Personalized Smoking Cessation Tool Based on Patient Lung CT Image
Phase: NA
Conditions: Smoking Cessation
Sponsor: Imbio

 
1 
 
 
 
 
 
CLINICAL RESEARCH PROTOCOL 
 
 
 
 
 
 
 
IMBIO—Personalized Smoking Cessation 
Randomized Controlled Trial 
 
 
 
 
 
 
 
IMBIO, LLC. 
NIH--National Cancer Institute 
 SBIR Grant # 2R44CA203050-02 
NCT #  03087617 
Date: March 10, 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator: 
           Lauren Keith,  PhD   (IMBIO, LLC) 
Sub-Investigators: 
Charlene McEvoy, MD, MPH   (HealthPartners Institute) 
Ella Kazerooni, MD  (University of Michigan Health Sciences) 
Michael Burke, EdD (Mayo Clinic) 
Harry Lando, PhD (University of Minnesota) 
 
 
 

 
2 
 
 
 
Table of Contents 
 
I. 
Summary  
 
 
 
 
 
 
 
Pg. 3 
 
II. 
Background, Rationale, Significance 
 
 
 
 
Pg. 3  
 
• General Background 
 
 
 
 
 
Pg. 3 
• Background on Health Belief Model  
 
 
 
Pg. 4 
• Background Information on IMBIO’s Quantitative   
 
Pg. 6 
Image Analysis 
 
 
III. 
Study Aims 
 
 
 
 
 
 
 
Pg. 6 
 
IV. 
Approach, Study Design  
 
 
 
 
 
Pg. 7 
• Trial Design 
 
 
 
 
 
 
Pg. 7 
• Recruitment & Consent        
 
 
 
 
Pg. 7 
• Randomization  
 
 
 
 
 
Pg. 8 
• Treatment Arms  
 
 
 
 
 
Pg. 8 
 
V. 
Data Collection/Management Processes 
 
 
 
Pg. 9 
 
VI. 
Data Analysis, Sample Size & Statistics  
 
 
 
Pg. 10 
 
VII. 
Title 21 FDA Device Trial Regulations  
 
 
 
Pg. 11 
 
VIII. 
Timeline  
 
 
 
 
 
 
 
Pg. 12 
 
IX. 
References 
 
 
 
 
 
 
 
Pg. 13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
3 
 
 
 
 
 
IMBIO-RCT Protocol 
 
I. 
Project summary 
Cigarette smoking is the leading preventable cause of premature disease and death in the United 
States[1]. Cigarette smoking affects nearly every organ of the body with cigarette smokers more likely than 
nonsmokers to develop respiratory and pulmonary diseases, lung and other cancers, and cardiovascular 
disease [1].  The total economic cost due to tobacco in the U.S. is over $289 billion a year, which includes at 
least $133 billion in direct medical care [1].  
 
• 
The primary aim of this project is to clinically validate the impact and effectiveness of the IMBIO 
Patient Report in encouraging patients to make a quit attempt.  We will do this in a randomized control 
trial (RCT) by comparing the report to usual care--with and without a proven telephone smoking 
cessation session--on high-risk smokers behavior in the context of a lung cancer screening program. 
 
It is hypothesized that incorporation of the IMBIO Patient Report into lung cancer screening can improve a 
patient’s readiness to make a quit attempt, and increase their use of smoking cessation Quitline and/or other 
smoking cessation resources, including medications. More specifically, it is further hypothesized that 
incorporation of the IMBIO Patient Report into smoking cessation counseling methodology can improve the 
behavioral intervention component of the Health Belief Model [38].  The IMBIO Patient Report would be the 
only smoking cessation product available to patient’s that provides truly personalized information and 
comparative detail. 
 
