Conditions: Smoking
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 606
Healthy volunteers: no

Brief summary:
This phase 3 randomized controlled trial will test Metabolism-Informed Smoking Treatment (MIST), a precision approach to smoking treatment that biologically tailors medication selection to nicotine metabolism.

Detailed description:
This is a randomized controlled trial to compare effects of MIST versus usual care (UC) interventions on the outcomes below.

Objectives:

* Abstinence as defined by biochemically-verified self-reported 7-day point prevalence abstinence at 6 m (1° study outcome) and 12 m (2° outcome).
* Clinical practice implementation as measured by participant self-reported medication adherence at months 1 and 3, self-reported receipt of prescription for smoking cessation medication after hospital discharge, and whether the prescription was tailored to the NMR result.

Exploratory Objective:

\- Longitudinal assessment of health care utilization visits (ER and hospitalization) for 12 months following hospital discharge.

Arms:
arm 1: At hospital discharge, participants randomized to the MIST precision care arm will receive a prescription for medication (either varenicline or NRT). Post discharge, participants will receive automated phone calls via TelASK to promote continued engagement. Medication prescriptions will be informed by nicotine metabolism (i.e., NMR result) such that faster metabolizers are prescribed varenicline and slower metabolizers are prescribed NRT. arm 2: At hospital discharge, participants randomized to the Usual Care arm will receive a prescription for medication (either varenicline or NRT). Post discharge, participants will receive automated phone calls via TelASK to promote continued engagement. Medication prescription will not be informed by nicotine metabolism.

Interventions: intervention 1: Post-discharge automated phone calls (IVR) with option to connect with a tobacco coach. intervention 2: Nicotine Replacement Therapy intervention 3: Varenicline intervention 4: Metabolism Informed Smoking Treatment (Nicotine metabolite ratio (NMR)-based selection of pharmacotherapy)
Intervention descriptions: intervention 1: Automated calls to assess smoking status, medication use, and additional support for quit attempt. intervention 2: FDA-approved forms of nicotine replacement therapy for smoking cessation. intervention 3: FDA-approved smoking cessation medication. intervention 4: Nicotine metabolite ratio (NMR)-based selection of pharmacotherapy. NMR is a blood test to measure how fast the body breaks down nicotine.

Protocol document:
ICF_001.pdf: 
VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Metabolism-Informed Smoking Treatment (MIST) 
Version #: 
Version Date: 
PI: 
7 
05-15-2024 
Hilary Tindle, MD 
  
 
 
 
 
1
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
 
Name of participant: __________________________________________ Date of Birth: ___________ 
 
Part I. The following is given to you to tell you about this research study.  Please read this form with 
care and ask any questions you may have about this study.  Your questions will be answered.  Also, 
you will be given a copy of this consent form.   
 
 
Vanderbilt University Medical Center (VUMC) is doing a research study called the Metabolism Informed 
Smoking Treatment study (MIST).  It is being funded by the National Institutes of Health (NIH). The MIST 
study uses information on how fast the body breaks down nicotine in order to help people quit smoking.   
We will be enrolling about 1000 smokers at VUMC. 
 
Quitting smoking can help prevent smoking-related diseases like cancer and heart disease and can help 
you live longer. After study enrollment you may receive a prescription for a 3 month supply of quit 
smoking medication to support a quit attempt.  We will ask you to complete 5 surveys during this 12 
month study.   Study contacts can be completed over the phone and/or through the mail.  You may be 
asked to come into our offices to complete a brief (5 minute) breath test around 6 months after joining 
the study.  Additional details are below in the “Procedures to be followed” section below. 
 
 
You are being asked to take part in this study because you are a current smoker who is willing to consider 
taking FDA-approved medication to help you quit smoking and you may have insurance coverage for quit 
smoking medication.   
 
You do not have to be in this research study. You may choose not to be in this study and get other 
treatments without changing your healthcare, services, or other rights.  You can stop being in this study 
at any time.  If we learn something new that may affect the risks or benefits of this study, you will be 
told so that you can decide whether or not you still want to be in this study.   Your medical record will 
Key Information about this study:  
The first section of this document contains some key points that the research team thought you 
would find important. The study is described in more detail after this section. If you do not 
understand something, please ask someone.  
Detailed Information: 
The rest of this document includes detailed information about this study (in addition to the 
information listed above). 
Date of IRB Approval: 09/16/2024
Date of Expiration: 09/15/2025


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Metabolism-Informed Smoking Treatment (MIST) 
Version #: 
Version Date: 
PI: 
7 
05-15-2024 
Hilary Tindle, MD 
  
 
 
 
 
2
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contain a note saying you are in a research study and may contain some research information about 
you.  Anyone you authorize to receive your medical record will also get this information. 
 
Good effects that might result from this study:  
There are benefits to science and humankind that might result from this study. This study may help in the 
development of effective interventions to increase participation in evidence-based smoking cessation 
treatment.  There may be no benefit to participation in this study. Participants in this study may benefit 
by being more efficiently connected to tobacco treatment resources. As a result, they may be helped to 
quit smoking; potential benefits to quitting smoking include:  
 
preventing smoking-related diseases like cancer and heart disease  
 
helping you live longer  
 
protecting your friends and family from secondhand smoke  
 
saving money that would be spent on cigarettes 
 
Procedures to be followed: 
 
A blood sample is required for this study. This blood test measures how fast your 
body breaks down nicotine.  
 
Surveys are also part of this study at baseline and in follow up over 12 months. 
 
Your doctor will be told that you are in the study.  
 
You will receive automated phone calls followed by unencrypted email and/or text 
message (your choice) to help you quit smoking. You can request a callback from a 
tobacco coach. 
 
You will be assigned by random, like the flip of a coin, to either a Usual Care group 
or a Precision Care group. 
o If you are in the Usual Care group, you will use the stop smoking medication 
that you discussed with the Tobacco Treatment Counselor.  
o If you are in the Precision Care group, you will use the stop smoking 
medication that is recommended based on the results of your blood test. 
o After study enrollment, you will be given up to a 3-month supply of one or 
more of the following FDA-approved stop smoking medications: 
 
Nicotine Replacement Therapy (such as patch, lozenge, or gum) 
 
Varenicline (also called Chantix) 
 
If you report that you quit smoking at the 6 month survey, you will be asked to 
provide a saliva or breath sample to verify this. 
 
During this 12-month study we will monitor your use of stop-smoking medicine, any 
ER/hospital visits, and review your medical records for up to 10 years after study 
Date of IRB Approval: 09/16/2024
Date of Expiration: 09/15/2025


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Metabolism-Informed Smoking Treatment (MIST) 
Version #: 
Version Date: 
PI: 
7 
05-15-2024 
Hilary Tindle, MD 
  
 
 
 
 
3
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completion to monitor for long term outcomes. 
 
After completing this 12-month study, you may be invited to participate in future 
studies 
 
We will ask you to provide your social security number so we can verify your insurance, your 
doctor, pay you for your participation, and to search databases such as the Tennessee Hospital 
Discharge Data System, state vital records, and CMS (Centers for Medicare and Medicaid) 
databases for information about health care received outside of Vanderbilt. 
Automated contacts and opportunity to connect with a tobacco coach:  Our partner, TelASK 
Technologies, will help us contact you after  study enrollment to offer additional support. During 
these calls you can ask for a callback from a tobacco coach who can answer your questions and 
help you to stay smoke-free. The coach can also help you to use your stop smoking medication 
correctly. The initial round of calls lasts 3 months.  To set up these calls, we will send your name, 
contact information, gender (male/female/unknown), and date of study enrollment to TelASK. 
During call backs the tobacco coach may ask you about audio recording for quality.  This will not 
affect your care and you can choose not to be recorded or stop the recording at any point. 
 
Surveys: You will be asked to complete a baseline survey which could take about 20 minutes to finish. 
During the study you will be contacted at 1, 3, 6, and 12 months after study enrollment by unencrypted 
email, text message, or phone (your choice) to complete a survey about your smoking and medication 
usage.  Costs for data, texts, and minutes are not paid by the study. Your telephone/wireless carrier’s 
standard charges may apply.  If we are not able to reach you by email/text/phone, we may mail the 
surveys to you. 
 
Confirming smoke free status: If you have quit smoking at the 6--month follow-up survey and you are 
not using nicotine replacement therapy at that time, we will ask you to complete a saliva sample which 
tests for nicotine levels in your saliva. If you are using nicotine replacement medicine at that time, we 
will ask you to complete a breath test instead of the saliva test. This breath test measures the amount of 
carbon monoxide in your lungs. If you have an upcoming appointment/hospitalization, study staff may 
also attempt to meet you in person. In case you are not able to come in person to our clinic, there is an 
option to do the breath test and/or the saliva test from home. The iCO™ personal Smokerlyzer® is a 
device that can be attached to your smart device and activated via an app. The results of the breath test 
are then sent to the study team. The saliva test is a small kit that you can complete at home and return 
by mail. All tests used to confirm smoke free status are collected only for the proposed research project, 
and only study staff will have access to these data. 
 
Possible side effects and risks that you may experience if you take part in this study:  
Date of IRB Approval: 09/16/2024
Date of Expiration: 09/15/2025


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Metabolism-Informed Smoking Treatment (MIST) 
Version #: 
Version Date: 
PI: 
7 
05-15-2024 
Hilary Tindle, MD 
  
 
 
 
 
4
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Blood draw: You are being asked to have your blood drawn. Risks of a blood draw are minimal and could 
include pain, allergic reaction, infection, or bleeding at the needle stick site. Rarely, we may be able to 
use stored blood. Finally, if the first test result is not valid, a new sample of blood may be needed.  
 
Symptoms that may go along with quitting smoking (unrelated to medications): The process of 
quitting smoking can be associated with many potential side effects including irritability, difficulty 
concentrating, changes in mood or behavior, and difficulty sleeping.  These symptoms are known to 
occur whether people use medication or not. In other words, these symptoms occur even in people 
taking placebo (sugar pill) while they are quitting smoking. People who have conditions such as 
depression or anxiety may tend to experience more symptoms when quitting smoking. It is important 
to remember that anyone is capable of quitting smoking, regardless of their health conditions.  If 
during the study you have any thoughts about suicide, immediately call 911 or go to the emergency 
room and ask them to contact your primary care doctor. When you are able, please contact study 
staff 615-701-MIST (6478). 
 
This study is intended for women who are not pregnant or breastfeeding because some of the 
medications to quit smoking should not be used during pregnancy or breastfeeding. During the 
study if you become pregnant or are breastfeeding, please notify your Primary care provider (PCP) and 
study staff. 
Possible side effects with stop smoking medications: Study staff have determined that you are 
medically eligible to receive these medications. Please notify your primary physician and the research 
team if you experience side effects of a medication. Study staff will call you to monitor the side 
effects. Dr. Hilary Tindle, the Primary Investigator, can be reached at 615-701-MIST (6478). 
 
 
Nicotine Replacement Therapy (NRT): 
Nicotine replacement therapy has been available for over two decades and is sold over the 
counter. Possible side effects of the patch include skin irritation or itching, which is commonly 
managed by rotating patch sites and/or applying an over-the-counter corticosteroid cream (such 
as 1% hydrocortisone), and trouble sleeping. Mouth, throat and nose irritation, heartburn, or 
hiccups may occur among people who use nicotine gum and lozenge. Many of the side effects of 
the lozenge or gum can be avoided by correct use of the medication. For the nicotine nasal 
spray and inhaler the most common side effects can include mouth/throat irritation, coughing, 
runny nose, and watery eyes.  In rare cases dizziness, headache, nausea, and rapid heartbeat 
can occur. Severe and/or life-threatening side effects include allergic reactions, such as swelling 
of your throat and tongue, chest pain, a fast and abnormal heartbeat and inability to think 
Date of IRB Approval: 09/16/2024
Date of Expiration: 09/15/2025


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Metabolism-Informed Smoking Treatment (MIST) 
Version #: 
Version Date: 
PI: 
7 
05-15-2024 
Hilary Tindle, MD 
  
 
 
 
 
5
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clearly or logically. 
 
Varenicline (also called Chantix): 
Common side effects of varenicline include nausea, sleep disturbance and vivid dreams, 
gastrointestinal symptoms, and vomiting.  Individuals with pre-existing psychiatric conditions may 
experience symptoms such as behavioral changes, agitation, depressed mood, and suicidal 
behavior during the process of quitting smoking with and without varenicline treatment.  In a 
large FDA-mandated trial (EAGLES, Lancet 2016) varenicline was found to be safe and effective in 
patients with and without pre-existing psychiatric conditions. Women who are pregnant or 
breastfeeding should not use varenicline. 
 
Expired carbon monoxide test and saliva cotinine test: There are no known serious adverse effects 
from these tests. The expired carbon monoxide test may sometimes cause people to feel mildly 
short of breath or cause cough during the test. 
 
Payments for your time spent taking part in this study: You can be reimbursed up to $280 for full 
participation in this study. Here is a breakdown. 
  
 
$10 - screening blood test  
 
$40 - completed baseline survey 
 
$20 each for completed surveys at months 1, 3, 6, and 12 
 
$100 for sample given for a saliva or breath test at 6 months. 
o Plus, up to $50 additional for travel for in-person testing. 
 
Your social security number is needed to provide you with a study payment card. 
 
Costs to you if you take part in this study: 
If you agree to take part in this research study, you and/or your insurance will not have to pay for the 
tests and treatments that are being done only for research.  However, you are still responsible for 
paying for the usual care you would normally receive for the treatment of your illness. This includes 
treatments and tests you would need even if you were not in this study. These costs will be billed to you 
and/or your insurance.  
You have the right to ask what it may cost you to take part in this study. If you would like assistance, 
financial counseling is available through the Vanderbilt Financial Assistance Program.  The study staff 
can help you contact this program. You have the right to contact your insurance company to discuss the 
costs of your routine care (non-research) further before choosing to be in the study. You may choose 
Date of IRB Approval: 09/16/2024
Date of Expiration: 09/15/2025


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Metabolism-Informed Smoking Treatment (MIST) 
Version #: 
Version Date: 
PI: 
7 
05-15-2024 
Hilary Tindle, MD 
  
 
 
 
 
6
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not to be in this study if your insurance does not pay for your routine care (non-research) costs and your 
doctor will discuss other treatment plans with you. 
 
