Metabolism-informed Care for Smoking Cessation
Phase: NA
Conditions: Tobacco Use, Tobacco Use Cessation
Sponsor: Vanderbilt University Medical Center

Protocol Version #: 2 
 
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Protocol Date: 6-6-2016 
 
 
 
 
 
 
 
 
Smoking, Nicotine metabolism, and Genetics: a Precision Medicine Pilot and Feasibility Study 
 
 
*Quinn Wells, MD Co-PI 
#Hilary Tindle, MD Co-PI 
*Matthew Freiberg, MD Co-PI 
*Department of Medicine, Division of Cardiology 
#Department of Medicine, Division of General Internal Medicine 
2220 Pierce Ave, Preston Research Building Rm 340 
Nashville, TN 37232 
Phone: 615-936-1819 
Email: quinn.s.wells@vanderbilt.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol Version #: 2 
 
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Protocol Date: 6-6-2016 
Table of Contents: 
 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Animal Studies and Previous Human Studies 
4.0 
Inclusion/Exclusion Criteria 
5.0 
Enrollment/Randomization 
6.0 
Study Procedures 
7.0 
Risks of Investigational Agents/Devices (side effects) 
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to Participants or Others 
9.0 
Study Withdrawal/Discontinuation 
10.0 
Statistical Considerations 
11.0 
Privacy/Confidentiality Issues 
12.0 
Follow-up and Record Retention 
13.0 
References 
 

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Protocol Date: 6-6-2016 
1.0 
Background 
Tobacco smoking is the leading preventable cause of disease and death in the US and the world.  Every year 
smoking kills nearly half a million Americans1 and costs the nation 1.6% of the GDP.2 As of 2013, 18% of U.S. 
adults smoke,3 and the prevalence is even higher in vulnerable groups such as minorities. Furthermore, 
African-American smokers smoke fewer cigarettes than white Americans, yet have disproportionally higher 
rates of smoking-related diseases.4 In all smokers, most quit attempts fail, and members of minority groups are 
even less likely to succeed,5 despite using FDA-approved pharmacotherapy. 
Nicotine mediates its addictive effects in the brain, where it binds to CNS receptors, including nicotinic 
acetylcholine receptors (nAChRs).6 Nicotine undergoes rapid (half-life ~two hours) and extensive hepatic 
metabolism to cotinine, primarily by the enzyme CYP2A6.7 Cotinine, in turn, is further metabolized to 3-
hydroxycotinine exclusively by hepatic CYP2A6.6 Genetic variation in pathways related to nicotine metabolism, 
primarily CYP2A6, have been associated with smoking related traits, including cigarette consumption,8-10 and 
response to treatment.11 
The ratio of 3-hydroxycotinine to cotinine, known as the nicotine metabolite ratio, or NMR, is a genetically- 
informed biomarker reflecting CYP2A6 activity and the rate of nicotine metabolism.12 A recent RCT in Lancet 
Respiratory Medicine found that the NMR can be used to individualize treatment for smokers.13 Specifically, 
subjects who were identified as “fast” metabolizers (as opposed to “slow” metabolizers) demonstrated a two-
fold improvement in cessation rates when treated with varenicline compared to nicotine replacement therapy 
(NRT). As a genetically-informed biomarker, NMR has been suggested as the tool of choice because it is 
inexpensive and has a relatively quick turnaround, lending feasibility to its role in guiding initial choice of 
pharmacotherapy. However, it is currently unknown whether a nicotine metabolism-guided approach utilizing 
NMR would be effective in a real world clinical environment.    
 
2.0 
Rationale and Specific Aims 
Without the use of proven quit aids, rates of smoking cessation are exceedingly low, with only 5-10% of 
smokers able to quit for 6 months or more.14 Approved drugs, including bupropion, NRT (i.e., patch, gum, 
lozenge, nasal spray, and inhalers), and varenicline, have each been shown to dramatically improve quit rates 
compared to placebo,15-18 and current guidelines do not preferentially recommend any agent as first line 
therapy.18 While this standard guideline-based approach does result in a 1.5 to 3-fold increase in success 
compared to placebo, the absolute rates of smoking cessation remain low. At one year, a quarter or less of 
smokers who use proven behavior therapy and pharmacotherapy remain abstinent.19 A precision medicine 
approach utilizing NMR to tailor pharmacologic treatment is promising but unproven to increase quit rates and 
reduce smoking-related diseases. 
 
