A Scalable e-Health Smoking Cessation Intervention for Socioeconomically Disadvantaged Veterans
Phase: PHASE1
Conditions: Cigarette Smoking-Related Carcinoma
Sponsor: Fred Hutchinson Cancer Center

RG1007109 
Contact PI: Heffner, Jaimee L. 
 
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Website Smoking Cessation Intervention for the Promotion of Smoking Cessation in Low-Income Veterans 
NCT NCT04502524 
Version 1, 4/15/20 
  
 

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Contact PI: Heffner, Jaimee L. 
 
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FRED HUTCHINSON CANCER RESEARCH CENTER 
Current version: 04/15/20  
 
 Version 1 
04/15/20 
 
 
Title of Protocol: 
A Scalable e-Health Smoking Cessation Intervention for Socioeconomically Disadvantaged Veterans 
 
Investigators List: 
Jaimee Heffner, PhD 
Assistant Member, FHCRC 
(206) 667-7314 
Edit Serfozo 
Project Coordinator, FHCRC  
(206) 667-2428 
Biostatistician: 
Kristin Mull, MS 
Statistical Research Associate, FHCRC 
(206) 667-5757 
 
SPONSOR:  National Cancer Institute 
  
Coordinating Center: 
Fred Hutchinson Cancer Research Center 
Additional Performance Sites: 
Site 
Investigator 
Phone Number 
Bedford VA Research Corporation, Inc.  
Megan M Kelly 
(781) 687-3317 
 
 
 

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PROTOCOL SYNOPSIS 
 
Protocol Title 
A Scalable e-Health Smoking Cessation Intervention for Socioeconomically 
Disadvantaged Veterans 
Protocol Number 
RG-1007109 
Protocol Sponsor 
National Cancer Institute 
Trial Phase 
Phase 1 
Trial Type 
Randomized pilot trial 
Clinical Indication 
Socioeconomically Disadvantaged Veteran Smokers 
Study Objectives 
Aim 1. Compare the relative acceptability of Vet Flexiquit vs. SmokefreeVET among 
socioeconomically disadvantaged US Veterans, as indicated by treatment 
satisfaction and objective measures of web site utilization. 
 
Aim 2. Preliminarily evaluate effects of Vet Flexiquit vs. SmokefreeVET on quit 
attempts and abstinence rates as well as readiness to quit and acceptance of 
smoking triggers—ACT’s theory-based mechanism of change. 
Study Design 
Randomized pilot trial  
Population 
Low income US Veteran smokers 
Primary Endpoints 
1. Acceptability of the intervention: 
a. Treatment satisfaction 
b. Website utilization (number of log ins, number of days used from first 
to last day) 
Secondary Endpoints 
1. Number of quit attempts 
2. Changes in readiness to quit from baseline to 3-months 
3. Changes in acceptance of smoking triggers as measured by the AIS from 
baseline to 3-month follow-up 
4. Cotinine-confirmed, self- reported abstinence from smoking  
Type of control 
Standard care: SmokefreeVet.gov 
Trial Blinding 
Eligible participants will be randomized via a web-based system at the baseline visit 
using an automated algorithm 
Treatment Groups  
2 arms; Vet Flexiquit or SmokefreeVET 
Treatment Schedule 
Vet Flexiquit contains 6 sessions designed to be completed in order, spaced out 
over a minimum of 3 days between sessions, with automated pacing and prompting 
from the program. Each session takes approximately 25 minutes to complete. 
The control intervention will be SmokefreeVET. This web site was designed to 
promote smoking cessation among Veterans by providing educational materials 
about cessation treatments, tools to cope with urges and relapse, how to stay 
motivated, and brief tips for Veterans with depression and anxiety, substance use 
disorders, HIV, and other physical and mental health problems. Content is 
consistent with US Clinical Practice Guidelines for tobacco treatment, which include 
heterogeneous techniques most closely aligned with cognitive behavioral therapy. 
Number of trial subjects 
n=50 
Estimated duration of trial 
9 months 
Duration of Participation 
3 months 
 
ABBREVIATIONS 
 
ACT 
Acceptance and Commitment Therapy 
 
 
 
 
 
 

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Table of Contents 
1.0 
GENERAL INFORMATION .................................................................................................................................................. 6 
1.1 
Protocol Title: A Scalable e-Health Smoking Cessation Intervention for Socioeconomically Disadvantaged 
Veterans ............................................................................................................................................................... 6 
1.2 
Sponsor Information: National Cancer Institute .................................................................................................. 6 
1.3 
Investigator Information: ..................................................................................................................................... 6 
1.4 
Contractors and Consultants for the Study (if applicable) ................................................................................... 7 
2.0 
INTRODUCTION TO THE PROTOCOL ................................................................................................................................. 7 
2.1 
Introduction ......................................................................................................................................................... 7 
2.2 
Clinical Data to Date ............................................................................................................................................ 8 
2.3 
Risks/Benefits....................................................................................................................................................... 9 
3.0 
OVERVIEW OF CLINICAL TRIAL .......................................................................................................................................... 9 
3.1 
Study Objectives .................................................................................................................................................. 9 
3.2 
Study Population .................................................................................................................................................. 9 
3.3 
Study Design ...................................................................................................................................................... 10 
3.4 
Primary Endpoints:............................................................................................................................................. 10 
3.5 
Estimated Accrual .............................................................................................................................................. 10 
3.6 
Name of Sponsor/Funding Source ..................................................................................................................... 10 
4.0 
SUBJECT ELIGIBLITY ......................................................................................................................................................... 10 
4.1 
Inclusion Criteria ................................................................................................................................................ 10 
5.0 
SUBJECT REGISTRATION .................................................................................................................................................. 11 
6.0 
TREATMENT PLAN ........................................................................................................................................................... 11 
6.1 
Intervention Overview: ...................................................................................................................................... 12 
6.2 
Concomitant Medication ................................................................................................................................... 13 
6.3 
1- and 3-Month Follow-up Data Collection........................................................................................................ 13 
6.4 
Participant compensation. ................................................................................................................................. 13 
7.0 
SUBJECT EVALUATION..................................................................................................................................................... 14 
7.1 
Data Collection Overview .................................................................................................................................. 14 
7.2 
Enrollment Procedures. ..................................................................................................................................... 15 
8.0 
SUBJECT DISCONTINUATION OF ACTIVE TREATMENT .................................................................................................... 16 
9.0 
CONCOMITANT MEDICATIONS ....................................................................................................................................... 16 
10.0 
ADVERSE EVENTS ............................................................................................................................................................ 16 
VERSE EVENTS .............................................................................................................................................................................. 16 
10.2 
Monitoring and Recording Adverse Events ....................................................................................................... 17 
10.3 
Grading Adverse Event Severity ......................................................................................................................... 17 
10.4 
Adverse Event Recording Period ........................................................................................................................ 17 
10.5 
Adverse Event Reporting Requirements ............................................................................................................ 17 
11.0 
DATA AND SAFETY MONITORING PLAN .......................................................................................................................... 18 
12.0 
DATA MANAGEMENT/CONFIDENTIALITY ....................................................................................................................... 18 