II. 
Background  
Cigarette smoking is the leading preventable cause of premature disease and death in the United 
States[1]. Cigarette smoking affects nearly every organ of the body with cigarette smokers more likely than 
nonsmokers to develop respiratory and pulmonary diseases, lung and other cancers, and cardiovascular 
disease [1].  The total economic cost due to tobacco in the U.S. is over $289 billion a year, which includes at 
least $133 billion in direct medical care [1].  
Recent U.S. government reimbursement decisions to provide lung cancer screening for high-risk current 
and former smokers are aimed at detecting lung cancer at an earlier stage when it can be more effectively 
treated. In 2013, based mainly on the results of the National Lung Screening Trial (NLST), the U.S. Preventive 
Services Task Force (USPSTF) concluded “with moderate certainty that annual screening for lung cancer with 
low density CT is of moderate net benefit in asymptomatic persons who are at high risk for lung cancer based 
on age, total cumulative exposure to tobacco smoke, and years since quitting smoking.” [2] As a result, the 
USPSTF issued a Grade B recommendation for lung screening using low-dose CT for adults aged 55-80 years 
who have a minimum 30-pack year smoking history and currently smoke or have quit smoking within the past 
15 years. [3]. Since January 2015, the Affordable Care Act (ACA) requires private insurers to cover such 
preventative services without cost sharing. In February 2015, the Center for Medicare and Medicaid Services 
(CMS) also announced its intent to reimburse providers for low-dose CT lung cancer screening of high-risk 
asymptomatic smokers. An estimated 7-10 million current and former smokers in the U.S. will be eligible for 
lung screening under these guidelines. 
Tobacco dependence is a chronic condition, with most smokers making repeated quit attempts before they 
achieve long-term success [4,5]. Multiple studies have shown that the occasion of an annual lung screening 
exam may offer an important “teachable moment” for engaging a patient’s interest in quitting, and encouraging 
them to make a serious quit attempt [6–8]. A retrospective analysis of 14,692 current smokers participating in 
the Lung Screening Study (LSS) arm of the NLST by Tammemagi et al showed that patients with suspicious 
findings on low dose CT scans quit smoking at higher rates regardless of whether the finding was found to be 
malignant [9]. Tammemagi’s analysis showed that smoking cessation rates increased as screening findings 
became more serious or suspicious for lung cancer. Moreover, smokers in the NLST study who had negative 
screening exams continued smoking at the same rates as smokers in the general population, suggesting little 

 
4 
to no decrease in smoking cessation as a result of a “normal” exam. Nonetheless, concerns about smokers 
interpreting a negative screening exam for cancer as a “clean bill of health” and license to continue smoking 
persist, and many primary care physicians are skeptical about lung screening, given the high rate of false 
positive findings and resulting complications from diagnostic interventions[10,11]. 
Smoking cessation counseling has been shown effective at encouraging quit attempts and increasing rates 
of long-term abstinence, even in resistant populations such as long-term smokers [12]. Multiple analyses have 
shown that incorporating smoking cessation interventions, even as simple as a single counseling session, into 
lung cancer screening programs have the potential to improve cost effectiveness of screening [13–19] by 20% 
to 45% [15]. Proactive telephone Quitlines [20,21] may offer a cost-effective intervention and offer the 
possibility of a standardized approach to counseling across the country. However, further research is needed 
into the timing and types of cessation interventions that can have the most impact within the context of a lung 
cancer screening program, as reported quit rates are low in this chronic smoker population. Despite their 
elevated risk, 65.4% percent do not attempt to quit [1]. Methods to improve the effectiveness of smoking 
cessation counseling in this resistant population would be highly valuable [22].   
Research supports that incorporating a patient’s personal clinical status for future health risks, for example, 
pulmonary function test results [23–25], into smoking cessation education can increase quit attempts and long-
term abstinence [26–35]. An increase in health concerns combined with enhanced self-control motivation 
improves the stage of readiness to quit [36].  While behavior change takes years to become established [37] 
“preliminary evidence suggests that the use of personal clinical feedback may improve motivation to quit 
smoking and, when combined with best practices treatment, could aid in the promotion of abstinence” [31].   
In this project, IMBIO plans to clinically validate a personalized Patient Report Tool, based on a smoker’s 
own screening CT images. The intent of the Report is to improve the impact of the “teachable moment” offered 
by lung cancer screening, by better communicating to smokers their personal clinical risks from continuing to 
smoke. These risks are based on the amount of emphysema present on their lung screening images, a clinical 
finding which is present in 30-40% of lung cancer screening exams.  Emphysema is a clinical marker for 
important disease outcomes such as lung cancer, other types of cancer, cardiovascular disease, etc. 
independent of other risk factors including smoking history. In Phase I, Imbio designed a patient-centered 
report based on its FDA-cleared Lung Density Analysis (LDA) software for lung CT images that shows strong 
promise for increasing quit attempts by motivating patients to access smoking cessation resources including a 
quitline, other formal cessation programs, and/or cessation medications. 
 
