Clinical trial NCT03521141
Conditions: Tobacco Use Cessation
Keywords: Tobacco Use Cessation Precision Medicine
Sponsor: Vanderbilt University Medical Center
Start date: 2018-05-18; Completion date: 2019-04-25
Enrollment: 67 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Precision Care (PC) interventions, developed with guidance from a Community Advisory Board (CAB), will be piloted in a Randomized Clinical Trial (RCT) of approximately 100 eligible, consenting daily smokers in the Southern Community Cohort Study (SCCS) who are willing to make a quit attempt with medication and who reside in TN or MS. Participants will be randomized 1:1:1 to 1 of 3 groups; (1) group one informs selection of medication with information on nicotine metabolism; (2) group two offers a genetically-informed lung cancer risk score, and (3) group 3 is Guideline-Based Care (GBC). All groups will be followed for 6 months. All RCT participants will receive FDA-approved smoking cessation medication, be referred to the shared TN/MS state quitline, and be offered the NCI "Clearing the Air" standard intervention. The primary outcome is feasibility of delivering the precision interventions in the SCCS population, as evidenced by ability to recruit, engage, and retain participants through end of study. Secondary outcomes, for which the study is not powered, will include risk perceptions, use of quit aids, lung cancer screening among those who are eligible, and smoking cessation.

Detailed description:
Cigarette smoking significantly increases the risk of cancer and improved cessation strategies are needed. Biologically-informed precision treatment could benefit smokers but is understudied.

Tennessee and Mississippi Smokers that responded to a previous survey indicating willingness to be contacted for a smoking cessation clinical trial will be assessed for eligibility via phone and, if eligible, provide verbal consent and administer a baseline survey. These participants will then mail in written consent, upon receipt of which their SCCS stored blood samples will be analyzed. During lab processing, a study tobacco counselor will call enrolled participants to assist with their quit plan and inform them of randomization status. Participants will complete telephone surveys at 1, 3, and 6 months. During the 6 month follow-up call, participants will also be given their previously-unreported lab results (i.e., information on nicotine metabolism or lung cancer risk). After receiving lab results, participants will complete a final brief questionnaire.

Arms: arm 1: GBC participants are 1) referred to the state quitline, 2) provided the NCI Clearing the Air smoking cessation program, and 3) asked to talk to their healthcare provider about potential lung cancer screening (LCS). Medication assignment is guided by standard guidelines and a conversation between the study tobacco counselor and the participant. Groups 1 and 2 also receive GBC counseling. arm 2: Group 1, nicotine metabolism. Medication is guided by nicotine metabolism. arm 3: Group 2, genetically-informed lung cancer risk score. Medication assignment is guided by standard guidelines and a conversation between the study nurse and the participant.
Interventions: intervention 1: Nicotine patch intervention 2: Varenicline intervention 3: Nicotine metabolism intervention 4: Genetically-informed lung cancer risk score intervention 5: NCI "Clearing the Air"
Intervention descriptions: intervention 1: FDA-approved smoking cessation pharmacotherapy intervention 2: FDA-approved smoking cessation pharmacotherapy intervention 3: Information on nicotine metabolism will be used to inform selection of medication. intervention 4: This intervention uses information from a person's genes and smoking and family medical histories to estimate lung cancer risk compared to current smokers. intervention 5: A booklet-led intervention designed by the NCI to support cessation at any stage of a quitter's journey, whether they are still thinking about quitting, have made the decision to quit, or have already taken steps to quit and just need help maintaining their new lifestyle.

Protocol documents:
Prot_SAP_001.pdf: 
Protocol Version #: 5 
 
    Page 1 
Protocol Date: 5-8-2018 
 
 
 
 
 
 
 
Developing precision smoking treatment in the Southern Community Cohort Study 
Brief title: Precision Interventions for Smoking in the Southern Community Cohort Study (PRISM-SCCS)  
 
NCT03521141 
 
 
 
 
*Hilary Tindle, MD, MPH Co-PI 
#Maureen Sanderson, PhD, RD, MPH Co-PI 
+Rebecca Selove, PhD, MPH Co-PI 
*Department of Medicine, Vanderbilt University 
#Department of Medicine, Meharry Medical College 
+Center for Prevention Research, Tennessee State University 
Dr. Tindle Phone: 
 