Our overarching hypothesis is that tailored smoking cessation therapy, guided by NMR, results 
in higher rates of tobacco cessation compared to usual care. However, there are important challenges to 
be addressed prior to conducting a full-scale randomized controlled trial (RCT) comparing tailored treatment to 
usual care. We must establish that sufficient numbers of subjects can be enrolled; procedures for specimen 
collection, processing, and data analysis must be in place; and patient attitudes should be determined and 
considered in the study design.  
 
The goal of this pilot project is to create infrastructure, establish feasibility, and provide necessary 
preliminary data to design and conduct a prospective randomized trial comparing tailored smoking 
cessation treatment to usual care. To accomplish this, we will enroll up to 50 outpatient smokers from the 
Vanderbilt Heart and Vascular Institute (VHVI). After consent, subjects will complete questionnaires, provide 
biologic samples, and have nicotine metabolic status determined (nicotine metabolic ratio (NMR)). Subjects will 
be assigned to either: 1) usual care for smoking cessation or 2)  personalized smoking cessation care which 
incorporates the NMR.  Biochemically confirmed abstinence (by exhaled carbon monoxide, using a threshold 
of < 10 parts per million (ppm)) will be determined at the six month follow up.20 For deliverables, we will: 1) 
demonstrate capacity to conduct large-scale personalized smoking cessation trials in the clinical environment, 
and 2) assess patient attitudes regarding personalized smoking treatment. 

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Aim 1. Develop infrastructure and procedures necessary to conduct a prospective randomized trial 
comparing tailored smoking cessation treatment to usual care. We hypothesize that we will successfully: 
1) enroll outpatient adult daily smokers; 2) collect, process, and store relevant biologic samples; 3) conduct 
follow-up assessments and accurately ascertain pertinent smoking cessation and patient reported outcome 
measures. 
 
Aim 2. Assess patient attitudes regarding personalized smoking therapy including: 1) interest in 
receiving personalized information, and 2) willingness to guide therapy based on personalized data. 
We hypothesize that a majority (>50%) of subjects will: 1) favorably view receiving personalized smoking 
information, and 2) express willingness to guide therapy based on personalized data.  
 
3.0 
Animal Studies and Previous Human Studies 
Our group has not performed prior animal or human studies related to NMR.  However, a recently published 
RCT in humans reported  NMR can be used to guide smoking cessation therapy.13 
 
4.0 
Inclusion/Exclusion Criteria 
Inclusion criteria:  Eligible subjects include adult (18 years of age or older) daily smokers who are seen in VHVI 
outpatient clinic or cardiology inpatients admitted to VUMC.  Current smoking is defined as smoking, on 
average, >5 cigarettes per day every day in the month prior to enrollment. Potential subjects must agree to 
participate and be willing to accept a medication prescription for tobacco cessation. Subjects must be eligible 
(i.e., no medical contraindications and willing to take) to receive at least two out of three FDA-approved 
smoking cessation medications (bupropion, varenicline, and NRT). The requirement of eligibility to take at least 
2 of 3 FDA approved medications is necessary for this study so that individuals can take advantage of the 
NMR-driven guidance of a nicotine medication (i.e., NRT for slow metabolizers) vs. a non-nicotine medication 
(i.e., varenicline or bupropion for fast/normal metabolizers).  
 
Exclusion criteria: In addition to medication contraindications, subjects will be excluded for inability to give 
informed consent  or participate due to serious psychiatric (e.g., psychosis, schizophrenia, hospitalization for 
psychiatric condition in the past 3 months or change in psychiatric medications in the past 3 months) or 
cognitive disorder (e.g., dementia, severe mental retardation); receiving palliative or hospice care; pregnant or 
breastfeeding; no access to a telephone or inability to communicate by telephone; unable to speak and read 
English.  Because levels of nicotine metabolites fall below detection over time we will exclude patients who 
have been completely abstinent from cigarettes for >3 days.  
 
In order to maximize participant safety, eligibility for medications will be reviewed by three separate members 
of the study team.  Initial screening will be conducted by the study RA at the time of enrollment.  Between 
enrollment and intervention phone call (~1 week) medication eligibility will be reviewed for each participant by 
the study PI Dr. Wells using a detailed chart review.  Finally, at the time of intervention phone call, medication 
eligibility will again be confirmed by the study counsellor, who is a trained smoking counsellor and nurse (RN).  
 
