Among smokers who also drink heavily, varenicline is safe and well-tolerated (129, 130). Recent 
evidence also suggests that varenicline reduces alcohol craving and consumption among smokers 
(129, 130, 131) and nonsmokers (131). The results of focus group interviews with heavy drinking 
smokers recently completed by Dr. Fucito suggest additional benefits of varenicline. In interviews, 
participants expressed greater ambivalence about changing their drinking than smoking. 
Varenicline can reduce alcohol use in the absence of specific advice to change drinking among 
smokers not actively seeking alcohol treatment (129, 130). Participants also expressed greater 
dissatisfaction with using nicotine replacement therapies than other smoking pharmacotherapies. 
In contrast, the nicotine patch yields lower smoking quit rates than varenicline among all smokers 
(132) and in at least one study was associated with greater alcohol use among smokers compared 
to varenicline (133). Taken together, providing a pharmacotherapy intervention that is efficacious 
for both problems along with an integrated behavioral treatment makes sense for the purposes of 
this study. The two studies will allow for an investigation of whether CBT for SA can improve 
varenicline’s efficacy for smoking cessation and drinking reductions in this population. 
 
We will also recruit heavy drinkers who are smokers as defined by the CDC: report smoking 100 
cigarettes or more in their lifetime and currently smoke at least twice weekly on average in the 
past 90 days. To verify smoking status, they must also have a urinary cotinine level of ≥30ng/mL 
by semi-quantitative urinalysis, and/or ≥2 on NicAlert dipstick. We propose this flexible definition 
of smoking for several reasons: 
 
(1) This is a pilot feasibility study. We do not want to miss the opportunity to learn which 
heavy drinking smokers are interested in an integrated treatment, perceive it to be helpful, 
and actually benefit from it, due to making the smoking eligibility too narrow. 
(2) Heavy drinking smokers are a diverse population. A sizeable portion of heavy drinkers 
smoke on a non-daily basis, only during drinking episodes. In 2010, the CDC reported that 
21.8% of smokers were nondaily smokers. Nondaily smokers also have the highest rates 
of alcohol dependence (135). 
(3) and seek smoking cessation treatment (136). 
(4) Nondaily smokers have similar treatment needs as daily smokers. There is evidence that 
they extract similar levels of nicotine as daily smokers at a given number of cigarettes 


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smoked per day, suggesting that this subgroup could also benefit from pharmacotherapy 
treatment (137). 
(5) Racial and ethnic minorities are more likely to report light or non-daily smoking (138, 139) 
so we do not want to limit our ability to recruit these populations of smokers. 
(6) The results of a pilot study showed that varenicline was more efficacious than placebo or 
nicotine replacement therapy for smoking cessation in light smokers (138). Likewise, a 
retrospective evaluation of 36,594 French smokers offered smoking cessation services 
demonstrated that varenicline doubled quit rates among light smokers compared to nicotine 
replacement therapy (140). 
 
3. Research Plan: Summarize the study design and research procedures using non-technical 
language that can be readily understood by someone outside the discipline. Be sure to 
distinguish between standard of care vs. research procedures when applicable, and include 
any flowcharts of visits specifying their individual times and lengths. 
 
This project involves three phases: (1) focus group interviews with heavy drinking smokers, (2) 
an open-label pre-pilot study with 10 heavy drinking smokers and (3) a randomized, controlled 
pilot study with 40 heavy drinking smokers. 
 
Phase 1: 
Focus Group Interviews: We will recruit up to 30 heavy drinking smokers to participate in 1 of 4 
focus group interview sessions (approximately 7-8 smokers per group). Prior to each focus group, 
smokers will provide informed consent and complete self-report assessments (approximately one 
hour) as part of an intake visit. The assessments will be used to determine participant eligibility 
and to obtain baseline information on participants’ smoking and drinking behavior. Participants 
will not complete all of the assessments that are listed for the pre-pilot and pilot RCT. Instead, they 
will complete an abbreviated intake to confirm they meet study eligibility and smoking and alcohol 
assessments. 
 
The focus group interview (approximately 90 minutes in length) will evaluate heavy drinking 
smokers’ perceptions about smoking and heavy drinking and their associated consequences, 
strategies they find helpful for managing these problems, and their preferences for components 
they would prefer in an integrated intervention to address both. We will use the results of the focus 
groups to create the pre-pilot version of the intervention that will take place in Phase 2 of the study. 
The PI, Dr. Lisa Fucito, along with Denise Romano, APRN, will facilitate the focus group 
interviews. Dr. Fucito and Ms. Romano will provide discussion prompts, moderate discussion, and 
maintain an open, supportive environment. They will utilize structured group discussion with 
standardized procedures (including audio-taping and think aloud methods). 
A research staff member will also be present to hand transcribe smokers’ responses as a back-up 
for the audio-recorders. The focus groups will be audiotaped and later transcribed. 
 
Participants will be compensated $15 for completing the intake and $45 for completing the focus 
group interview. 
 
At the end of the focus groups, transcripts will be reviewed and analyzed according to standardized 
coding procedures such as noting consistent themes, their frequency, and listing representative 


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quotations from transcripts. We will analyze detailed field notes from interviews with a content 
analysis approach that incorporates data display matrices to identify themes across participants. 
Questionnaire data will be analyzed descriptively, focusing on severity and frequency of smoking 
behavior and alcohol use. Common themes among smokers’ suggestions will guide the 
intervention components for the pre-pilot study and pilot RCT in Phases 2 and 3. 
 
We will not directly advertise the focus groups. Instead, we will rely on referrals from the 
Substance Abuse Treatment Unit clinic and from an ongoing study of varenicline for heavy 
drinking smokers, entitled “Multi-Site Study: Varenicline Treatment of Alcohol Dependent 
Smokers” (HIC#1106008598). The latter study is recruiting heavy drinking smokers for a clinical 
trial. A high percentage of potential participants who are screened are ineligible for the trial. 
Individuals who are not eligible for the varenicline trial will be provided with an opportunity to 
screen for this focus group study upon completion of their intake for the clinical trial 
(HIC#1106008598). 
 
Phase 2: 
Open-label Pre-Pilot Study: Heavy drinkers interested in quitting smoking (N=10) assigned to 8 
sessions over 12 weeks of CBT for SA + 12 weeks of varenicline. 
 
During this phase of the project, Dr. Fucito will develop and refine an integrated cognitive- 
behavioral psychotherapy intervention for smoking and heavy drinking (CBT for SA) and related 
therapist training materials in collaboration with study consultants. An initial manual will be tested 
in an iterative fashion with a small sample of heavy drinkers interested in quitting smoking (N=10). 
Dr. Fucito will be the study therapist for these participants. The same sample selection criteria, 
recruitment methods, study procedures, and assessments described for the RCT pilot study below 
will be used. Dr. Fucito will then review the results of the pre-pilot study with consultants to devise 
the final manual, therapist training materials, and adherence/competence process rating system for 
the RCT. 
 
Several strategies will be utilized to evaluate the feasibility, utility, and acceptability of the 
manualized interventions. All sessions will be audiotaped. Participants will complete therapy 
satisfaction questionnaires after each session to rate positive and negative session aspects, their 
comprehension of the session content, perceived utility of the material, and their intentions to 
follow through with session assignments and recommendations. Participants’ reported utilization 
of previously taught strategies/techniques at the beginning of sessions will also provide an index 
of the utility of specific intervention components. Dr. Fucito will record her experience 
implementing the interventions after each session. A trained RA will conduct taped individual 
structured exit interviews with participants to further assess participants’ satisfaction with the 
interventions. Descriptive statistics will be used to analyze all of these process outcomes. After 
conducting psychotherapy sessions, Dr. Fucito will review session tapes, participant feedback and 
progress, and her experience conducting the sessions with consultants at regular meetings. The 
sessions will continue to be modified until they are deemed acceptable by participants based on 
satisfaction questionnaires. 
 
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RCT Pilot Study: Heavy-drinking smokers interested in either quitting smoking or reducing their 
drinking (N=40) will be randomly assigned to 1 of 3 treatment conditions. At intake, participants 
will be asked which behavior they would like to change using scores on the Contemplation Ladder 
(see measures section). If participants have the same score for both, we will ask them to choose 
which one they would like to change. 
For participants who state that they would prefer to quit smoking, we will randomly assign them 
to: 
(1) up to 12 sessions over 12 weeks of CBT for SA + 12 weeks of varenicline or 
(2) up to 12 sessions over 12 weeks of standard smoking counseling (SC) + 12 weeks of 
varenicline 
For participants who state that they would prefer to reduce their drinking, we will randomly assign 
them to: 
(1) up to 12 sessions over 12 weeks of CBT for SA + 12 weeks of varenicline or 
(2) up to 12 sessions over 12 weeks of standard alcohol counseling (AC)+ 12 weeks of 
varenicline . 
 
A detailed flow-chart of study procedures for Phase 3 is provided in the tables below based on 
participant condition assignment for either phase (i.e., CBT for SA, SC, or AC). Phase 2 will follow 
the same timeline except pre-pilot participants will not be asked to attend 2 research follow-up 
appointments. 
 
Table of Study Procedures - Pre-Pilot 
Timeframe 
Study Phase 
Study Procedures 
Week -1 
Intake 
Assessment & screening 
Week 0 
Treatment 
Receive counseling, start varenicline, health feedback 
Week 1 
Treatment 
Receive counseling & varenicline 
Week 2 
Treatment 
Receive counseling & varenicline 
Week 3 
Treatment 
Receive counseling & varenicline 
 
 
 
Week 5 
Treatment 
Receive counseling, varenicline, health feedback 
 
 
 
Week 7 
Treatment 
Receive counseling & varenicline 
 
 
 
Week 9 
Treatment 
Receive counseling,varenicline, health feedback 
Week 10 
Treatment 
 
Week 11 
Treatment 
Final counseling appointment, stop varenicline, health feedback 
 
 
Table of Study Procedures - Pilot 
Timeframe 
Study Phase 
Study Procedures 
Week -1 
Intake 
Assessment & screening 
Week 0 
Treatment 
Receive counseling, start varenicline, health feedback 
Week 1 
Treatment 
Receive counseling & varenicline 
Week 2 
Treatment 
Receive counseling & varenicline 
Week 3 
Treatment 
Receive counseling & varenicline 
Week 4 
Treatment 
Optional treatment/research appointment 
Week 5 
Treatment 
Receive counseling, varenicline, health feedback 
Week 6 
Treatment 
Optional treatment/research appointment 
Week 7 
Treatment 
Receive counseling & varenicline 
Week 8 
Treatment 
Optional treatment/research appointment 


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Week 9 
Treatment 
Receive counseling & varenicline 
Week 10 
Treatment 
Optional treatment/research appointment 
Week 11 
Treatment 
Final counseling appointment, final health feedback, stop varenicline 
Week 15 
Follow-up 
Research follow-up appointment 
Week 27 
Follow-up 
Research follow-up appointment 
 
 
 
The following procedures only apply to Phases 2 and 3 of the study. 
Recruitment: 
Participants will be recruited through advertisements, press releases, posters/flyers, scratch pads, 
mailings to physicians, fax referral forms from physicians, and through websites (e.g., 
www.quitnet.com, www.google.com, www.craigslist.com, www.facebook.com). Participants will 
also be recruited through the Yale New Haven Hospital Tobacco Treatment Service. Patients who 
enroll in the Service and meet study eligibility criteria, will be given the option to participate. 
Prospective participants will be screened by phone and via a web-based screener on initial 
eligibility criteria. 
 
Screening (Week -1): 
Those who appear eligible on the basis of a phone screen or webscreener will be invited to attend 
an intake appointment with a study investigator or a research assistant at the Substance Abuse 
Treatment Unit (SATU), Yale New Haven Hospital Tobacco Treatment Service, or the Connecticut 
Mental Health Center (CMHC), where informed consent will be obtained prior to any other 
procedures. Following this, the participant will meet with a research assistant for an intake session. 
Participants will be asked to provide a photo ID (i.e., driver’s license, passport, state ID) to verify their 
identity and contact information. Complete medical and tobacco use histories, breath CO levels, breath 
alcohol levels will be obtained from all participants as well as urine samples for laboratory screening 
tests, including urine drug screening. Participants who screen positive for drugs, other than marijuana, 
will not be eligible for the study. Urine drug screens are performed using dip sticks which provide 
immediate results. The dip sticks are disposed of after obtaining drug screening results and no urine 
samples are further retained for this purpose. The results of urine drug screening are not included in 
the participant’s research record. 
 