Dr. Tindle Email: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol Version #: 5 
 
    Page 2 
Protocol Date: 5-8-2018 
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 
 


Protocol Version #: 5 
 
    Page 3 
Protocol Date: 5-8-2018 
1.0 
Background 
Cigarette smoking significantly increases the risk of multiple cancers, accounting for more than 30% of all 
cancer deaths and 80% of deaths from lung cancer 1. Compared to whites, African Americans have lower 
cessation rates and are disproportionately burdened by lung cancer2,3, underscoring the urgent need for 
improved smoking cessation strategies in these underserved groups. Personalizing standard care 4 with 
biological data to enhance accuracy of lung cancer risk 5 or measure speed of nicotine metabolism to inform 
pharmacotherapy choice 6 is a promising, yet understudied, approach in low income minority smokers. 
 
The Southern Community Cohort Study (SCCS) is comprised of adults who were ages 40-79 at cohort entry 
and who reside in twelve states throughout the southeastern US. The majority (86%) were enrolled at 71 
CHCs, which continue to serve as study partners, with recruitment completed in 2009. In addition to annual 
passive follow up of the SCCS from 2008 to 2012 via linkage with national and state mortality and cancer 
registries, the entire surviving cohort was re-contacted to participate in a follow-up self or telephone 
administered survey, with a nearly 70% response rate. The follow-up survey elicited information on new health 
outcomes and updated information on exposures and lifestyle factors, including smoking. Smoking-related 
questions were added to the 3rd follow up in order to probe participants’ motivation, use of quit aids, receipt of 
provider advice, quit attempts, and cessation.  
 
Through the SCCS, genetic polymorphisms in cytochrome P450 2A6 (CYP2A6), a primary driver of 
metabolism of nicotine and carcinogenic tobacco-specific nitrosamines, have been found to predict lung cancer 
risk in African-American male smokers7. Additionally, it has been found that individuals who metabolize 
nicotine and nitrosamine more quickly, termed “fast/normal” metabolizers, have a 45% higher risk of lung 
cancer compared to so-called “slow” metabolizers8.  
 
2.0 
Rationale and Specific Aims 
 
Biologically informed precision treatment could benefit smokers in several ways. Biological tailoring may 
increase the salience of messaging about smoking-related disease and advice to quit. This in turn could 
reduce the optimistic bias, a tendency to underestimate one’s own health risk, which hinders cessation efforts9, 
thereby increasing motivation to quit. Data has demonstrated that the nicotine metabolite ratio (NMR), a 
biomarker reflecting CYP2A6 activity, can inform choice of smoking cessation pharmacotherapy, such that 
“fast/normal” metabolizers are twice as likely to quit smoking on varenicline compared to “slow” metabolizers6. 
Additionally, smokers who are presented results from a commercially available, gene-based lung cancer risk 
assessment, Respiragene, are more likely to undergo lung cancer screening10-13.  Respiragene recipients were 
also more likely to use nicotine replacement therapy (NRT) and quit smoking5,14-16.Though promising tools to 
help engage smokers in cessation treatment, these individual, biologically informed feedback interventions 
have not yet been studied in community smokers in the US. 
 
Our overarching aim is to leverage the SCCS and the U54 Community Outreach Core Community 
Advisory Board (CAB) to guide the development of two precision care (PC) interventions for smoking 
cessation: PC-NMR and PC-Respiragene. Both will be tailored to attitudes and beliefs of low 
socioeconomic status (SES) community smokers in the southeastern US, where tobacco use 
prevalence is one of the highest in the country. PC is rooted in the PRIME Model of behavior change17-19, 
which reflects a multi-faceted view of motivation for tobacco cessation. We will assess feasibility of PC in 
SCCS participants who smoke and conduct a 3-arm randomized controlled trial (RCT) to determine preliminary 
estimates of PC interventions vs. standard guideline-based care (GBC) on engagement4,20, smoking cessation, 
and likelihood of undergoing recommended lung cancer screening if eligible21. Our hypothesis is that, 
compared to GBC, PC participants will exhibit higher smoking cessation and lung cancer screening rates. 
These effects will be explained by lower optimistic bias, higher self-efficacy and motivation to quit, and use of 
proven quit aids (medication, behavior therapy via state quit line). 
 