 
5.0 
Enrollment/Randomization 
Our preliminary estimates from historical electronic health record (EHR) data suggest that approximately 9% of 
VHVI outpatients are current smokers.  This is likely an underestimate in light of the known under-
ascertainment of smoking status in the EHR.   This translates into a minimum of 120 unique smokers per 
month. To maximize subject identification, we will use multiple methods of recruitment.  Patients are routinely 
asked about their smoking status during every visit to the VHVI clinic during intake.  Data on existing, identified 
VHVI smokers will be pulled  from the Research Derivative (RD), which will include patients’ names, phone 
numbers, and medical record numbers.  These identified smokers will be called by study staff or staff of the 
Clinical Trials Center (CTC) (up to 10 times per patient) to assess eligibility and interest to join the study.  Chart 

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review of eligibility will be done at the time of the call.  Interested and eligible patients will be invited to enroll in 
person either at the VHVI clinic or at the CTC, depending on patient preference and staff availability. Interested 
patients or their providers may also contact study staff directly based on information contained in study posters 
that will be displayed throughout the VHVI clinic.  As an alternative, staff may also utilize the Electronic Health 
Record (EHR-StarPanel) to identify VHVI smokers who have clinic appointments and approach these smokers 
for interest and eligibility in clinic.  Chart review would be done prior to approaching the patient. Finally, Lesa 
Abney, RN, of the Tobacco Treatment Service (TTS), an inpatient tobacco treatment service that treats 
patients admitted to VUMC may be used to identify additional potential participants.  Ms. Abney will assess 
eligibility of cardiology inpatients, who she treats at the bedside.  Patients who screen eligible and are 
interested will then be approached by study staff.    Regardless of recruitment methods, study staff will confirm  
eligibility and, if appropriate, discuss the informed consent document with the prospective study participant. 
After agreeing to consent, the participant will complete a standardized questionnaire assessing his or her 
attitudes regarding personalized smoking cessation therapy.  Participants will be randomized in blocks of 10, 
stratified based on self-reported baseline cigarettes per day. 
 
6.0 
Study Procedures 
 
Baseline Data Collection  
 
Upon enrollment patients will be given an initial survey detailing smoking history, smoking related traits (e.g. 
smoking intensity, measures of addiction, prior quit attempts, use of other tobacco products), and attitudes 
regarding personalized medicine. Participants will be compensated $10 for their completion of the survey. 
 
Biospecimen collection, processing, and storage 
To minimize risk, a total of 30 mL (well below the accepted cutoff of 50 mL for “minimal risk”) of whole 
blood will be collected into 3 EDTA coated tubes (lavender top vacutainers), labeled appropriately, 
placed on ice. Two tubes will be transported to the laboratory space of Dr. Wells to be immediately 
processed by centrifugation.  The plasma fraction will be aliquoted into storage vials and stored at -
80°C in temperature monitored freezers located on the 12th floor MRBIV.  Dr. Wells has dedicated 
space and personnel housed in the lab of Dr. Dan Roden, Professor of Medicine and Pharmacology 
and Assistant Vice-Chancellor for Personalized Medicine. The Lab consists of ~2,000 contiguous 
square feet and includes all equipment, supplies, and personnel required for sample processing and 
storage.   The third blood sample (~10 mL) will be collected in an EDTA coated vial and transferred to 
the VUMC reference laboratory for measurement of nicotine, cotinine, 3-OH-cotinine. The VUMC 
laboratory currently contracts with ARUP national reference laboratory, which conducts this assay using 
quantitative high performance liquid chromatography-tandem mass spectrometry using CLIA approved 
protocols and quality control. Results are reported within 2-5 days from sample collection. 
(http://ltd.aruplab.com/tests/pub/0092361)  At approximately 1 month, a subset of participants will be 
selected to follow up in person, where they will have up to 10 mL of blood drawn to biochemically 
assess adherence by measurement of smoking cessation drug levels.  These samples will be shipped 
to the laboratory of Dr. Rachel Tyndale at the University of Toronto, Canada, where drug and 
metabolite levels will be measured using established assays.  
 
Nicotine metabolite ratio (NMR) measurement 
As described above, subject samples will be processed through ARUP Laboratory as they would for 
standard clinical care.  Results are available within 2-5 days from the time of blood draw.  
Slow metabolizers will be defined by a NMR <0.31 and fast metabolizers will be defined by a NMR ≥ 
0.31 .13  Once available, subject NMR values will be entered into the study’s secure REDCap database 
by study personnel.   
 