Payment in case you are injured because of this research study: 
If it is determined by Vanderbilt and the Investigator that an injury occurred as a direct result of the 
tests or treatments that are done for research, then you and/or your insurance will not have to pay 
for the cost of immediate medical care provided at Vanderbilt to treat the injury. 
 
There are no plans for Vanderbilt to pay for any injury caused by the usual care you would normally 
receive for treating your illness or the costs of any additional care. There are no plans for Vanderbilt to 
give you money for the injury. 
 
Who to call for any questions or in case you are injured: 
If you should have any questions about this research study or if you feel you have been hurt by being a 
part of this study, please contact the Principal Investigator, Dr. Hilary Tindle, at 615-701-MIST (6478). 
 
For additional information about giving consent or your rights as a person in this study, to discuss 
problems, concerns, and questions, or to offer input, please feel free to call the VUMC Institutional 
Review Board Office at (615) 322-2918 or toll free at (866) 224-8273. 
 
Reasons why the study doctor may take you out of this study:  
Under some situations the study physician may remove you from the study, for example, if your blood 
test was invalid. 
 
What will happen if you decide to stop being in this study? 
If you decide to stop being a part of the study, you must tell the study doctor, Dr. Hilary Tindle, in writing. 
Her mailing address is 2525 West End Avenue, Suite 450, Vanderbilt University Medical Center, 
Nashville, TN 37203.  Deciding to not be part of the study will not change your regular medical care in 
any way. 
 
Clinical Trials Registry:  
A description of this clinical trial will be available on www.clinicaltrials.gov, as required by U.S. Law.  This 
Web site will not include information that can identify you.  At most, the website will include a summary 
of the results.  You can search this Web site at any time. 
Date of IRB Approval: 09/16/2024
Date of Expiration: 09/15/2025


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Metabolism-Informed Smoking Treatment (MIST) 
Version #: 
Version Date: 
PI: 
7 
05-15-2024 
Hilary Tindle, MD 
  
 
 
 
 
7
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Information on Confidentiality, Authorization to Use/Disclose Protected Health Information, and 
Agreement to Participate in Study.  
Confidentiality:   
Vanderbilt may share your information, without identifiers, to others or use it for other research 
projects not listed in this form. Vanderbilt, Dr. Tindle and her staff will comply with any and all laws 
regarding the privacy of such information.  There are no plans to pay you for the use or transfer of 
this de-identified information. 
 
All efforts, within reason, will be made to keep your personal information in your research record 
confidential. Total confidentiality cannot be guaranteed. To prevent a breach of confidentiality, 
these measurements and test results will be given a code and only the study staff will know the 
code. The name that belongs to the code will be kept in a locked file cabinet or on a computer with a 
password. Only Dr. Tindle and the research team will have access to your name. Your measurements 
and clinic data may be used indefinitely, and they may also be shared with other research groups; 
but they will be destroyed when no longer needed. 
 
This study has support from the National Institutes of Health (NIH). Your study information is protected 
by a Certificate of Confidentiality.  This Certificate allows us, in some cases, to refuse to give out your 
information even if requested using legal means.  
  
It does not protect information that we have to report by law, such as child abuse or some infectious 
diseases.  The Certificate does not prevent us from disclosing your information if we learn of possible 
harm to yourself or others, or if you need medical help.  
  
Disclosures that you consent to in this document are not protected. This includes putting research data 
in the medical record or sharing research data for this study or future research. Disclosures that you 
make yourself are also not protected.  
 
Breach of confidentiality: Your medical records will be reviewed, and relevant medical information will 
be collected and stored in a secure electronic database at Vanderbilt University Medical Center. This data 
will be password protected and only select research team members will have access to the password. 
However, despite these protections it is possible that this database could be compromised, and a breach 
of confidentiality could occur. 
   
Privacy: 
Date of IRB Approval: 09/16/2024
Date of Expiration: 09/15/2025


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Metabolism-Informed Smoking Treatment (MIST) 
Version #: 
Version Date: 
PI: 
7 
05-15-2024 
Hilary Tindle, MD 
  
 
 
 
 
8
This box is for 
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Any samples and information about you may be made available to others to use for research.  To protect 
your privacy, we will not release your name.  You may not receive any benefit as a result of the tests done 
on your samples.  These tests may help us, or other researchers learn more about causes, risks, and 
treatments around smoking or how to prevent this and other health problems.  
 
Your samples may be used to make new products or tests. These may have value and may be developed 
and owned by the study staff, Vanderbilt University, and/or others. If this happens, there are no plans 
to provide money to you. At any time, you may ask to have your sample destroyed; however, we will not 
be able to destroy research data that has already been gathered using your sample. Also, if your identity 
was removed from the samples, we will not be able to locate and destroy them. 
 
Study Results: Results will be published in a peer reviewed medical journal and will not be made otherwise 
available to participants of the study. 
 
Authorization to Use/Disclose Protected Health Information 
What information is being collected, used, or shared? 
To do this research, we will need to collect, use, and share your private health information.  By signing 
this document, you agree that your health care providers (including both Vanderbilt University Medical 
Center and others) may release your private health information to us, and that we may use any and all 
of your information that the study team believes it needs to conduct the study.  Your private 
information may include things learned from the procedures described in this consent form, as well as 
information from your medical record (which may include information such as HIV status, drug, alcohol 
or STD treatment, genetic test results, or mental health treatment).    
  
Who will see, use or share the information? 
The people who may request, receive or use your private health information include the researchers and 
their staff.  Additionally, we may share your information with other people at Vanderbilt (Ingram Cancer 
Center Data Safety Monitoring Committee), for example if needed for your clinical care or study 
oversight.  By signing this form, you give permission to the research team to share your information with 
others outside of Vanderbilt University Medical Center.  This may include the sponsor of the study 
(National Institutes of Health) and its agents or contractors, outside providers, study safety monitors, 
government agencies, other sites in the study, data managers and other agents and contractors used by 
the study team.   We try to make sure that everyone who sees your information keeps it confidential, 
but we cannot guarantee that your information will not be shared with others.  If your information is 
disclosed by your health care providers or the research team to others, federal and state confidentiality 
laws may no longer protect it.  
Date of IRB Approval: 09/16/2024
Date of Expiration: 09/15/2025


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Metabolism-Informed Smoking Treatment (MIST) 
Version #: 
Version Date: 
PI: 
7 
05-15-2024 
Hilary Tindle, MD 
  
 
 
 
 
9
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
  
Do you have to sign this Authorization? 
You do not have to sign this Authorization, but if you do not, you may not join the study. 
  
How long will your information be used or shared? 
Your authorization for the collection, use, and sharing of your information does not expire.  Additionally, 
you agree that your information may be used for similar or related future research studies. 
  
What if you change your mind? 
You may change your mind and cancel this authorization at any time.  If you cancel, you must contact the 
Principal Investigator in writing to let her know by using the contact information provided in this consent 
form.  Your cancellation will not affect information already collected in the study, or information that has 
already been shared with others before you cancelled your authorization. 
 
Unless told otherwise, your consent to use or share your PHI does not expire. If you change your mind, 
we ask that you contact Dr. Tindle in writing and let her know that you withdraw your consent. Her 
mailing address is 2525 West End Avenue Suite 450, Nashville, TN 37203. At that time, we will stop 
getting any more data about you. However, the health data we stored before you withdrew your consent 
may still be used for reporting and research quality. 
 
If you decide not to take part in this research study, it will not affect your treatment, payment or 
enrollment in any health plans or affect your ability to get benefits. You will get a copy of this form 
after it is signed.  
 
STATEMENT BY PERSON AGREEING TO BE IN THIS STUDY 
 
I have read this consent form and the research study has been explained to me verbally.  All my 
questions have been answered, and I freely and voluntarily choose to take part in this study.    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
Patient/Volunteer Signature 
 
 
 
 
 
Consent obtained by RA: 
 
 
Date of IRB Approval: 09/16/2024
Date of Expiration: 09/15/2025


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Metabolism-Informed Smoking Treatment (MIST) 
Version #: 
Version Date: 
PI: 
7 
05-15-2024 
Hilary Tindle, MD 
  
 
 
 
 
10 
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Date and Time:  
 
Signature of RA obtaining consent: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name and Title 
 
 
 
 
 
Date of IRB Approval: 09/16/2024
Date of Expiration: 09/15/2025


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Metabolism-Informed Smoking Treatment (MIST) 
Version #: 
Version Date: 
PI: 
7 
05-15-2024 
Hilary Tindle, MD 
  
 
 
 
 
11 
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Part 2.  
 
 
Consent for Genetic Research 
 
The purpose of this study is to look at genes (DNA) and how they affect health and disease. Genes 
are the instruction manual for your body. The genes you get from your parents decide what you 
look like and how your body behaves. They can also tell us a person’s risk for certain diseases and 
how they will respond to treatment.   
 
You are being asked to give a blood and/or saliva (spit) sample for genetic research.  In most cases, 
this blood sample can be part of the same blood draw from Part I. What we learn about you from 
this sample will not be put in your health record.  Your test results will not be shared with you or 
your doctor. No one else (like a relative, boss, or insurance company) will be given your test results. 
 
A single blood sample up to 15 ml (3 teaspoons) will be drawn from a vein in your arm using a 
needle. This will take about 5 minutes of your time.  
 
A saliva sample of approximately 2 ml (about half a teaspoon) may be collected using a tube you will 
spit into if a blood sample cannot be obtained. Most people take between 2 and 5 minutes to 
provide a saliva sample.  
 
 
Blood samples – You may feel bothered or pained from the needle stick.  You may have a bruise, or 
the site may get infected.  It is rare, but some people faint. 
 
One risk of giving samples for this research may be the release of your name that could link you to 
the stored samples and/or the results of the tests run on your samples. This may cause problems 
with insurance or getting a job.  
 
To prevent this, these samples will be given a code.  Only the study staff will know the code.  The 
name that belongs to the code will be kept in a locked file cabinet or on a computer with a 
password.  Only study staff will have access to your name.    
 
Health insurance companies and group health plans may not use your genetic information when 
making decisions regarding your eligibility or premiums. Employers with 15 or more employees may 
not use your genetic information that comes from this research when deciding to hire, promote, or 
fire you or when setting the terms of your employment.  
 
Date of IRB Approval: 09/16/2024
Date of Expiration: 09/15/2025


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Metabolism-Informed Smoking Treatment (MIST) 
Version #: 
Version Date: 
PI: 
7 
05-15-2024 
Hilary Tindle, MD 
  
 
 
 
 
12 
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Your sample will be used to make DNA that will be kept for an unknown length of time (maybe 
years) for future research.  The sample will be destroyed when it is no longer needed. 
Your samples, genotypes or other laboratory measures obtained from your sample, and information 
from your medical record and from this study may be shared with others to use for research.  To 
protect your privacy, we will not release your name or other personal information that could identify 
you. 
 
You will not receive any benefit as a result of the tests done on your samples.  These tests may help 
us learn more about the causes, risks, treatments, or how to prevent this and other health problems.  
 
Giving samples for research is your free choice and you may be in the study even if you do not want 
your samples used or stored for gene research. 
 
At any time, you may ask to have your sample destroyed.  You should contact study staff at 615-936-
6668 to have your sample destroyed and no longer used for research.  We will not be able to destroy 
research data that has already been gathered using your sample.  Also, if your identity was removed 
from the samples, we will not be able to locate and destroy them.   
 
There will be no costs to you for any of the tests done on your samples.  You will not be paid for the 
use of your samples. 
 
Information about you (medical record and study related, also known as phenotype data) and 
information derived from your blood/saliva sample (also known as genotypes) may be submitted in 
coded form to a controlled access government health research database for broad sharing for future 
gene research on health and disease with other Universities, non-profit institutes, for-profit 
companies, and government institutes.  
 
We will not share any personal identifiers when sharing information about you or your blood/tissue 
sample. The genetic information derived from your blood/saliva sample will not be placed into your 
medical record, and the results of the genetic analysis will not be shared with you.  
 
Donating your data may involve a loss of privacy, but information about you will be handled as 
confidentially as possible. Study data will be physically and electronically secured. As with any use of 
electronic means to store data, there is a risk of breach of data security.  Genetic information that 
results from this study does not have medical or treatment importance at this time.  However, there 
Date of IRB Approval: 09/16/2024
Date of Expiration: 09/15/2025


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Metabolism-Informed Smoking Treatment (MIST) 
Version #: 
Version Date: 
PI: 
7 
05-15-2024 
Hilary Tindle, MD 
  
 
 
 
 
13 
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
is a risk that information about taking part in a genetic study may influence insurance companies 
and/or employers regarding your health.   
 
Taking part in a genetic study may also have a negative impact or unintended consequences on family 
or other relationships.  It is possible that future research could one day help people of the same race, 
ethnicity, or sex as you.  However, it is also possible through these kinds of studies that genetic traits 
might come to be associated with your group.  In some cases, this could reinforce harmful stereotypes. 
 
There will be no direct benefit to you from allowing your data to be kept and used for future research. 
However, we hope we will learn something that will contribute to the advancement of science and 
understanding of health and disease.  
 
If the data or any new products, tests or discoveries that result from this research have potential 
commercial value, you will not share in any financial benefits.  If you decide later that you do not want 
your information to be used for future research, you can notify the investigator in writing at: Dr. Hilary 
Tindle, Vanderbilt University Medical Center, 2525 West End, Suite 450, Nashville, TN 37203, and any 
remaining data will be destroyed.  However, we cannot retract any data that has been shared with 
other researchers. 
 
Please check Yes or No to the questions below: 
 
My blood/saliva sample may be used for gene research in this study.  
 
  
 Yes  
 No 
 
My blood/saliva sample may be stored/shared for future gene research at VUMC.   
 
 
 Yes  
 No 
 
My blood/saliva sample may be stored/shared for future gene research for other health problems (such 
as cancer, heart disease, etc.). 
 