Protocol Version #: 5 
 
    Page 4 
Protocol Date: 5-8-2018 
To accomplish our aim, daily smokers who are SCCS participants and providers at SCCS Community Health 
Centers (CHC), in Mississippi or Tennessee will be surveyed to assess their attitudes and beliefs about 
precision smoking treatment. Survey results will inform CAB-guided development of the PC study 
interventions. PC interventions will then be piloted in a RCT of up to 100 SCCS daily smokers willing to make a 
quit attempt with medication and be randomized 1:1:1 to PC-NMR, PC-Respiragene, or GBC and followed for 
6 months. All RCT participants are referred to the shared TN/MS state quitline and provided the NCI “Clearing 
the Air” standard intervention. 
 
An overview of Aims 1 
and 2, which are now 
completed, is shown to 
the left.  
 
Aim 1: Survey up to 
1400 TN and MS SCCS 
smokers and up to 45 
selected CHC providers 
to assess attitudes and 
beliefs on smoking-
related health risk 
perceptions, precision 
smoking treatment, and 
willingness to engage in 
a smoking cessation 
trial of PC.  
Aim 2: With continuous input from the CAB, develop two PC interventions, PC-NMR and PC-
Respiragene, for use among diverse, low-socioeconomic status community smokers in the SCCS.  
Aim 3: Conduct a 3-arm RCT to pilot PC interventions for feasibility and to determine preliminary 
estimates of biochemically-validated smoking cessation at 6 months vs. GBC. We hypothesize that, 
compared to GBC, PC participants will exhibit higher smoking cessation and lung cancer screening rates. 
(Illustration of Aim 3 is shown below on p. 8).  
3.0 
Animal Studies and Previous Human Studies 
Our group has not performed prior animal or human studies related to the proposed PC interventions.   
4.0 
Inclusion/Exclusion Criteria 
AIM 1: 
Patient Inclusion Criteria: Eligible participants include adult (18 years of age or older) self-identified 
current smokers who are SCCS Participants. 
 
 
Provider Inclusion Criteria: Eligible participants include independent providers at selected CHCs as 
provided by CHC CEOs. 
 
 
AIM 3: 
Inclusion Criteria:  Eligible participants include adult (18 years of age or older) daily smokers (i.e., 
indicated they were smoking > 5 cigarettes per day on most recent survey) who are SCCS participants 
and agreed to be contacted in the Aim 1 survey. Participants must have a stored blood sample with the 
Surveys inform PC-NMR and PC-Respiragene interventions 
(Aim 2) and identify potential participants for Aim 3.
Patient-participant survey
• 
Up to  1400 TN/MS SCCS smokers 
• 
Assesses health risk perceptions, attitudes + beliefs about 
personalized smoking treatment, interest in trial participation
• 
SCCS staff conducts 2 mailings + phone f/u as needed
Provider survey
• 
Up to  45 SCCS providers from select clinics in TN, MS
• 
Assesses attitudes + beliefs on personalized smoking 
treatment
• 
Conducted via email
Figure 1. Developing Personalized Smoking Treatment in the Southern Community Cohort Study
CAB Subcommittee meetings facilitated by research team 
members
CAB Subcommittee meetings
• 
Solicit feedback on draft surveys for Aim 1 (prior to mailing)
• 
Assess baseline opinions on draft PC-NMR & PC-Respiragene 
materials; assess cultural, literacy appropriateness 
• 
Iteratively revise education materials with ongoing CAB input 
& feedback
• 
Subcommittee meetings interspersed with email 
correspondence between research team, CHE + CAB 
subcommittee members
•
•
Aims 1 + 2 inform each other: CAB Subcommittee members give initial feedback on questionnaire drafts for Aim 1; For Aim 2, in subsequent meetings during year 1, 
CAB Subcommittee members are presented with questionnaire results from Aim 1, which further inform their iterative development of the PC interventions, guided by 
the CAB Community Health Education (CHE) and research staff. The CAB Subcommittee consists of 10-15 members, including current and former smokers.
Aim 2 - CAB-guided intervention development 
Aim 1 - Survey patients and providers


Protocol Version #: 5 
 
    Page 5 
Protocol Date: 5-8-2018 
SCCS and an established PCP. Participants must agree to participate and be willing to accept a 
medication prescription for tobacco cessation. Participants must be eligible (i.e., no medical 
contraindications) to receive at least 1 non-nicotine FDA-approved smoking cessation medication (i.e., 
varenicline) and NRT. Smokers across the motivational spectrum (all levels of readiness to quit) are 
eligible.  
 