Study Intervention, medication provision and blinding 

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Medication Costs 
All medications accepted by participants at the initial intervention phone call will be provided to 
participants free of charge.  Medications may be shipped to patients free of charge where appropriate.  
Subjects in the usual care arm who are still smoking at 6 months will have an opportunity to receive a 
prescription for smoking cessation therapy at the end of study (see below). Participants who wish to 
receive prescriptions at that point will be responsible for the cost of medications.   
 
Usual Care Group 
All subjects, including those assigned to usual care, will receive phone calls from clinical personnel 
within 1 month of enrollment.  In order to minimize inconvenience, subjects will be asked their preferred 
times to be called at the time of enrollment.  With the aid of a written script, staff will provide participants 
a verbal description of smoking cessation medications they are eligible to take (as determined by study 
physician), including efficacy and common side effects.  If subjects would like to take a smoking 
cessation medication, they will be allowed to choose from those they are medically able to receive, and 
the study physician will call in a prescription to an outpatient pharmacy (with which arrangements have 
been made to have medication costs billed to the study rather than the subject).  Regardless of whether 
subjects choose to receive a prescription for a medication, they will be offered referral to their state 
Tobacco Quit Line for smoking cessation counselling via an online portal.  This portal will track the 
patient’s progress through the quit line process and these data may be collected for research purposes.   
Verbal instructions will be provided to participants given prescriptions to contact their primary provider 
and the research study staff (during regular business hours) in case of adverse effects of a medication.  
They will also be instructed to call 911 if they believe they are having a medical emergency. 
 
Personalized Care Group 
All subjects, including those assigned to personalized care, will receive phone calls from clinical 
personnel within 1 month of enrollment.  In order to minimize inconvenience, subjects will be asked 
their preferred times to be called at the time of enrollment.  Staff contacting subjects in the personalized 
care group will have access to NMR values when they become available in the study’s secure REDCap 
database.  With the aid of a written script, staff will provide participants a personalized (based on 
NMR) verbal description of smoking cessation medications they are eligible to take (as determined by 
study physician), including efficacy and common side effects.  If subjects would like to take a smoking 
cessation medication, they will be allowed to choose from those they are medically able to receive, and 
the study physician will call a prescription into an outpatient pharmacy (with which arrangements have 
been made to have medication costs billed to the study rather than the subject).  Regardless of whether 
subjects choose to receive a prescription for a medication, they will be offered referral to their state 
Tobacco Quit Line for smoking cessation counselling via an online portal.  This portal will track the 
patient’s progress through the quit line process and these data may be collected for research purposes.  
Verbal instructions will be provided to participants given prescriptions to contact their primary provider 
and the research study staff (during regular business hours) in case of adverse effects of a medication.  
They will also be instructed to call 911 if they believe they are having a medical emergency.     
 
 
Follow up phone calls 
Study RAs will call subjects at approximately 1, 3 and 6 months post-intervention phone call to assess 
smoking behavior, self-reported adherence, and side effects including neuropsychiatric side effects.  
Study personnel will make up to 10 calls per follow up at different times of day and days of the week 
and call subjects’ alternate contacts when needed.  Participants will receive $10 for each phone call 
that they complete.   
 
Single arm crossover for subjects in Usual Care Group 

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Subjects in the Usual Care Group who are still smoking at 6 month follow up will receive an additional 
intervention from study staff.  With the aid of a written script, staff will provide participants a 
personalized (based on 
NMR)  
verbal description of smoking 
cessation medications they 
are eligible to take (as 
determined by study 
physician), including efficacy 
and common side effects.  If 
subjects would like to take a 
smoking cessation 
medication, they will be 
allowed to choose from those 
they are medically able to 
receive, and a prescription will 
be called into an outpatient 
pharmacy by the study 
physician.  The intent of this  
design is to assess the impact 
of a personalized message on 
medication uptake in 
participants who failed to quit with the usual care treatment.  The cost of medications will be the 
responsibility of participants who chose to have prescriptions filled.  Participants provided prescriptions 
will be called by study staff in approximately 2 weeks to assess whether they have filled their 
prescriptions and are taking the medication.  
 