The IMBIO Patient Report (Figure 1) is based on the Health Belief Model [38] and includes five sections:   
1) Image Section: visual feedback and quantitative results based on the quantitative image analysis of 
the patients own CT images. 
2) Comparative Section:  mapping the patient’s lung health status to a corresponding cohort of 
participants. 
3) Health Outcomes Section: information about the long-term consequences of smoking on a number 
of related health outcomes for the associated patient cohort. 
4) Quit Now Section:  stating the benefits of making a quit attempt 
5) Outreach Section: contact information for smoking cessation support. 
 
It is hypothesized that incorporation of the Report into lung cancer screening will improve a patient’s readiness 
to quit, motivation to make a quit attempt, and increase their use of a smoking cessation quitline and/or other 
smoking cessation resources including medications. In addition, it is hypothesized that incorporation of the 
Report into smoking cessation counseling will improve the effectiveness of the behavioral intervention.  
 
Background on Health Belief Model Methodology Incorporated into the Report 
 
Patient-centered Report Design - The Report’s novel image-based design reflects the constructs of the 
Health Belief Model, widely supported to trigger health-promoting behavior including smoking cessation [38]. 
The six constructs of the Health Belief Model are listed below with a description of how the Report addresses 
each construct. 
• 
Perceived susceptibility refers to a patient’s belief in the likelihood of getting a disease or condition 
caused by smoking cigarettes. The Report’s Image section illustrates the patient’s current lung health and 

 
5 
highlights their personal health risk based on information from his or her CT scan. The opportunity to see 
their own lungs was considered highly interesting and motivating to Phase I study participants. The image 
engaged the participants and drew them emotionally into the Report. To enhance understanding of the 
images, the typical colors used in Radiology to indicate healthy lung (dark gray) and disease (red), were 
discarded in favor of pink to indicate healthy lung tissue and black to indicate disease. The addition of an 
outline showing a torso to contextualize the lung images greatly improved the participants’ comprehension.  
• 
Perceived severity refers to a patient’s beliefs about the seriousness of the illnesses that they risk 
contracting due to smoking cigarettes. The Report’s Comparative section places the patient in a cohort that 
highlights how the patient’s health compares with the large population of smokers who in the NLST study. 
The patient will also see, in the Health Outcome section, detail on long-term health outcomes of their 
corresponding NLST cohort, personalizing the impact of smoking on their overall health.  The fact that 
patients are at increased risk for such debilitating outcomes as lung cancer and other cancers, and even 
mortality from continued smoking personalizes and underscores the severity dimension. Presenting these 
risk factors graphically dramatically improved the understanding of the related health risks by Phase I 
participants. 
• 
Perceived benefits refers to the benefits of quitting smoking cigarettes. The Report’s Quit Now section 
highlights the benefits to the patient if they stop smoking. The section outlines how their health will improve 
both in the short and longer-term [39], and focuses on those outcomes considered most important to the 
Phase I participants. An additional outcome from Phase I was the need to create multiple versions of this 
section corresponding to milder, intermediate and more extensive emphysema, such that the potential 
benefits of quitting smoking are perceived as realistic for the particular individual. 
• 
Perceived barriers refers to real or imagined barriers for the patient to quit smoking cigarettes.  The 
Report Outreach section includes personalized contact information for a quitline.  It strongly emphasizes 
the benefits of accessing smoking cessation resources and the increased likelihood of long-term success 
via multiple quit attempts.  It frames past quit attempts as learning experiences and notes that those who 
keep trying have a high likelihood of quitting. The Phase I participants were very concerned about who 
would answer the phone, and wanted to know if the counselor on the other end would be a past smoker. 
Most participants expressed reservations about calling, and said that they did not want to be judged. The 
Outreach section addresses these concerns via supportive language and information about what can be 
expected from the phone call. 