If participants meet initial eligibility criteria, they will then be evaluated for final medical eligibility 
by a study advanced practice nurse or study physician. The research assistant and nurse/physician 
will review the risks, benefits and procedures involved in study participation and help eligible 
participants select a potential quit date which they will then finalize with their smoking counselor. 
Before starting varenicline, pregnancy tests will be performed on all females of child bearing 
potential. If a participant is found to be pregnant, she will be excluded from the study and referred 
for other smoking cessation treatment. Those participants who meet inclusion criteria following 
the intake appointment will be assigned to 1 of 3 study groups (CBT for SA, SC, or AC) depending 
on the study phase. In the pre-pilot study, all participants will be assigned to CBT for SA and 
varenicline. In the pilot study, participants will be randomly assigned to either CBT for SA, SC, 
or AC plus varenicline. Participants will be blind to participant counseling assignment. Research 
and clinical staff will not be informed of the study hypotheses. Randomization will be stratified by 
gender (male, female) in order to balance treatment groups with respect to the proportion of women 
and men. 


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Treatment Phase - CBT for SA (Weeks 0 to 11): 
Participants will begin varenicline on the first day of counseling. 
Pre-pilot: In the pre-pilot study, Dr. Fucito will work with participants to identify the ideal smoking 
quit date. It is anticipated that participants will quit smoking within the first 2 weeks of treatment. 
This date will then be finalized for the RCT pilot study. At the first session (Week 0), clients will 
receive their personalized smoking, drinking, and health feedback report which they will review 
with their study therapist. The personalized feedback information will be repeated 3 more times 
during treatment to monitor participants’ progress (i.e., Weeks 5, 8 or 9, and 11 – end of treatment). 
Participants will attend appointments to complete research assessments with a research assistant 
and receive individual counseling with a study therapist. Sessions will be weekly for the first 4 
weeks (weeks 0, 1, 2, 3), then bi-weekly (weeks 5, 7, and 9). They will then return the two weeks 
later (Week 11) for termination. Counseling will focus on teaching skills to manage smoking cues 
and create environmental conditions that promote behavior change as well as behavioral activation 
and anger management techniques to promote positive mood. Participants will learn these skills 
generally and how to specifically apply them to quitting smoking and reducing their drinking. 
Sessions will utilize a motivational style to minimize participant resistance and emphasize personal 
responsibility for change. Smoking and alcohol use will be discussed at every session and 
participants will monitor both behaviors outside of session. Sessions will involve open-ended 
discussions of smoking and drinking patterns, pros and cons of smoking and drinking, how 
drinking and smoking are associated, history of prior quit attempts for both, the role of alcohol in 
smoking relapse, normative feedback on drinking, and preliminary drinking goal setting. 
Participants will be advised to consider abstaining from drinking for the first 2 weeks of quitting 
smoking and ideally for the duration of smoking cessation treatment, regardless of their long-term 
drinking goals. They will also be provided with specific strategies for moderating their alcohol 
use. Counseling will also include a review of participants’ reactions to varenicline and medication 
compliance. We will reduce the varenicline dose for any participants who report difficulty 
tolerating higher doses. 
 
Pilot RCT: 
In the pilot study, study therapists will work with participants to plan a smoking quit date within 
the first 2 weeks of treatment. For participants receiving treatment through the Yale New Haven 
Hospital Tobacco Treatment Service, Dr. Fucito will serve as the study therapist. The smoking 
cessation treatment provided to study participants by Dr. Fucito through the Tobacco Treatment 
Service in this study is a reimbursable service and not a research cost. At the first session (Week 
0), clients will receive their personalized smoking, drinking, and health feedback report which they 
will review with their study therapist. The personalized feedback information will be repeated 2 
more times during treatment to monitor participants’ progress (i.e., 1 time between Weeks 5-7 and 
Week 11 – end of treatment). Participants will attend appointments to complete research 
assessments with a research assistant and receive individual counseling with a study therapist. 
Sessions will be weekly for the first 4 weeks (weeks 0, 1, 2, 3), then the option to have bi-weekly 
thereafter (weeks 5, 7, and 9) or to continue weekly sessions until termination. They will then 
return for a final visit for termination (Week 11). Regardless of their decision, we will inform them 
that in order to get a final feedback report they will need to come in at Week 9 or 10 for a blood 
draw. Counseling will focus on teaching skills to manage smoking and drinking cues and create 
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skills, and anger management techniques to promote positive mood. Participants will learn these 
skills generally and how to specifically apply them to quitting smoking and reducing their drinking. 
Sessions will utilize a motivational style to minimize participant resistance and emphasize personal 
responsibility for change. Smoking and alcohol use will be discussed at every session and 
participants will monitor both behaviors outside of session. Sessions will involve open-ended 
discussions of smoking and drinking patterns, pros and cons of smoking and drinking, how 
drinking and smoking are associated, history of prior quit attempts for both, the role of alcohol in 
smoking relapse, normative feedback on drinking, and preliminary drinking goal setting. 
Participants will be advised to consider abstaining from drinking for the first 2 weeks of quitting 
smoking and ideally for the duration of smoking cessation treatment, regardless of their long-term 
drinking goals and to consider reducing their smoking during the first 2 weeks of making drinking 
changes and ideally for the duration of alcohol treatment, regardless of their long-term smoking 
goals. They will also be provided with specific strategies for moderating their alcohol use and 
reducing their smoking. Counseling will also include a review of participants’ reactions to 
varenicline and medication compliance. We will reduce the varenicline dose for any participants 
who report difficulty tolerating higher doses. 
 
Treatment Phase – SC (Weeks 0 to 11) 
Participants will begin varenicline on the first day of counseling and plan a smoking quit date 
within the first 2 weeks of treatment. At the first session (Week 0), clients will receive their 
personalized smoking and health feedback report which they will review with their study therapist. 
The personalized feedback information will be repeated 2 more times during treatment to monitor 
participants’ progress (i.e., 1 time between Weeks 5-7 and Week 11 – end of treatment). 
Participants will attend appointments to complete research assessments with a research assistant 
and receive individual counseling with a study therapist. Sessions will be weekly for the first 4 
weeks (weeks 0, 1, 2, 3), then the option to have bi-weekly thereafter (weeks 5, 7, and 9) or to 
continue weekly sessions until termination. They will then return for a final visit for termination 
(Week 11). Regardless of their decision, we will inform them that in order to get a final feedback 
report they will need to come in at Week 9 or 10 for a blood draw. In the SC control condition, 
counseling will focus on teaching skills to manage smoking cues and create environmental 
conditions that promote behavior change as well as behavioral activation, relaxation skills, and 
anger management techniques to promote positive mood. Participants will learn these skills 
generally and how to specifically apply them to quitting smoking. Sessions will utilize a 
motivational style to minimize participant resistance and emphasize personal responsibility for 
change. Smoking will be discussed at every session and participants will monitor their behavior 
outside of session. Sessions will involve open-ended discussions of smoking patterns, pros and 
cons of smoking, history of prior quit attempts for smoking, and preliminary smoking goal setting. 
. Consistent with Tobacco Clinical Practice Guidelines for smoking cessation in heavy drinkers(81), 
participants will also receive brief advice to consider abstaining from alcohol or moderating their 
alcohol use for at least 2 weeks after quitting smoking and preferably during the duration of 
treatment. They will be provided with specific strategies for reducing their smoking. Counseling 
will also include a review of participants’ reactions to varenicline and medication compliance. We 
will reduce the varenicline dose for any participants who report difficulty tolerating higher doses. 
 
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Participants will begin varenicline on the first day of counseling and plan a smoking quit date 
within the first 2 weeks of treatment. At the first session (Week 0), clients will receive their 
personalized drinking and health feedback report which they will review with their study therapist. 
The personalized feedback information will be repeated 2 more times during treatment to monitor 
participants’ progress (i.e., 1 time between Weeks 5-7 and Week 11 – end of treatment). 
Participants will attend appointments to complete research assessments with a research assistant 
and receive individual counseling with a study therapist. Sessions will be weekly for the first 4 
weeks (weeks 0, 1, 2, 3), then the option to have bi-weekly thereafter (weeks 5, 7, and 9) or to 
continue weekly sessions until termination. They will then return for a final visit for termination 
(Week 11). Regardless of their decision, we will inform them that in order to get a final feedback 
report they will need to come in at Week 9 or 10 for a blood draw. In the AC control condition, 
counseling will focus on teaching skills to manage drinking cues and create environmental 
conditions that promote behavior change as well as behavioral activation, relaxation skills, and 
anger management techniques to promote positive mood. Participants will learn these skills 
generally and how to specifically apply them to reducing their drinking. Sessions will utilize a 
motivational style to minimize participant resistance and emphasize personal responsibility for 
change. Drinking will be discussed at every session and participants will monitor their behavior 
outside of session. Sessions will involve open-ended discussions of drinking patterns, pros and 
cons of drinking, history of prior attempts at changing drinking, and preliminary drinking goal 
setting. Participants will also receive brief advice to consider reducing their smoking to support 
long-term improvements in drinking. They will be provided with specific strategies for reducing 
their drinking. Counseling will also include a review of participants’ reactions to varenicline and 
medication compliance. We will reduce the varenicline dose for any participants who report 
difficulty tolerating higher doses. 
 
A total of 40 participants will be randomized to the RCT. 
 
Varenicline Titration Schedule: 
Tablets contain either 0.5 mg or 1mg active varenicline. Whenever participants start the study 
medication their dose will be slowly increased as follows: 
Days 1-3: one 0.5mg tablet once per day 
Days 4-7: one 0.5mg tablet twice per day 
Day 8 – Week 11: one 1mg tablets twice per day 
 
If participants experience any unpleasant side effects their medication dosage can be decreased. The 
study physician or nurse will check in with you by phone three days after you start your medication. 
 
3-Day Call Back Phone Call: 
In both conditions, within 3 days of either quitting smoking or changing their drinking, , 
participants will be briefly contacted by their study therapist to assess their experience 
quitting/reducing. 
 
Research Follow-up (Phase 3 only: Weeks 15 and 27): 
Participants will return 4 weeks and 16 weeks after completing treatment to complete an exit 
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Participants will complete a SAFTEE (Systematic Assessment for Treatment Emergent Events) at 
each research appointment. Medication will be dispensed at the counseling appointments, and any 
unused medication will be returned. Breath CO levels, breath alcohol levels, blood pressure, 
weight, and self-reports of tobacco and alcohol use will be obtained at each appointment, and 
questionnaires will be administered. Urine cotinine and ethyl glucuronide levels will be measured 
at intake and Weeks 0, 11, 15, and 27 to provide indices of smoking and alcohol exposure. Blood 
samples for health feedback will be obtained at intake, Weeks 2-3 (pre-pilot only), 5-7, and 9- 10. 
A urine pregnancy test will be done for all menstruating before beginning the study and monthly during 
treatment. A positive pregnancy test will result in the participant being excluded from the study. Four 
weeks and 16 weeks after the treatment phase of the study is completed (i.e., Weeks 15 and 27), 
participants in Phase 3 only will return to the clinic to assess cigarette and alcohol use, breath CO, 
urine cotinine ethyl glucuronide, weight gain, and adverse events. 
 