 Yes  
 No 
 
 
Patient/Volunteer Name: 
Date: _____________ 
Date of IRB Approval: 09/16/2024
Date of Expiration: 09/15/2025


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Metabolism-Informed Smoking Treatment (MIST) 
Version #: 
Version Date: 
PI: 
7 
05-15-2024 
Hilary Tindle, MD 
  
 
 
 
 
14 
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
Part 3.  
 
 
 Additional 12-month quit test 
 
Confirming smoke free status: If you have quit smoking at the 12-month follow-up survey and you are 
not using nicotine replacement therapy at that time, we will ask you to complete a saliva sample which 
tests for nicotine levels in your saliva. If you are using nicotine replacement medicine at that time, we 
will ask you to complete a breath test instead of the saliva test. This breath test measures the amount of 
carbon monoxide in your lungs. If you have an upcoming appointment/hospitalization, study staff may 
also attempt to meet you in person. In case you are not able to come in person to our clinic, there is an 
option to do the breath test and/or the saliva test from home. The iCO™ personal Smokerlyzer® is a 
device that can be attached to your smart device and activated via an app. The results of the breath test 
are then sent to the study team. The saliva test is a small kit that you can complete at home and return 
by mail. All tests used to confirm smoke free status are collected only for the proposed research project, 
and only study staff will have access to these data. 
 
 
Possible side effects and risks of expired carbon monoxide test and saliva cotinine test: There are no 
known serious adverse effects from these tests. The expired carbon monoxide test may sometimes 
cause people to feel mildly short of breath or cause cough during the test. 
 
 
Payments for your time spent taking part in this additional quit test: You can be reimbursed up to $150 
for completing the quit test. Here is a breakdown. 
  
 
$100 for sample given for a saliva or breath test at 12-months. 
o Plus, up to $50 additional for travel for in-person testing. 
 
 
STATEMENT BY PERSON AGREEING TO ADDITIONAL SAMPLE 
 
I have read this additional consent section, and the research procedure has been explained to me 
verbally.  All my questions have been answered, and I freely and voluntarily choose to take part in this 
additional sample collection.    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
Patient/Volunteer Signature 
 
 
 
Date of IRB Approval: 09/16/2024
Date of Expiration: 09/15/2025


VUMC Institutional Review Board 
Informed Consent Document for Research 
 
Study Title: 
Metabolism-Informed Smoking Treatment (MIST) 
Version #: 
Version Date: 
PI: 
7 
05-15-2024 
Hilary Tindle, MD 
  
 
 
 
 
15 
This box is for 
IRB USE ONLY 
Do not edit or delete 
 
 
 
 
Consent obtained by:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Date and Time:  
 
Signature of staff obtaining consent: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name and Title 
 
Date of IRB Approval: 09/16/2024
Date of Expiration: 09/15/2025

Prot_SAP_002.pdf: 
Protocol Version #: 15 
 
1 
Protocol Date: April 26, 2024 
 
 
 
 
Metabolism Informed Smoking Treatment in Medicaid and Medicare Patients: 
The MIST RCT 
 
 
Hilary A. Tindle, MD, MPH  
Department of Medicine - Division of General Internal Medicine & Public Health 
2525 West End Avenue, Suite 450 
Vanderbilt University Medical Center 
Nashville, TN 37203 
 
 
 
 
 
 
 
Co-Investigators: 
 
Matthew Freiberg, MD - Vanderbilt University Medical Center 
 
Robert Greevy, PhD - Vanderbilt University Medical Center 
 
Saul Shiffman, PhD – University of Pittsburgh 
 
Quinn Wells, MD - Vanderbilt University Medical Center 
 
 
 
 
 
 
 
 
 
 
 
 
NCT04590404 
 
 
 
 


Protocol Version #: 15 
 
2 
Protocol Date: April 26, 2024 
Table of Contents: 
 
Study Schema 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Previous Human Studies 
4.0 
Detailed Study Overview 
5.0 
Study Procedures 
6.0 
Risks  
7.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk 
to Participants or Others 
8.0 
Study Withdrawal/Discontinuation 
9.0 
Statistical Considerations 
10.0 Privacy/Confidentiality  
11.0 References 
 
 


Protocol Version #: 15 
 
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Protocol Date: April 26, 2024 
1.0 Background 
 
Every year smoking kills almost 500,000 Americans and costs the nation 1.6% of the 
gross domestic product. [1] Over 20 million U.S. smokers attempt to quit smoking 
annually, yet two-thirds or more are not treated with proven cessation medications. 
[2, 3] When medication is provided, it is not biologically tailored. Metabolism 
Informed Smoking Treatment (MIST) increases precision of smoking treatment by 
leveraging speed of nicotine metabolism to optimize pharmacotherapy.  
 
MIST matches the right patient to the right drug. MIST seeks to overcome one of 
the most serious limitations of the current standard of care for smoking treatment, 
which is the generic (i.e., non-biologically tailored) nature of medication selection. 
[4] About 60% of smokers are “normal” (i.e., faster) metabolizers of nicotine for 
whom nicotine replacement therapy (NRT) produces sub-optimal results. [5] Yet 
about 90% of all smokers who use cessation medication use nicotine replacement, 
resulting in widespread therapeutic mismatch. [2] For these “normal” metabolizers, 
Varenicline shows evidence of improved quit rates over NRT among normal, but not 
slow, metabolizers. [5]  
 
The nicotine metabolite ratio -- NMR --is a validated, reproducible biomarker 
for nicotine metabolism. A large body of research has established the nicotine 
metabolite ratio (NMR) as a validated biomarker of nicotine metabolism that 
predicts smoking behavior and therapeutic response to cessation pharmacotherapy. 
Measurements of plasma NMR are reliable across analytical methods and laboratory 
sites, unaffected by sampling time or storage temperature, and for regular daily 
smokers, are consistent despite variation in smoking. [6-8] Finally, NMR reflects 
both genetic and environmental influences on nicotine metabolism, and therefore 
may have even greater predictive power than genetic markers. [9] 
 
NMR is associated with smoking-related traits and overall treatment 
response. Fast/normal (i.e., higher NMR) vs. slower metabolizers smoke more 
cigarettes per day, [10-12] smoke more intensely, [13] exhibit enhanced abstinence-
induced neural responses to smoking cues in craving-specific brain regions,[14] and 
have greater thalamic nicotinic receptor availability in early abstinence. [15] 
Collectively, these metabolism-associated physiologic differences explain in part 
why fast/normal metabolizers have greater difficulty in quitting and consistently 
have the lower quit rates at end-of-treatment. [16-18] 
 
Centers for Medicare and Medicaid (CMS) -enrolled smokers bear a 
disproportionate burden of smoking related illness and many want to quit 
smoking yet are undertreated.  
Medicaid. At 37%, the national smoking prevalence among Medicaid enrollees far 
exceeds the national average in the general population. [19] In Tennessee, smoking 
prevalence among Medicaid (TennCare) adults is higher than among privately-
insured low-income TN residents and higher than the 22.1% average statewide. [19] 


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Protocol Date: April 26, 2024 
As many as half of Medicaid-insured smokers make a quit attempt each year, but, on 
average, only about 6.5% are successful, [20] due in part to the low rates of use of 
covered smoking cessation pharmacotherapy (< 10%). [19] This low rate of 
medication use reflects low knowledge among patients (36%) and providers (60%) 
about smoking cessation treatment benefits. [21] Expansion of medication coverage 
increases the likelihood that enrollees will attempt to quit (from 10.2% to 20.3%), 
utilize the medication benefit, and quit successfully (from 3.8% to 9.1%). [20, 22] 
Concomitant with this reduction was a statewide decrease in the hospitalization 
rate of Medicaid covered patients. [23]   
Medicare. Medicare smokers are generally older and as expected, smoke at rates 
that tend to be lower than the national average (10.2%-12.5%), [24, 25] yet they are 
heavily burdened by smoking-related disease and report significantly lower 
physical and mental health related quality of life relative to non-smokers of similar 
age. [26] Over four of every ten Medicare smokers attempt to quit each year, yet quit 
rates have remained stagnant in recent years, due in part to low rates of use of 
pharmacotherapy among smokers with pharmacy benefits (16% overall: 9% 
varenicline, 4% bupropion, 1% NRT alone, 2% some combination). [27, 28] 
Similarly, Medicare enrollees quit smoking twice as often when they receive quitline 
counseling and pharmacotherapy, compared to Usual Care consisting of self-help 
materials (19.3% vs. 10.2%). [29] In a population of smokers hospitalized and 
counseled by the tobacco treatment service, Medicare enrollees exhibited higher 
willingness than commercially-insured patients to accept smoking treatment.[30] 
Finally, CMS has the infrastructure for the widespread implementation of MIST 
nationwide to help millions of those who have prescription medication benefits and 
who could be seamlessly offered this precision approach by their health care 
provider. 
 
2.0 
 Rationale and Specific Aims 
 
2.1 Rationale 
 
Smoking is the leading preventable cause of disease and death in the world and the 
US. [31] Smokers who receive insurance coverage through the Centers for Medicare 
and Medicaid (CMS) are at high risk of smoking-related disease yet are profoundly 
undertreated despite having pharmacy benefits for FDA-approved smoking 
cessation medications. [20, 24] We propose Metabolism-Informed Smoking 
Treatment (MIST), a precision approach that biologically tailors medication to 
nicotine metabolism, in hospitalized smokers enrolled in CMS. Nicotine metabolism 
predicts nicotine dependence, cessation success, and outcomes with 
pharmacotherapy. [5, 10-13, 16-18]  
 
Nicotine is rapidly metabolized in the liver primarily by the cytochrome P450 
enzyme CYP2A6 to cotinine, which is further metabolized to 3-hydroxycotinine (3-
HC) by CYP2A6. [32, 33] The NMR (ratio of 3-HC to cotinine) reflects CYP2A6 
activity and the rate of nicotine metabolism, and to date is the only biomarker to 


Protocol Version #: 15 
 
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Protocol Date: April 26, 2024 
predict a therapeutic response in a smoking cessation RCT. [5, 10] Overall, about 
2/3rd of smokers are “normal” metabolizers, while ~1/3 are “slow” metabolizers. 
[5] In a landmark RCT, among normal metabolizers, varenicline doubled cessation 
rates over NRT (patch) at end of therapy (39% vs. 23%) and 6 months (23% vs. 
13%). [32, 34] Slow metabolizers had more side effects but no cessation benefit 
from varenicline. The number needed to treat (NNT) for one normal metabolizer to 
quit was 4.9 for varenicline vs. 26 for NRT patch, establishing a strong scientific 
premise to pair normal metabolizers with varenicline and slow metabolizers with 
NRT. [5]  
 
Informed by our preliminary data, we propose a scientifically rigorous RCT design 
of approximately 1,000 adult CMS beneficiaries or those with prescription coverage, 
who are daily smokers hospitalized at Vanderbilt University Medical Center (VUMC) 
to compare effects of MIST vs. UC on: abstinence (1° aim), implementation in clinical 
practice (2° aim), and health care utilization and mortality (exploratory). All 
participants will receive UC for tobacco treatment, including: (1) bedside tobacco 
consult; (2) a prescription for varenicline or NRT; and (3) automated phone calls via 
TelASK to promote engagement after study enrollment. Medication prescriptions 
will be NMR-guided for MIST participants and patient-provider selected for UC 
participants. Type of NRT (e.g., inhaler, gum, patch, etc.) will be informed by 
insurance type. For example, some plans in Medicare Part D cover only prescription 
NRT (inhaler, nasal spray) while most state Medicaid programs only cover over-the-
counter (OTC) meds (e.g., patch, gum, lozenge). The research team will work with 
PCPs and their staff to facilitate smoking treatment after study enrollment and will 
track pharmacy records for PCP-generated prescriptions for patients who continue 
smoking. PCPs of patients in MIST will be given the NMR results, while PCPs of UC 
participants will not. Phone surveys will be conducted at approximately 1, 3, 6, and 
12 months to assess medication adherence and smoking status, with biochemical 
validation of abstinence at 6 and 12 months via salivary cotinine for those not using 
nicotine-containing products at the time of testing. For those using nicotine-
containing products at the time of testing, carbon monoxide or anabasine (if 
available) will be used. See Table 2 for cut-off values. If feasible within the study 
timeline and staffing, health care utilization and mortality will be tracked passively 
over 12 months via existing databases (e.g., Tennessee Hospital Discharge Data 
System, TN HDDS) via exploratory Aim 3. Investigators have complementary and 
broad expertise to conduct MIST, the first large RCT to incorporate NMR results into 
clinical treatment of smoking.  
 
2.2 Specific Aims 
 
The specific aims of the study will compare the effects of MIST vs. UC on:  
 
• AIM 1: Abstinence as defined by biochemically-verified self-reported 7-day 
point prevalence abstinence at 6 m (1° study outcome) and 12 m (2° 
outcome).  


Protocol Version #: 15 
 
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Protocol Date: April 26, 2024 
o H1: MIST will produce higher abstinence rates.  
 
• AIM 2: Implementation in clinical practice as reflected by: (2a) Patient’s self-
reported medication adherence at 1, 3 m; (2b) PCP prescription for smoking 
cessation medication any time after study enrollment, controlling for 
participant’s abstinence; and (2c) whether the prescription is matched to 
NMR.  
o H2: MIST will produce higher rates of adherence, PCP medication 
prescription after study enrollment, and NMR-matching of 
prescriptions.  
 
• AIM 3: A healthcare composite outcome (exploratory) comprised of 
healthcare utilization visits (ER & hospitalizations) and mortality (all-cause & 
cause-specific) ascertained via the VUMC EHR, CMS databases, state vital 
records, and TN HDDS.  
o H3: MIST will reduce health care utilization and death compared to 
UC. 
 
2.3 Significance – Projected Impact of Completed Aims 
 
Results could establish MIST as a fundamentally new framework for treatment of 
smoking, with significant scientific and clinical implications. Given that varenicline 
and nicotine replacement differ profoundly in cost and side-effect profiles, MIST has 
the potential to optimize overall population outcomes including cost-effectiveness, 
which is an important future direction for this research. Results could elucidate and 
reduce disparities in cessation and smoking-related illness. [35] From a population 
health perspective, MIST implementation in CMS could positively impact about 20 
million smokers. 
 