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13.0 
STATISTICAL CONSIDERATIONS ....................................................................................................................................... 19 
13.1 
Study Design ...................................................................................................................................................... 19 
13.2 
Primary/Secondary Endpoints/Hypotheses and Analytical Methods ................................................................ 19 
13.3 
Sample Size and Power ...................................................................................................................................... 20 
13.4 
Randomization ................................................................................................................................................... 20 
13.5 
Ethnic and Gender Distribution Chart ................................................................................................................ 20 
14.0 
INVESTIGATOR OBLIGATIONS ......................................................................................................................................... 21 
15.0 
REFERENCES .................................................................................................................................................................... 21 
APPENDICES ................................................................................................................................................................................. 24 
 
 
 
 

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1.0 
GENERAL INFORMATION 
 
This document is a clinical research protocol for a two-arm pilot trial that will be conducted in compliance with 
the IRB-approved protocol, associated Federal regulations, and all applicable IRB requirements. The research 
plan is consistent with Stage Ib of the NIDA Behavioral Therapies Development Model [33]. Specifically, we will 
conduct a pilot feasibility trial of Vet Flexiquit (n=25) vs. a standard care comparison web site (n=25). 
 
Rationale: Although cigarette smoking rates have declined in the US over the past 50 years, there has been an 
upturn in smoking among military personnel in the last several decades. With over 8 million Veteran enrollees, 
the Veterans Health Administration serves 75% of low-income and disabled Veterans. Less than 5% of Veterans 
receiving care through VHA access intensive treatment for smoking cessation, and these services employ a 
standard approach to cessation counseling that is most relevant for smokers who are ready to quit. To optimize 
acceptability, reach, and effectiveness, cessation treatments for Veteran smokers should be appropriate for all 
levels of readiness to quit. In this study, we propose pilot testing Vet Flexiquit, a program designed for US 
Veteran cigarette smokers at all stages of readiness to quit. Specifically, we propose a pilot feasibility trial (n=50) 
comparing Vet Flexiquit to a standard care comparison web site (SmokefreeVET.gov). The primary goals of the 
pilot study are to compare Vet Flexiquit to SmokefreeVET on acceptability (i.e., user satisfaction and website 
utilization) and efficacy for impacting theory-based change processes and promoting smoking cessation. This 
pilot project is significant and innovative in four key respects: (1) it addresses the top cause of cancer and other 
preventable diseases among socioeconomically disadvantaged US Veterans served by VHA, (2) it applies a novel 
treatment approach and advances the science of ACT for smoking cessation by testing its effectiveness for 
smokers at all stages of readiness to quit rather than only among smokers who are ready to quit, (3) web-based 
delivery has high potential reach, cost-effectiveness, and scalability within VHA, a health care setting where 
tobacco cessation is under-resourced; and (4) gamification and inclusion of virtual coaches as engagement 
strategies are substantially different than standard web-based tobacco treatments, including SmokefreeVET. If 
found to be effective in a larger trial, Vet Flexiquit would be well-positioned for VHA-wide scale-up due to its low 
maintenance cost and high potential reach, and the core program could be built upon in innovative ways (e.g., 
capability for virtual coaches to understand and respond to natural language) to further improve engagement 
and outcomes.    
 
Objectives:  
Aim 1. Compare the relative acceptability of Vet Flexiquit vs. SmokefreeVET among socioeconomically 
disadvantaged US Veterans, as indicated by treatment satisfaction and objective measures of web site 
utilization. 
 
Aim 2. Preliminarily evaluate effects of Vet Flexiquit vs. SmokefreeVET on quit attempts and abstinence rates as 
well as readiness to quit and acceptance of smoking triggers—ACT’s theory-based mechanism of change. 
 
NOTE: The Bedford VA will be the study performance site and will manage all elements of the trial involving direct 
interaction with participants (i.e., recruitment, enrollment, data collection, etc).  Fred Hutch will be responsible only for 
hosting and maintaining the intervention sites and conducting data analysis at the conclusion of the trial.   
 
1.1 
Protocol Title: A Scalable e-Health Smoking Cessation Intervention for Socioeconomically Disadvantaged 
Veterans 
1.2 
Sponsor Information: National Cancer Institute  
1.3 
Investigator Information:  
Principal Investigator: Jaimee Heffner, PhD, (206) 667-7314 
Principal Investigator: Megan Marie Kelly, PhD, (781) 687-3317, Edith Nourse Rogers Memorial VA 
Medical Center/University of Massachusetts 

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1.4 
Contractors and Consultants for the Study (if applicable) 
Consultant: Maria Karekla, PhD (University of Cyprus) 
 
 
2.0 
INTRODUCTION TO THE PROTOCOL 
 
2.1 Introduction 
 
2.1.1. Significance and Innovation. Smoking remains the leading preventable cause of death and morbidity 
among US Veterans. Cigarette smoking is responsible for over 440,000 deaths annually and causes 32% of all 
cancer deaths [1, 2]. In addition, smoking adds $193 billion in health care expenditures and productivity losses 
each year in the US [3]. The Veterans Health Administration (VHA), which has over 1 million smokers among its 
8.4 million enrollees [4], spends $2.7 billion per year treating smoking-related health problems [5]. Although 
smoking rates have declined in the US over the past 50 years, there has been an upturn in smoking among 
military personnel in the last two decades [6], and the prevalence of current smoking among Veterans is higher 
than among non-Veterans [6, 7]. Elevated prevalence of smoking is most substantial among male Veterans, who 
comprise the vast majority (94%) of those Veterans served by VHA [4]: smoking prevalence among Veteran vs. 
non-Veteran men is 50% vs. 35% for ages 18-25, 46% vs. 36% for ages 26-34, and 32% vs. 26% for ages 35-49 [7]. 
 