 
6 
• 
Cues to action refer to the belief that a cue, or trigger, is necessary for prompting engagement in health-
promoting behaviors. The lung cancer screen, 
CT scan, and the Report listing information on 
accessing smoking cessation, are cues to action, 
which motivate the patient to quit smoking. 
• 
Self-efficacy refers to the individual’s perception 
of his or her ability to quit smoking. Multiple 
sections of the Report help build patient 
confidence in their ability to quit smoking. The 
Report stresses the importance of persevering 
and notes that successful quitting often follows 
multiple quit attempts.  
As noted previously, lung cancer screening 
programs have excellent potential to provide a 
teachable moment.  McBride and colleagues 
recommend the consideration of three characteristics 
prior to defining an event as a teachable moment. 
These include the impact of: (1) the event on risk 
perceptions and outcome expectancies, (2) the 
emotional response associated with the event, and 
(3) impact of the event on social role and self-
concept [40]. Making the impacts of smoking more 
visible to the patient through an emphasis on areas 
of emphysema in the Image section, in addition to 
the Comparative and Heath Outcomes sections, will 
significantly increase the likelihood that the patient 
will have an awareness of smoking risk and an emotional response associated with lung cancer screening.  
While the Report builds on the teachable moment and is hypothesized to create a ‘cue to action’, behavior 
change is not often a single event.  The Stages of Change model [41] outlines how a change in behavior can 
occur gradually from a patient being uninterested (precontemplation) to considering a change (contemplation), 
to deciding and preparing to make a change (stages of change).  The Report’s five sections help ensure that 
the patient is engaged at their current “stage” and motivated to move through subsequent stages toward 
lifelong change.  For those patients in the precontemplation stage the image and comparison section will 
increase engagement.  Those in the contemplation stage may focus more on the Outreach or Quit Now 
section.  In the preparation stage, patients will find encouragement in the Health Outcomes and Quit Now 
section.  As patients enter the action stage they will uncover support in the Outreach section.  The final stage 
of maintenance and relapse prevention will be supported by services listed in the Outreach section and 
through yearly lung cancer screens.  Each year the patient will receive a lung cancer screen and their Report; 
this cycle will further increase the likelihood that the behavior change of smoking cessation is established long-
term [41]. While yearly lung cancer screens may support long-term change, testing the impact of yearly lung 
cancer screen with the Report is beyond the scope of this Phase II project, which assesses one lung cancer 
screen. 
 
Background Information on IMBIO’s Quantitative Image Analysis 
 
It is well established that the presence of CT-detected low attenuation areas in the lung parenchyma is an 
important risk factor for lung cancer and other comorbidities of smoking such as pulmonary and cardiac 
disease. While a causal relationship is not presumed, it is known that chronic obstructive pulmonary disease 
(COPD), lung cancer, and other smoking-related diseases share common pathogenic mechanisms, including 
chronic inflammation, oxidative stress and impaired mucociliary function. Multiple studies in large patient 
populations have established a strong relationship between the amount of low attenuation areas present on a 
CT exam and a patient’s risk for developing lung cancer [42–47]. These studies revealed that low attenuation 
areas is an important risk factor for lung cancer, independent of other factors including a person’s age, gender 
and smoking history. 
Figure 1 

 
7 
CT typically provides excellent anatomical detail with highly reliable image quality, and is thus amenable to 
quantitative techniques for detecting and characterizing the presence and the extent of low attenuation areas. 
Li et al. evaluated 565 lung cancer screening exams by computer-aided quantitative assessment of the 
percentage volume of the lung having low attenuation [42].  This study found that the amount of low 
attenuation lung tissue was an independent predictor for lung cancer risk, even after adjusting for smoking 
status and pack-years of smoking. Mets et al. developed a risk score calculated from the relative volume of low 
attenuation lung tissue under combined with other patient-specific clinical data such as BMI and smoking 
history to identify patients with clinically significant airflow restriction in a lung screening population [54], which 
has also been shown to predict important outcomes [48].  
Imbio’s quantitative lung analysis will automatically analyze a chest CT and quantify the percentage of lung 
volume with low attenuation. The algorithm, as a first step, automatically segments CT lung images into voxels 
corresponding to lung parenchyma and voxels corresponding to other tissues or background noise. A total 
volume of lung parenchyma is calculated for the patient. Low attenuation voxels are then identified based 
either on a dual-threshold technique or a classifier trained to identify radiologist-confirmed low attenuation 
areas of varying severity. Once low-attenuation voxels are identified, the total percent of lung with low 
attenuation can be calculated.  
 
III. 
Study Aims  
 
 
Primary study endpoints  
• 
Calling a Quitline number. 
 
Secondary study endpoints  
• 
Smoking cessation as measured by salivary cotinine testing. 
 