MIST is the first full scale RCT to test the impact of a metabolism informed approach 
to smoking treatment in clinical practice. This project will enroll smokers from 
VUMC, a Learning Healthcare System and national leader in precision medicine with 
the infrastructure to implement the MIST intervention. While precision medicine 
has become a popular scientific trend, this team recognizes the need to rigorously 
test interventions such as MIST to accurately and responsibly determine their utility 
for clinical care. If implemented broadly, Metabolism Informed Smoking Treatment 
(MIST) could double abstinence for 6 of every 10 smokers, yet its efficacy has not 
been tested in clinical practice. MIST may especially help populations who bear a 
disproportionate burden of smoking-related illness and are undertreated despite 
having full coverage of smoking cessation pharmacotherapy, such as CMS 
beneficiaries who smoke. 
 
3.0 Previous Human Studies 
 


Protocol Version #: 15 
 
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Protocol Date: April 26, 2024 
Data establishing the scientific premise of the current proposal come from a large (N 
= 1,246) prospective placebo-controlled RCT, led by our team member Dr. Tyndale, 
that randomized subjects by nicotine metabolite ratio (NMR) group (i.e., “normal” vs 
“slow,” using a threshold of 0.31) to placebo, nicotine patch, or varenicline. [5] 
Varenicline improved quit rates over NRT at end of therapy (OR 1.89, 95% CI 1.02– 
3.45) and 6 months (OR 2.17, 95% CI 1.38–3.42) (all p=0.001) among normal, but 
not slow, metabolizers. In contrast to the current proposal, the prior study treated 
NMR as an explanatory variable and did not incorporate knowledge of nicotine 
metabolism into selection of smoking cessation medication or any part of clinical 
treatment. 
 
To demonstrate feasibility of this proposal, we conducted and published a pilot RCT 
of 81 adult daily smokers with medical comorbidity to a metabolism-informed 
intervention vs. a robust control, established infrastructure to track participants, 
and collected outcome data. [36] Participants reported perceptions of the 
metabolism-informed intervention, underwent blood draw for NMR, and received 
expert cessation counseling. For intervention participants, medication selection was 
informed by NMR result (normal (≥0.31) vs. slow (< 0.31)) using the threshold by 
Tyndale and colleagues. [5] The primary outcome was feasibility of offering NMR in 
a clinical population, reflected by attitudes toward the precision intervention and by 
match rates between NMR and medication. Secondary endpoints (cessation, 
confidence, medication use, smoking status) were assessed over 6 months for 
feasibility. The median NMR for slow metabolizers was 0.22 [0.18–0.27] and for 
normal metabolizers was 0.54 [0.38– 0.82], similar to the distribution observed in 
the literature.[5] Over 90% of participants endorsed the idea of metabolism 
informed care and all but two were prescribed medication. Despite very high 
varenicline prescription rates of ~60% in both treatment arms, NMR-medication 
matching was markedly higher among intervention (36/43; 84%) versus control 
(21/36; 58%) participants. Put another way, 42% of control participants were 
“mismatched,” as compared to only 16% in intervention (p = 0.02). At the 6 month 
follow up time point, 80% of participants were reached. While this pilot RCT was 
not powered for abstinence, medication adherence, or other cessation-related 
outcomes, these were assessed as part of the feasibility of outcome data collection. 
Self-reported rates of medication use and side effects at 3 months, and 7-day point 
prevalence abstinence at 6 months, did not differ statistically between treatment 
arms. From this pilot study we concluded that: (1) Smokers viewed the metabolism 
informed treatment favorably and were willing to use medication based on NMR 
test results, with 3-fold increased concordance (matching) between nicotine 
metabolism status and medication in the intervention arm; at the same time, (2) 
Nearly 1/2 of patients in UC received medications that were not matched with their 
NMR, underscoring the generic nature of UC despite high prescription rates of 
varenicline in both treatment arms of the study. 
 
4.0 Detailed Study Overview 
 


Protocol Version #: 15 
 
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Protocol Date: April 26, 2024 
Eligible participants are consented and enrolled into the study during their 
inpatient hospital stay, participants may also be enrolled in the ER and observation 
unit. Potential participants may also be recruited from procedural or other same day 
settings, such as same day surgeries, pre-op or admission planning visits, or health 
screenings involving imaging or procedures, such as lung cancer screening. This 
process includes: (1) Screening, enrollment, randomization; (2) Post-enrollment 
treatment support; (3) Outcome ascertainment via survey, biochemical samples, 
and passive follow up using health system databases. 
1. Screening, enrollment, randomization 
• Screening & enrollment 
o Initial Certified Tobacco Treatment Specialist (CTTS) (tobacco 
counselor) assessment and tobacco cessation counseling (with initial 
screening consent for NMR).  
o Confirmation of eligibility and assessment of inclusion and exclusion 
criteria by study RA, including NMR result and verification by 
pharmacy personnel through procedures such as insurance test 
claims. 
o The screening consent for the NMR test will occur before the main 
consent for study enrollment. To accommodate patients who are 
eligible for the study but who request more time to consider 
enrollment, study staff may obtain screening consent and then 
complete remaining enrollment steps such as blood draw at a later 
time (e.g., after study enrollment/clinic visit).  
o Patients will be randomized after study staff ensures they have met 
all criteria, including a valid NMR result. Blood for NMR testing may 
be collected via a fresh blood draw or using stored clinical samples. 
The NMR results will be analyzed after study staff completes the 
screening consent process with the patient. Study enrollment forms 
may be completed remotely, as needed, due to the time constraints of 
meeting participants in-person.  
o Study staff verifies patient contact information as part of the 
enrollment process.  Due to time constraints, verification of contact 
information will be prioritized immediately after the screening 
consent process.  
o If the main consent process takes place remotely, the consenting 
structure will remain the same (i.e. screening consent will be 
completed prior to the main consent). In this case, study staff will 
electronically provide a copy of all applicable study documents to the 
patient prior to verbally reviewing all elements of the consent. If no 
electronic delivery of the main consent is possible, a paper copy of 
the main consent will be provided in-person or mailed to the patient 
before verbal review over the phone. 
o Baseline survey may be completed remotely, as needed, due to the 
time constraints of meeting participants in-person.  
o Participants will be compensated with $10 for the screening blood 
draw and $40 for completion of the baseline survey. 


Protocol Version #: 15 
 
9 
Protocol Date: April 26, 2024 
 
• Randomization  
o Randomization will take place after a valid NMR has resulted.  As 
noted above, in the case that a participant meets all other criteria, but 
NMR is not resulted, a patient may be consented but will not be 
randomized until after the NMR is resulted.  
o In the rare event that an NMR sample results as invalid (nicotine 
unable to be detected in sample) after the participant has been 
enrolled, the study team will obtain a backup sample within 
approximately a week of study enrollment. This sample will either be 
a stored clinical sample or the study team will coordinate a new 
blood draw. As needed, a courier service will be used to retrieve and 
deliver this sample.  
o Study medication will be provided by a VUMC or outside pharmacy 
after study enrollment either in-person or mailed to the participant’s 
home. Participants who are unable to pay for their insurance co-pays 
for smoking cessation medication may be referred to existing 
programs at Vanderbilt University Medical Center to facilitate 
obtaining medication. In the infrequent instance where charges 
related to the study are mistakenly billed to the participant, the study 
team will reimburse the participant via a gift card. 
o Participant will be provided with study information including a copy 
of the consent document and, for those randomized to the MIST arm, 
information on the NMR test.  
 
2. Post-enrollment treatment support 
Beginning at approximately 3 days and weeks 2, 4, 6, 8, 10, and 12 post-enrollment 
the participant will receive automated Interactive Voice Response (IVR) support 
calls from TelASK to assess smoking status and medication receipt/adherence. 
Participants may also opt to speak with a study Tobacco Treatment Specialist if 
needed. At 6 months, all participants (regardless of smoking status) will be offered a 
second cycle of IVR calls. To maintain the study timeline, participants recruited in 
the final year of the study will not be offered the second cycle of IVR calls. 
 
3. Outcome ascertainment 
At approximately 1-, 3-, 6-, and 12-months participants will complete follow up 
surveys via: 
• Text message or email, based on the participant’s preference, containing a 
link to the REDCap follow up survey. If the participant prefers phone contact, 
a study team member will call. Compensation is $20 per completed survey. If 
participants fail to respond to 6, 12 month surveys, they may be contacted 
by phone call or mailed survey.   
• 
If the participant cannot remotely complete items related to follow up. 
including surveys, we will make all efforts to coordinate with the patient 
during any pending appointments at VUMC so they can complete their 


Protocol Version #: 15 
 
10 
Protocol Date: April 26, 2024 
survey on a day when they are already scheduled to be at VUMC (e.g. study 
RA will travel to the One Hundred Oaks clinic of other VUMC clinics to meet 
participant).  
When study staff is unable to reach participants for follow up surveys after several 
attempts, the next step will be to reach out to alternative contacts provided by the 
participant at enrollment. An alternative contact that is a reliable close relative (i.e., 
spouse, significant other, or caregiver) can opt to complete a survey on the 
participant’s behalf as a proxy. This survey will be considered complete “by-proxy” 
in the study database.  
Biochemical Validation of self-reported tobacco abstinence at 6 and 12 
months.  
• Participants are asked to complete a carbon monoxide (CO) test or salivary 
cotinine test to confirm quit smoking status if they indicate on the survey 
that they have quit smoking. $100 will be offered for completion of 
biochemical validation at each of the 6 and 12 month timepoints. $50 will be 
offered for travel reimbursement at each of the 6 and 12 month timepoints if 
patients complete biochemical validation in person.  
 
Compensation. Total compensation for full study participation is $430.00.  
 
5.0 Study Procedures 
 
5.1 Tobacco Treatment Service Consult 
 
The VUMC inpatient Tobacco Treatment Service (TTS) will typically be the first 
point of contact for recruitment. ViTAL (the Vanderbilt Center for Tobacco, 
Addiction and Lifestyle) Center research staff may also visit smokers directly to 
initiate the NMR blood draw, followed by the tobacco clinician (CTTS) consult. The 
TTS program is an evidence-based clinical service for Vanderbilt University Hospital 
(VUH) hospitalized patients who smoke. [37] Patients admitted to VUH reach the 
TTS as follows: (1) Routine smoking status documentation in the EHR at admission 
by a nurse produces a daily list of smokers which the CTTS accesses in Epic; (2) 
Following an “opt out” design, a CTTS visits smokers to offer brief bedside 
counseling and medication support.  Patients may opt to decline the consult.  For 
each consult, the CTTS reviews the medical chart and at the bedside, assesses 
tobacco use patterns, offers counseling, and recommends FDA-approved smoking 
cessation pharmacotherapy to manage nicotine withdrawal and promote cessation. 
A typical bedside or phone discussion lasts 15-20 minutes.  
 
5.2 Screening and Recruitment 
 
Screening will take place by phone or in-person. During the course of a tobacco 
treatment consult, the CTTS will screen each smoker for preliminary study eligibility 
using the Counselor Screening Form (CSF), including consent to speak with study 


Protocol Version #: 15 
 
11 
Protocol Date: April 26, 2024 
staff. The CTTS will also inform the patient that there is a mandatory blood test 
required to participate in the study. The CTTS or study staff (research assistant 
(RA)) will obtain consent on the Screening Consent Form to perform the NMR blood 
test. The CTTS and/or RA will check for an existing and valid NMR result in the 
patient’s EHR. If no previous NMR results are available, the study team may order an 
NMR test to be performed on a blood sample that has already been obtained and is 
available for testing.  The study team may also order a new blood draw for the NMR.   
 
The RA will visit or call those patients who are preliminarily eligible based on the 
CSF to verify eligibility, explain the study in detail using a written handout, and 
obtain informed consent.  Screening for eligibility will include reviewing the 
patient’s chart in the EHR (e.g., review of CTTS progress note, admission notes, and 
other medical records as needed) and completion of the RA Screening Form (RASF). 
As needed, the RA will also query the care team to determine exclusion criteria.  If 
the patient wishes to have more time to consider study participation, he or she will 
be given the name of the RA and study phone number.  Because hospital lengths of 
stay tend to be short (3-5 days), it is possible that the patient will be discharged 
before being able to fully enroll in the study.   
 
5.3 Inclusion Criteria 
 
Inclusion Criteria  
• 18 years old or older 
• be enrolled in or pending approval for an insurance plan that supports 
prescription coverage for smoking cessation medication (including Medicare 
part D, Medicaid, private insurance, Federal or other governmental, or other 
insurance) or willing and able to purchase smoking cessation medication and pay 
for healthcare out of pocket to facilitate delivery of medications  
• have a regular provider/PCP or have access to a free or low cost clinic for 
regular clinical care that can prescribe smoking cessation medication; if 
patient does not have a PCP, the study team may collaborate with the patient 
to establish a primary care provider 
• agree to quit or try to quit smoking upon study enrollment 
• be a daily smoker when smoking normally during the month prior to 
entering the study 
• be medically eligible to use varenicline* 
• be medically eligible to use nicotine replacement therapy ** 
• have received medication recommendations from a tobacco counselor 
• agree to take smoking cessation medication (i.e., varenicline OR nicotine 
replacement therapy) home and consider using it 
• have a cell phone or landline that can be reached directly (i.e., without 
transfer) 
• have a permanent address where they live and can receive mail 
• estimated life expectancy of at least one year or greater 
_________________________________________________________________________________________ 


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*Medical eligibility to take varenicline is defined by absence of the following: 
o Serious brain condition that impairs cognition (including but not 
limited to   dementia, delirium, brain tumors/metastases, 
uncontrolled seizures (i.e., seizures within the past 3 mo.))       
o pregnancy/planning to become pregnant/breastfeeding in the next 
year 
o history of allergic reaction to varenicline 
o unstable/uncontrolled mental health condition:   
a. altered mental status (e.g., delirium, hallucinations) OR 
b. serious psychiatric symptoms in the past 6 months as defined 
by suicidal ideation or attempt, hospitalization or ED visit 
involving a psychiatric condition (e.g., depression, anxiety, 
bipolar, schizophrenia, schizoaffective disorder, PTSD, 
substance use (e.g., overdose, other related) OR  
c. changes in psychiatric medication within the past 3 months  
o if alcohol use; history of blackouts or seizures with drinking 
 
** Medical eligibility to use nicotine replacement therapy is defined by absence of 
the following: 
o unstable from cardiovascular perspective 
o current or history of Buerger’s disease (also called thromboangiitis 
obliterans) 
o pregnant/planning to become pregnant/breastfeeding in the next 
year 
 
5.4 Exclusion Criteria 
 
Exclusion Criteria 
• insufficient time to perform and complete the enrollment process 
• barrier to effective communication (including low English proficiency) 
• not cognitively able to participate in the study 
• too ill, on hospice, or physically unable to participate in the follow-up process  
• previously completed the MIST study or is currently enrolled in a quit 
smoking study that involves a medication-based treatment 
• estimated life expectancy of less than one year 
 
 
5.5 Informed Consent 
 
Informed consent for NMR Screening: Potentially eligible smokers who are 
counseled in the hospital or by phone by a CTTS will be told briefly about the study 
and, if interested, the CTTS will obtain a signed screening consent from the patient 
for NMR sample. An RA may also obtain screening consent for NMR.   
 