EHR data collection 
Prospective participants who are identified smokers in the VHVI clinic will have their EHR examined by study 
staff to determine eligibility, and EHR data collected in the screening form will be retained for future analysis. 
For enrolled participants, research staff will review the participant’s EHR to collect relevant clinical data.  Staff 
may review participant records for up to 5 years after enrollment.   
 
Outcome assessment 
Subject outcomes will be assessed by phone approximately 1, 3 and 6 months post-intervention phone call.  At 
follow up, a research assistant will complete interviews assessing smoking behavior, self-reported side effects, 
and measures of patient engagement and attitudes toward precision medicine. At approximately 1 month, a 
subset of participants will be selected to complete follow-up in person, where, in addition to an interview, they 
will have blood drawn to biochemically assess adherence by measurement of smoking cessation drug levels.  
Subjects will receive an additional $10 for completing 1 month follow up in person.  At approximately 6 months, 
subject outcomes may be assessed in person. Subjects self-reporting abstinence may have smoking status 
confirmed biochemically using end expired carbon monoxide.  Biochemically validated abstinence will be 
defined as end expired carbon monoxide less than 10 ppm. Participants will receive $10 for each of these 
completed calls and an additional $10 if they participate in an end-expired carbon monoxide test at 6 months. 
This will be sent by mail in the form of a check.  Participants in the single arm crossover group (i.e., those in 
the Usual Care group who were still smoking at 6 months) who accepted medication prescriptions will receive 
phone calls approximately 2 weeks after the second personalized intervention to assess whether they have 
filled the prescription. The most any one participant can be compensated (completing all surveys, the 
additional blood draw and biochemical validation) is $60.00 over the course of approximately 6 months. 
 
7.0 
Risks 
Follow-up and Outcome Measures Summary 
 
Baseline 
1 mo* 
3 mo* 
6 mo* 
2 weeks# 
Outcomes 
 
 
 
 
 
Demographics 
X 
 
 
 
 
Smoking behavior 
X 
X 
X 
X 
X 
Side effect screening 
X 
X 
X 
 
 
Attitudes & Beliefs 
X 
 
 
X 
 
Patient satisfaction 
 
 
 
X 
 
Biochemical validation 
of cessation 
 
 
 
X 
 
Biochemical validation 
of adherence (subset of 
participants) 
 
X 
 
 
 
Medication use 
 
X 
X 
 
X 
*Relative to intervention phone call  
# Relative to 6-month follow-up (applies to subjects who are still smoking in Usual Care) 

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Risks of blood draw: Pain, redness, soreness, bruising, or infection may occur at the needle stick site. Rarely, 
some patients faint.  We will protect against phlebotomy-related risk by collecting samples at the time of clinical 
sample collection when possible. 
 
Expired Carbon Monoxide Test:  There are no known serious adverse effects from this test.  Sometimes 
people feel mildly short of breath or cough during the test.   
 
Breach of Confidentiality: Medical information will be stored in a secure database. However, it is possible this 
database could be corrupted.  Participant data will be collected using password-protected and encrypted 
computers, electronic medical records, and electronic participant tracking spreadsheets stored on a secure 
server.  To prevent the loss of data, all electronic information is stored within the VUMC firewall and is 
password-protected. Only study staff will have access to the study data.  Data quality (including visits 
completed during intervention window, data missingness, and recruitment rates) will be monitored monthly by 
the database manager and systematic data problems will be reported to the PI (Dr. Wells).   
 
Adverse drugs reactions:  Subjects in this study will receive one of three FDA-approved smoking cessation 
therapies (NRT, varenicline, or bupropion) and will have the potential to experience drug-related side effects.  
Nicotine replacement therapy is generally very safe (it is sold over the counter).  However, possible side effects 
include skin irritation or itching (patch), dizziness, headache, nausea, and rapid heartbeat.  Common side 
effects of varenicline include nausea, sleep disturbance and vivid dreams, gastrointestinal symptoms, and 
vomiting.  Very rarely, patients, particularly those with unstable psychiatric conditions, may experience 
symptoms such as behavioral changes, agitation, depressed mood, and suicidal behavior during varenicline 
treatment.  Common side effects of bupropion include dry mouth, irritability, and difficulty sleeping. A large trial 
of over 8000 patients was presented at the Society for Research on Nicotine and Tobacco in Chicago in 
March, 2016, and did not demonstrate any difference in neuropsychiatric symptoms (including suicidal ideation 
and suicidal behavior) between patients on varenicline, bupropion, or nicotine replacement therapy (EAGLES; 
ClinicalTrials.gov Identifier: NCT01456936).  Very rarely, patients can have seizures, especially in those with a 
history of seizures. To protect against risk from pharmacotherapy usage, this study will only use FDA-approved 
smoking cessation medications and tobacco treatment providers will screen patients to identify 
contraindications to NRT, bupropion or varenicline. Written and verbal instructions will be provided to patients 
given medication to contact their primary physician and the research PI, Quinn Wells, in case of adverse 
effects of a medication.  Additionally, RAs will call subjects at regular intervals (as described above) to monitor 
for serious side effects including neuropsychiatric side effects.  Study personnel will make up to 10 calls per 
week at different times of day and days of the week and call subjects’ alternate contacts when needed.  
Ultimately, the PI (Dr. Wells) will review any serious adverse events and report them appropriately to the IRB. 
 