Retention of Participants: 
To enhance retention, participants will be paid $10 for attending the intake and research 
appointments, and $20 each for the research follow-up appointments. The pre-pilot study involves 
an intake session and 8 research appointments for a total of $90 per participant. The RCT study 
involves an intake session, up to 12 research appointments, and two follow up sessions for a total 
of up to $170 per participant. Several procedures used to enhance adherence and retention include: 
(1) obtaining participant contact information and ≥2 collateral informants at enrollment; (2) 
thoroughly explaining study procedures; (3) rapidly assigning participants to treatment; (4) 
uniformly implementing procedures for non-adherence across study conditions; (5) providing 
appointment cards and reminder calls for all appointments; (6) contacting participants who miss 
sessions; (7) closely monitoring side effects, symptoms, clinical status, and participant concerns; 
(8) ensuring availability of staff for addressing concerns; and (9) reimbursing participants for time 
and effort(82). Participants who drop out of treatment or are lost to follow-up will be compared to 
study completers to inform the interpretation of study results and improve retention rates in the 
next phase of intervention testing. Scheduled research data will continue to be obtained for 
participants who need to withdraw from treatment or who discontinue treatment. 
 
For participants who discontinue the study during the treatment phase and are unreachable by 
phone or unresponsive to phone calls, we will mail a letter with a follow-up questionnaire and self- 
addressed stamped envelope. Some participants may indicate that they are unable to come to the 
clinic for an interview. If these participants are willing to meet a member of the research team at a 
public place, we will meet with them to collect follow-up data, including a breath carbon monoxide 
test, urine cotinine and ethyl glucuronide, weight, and, questionnaire data. 
 
Study Counselors: 
Dr. Fucito will be the pre-pilot study therapist. Four to six study therapists with experience in CBT 
and motivational substance abuse interventions will be the RCT therapists. Dr. Fucito is available 
to serve as one of the study therapists for the RCT but other therapists will be prioritized over Dr. 
Fucito; Dr. Fucito will serve as the study therapist for participants enrolled through the Tobacco 
Treatment Service at Yale New Haven Hospital. Therapists will be crossed across treatment 
conditions (i.e., all therapists will provide all treatments). Therapists will not be informed of the 
study hypotheses to reduce potential demand characteristics. The crossed design has the advantage 
of reducing potential therapist effects on treatment outcome(83). Although a contamination across 
conditions is a potential disadvantage of this crossed design(83), the design has the advantage of 


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reducing potential therapist effects which are large and could be problematic given the small 
sample size (84). To reduce contamination, therapists will be carefully selected and trained, 
provided with close supervision, and only informed of treatment assignment on the day of the 
session, therapy will be delivered using treatment manuals, and therapist will also be added as a 
random factor in analyses(84). 
 
Counselor Training Seminars and Guided Feedback: 
Counselors will receive careful training and close supervision by Dr. Fucito. Prior to treating 
participants, counselors will attend a training seminar over the span of 1 week (approximately 1 
hour per day for each counselor for the CBT for SA, SC, and AC conditions). Counselor training 
will largely focus on learning how to deliver personalized health feedback about smoking- and 
drinking-related risks and cognitive-behavioral techniques to promote changes in smoking and 
drinking for heavy drinking smokers. Treatment manuals will be developed for all counseling 
conditions. 
 
Counselor Certification: 
Following this training, counselors will be assigned a training case that will be audiotaped. 
Specialist performance on the training cases will be evaluated on the basis of ratings by Dr. Fucito 
on an adapted version of the Yale Adherence and Competence Scale (YACS) (85) created 
specifically for this study by Dr. Fucito. Dr. Fucito will listen to counseling sessions from each 
counselor, rate sessions using the YACS, and give guided feedback to counselors in both 
conditions to help them develop their skills and meet certification standards that would permit 
them to receive Pilot Study participants. Dr. Fucito will certify counselors who use sufficient 
counseling strategies (an average of 4 on a 7-point scale across all adherence items) with a 
minimum of adequate skill (an average of 4 on a 7-point scale across all competence items). Dr. 
Fucito will continue to coach counselors until they become certified. During this training phase, 
there will be some leeway to alter the counseling protocols based on feedback from counselors and 
participants. 
 
Counselor Supervision: 
The CBT for SA and SC alone counseling procedures will be overseen by Dr. Fucito, with input 
from study consultants on an ongoing basis, and they will respond to problems and issues as they 
arise. Beginning with all training cases and continuing throughout the Phase II pilot study, all 
counselors will receive regular supervision and re-training on an individual and group basis. 
Supervision sessions will include review of study procedures, updates of case materials, review of 
digital recordings, and opportunities to discuss supervisor ratings. Continual review and 
supervision will help ensure that counselors’ skills remain at a high level and prevent the use of 
counseling techniques or strategies that are inconsistent with the counseling protocol. Supervision 
will ensure that counselors are primarily providing integrated cognitive-behavioral techniques for 
smoking and heavy drinking in the CBT for SA condition and primarily providing standard 
smoking counseling for the SC alone condition and standard alcohol counseling in the AC alone 
condition. 
 
Adherence and Competence Ratings: 
Establishing discrimination between the three conditions (CBT for SA versus SC or AC) is a 
priority. After completion of intervention delivery, tape ratings for fidelity analyses will be 


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conducted by 5 experienced raters blind to counselors’ intervention condition. All therapy sessions 
will be digitally tape recorded and saved for supervision and training of study counselors and 
fidelity analysis. Consistent with other psychotherapy studies (e.g., Project MATCH)(79), a 
percentage of tapes collected post-intervention will be rated and assessed [i.e., approximately 20% 
(88/440)] which will consist of an equal number of tapes for each rater broken down as 44/44 for 
CBT for SA versus SC. Prior to tape rating, raters will receive training in fidelity analysis. 
Following training, intrarater reliability will be established by having all 5 raters rate an initial 
sample of approximately 10 tapes. A second calibration sample of 5 tapes will then be conducted 
to focus additional training efforts on items where reliability is not adequate (i.e., 5 raters x 5 
tapes). A third calibration sample of 5 tapes will be conducted midway through the study tape 
rating phase to ensure raters maintain high levels of reliability (i.e., 5 raters x 5 tapes). All session 
recordings will be accessed via a secure server. Recordings will be loaded onto this server and 
accessed as links after logging in with a password. All recordings will be available to play but not 
to download, ensuring that confidential session data is not saved anywhere but on the secure server. 
This method has been used successfully by our research team for fidelity analysis in prior research. 
Thus, the requisite knowledge, programming, and infrastructure is in place to implement this 
system for the current study. 
 
Assessments 
 
We plan to assess a range of pretreatment participant characteristics, process measures, measures 
of treatment safety, and treatment outcomes. Intake assessments are designed to ensure that 
patients meet eligibility criteria and assess important predictor variables. After the narrative 
description of all assessments provided below, a schedule of the assessments is presented in Table 
2. 
 
Screening Measures 
 
Medical History and Demographic Questionnaires: These questionnaires will obtain: (1) basic 
demographic information including age, gender, marital status, employment status, occupation and 
(2) alcohol/drug history. Medical history will also be obtained prior to randomization. The medical 
history and demographic measures will be administered for screening. 
 
Diagnostic and Substance Use History: Sections of the Structured Clinical Interview (SCID) will 
be used to provide current and lifetime diagnoses of substance use and other Axis I psychiatric 
disorders at the recruitment session for all study phases. Specifically, participants will be 
characterized on their history of alcohol, drug, eating, panic disorder, psychosis, and mood 
disorders. The alcohol and nicotine sections of the SCID will be repeated at the end of treatment 
(EOT) and at follow up appointments. 
 
Vitals – Two blood pressure readings will be obtained at each visit; the first by a research assistant 
and the second by the study physician or nurse. 
 
Body Weight: will be measured at baseline, during treatment, and at follow-up in order to evaluate 
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Menstrual Cycle Assessment: All women will be assessed for their menstrual/gynecological 
status by self-report. Additionally, retrospective assessments of premenstrual symptoms will be 
obtained. 
 
The Clinical Institute Withdrawal Assessment for Alcohol (Revised) (CIWA-AR): will be used to 
assess alcohol withdrawal symptoms for all study phases. The CIWA is a reliable 10-item 
instrument designed to assess severity of current withdrawal syndrome(86). 
 
Columbia Suicide Severity Rating Scale: This questionnaire assesses past and current suicidal 
ideation, intent, and attempts (97). It will be used to monitor the possible suicidality of all study 
participants for all study phases, as well any potential contraindications. This will be assessed at 
all timepoints. 
 
Urine pregnancy – A urine pregnancy test will be performed at baseline and monthly during 
treatment. Tests will be administered at the next assessment point for all menstruating female 
participants who miss the pregnancy test at their prior appointment. In addition, a menstrual cycle 
timeline is completed at each appointment during treatment, and if their menses is late, a urine 
pregnancy test will be obtained. Pregnant women will be referred for other treatment. 
 
Biological Markers of Tobacco and Alcohol Use 
 
Carbon monoxide levels and urine cotinine levels will be monitored at intake to determine 
participant eligibility and to verify smoking abstinence during treatment. Although CO levels are 
typically used to verify abstinence during treatment, measurement of urine cotinine levels should 
cover a wider time window than exhaled carbon monoxide. Carbon monoxide levels will be 
measured using a Vitalograph Breath CO, from Vitalograph Inc. (Lenexa, Kansas), which is a 
precision instrument for detecting carbon monoxide in exhaled breath. Carbon monoxide is known 
to have a half-life of 2 hours in an active human (87). This instrument measures CO in the range 
of 0-500 ppm and has no cross sensitivity to hydrogen or other positive ions. Dr. Peter Jatlow will 
measure Cotinine levels in urine. Urine samples for cotinine will be obtained at intake and Weeks 
0, 11, 15, and 27. Comparison of CO and cotinine during treatment with intake values will provide 
a within participant quantitative measure of changes in nicotine exposure and thus allow 
characterization of partial responders. Only a breath CO will be obtained for Phase 1 screening. 
 
Ethyl glucuronide (EtG) provides a sensitive and reliable biomarker of recent alcohol consumption 
and is detectable in urine for up to three days after drinking depending upon the amount 
consumed[117-120]. A urine sample will be obtained at intake, Weeks 0, 11, 15 and 27. 
Comparison of urine EtG levels during treatment taken monthly with baseline values will provide 
a within participant quantitative approximation of relative changes in alcohol exposure. For other 
time-points, EtG concentrations will be assayed only if a subject self-reports abstinence or no 
heavy drinking and will be used in secondary analyses of composite outcomes based on self-report 
confirmed by EtG (see statistical section). Heavy exposure to non-beverage sources of ethanol 
such as some mouthwashes and hand washes, particularly the latter, can confound interpretation 
of urinary EtG assays and will be monitored. Normalization to urine creatinine concentration will 
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The EtG assays will be performed at Yale. Yale researchers are currently characterizing the 
relationship between EtG concentration over time and their inter-individual and within individual 
variation over a range of ethanol doses (RO1AA018664) to develop more definitive cut-offs that 
can be used to confirm no heavy drinking. However, current knowledge of the pharmacokinetics 
of EtG allows the following conclusions. A concentration <100 ng/mL indicates that any alcohol 
consumption during the past 24 hrs is unlikely[120]. A concentration >500 ng/mL refutes a self 
report of "no heavy drinking" in the past 1-3 days[121] with several unavoidable limitations 
intrinsic to the pharmacokinetics of EtG. A low EtG concentration could be either consistent with 
light drinking during the prior 24 hours or with heavy drinking several days previously. Even light 
drinking on the day of the clinic visit, a short time prior to sample collection, could exceed 
500ng/mL. Thus, final interpretations regarding heavy drinking for biochemical confirmation of 
self-report require integration with information from self-reports about the recency and quantity 
of alcohol consumed. Dr. Jatlow and a second reviewer will make these determinations without 
knowledge of the participant’s clinical course or treatment condition. EtG Assay: Aliquots of spot 
urine samples will be stored at -20degrees within one hour of collection and subsequently 
transferred to a -70 degree freezer for longer-term storage. EtG will be measured using LC coupled 
to tandem mass spectrometry (LC/MS/MS) in the negative ion mode with deuterium labeled EtG 
as internal standard. This procedure, modified from published assays [119, 122] is validated and 
running. 
 