2.1.2 Veterans who smoke, particularly those receiving care through VHA, are a socioeconomically 
disadvantaged population. As stated in the FOA under which this application is being submitted (i.e., PAR-18-
250, “Improving Smoking Cessation in Socioeconomically Disadvantaged Populations via Scalable 
Interventions”), Veterans represent an important subgroup of socioeconomically disadvantaged smokers. VHA 
serves an estimated 75% of all low-income and disabled Veterans [6]. Although VHA has always served as a 
safety-net health care provider in the US, the Affordable Care Act and health care reform have increased the 
proportion of VHA users who are low-SES [8-10]. Only 40% of Veterans served by VHA are in the labor force, and 
the median household income is just $35,999 [4]. Consistent with larger US population trends, within VHA, 
current smoking is associated with the lowest levels of income, educational attainment, and employment [11].  
 
2.1.3. Novel interventions are needed to help Veterans quit smoking. There are a number of limitations to the 
smoking cessation treatment approaches currently available to socioeconomically disadvantaged Veterans 
receiving care through VHA, which include local options for group and individual counseling as well as centrally 
managed population health programs like the VA quitline, text messaging program, Stay Quit Coach app, and 
SmokefreeVET web site. Two major limitations are: (1) mismatch on readiness to quit: they rely on standard 
treatment approaches that are designed to meet the needs of smokers who are planning to quit in the near 
future (e.g., next 30 days), which is only approximately 20% of current smokers [12], and (2) low accessibility 
and/or engagement: traditional cessation programs like group or individual counseling are under-resourced to 
assist even those Veterans who are highly motivated to quit [6, 13] and they have limited reach, with only 
0.9%of Veteran smokers served by the VHA receiving the US Public Health Service recommendation [14] of four 
or more sessions of intensive (≥10 min) cessation support [13]. Digital cessation interventions are more 
accessible, particularly where tobacco cessation is under-resourced, but maintaining engagement with 
electronic health (e-Health) interventions is a challenge [15] that requires innovative design solutions. These 
limitations of current treatment options are problematic not just for Veterans but for socioeconomically 
disadvantaged smokers more broadly, as they are less likely to be planning to quit in the near future, less likely 
to make a quit attempt, and, when they do attempt to quit, less likely to engage with traditional treatments and 
instead make unaided quit attempts relative to smokers who are not socioeconomically disadvantaged [16, 17].  
 
2.1.4. ACT is an effective new treatment option for smokers ready to quit. Acceptance and Commitment 
Therapy (ACT) [18, 19] is similar to standard smoking cessation treatment in that it promotes awareness of the 
cues that trigger smoking behavior, but different in that ACT teaches skills to promote acceptance of triggers 

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(e.g., mindfulness) rather than trigger avoidance. Empirical support for ACT comes from six trials that enrolled 
over 3,600 smokers. Collectively, these studies support the feasibility and efficacy of ACT in comparison with 
pharmacotherapy-only treatments and traditional behavioral treatments.  In 5 of 6 studies, quit rates for ACT 
were superior to control group quit rates at both short- (i.e., 3 months) and long-term (6 to 12 months) follow-
up, and in the most recent study conducted by Dr. Heffner and colleagues (R01CA166646: PI: J. Bricker), both 
ACT and the comparison treatment produced similarly high quit rates at 1-year post-randomization (24% vs. 
26%, p=.334) [20]. Importantly, ACT is acceptable and shows evidence of efficacy for smokers with mental health 
conditions [21-24], which are highly prevalent among Veterans [13] and among low SES smokers more broadly 
[25], may interfere with quitting [26], and are not addressed in standard cessation treatments. Taken together, 
these findings suggest that ACT is at least as effective, if not more effective, than standard treatment 
approaches and that it uniquely addresses some of the challenges to cessation among low SES smokers. 
 
2.1.5. Flexiquit: Engaging, web-based ACT for smokers at all levels of quit readiness. Previous trials of ACT for 
smoking cessation restricted enrollment to smokers who were ready to quit, and the intervention focused on 
action-oriented strategies for coping with cravings. However, ACT can also be employed to motivate smokers at 
lower levels of quit readiness by placing greater emphasis on the ACT components of awareness and enactment 
of personal values at the outset of the treatment. Our collaborator, Dr. Karekla, developed the first ACT program 
designed for smokers at all stages of readiness to quit. This web-based program, Flexiquit, is also innovative in 
its use of gamification and virtual coaches to motivate user interaction. These strategies are designed to 
increase engagement, and ultimately cessation outcomes, among smokers at all levels of quit readiness by 
making the experience pleasurable through novelty and interactivity, instilling hope through personal quitting 
narratives shared by the virtual coach who is represented as a supportive peer who was able to quit successfully, 
and triggering the desired behavior with reminders and motivational “sparks” delivered both in-program and via 
email (from Fogg’s Behavior Model for Persuasive Design [27]). Additionally, the virtual coach as the 
embodiment of a supportive peer fits VHA organizational values. VHA is the country’s largest employer of peer 
support specialists, recognizing the unique importance of peer support to Veterans—particularly those with 
mental health conditions—who may feel isolated and unable to relate as well to non-Veterans (see letter of 
support from Patricia Sweeney, VISN 1 MIRECC Peer Education Director).  
 
2.1.6. Flexiquit is packaged for scalability. A significant benefit of web-based interventions is that they have 
high potential reach and scalability. Currently, 76-80% of Veterans use the internet at home or on mobile 
devices [28, 29]. In addition, 56-76% of Veterans are interested in using web-based VHA health-related programs 
[28, 29]. Not only do web-based treatments have strong appeal to consumers [30], they are also highly 
transportable into clinical settings relative to individual or group interventions that require practitioners to be 
willing and able to implement a new treatment model with an acceptable level of fidelity [31]. The cost-
effectiveness of web-based treatments is also 5 to 10 times greater than other models of treatment delivery 
such as clinic-, workplace-, and telephone-based interventions [32]. In settings that serve predominantly low-SES 
smokers, like VHA or Federally Qualified Health Centers, low-cost tobacco interventions effectively reduce 
organizational and individual financial barriers to treatment utilization and increase scalability. 
 