8.0 
Reporting of Adverse Events or Unanticipated Problems Involving Risk to Participants or Others 
Any adverse events will be reported to the IRB according to IRB policies and procedures.  
 
9.0 
Study Withdrawal/Discontinuation 
Individuals who wish to withdraw from the study may do so at any time by contacting the Principal Investigator 
(Dr. Wells) in writing without penalization or change to their medical care. Any data collected prior to 
withdrawing from the study will be analyzed as enrolled unless requested for full withdrawal by the participant. 
 
10.0 
Statistical Considerations 
This pilot project is intended to create infrastructure, establish feasibility, and provide necessary preliminary 
data to design and conduct a prospective RCT comparing tailored smoking cessation treatment to usual care.  
As such, we are not powered to detect differences between treatment groups in regards to primary or 
secondary outcomes.  However, we will conduct descriptive and exploratory analyses of collected data as well 
as assess for between-group differences.   
Aim 1. Develop infrastructure and procedures necessary to conduct a prospective randomized trial 

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comparing tailored smoking cessation treatment to usual care.  
Hypothesis: We hypothesize that we will successfully: 1) enroll adult daily smokers from an outpatient clinic; 2) 
collect, process, store, and analyze relevant biologic samples; and 3) conduct follow-up assessments and 
accurately ascertain pertinent smoking cessation and patient care outcome measures. 
Primary analysis: As a primary analysis, for each group we will calculate descriptive statistics for relevant 
demographic and clinical parameters, rates of enrollment and loss to follow-up, smoking cessation, and side 
effects.  These data will be critical to inform future prospective studies.  
 
Aim 2. Assess patient attitudes regarding personalized smoking therapy including: 1) interest in 
receiving personalized information, and 2) willingness to guide therapy based on personalized data. 
Hypothesis: A majority (>50%) of subjects will: 1) favorably view receiving personalized smoking information; 
and 2) express willingness to guide therapy based on personalized data.  
Primary analysis: As a primary analysis, we will calculate the proportion of subjects that provided favorable 
responses (4 or 5 on Likert Scale) for questions addressing: 1) willingness to receive patient-specific smoking 
data; and 2) willingness to use these data to guide therapy, as reflected by the % who fill the prescription that 
is recommended by the NMR test results. We will also calculate rates of self-reported adherence, use of the 
quit line, and cessation at each follow up.  
 
 
11.0 
Privacy/Confidentiality Issues 
Data will be placed into a password-protected, web-based database by study personnel.  Only the research 
staff, the PI and co-investigators will have access to this data.  A unique identification number will be used to 
protect the confidentiality of the study participants. 
 
Protected Health Information (PHI) will be used in this study.  The investigators will comply with the patient 
privacy guidelines of Vanderbilt University Medical Center and the rules outlined by the Health Insurance 
Portability and Accountability Act (HIPAA). 
 
All research samples obtained for this study will be assigned a unique number.  The key linking this unique 
number to PHI will be kept in a locked file.  Only the investigator, co-investigators and research personnel will 
have access to the key and information that identifies participants as being in this study. Digital records will be 
stored on password-protected computers/servers.  Digital data files will be coded so that the participant name 
or other such identifiers are not in the filename. 
 
 
12.0 
Follow-up and Record Retention 
Subjects will be followed up through approximately 6 months after intervention phone call or  post-
pharmacotherapy start date, if applicable (as outlined above in Study Procedure).  Records will be kept 
indefinitely but will be destroyed if no longer needed. 
 