Breath alcohol tests (BAC) will be conducted at each appointment to assess recent alcohol 
consumption. Participants will be asked to blow into a small tube for five seconds. The purpose of 
this test is to determine if participants can give consent and/or complete assessments and to assess 
potential risk of harm (e.g., driving above the legal limit). Potential participants will not be able to 
provide consent unless they have a blood alcohol level of .00. Research assessments may be 
administered to participants who have blood alcohol levels of less than or equal to .04. Participants 
who have blood alcohol levels higher than .00 will be reassessed to determine if their blood alcohol 
level is rising. Participants with blood alcohol levels above the legal drinking limit, who also drove 
to their appointment, will be asked to take alternate transport. The study staff will arrange for a 
taxi for participants in this case. Blood alcohol levels will be assessed prior to screening and focus 
groups for Phase 1. Participants who have blood alcohol levels higher than .00 will not be permitted 
to participate in the focus group interview. They will be rescheduled to attend another session. 
 
Health Profile Measures - General Health Biomarkers (these will all be measured at intake and 
then weeks 2 or 3 (pre-pilot only), between 5 and 7 (treatment midpoint), and 9 or 10 (treatment 
completion)) 
 
Blood Chemistry Profiles: This comprehensive metabolic evaluation is used to assess general 
health and any potential adverse effects of the medication. The profile includes an evaluation of 
kidney and liver functions, renal function, glucose, cholesterol levels and blood count. 
 
C-reactive protein test (CRP) and other makers of inflammation will be conducted at intake, then 
weeks 2 or 3,treatment midpoint (i.e., between Weeks 5 and 7), and treatment completion (i.e., 9 
or 10). A CRP test is a blood test that measures the amount of a protein called c-reactive protein 
in the blood, C-reactive protein measures levels of inflammation in the body. Heavy alcohol 
consumption and smoking can cause such inflammation, thus inflammatory markers could act as 


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a measure of physical damage done to the body as a result of both. By repeating the tests during 
treatment, we will be able to observe whether decreases in heavy drinking and/or smoking are 
associated with decreases inflammatory markers. 
 
Plasma carotenoids: Carotenoids are an important component of the antioxidant defense system in 
humans. Blood samples will be obtained at intake, at Weeks 3, treatment midpoint (i.e, between 
Weeks 5 and 7), and treatment completion (i.e., 9 to measure levels of plasma carotenoids. 
Participants will be informed of their carotenoid levels as part of their health feedback. This is 
assessed for the pre-pilot only. 
 
Lung Function will be measured using a portable spirometer. At intake and Weeks 3 (pre-pilot 
only), between 5 and 7, and 9 or 10, participants will be asked to exhale a deep breath into a sensor 
for a minimum of six seconds, three different times. Participants will be presented with a brief 
description of the measures and a qualitative interpretation of the test results (i.e., normal 
functioning, mild/moderate/severe impairment, normal or reduced airflow, lung age, etc.). 
 
Health Profile Measures - Cancer Risk 
Lung cancer and oral cancer risks: Self-report data provided at intake pill be put into empirically 
derived cancer risk calculators. Cancer risks will be calculated at intake. Participants will be 
presented with a brief description of the cancer risks and a qualitative interpretation of the 
calculated results in their Week 0 feedback. These risks will not be calculated for subsequent 
feedback weeks because the short duration of smoking cessation and reductions in drinking will 
not likely have an impact on this calculation in the short term. This is assessed for the pre-pilot 
only. 
 
The oral cancer risk calculator models the excess odds ratio to assess risk by total exposure (pack- 
years) and its modification by exposure rate (cigarettes/day) (124-126). 
 
The CLEAR lung cancer risk prediction tool (123) will be used to quantify a smoker’s risk of 
developing lung cancer in the next five, 10, or 15 years. This tool is based on the participant’s age, 
sex, smoking history, medical history, family history of cancer, and past exposures to asbestos or 
wood dust. 
 
Nicotine and Alcohol Use Measures 
 
Smoking and Alcohol Use History Questionnaire: At intake for all study phases, this questionnaire 
will assess basic smoking status and history such as number of years smoked, type of cigarettes 
smoked, number and length of quit attempts, amount of money spent on smoking, concomitant 
smoking related health symptoms and syndromes. Similar questions will be asked about drinking 
history: age of first use, number and length of quit attempts, amount of money spent on drinking, 
concomitant drinking related health symptoms and syndromes. 
 
Timeline Followback Interview (TLFB): This standardized, validated, and reliable experimenter- 
administered rating scale will be used to obtain quantity and frequency estimates of nicotine, 
alcohol and other drug consumption for a 90-day period prior to study enrollment for all study 
phases (88). It uses a calendar prompt and a number of other memory aids (e.g., holiday, payday, 


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and other personally relevant dates) to facilitate accurate recall of drug use during the targeted 
period, and it has demonstrated adequate levels of reliability and validity when administered as an 
in-person interview. We will use the calendar to record alcohol and tobacco use on a daily basis 
throughout the study. 
 
Fagerström Test for Nicotine Dependence: This six item scale (89) will be used to measure severity 
of dependence on nicotine at intake for all study phases. It has an internal consistency of .61, and 
its total score is closely related to biochemical measures of intensity of smoking. An additional 
dichotomous item will be added to assess whether the participant wakes in the middle of the night 
to smoke. 
 
Nicotine Withdrawal Checklist: This questionnaire (90) measures the severity of eight withdrawal 
symptoms on five point Likert scales. This will allow an examination of the relationship between 
self-reported levels of nicotine withdrawal, biochemical measures of nicotine use, cigarette 
craving, cigarette consumption, and sleep disturbance. This will be assessed at all timepoints. 
 
Tiffany Questionnaire of Smoking Urges-Brief (QSU-Brief): The QSU-Brief is a ten-item 
questionnaire that assesses the structure and function of smoking urges (91). Participants will be 
asked to indicate how strongly they agree or disagree with each statement on a Likert-type scale 
of 1 (strongly agree) to 7 (strongly disagree). The Tiffany scale characterizes urges to smoke in 
response to two separate factors. The first factor is characterized by both desire and intention to 
smoke, and the second is related to relief from nicotine withdrawal or negative affect. This will be 
assessed at all timepoints. 
 
Contemplation Ladders for Smoking and Drinking: The Contemplation Ladders are 1-item 
measure of readiness to change rated on an 11-point scale (e.g., 0 = no thought of quitting to 10 = 
taking action to quit). The Smoking and Alcohol ladders will be administered at intake. 
 
Alcohol Dependence Scale (ADS): This 25-item questionnaire assesses the severity of alcohol 
dependence including withdrawal symptoms, tolerance, impaired control over drinking, 
compulsion to drink, and drink-seeking behavior (93). This will be assessed at intake. 
 
Obsessive Compulsive Drinking Scale (OCDS): This 14-item questionnaire assesses thoughts 
about drinking, urges to drink, and the ability to resist these thoughts and urges (94). This will be 
assessed at all timepoints. 
 
Alcohol Use Disorders Identification Test (AUDIT): This ten-item questionnaire developed by the 
World Health Organization screens for hazardous or harmful alcohol consumption (134). 
Participants' AUDIT score will be provided to them on their personalized feedback report to given 
them an indication of their potential risk of harm from drinking. 
 
Short Inventory of Problems (SIP-2R): This fifteen-item questionnaire measures physical, social, 
intrapersonal, impulsive, and interpersonal consequences of alcohol consumption and will be 
included in participant’s personalized feedback reports (135). 
 
Psychological Related Measures 


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Positive and Negative Affect Schedule (PANAS): The PANAS is a self-report scale that contains 
two subscales to assess positive and negative mood. Both subscales contain 10 items that are 
measured on a Likert-type scale of 1 (not at all) to 5 (extremely) (96). This will be assessed at all 
timepoints. 
 
Coping strategies to avoid cues: A questionnaire will be designed for this study to assess the 
participants’ use of cognitive and behavioral coping strategies to avoid smoking and alcohol cues. 
This will be assessed at all timepoints. 
 
Acceptance and Action Questionnaire II (AAQ II) (114): This 7-item questionnaire will measure 
the construct of psychological flexibility using a 7-point Likert type scale. It will be assessed at 
intake, week 11, and week 27. 
 
Avoidance and Inflexibility Scale (AIS) (115): This 13-item scale will measure distress intolerance 
or inflexibility in response to smoking-related thoughts, feelings, and body sensations. This scale 
uses a 5-point Likert-type scale and will be assessed at intake, week 11, and week 27. 
 
Depression Anxiety Stress Scale 21(DAAS-21) (116) : This 21-item self-report contains 3 
subscales to assess depression, anxiety, and stress. All subscales contain 7 items using a 4-point 
Likert type scale. It will be assessed at all timepoints. 
 
Social Network Information: Participants will be asked to list up to 9 people who provide them 
with emotional support or instrumental support and who are important. One additional name will 
be allowed if participants have a romantic partner. Network sizes, therefore, can range from 0 to 
10. Participants will also indicate how many of these individuals smoke cigarettes and drink 
alcohol. 
 
Cognitive Measures 
 
Stroop Task (67): This task will be used to evaluate the effect of counseling on changes in self- 
control strength in response to smoking cues. Participants will be shown smoking-related, 
drinking-related words and neutral words matched for frequency and length in the English 
language that are displayed in 1 of 4 different ink colors. They will be asked to identify the color 
that they see (i.e., the color the word is printed in) and ignore what the word says (i.e., inhibit 
response to read word). Words will be presented in blocks with neutral words presented before 
smoking- and drinking-related words. Practice sessions will be administered for both tasks before 
the first test trials. This task will be administered at intake and Weeks 0, 5, and 11. 
 
Medication Related Measures 
Adverse Events Checklist (SAFTEE)(100): A checklist format will be used to obtain information 
about adverse events. This checklist will include the most commonly reported adverse events for 
varenicline with severity rated on a scale from 0 (minimal) to 3 (severe). In addition, participants 
will be asked to report any other concerns, which will be recorded individually. This information 
will be collected at all study time points. 


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Pill Counts: The number of returned varenicline pills will be used to monitor medication 
adherence. 
 
Other Psychological Measures 
Pittsburgh Sleep Quality Index (PSQI)(101): The PSQI will be used to evaluate habitual sleep 
quality, self-reports of quantitative aspects of sleep (e.g., duration, latency) and insomnia 
symptoms (perceived). It has a diagnostic sensitivity and specificity for distinguishing “good” vs. 
“poor” sleepers. This will be assessed at all timepoints (pre-pilot only) and intake and end of 
treatment for the RCT pilot. 
 
Barratt Impulsivity Scale, Version 11 (BIS-11) (105): This 30-item questionnaire will assess 
general impulsiveness and specific impulsiveness along 3 domains (attentional impulsiveness 
[attention and cognitive instability], motor impulsiveness [motor and perseverance], nonplanning 
impulsiveness [self-control and cognitive complexity]).Items are scored on a 4-point scale. This 
will be assessed at intake. 
 
Emotion Regulation Questionnaire (ERQ) (106). The ERQ is a 10-item self-report measure designed 
to assess individual differences in the use of two regulation processes: cognitive reappraisal and 
expressive suppression on 7-point scale. This will be assessed at intake.. 
 
Brief Self-Control Scale (B-SCS) (107). This 13-item measure of self-control is correlated with 
better adjustment, lower scores on measures of binge eating and alcohol abuse, lower ratings of 
psychopathology and anger, higher self-esteem, and a number of other measures of adjustment. 
This will be assessed at intake.. 
 
Treatment Evaluation 
 
Client Session Report: Participants will complete a questionnaire at the end of each counseling 
session that is based on selected items from the Therapy Session Report (TSR)(108). The items 
will include: (1) an overall evaluation of the session from perfect to very poor; 2) a rating of 
therapist helpfulness from completely to not-at-all; (3) a rating of how well the participant felt 
understood by the therapist; (4) a rating of the extent to which the participant is looking forward 
to the next session; and (5) a rating of overall satisfaction with the session. During the pre-pilot, 
participants will be asked to evaluate specific treatment components that were discussed in each 
session (e.g., presentation of health feedback, discussion of social networks). 
 