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Informed consent for full study enrollment: Study staff will perform informed 
consent. Potential participants will be told that their participation is completely 
voluntary, and that they can opt out at any time or refuse to participate in any 
portion of the study. During the consent process, potential participants will be 
informed of all study procedures, including possible side effects of medications 
used. The informed consent document will state that the study is being done as a 
collaboration between VUMC and TelASK. Potential participants will be informed 
that in order to make the phone calls, TelASK will be given information such as their 
name, study ID, phone number, sex, preference for time of call, and the date that 
they are discharged from the hospital or enrolled in the study. There is a small but 
potential risk of data breach with this transfer of information. However, TelASK- 
generated IVR calls are becoming an integral part of the clinical care of smoking in 
multiple healthcare systems across North America. The consent will indicate that 
participants may be invited to participate in future studies. 
 
Whenever possible, the consent process will be conducted electronically using 
REDCap, a secure, web-based, HIPAA-compliant, data collection platform. REDCap 
has a user management system that allows project owners to grant and control 
varying levels of access to other users (e.g., viewing of data collection instruments 
and data may be specified as read only). Patient signatures can be obtained as typed 
or written signature via stylus/cursor.  After consenting, patients will be provided 
with a printed or e-mailed pdf copy of the consent document or a web link to the 
consent. The web link provides access to a ROCKET site containing their signed 
consent form.  Signed consent documents will NOT be housed electronically on 
ROCKET.   
 
 
5.6 Baseline Survey and EHR Data (see Table 1, baseline column) 
 
Baseline data are collected from the medical chart, Counselor Screening Form, RA 
Screening Form, as well as the Baseline Survey. Data collection will include items 
such as: Sociodemographic factors (age, sex, education, race/ethnicity, employment, 
living situation, health insurance type), admitting diagnosis category (cardiac/non-
cardiac), tobacco use history (years of smoking; use of other tobacco products; 
Heaviness of Smoking Index, [38] measures of nicotine dependence (cigarettes 
smoked/day in month before admission and time to first morning cigarette)), rules 
for smoking in home, [39]alcohol use (AUDIT-C a 3-item survey assessing frequency 
and quantity of alcohol consumption that predicts problem drinking), [40] 
depressed mood and anxiety (PHQ-4, a validated screening test for depression and 
anxiety),[41] intention to remain abstinent from tobacco after study enrollment, 
pre-existing medical conditions, past use of FDA-approved smoking cessation 
medications, confidence to quit [42, 43], social support for quitting, perceived health 
risks of smoking and benefits of quitting,[44] optimism/pessimism as captured by 
the Life Orientation Test,[45] delay discounting Task (5 Trial Delay Discounting, 


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Tangney et al. Brief Self-Control Scale), [46-48] and detailed contact information for 
the patient and an alternative contact. 
 
Some of these data are routinely collected by the CTTS and entered into the EHR 
and/or TTS electronic database; other data are collected by the study RA using a 
password protected iPad or computer connected to the hospital’s secure wireless 
connection. Study RAs will administer the baseline questionnaire via REDCap[49] 
(or paper, if needed). All baseline data are entered securely into REDCap. If needed 
during a power loss, paper forms will be used during enrollment and stored 
securely in a locked cabinet that only study staff will have the ability to access. 
 
 
5.7 Baseline blood sample collection 
 
During screening/enrollment, we will attempt to collect a blood sample of 
approximately 15 ml (3 teaspoons) at the bedside or at an outpatient lab such as 
VUMC OHO or Cool Springs by clinical phlebotomy/study staff.  Blood samples will 
be used for determination of nicotine and metabolites (for NMR) and future 
analysis of genetics and other potentially relevant biological markers. Participants 
will be asked to consent for these data to be collected for the proposed research 
project and for potential future research.  Participants will be advised that blood 
may be discarded under certain circumstances (e.g., if they elect to not enroll in the 
study or are deemed ineligible after the NMR blood draw). 
 
Blood sample for NMR test: Often temporarily stored blood is available through 
the Clinical Pathology Laboratory that can be used for NMR testing.  When no 
stored blood is available, or if time constraints preclude locating and pulling stored 
blood, a fresh blood sample will be collected for NMR testing. Stored blood may be 
used when a patient’s health precludes a fresh blood draw, not limited to anemia 
(where hemoglobin lab results are less than 8), hemophilia, and other appropriate 
disorders or states.  
 
 Blood sample for future potential genetic and other analyses: 
The NIH’s precision medicine initiative, All of Us, aims to understand how genetics, 
in conjunction with a person’s environment and lifestyle, can optimize prevention 
and treatment of illness. The GSCAN results recently published in Nature Genetics 
[50] identified hundreds of new genetic variants related to smoking initiation, rate, 
maintenance, cessation, and substance use. New information continues to become 
available regarding the role of genetic variation in smoking cessation and response 
to pharmacotherapy and substance use more broadly.  In instances where stored 
blood is used and supply is limited, NMR test will be prioritized. If a sufficient blood 
sample cannot be obtained for future genetics research, study staff will collect 
saliva instead.  
 
5.8 Randomization 


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Patients can be randomized into the study once the NMR test has resulted. 
Randomization will be stratified on three factors: (1) primary admitting diagnosis 
(cardiac vs. other); (2) cigarettes/day (≥10, <10); (3) primary insurance (Medicaid, 
Medicare with Part D, Private Insurance, Federal/Other Governmental/Other 
Insurance); and (4) NMR status (“normal”/”slow”) to ensure that the treatment 
groups are balanced. After the patient enrolls, the RA will be directed to the 
electronic randomization screen in REDCap, which, once submitted, automatically 
assigns the participant to a randomization group.  
 
Blinding: The nature of the study precludes blinding of patients or research staff to 
the study condition. 
 
Participants will receive a handout describing their assigned treatment. For those 
randomized to the MIST (precision) arm, the handout will include information on 
the NMR result and recommended medication. In the event that a participant is 
enrolled before a valid NMR result is received, study staff may contact the 
participant via phone/text/email (per participant preference) to notify of 
randomization status and initiate post-randomization procedures including 
facilitation of smoking cessation medication. Those randomized to the Usual Care 
arm will receive their NMR result at study completion, 12 months post-study 
enrollment; participants in the Usual Care arm who withdraw from the study will 
not be provided precision care information. 
 
5.9 Outcome Assessments – Surveys (Table 1) and Biochemical Samples 
(Table 2) 
 
Follow up surveys: (Table 1) See Page 32 for full table. A brief follow up survey 
will be sent to participants through a REDCap-enabled Twilio survey link via 
email/text message based upon participants preference as stated at enrollment. The 
surveys will be sent to participants at approximately 1, 3, 6, and 12 months after 
study enrollment. For completeness, smoking status and medication usage 
outcomes will be assessed at all follow-up time points. Participants who do not 
respond to survey invites sent through email or text will be contacted by phone and 
mail. If the participant cannot complete the follow up survey remotely, we will make 
all efforts to coordinate with the patient during any pending appointments at VUMC 
so they can complete their survey on a day when they are already scheduled to be at 
VUMC (e.g. study RA will travel to the One Hundred Oaks clinic of other VUMC 
clinics to meet participant) If these modes are insufficient to complete surveys, 
alternative contacts (participant’s proxy) will be contacted. When needed, , study 
staff call participants to administer the survey, making approximately 24 attempts 
over 4 to 8 weeks. If unsuccessful, participants may be mailed an abbreviated survey 
containing only the primary and secondary outcome measures.  We have 
successfully administered similar questionnaires for prior studies of hospitalized 
smokers and low-income smokers residing in the Mid-South, Mid-Atlantic, and New 


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England regions. Study staff also offer to meet participants at their clinic visits for 
convenience. Study staff may also extract information from the EHR fields such as 
smoking status and cigarettes per day, use of other tobacco products, and smoking 
cessation medication use. 
 
Biochemical Samples 
Aim 1: Biochemical Verification of Self-Reported Abstinence (Table 2, Row 1)  
For participants who self-report abstinence at the 6 month and/or 12 month follow 
up surveys, study staff will attempt to biochemically-verify the self-report. Based on 
prior experience with challenges in obtaining biochemical verification, there will be 
several options including: (1) saliva cotinine (in- person or mailed); (2) end-expired 
carbon monoxide (in-person or remote) if participants are unwilling or unable to 
verify with cotinine (e.g., actively using NRT).  Standard saliva cotinine kits will be 
analyzed by Salimetrics Laboratory or other comparable lab. Smoking abstinence 
can also be confirmed through in-person or remote carbon monoxide (CO) testing (if 
a participant is on NRT).  If a participant is unable to complete an in-person CO, then 
a personal CO device (such as a CoVita iCO Smokerlyzer) may be mailed to the 
participant to complete the CO reading remotely.  We have successfully used this 
protocol for mailed cotinine samples and CO testing in the past. Smoking abstinence 
will be defined conservatively according to recommended standards.  
The following cessation milestones will be assessed in addition to point prevalence 
abstinence (PPA): 
i. 
Initial abstinence is defined as the first instance in which the 
participant refrains from smoking for at least 24 hours; duration 
of initial abstinence will also be assessed.  
ii. 
Initial lapse, defined as the first episode of ANY smoking, even a 
puff, after achieving initial abstinence, will also be assessed. 
iii. 
Continuous abstinence is defined as no smoking, even a puff, since 
study enrollment (i.e., achieved PPA at 1, 3, 6, and 12 mo +no 
smoking in between surveys + biochemical validation of self-
reported (SR) PPA at 6, 12 mo). Participants who are unable to 
biochemically verify abstinence will be assumed to be smoking, by 
convention, but sensitivity analyses will consider a range of 
possible odds ratios (1, 2, and 5) linking loss to follow-up and 
smoking. [51] 
 
 
 


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AIM 2 - Clinical Implementation as assessed by Medication use and PCP 
Engagement (Table 2, Rows 2, 3). These outcomes probe the extent to which MIST 
vs UC are taken up and implemented by patients and providers. Patient engagement 
is assessed by medication use and adherence. Provider engagement is assessed by 
writing a prescription for FDA approved medication any time after study 
enrollment.  
a. Self-reported medication adherence over the past 7 days will be assessed 
via survey. Participants are asked if they have taken study medication 
each day and for skipped or missed doses, reasons are elicited (e.g., forgot 
to take it/ felt I didn’t need it/experienced side effects/ felt the 
medication wasn’t working/other, etc.). Participants are also asked about 
OTC and non-study medication use. Using our pilot protocol, participants 
are considered adherent at each survey if they report taking their 
medication for at least 5 of the past 7 days. 
 
b. PCP-generated prescriptions for smoking cessation medication will be 
assessed by patient self-report and where possible, verified by sources 
such as VUMC EHR, TennCare and Medicare pharmacy data. The outcome 
will also be assessed in the subset of participants who self-report 
smoking on study surveys. Type of medication prescribed will also be 
tracked to calculate % concordance between NMR result and medication 
(i.e., % of fast metabolizers prescribed varenicline, % slow metabolizers 
prescribed NRT).  
 