Exclusion Criteria: Inability to give informed consent or participate due to serious psychiatric (e.g., 
psychosis, schizophrenia, hospitalization for psychiatric condition in the past 6 months) or cognitive 
disorder (e.g., dementia,that prevents them from completing study procedures); enrolled or scheduled 
to be enrolled in another smoking cessation program; no access to a telephone or inability to 
communicate by telephone; unable to speak and read English; history of seizures; pregnant or 
breastfeeding. 
 
5.0 
Enrollment/Randomization 
For AIM 1 provider participants, we will first obtain name and contact information for CHC CEOs from the 
SCCS. CEOs for selected CHCs will be mailed an introductory letter directing them to an emailed REDCap 
survey, the purpose of which is to obtain, at the discretion of the CEO, CHC providers’ names, credentials, and 
email addresses. This email will be re-sent 2 times at 2 week intervals in order to ensure maximum response 
rates. Using the obtained email addresses, we will email the AIM 1 provider REDCap survey, which assesses 
providers’ current tobacco treatment practices as well as attitudes toward personalizing smoking cessation 
treatment. This email will be sent to non-responding providers 2 times at 2 week intervals in order to ensure 
maximum response rates. 
 
For AIM 1 patient participants, we will use the well-established SCCS procedures for entry into, and follow-up 
within, the SCCS. Mailed packets will include a pre-addressed and postage-paid return envelope, with only the 
SCCS participant number for identification. The packets will also contain an introductory letter describing the 
research, and  an AIM 1 questionnaire to complete. . To ensure maximum response rate, participants will be 
mailed up to  three times;. Participants will mail back the questionnaire and, upon receipt of these items, will be 
considered potentially eligible for the AIM 3 pilot RCT.  
 
Respondents to the AIM 1 survey who report that they have a PCP and who have an SCCS stored blood 
sample will be mailed an AIM 3 invitation letter and informed consent with a pre-paid return envelope. These 
patients will be screened for eligibility by phone and, for those providing verbal consent, given the AIM 3 
baseline questionnaire by phone. Upon return of the signed written consent form, the participant’s labs will be 
run using their stored blood. When these results are available, participants will be called and informed of their 
randomization assignment (PC-NMR, PC-Respiragene, GBC). The baseline questionnaire for the RCT will 
contain questions on lifestyle factors, readiness to quit, and smoking patterns as described below. Computer-
assisted telephone interviewing will also be used for completion of study questionnaires by phone using the 
study call line; study staff will contact non-responders by mail or phone. 
 
Eligible patients will be randomized according to a stratified permuted block randomization scheme.  
Stratification will be based on cigarettes per day. Randomization will be proceeded within strata according to a 
permuted block scheme with a block size, or balancing interval, varying randomly between 3 or 6 according to 
the outcome of a computer generated random number. This will ensure that the cumulative number of 
assignments to each treatment is in balance after making each block of assignments. 
 
6.0 
Study Procedures 
Baseline Data Collection  
For Aim 1, participants will be mailed a questionnaire and a postage-paid return envelope. The survey will 
assess current smoking behavior as well as attitudes toward smoking cessation, precision medical care, and 
participants’ perceptions of health risk. This survey will be mailed up to 3 times. 


Protocol Version #: 5 
 
    Page 6 
Protocol Date: 5-8-2018 
 
Aim 1 and Aim 2 inform each other as outlined in Figure 1 below. Aim 3 is an RCT piloting the use of the 
behavioral and educational interventions developed in AIM 2 within a low-income population, a subset of our 
Aim 1 participants as described above.  
 
Respiragene measurement 
For Aim 3, participants will undergo Respiragene testing, a genetic test that assesses lung cancer risk. 
Respiragene can be run on stored blood samples from the SCCS. If blood is not available, saliva could be 
used as a back-up.  Risk level is stratified as high, higher and highest risk based on genetic markers. The 
VUMC lab that has performed most of the SCCS analyses to date will perform the Resiragene analysis. Those 
in the Respiragene arm of the study will receive the results of their Respiragene lab test during their first quit 
attempt. All others will receive their results at the end of the study. This final results call will be offered to all 
participants around the Month 6 follow up.. 
 