Client Treatment Evaluation Form: Participants will be asked at termination to rate components of 
the study treatment and provide reasons for termination (where relevant). 
 
Table 1. Schedule of Assessments 
Construct 
Assessments 
Administered 
 
Baseline and Outcome Measures 
Intake 
Treatment 
(Wks 0-11) 
Follow-Ups 
(Phase 3 only, 
Wks 15 & 27) 
 
Demographic 
/Screening 
Demographic Interview 
X 
 
 
SCID-I 
X 
11 (alcohol 
& drug) 
X (alcohol 
and  drug) 
C-SSRS 
X 
X 
X 


29 
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APPROVED BY THE YALE UNIVERSITY IRB 7/10/2018 VALID THROUGH 7/16/2019 
 
 
Medical History 
X 
 
 
Clinical Institute Withdrawal 
Assessment for Alcohol 
X 
 
 
 
 
 
 
 
 
Laboratory/ 
Medical 
Physical Exam 
X 
 
 
EKG (if applicable) 
X 
 
 
Urine Drug Screen 
X 
 
 
Urine Pregnancy Screen 
X 
0,5,98 
 
Weight and Vital Signs 
X 
X 
X 
Menstrual Cycle Assessment 
X 
X 
 
Blood Chemistry Profile 
X 
3,7,9 
 
Plasma Carotenoids (pre-pilot 
only) 
X 
3, 7, 9 
 
Inflammationmarkers 
X 
3, 7, 9 
 
Spirometer 
X 
3, 7, 9 
, , 
 
Cancer Risk Calculations (pre- 
pilot only) 
X 
3, 7, 9 
 
Biochemical 
Measures of 
Alcohol/Nicotine 
Use 
Carbon Monoxide Breath Test 
X 
X 
X 
Breath Alcohol Test 
X 
X 
X 
Urine Cotinine 
X 
0,11 
X 
Urine EtG Level 
X 
0,11 
X 
 
 
 
 
 
Alcohol/Nicotine 
Use Measures 
Smoking and Alcohol History 
X 
 
 
Timeline Followback History 
X 
X 
X 
Fagerström Test for Nicotine 
Dependence 
 
0,11 
 
ADS 
X 
 
 
Nicotine Withdrawal Checklist 
X 
X 
X 
QSU-Brief 
X 
X 
X 
Contemplation Ladders for 
Smoking and Drinking 
X 
 
 
OCDS 
X 
X 
X 
Stroop Task 
 
0,5,11 
 
AUDIT 
X 
 
 
SIP-2R 
X 
10 
 
 
 
 
 
 
Psychological 
PANAS 
X 
X 
X 
Cue Avoidance Coping Strategies 
X 
X 
X 
AAQ-II 
X 
11 
27 
AIS 
X 
11 
27 
DAAS-21 
X 
X 
X 
Social Network Information 
X 
 
 
PSQI 
X 
X (pre-pilot 
only) 
X 
BIS-II 
X 
 
 
ERQ 
X 
 
 
B-SCS 
X 
 
 
 
Treatment 
Evaluation 
Client Session Report 
 
X 
 
Client Treatment Evaluation Form 
 
Week 11 
 
Medication 
Measures 
SAFTEE 
X 
X 
X 
Pill Counts 
 
X 
 


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31 
Version 12 
APPROVED BY THE YALE UNIVERSITY IRB 7/10/2018 VALID THROUGH 7/16/2019 
 
calculate sample size) for a later, full-scale RCT of CBT for SA. Prior to assessing primary 
analyses, Dr. Fucito will conduct: (1) univariate analyses to verify normality assumptions and (2) 
bivariate analyses to evaluate baseline equivalence between groups and significant covariates. If 
normality is an issue, Dr. Fucito will perform non-parametric analyses. 
 
 
If this section (or one of its parts, A or B) is not applicable, state N/A and delete the rest of the 
section. 
 
A. DRUGS and BIOLOGICS 
 
1. Identification of Drug or Biologic: What is (are) the name(s) of the drug(s) or 
biologic(s) being used? Identify whether FDA approval has been granted and for what indication(s). 
 
We will be using varenicline (Chantix) 0.5 and 1 mg. The FDA has approved varenicline for smoking 
cessation and will be used at the approved dose of 2 mg/day for this study. 
 
All protocols which utilize a drug or biologic not approved by, but regulated by, the FDA must 
provide the following information: 
 
Not applicable to this project. 
 
a. What is the Investigational New Drug (IND) number assigned by the FDA? 
 
b. Who holds the IND? 
 
Alternatively, an exemption from IND filing requirements may be sought for a clinical 
investigation of a drug product that is lawfully marketed in the United States. If there is no IND and 
an exemption is being sought, review the following categories and complete the category that applies 
(and delete the inapplicable categories): 
 
Exempt Category 1 
The clinical investigation of a drug product that is lawfully marketed in the United States can be 
exempt from IND regulations if all of the following are yes: 
 
i. The intention of the investigation is NOT to report to the FDA as a well-controlled study in support 
of a new indication for use or to be used to support any other significant change in the labeling for 
the drug. 
Yes 
No 
ii. The drug that is undergoing investigation is lawfully marketed as a prescription drug product, and 
the intention of the investigation is NOT to support a significant change in the advertising for the 
product. 
Yes 
No 
iii. The investigation does NOT involve a route of administration or dosage level or use in populations 
or other factor that significantly increases the risks (or decreases the acceptability of the risks) 
associated with the use of the drug product. 
Yes 
No 
iv. The investigation will be conducted in compliance with the requirements for institutional (HIC) 
SECTION VI: RESEARCH INVOLVING DRUGS, BIOLOGICS, PLACEBOS AND DEVICES 


32 
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APPROVED BY THE YALE UNIVERSITY IRB 7/10/2018 VALID THROUGH 7/16/2019 
 
review and with the requirements for informed consent of the FDA regulations (21 CFR Part 50 
and 21 CFR Part 56). 
Yes 
No 
v. The investigation will be conducted in compliance with the requirements regarding promotion and 
charging for investigational drugs. 
Yes 
No 
 
Exempt Category 2 (all items i, ii, and iii must be checked to grant a category 2 exemption) 
 
i. The clinical investigation is for an in vitro diagnostic biological product that involves one or 
more of the following (check all that apply): 
Blood grouping serum 
Reagent red blood cells 
Anti-human globulin 
 
ii. The diagnostic test is intended to be used in a diagnostic procedure that confirms the 
diagnosis made by another, medically established, diagnostic product or procedure; and 
 
iii. The diagnostic test is shipped in compliance with 21 CFR §312.160. 
 
Exempt Category 3 
 
The drug is intended solely for tests in vitro or in laboratory research animals if shipped in 
accordance with 21 CFR 312.60 
 
Exempt Category 4 
 
A clinical investigation involving use of a placebo if the investigation does not otherwise 
require submission of an IND. 
 
2. Background Information: Provide a description of previous human use, known risks, and data 
addressing dosage(s), interval(s), route(s) of administration, and any other factors that might 
influence risks. If this is the first time this drug is being administered to humans, include relevant 
data on animal models. 
 
Varenicline has been used extensively in humans. It is an approved treatment for smoking cessation, 
and will be used at the approved dosage of 2 mg daily in this study. The most common side effects 
include nausea, insomnia, abnormal dreams, constipation, flatulence, and/or vomiting. Less frequent 
side effects may include dry mouth, dyspepsia, sleep disorder, anxiety, headache, dizziness, fatigue, 
abdominal pain, gastroesophageal reflux disease, nightmare, dysgeusia, somnolence, lethargy, 
rhinorrhea, dyspnoea, upper respiratory tract disorder, rash, pruritis, increased/decreased appetite, 
diarrhea, gingivitis, chest pain, influenza like illness, edema (swelling), thirst, abnormal liver function 
tests, increased weight, arthralgia (joint pain), back pain, muscle cramps, musculoskeletal pain, 
myalgia (muscle pain), disturbance in attention, dizziness, sensory disturbance, anxiety, depression, 
emotional disorder, irritability, restlessness, polyuria (increased urination), menstrual disorder, 
epistaxis (nosebleed), respiratory disorders, hyperhidrosis (excessive sweating), hot flush, hypertension 
(high blood pressure). The safety of varenicline during pregnancy has not been established. 


33 
Version 12 
APPROVED BY THE YALE UNIVERSITY IRB 7/10/2018 VALID THROUGH 7/16/2019 
 
There have been reports of agitation, hostility, depressed mood, changes in behavior and thinking, 
suicidal ideation, and suicidal behavior related to varenicline (Chantix). We will monitor patients for 
these symptoms, and ask them to contact us immediately and discontinue varenicline (Chantix) if they 
experience any of them. 
 
There have been reports of angioedema [swelling of the face, mouth (tongue, lips, gums), extremities, 
and neck] and infrequent reports of life-threatening angioedema requiring emergency medical care due 
to respiratory compromise in people taking varenicline (Chantix). There have been reports of rare but 
serious skin reactions, including Stevens-Johnson Syndrome and Erythema Multiforme (symptoms 
include a blistering rash and peeling skin). Patients will be advised to discontinue varenicline (Chantix) 
and immediately seek medical care if they experience either of these reactions. 
 
There have also been reports of traffic accidents, near-miss accidents in traffic, or accidental injuries 
in patients taking varenicline (Chantix). In some cases patients reported somnolence, loss of 
consciousness or difficulty concentrating that resulted in impairment or concern about impairment in 
driving or operating machinery. We will advise patients to use caution driving or operating machinery 
or engaging in other potentially hazardous activities until they know how varenicline (Chantix) affects 
them. 
 
In a review of a study of 700 patients with documented stable cardiovascular disease (other than or in 
addition to hypertension) diagnosed at least 2 months prior to the screening visit (120), the FDA noted 
that varenicline was associated with more cardiovascular events (e.g., chest pain, nonfatal heart attack, 
need for coronary revascularization, new or hospitalization for peripheral artery disease) than placebo 
(121). The differences were small. A recent meta-analysis of studies of patients without known 
cardiovascular disease(122) also found that the rate of serious cardiovascular events was higher among 
the patients who received varenicline (1.06% compared to the clients who received placebo (0.82) 
although the rate was low in both groups. Varenicline more than doubled the smoking quit rate in these 
studies compared to placebo. The FDA concludes that the absolute risk of cardiovascular adverse 
events with Chantix, in relation to its efficacy, is small 123). All participants will receive a physical 
examination and, if clinically warranted, an EKG, will be required to be medically stable, and will be 
advised of this risk in the consent form. 
 
As the safety of varenicline has not been established in pregnant and nursing women, they will be 
excluded from participation. A urine pregnancy test will be performed at baseline and monthly during 
treatment. Tests will be administered at the next assessment point for all menstruating female 
participants who miss the pregnancy test at their prior appointment. In addition, a menstrual cycle 
timeline is completed at each appointment during treatment, and if their menses is late, a urine 
pregnancy test will be obtained. Pregnant women will be referred for other treatment. 
 
The use of this medication with heavy drinking smokers is experimental with regard to alcohol 
consumption. Varenicline is approved for smoking cessation and many smokers are heavy drinkers. 
Alcohol use while taking varenicline is not contraindicated according to the product information for 
the drug. 
 
On March 9, 2015, the FDA updated the label for varenicline to include potential alcohol 
interaction, rare risk of seizures, and studies of side effects on mood, behavior, or thinking. This 
update includes evidence of patients who drank alcohol during treatment with varenicline 
experiencing decreased tolerance to alcohol, including increased drunkenness, unusual or 


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36 
Version 12 
APPROVED BY THE YALE UNIVERSITY IRB 7/10/2018 VALID THROUGH 7/16/2019 
 
 
b) Is the device provided free of charge to subjects? 
Yes 
No 
 
5. What is the PI’s assessment of risk level (significant or non-significant) associated with the use of 
the device? 
 
Significant Risk (SR) Device Study: A study of a device that presents a potential for serious 
risk to the health, safety, or welfare of a participant and 1) is intended as an implant; 2) is used in 
supporting or sustaining human life; or otherwise prevents impairment of human health; 3) is of 
substantial importance in diagnosing, curing, mitigating or treating disease, or otherwise prevents 
impairment of human health; or 4) otherwise presents a potential for serious risk to the health, 
safety, or welfare of a participant. 
 