2.2 Clinical Data to Date 
 
2.2.1. Flexiquit preliminary acceptability and efficacy. Flexiquit was evaluated in 105 university student 
smokers, aged 18-28 years old (M age=22.50, SD=2.56; 45 females). Participants were randomly assigned in a 
2:1 ratio to either Flexiquit (n=70) or a wait-list control (n=35) group. Results indicated that program content 
was highly acceptable, even among those who had no intention to quit. Overall, 89% said the content was easy 
to understand, 74% found it very interesting, and 60% completed all 6 sessions. Qualitative comments suggested 
that participants were surprised by how much they learned and how much more motivated they were to 
consider cessation, even when they had started the program out of curiosity and had no intention to quit. The 
most commonly suggested improvements to the program were technical and a direct result of the limited 
development budget for the initial pilot work: e.g., improved graphics for the virtual coach and technical 

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improvements to improve usability across web browsers and on smartphones. Compared to a wait-list control 
group, quit rates for Flexiquit were significantly higher at post-treatment (51.9% vs. 14.3% in the waitlist control 
group, OR = 6.46, 95% CI = 1.76 – 23.71, p = .005), demonstrating a strong signal for efficacy. 
 
2.3 Risks/Benefits 
Patients will be told that the study may involve the following risks and/or discomforts. Some participants may 
quit smoking during this study and experience the physical and psychological consequences of smoking 
abstinence, such as nicotine withdrawal symptoms. Participants will be informed of the discomfort associated 
with nicotine withdrawal, including common withdrawal symptoms, and that nicotine withdrawal may 
exacerbate some psychiatric symptoms (e.g., depressive symptoms).  Participants will also be informed of the 
possibility that the interventions provided as part of the study may not be effective in helping them to quit 
smoking. Additionally, some participants may feel emotional upset while answering some of the research 
questions. There is also a small risk of breach of confidentially.  
 
Participants in this research will receive access to a web-based smoking cessation intervention at no cost. This 
research may help some participants quit smoking or cut back on how much they smoke, thus dramatically 
reducing their chances of developing tobacco-related health conditions. Findings from this research will provide 
knowledge about ways to better help socioeconomically disadvantaged Veterans quit smoking. 
 
3.0 
OVERVIEW OF CLINICAL TRIAL 
 
3.1 Study Objectives 
 
3.1.1 
Primary Objectives: Compare the relative acceptability of Vet Flexiquit vs. SmokefreeVET among 
socioeconomically disadvantaged US Veterans, as indicated by treatment satisfaction and objective 
measures of web site utilization. 
3.1.2 
Secondary Objectives: Preliminarily evaluate effects of Vet Flexiquit vs. SmokefreeVET on quit attempts 
and abstinence rates as well as readiness to quit and acceptance of smoking triggers—ACT’s theory-
based mechanism of change. 
 
3.2 Study Population 
Participants will be 50 US Veteran cigarette smokers who are interested in using a web-based intervention 
designed to motivate and support smoking cessation.  
 
Inclusion of Women & Minorities 
We will actively seek both male and female participants. Consistent with the US Veteran population served by 
VHA, we expect that, without targeted recruitment, the sample would be predominantly (94%) male. To allow 
for exploration of sex differences in the acceptability or efficacy of treatment, we will oversample women to 
achieve 25% representation in the sample. To do so, we will advertise in Women’s Health clinics and use 
electronic medical records to identify all potentially eligible women and contact them until the 25% target is 
met.  
 
We will also make every effort to ensure that members of diverse racial/ethnic groups are adequately 
represented in the study. The Bedford VAMC population is about 3% Hispanic/Latino, approximately 1% Native 
American and 4% Black/African American. This study will aim to be representative of the national racial/ethnic 
diversity among Veterans and include about 19% representation of minorities, following similar methods of 
targeted recruitment as described above. However, given the small percentages of women and minorities 
represented at the Bedford VAMC, future research on Vet Flexiquit would be needed to evaluate the impacts of 
this intervention specifically on women and minorities. 
 

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3.3 Study Design 
The research plan is consistent with Stage Ib of the NIDA Behavioral Therapies Development Model [33]. We will 
conduct a pilot feasibility trial in which participants are randomized to one of two websites—Vet Flexiquit (n=25) 
or a standard care comparison web site (SmokefreeVET) (n=25). Participants will be asked to complete follow up 
surveys at 1 and 3 months via telephone or VA Video Connect. 
 
3.4 Primary Endpoints:  
• 
Satisfaction with assigned treatment at 3-months post-randomization 
• 
Website utilization: number of server-recorded logins to assigned website at 3-months; duration of 
website use from first to last login 
 
3.4.1 
Secondary Endpoints:  
• 
Number of quit attempts at 3-months 
• 
Cotinine-confirmed, self-reported abstinence from smoking in the 7 days prior to the 3-month follow-up 
• 
Cotinine-confirmed, self-reported abstinence from smoking in the 30 days prior to the 3-month follow-
up 
• 
Self-reported abstinence from all nicotine and tobacco products (except nicotine replacement therapy) 
in the 7 days prior to the 3-month follow-up 
• 
Change in readiness to quit as measured by the Contemplation Ladder from baseline to 3-month follow-
up 
• 
Change in acceptance of smoking triggers as measured by the AIS from baseline to 3-month follow-up 
 
3.5 Estimated Accrual 
We estimate that the 50 subjects for the proposed study will be recruited over the course of approximately 9 
months. Of the 50 participants randomized into the pilot study, we project a 15% attrition rate, resulting in an 
estimated sample of 42 treatment completers across the two treatment groups.   
 
3.6 Name of Sponsor/Funding Source 
National Cancer Institute - 1R21CA236980 
 
4.0 SUBJECT ELIGIBLITY 
 
4.1 Inclusion Criteria  
 
4.1.1 Demographic Criteria 
• 
Participants must be a US Veteran 
• 
Participants must be age 18 or older 
• 
Participants must be low-income, as defined by falling below VHA national income threshold for no-cost 
healthcare 
4.1.2 Smoking Criteria 
• 
Participants must be a current smoker, averaging at least 5 cigarettes/day for the last 30 days 
4.1.3 Treatment accessibility Criteria 
• 
Participants must have weekly Internet access for the next 3 months 
• 
Participants must self-report current use of a personal email address to receive the link to their assigned 
web site 

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• 
Participants must self-report being willing to complete all study activities 
• 
Participants must be willing to receive study-related text messages 
• 
Exclusion Criteria 
• 
Currently taking part in any other smoking cessation treatment such as the nicotine patch, nicotine gum, 
Zyban, in-person counseling, telephone counseling, using a web-based or app-based cessation program 
• 
Have recent (past 30 days) substance use disorder, suicidal ideation, or psychiatric hospitalization 
• 
Previous participation in the treatment development stage of Vet Flexiquit 
• 
Prior use of the SmokefreeVET web site 
• 
Member of the same household as another research participant 
• 
Woman who is pregnant or breastfeeding, or planning to become pregnant 
 
5.0 
SUBJECT REGISTRATION 
 
Participants will primarily be recruited from Dr. Kelly’s Tobacco Cessation Program at the Bedford VAMC, but we 
will recruit throughout the Bedford VA. 
 