 
 
 
 
 
 
 
 
 
 

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13.0 References 
 
1. 
World Health Organization. WHO urges more countries to require large, graphic health warnings on 
tobacco packaging: the WHO report on the global tobacco epidemic, 2011 examines anti-tobacco mass-
media campaigns. Cent. Eur. J. Public Health. 2011;19:133–151.  
2. 
World Health Organization. Assessment of the Economic Costs of Smoking. Economics of tobacco 
toolkit. 2011;:1–116.  
3. 
Agaku IT, King BA, Dube SR, Centers for Disease Control and Prevention (CDC). Current cigarette 
smoking among adults - United States, 2005-2012. MMWR Morb Mortal Wkly Rep. 2014;63:29–34.  
4. 
Ho JY, Elo IT. The Contribution of Smoking to Black-White Differences in U.S. Mortality. Demography. 
2012;50:545–568.  
5. 
Trinidad DR, Pérez-Stable EJ, White MM, Emery SL, Messer K. A nationwide analysis of US 
racial/ethnic disparities in smoking behaviors, smoking cessation, and cessation-related factors. Am J 
Public Health. 2011;101:699–706.  
6. 
Benowitz NL. Pharmacology of nicotine: addiction, smoking-induced disease, and therapeutics. Annu 
Rev Pharmacol Toxicol. 2009;49:57–71.  
7. 
Hukkanen J, Jacob P, Benowitz NL. Metabolism and disposition kinetics of nicotine. Pharmacol Rev. 
2005;57:79–115.  
8. 
Thorgeirsson TE, Gudbjartsson DF, Surakka I, Vink JM, Amin N, Geller F, Sulem P, Rafnar T, Esko T, 
Walter S, Gieger C, Rawal R, Mangino M, Prokopenko I, Mägi R, Keskitalo K, Gudjonsdottir IH, 
Gretarsdottir S, Stefansson H, Thompson JR, Aulchenko YS, Nelis M, Aben KK, Heijer den M, Dirksen 
A, Ashraf H, Soranzo N, Valdes AM, Steves C, Uitterlinden AG, Hofman A, Tönjes A, Kovacs P, 
Hottenga J-J, Willemsen G, Vogelzangs N, Döring A, Dahmen N, Nitz B, Pergadia ML, Saez B, De 
Diego V, Lezcano V, Garcia-Prats MD, Ripatti S, Perola M, Kettunen J, Hartikainen A-L, Pouta A, 
Laitinen J, Isohanni M, Huei-Yi S, Allen M, Krestyaninova M, Hall AS, Jones GT, van Rij AM, Mueller T, 
Dieplinger B, Haltmayer M, Jonsson S, Matthiasson SE, Oskarsson H, Tyrfingsson T, Kiemeney LA, 
Mayordomo JI, Lindholt JS, Pedersen JH, Franklin WA, Wolf H, Montgomery GW, Heath AC, Martin NG, 
Madden PAF, Giegling I, Rujescu D, Jarvelin M-R, Salomaa V, Stumvoll M, Spector TD, Wichmann H-E, 
Metspalu A, Samani NJ, Penninx BW, Oostra BA, Boomsma DI, Tiemeier H, van Duijn CM, Kaprio J, 
Gulcher JR, ENGAGE Consortium, McCarthy MI, Peltonen L, Thorsteinsdottir U, Stefansson K. 
Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior. Nat Genet. 
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Fujieda M, Yamazaki H, Saito T, Kiyotani K, Gyamfi MA, Sakurai M, Dosaka-Akita H, Sawamura Y, 
Yokota J, Kunitoh H, Kamataki T. Evaluation of CYP2A6 genetic polymorphisms as determinants of 
smoking behavior and tobacco-related lung cancer risk in male Japanese smokers. Carcinogenesis. 
2004;25:2451–2458.  
10. 
Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in 
adult Caucasians. Pharmacogenetics. 2004;14:615–626.  
11. 
Chen L-S, Bloom AJ, Baker TB, Smith SS, Piper ME, Martinez M, Saccone N, Hatsukami D, Goate A, 
Bierut L. Pharmacotherapy effects on smoking cessation vary with nicotine metabolism gene (CYP2A6). 
Addiction. 2014;109:128–137.  

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12. 
Dempsey D, Tutka P, Jacob P, Allen F, Schoedel K, Tyndale RF, Benowitz NL. Nicotine metabolite ratio 
as an index of cytochrome P450 2A6 metabolic activity. Clinical Pharmacology & Therapeutics. 
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