 
 
 
 
 
 
IV. 
APPROACH & STUDY DESIGN 
Phase I Summary 
In the earlier pilot project, Imbio designed a report that would increase a patient’s motivation to make a quit 
attempt following a lung cancer screen by showing them the impact of smoking on their overall lung health 
(See complete Phase I final report in Appendix 1).  
All goals of the pilot project were successfully achieved, via multiple rounds of interviews and focus group 
discussions conducted with high-risk smokers recruited by the HealthPartners Institute. Multiple versions of the 
Report were created and tested in the qualitative research using historical screening images for the Image 
section and fictional risk metrics for the Comparative section. Information gathered from each round informed 
the design of the subsequent round to improve participant comprehension and increase emotional impact of 
the Report.  
 The final round of focus groups, a questionnaire incorporating the Contemplation Ladder and Smoking 
Hazard scales, as well as a Self-efficacy Scale was used to assess the overall psychological impact of the 
Report design. Responses supported the hypothesis that a personalized version of the Report would likely 
have a positive impact on a participants’ motivation to make a quit attempt, by increasing their hazard 
perception, and strengthening their belief in their ability to quit.  Final focus group feedback indicated that 
participants were engaged by the Report and were very optimistic about its potential impact on smokers. 
Participants felt confident the Report would encourage smokers to make a quit attempt, especially when 
included as part of a smoking cessation discussion with a medical professional.  
 In conclusion, all milestones were successfully completed for the Phase I pilot.  The Report design was 
dramatically improved for comprehension, personalization, and motivational content and design, and shows 
strong promise to increase quit attempts by motivating patients to access smoking cessation resources 
including a quitline, other formal cessation programs, and/or cessation medications. 
 
Randomized Control Trial Study Design 

 
8 
The RCT will enroll approximately 400 self-selecting participants (200 at HealthPartners, and 200 at The 
University of Michigan) using a 2 by 2 factorial design from lung cancer screening programs at HealthPartners 
and the University of Michigan Heath Services.  
 
INCLUSION CRITERIA: 
Specific Inclusion Criteria (based on NLST guidelines) include the following: 
• 
Age 55-74 
• 
Smoking history of > 30-pack years 
• 
Currently actively smoking cigarettes 
• 
Ability to read, write and communicate in English 
• 
Screening CT scheduled at the HP Specialty Center (401 Phalen Blvd.  St. Paul) 
• 
Available by telephone for counseling and/or follow-up communications 
 
EXCLUSION CRITERIA 
• 
Clinically significant health problems that make projected lifespan < 2-years 
• 
LungRads Category 3 or 4 resulted out on screening CT 
 
Recruitment and Consent - Randomized Controlled Trial participants will be recruited through the 
University of Michigan (200 participants) Health System and the HealthPartners Institute (200 
participants).   
• 
At HealthPartners, patients scheduled at HealthPartners Specialty Center will be given an 
informational flyer and consent form with return envelope during check-in for their Screening CT.   
• 
Patients interested in participating in the study will be asked to contact the study coordinator by 
telephone within 72-hours (3-days) of their CT scan.  During that call the coordinator will review the 
study requirements, read the consent form to the participant and attest to the patient’s willingness to 
participate in the study.  Participant will be asked to mail the last (signature) page of the consent to 
the coordinator in the envelope provided for back up hard copy. 
• 
Consent forms will specifically request permission to share actual CT images with IMBIO in order to 
print a Patient Report based on the patient’s own CT images.  Specific permission will also be 
sought to share the Patient Report CT screening results with Mayo TTS and the Quitline 
representative. 
• 
Following the screen, a radiologist will analyze the CT scan image and send the results to the 
patient’s PCP. If the scan is read as a category 1 or 2 in the Lung CT Screening Reporting and 
Data System (Lung-RADS) [49], patients who have consented to study participation will be 
randomized to one of four treatment arms. If the scan is read as a category 3, 4A, 4B, or 4X in 
Lung-RADS the patient will be contacted by their primary care physician’s office and told to 
schedule a follow up appointment.  They will be sent a letter informing them they are not eligible for 
participation in the study after ordering physician has notified them of results and follow-up plans.  
 
Randomization 
Upon attestation of consent, eligible participants will be randomly assigned to one of four conditions 
using a central RedCap database:  
1. Usual Care (w/ MN Quitline phone number); 
2. Usual Care + Report (w/ IMBIO Quitline number); 
3. Usual Care + Counseling; Or 
4. Usual Care + Report (w/ IMBIO Quitline number) + Counseling incorporating results of 
report.   
 
Those patients randomized to receive the Report will have their radiology images loaded onto a 
secure flash drive by radiology staff.  The images will be uploaded into a HIPAA-compliant web-
based portal hosted by IMBIO for processing and generation of the Reports, which can then be 
downloaded and printed. 
 

 
9 
Randomization letters, usual care letters and/or reports (Groups 2 & 4) will be mailed to 
participants.  (For participants randomized to Groups 1 & 3, generation and mailing of reports will 
be delayed until study participation has finished.) 
 