Nicotine metabolite ratio (NMR) measurement 
For Aim 3, participants  will also undergo nicotine metabolite ratio (NMR) testing of stored biological samples 
(blood will be used when possible and is preferred; saliva can be used as a substitute).  NMR testing helps to 
determine how quickly a participant’s body breaks down nicotine, which will inform his or her provider about 
whether nicotine replacement therapy (NRT) or varenicline is more effective to help the participant quit 
smoking. Samples will be securely shipped to Canada for testing. Slow metabolizers will be defined by an 
NMR <0.31 and fast metabolizers will be defined by an NMR 0.316. Those in the NMR arm of the study will 
receive the results of their NMR lab test and their medication will be selected based on their NMR status. At 
the end of the study, those who were not in the NMR arm will receive their NMR results. This final results call 
will be offered to all participants around the Month 6 follow up.  
 
Medication provision and blinding 
 
Guideline Based Care Group 
All participants assigned to guideline based care (GBC) will be referred to the state quitline and will 
receive a smoking cessation intervention through the National Cancer Institute’s (NCI) “Clearing the Air” 
program.  Additionally, as part of clinical care, the primary care provider (PCP) will document guideline-
based treatment recommendations and provide participants with prescriptions sufficient for a 3-month 
course of pharmacotherapy chosen at the clinical discretion of the provider. Written and verbal 
instructions will be provided to participants given medication to contact their primary provider and the 
research study staff (during regular business hours) to address any questions about medication.  
Participants will be instructed to call 911 if they believe they are having a medical emergency.  GBC 
participants will also receive Respiragene and nicotine metabolite ratio (NMR) testing on their SCCS 
stored blood sample and will be informed of these results at the end of the study. 
 
Respiragene Precision Care Group (PC-Respiragene) 
All participants assigned to Respiragene precision care will receive guideline-based care, including a 
referral to the state quitline, as described above. Additionally, the PCP will have clinical decision 
support regarding the interpretation of the Respiragene test. Study staff will discuss results of the 
Respiragene test with the participant and the PCP will provide participants with prescriptions sufficient 
for a 3-month course of pharmacotherapy chosen at the clinical discretion of the provider based on 
guidelines relevant to differential health risks.  
 
NMR Precision Care Group (PC-NMR) 
All participants assigned to NMR precision care will receive guideline-based care, including a referral to 
the state quitline, as described above. Additionally, the PCP will have  clinical decision support 
regarding the interpretation of NMR from the study team. Using the NMR data, the PCP will discuss 


Protocol Version #: 5 
 
    Page 7 
Protocol Date: 5-8-2018 
results with the participant and provide participants with prescriptions sufficient for a 3-month course of 
pharmacotherapy based on NMR results (NRT for “slow” metabolizers and non-nicotine smoking 
cessation medication (varenicline) for “fast/normal” metabolizers).  Participants who do not wish to 
receive varenicline, may have the option of a higher nicotine patch dose that has been studied 
previously. In this previous study, there were no significant differences between treatment arms in the 
frequency of severe side effects and serious adverse events or blood pressure during treatment (p > 
.10).22   
 
Participants may receive prescriptions through their own pharmacies or through a mail order pharmacy. 
 
Check-in phone calls 
Study staff will call participants at approximately 2 weeks after the study results call, and again approximately 
1- 2 months following the results call, to encourage medication adherence and assess self-reported tolerance.  
If additional communication is needed, a tobacco counselor can be available for extra calls.  
 