5.1 Subject Identification and Pre-Enrollment Screening:  
 
Participants will primarily be recruited from Dr. Kelly’s Tobacco Cessation Program at the Bedford VAMC. Based 
on the characteristics of Veterans in this clinic, 400 Veterans would meet eligibility criteria for the study during 
the enrollment period. We will also recruit from the Mental Health Service Line. Approximately 1840 other 
Veterans at the Bedford VAMC would meet study criteria. Therefore, we do not anticipate difficulty recruiting 
the proposed number of participants, which would be 3% of eligible Veterans. Monitoring of recruitment will be 
done weekly and reported and discussed during weekly conference calls. We anticipate that this granular 
attention to ongoing recruitment will lead to successful enrollment of participants. 
 
Potential participants will be screened by phone to determine eligibility. These screens will be scripted and 
completed by trained interviewers. Eligible individuals will be invited to complete the first study visit by 
telephone. At the beginning of that visit, participants will be provided with detailed information about the study, 
and verbal consent will be obtained following the guidelines of the Bedford VAMC Institutional Review Board. 
Following informed consent, participants will complete remaining study procedures. Those ineligible to 
participate will be provided with information about other resources to help them quit smoking. 
 
 
6.0 
TREATMENT PLAN 
 
Figure 1. Study Flow Chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
Access to VetFlexiquit  
& associated text 
messages 
3-month 
Follow-up 
(phone or VA 
Video 
Connect)  
Enrollment/ 
Randomization 
Informed 
Consent & 
Baseline 
Assessment 
(phone) 
Access to SmokefreeVet 
& associated text 
messages 
1-month 
Follow-up 
(phone) 
Screening 
(phone) 

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6.1 Intervention Overview:  
Both web-based interventions will be accompanied by a text messaging program that includes: (1) motivational 
messages, and (2) reminders to use the assigned program. The content of the motivational messages will differ 
based on the distinct treatment approaches employed in each arm (see Table 2 below). Both web sites (Vet 
Flexiquit and SmokefreVET) will cover core smoking cessation content areas [14], including coping skills, 
motivation, and relapse prevention. Key differences in the interventions are described below in Table 2. 
 
Table 2 
 
 
Vet Flexiquit Content. Consistent with the original Flexiquit program, Vet Flexiquit will contain 6 sessions 
designed to be completed in order, spaced out over a minimum of 3 days between sessions, with automated 
pacing and prompting from the program. Each session takes approximately 25 minutes to complete. Text 
messages reminders are used to prompt completion of the next session. Because Vet Flexiquit is designed for 
smokers at all stages of readiness to quit smoking, prompts to reduce smoking and set a quit date do not 
happen until later sessions. At the end of the program, users are sent an email with all session handouts.  
 
Session 1 introduces the virtual coach, who provides an overview of the program and shares her own story of 
quitting. Users complete an interactive game to identify personal values guiding quitting and review quit stories 
from other Veterans. Session 2 focuses on trigger awareness through interactive questions, graphs, pictures, and 
experiential exercises and metaphors, and it introduces the ACT concept of creative hopelessness—recognizing 
that efforts to control thoughts, feelings, or sensations related to smoking can be counterproductive. Session 3 
completes the topic of creative hopelessness and introduces cognitive defusion—i.e., psychological distancing 
from thoughts—as an alternative to thought control. Session 4 completes the topic of cognitive defusion, 
encourages setting a quit date in the next week, and prompts users to practice defusing from thoughts that they 
won’t be able to quit as part of quit planning. Session 5 starts with a reflection on the past week’s successes and 
difficulties, introduces the acceptance strategy of willingness as a means of handling smoking triggers, and 
covers relapse prevention via self-compassion and re-commitment to quitting. Session 6 also starts with a 
reflection on the past week’s successes and difficulties, reviews content from previous sessions, and ends with a 
video emphasizing the importance of letting go of the need to control internal experiences like feelings, 

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sensations, and thoughts. Like SmokefreeVET, Vet Flexiquit will include links to VHA resources like the VA 
Quitline, local and national tobacco cessation resources, information about smoking cessation medications, and 
a link to the VA Crisis Line. As such, differential encouragement of non-study treatments will not be a 
confounding factor in evaluating the novel content of Vet Flexiquit. 
   
SmokefreeVET Content. The control intervention will be SmokefreeVET. This web site was designed to promote 
smoking cessation among Veterans by providing educational materials about cessation treatments, tools to cope 
with urges and relapse, how to stay motivated, and brief tips for Veterans with depression and anxiety, 
substance use disorders, HIV, and other physical and mental health problems. Content is consistent with US 
Clinical Practice Guidelines [14] for tobacco treatment, which include heterogeneous techniques most closely 
aligned with cognitive behavioral therapy [46]. Because the web site is publicly available, a local copy will be 
permitted for study purposes in order to (1) prevent changes to the site while the study is ongoing, and (2) mask 
the name of the site to prevent treatment contamination or bias. 
 
6.2 Concomitant Medication  
Individuals who report using any quit smoking treatment, including FDA-approved quit smoking medications 
(e.g., nicotine patch, nicotine gum, Zyban), during the screening phase will not be eligible to participate in the 
study. At the 1-month phone check in appointment and at the 3-month follow-up assessment, participants will 
be asked about their use of FDA-approved quit-smoking medications. Initiating use of these medications during 
the study is allowed.  
 
6.3 1- and 3-Month Follow-up Data Collection 
Participants will be invited to complete follow-up assessments at 1-month and 3-months post-randomization. All 
assessments will be administered by telephone or VA Video Connect by trained study staff. A complete schedule 
of assessments can be found in section 7.0 Subject Evaluation, but will assess smoking, adverse events, and 
concomitant treatment.  
 