 
Synopsis of Treatment Arms 
 
Usual Care - Subjects participating in lung cancer screening through HealthPartners and the University of 
Michigan Health System are referred for screening from their primary care physician (PCP). HealthPartners 
and the University of Michigan Health System require PCPs to document in the medical order system that 
current smokers who require a lung cancer screen have been offered smoking cessation counseling prior to 
providing the screen, in accordance with CMS guidelines [50]. Once a patient is cleared for screening, they are 
able to schedule an appointment at an affiliated lung cancer-screening site.   Following radiologist reading of 
the scans, eligible study patients randomized to the usual care group will receive a standard results letter in the 
mail notifying them of screening results with a phone number that will lead them to the state of MN Quitline.  
The phone number will differ from the MN Quitline number in order to capture calling data.  The phone number 
will provide a short voice message to recipients and then transfer them to the MN or MI Quitline depending on 
their location. 
 
 
Tobacco Dependence Counseling 
Counseling will consist of one 45-minute session by telephone to occur within two weeks (preferably no 
more than 10-days) after the lung cancer screen. Counseling sessions will be in accordance with established 
cessation counseling protocols developed at the Mayo Clinic. Tobacco Treatment Specialists (TTS) will have a 
complete list of local resources and will facilitate participant enrollment and/or use of medications at the time of 
the call.  
 Michael V. Burke, EdD.,Treatment Program Coordinator for the Mayo Clinic Nicotine Dependence Center 
will oversee the coordination and supervision of the Mayo Tobacco Treatment Specialists (TTS). 
Approximately three TTS will be trained to ensure consistent counseling methodology. TTS follow a validated 
approach when providing smoking cessation counseling over the phone [51–53].  TTS utilize a patient 
centered approach grounded in Motivational Interviewing skills [54–58] to elicit perceived benefits for stopping 
smoking and to enhance self-efficacy for stopping. Specific cognitive and behavioral strategies are 
collaboratively developed to engage evidence-based strategies for initiating a quit attempt and preventing 
relapse. A major emphasis of a call is to enroll the caller in formal cessation programs and/or convince them to 
use FDA approved medication as part of a quit attempt. At the close of each call, TTS confirm that callers are 
aware of the smoking cessation services available to them. Study participants who desire further smoking 
cessation support after their 45-minute session will be connected with the appropriate organization: 
HealthPartners Connect  (HP commercial plan), or MN QuitPlan (HP Medicare).  Study participants will be 
strongly encouraged to take advantage of available cessation resources. All participant feedback and 
questions on the follow up letter and/or Report will be documented.  TTS will attempt to reach participants six 
times on different days and times of day before recording them as non-respondent. 
 
     IMBIO Patient Report- Research coordinators at the University of Michigan and HealthPartners will be 
provided access to Imbio’s HIPAA-compliant web portal to upload image data and generate Reports. Following 
consent and lung screen, research coordinators will manually upload the study participants’ images and 
download a resulting Report which will be mailed to the participants whose treatment arm includes the Report. 
Radiologists have been designated at both sites to review and approve the Report prior to mailing to 
participants.   
 
     Tobacco Dependence Counseling plus Patient Report-  This arm will consist of the mailed report, which 
the TTS counseling call will incorporate into tobacco cessation discussion.   
 
V. 
Data Collection Processes-  
 

 
10 
Outcomes will be assessed at 3 weeks, 3 months, and 6 months. Timing of outcome follow up will begin at 
time of consent attestation. There will be assessment of participant self-reported use of resources including 
enrollment in face-to-face cessation programs, calls to quitlines, use of medications, and other smoking 
cessation services. Participants reporting abstinence at three and six month follow up will be asked to submit 
saliva cotinine samples to confirm self-reports.   
 
A survey to assess readiness to quit, motivation to make a quit attempt, use of a smoking cessation 
quitline, quit attempts and long-term smoking abstinence will be developed by Dr. Harry Lando.   
University of Minnesota Office of Measurements Services (Measurement Services) will administer 
follow up calls to assess readiness to quit, motivation to make a quit attempt, use of a smoking 
cessation quitline, quit attempts and long-term smoking abstinence.  Measurement Services will be 
blinded to participant’s conditions.  All participants will receive follow up calls at 3 weeks, 3 months, 
and 6 months to assess calls to the quitline, readiness to quit, quit attempts, use of cessation aids 
(programs and medications), as well as current smoking following receipt of their lung cancer 
screen results. 
 