Health care utilization and mortality composite (Table 2, Row 4):  
Table 2: Main Outcome Measures by Study Aim  
Outcome 
Measure 
Data sources 
Survey 
Other source 
AIM 1: 
Abstinence  
SR at 1, 3, 6, 12 m 
 
Biochem. validation at 
6 m (primary study 
outcome) and 12 m* 
X 
Biochemical validation at 6, 
12 m* via saliva cotinine <10 
ng/ml or expired CO <10ppm 
AIM 2: 
Medication 
adherence             
SR at 1, 3, 6, 12 m 
 
 
X 
CMS pharmacy records 
AIM 2:  
PCP 
engagement  
PCP prescription for 
smoking cessation 
medication any time 
after study enrollment 
X 
EHR, CMS pharmacy records 
AIM 3:  
Healthcare 
composite  
 
Hospitalization, ED 
visits, deaths 
--- 
EHR, TN state vital records, 
TN HDDS, CMS database 


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a. This composite clinical outcome will be assessed by passive query of the 
VUMC EHR, the Tennessee Medicaid (TennCare) database, and the 
Department of Health Hospital Discharge Data System. The composite 
variable includes any evidence of a documented incident inpatient 
hospitalization, ER visit, or death during the follow up period. Death will 
be defined as death due to any cause as determined by National Death 
Index or death certificate data from Tennessee State Vital Record Files. 
Cause-specific mortality will be determined via death certificates 
obtained from the Tennessee State Vital Records, which has death 
certificates for all deaths in Tennessee and for Tennessee residents who 
die in adjoining states. Passive surveillance of 12-month clinical 
composite outcomes takes place at VUMC and non-VUMC facilities, as 
described further below.    
i. 
At VUMC facilities. Hospitalization and ER visits at VUMC are 
tracked by Drs. Freiberg and Wells, leveraging VCREATE and V-
SERCH Center resources including validated EHR algorithms to 
extract clinical outcomes including ER visits, hospitalizations and 
mortality.    
ii. 
At non-VUMC facilities. We have established links between VUMC 
EHR data and external databases including Tennessee Medicaid 
and the Hospital Discharge Data System (TN-HDDS). The TN-HDDS 
collects patient-level discharge information in visits from all 
hospitals licensed by the Tennessee Department of Health (TN 
DOH), including rehabilitation hospitals, psychiatric units within 
acute care hospitals, and free-standing ambulatory surgical 
treatment centers. Tennessee Medicaid (TennCare) maintains an 
extensive electronic data system and records of all their 
healthcare encounters, including pharmacy prescriptions filled.  
 
b. Vital status may be ascertained by study staff reviewing VUMC medical 
records, utilizing automated electronic health record (EHR) deceased 
notifications, conducting obituary searches, participant proxy contacts, 
and PCP/provider offices.  Death certificate data from the Tennessee 
Office of Vital Records may also be used to identify all deaths occurring 
within Tennessee, and deaths of Tennessee residents that occur in 
surrounding states. Vanderbilt’s Health Policy Department processes 
these data for research and public health surveillance activities via data 
use agreements with the TN DOH. Finally, data from the National Death 
Index or related databases that include information on mortality may be 
queried. 
MIST Ancillary study - Validation of EHR-derived smoking status with survey 
and biochemically-validated smoking abstinence in the MIST RCT: If EHR-
derived self-reported outcomes were valid, then large health care systems and their 


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EHRs could become a new frontier for tobacco control including large observational 
studies and multisite pragmatic clinical trials. Smoking cessation RCTs conducted 
within a health system thus offer a unique opportunity to determine the accuracy of 
smoking status as captured in the EHR. 
 
a. AIM 1: Using biochemical validation as the reference for abstinence at 6 
months, determine the reliability of EHR-based and survey sources of 
smoking status among MIST trial participants. Hypothesis: EHR based 
smoking status and research survey smoking status will have a high 
sensitivity, specificity, positive predictive value and negative predictive 
value as compared to biochemical validation among participants in the 
MIST study. 
b. AIM 2: Demonstrate the application of EHR-based smoking status in 
analyses of the impact of NMR-guided prescribing practice on smoking 
cessation in the MIST trial. Hypothesis: EHR-based smoking status may 
be incorporated into analyses that use smoking abstinence as an outcome 
(e.g., 7-day point prevalence abstinence (PPA) at 6 months, the primary 
outcome of the MIST parent trial) through either an extension of existing 
multiple imputation methods or through direct use of EHR-based 
smoking status as an outcome. 
 
The ability to leverage electronic health records for tobacco and cancer related 
research would allow investigators to efficiently and powerfully examine the role of 
smoking, smoking cessation and cancer among diverse populations, including 
people actively attempting to change their smoking behavior. 
 
5.10 Compensation 
 
Participants can be compensated up to a total of $430 for full participation in this 
research study. Participants will receive $10 for the screening blood draw and $40 
for completion of the baseline survey. For completion of the follow up surveys at 1, 
3, 6, and 12 month study timepoints participants will receive $20 per survey. In 
addition to survey completion, participants who report quitting smoking on the 6 
and 12 month surveys will be asked to provide either a saliva sample or complete a 
CO test, used for biochemical validation of self-reported abstinence.  For completion 
of biochemical validation at the 6 and 12 month timepoints, participants will receive 
$100 per timepoint. $50 will be offered for travel reimbursement at each of the 6 and 12 
month timepoints. Similar compensation has been used in a previous research studies 
and was deemed by the VUMC Institutional Review Board (IRB) to be an 
appropriate, non-coercive, amount of funds for involvement in a clinical research 
project.  
 


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5.11 Retention 
Baseline visit: Retention efforts begin at baseline by ensuring that everything 
possible is done to maximize the likelihood of the participant enjoying the 
experience of participating in the study. Retention is supported by explaining the 
informed consent and what may happen in the study, and by collecting complete 
contact information, including both the address where the participant currently 
resides as well as multiple contact numbers if available.  Participants will be asked 
to provide contact information for at least one alternative contact who may know 
their whereabouts if we are ever unable to get in touch with the participant. 
Alternative contacts can include friends or family members; an alternative contact 
who is a close relative (ie. spouse, significant other, or caregiver) can opt to be the 
participant’s proxy. Participants will also be asked to provide an email address. The 
Interactive Voice Response (IVR) that all participants receive beginning 3 days after 
study enrollment and spanning 3 months also promotes retention through repeated 
contact via phone, text, or email according to the participant’s preferred method of 
contact. 
Additional strategies to promote retention and follow-up: Study participants 
will be asked to contact the study team if their phone number, address or PCP 
information changes between study visits; if needed, study staff may assist in re-
establishing a primary care provider. The study team may collaborate with the 
participants PCP by contacting the PCP’s clinic staff and/or sending an electronic 
message through the EHR to the PCP directly to inquire about the status of a patient 
for follow up on medication adherence, smoking status, or general issues regarding 
follow up participant contact information. For assessing abstinence, if the 
participant cannot complete the salivary cotinine test or remote CO monitoring and 
instead must come into the clinic for the CO breath test, we will make all efforts to 
coordinate with the patient during any pending appointments at VUMC so that they 
can take the CO test on a day when they are already scheduled to be at VUMC (e.g., 
study RA will travel to the One Hundred Oaks clinic or other VUMC clinics to meet 
participant).   
 
6.0 Risks 
 
The potential risks to subjects are not more than those of standard smoking 
cessation treatment. These include possible psychological distress from speaking 
with a counselor or answering questions about their smoking, discomfort or 
bruising from a blood draw, loss of confidentiality due to breach of protected health 
information, potential side effects of the process of quitting smoking, and potential 
side effects of smoking cessation medications, all of which are FDA-approved.   
 
6.1 Smoking Cessation Medication Side Effects 
 


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In order to protect against potential risks associated with smoking cessation 
pharmacotherapy, this study involves FDA-approved medications according to label 
usage for smoking cessation aids. There is a risk of adverse side effects from FDA-
approved smoking cessation medications, but this risk is not higher than that 
experienced by people taking the same medications outside of this research study.  
 
The smoking cessation treatments in this study consist of counseling from trained 
tobacco treatment counselors in combination with safe and effective FDA-approved 
medications prescribed by the participants’ inpatient team and/or PCPs. This 
combination of medication and counseling is the standard of care for smoking 
cessation treatment, and for those who successfully quit smoking, results in 
prolongation of life and improved quality of life.  
 
Medication eligibility will be reviewed by two separate members of the study team 
(e.g., CTTS and PI or study coordinator and PI) to identify potential 
contraindications to nicotine replacement or varenicline.  
• Nicotine replacement therapy (NRT): NRT is generally very safe, and several 
preparations have been sold over the counter for decades which is an 
indication of the FDA’s view of their relative safety. The most common side 
effect of the patch is skin irritation or itching where the patch is applied, 
which is commonly managed by rotating patch sites and/or applying an OTC 
corticosteroid cream (such as 1% hydrocortisone).  For nicotine 
lozenge/gum the most common side effects are mouth irritation, heartburn, 
hiccups. Many of the side effects of the lozenge/gum can be avoided by 
proper technique of the medication.  For the nicotine inhaler and nasal spray, 
the most common side effects can include mouth/throat irritation, coughing, 
runny nose, watery eyes.  In rare cases dizziness, headache, nausea, and 
rapid heartbeat can occur.  
• Varenicline: Common side effects of varenicline include nausea and other 
gastrointestinal symptoms, sleep disturbance, and vivid dreams. The FDA-
mandated EAGLES trial has established these medications as safe and 
effective. [52]  
• Written and verbal instructions will be provided to patients to contact their 
PCP or the research study staff in case of adverse events that could possibly 
be medication-related. The IVR system (automated calls from approximately 
3-days post hospital discharge (hospitalized patients) or 3-days post 
randomization (outside of hospital) to approximately 12 weeks post 
discharge or randomization, respectively) which helps protect participants 
by providing them with “on-demand’ counseling designed to trouble-shoot 
any difficulties with study medication. 
 
Advice for Participants 
 
Participants may want to discontinue their medications due to possible side effects. 
Before medication is discontinued participants will be encouraged to adjust their 


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Protocol Date: April 26, 2024 
medication routine. For example, placing the patch on a different arm or place on 
the body and possibly even recommending a different brand of patch if allergic to 
latex or having a reaction to the adhesive. For oral NRT, patients will be reminded of 
proper usage of the product (gum, lozenge, inhaler, etc.) in order to avoid some of 
the most common and undesirable side effects.  
 
For certain common side effects of FDA approved smoking cessation medication, 
such as mild-moderate gastrointestinal (GI) problems or mild-moderate sleep 
problems, study staff will provide the following advice: 
o For moderate GI problems, study staff will remind the participant of 
proper administration (e.g., taking varenicline medication with food and 
water or milk) and reiterate that these side effects typically improve 
within 2-3 weeks after initiation of medication. 
o For moderate sleep problems, study staff will remind participants of 
proper use (e.g., may remove patch at night or take the evening dose of 
varenicline earlier in the day or skip the evening dose, etc.) and will 
reiterate that the side effect typically improves within 2-3 weeks after 
initiation of medication  
o Participants will also be reminded that many of these symptoms can 
accompany the process of quitting smoking itself, regardless of 
medication use.  
For participants who normally drink caffeine or take caffeine pills, study staff will 
make the participant aware that chemicals (i.e., polyaromatic hydrocarbons) in 
cigarette smoke metabolize/break-down caffeine, so generally smokers “need” more 
caffeine when they are smoking at their usual rate. However, as smoking is reduced 
or stopped altogether, caffeine levels may rise, causing a person to feel jittery, 
irritable, nauseated, etc.  Participants may be instructed to reduce caffeine intake by 
half, and thereafter to adjust caffeine intake to comfort. 
 
6.2 Venous Blood Draw 
 
This is a routine procedure that is considered standard of care in clinical medicine. 
For participants who consent to provide a genetic sample in addition to the NMR, 
we will attempt to collect a single blood sample of approximately 15 ml (3 
teaspoons) at the bedside or at an outpatient lab by clinical phlebotomy/study staff. 
This blood will be utilized for the enrollment consented NMR test and future genetic 
analysis. Blood for genetics will be discarded if a participant does not consent to 
genetics.  The blood draw will be performed by trained personnel using universal 
precautions to protect both the participant and personnel. The risks to subjects are 
minimal, but may include pain, allergic reaction, infection, or bleeding at the needle 
stick site. These usually resolve without any specific medical therapy over the 
course of minutes to days.  
 
6.3 Nicotine Metabolite Ratio (NMR) and Salivary Cotinine Testing 


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Protocol Date: April 26, 2024 
 
There are no known serious adverse effects from these tests. Nicotine metabolites 
(ratio of 3-hydroxycotinine to cotinine) will not be clinically reported beyond the 
study (i.e., NMR results only given to hospital team and provided to the PCP as 
described above). 
 
7.0 Reporting of Adverse Events or Unanticipated Problems involving Risk 
to  
      Participants or Others 
 
7.1 Specification of Adverse Events 
 
An Adverse Event (AE) is defined as any untoward or unfavorable medical 
occurrence or undesirable experience associated with the use of a medical product 
in a human participant, including any abnormal sign (for example, abnormal 
physical exam or laboratory finding), symptom, or disease, temporally associated 
with participation in the research, whether or not it is considered related to 
participation in the research. AEs are graded as follows: 
• Mild (no limitation of usual activities), 
• Moderate (some limitation of usual activities), or  
• Severe (inability to carry out usual activities) 
 
AEs will be attributed according to the relationship to the study drug and/or 
procedure as: 
• Unknown, 
• Unrelated related, 
• Possibly related, 
• Related 
 
An AE can therefore be any new sign, reaction, symptom, event, disease or a 
worsening in frequency or severity of a preexisting condition that occurs during the 
course of the study. Stable chronic conditions that were present prior to study entry 
and do not worsen are not considered AEs. An event is considered “related” if it is 
likely to have resulted from participation in the research study and is considered 
“unanticipated” when it was unforeseeable at the time of its occurrence. An 
unanticipated problem (UP) involving risk to participants or others is “Any 
event that was (1) unanticipated, (2) related, and (3) places participants or others at 
a greater risk of physical or psychological harm than was previously known or 
recognized.” 
 
A serious adverse event is defined as any adverse event that results in any of the 
following outcomes:  
• Death 
• life-threatening adverse event 
• inpatient hospitalization or prolongation of existing hospitalization 


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• persistent or significant disability/incapacity 
• congenital anomaly/birth defect.  
 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse event when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
 
Unexpected adverse event is defined as any adverse event, the specificity or 
severity of which is not consistent with the risk information described in the general 
investigational plan.   
 
Suspected Adverse Drug Reaction is any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event. Reasonable 
possibility means there is evidence to suspect a causal relationship. It is considered 
unexpected if it is not consistent with the risk information described in the general 
investigational plan. A suspected adverse drug reaction will be defined as a 
recorded adverse event that is unexpected and deemed to be possibly, probably, or 
definitely related to the study drug. 
 
7.2 Methods and Time for Assessing, Recording, and Analyzing Safety 
Parameters 
 
Participant health status will be assessed during the baseline survey to document 
any chronic conditions or symptoms that existed prior to the study. This list will be 
reviewed and compared to reported events throughout the study. If the participant 
reports the same symptom, occurring at the same severity, during subsequent visits, 
the symptom should not be recorded as an Adverse Event (AE). However, if the 
event is new (not previously reported) or the severity has worsened, as determined 
by RA, then the AE should be reported. 
 
In the case of unresolved AEs, study staff will update the AE log if they become 
aware of follow-up information. 
 
All AEs will be assessed to determine if they meet criteria for a Serious Adverse 
Event (SAE).  If the AE is serious, then appropriate reporting measures will be 
followed (see section 7.5). Investigators will consult with the IRB or NIH, if 
uncertain how to classify an event.  
 