At follow-up, we will make reminder calls 2-3 days before the scheduled appointment, which will take place by 
phone or VA Video Connect (VVC). Following our data collection protocol used in previous trials, we will collect 
email, phone number, mailing address, and contact information on at least two collateral contacts. These 
methods yielded an 85% follow-up rate in our other studies of digital health interventions for smoking cessation. 
If completion rates are substantially lower after the first 20 participants have been contacted for follow-up, we 
will consider adding postcards containing only the two primary outcome questions to the multimodal survey 
protocol, following the mailing of the full survey. 
 
6.4 Participant compensation. 
Participants will receive an incentive of a $15 gift card for completing the briefer, 1-month visit and a $25 gift 
card for the baseline and 3-month follow-up visit. 
 
 

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7.0 
SUBJECT EVALUATION 
 
7.1 Data Collection Overview 
Table 1. Schedule of assessments for pilot trial 
Measure 
 
Screening 
(phone) 
 
Baseline 
(person) 
 
1-month 
follow-up 
(phone) 
 
3-month 
follow-up 
(Phone or 
VA Video 
Connect)  
Primary Purpose 
Eligibility criteria (~11 items) 
X 
Eligibility 
Demographics (~10 items) 
X 
Eligibility, sample 
description 
FTND (6 items) 
X 
Sample description 
Contemplation Ladder (1 item) 
X 
X 
X 
Sample description, 
stratification, efficacy 
Outside tobacco treatment use (~2 items) 
X 
X 
Acceptability, efficacy 
Treatment satisfaction (~8 items) 
X 
Acceptability 
Tobacco/Nicotine use (~12 items) 
X 
X 
X 
Efficacy 
Avoidance and Inflexibility Scale (27 items) 
X 
X 
Mechanism of change 
Saliva Cotinine 
 
X 
Efficacy 
Total number of items 
11 items 
57 items 
15 items 
59 items 
Estimated duration 
 
5-10 min 
25-30 min 
10 min 
25-30 min 

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7.1.1 
Assessments/On-Study Clinical Evaluations. A complete schedule of assessments is provided in Table 1. 
Eligibility, sample description, and stratification variables: Demographics assessed at baseline will include age, 
gender, education, employment, income, number of dependents, and marital status. The baseline survey will 
also assess smoking and quitting history for purposes of sample description. The 6-item Fagerström Test for 
Nicotine Dependence (FTND) [40] will be used to assess degree of physical dependence on nicotine and the 1-
item Contemplation Ladder [39] will be used to assess readiness to quit smoking. 
Acceptability will be assessed using measures of treatment utilization and satisfaction. The primary treatment 
utilization outcome will be number of log-ins to the assigned web site, with a secondary outcome of time from 
first to last use. Consistent with our prior studies, satisfaction will be assessed with 8 items on the 3-month 
outcome survey, covering both overall satisfaction and satisfaction with specific program components. 
Specifically, the satisfaction survey contains forced-choice response items assessing overall satisfaction, whether 
participants would recommend the program to a friend, and satisfaction with the program’s content, 
organization, and ease of use. Open-ended questions will inquire about what participants liked most and least 
about their assigned program. Acceptability measures will be administered last to prevent unblinding of 
intervention group assignment until the end.  
Efficacy for smoking cessation will be assessed as the 7-day point prevalence abstinence at 3-months post-
randomization (“Have you smoked at all, even a puff, in the last 7 days?”), biochemically confirmed by saliva 
cotinine < 10 ng/mL on a NicAlert test strip, Secondary efficacy endpoints include: (1) cotinine-confirmed 30-day 
point prevalence abstinence at 3-months post-randomization, (2) self-reported 7-day PPA from any nicotine or 
tobacco products other than FDA-approved cessation medications, and (3) increase in readiness to quit on the 
Contemplation Ladder. Use of all nicotine and tobacco products will be measured at baseline and each follow-
up. For all endpoints involving biochemical verification, abstinence from smoking will limited to self-report only 
participants who are using other sources of nicotine (either therapeutic or non-therapeutic), as saliva cotinine 
testing cannot distinguish between smoked tobacco and other sources of nicotine. Saliva cotinine test strips will 
be sent by mail to Veterans a few days ahead of their 3-month follow-up visit via telephone or VA Video Connect 
(VVC). Veterans will be instructed on how to use the test strip and how to read it, and will report the results to 
study staff over telephone or VVC. Veterans can then throw away the test strip after it has been used. 
Efficacy for impacting ACT’s theory-based mechanism of change will be assessed using the 27-item Avoidance 
and Inflexibility Scale (AIS) [43] at baseline and 3-month follow-up to measure changes in acceptance of smoking 
triggers. 
 
Other measures. Use of other behavioral and pharmacological interventions for tobacco cessation will be 
assessed at each follow-up point. 
 
7.2  
Enrollment Procedures. 
 
At the beginning of the first telephone visit, participants will be provided with detailed information about the 
study, and verbal consent will be obtained following the guidelines of the Bedford VA Medical Center 
Institutional Review Board (details below). Following informed consent, participants will complete study 
procedures as outlined in the research plan. Potential subjects who screen ineligible to participate will be 
provided with information about other resources to help them quit smoking. 
 
Our methods allow for remote study visits (phone/VA Video Connect) in light of the COVID-19 pandemic. It is 
not practicable to obtain written informed consent in a timely manner and asking people who may be self-
quarantining to mail back a signed consent form may pose risk to the participants. Therefore, we will be 
implementing a verbal consent process. We will review an information sheet about the study and ask if they 
have any questions. We will assure the privacy of participants by asking them to use a private space, rather than 

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a shared office or common area, to speak with us. The information sheet will explain in simple terms the risks 
and benefits to the patient. The information sheet will contain a statement that the consent is freely given, that 
the patient is aware of the risks and benefits of entering the study, and that the patient is free to withdraw from 
the study at any time. Consent will be obtained after a thorough explanation of the study by the PI or other 
study personnel (e.g., research assistant, postdoctoral fellow), and an opportunity for the participant to ask 
questions about the study. This discussion will take place under conditions in which the participant has adequate 
time to consider the benefits and risks associated with his/her participation in the study. 
 
Only participants capable of giving informed consent will be admitted into the study.  Informed consent will be 
obtained by trained and highly qualified research personnel. The research staff member that conducts the 
informed consent process will ask each participant to verify that the information in the consent form is 
understood.  The staff member will review understanding of the consent form, including information pertinent 
to study participation. During the informed consent process, we will assess whether the Veteran is competent to 
provide informed consent. We will determine whether the Veteran is oriented to time, place, and person. We 
will ask questions to understand whether the Veteran understands the basics about what the study protocol 
involves. We will assess whether the consequences of participating in the study are understood. We will also 
assess whether the Veteran is able to clearly and voluntarily express his or her preference for participating in the 
study. If the Veteran is not able to do these things, we will determine that the Veteran is not competent to 
provide informed consent and we will end the informed consent process. Only once all questions have been 
answered and the participant understands the purpose of the study and study procedures will the participant be 
asked for verbal consent. 
 