Given the large number of subjects, Office of Measurement Services will input the survey into the 
Computer-Assisted Telephone Interviewing (CATI) Software[59] and train staff to ensure a consistent and 
effective approach.  
 
Dr. Steve Hecht at the University of Minnesota will manage cotinine analysis.  Participants reporting 
abstinence at 3 and 6 months will be asked to submit saliva samples by mail.  A second consent form specific 
to cotinine collection will be mailed with the collection kit. 
 
All participants will receive $20 after each of the first and second follow-up calls, and $70 after the final follow-
up call.  Participants who report abstinence will be provided an additional incentive of $50 to provide a saliva 
sample for a cotinine analysis. A maximum of $160 will be provided to participants as compensation for their 
time and as an incentive for their participation.  Compensation will be provided as Target gift cards, mailed to 
patients address on record after confirmation of follow-up completion by University of MN Office of 
Measurement Services (OMS). 
 
 
Data management - Data will be stored in a secured, centrally located REDCap database. Investigators 
will oversee the REDCap database setup, data management, audit and edit plans to ensure data accuracy and 
completeness, and creation of the study’s codebook with precise definitions and coding of all variables. A 
double-checking mechanism will be set up to ensure data completeness and accuracy. Strategies are set up 
for handling missing data, which are described below.  
 
VI. 
Data Analysis, Sample Size and Statistics - David Vock, PhD, a biostatistician with the University 
of Minnesota School of Public Health, will analyze data from the RCT.  Similar to standard methods 
for factorial designs in other therapeutic areas, analyses to address the primary aims will be a test 
of the main effect of the randomized interventions (i.e., report type and counseling type). All 
analyses will be by intention-to-treat, and include all participants randomized, regardless of whether 
they are lost to follow-up. The primary outcome measures will be a dichotomous comparison of 24-
hour quit attempts (yes/no) at the time of the three-week follow-up, three-month follow-up, and six-
month follow up and subject-reported readiness to quit based on the contemplation ladder among 
those who have not quit smoking. Secondary outcomes include cotinine-verified abstinence at three 
and six-months and use of smoking cessation services (dichotomous outcome) at 3 weeks, 3 and 6 
months. Initially assessment will focus on the main effect of Report condition (Report vs. Usual 
Care) averaging or “pooling over” the Counseling condition on the continuous (readiness to quit) 
and dichotomous outcomes (24-hour quit attempt, abstinence, use of smoking cessation services) 
using a two sample t-test of the difference in the mean response and two-sided Wald-type test [60] 
of the difference in proportions, respectively, with a 0.05 significance level. Exact tests (e.g., 
Barnard’s exact test) may be used if the number of successes (e.g., quit attempts, abstinence) is 

 
11 
small. Separate analyses will be performed at each measurement time point (e.g., three-weeks, 
three-months, and six-months). A similar set of analysis can be performed to assess the main effect 
of the counseling condition.  Logistic and linear models (for the dichotomous and continuous 
outcomes) with covariates for report condition, counseling condition, and their interaction will be 
used to assess if the Report and Counseling conditions significantly interact. If the interaction is 
significant, there will be an examination of whether there is a significant difference between the 
Report and Usual Care within each level of the Counseling condition.  As an exploratory analysis to 
help guide future studies, a logistic regression model with quit attempt (yes/no) as the response will 
be utilized.  Possible covariates include intervention group, gender, age, number of pack years, 
interest in quitting at baseline, risk perception at baseline, number of previous quit attempts, and 
findings from the CT scan, and their interaction with the Report condition. Similar models could be 
constructed for the other outcomes (abstinence, use of use of smoking cessation services). 
Additional linear regression models will be constructed for the other outcomes (readiness to quit). 
Additionally examination will be on whether or not changes in readiness to quit at 3 weeks mediate 
quit attempts, use of smoking cessation resources, and abstinence at 3 and 6 months using 
structural equation modeling. 
  
 
 
Sample Size: The proposed RCT is powered for a main effects analysis of the Report (averaged over the 
Counseling condition) for the following outcomes a) at least one 24-hour quit attempt within 6 months of the 
CT scan b) accessing either formal cessation programs and/or FDA-approved medications within 6 months 
and c) readiness to quit as measures by the contemplation ladder. 
 