Significant Risk Devices require an Investigational Device Exemption (IDE) issued by the FDA. 
What is the IDE number assigned by the FDA? 
Did the FDA approve this IDE as Category A (experimental/investigational) or as Category B 
(non-experimental/investigational)? 
Who holds the IDE? 
Non-Significant Risk (NSR) Device Study: A study of a device that does not meet the 
definition for a significant risk device and does not present a potential for serious risk to the health, 
safety, or welfare of participants. Note that if the HIC concurs with this determination, an IDE is 
not required. 
 
6. Abbreviated IDE or Exempt IDE: There are abbreviated requirements for an IDE and there also 
are exemptions to the requirement for an IDE. See the criteria in the HIC Application Instructions, 
Section VI.B.4 at  http://ycci.yale.edu/comply/Images/10605-FM.A_NewStudyRequest_tcm426-65904.pdf 
to determine if these pertain to this study. 
 
Abbreviated IDE or Exempt IDE – If criteria set forth in the HIC Application Instructions 
are met, copy and paste the completed relevant section from the Instructions into this application. 
 
7. 
Investigational device accountability: 
a. State how the PI, or named designee, ensures that an investigational device is 
used only in accordance with the research protocol approved by the HIC, and 
maintains control of the investigational device as follows: 
Maintains appropriate records, including receipt of shipment, inventory at the 
site, dispensation or use by each participant, and final disposition and/or the return of the 
investigational device (or other disposal if applicable): 
Documents pertinent information assigned to the investigational device (e.g., date, quantity, batch 
or serial number, expiration date if applicable, and unique code number): 


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38 
Version 12 
APPROVED BY THE YALE UNIVERSITY IRB 7/10/2018 VALID THROUGH 7/16/2019 
 
Participants will be excluded from either study if they: 
(1) meet criteria for alcohol dependence in the past 12 months that is clinically severe defined by; a) a 
history of seizures, delirium, or hallucinations during alcohol withdrawal; 
b) a Clinical Institute Withdrawal Assessment scale (Sullivan et al., 1989) score of > 8; 
c) report drinking to avoid withdrawal symptoms, or d) have had prior treatment of 
withdrawal; 
d) have required medical treatment of alcohol withdrawal within the past 6 months; 
(2) are currently enrolled in alcohol treatment; 
(3) meet criteria for drug dependence in the past 12 months; with the exception of marijuana dependence 
(4) exhibit serious psychiatric illness (i.e., schizophrenia, bipolar disorder, severe major depression, panic 
disorder, borderline personality disorder, organic mood or mental disorders by history or psychological 
examination; 
(5) report current suicidality (past 12 months), or report any suicide attempts within the past year, 
assessed with the Columbia Suicide Severity Rating Scale. Individuals with a history of any suicide 
attempts need to be evaluated by the study psychiatrist for inclusion in the stdy; 
(6) exhibit current, clinically significant physical disease or abnormality based on medical history, 
physical examination, or routine laboratory evaluation including: 
(a) any unexplained elevations in liver enzymes (i.e., transaminases, bilirubin); 
(b) clinically significant, unstable cardiovascular disease/uncontrolled hypertension; 
(c) hepatic or renal impairment; 
(d) severe obstructive pulmonary disease; 
(e) diabetes mellitus requiring insulin or certain oral medications (i.e., sulfonylureas) and an A1C 
hemoglobin test score of > 7 for participants not prescribed these medications; 
(f) baseline systolic blood pressure higher than 150 mm Hg or diastolic blood pressure higher 
than 95 mm Hg; 
(7) are cognitively impaired; 
(8) are unable to read/understand English; 
(9) are a female of childbearing potential who is pregnant, nursing, or not practicing effective 
contraception (oral, injectable, or implantable contraceptives, intrauterine device, or barrier method with 
spermicide); 
(10) report new onset of psychiatric disorders or new psychotropic medications within the past 3 months, 
except individuals who are on a stable dose of a Selective Serotonin Reuptake Inhibitor for at least two 
months or who report occasional use of prescription sleep aids that they are willing to discontinue; 
(11) have used another investigational drug within 30 days or have used medications to treat alcohol (e.g., 
naltrexone, topiramate, acamprosate, disulfiram) or nicotine use (e.g., clonidine, varenicline, bupropion, 
nicotine replacement) in the past 3 months or intend to use these medications; (prior use of nicotine 
replacement in situations where smoking is not permitted (e.g., planes) without the intention to quit 
smoking is not exclusionary at screening) 
(12) intend to donate blood or blood products during the treatment phase of the study; 
(13) have a history of serious hypersensitivity reactions or skin reactions to varenicline 
(14) history of seizures or use of medications known to lower seizure threshold 
 
4. How will eligibility be determined, and by whom? 
The study physician and/or advanced practice nurse will evaluate eligibility for the study based on 
medically related inclusion and exclusion criteria. The principal investigator will sign off on final 
eligibility for the study after review of the screening data and the advanced nurse 
practitioner/physician’s evaluation. 
 
5. Indicate recruitment methods below. Attach copies of any recruitment materials that will be used. 


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41 
Version 12 
APPROVED BY THE YALE UNIVERSITY IRB 7/10/2018 VALID THROUGH 7/16/2019 
 
i. Describe why it would be impracticable to obtain the subject’s authorization for 
use/disclosure of this data; 
ii. If requesting a waiver of signed authorization, describe why it would be 
impracticable to obtain the subject’s signed authorization for use/disclosure of this 
data; 
 
The majority of potential participants first contact research staff by phone. In our 
experience, very few individuals present in person to inquire about the study and complete 
the pre-screening process. During the phone screening process, individuals provide verbal 
consent. The collection of PHI is limited to information that is necessary to confirm basic 
eligibility such as age. If an individual is not eligible, no other PHI or contact information 
is obtained. If an individual meets pre-screening eligibility and would like to schedule an 
in-person screening appointment, his/her name and phone number is then obtained. This 
information is obtained in order to identify the individual on the day of screening (i.e., 
potential participants need to provide valid identification at intake) and to provide the 
individual with a reminder call the day before the appointment. It would not be practical to 
have potential participants provide signed authorization at the time of recruitment over the 
phone. It presents an extra hurdle and potential waste of time for potential individuals when 
inquiring about the study. This system provides a more efficient method for pre-screening 
individuals and ensuring that the majority of individuals who are scheduled for an in-person 
intake appointment are likely to be eligible. 
 
Potential participants may first contact research staff through the webscreener. During the 
webscreening process, participants are not permitted to advance to the screening survey 
until they select the “yes” option agreeing that they have read and understood the 
disclaimer. The collection of PHI is limited to information that is necessary to confirm 
basic eligibility such as age, information to contact the individual with their eligibility 
status such as email and phone number (the latter is optional, the former is not), and IP 
address. Once the participant’s eligibility has been reviewed and they have been contacted, 
their webscreener entry will be deleted. 
 
By signing this protocol application, the investigator assures that the protected 
health information for which a Waiver of Authorization has been requested will not 
be reused or disclosed to any person or entity other than those listed in this 
application, except as required by law, for authorized oversight of this research 
study, or as specifically approved for use in another study by an IRB. 
 
Researchers are reminded that unauthorized disclosures of PHI to individuals outside of the Yale 
HIPAA-Covered entity must be accounted for in the “accounting for disclosures log”, by subject 
name, purpose, date, recipients, and a description of information provided. Logs are to be 
forwarded to the Deputy HIPAA Privacy Officer. 
 
 
SECTION VIII: CONSENT/ ASSENT PROCEDURES 


42 
Version 12 
APPROVED BY THE YALE UNIVERSITY IRB 7/10/2018 VALID THROUGH 7/16/2019 
 
1. Consent Personnel: List the names of all members of the research team who will be obtaining 
consent/assent. 
 
Initial consent will be obtained by the research assistant at the screening appointment, however, 
one of the study investigators will meet with the participant to review the consent document prior 
to final determination of eligibility, and at the beginning of any study procedures beyond those 
needed for determining eligibility. Obtaining consent will be: Lisa Fucito, Susan Neveu, Denise 
Romano, Christine Nogueira, Tess Hanrahan, and Abedalrazaq Alkukhun. 
 
2. Process of Consent/Assent: Describe the setting and conditions under which consent/assent will 
be obtained, including parental permission or surrogate permission and the steps taken to ensure 
subjects’ independent decision-making. 
 
The entire consent form will be reviewed in detail with the participant in a private, one-on-one 
setting at the first intake appointment. All risks and potential benefits will be described. Any 
questions the participant may have will be addressed. If the participant wishes, they may take the 
consent form home and consider it further before signing. They may also request to speak to 
anyone on the research team about questions they have or to consult others, including their 
physician and family members. Once the participant has signed the consent, they may withdraw 
consent at any time. Informed consent must be obtained prior to performance of any protocol 
specific procedures. For all participants, the advanced practice nurse or study physician will review 
the risks of the study medication at intake. 
 
2. Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Indicate how the 
personnel obtaining consent will assess the potential subject’s ability and capacity to consent to the 
research being proposed. 
 
We will not be enrolling participants with limited decision-making capacity. We plan to exclude 
individuals with current serious psychiatric or medical illnesses. During the consenting process, 
the research assistant will read and review the consent form with the prospective participant. The 
research assistant will then ask the potential participant various questions about the consent form 
and study protocol to ensure the prospective participant sufficiently understands the study and the 
nature of their consent to participate. 
 
3. Documentation of Consent/Assent: Specify the documents that will be used during the 
consent/assent process. Copies of all documents should be appended to the protocol, in the same 
format that they will be given to subjects. 
 
The adult compound consent/HIPAA form will be used and is appended for your review. 
 
4. Non-English Speaking Subjects: Explain provisions in place to ensure comprehension for 
research involving non-English speaking subjects. Translated copies of all consent materials must 
be submitted for approval prior to use. 
 
This project will not enroll non-English speaking participants. 


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44 
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There have been reports of agitation, hostility, depressed mood, changes in behavior and thinking, 
suicidal ideation, and suicidal behavior related to varenicline (Chantix). We will monitor patients for 
these symptoms, and ask them to contact us immediately and discontinue varenicline (Chantix) if they 
experience any of them. A recent review of neuropsychiatric events across 17 placebo-controlled trials 
of varenicline for smoking cessation demonstrated that varenicline increased risk of nausea but did not 
increase the risk for suicidal events, depression, or aggression/agitation (141). The study concluded 
that varenicline has substantial benefit for smoking cessation without evidence of risk of serious 
psychiatric events among individuals with and without a recent psychiatric history. 
 
There have been reports of angioedema [swelling of the face, mouth (tongue, lips, gums), extremities, 
and neck] and infrequent reports of life-threatening angioedema requiring emergency medical care due 
to respiratory compromise in people taking varenicline (Chantix). There have been reports of rare but 
serious skin reactions, including Stevens-Johnson Syndrome and Erythema Multiforme (symptoms 
include a blistering rash and peeling skin). Patients will be advised to discontinue varenicline (Chantix) 
and immediately seek medical care if they experience either of these reactions. 
 
There have also been reports of traffic accidents, near-miss accidents in traffic, or accidental injuries 
in patients taking varenicline (Chantix). In some cases patients reported somnolence, loss of 
consciousness or difficulty concentrating that resulted in impairment or concern about impairment in 
driving or operating machinery. We will advise patients to use caution driving or operating machinery 
or engaging in other potentially hazardous activities until they know how varenicline (Chantix) affects 
them. 
 
There have been reports of seizures in patients taking varenicline (Chantix) with and without a prior 
seizure history. We will warn patients about these risks. We currently exclude individuals who have 
ever experienced a seizure. Patients will be advised to discontinue varenicline and immediately seek 
medical care if they experience this reaction. 
 