Table 1:  RCT Data Collection Table for 
Aim 3 
 
Follow up 
Assessments 
B
L 
1 
mo 
f/u 
Infor
mal 
Chec
k-in 
(2) 
3 
m
o 
f/u 
6 
m
o 
f/u 
Smoking 
status 
X 
X 
 
X 
X 
Cigarettes per 
day 
X 
X 
 
X 
X 
Health risk 
perceptions 
X 
X 
 
X 
X 
Lung cancer 
screening 
X 
X 
 
X 
X 
Notify of PC 
results* 
 
X 
 
 
X 
Calls to 
support med 
 
X 
X 
X 
 


Protocol Version #: 5 
 
    Page 8 
Protocol Date: 5-8-2018 
 
Outcome assessment 
Subject outcomes will be assessed via phone calls at 
approximately 1, 3, and 6 months, as shown in Table 1.  At 
follow up, an RA who is separate from intervention staff will 
complete interviews assessing smoking behavior, 
medication use and self-reported side effects, patient 
health risk perceptions and attitudes toward the PC 
interventions, and whether the patient received a lung cancer screening. Participants reporting abstinence at 
six months will be mailed a standard salivary cotinine kit for biochemical validation of smoking abstinence, 
defined as ≤ 10 ng/ml. 
 
7.0 
Risks 
Nicotine Metabolite Ratio (NMR), Respiragene, & Salivary Cotinine Test:  There are no known serious adverse 
effects from these tests. 
 
Breach of confidentiality: All efforts, within reason, will be made to keep personal information in the research 
records confidential. Total confidentiality cannot be guaranteed. To prevent a breach of confidentiality, 
participant data will be collected using password protected and encrypted computers, and electronic participant 
tracking spreadsheets stored on a secure server.  All paper records will be locked in secure areas and 
accessible to study staff only. To prevent the loss of data, all electronic information is password protected on 
anti-virus software enabled computer systems. Only study staff will have access to the study data on Shared 
File Areas.  Participants will be identified on study forms and in the database by a participant number.  
Participant names and contact information will be stored in a separate file. 
    
Adverse drugs reactions:  Participants in this study may receive one of two FDA-approved smoking cessation 
therapies (NRT or varenicline) and will have the potential to experience drug-related side effects.  Nicotine 
replacement therapy is generally very safe and several preparations of it have been sold over the counter for 
decades).  However, possible side effects include, but are not limited to, skin irritation or itching (patch), 
dizziness, headache, nausea, mouth/throat irritation (inhaler/nasal spray), 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.  In a large FDA-mandated trial (EAGLES, Lancet 2016)  all three of these medications were found to 
be safe and effective in patients with and without pre-existing psychiatric conditions.23 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 or varenicline. Written and 
verbal instructions will be provided to patients given medication to contact their primary physician and the 
research PI, Hilary Tindle, in case of adverse effects of a medication.  Additionally, study staff will call 
participants during active treatment to monitor for medication side effects. Ultimately, the PI (Dr. Tindle) 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 serious adverse events will be reported to the IRB and NIH according to appropriate policies and procedures. 
Serious adverse events are defined as untoward or undesirable medical events, related to study procedures, 
that 1) are of at least moderate severity as reported by participants at follow-up; 2) require hospitalization or ER 
visit; 3) are life-threatening or cause death or permanent impairment/disability; or 4) require intervention to 
prevent death or permanent impairment/disability. 
 
9.0 
Study Withdrawal/Discontinuation 
adherence, 
tolerance 
CO-validated 
abstinence 
 
 
 
 
X 
*Participants in PC arms (Respiragene, 
NMR) notified of results; GBC participants 
are contacted to match for time 


Protocol Version #: 5 
 
    Page 9 
Protocol Date: 5-8-2018 
Individuals who wish to withdraw from the study may do so at any time by contacting the Principal Investigator 
(Dr. Tindle) 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. 
The PI and study personnel withhold the right to withdraw participants from the study if they are non-compliant 
with study procedures or if there is a perceived imminent medical threat to 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 pilot RCT comparing precision smoking cessation treatment to usual 
care.  As such, the primary outcome is feasibility and the study is not powered to detect differences between 
treatment groups for smoking cessation.  However, we will conduct descriptive and exploratory analyses of 
collected data as well as assess for between-group differences in this clinical outcome. 
 