Power for these primary hypotheses are shown in Table 2 assuming 400 total subjects under different 
assumptions concerning the average response within each of the randomized groups. A difference of 20% 
and 12.5% is considered between the Report and Usual Care conditions to be of interest for the 
percentage of subjects with at least one 24-hour quit attempt and accessing cessation 
programs/medication within 6 months. Similarly, an average difference of 1.5 on the contemplation ladder 
is considered meaningful. Table 2 indicates there is sufficient power to detect these differences and even 
reasonable power across many scenarios to detect smaller effects for the main effect of the Report. 
Additionally, Table 2 demonstrates that there is adequate power to detect a significant effect of the Report 
within each level of the counseling condition at the 0.1 significance level.  
 
Concerning 6-month abstinence, differences were considered between the Report and Usual Care 
between 5-10% to be meaningful.  As a Phase II study, it is not powered to detect a significant main effect 
for the Report for the 6-month abstinence outcome. However, Table 3 demonstrates that across a range of 
plausible scenarios there is sufficient power for a composite test of whether or not the probability of 
abstinence at 6 months is the same across all 4 arms and whether or not the Report + Counseling is 
different than Usual Care. 
As part of the analysis, it is expected that Report Only compared to Usual Care will significantly increase 
readiness to quit, quit attempts, and accessing of programs/medications.  It is also expected that the Report + 
Counseling will produce 
significantly higher 7-day point 
prevalence abstinence at 6 
months than Usual Care with 
the other two conditions 
intermediate. In particular, it is 
expected that the combination 
of counseling and the Report 
will be more effective in 
increasing readiness to quit, 
quit attempts, use of formal 
programs and/or medications 
and abstinence than the other 
three conditions.  Additionally, 
it is expected that 5% in the 
Table 2: Power to test a difference in a) the proportion of subjects achieving at least one 24-
hour quit attempt, b) the proportion accessing formal cessation programs and/or FDA-
approved medications, or c) the mean readiness to quit on the contemplation ladder between 
the Imbio report and usual CT scan report. Power calculations assume total N=400 and the 
use of a two-sided test with a 0.05 significance level for the main effect and 0.10 significance 
level for the effects within each counseling condition level. The power calculation for 
readiness to quit assume a standard deviation of 2.9 on the contemplation ladder.     

 
12 
Usual Care condition will make a quit attempt (24-hour quit) versus 15% in the Report condition at the time of 
the 3-week follow-up. The Report will yield significantly greater percentage of subjects reporting a quit attempt 
at 3 and 6 months.  
 
VII. 
 Title 21 FDA Device Trial Regulations 
 
 
The IMBIO Patient Smoking Cessation Report is currently preparing to undergo the proposed RCT in 
preparation for eventual FDA approval as a medical device.  This trial will be run under the non-significant risk 
(NSR) section of Title 21 FCR 812.2(b) and will follow the abbreviated trial requirements contained therein.  
CFR 812.2(b) is uploaded with this application.  Also uploaded is Title 21 CFR 56.111, which gives the IRB 
criteria for approval of NSR clinical device research under the abbreviated requirements associated with FCR 
812.2(b). 
The IMBIO Patient Smoking Cessation Report, as an NSR device, is not required to seek IDE approval through 
the FDA prior to starting the clinical trial proposed in this application.  IRB agreement that this device qualifies 
as an NSR device will suffice in lieu of a formal IDE application, as long as said determination of NSR status is 
transcribed into formal IRB minutes. 
This clinical trial will be monitored by the sponsor of the trial, IMBIO, LLC, in accordance with the monitoring 
requirements found in Title 21 CFR 812.46. 
Following the conclusion of the clinical trial proposed in this application, the sponsor will approach the FDA for 
approval or clearance as a medical device.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VIII. 
Study Timeline 
 

 
13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Oct
Nov
Dec
Jan
Feb
Mar
Apr
May
June
July
Aug
Sept
Oct.
Nov.
Dec.
Jan
Feb
Mar
Apr
May
June
July
Aug
Sept
Oct.
Nov.
Dec.
Jan
Feb
Mar
Apr
May
June
July
Aug.
Cessation counseling cond. 3-4
Participant Lung screening
Install Imbio Software/determine 
approach
IRB complete for U of MN, MI, and 
Mayo
 Phase II Work Plan
Training TTS
2019
2017
2016
2018
Recruit RCT participants
6-month follow up call 
Disseminate research findings.
Write Final Report
Quitline support cond. 1-2
3-week follow up call
SUBMIT mayo IRB application (with 
questionaire developed in SA2)
3-month follow up call

 
14 
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