There have been reports of reduced tolerance to alcohol in patients taking varenicline (Chantix). In 
some cases, patients reported increased intoxication, unusual or aggressive behavior, or an inability to 
remember things that had happened. We will warn patients about these risks and encourage 
participants to be careful about their alcohol intake until they know how varenicline affects them. 
 
In post-marketing, the FDA identified 48 cases of adverse events involving decreased tolerance to 
alcohol (n=11) or aggressive behavior (n=37) in patients taking Chantix and who also consumed 
alcohol that occurred since Chantix (varenicline) was approved in 2006. The Chantix label has 
been updated with the warning that some people have reported increased drunkenness, unusual or 
sometimes aggressive behavior, or memory loss of events while consuming alcohol during 
treatment with varenicline. As a result, we will advise participants of this potential and instruct 
them to decrease their drinking and contact us if they find varenicline affects their ability to tolerate 
alcohol. 
 
There may be a small increase in cardiovascular events associated with varenicline (Chantix) 
compared to placebo. In a review of a study of 700 patients with documented stable 
cardiovascular disease (other than or in addition to hypertension) diagnosed at least 2 months 
prior to the screening visit (120) the FDA noted that varenicline was associated with more 
cardiovascular events (e.g., chest pain, nonfatal heart attack, need for coronary 


45 
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APPROVED BY THE YALE UNIVERSITY IRB 7/10/2018 VALID THROUGH 7/16/2019 
 
revascularization, new or hospitalization for peripheral artery disease) than placebo (121). The 
differences were small. A recent meta-analysis of studies of patients without known 
cardiovascular disease (122) also found that the rate of serious cardiovascular events was higher 
among the patients who received varenicline (1.06% compared to the clients who received 
placebo (0.82) although the rate was low in both groups. Varenicline more than doubled the 
smoking quit rate in these studies compared to placebo. The FDA concludes that the absolute risk 
of cardiovascular adverse events with Chantix, in relation to its efficacy, is small (123). All 
participants will receive a physical examination and, if over the age of 40 or if clinically 
warranted, an EKG to determine eligibility. Individuals with clinically significant, unstable 
cardiovascular disease/uncontrolled hypertension will be excluded. Consistent with guidance 
from the FDA, we will advise individuals of this risk and to discontinue the medication and seek 
immediate medical attention if they experience any of the following symptoms: Shortness of 
breath, Chest pain or New or worse pain in legs when walking. 
 
Pregnant or nursing women will be excluded from this study since this medication may have 
harmful consequences to the baby. We also ask that you use a reliable form of birth control during 
the study. Acceptable methods of birth control include  abstinence,  the  birth  control pill, 
intrauterine device, injection of Depo-Provera, Norplant, tubal ligation, and barrier methods such 
as condoms or the diaphragm in combination with a spermicide. Female participants of 
childbearing potential will be informed to alert study staff in the event that they change from their 
birth control plans, or if despite their plans, think they may be pregnant. A urine pregnancy test 
will be done at baseline and then monthly during treatment. A positive pregnancy test will result 
in the participant being excluded from the study. In this case, we will provide the participant with a 
referral for other treatment. 
 
Research assessments are all noninvasive, and should add no risk. The major disadvantages are the 
time taken to complete them and possible breach of confidentiality. Our past experience with these 
measures indicates that they are acceptable to subjects. Careful efforts aimed at maintaining 
confidentiality will be made. This is described in detail below. 
 
Breath tests and urine collections should add no risks other than those normally associated with these 
procedures. We will draw approximately 4 ounces of blood over the entire course of the study; 3 ounces 
each at intake and Weeks 2 or 3 (pre-pilot only), between 5 and 7 and 9 or 10. Research assistants who 
are trained in phlebotomy will conduct blood drawing. This is a very small amount of blood. The most 
common risks to providing blood samples are the potential for bruising at the site, brief pain, and, 
rarely, infection. A rare risk is also fainting. 
 
2. Minimizing Risks: Describe the manner in which the above-mentioned risks will be minimized. 
Effective screening will exclude all subjects who would be at greater risk for complications because 
of unstable medical or psychiatric illnesses. Subjects will be seen regularly and will be monitored for 
any adverse reactions. Participants will be advised that there have been reports of agitation, hostility, 
depressed mood, changes in behavior and thinking, suicidal ideation, and suicidal behavior related to 
varenicline (Chantix). We will monitor them for these symptoms and ask that they contact us 
immediately and discontinue varenicline (Chantix) if they experience any of them. The Columbia 
Suicide Severity Rating Scale will continue to be administered weekly to assess suicidal ideation and 
behavior. Subjects will be advised to discontinue varenicline (Chantix) and immediately seek medical 
care if they experience either angioedema or serious skin reactions. We will advise participants to use 
caution driving or operating machinery or engaging in other potentially hazardous activities until they 
know how varenicline (Chantix) affects them. 


46 
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APPROVED BY THE YALE UNIVERSITY IRB 7/10/2018 VALID THROUGH 7/16/2019 
 
 
With respect to recent data on cardiovascular risks and varenicline, we will give all participants who 
are over the age of 40, or who clinically warrant, an EKG prior to participation, monitor them for 
symptoms of cardiovascular disease, and ask them to discontinue varenicline (Chantix) and to seek 
immediate medical assistance if they experience any of the following symptoms: shortness of breath, 
chest pain, new or worse pain in legs when walking. 
 
Given the uncertain effects of nicotine patch during pregnancy, the following precautions will be taken 
for women: 1) urine pregnancy tests will be performed at intake and pregnant or nursing women will be 
excluded from participation and referred to other smoking cessation programs; 2) women must agree to 
use a reliable method of birth control while they are in the study and to alert the principal investigator 
if she departs from her birth control plans or if, in spite of adherence to these plans, she thinks she 
might be pregnant; 3) a urine pregnancy test will be performed again at Week 0 (before starting 
varenicline) and Weeks 4; if a woman becomes pregnant, she will be withdrawn from the study and 
referred to alternative treatments; 4) a menstrual cycle timeline will be completed at each appointment 
during treatment, and if the woman’s menses is late, a urine pregnancy test will be obtained. 
 
All efforts will be made to protect subjects’ confidentiality. This is described in detail below. 
 
3. Data and Safety Monitoring Plan: Include an appropriate Data and Safety Monitoring Plan 
(DSMP) based on the investigator’s risk assessment stated below. (Note: the HIC will make the 
final determination of the risk to subjects.) For more information, see the Instructions, page 24. 
 
a. 
What is the investigator’s assessment of the overall risk level for subjects 
participating in this study? 
 
We view the use of varenicline and counseling for smoking among heavy drinking smokers to 
represent moderate risk to subjects. 
 
b. 
If children are involved, what is the investigator’s assessment of the overall risk 
level for the children participating in this study? 
 
Not applicable 
 
c. 
Copy, paste, and then tailor an appropriate Data and Safety Monitoring Plan 
from http://www.yale.edu/hrpp/forms-templates/biomedical.html for 
i. Minimal risk 
ii. Greater than minimal/moderate risk 
iii. High risk 
 
The DSM plan must designate an experienced, qualified professional (usually the PI) who 
can distinguish a serious adverse event (SAE) from a non-serious adverse event (AE). 
Dr. Fucito is responsible for monitoring the data, assuring protocol compliance, and conducting 
the safety reviews quarterly. During the review process Dr. Fucito will evaluate 
whether the study should continue unchanged, require modification/amendment, continue 


47 
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or close to enrollment. Either Dr. Fucito, the Human Investigation Committee (HIC) or Human 
Subjects Committee (HSC) or the National Institutes of Health have the authority to stop or 
suspend the study or require modifications. 
 
The pre-pilot and the pilot are open-label studies of an FDA-approved smoking cessation 
medication that is not contraindicated for this population/./As it it not a Phase III trial, the safety 
of the patients will be monitored by Dr Fucito, Dr. O’Malley, the study nurse practitioner Denise 
Romano, APRN, and the Study Physician Srinivas Muvvala, MD, during Dr. O’Malley’s weekly 
Clinical Trials meeting in which study participants are reviewed and monitored. 
 
Although we have assessed the proposed study as one of moderate risk, the potential exists for 
anticipated and/or unanticipated adverse events, serious or otherwise, to occur since it is not 
possible to predict with certainty the absolute risk in any given individual or in advance of first- 
hand experience with the proposed study methods. Therefore, we provide a plan for monitoring 
the data and safety of the proposed study as follows: 
 
Adverse events will be monitored for each subject participating in the study and attributed to the 
study procedures / design by Dr. Fucito according to the following categories: 
a.) Definite: Adverse event is clearly related to investigational agent/participation. 
b.) Probable: Adverse event is likely related to investigational agent/participation. 
c.) Possible: Adverse event may be related to investigational agent/participation. 
d.) Unlikely: Adverse event is likely not to be related to the investigational 
agent/participation. 
e.) Unrelated: Adverse event is clearly not related to investigational agent/participation. 
 
The following scale will be used in grading the severity of adverse events noted during the study: 
1 
Mild adverse event 
2 
Moderate adverse event 
3 
Severe unanticipated adverse event resulting in inpatient hospitalization or prolongation of 
existing hospitalization, a persistent or significant disability/incapacity, or a congenital 
anomaly/birth defect; 
4 
Life threatening event or 
5 
Fatal adverse event. 
 
In addition to grading the adverse event, the Dr. Fucito will determine whether the adverse event 
meets the criteria for a Serious Adverse Event (SAE). An adverse event is considered serious if it: 
1. 
is life-threatening 
2. 
results in in-patient hospitalization or prolongation of existing 
hospitalization 
3. 
results in persistent or significant disability or incapacity 
4. 
results in a congenital anomaly or birth defect OR 
5. 
results in death 
6. 
based upon appropriate medical judgment, may jeopardize the subject’s 
health and may require medical or surgical intervention to prevent one of 
the other outcomes listed in this definition, or 
7. 
adversely affects the risk/benefit ratio of the study 


48 
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The DSM plan must indicate that serious adverse events will be reported to the local IRB 
and to the NIAAA project officer within 48 hours. 
 
Subjects will be closely monitored for treatment response and safety through regular assessment 
sessions; these will include breath alcohol screens and assessment of psychiatric status. Although 
in our experience this is a very rare event in behavioral trials and trials of the nicotine transdermal 
patch, subjects who show significant deterioration (e.g., increased substance use or psychiatric 
symptoms that cannot be managed within the protocol, including significant suicidal or homicidal 
ideation) will be regarded as symptomatic failures, withdrawn from the treatment arm of the study, 
and referred for appropriate treatment (typically a more intensive level of care). The independent 
evaluator (study physician) will make the final determination as to whether a subject should be 
withdrawn from the treatment arm of the study. At the time of withdrawal, endpoint ratings will 
be made which include the full termination assessment battery. 
Subjects in all conditions are also able to call the Substance Abuse Treatment Unit (i.e., the clinic 
location for the trial) on-call clinician at any time should questions or concerns arise; emergency 
services are available through SATU and the Connecticut Mental Health Center. 
 
Subjects who experience a significant psychiatric or medical problem requiring an overnight 
hospitalization at an acute care facility will be considered to have experienced an SAE. In general, 
most SAEs will result in inpatient care and thus a transfer from our outpatient research clinic at 
SATU. Dr. Fucito is experienced with these procedures as a clinician at SATU and has worked out 
similar procedures to be followed for this trial. 
 
The Principal Investigator, Dr. Fucito, will report the following types of adverse events to the Yale 
University Human Investigation Committee (HIC) and the NIAAA Project Office (Joanne Fertig, 
Ph.D.): a) serious AND unanticipated AND possibly, probably or definitely related events; b) 
anticipated adverse events occurring with a greater frequency than expected; and c) other 
unanticipated problems involving risks to subjects or others. 
 
These adverse events or unanticipated problems involving risks to subjects or others will be 
reported to the both the Yale HIC and NIAAA within 48 hours of it becoming known to Dr. Fucito. 
The procedures for SAE reporting include written documentation using the clinical notes related 
to the adverse event and specific forms detailing the event with a sign-off by all appropriate 
supervisory personnel. Communication of recommendations and decisions from all parties (Yale 
Human Investigation Committee) will be made back to Dr. Fucito in a timely manner. 
 