7.3 Procedures for Eliciting Reports of and for Recording and Reporting 
Adverse Events 


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Protocol Date: April 26, 2024 
 
Medical conditions/pre-existing conditions (Table 3) and medical symptoms (Table 
4) will be assessed at baseline.  Medical symptoms will be assessed at follow up 
timepoints. All events, including changes in severity of any of the below mentioned 
medical symptoms, will be documented in a study database.  
 
Table 3: Medical Condition/Pre-existing Conditions Checklist 
 
Medical Condition/Pre-existing Conditions Checklist 
A 
Anemia or “low blood” 
B 
Congestive Heart Failure, also called weak heart or fluid on the lungs 
C 
Dementia or “Alzheimer’s” 
D 
Diabetes or high blood sugar or “sugar” 
E 
Liver Disease or a bad liver or Cirrhosis 
F 
Chronic Hepatitis B 
G 
Chronic Hepatitis C 
H 
High cholesterol, lipids, or triglycerides 
I 
Hypertension or high blood pressure 
J 
Pancreatitis 
K 
Bad nerves in your feet causing pain and numbness (neuropathy) 
L 
Bad circulation in your legs or feet 
M 
Chronic lung disease (emphysema, asthma, chronic bronchitis or chronic 
obstructive lung disease) 
N 
Kidney Failure (or bad kidneys) 
O 
Stroke or “mini” stroke (Transient Ischemic Attack) 
P 
Pneumonia 
Q 
Shingles 
R 
TB or Tuberculosis 
S 
Post-Traumatic Stress Disorder 
T 
Schizophrenia (hearing voices or seeing things that others 
don’t)/schizoaffective disorder 
U 
Depression (depressive disorder) 
V 
Anxiety (anxiety disorder) 
W 
Bipolar Disorder 
 
X 
 
 
Any kind of Cancer (please list type below) 
 
1._________________________ 
2.__________________________ 
3.__________________________ 
4.__________________________ 
5.__________________________ 
 


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Protocol Date: April 26, 2024 
Y 
Human Immunodeficiency Virus (HIV) or Acquired Immunodeficiency 
Syndrome (AIDS) 
 
Table 4: Medical Symptoms 
 
Medical Symptoms 
No 
Yes→Date of the 
symptom(s)and severity of 
the symptom(s) (mild, 
moderate, severe) 
A. Agitation and/or Irritability 
B. Anger and/or hostility 
C. Depressed mood 
D. Anxiety (includes nervousness and panic  
attacks) 
E. Restlessness 
F. Insomnia  
G. Abnormal dreams and/or nightmares 
H. Headaches 
I. Dizziness 
J. Nausea and/or vomiting 
K. Abdominal Pain 
L. Fatigue 
M. Hiccups 
M. Cough 
O. Mouth/Throat Irritation 
P. Skin irritation 
Q. Heartburn 
 
7.4 Adverse Event (AE) Reporting 
 
All adverse events (AE) and unanticipated problems (UP) will be reported to the IRB 
by the study team within the mandated time frames. Ultimately, the PI and study 
coordinator will review any serious adverse events and report them to the IRB and 
NIH. 
 
The PI will report AE and UP to the VUMC IRB in accordance with IRB policies: 
• Required reporting to the IRB within 7 calendar days of the Investigator’s 
knowledge of the problem which includes serious adverse events, injuries, 
side effects, deaths, or other problems occurring at VU, VUMC or other 
locations in which the Investigator is responsible for the conduct of the 
research and the VUMC IRB serves as the IRB of Record: 
o Any serious AE that in the Investigator’s opinion was 
unanticipated or unexpected, involved risk to participants or 


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Protocol Date: April 26, 2024 
others and was at least possibly related to the research 
procedures; and/or 
o Any noncompliance with the IRB-approved protocol that 
increased risk or affected the participant’s rights, safety, or 
welfare. 
 
• Any UP listed above requires reporting to the IRB even after the participant 
has completed the study or after the participant has withdrawn from the 
study including after study closure. 
 
7.5 Data Safety and Monitoring Board 
 
The Data and Safety Monitoring Board (DSMB) will monitor the MIST trial. The 
DSMB will act in an advisory capacity to the study PIs to monitor participant safety, 
data quality and evaluate the progress of the studies being conducted.  
 
The DSMB is responsible for ensuring subject safety (by reviewing blinded and 
unblinded safety data on a regular basis and assessing the safety of study 
procedures) and for monitoring the overall conduct of the studies. The DSMB will 
monitor enrollment, follow up and adverse events.  
 
The DSMB is an independent group advisory to the PI and study team, and is 
required to provide recommendations about conduct of the trial.  In addition, the 
DSMB is asked to make recommendations, as appropriate, about: 
• Benefit/risk ratio of procedures and participant burden 
• Selection, recruitment, and retention of participants 
• Protocol violations and adherence to protocol requirements  
• Completeness, quality, and analysis of measurements  
• Amendments to the study protocol and consent forms 
• Participant safety 
• Notification of and referral for abnormal findings 
 
The DSMB will consist of 3 members and strong consideration will be given to 
include at least one investigator with expertise in smoking cessation, 1 statistician, 
and 1 investigator with expertise in clinical trials. The DSMB will meet twice during 
the course of the study, which will be scheduled after approximately one third and 
approximately two thirds of the target number of participants have reached the final 
outcome. The DSMB has the authority to assess the option of stopping early for 
overwhelming benefit demonstrated in the primary study endpoint, or for safety 
concerns. The panel will make recommendations about the continuation, 
modification, or termination of the study to the study steering committee. 
Unscheduled meetings can be requested by any party with the responsibility of 
overseeing the study.  


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Protocol Date: April 26, 2024 
 
 
8.0 Study Withdrawal/Discontinuation 
 
Study withdrawal: A participant can voluntarily withdraw from the study at any 
point in time throughout the course of the study. The participant will not be 
penalized in any way for voluntarily withdrawing from the study. To withdraw, the 
patient will be asked to inform the research team in writing of their intent to 
withdraw including their reason for leaving the study. Participants who withdraw 
from the study will no longer be eligible for compensation for any study procedure 
that was not completed prior to withdrawal. If, during the enrollment and 
randomization process, or shortly thereafter, it comes to the attention of the study 
staff that a participant has become ineligible (e.g., patient’s medical condition 
deteriorates while in hospital such that they are now too ill to participate; patient 
develops a medical condition that makes them ineligible to use smoking cessation 
medication, etc.), then the team would cease the enrollment process and/or 
administratively withdraw the participant.   
 
Medication discontinuation: Participants who choose on their own to discontinue 
medication may do so. Other conditions may prompt study staff to recommend 
medication discontinuation. For example, pregnancy and lactation are exclusion 
criteria for the study. If during the study a participant informs study staff of a 
pregnancy, the participant will be asked to discontinue study medication and to visit 
the PCP for a confirmatory pregnancy test. Other conditions that would prompt 
study staff to recommend discontinuation of medication include side effects that 
could not be managed with usual good clinical practice. All participants who 
discontinue their medication for any reason will be followed and analyzed by 
intention to treat.  
 
9.0 Statistical Considerations 
 
9.1 Aim 1 
 
The primary study outcome is biochemically-verified self-reported 7-day point 
prevalence abstinence at 6 months as defined by salivary cotinine level < 10 ng/ml 
or expired CO <10 ppm. A secondary outcome is biochemically-verified self-
reported 7-day point prevalence abstinence at 12 months. Brief surveys will be 
conducted at 6 and 12 months after study enrollment to determine self-reported 
abstinence. Biochemical validation of smoking status is accomplished via mailed 
salivary cotinine samples or expired CO. 
 
Analysis:  
The effect of MIST vs. UC on biochemically-verified abstinence at 6 months will be 
estimated via a relative risk of abstinence and tested at a 5% significance level via a 
chi-squared test with Yates' continuity correction. The same method will be applied 


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Protocol Date: April 26, 2024 
to the secondary outcome at 12 months. Anticipated loss to follow up is accounted 
for in the expected approximate UC abstinence rates where persons lost to follow up 
will be treated as non-abstinent.  However, sensitivity analyses will consider a range 
of possible odds ratios (1, 2, and 5) linking loss to follow-up and smoking. [51] 
Exploratory analyses testing for effect heterogeneity will use multivariate logistic 
regression models adjusting for the main effect of a potential modifier and testing 
for an interaction with the effect of MIST. The potential effect modifiers to be 
explored are age, race, sex, NMR, and pre-intervention plan to quit. 
 
Power:  
Conservatively assuming a biochemically validated abstinence rate of 10% under 
UC, a chi-squared test on 1000 patients (at 6 months) will detect a MIST abstinence 
rate of 16.2% (Risk Difference=6.2%, Relative Risk=1.62, Odds Ratio=1.74) with 
80% power. Assuming a 15% biochemically validated abstinence rate under UC (at 
12 months), a 22.2% rate under MIST (RD=7.2%, RR=1.48, OR=1.62) is detectable 
with 80% power. Power was estimated via simulating 20K datasets under the 
settings above in the statistical program R and were checked against the simplified 
estimates of the pwr package. 
 
9.2 Aim 2 
 
A secondary outcome is participant self-reported medication adherence assessed at 
the 1- and 3-month surveys (Aim 2a). Another secondary outcome is PCP 
prescriptions for smoking cessation medication after study enrollment for 
participants who continue to smoke. Pharmacy data from CMS will also be used to 
supplement participant's self-report of whether they received smoking cessation 
medication prescriptions from their PCP after study enrollment (Aim 2b) and 
whether the prescriptions were matched to NMR (Aim 2c). 
 
Analysis:  
To account for the longitudinal structure of the data with observations at months 1, 
3, 6, and 12, Aim 2 analyses will utilize general estimating equations (GEE) with an 
autoregressive (AR1) correlation structure adjusting for self-reported smoking 
status and age, race/ethnicity, education, and dependence (baseline FTND score) in 
a multivariate logistic GEE model. Each of the following three models will estimate a 
common odds ratio for MIST vs UC for the outcome of interest. All patients will be 
included in the analyses and missing covariate data will be multiply imputed via 
predictive mean matching imputation. Standard errors will be estimated via Rubin's 
rules and statistical significance tested via Wald tests. Unobserved adherence status 
or prescriptions will be treated as non-adherent or not received, respectively. H2a: 
We will estimate the odds ratio for being adherent in the 3 months post-enrollment. 
H2b: We will estimate the odds ratio for receiving a PCP prescription for a smoking 
cessation medication in the 12 months post-enrollment. PCP prescriptions occurring 
between any two time points, e.g. months 3 and 6, will be attributed to the latter 
time point for analysis. H2c: We will estimate the odds ratio for receiving an NMR-


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Protocol Date: April 26, 2024 
matching PCP prescription. Exploratory and sensitivity analyses: For each of the 
three outcomes, exploratory analyses will test for interactions between the MIST 
effect and month of follow up; and for interactions between the MIST effect and 
medication type (NRT or varenicline). Sensitivity analyses will vary the correlation 
structure assumptions to ensure the main conclusions are robust to model 
specifications. 
 
Power:  
For all hypotheses related to clinical implementation, we conservatively estimate 
power by focusing on the first observation time point. Under a common odds ratio, 
power will be higher when analyzing all time points together. H2a: Assuming a self-
reported adherence rate of 50% under UC, analysis of 1000 patients (at 3 months) 
will detect a MIST adherence rate of 59.0% (Risk Difference=9.0%, Relative 
Risk=1.18, Odds Ratio=1.44) with 80% power. H2b: Because self-reported 
abstinence at a given time point will be a very strong predictor of not receiving a 
PCP prescription for smoking cessation medication at the following time point, with 
regard to statistical power the sample sizes will be effectively reduced by the 
respective quit rates. For this effective sample size reduction, we conservatively 
assume quit rates of 15% for UC and 25% for MIST. Assuming a PCP prescription 
rate of 30% under UC, a 39.8% rate under MIST (RD=9.8%, RR=1.33, OR=1.54) is 
detectable with 80% power. H2c: Similarly, assuming an NMR-matching PCP 
prescription rate of 15% under UC, a 23.2% rate under MIST (RD=8.2%, RR=1.55, 
OR=1.71) is detectable with 80% power. Power was estimated via simulating 20K 
datasets under the settings above in the statistical program R and were checked 
against the simplified estimates of the pwr package. 
 
9.3 Aim 3 
 
Passive surveillance of 12-month clinical composite outcomes (ER visit, 
hospitalization, or death) in VUMC and non-VUMC facilities is also conducted by 
specific members of the research team. 
 
Analysis:  
The effect of MIST vs UC on the Aim 3 primary outcome of a healthcare composite 
outcome consisting of hospitalization, emergency department visit, and/or death 
within 12 months will be estimated via a relative risk of the composite outcome and 
tested at a 5% significance level via a Chi-squared test with Yates' continuity 
correction. The same method will be applied to the secondary outcomes of 
hospitalization, ED visit, and mortality analyzed separately. Exploratory analyses 
testing for effect heterogeneity will use multivariate logistic regression models 
adjusting for the main effect of a potential modifier and testing for an interaction 
with the effect of MIST. The same modifiers as in Aim 1 will be tested. All analyses 
will be reported as primary, secondary, or exploratory as specified here. 
 
Power:  


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Protocol Date: April 26, 2024 
The composite health care and mortality outcomes are gathered via VUMC EHR, 
state vital records, and the existing Tennessee HDDS, thus patients are presumed to 
not have an event unless one is observed. Conservatively assuming a composite 
outcome rate of 50% under UC (which is based on EHR estimates from VUMC 
smokers in care), a Chi-squared test will detect a MIST rate of 41.0% (RD=-9.0%, 
RR=0.82, OR=0.70) with 80% power. Assuming rates for UC of 10%, 20%, and 30% 
respectively for mortality, ED visits, and hospitalizations, a Chi-squared test on 1000 
patients will detect with 80% power MIST rates of, respectively, 5.1%, 13.2%, and 
22.0% (RD=-4.9%, -6.8%, 8.0%; RR=0.51, 0.66, 0.73; OR=0.48, 0.61, 0.66). 
 