Aim 1: Survey up to 1400 TN and MS SCCS smokers to assess attitudes and beliefs on smoking-related 
health risk perceptions, precision smoking treatment, and willingness to engage in a smoking 
cessation trial of PC. We anticipate a response rate of up to 70% of contacted participants. 
Primary Analysis: Analysis of survey data will utilize the following general strategies: to test statistical 
differences in the frequency distributions of variables of interest, we will calculate t-tests for continuous 
parameters of interest, and chi-square tests for categorical parameters of interest. Participants will be 
categorized according to objective and subjective classifications of smoking-related disease risks. The 
objective measurement of lung cancer risk will be calculated using the validated PLCOM2012 model 
(Tammemagi NEJM 2013). Subjective measures of disease risks will be obtained via participant 
response to the study survey, as to whether the participant believes their risks for heart attack, cancer 
or lung cancer are lower, about the same, or higher than other smokers their age. Pearson correlation 
coefficients will be calculated to evaluate the relation between objective and subjective lung cancer 
risk estimates. Regression analyses will be used to calculate risk ratios and 95% confidence intervals 
for the associations between objective lung cancer risk, subjective disease risks, and use of smoking 
cessation aids or interest in precision smoking treatment. Regression statistical models will include 
variables for potential confounders such as age, race, sex, education, alcohol intake, and family 
history of lung cancer diagnosis in a first degree relative. P-values for trend tests will be calculated by 
treating ordinal variables as continuous in statistical models. Potential interactions will be evaluated 
by completing likelihood ratio tests comparing statistical models with and without the addition of 
cross-product terms. 
 


Protocol Version #: 5 
 
    Page 10 
Protocol Date: 5-8-2018 
 
Aim 3: Conduct a 3-arm 
RCT (Figure 2) to pilot PC 
interventions for feasibility 
and to determine 
preliminary estimates of 
biochemically-validated 
smoking cessation at 6 
months vs. GBC.  
Hypothesis: PC interventions 
will be acceptable to 
participants and feasible to 
administer. 
Secondary hypotheses 
(exploratory): Compared to 
GBC, PC participants will 
exhibit higher smoking 
cessation and lung cancer 
screening rates. 
Primary Analysis: We will 
assess engagement in 
smoking cessation treatment 
as measured by: (1) 
connection with the study 
tobacco treatment counselor, 
(2) connection with the state 
quitline and (3) use of study-
provided medication. We will 
also obtain preliminary 
estimates of behavior change 
at 6 months, including: 1) 
biochemically-validated 
smoking cessation and 2) 
rates of lung cancer screening 
for individuals who meet screening criteria. We will also collect information on process measures such as 
enrollment, educational material format, and costs per patient treated. Note, the current pilot RCT will not be 
powered to demonstrate significant differences in cessation rates by study group.  
 
Privacy/Confidentiality Issues 
Participant data will be collected using password protected and encrypted computers, and electronic 
participant tracking spreadsheets stored on a secure server.  All paper records will be locked in secure areas 
and accessible to study staff only.  To prevent the loss of data, all electronic information is password protected 
on anti-virus software enabled computer systems. Only study staff will have access to the study data on 
Shared File Areas.  A participant number will identify all participants on study forms and in the database.  
Participant names and contact information will be stored in a separate file.   
 
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). Surveys will be associated with a participant number and all patient 
identified information will be managed by the SCCS offices in Jacksonville, FL, where they will be stored. The 


Protocol Version #: 5 
 
    Page 11 
Protocol Date: 5-8-2018 
Survey Research Shared Resource will receive identified information in order to make necessary phone calls; 
study staff associated with Vanderbilt, Meharry, and TSU will receive only de-identified data files. 
 
11.0 
Follow-up and Record Retention 
Participants will be followed up through approximately 12-months after enrollment (as outlined above in Study 
Procedure).  Records will be kept indefinitely but will be destroyed if no longer needed. 
 