It will be the responsibility of the site PI (Dr. Kelly) to assure that informed consent is obtained from each 
participant prior to the performance of any protocol procedures and in accordance with current state and 
federal regulations. 
 
8.0 
SUBJECT DISCONTINUATION OF ACTIVE TREATMENT 
 
Participants can choose to discontinue their participation in this study at any time for any reason.  
 
9.0 
CONCOMITANT MEDICATIONS  
 
Individuals who report using any other quit smoking treatment, including FDA-approved quit smoking 
medications (e.g., nicotine patch, nicotine gum, Zyban), during the screening phase will not be eligible to 
participate in the pilot study. At the 1-month telephone check in and during the 3-month follow-up assessment, 
participants will be asked about their use of FDA-approved quit-smoking medications. Initiating use of these 
medications during the study is allowed. 
 
10.0 ADVERSE EVENTS 
VERSE EVENTS 
This is a low-risk study with no intervention agent/drug. Because this is a smoking cessation intervention, some 
participants may quit smoking cigarettes and may experience the physical and psychological consequences of 
smoking abstinence, such as nicotine withdrawal symptoms. As part of the informed consent procedures, 
participants will be informed about potential nicotine withdrawal symptoms and effects of abstinence. The 
intervention provides strategies designed to cope more effectively with symptoms of nicotine withdrawal. 
Finally, participants will be given information on pharmacotherapy for smoking cessation (e.g., nicotine patch) 
and how to obtain these medications. Any adverse events detected during this study will be recorded in the 
Adverse Event Summary Form and will be reported as follows.  

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Participants who report feeling upset as a result of responding to study assessment items will be given the 
option to speak with the site PI for the pilot trial. Dr. Kelly is a clinical psychologist. The PIs will consult as needed 
to address any adverse events that are reported by participants.  
Dr. Kelly will follow VA IRB requirements for reporting of Adverse Events.  
10.1.1 Unexpected Adverse events. 
In general, unexpected events (UEs) include any event, adverse or otherwise, that was not described as part of 
the study risks. An adverse event (AE) is any unexpected medical or psychiatric occurrence in a patient or clinical 
investigation subject administered an intervention, which does not necessarily have a causal relationship with 
the treatment. This includes any clinical or laboratory change that does not commonly occur in that subject and 
is considered clinically significant. All observed or volunteered AEs regardless of treatment group or suspected 
causal relationship to the study treatment will be recorded throughout the study and reported to the PIs. The 
PIs will collaboratively determine whether there is a causal relationship between the study treatment and AEs. 
Withdrawal from the study as a result of an AE or of therapeutic measures taken to treat an AE shall be at the 
discretion of the PIs. 
Serious Adverse Event. FDA 21CFR312.32 defines a serious adverse event (SAE) as any adverse experience that 
results in any of the following outcomes: death; a life threatening adverse drug experience; inpatient 
hospitalization or prolongation of existing hospitalization; a persistent or significant disability/incapacity; or a 
congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious adverse experiences when, based on appropriate judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes in this definition. The judgment of whether a particular AE meets the above criteria for an SAE 
shall be at the discretion of the PIs. It will be the responsibility of the site PI to report all SAEs and/or make 
referrals for appropriate care.  
 
10.2 Monitoring and Recording Adverse Events 
Adverse events will be monitored during the 1-month phone check in appointment and at the 3-month follow 
up, in person study visit.  
 
10.3 Grading Adverse Event Severity 
All AEs will be graded in severity according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
Version 5.0. If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: Grade 1 
(mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or Grade 5 (fatal) to describe the 
maximum intensity of the adverse event.  
 
10.4 Adverse Event Recording Period 
The PIs will be notified within 24 hours by the VA study coordinator after learning of any adverse events or of 
any early terminations due to an adverse event. 
All adverse events will be recorded and reported to the VA IRB per the VA institutional guidelines. 
 
10.5 Adverse Event Reporting Requirements  
A summary of the investigation including all adverse events and how they were handled, enrollment, drop-outs 
and reason for discontinuation and any protocol modifications will be provided to the VA IRB and to the Fred 
Hutchinson Cancer on an annual basis. 
Annual Reports will contain:  
a. The number of adverse events and an explanation of how each event was handled  
b. The number of complaints and how each complaint was handled  
c. The number of subject withdrawals and an explanation of why the subject withdrew or was 
withdrawn  

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d. The number of protocol deviations and how each was handled  
Any serious and unexpected event may prompt changes in the study protocol. Any such change will be approved 
by the VA IRB before implementation. 
10.5.1 Reporting to Sponsor 
Dr. Heffner’s study team will report all SAEs to the funding agency within 72 hours of their discovery. 
10.5.2 Reporting to IRB 
The investigators or designee must report events to the FHCRC and to the VA IRB in accordance with the policies 
of the local IRB. The site PI (Dr Kelly) will be responsible for making SAE reports to the VA IRB and to Fred 
Hutchinson Cancer Research Center study staff.  
 
 
11.0 DATA AND SAFETY MONITORING PLAN 
 
Institutional support of trial monitoring will be in accordance with the Fred Hutch/University of Washington 
Cancer Consortium Institutional Data and Safety Monitoring Plan. 
 
Given that this is a low-risk, pilot trial of two behavioral interventions for smoking cessation, monitoring of 
participant safety and data quality will be overseen jointly by the PIs, who will have bi-monthly conference calls 
to discuss study progress, including recruitment and retention, adverse events, and protocol adherence. 
 