10.0 Privacy/Confidentiality 
 
10.1 Data Collection and Retention 
 
All study data will be captured electronically and stored via a secure, web-based 
data capture system, REDCap and an Access database. Paper forms will be used 
during enrollment, if needed, and stored securely in a locked cabinet that only study 
staff will have the ability to access. Records will be kept indefinitely but will be 
destroyed if no longer needed. 
 
 
10.2 Quality Control Process 
 
Quality control measures for capturing data: Study databases will include 
detailed specifications for completion of data, including rules for question skip logic, 
built-in validation rules for error checks, as well as computer algorithms to check 
for out-of-range codes and internal inconsistencies. Study staff will be trained in 
methods for responsible and complete data collection.  All data, regardless of 
capture method, will be reviewed for logic, skip patterns, response ranges, out-of-
range codes, and internal inconsistencies, and converted to SAS (or equivalent 
statistical package) datasets for analysis. 
 
Call back quality assurance: Study tobacco treatment counselors/coaches will 
have dedicated, protocolized training in tobacco treatment. A subset of calls will be 
monitored by the study coordinator and/or Principal Investigator (PI) for quality 
assurance. 
 
 
10.3 Data Security and Confidentiality 
 
To prevent the loss of data, all electronic information is stored within the VUMC 
firewall and is password-protected. If there are any hard-copy, original consent 
forms and other study documents including participant names and contact 
information will be kept in binders and locked in a filing cabinet. Electronic 
participant data will be placed into a password-protected, web-based database on 


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Protocol Date: April 26, 2024 
encrypted computers and iPads by study personnel. Electronic medical records, and 
electronic participant tracking spreadsheets will be stored on a secure server. Only 
the research staff, the study PI and co-investigators will have access to this 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.  
 
A unique identification number will be used to protect the confidentiality of the 
study participants. This number will be assigned at the time of study enrollment. 
Only the investigator, coinvestigators and research personnel will have access to the 
key and information that identifies participants as being in this study. Digital data 
files will be coded so that the participant name or other such identifiers are not in 
the filename. Participants will be asked to complete a Release of Information, giving 
study staff permission to share study-related information with each participant's 
primary care provider via phone, mail, fax, email.  
 
All procedures are in accordance with best practices for Federal Health IT as 
determined by the Office of the National Coordinator for Health Information 
Technology (ONC).  Protected health information will not be exchanged outside of 
the approved study personnel at VUMC. 
 
Data Security and Confidentiality - TelASK 
The informed consent document will state clearly to patients that the study is being 
done as a collaboration between VUMC and TelASK, a company that makes 
automated phone calls. Subjects will be informed that in order to make the phone 
calls, TelASK will be given information such as their name, study ID, phone number, 
sex, preference for time of call, and the date that they are discharged from the 
hospital or enrolled. During the study, TelASK will establish a secure website to 
view call results in real time, quit status, and "on-demand" counseling requests. Data 
will be transferred to TelASK via HIPAA-compliant secure FTP. This plan is 
consistent with what the VUMC IRB has approved for our ongoing NIH funded study 
of hospitalized smokers (5R01HL11182107: PIs Rigotti and Tindle). Upon 
completion of the study, data will be transmitted back to VUMC's secure password-
protected computer system.  All patient data will be purged from TelASK's data files.  
 
Data Security and Confidentiality – Samples 
Blood samples used for NMR will be collected and labeled using information such as 
the study participant number, and/or MRN and stored in a secure location until 
NMR analysis is conducted by Vanderbilt Pathology Laboratory Services (VPLS), 
ARUP (currently contracts with VUMC) or other equivalent laboratory. 
 
Blood or saliva for future analyses of genetics and other potentially relevant 
biological markers will be collected, de-identified, and stored in a secure location, in 
the laboratory of Dr. Quinn Wells in Light Hall.  
 


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Protocol Date: April 26, 2024 
Salivary cotinine/CO samples collected for biochemical validation of self reported 
abstinence will be labelled with study participant number. 
 
 
 
 


Protocol Version #: 15 
 
34 
Protocol Date: April 26, 2024 
Table 1: Survey and Abstracted Electronic Health Record Data  
Construct 
 
Measures 
Source 
Baseline timepoint (CSF, 
RASF, Baseline survey) 
1 
m 
3 
m 
 
6 
m 
 
12 
m 
Sociodemographic 
Factors 
Age, sex, education, race/ethnicity, employment, living 
situation, health insurance type 
Patient 
X 
 
 
 
 
Medical 
Condition/Pre-
existing 
Conditions 
Checklist 
Pre-existing condition – VACS [53]; WHI Extension 
Study, HIV/AIDS [54] (Coronary heart disease, chronic 
obstructive pulmonary disease, stroke, cancer, 
hypertension, diabetes, hyperlipidemia) 
Patient/
EHR/Pr
oxy 
X 
 
 
 
 
Pregnancy 
X 
X 
X 
X 
X 
COVID-19 (infection status, amount smoked, 
influence on quit attempt) 
 
X 
 
 
 
 
Medical Symptom 
Screening 
Adverse Events 
Patient/
EHR/Pr
oxy 
X 
X 
X 
X 
X 
Tobacco Related 
Variables  
Nicotine dependence  
Fagerstrom Test of Nicotine Dependence (FTND) [55] 
Patient/
Proxy 
 
X 
 
 
 
 
Tobacco use 
Baseline: cigarettes per day, years smoked, other 
tobacco use 
Follow-up: duration of abstinence after enrollment, 
cigarette and other tobacco product use in the past 7 
days  
X 
X 
X 
X 
X 
Electronic cigarette use  
Baseline: use in the past 30 days,  frequency of use [56]  
Follow-up: use since enrollment, in past 7 days 
X 
X 
X 
X 
X 
Smoking in home 
Rules for smoking in home [39] 
X 
 
 
X 
 
Smoking cessation beliefs 
Confidence in ability to quit (10-point Likert scale) [57] 
X 
X 
X 
X 
X 
Quit attempt 
X 
X 
X 
X 
X 


Protocol Version #: 15 
 
35 
Protocol Date: April 26, 2024 
Definition: intentional tobacco abstinence lasting >24 
hours.  
Baseline: past year  
Follow-up: since enrollment or since last follow-up 
contact 
Tobacco cessation treatment 
Definition:  FDA-approved cessation medications, 
behavioral support (telephone quit line, text-message 
support, in-person counseling, internet programs, 
mobile phone applications), other 
Baseline: Prior use 
Follow-up: Use since enrollment or since last follow-up 
contact, adherence 
 
Patient/
Proxy 
X 
X 
X 
X 
X 
Medication Satisfaction  
Treatment Satisfaction Questionnaire for Medication 
(TSQM) (version 1.4)[58] 
 
 
 
X 
X 
Social support for quitting smoking 
Number of people available for support. [59] 
Patient  
X 
 
 
 
 
Other Substance 
Use  
Alcohol use 
Alcohol Use Disorders Identification Test (AUDIT-C), 
heavy drinking-only on follow ups[60, 61] 
Patient/ 
EHR/Pr
oxy 
X 
X 
X 
X 
X 
Drug use 
Marijuana, cocaine, opioids, stimulants, drugs by 
injection (Veterans Aging Cohort Study -VACS, 
modified)[61] 
Patient/
Proxy 
X 
 
 
X 
X 
Psychological 
Factors and 
Quality of Life 
Depression and anxiety symptoms 
Patient Health Questionnaire (PHQ-4) [41] 
Patient/
EHR/Pr
oxy 
X 
X 
X 
X 
X 
Resiliency 
Brief Resilience Scale (BRS) [63] 
Patient/
Proxy 
  
X 
 
 
 
 
Optimism/pessimism 
Life Orientation Test (LOT-R) [45] 
X 
 
 
X 
X 
Quality of life 
X 
X 
 
X 
X 


Protocol Version #: 15 
 
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Protocol Date: April 26, 2024 
Baseline, Follow up months 6/12: Medical Outcomes 
Study - Short Form (SF-1) [64], quality of life (EQ-5D-5L) 
[64] 
Follow-up month 1: SF-1 only 
Delay discounting Task  
5 Trial Delay Discounting [46-48] 
X 
 
 
 
 
Risk Assessment 
Objective Risks of Lung Cancer, CHD 
• Tammemagi Risk Calculator:  includes age 
[numeric, years], race [pick 1], smoking status 
[current/former/never], CPD [numeric], years 
smoked [numeric], COPD/emphysema/chronic 
bronchitis [Y/N], personal hx any cancer [Y/N], 
family hx lung cancer [Y/N], BMI [weight in 
kg/height in meters2]) [65] 
Patient/
EHR 
X 
 
 
 
 
• Framingham Risk Score for Coronary Heart 
Disease (includes age [numeric, years, range 30-
79], sex [M/F], smoking status [Y/N], Total 
Cholesterol [numeric, mg/dL or mmol/L, max 
1000], HDL cholesterol [numeric, mg/dL or 
mmol/L, max 150], Systolic BP [numeric, mm Hg, 
max 300], Blood pressure being treated with 
meds [Y/N]) [66, 67] 
X 
 
 
 
 
Perceived Health Risk 
Risk of smoking, benefit of quitting (5-point Likert 
scales) [44] 
Patient  
X 
 
 
 
 
Healthcare 
Related Variables 
Hospital course 
Length of hospital stay, discharge diagnosis 
EHR 
X 
 
 
 
 
Post-enrollment care coordination 
PCP visit, discussion of tobacco cessation treatment 
 
Patient/
Proxy 
 
X 
X 
X 
X 
Health care utilization 
Post-enrollment ED visits, hospital re-admission (items 
from the National Health Interview Survey) 
Patient/ 
EHR, 
state, 
federal 
 
X 
X 
X 
X 


Protocol Version #: 15 
 
37 
Protocol Date: April 26, 2024 
DB/Pro
xy 
Program 
Feedback 
 
 
Services provided by the study  
Automated phone calls, counselor contact feedback 
 
Patient/
Proxy 
 
X 
X 
X 
X 


Protocol Version #: 15 
 
38 
Protocol Date: April 26, 2024 
11.0 References 
 
 
1. 
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. Central European 
journal of public health 2011, 19(3):133, 151. 
2. 
Shiffman S, Brockwell SE, Pillitteri JL, Gitchell JG: Use of smoking-cessation 
treatments in the United States. Am J Prev Med 2008, 34(2):102-111. 
3. 
Steinberg MB, Akincigil A, Delnevo CD, Crystal S, Carson JL: Gender and age 
disparities for smoking-cessation treatment. Am J Prev Med 2006, 
30(5):405-412. 
4. 
Treating tobacco use and dependence: 2008 update U.S. Public Health 
Service Clinical Practice Guideline executive summary. Respiratory care 
2008, 53(9):1217-1222. 
5. 
Lerman C, Schnoll RA, Hawk LW, Jr., Cinciripini P, George TP, Wileyto EP, Swan 
GE, Benowitz NL, Heitjan DF, Tyndale RF: 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. The Lancet Respiratory medicine 2015, 3(2):131-
138. 
6. 
Lea RA, Dickson S, Benowitz NL: Within-subject variation of the salivary 
3HC/COT ratio in regular daily smokers: prospects for estimating 
CYP2A6 enzyme activity in large-scale surveys of nicotine metabolic 
rate. Journal of analytical toxicology 2006, 30(6):386-389. 
7. 
St Helen G, Novalen M, Heitjan DF, Dempsey D, Jacob P, 3rd, Aziziyeh A, Wing 
VC, George TP, Tyndale RF, Benowitz NL: Reproducibility of the nicotine 
metabolite ratio in cigarette smokers. Cancer epidemiology, biomarkers & 
prevention : a publication of the American Association for Cancer Research, 
cosponsored by the American Society of Preventive Oncology 2012, 21(7):1105-
1114. 
8. 
Tanner JA, Novalen M, Jatlow P, Huestis MA, Murphy SE, Kaprio J, Kankaanpaa 
A, Galanti L, Stefan C, George TP et al: Nicotine metabolite ratio (3-
hydroxycotinine/cotinine) in plasma and urine by different analytical 
methods and laboratories: implications for clinical implementation. 
Cancer epidemiology, biomarkers & prevention : a publication of the American 
Association for Cancer Research, cosponsored by the American Society of 
Preventive Oncology 2015, 24(8):1239-1246. 
9. 
Chenoweth MJ, Novalen M, Hawk LW, Jr., Schnoll RA, George TP, Cinciripini PM, 
Lerman C, Tyndale RF: Known and novel sources of variability in the 
nicotine metabolite ratio in a large sample of treatment-seeking 
smokers. Cancer epidemiology, biomarkers & prevention : a publication of the 
American Association for Cancer Research, cosponsored by the American Society 
of Preventive Oncology 2014, 23(9):1773-1782. 
10. 
Dempsey D, Tutka P, Jacob P, 3rd, Allen F, Schoedel K, Tyndale RF, Benowitz 
NL: Nicotine metabolite ratio as an index of cytochrome P450 2A6 
metabolic activity. Clinical pharmacology and therapeutics 2004, 76(1):64-72. 


Protocol Version #: 15 
 
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Protocol Date: April 26, 2024 
11. 
Gambier N, Batt AM, Marie B, Pfister M, Siest G, Visvikis-Siest S: Association of 
CYP2A6*1B genetic variant with the amount of smoking in French 
adults from the Stanislas cohort. The pharmacogenomics journal 2005, 
5(4):271-275. 
12. 
West O, Hajek P, McRobbie H: Systematic review of the relationship 
between the 3-hydroxycotinine/cotinine ratio and cigarette 
dependence. Psychopharmacology 2011, 218(2):313-322. 
13. 
Strasser AA, Benowitz NL, Pinto AG, Tang KZ, Hecht SS, Carmella SG, Tyndale 
RF, Lerman CE: Nicotine metabolite ratio predicts smoking topography 
and carcinogen biomarker level. Cancer epidemiology, biomarkers & 
prevention : a publication of the American Association for Cancer Research, 
cosponsored by the American Society of Preventive Oncology 2011, 20(2):234-
238. 
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