The DSM plan must indicate that an annual report will be submitted to the NIAAA Project 
Officer summarizing all adverse events. 
The Yale Human Investigation Committee requires yearly reporting of all SAEs (including those 
that are anticipated and unrelated). This annual report will also be submitted to the NIAAA Project 
Officer (Joanne Fertig, Ph.D.). 
 
The DSM plan must specify that female subjects who are pregnant, nursing, or not using 
effective methods of birth control will be excluded from studies involving the administration 
of alcohol and/or drugs. 


49 
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APPROVED BY THE YALE UNIVERSITY IRB 7/10/2018 VALID THROUGH 7/16/2019 
 
 
Given the uncertain effects of varenicline use during pregnancy, the following precautions will be 
taken for female subjects: 1) urine pregnancy tests will be performed at intake and pregnant or nursing 
women will be excluded from participation and referred to other smoking cessation and alcohol 
treatment programs; 2) women must agree to use a reliable method of birth control while they are in 
the study and to alert Dr. Fucito and/or study staff if she departs from her birth control plans or if, in 
spite of adherence to these plans, she thinks she might be pregnant; 3) a urine pregnancy test will be 
performed again at the visit before starting varenicline; if a woman becomes pregnant, she will be 
withdrawn from the study and referred to alternative treatments; 4) a menstrual cycle timeline will be 
completed at each appointment during treatment, and if the woman’s menses is late, a urine pregnancy 
test will be obtained. 
 
If the study has a follow-up phase, there must be a specific plan for referral to treatment 
during follow-up of any respondent requiring additional intervention due to significantly 
increased alcohol consumption or serious psychiatric/medical symptoms. 
 
The same procedures for monitoring subjects for potential serious adverse events and/or the need 
for additional treatment will be used during the research follow-up phase including the regular use 
of breath alcohol screens and assessment of psychiatric status. 
 
Subjects who show significant deterioration (e.g., increased substance use or psychiatric symptoms 
including significant suicidal or homicidal ideation) will be referred for appropriate treatment 
(typically a more intensive level of care) in consultation with the study physician. 
 
The DSM plan must indicate that all adverse events during follow-up will be reported (SAEs 
within 48 hours) to the IRB and NIAAA. 
 
During follow-up, subjects will also able to call the Substance Abuse Treatment Unit (i.e., the 
clinic location for the trial) on-call clinician at any time should questions, concerns, or the need 
for emergency services arise. 
 
During the follow-up period, Dr. Fucito will report the following types of adverse events to the 
Yale University Human Investigation Committee (HIC) and the NIAAA Project Office (Joanne 
Fertig, Ph.D.): a) serious AND unanticipated AND possibly, probably or definitely related events; 
b) anticipated adverse events occurring with a greater frequency than expected; and c) other 
unanticipated problems involving risks to subjects or others. 
 
These adverse events or unanticipated problems involving risks to subjects or others will be 
reported to the both the Yale HIC and NIAAA within 48 hours of it becoming known to Dr. Fucito. 
The procedures for SAE reporting include written documentation using the clinical notes related 
to the adverse event and specific forms detailing the event with a sign-off by all appropriate 
supervisory personnel. Communication of recommendations and decisions from all parties (, Yale 
Human Investigation Committee) are made back to Dr. Fucito in a timely manner. 
 
d. For multi-site studies for which the Yale PI serves as the lead investigator: 
i. How will adverse events and unanticipated problems involving risks to subjects or 
others be reported, reviewed and managed? 


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52 
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APPROVED BY THE YALE UNIVERSITY IRB 7/10/2018 VALID THROUGH 7/16/2019 
 
A Certificate of Confidentiality from the National Institute of Alcohol Abuse and 
Alcoholism/Department of Health and Human Services has been obtained. This certificate protects 
the confidentiality of all research records generated by this study. Individually identifiable health 
information will be protected in accordance with the Health Insurance Portability and Accountability 
Act of 1996. All research personnel will be trained on HIC and HIPAA procedures. 
 
h. Are any of the study procedures likely to yield information subject to mandatory reporting 
requirements? (e.g. HIV testing – reporting of communicable diseases; parent interview -incidents 
of child abuse, elderly abuse, etc.). Please verify to whom such instances will need to be reported. 
 
All information collected will remain confidential except when we are legally required to disclose 
such information by law. These circumstances include knowledge of abuse of a child or elderly 
person, threats of harm to self or others, and threats of harm to property. Subjects will be informed 
of this limit to confidentiality as it is stated in the informed consent document. 
 
 
Potential Benefits: Identify any benefits that may be reasonably expected to result from the 
research, either to the subject(s) or to society at large. (Payment of subjects is not considered a 
benefit in this context of the risk benefit assessment.) 
 
There is a need to improve smoking cessation therapies. The purpose of this study is to determine 
the overall effectiveness of a combined psychotherapy intervention for smoking and alcohol for 
improving smoking quit rates and drinking outcomes in heavy-drinking smokers. By addressing 
barriers to treatment (i.e., alcohol use), this study may help to engage more smokers into treatment 
and reduce the enormous health care costs and loss of lives associated with cigarette smoking. 
 
 
1. 
Alternatives: What other alternatives are available to the study subjects outside of the research? 
 
Alternatives to treatment in this study are current approved over the counter smoking cessation 
treatments such as nicotine replacement therapy. Participants may get prescriptions from their 
physicians for bupropion, the nicotine nasal spray, or the nicotine inhaler; however they may not 
use these devices while participating in this research study. Study drugs will not be available once 
participants complete this study. Alternative alcohol treatments include other pharmacotherapies 
such as naltrexone and disulfiram for which participants may get prescriptions from their 
physicians. 
 
2. 
Payments for Participation (Economic Considerations): Describe any payments that will be 
made to subjects, the amount and schedule of payments, and the conditions for receiving this 
compensation. 
SECTION X: POTENTIAL BENEFITS 
SECTION XI: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS 


53 
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APPROVED BY THE YALE UNIVERSITY IRB 7/10/2018 VALID THROUGH 7/16/2019 
 
For Phase 1 focus groups, participants will be paid $10 for attending the intake appointment 
and $50 for completing the focus group session. 
 
For Phase 2 (pre-pilot), participants will be paid $10 for attending the intake and research 
appointments (8 total) for a total of $90. 
 
For Phase 3 (RCT pilot study) participants will be paid $10 for attending an intake session, 
$10 for each research appointment (up to 12 total), and $20 for each research follow-up sessions 
(2 total) for a total of up to $170 per participant. 
 
3. 
Costs for Participation (Economic Considerations): Clearly describe the subject’s costs 
associated with participation in the research, and the interventions or procedures of the study that 
will be provided at no cost to subjects. 
 
Participants will not be charged for experimental aspects of the treatment. Participants who are 
treated outside of the Tobacco Treatment Service will receive free counseling and free varenicline. 
Their insurance will not be billed for their treatment. For participants treated through the Tobacco 
Treatment Service, standard counseling and varenicline costs will be billed to their insurance. 
Depending upon insurance coverage, there may be a co-pay for these visits. Assistance by staff 
will be given to help determine coverage and/or co-pay if requested. The nicotine replacement 
products will be provided free of charge. 
 
If subjects chose to continue counseling and/ or varenicline beyond the treatment portion of the 
study, these costs will not be covered by the study or they can choose to enroll in the Tobacco 
Treatment Service and have their treatment billed through their insurance. 
 
4. 
In Case of Injury: This section is required for any research involving more than minimal risk. 
a. 
Will medical treatment be available if research-related injury occurs? 
b. 
Where and from whom may treatment be obtained? 
c. 
Are there any limits to the treatment being provided? 
d. 
Who will pay for this treatment? 
e. 
How will the medical treatment be accessed by subjects? 
 
If a participant is injured as a direct result of participation in this study, treatment will be provided. 
The participant and/or his or her insurance carrier will be expected to pay the costs of this 
treatment. No additional financial compensation for injury or lost wages is available. Participants 
will not waive their legal rights by participating in this study. 
 
If immediate information is needed about the study, participants will be instructed to contact the 
study physician or Dr. Fucito. 


54 
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APPROVED BY THE YALE UNIVERSITY IRB 7/10/2018 VALID THROUGH 7/16/2019 
 
1. 
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2. 
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3. 
USDHHS. The health consequences of smoking: a report of the Surgeon General. Washington, 
D.C.: Centers 
for Disease Control and Prevention, National Center for Chronic Disease 
Prevention and Health Promotion, Office on Smoking and Health. ; 2004. 
4. 
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5. 
Lowenfels A, Maisonneuve P, Cavallini G, Ammann R, Lankisch P, Andersen J, et al. Prognosis 
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Gastroenterol. 1994 Sep;89(9):1467-71. 
6. 
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and alcohol abuse on mortality. J Gen Intern Med. 1991;6(4):299-304. 
7. 
Znaor A, Brennan P, Gajalakshmi V, Mathew A, Shanta V, Varghese C, et al. Independent and 
combined effects of tobacco smoking, chewing and alcohol drinking on the risk of oral, pharyngeal and 
esophageal cancers in Indian men. Int J Cancer. 2003 Jul;105(5):681-6. 
8. 
Durazzo T, Cardenas V, Studholme C, Weiner M, Meyerhoff D. Non-treatment-seeking heavy 
drinkers: effects of chronic cigarette smoking on brain structure. Drug Alcohol Depend. 2007 
Feb;87(1):76-82. 
9. 
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cessation: a longitudinal study. Prev Med. 1999 Jul;29(1):57-62. 
10. 
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and success at smoking cessation. Addict Behav. 1990;15(3):197-207. 
11. 
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quitters: a report from the Normative Aging Study. Addict Behav. 1992;17(4):367-77. 
12. 
Hays J, Schroeder D, Offord K, Croghan I, Patten C, Hurt R, et al. Response to nicotine 
dependence treatment in smokers with current and past alcohol problems. Ann Behav Med. 
1999;21(3):244-50. 
13. 
Hughes J, Kalman D. Do smokers with alcohol problems have more difficulty quitting? Drug 
Alcohol Depend. 2006 Apr;82(2):91-102. 
14. 
Hymowitz N, Cummings K, Hyland A, Lynn W, Pechacek T, Hartwell T. Predictors of smoking 
cessation in a cohort of adult smokers followed for five years. Tob Control. 1997;6 Suppl 2:S57-62. 
15. 
Kahler C, Borland R, Hyland A, McKee S, Thompson M, Cummings K. Alcohol consumption 
and quitting smoking in the International Tobacco Control (ITC) Four Country Survey. Drug Alcohol 
Depend. 2009 Mar;100(3):214-20. 
16. 
McClure J, Wetter D, de Moor C, Cinciripini P, Gritz E. The relation between alcohol 
consumption and smoking abstinence: results from the Working Well Trial. Addict Behav.27(3):367-79. 
17. 
Cooney N, Cooney J, Perry B, Carbone M, Cohen E, Steinberg H, et al. Smoking cessation 
during alcohol treatment: a randomized trial of combination nicotine patch plus nicotine gum. Addiction. 
2009 Sep;104(9):1588-96. 
18. 
Grant K, Northrup J, Agrawal S, al e. Smoking cessation in outpatient alcohol treatment. 
Addictive Disorders and their Treatment. 2003;2:41-6. 
19. 
Reid M, Fallon B, Sonne S, Flammino F, Nunes E, Jiang H, et al. Smoking cessation treatment in 
community-based substance abuse rehabilitation programs. J Subst Abuse Treat. 2008 Jul;35(1):68-77. 
20. 
Campbell B, Wander N, Stark M, Holbert T. Treating cigarette smoking in drug-abusing clients. J 
Subst Abuse Treat.12(2):89-94. 


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56 
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APPROVED BY THE YALE UNIVERSITY IRB 7/10/2018 VALID THROUGH 7/16/2019 
 
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