 
12.0 
References  
1. 
American Cancer Society. Cancer Facts & Figures 2012.  https://www.cancer.org/content/dam/cancer-
org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2012/cancer-facts-and-figures-
2012.pdf. Accessed December 14, 2017. 
2. 
Barbeau EM, Krieger N, Soobader MJ. Working class matters: socioeconomic disadvantage, 
race/ethnicity, gender, and smoking in NHIS 2000. Am J Public Health. 2004;94(2):269-278. 
3. 
Agrawal A, Sartor C, Pergadia ML, Huizink AC, Lynskey MT. Correlates of smoking cessation in a 
nationally representative sample of U.S. adults. Addict Behav. 2008;33(9):1223-1226. 
4. 
Fiore MC, Jaen CR, Baker TB, et al. Treating tobacco use and dependence: 2008 Update. Rockville, 
MD: Public Health Service; 2008. 
5. 
Young RP, Hopkins, R.J. Genetic susceptibility testing to lung cancer and outcomes for smokers. Tob 
Control. 2012. 
6. 
Lerman C, Schnoll RA, Hawk LW, Jr., et al. Use of the nicotine metabolite ratio as a genetically 
informed biomarker of response to nicotine patch or varenicline for smoking cessation: a randomised, 
double-blind placebo-controlled trial. Lancet Respir Med. 2015;3(2):131-138. 
7. 
Wassenaar CA, Ye Y, Cai Q, et al. CYP2A6 reduced activity gene variants confer reduction in lung 
cancer risk in African American smokers--findings from two independent populations. Carcinogenesis. 
2015;36(1):99-103. 
8. 
Bize R, Burnand B, Mueller Y, Cornuz J. Effectiveness of biomedical risk assessment as an aid for 
smoking cessation: a systematic review. Tob Control. 2007;16(3):151-156. 
9. 
Dillard AJ, McCaul KD, Klein WM. Unrealistic optimism in smokers: implications for smoking myth 
endorsement and self-protective motivation. J Health Commun. 2006;11 Suppl 1(sup001):93-102. 
10. 
Montes U, Seijo LM, Campo A, Alcaide AB, Bastarrika G, Zulueta JJ. Factors determining early 
adherence to a lung cancer screening protocol. Eur Respir J. 2007;30(3):532-537. 
11. 
Patel D, Akporobaro A, Chinyanganya N, et al. Attitudes to participation in a lung cancer screening 
trial: a qualitative study. Thorax. 2012;67(5):418-425. 
12. 
Young RP, Hopkins RJ. Increasing smokers' risk perception improves CT screening participation. 
Thorax. 2012;67(9):834-835; author reply 835. 
13. 
Rigotti NA, Regan S, Levy DE, et al. Sustained care intervention and postdischarge smoking cessation 
among hospitalized adults: A randomized clinical trial. JAMA. 2014;312(7):719-728. 
14. 
Smerecnik C, Grispen JE, Quaak M. Effectiveness of testing for genetic susceptibility to smoking-
related diseases on smoking cessation outcomes: a systematic review and meta-analysis. Tob Control. 
2012;21(3):347-354. 
15. 
Hopkins RJ, Young RP, Hay BA, Gamble GD. Lung Cancer Risk Testing Enhances NRT Uptake And 
Quit Rates In Randomly Recruited Smokers Offered A Gene-Based Risk Test [Abstract]. Paper 
presented at: American Thoracic Society 2012 International Conference2012; San Francisco, CA. 
16. 
Young RP, Hopkins RJ, Smith M, Hogarth DK. Smoking cessation: the potential role of risk assessment 
tools as motivational triggers. Postgrad Med J. 2010;86(1011):26-33; quiz 31-22. 


Protocol Version #: 5 
 
    Page 12 
Protocol Date: 5-8-2018 
17. 
West R, Sohal T. "Catastrophic" pathways to smoking cessation: findings from national survey. BMJ. 
2006;332(7539):458-460. 
18. 
McEwen A, West, R. The PRIME approach to giving up smoking. Practice Nursing. Vol 212010:145-
153. 
19. 
West R, Brown J. Theory of Addiction. 2 ed. Hoboken, NJ: Wiley-Blackwell; 2013. 
20. 
Shelley D, Cantrell J. The effect of linking community health centers to a state-level smoker's quitline 
on rates of cessation assistance. BMC Health Serv Res. 2010;10:25. 
21. 
Black WC, Gareen IF, Soneji SS, et al. Cost-effectiveness of CT screening in the National Lung 
Screening Trial. N Engl J Med. 2014;371(19):1793-1802. 
22. 
Schnoll RA, Wileyto EP, Leone FT, Tyndale RF, Benowitz NL. High dose transdermal nicotine for fast 
metabolizers of nicotine: a proof of concept placebo-controlled trial. Nicotine Tob Res. 2013;15(2):348-
354. 
23. 
Anthenelli RM, Benowitz NL, West R, et al. Neuropsychiatric safety and efficacy of varenicline, 
bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-
blind, randomised, placebo-controlled clinical trial. The Lancet. 2016.