12.0 DATA MANAGEMENT/CONFIDENTIALITY 
 
The investigator will ensure that data collected conform to all established guidelines. Each subject is assigned a 
unique subject number to protect subject confidentiality. Only VA IRB-approved project staff will have access to 
study data. All data will be maintained on a secure-access drive in permission-restricted folders only accessible 
to VA project staff. All workstations and servers are physically secured in locked offices, reside behind the VA 
firewall, and fully participate in Windows NT security. The data study folder will be further safe-guarded against 
unauthorized access by network user login authentication controls. 
In no case will patient identifiers or data be provided to any person or entity outside the VA IRB-approved 
project team. Protected health information will not be disclosed, copied, transmitted by email, or transmitted in 
total or in part to anyone not connected with the approved protocol and not approved by the VA IRB. We will 
limit our acquisition of identifiable information to the minimum amount of information necessary to link subject 
data, obtain contact information for recruitment of subjects, and collect pertinent data necessary to complete 
the study aims.  
Any data included in manuscripts or publications stemming from this study will be presented as aggregate data 
only, and in a way that no individual could be identified.  At the end of the study, after all manuscripts are 
published, all identifiable files and crosswalks will be destroyed in accordance with the VA IRB policy. Electronic 
media used to store all data will be cleaned or destroyed so the data is not retrievable. As a result of these 
measures, we do not expect any invasion of privacy or breach of confidentiality. 
 
When any study personnel are no longer a part of the research team, the PI will remove that person’s access to 
all study data and notify the VA Information Security Officer of such action. 
 
Datatope will host the intervention websites behind Fred Hutch firewall. Datatope will have access to participant 
first name, email address, mobile phone number for delivering the website intervention and the accompanying 
text messages. All of the text communication with study participants will occur over Secure Sockets Layer (SSL) 

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and no information or phone number will be shared by anyone other than VA IRB approved study staff. 
Datatope will be randomizing participants to one of two websites and will have access to stratification variables 
needed for the randomization.  
 
Both Vet FlexiQuit and a copy of SmokefreeVET will be hosted internally by FHCRC so that we can collect 
website utilization data for all participants. Paper research files will be kept at the Bedford VAMC in a locked 
cabinet where data will be encoded with ID numbers and on a secure VA SharePoint site that will be used 
solely for this study. IDs will be unrelated to any identifying information. Data will be checked for 
inconsistencies, omissions, and errors. The research assistant will receive training in data management and 
confidentiality procedures and will be responsible for data entry and management. 
 
13.0 STATISTICAL CONSIDERATIONS 
13.1 Study Design  
Pilot randomized controlled trial with two intervention arms. 
13.2 Primary/Secondary Endpoints/Hypotheses and Analytical Methods 
Although we do not expect to find statistically significant differences between treatments due to the 
underpowered feasibility trial design, we will nonetheless conduct inferential analyses in addition to 
determining effect size estimates as part of our efforts to characterize the signal for acceptability and efficacy of 
Vet Flexiquit. To evaluate Sex as a Biological Variable, we will descriptively examine results broken down by sex 
to determine potential relationships between sex and outcomes that could be explored in future work. 
 
Analyses will be conducted as follows: 
Aim 1. Compare the relative acceptability of Vet Flexiquit vs. SmokefreeVET among socioeconomically 
disadvantaged US Veterans, as indicated by treatment satisfaction and objective measures of web site 
utilization. Satisfaction ratings with Flexiquit components of virtual coaches, gamification, and interactive ACT 
exercises will be presented descriptively. Treatment satisfaction items are reported on a Likert-type scale, with 
response choices ranging from “not at all satisfied” to “very satisfied”.  We will dichotomize values at a 
threshold of “somewhat satisfied” or higher. We will test for differences between arms using a logistic 
regression model with adjustment for the stratification variable, baseline readiness to quit (high vs. low) (see 
Section 13.4), as well as adjustment for any baseline variables that differ between study arms and are associated 
with the outcome (i.e., potential confounders).  To compare treatment effects on the count outcome number of 
logins, we will use negative binomial regression with adjustment for the stratification variable, baseline 
readiness to quit (high vs. low), as well as adjustment for any baseline variables that differ between study arms 
and are associated with the outcome (i.e., potential confounders). We will use the same method to compare 
treatment groups on the secondary acceptability outcome of duration of site usage (number of days elapsed 
from first to last use). Adjustment of analysis models for the stratification variable ensures that the data analysis 
is aligned with the study design. 
 
Aim 2. Preliminarily evaluate the effects of Vet Flexiquit vs. SmokefreeVET on quit attempts and abstinence rates 
as well as readiness to quit and acceptance of smoking triggers—ACT’s theory-based mechanism of change. 
Binary endpoints of abstinence include: (1) both cotinine-confirmed and self-reported abstinence from smoking 
in the 7 days prior to the 3-month follow-up, (2) both cotinine-confirmed and self-reported abstinence from 
smoking in the 30 days prior to the 3-month follow-up, and (3) self-reported abstinence from all nicotine and 
tobacco products (except nicotine replacement therapy) in the 7 days prior to the 3-month follow-up. To 
compare each of these binary endpoints of smoking abstinence between arms, we will use a logistic regression 
model with adjustment for the stratification variable, baseline readiness to quit (high vs. low), as well as 
adjustment for any baseline variables that differ between study arms and are associated with the outcome (i.e., 
potential confounders). To compare the count outcome number of quit attempts between arms, we will use a 

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negative binomial model with adjustment for the stratification variable, baseline readiness to quit (high vs. low), 
as well as adjustment for any baseline variables that differ between study arms and are associated with the 
outcome (i.e., potential confounders). Change score endpoints include change in AIS scores and change in 
Contemplation Ladders scores. To compare each of these endpoints between study arms, we will calculate 
change score as follow-up minus baseline score and use a linear regression model with adjustment for the 
baseline value of the measure of interest and for the stratification variable, baseline readiness to quit (high vs. 
low), as well as adjustment for any baseline variables that differ between study arms and are associated with 
the outcome (i.e., potential confounders). 
 
Missing data: Consistent with the Russell standard for smoking cessation trials, participants with missing 
smoking data will be considered non-abstinent [48] in the primary analysis. As a sensitivity analysis, we will also 
report abstinence rates using multiple imputation and complete case analyses. Treatment acceptability and 
mechanism of change (i.e., AIS scores) will be analyzed using complete case analysis, as there is no reasonable 
method of imputing these data. 
13.3 Sample Size and Power 
 
Sample Size: We plan to accrue a total of 50 participants in the pilot trial for a balanced design. A sample size of 
25 per arm is consistent with the NIDA Stage Model of behavioral treatment development, which suggests that 
pilot trials should include approximately 15-30 participants per arm in order to test intervention feasibility [33 
 
Power: As a pilot treatment development project, this study is not designed for power to detect statistically 
significant differences by treatment group. However, we plan to compare the outcomes of the two interventions 
to obtain a preliminary estimate of effect size. We will use these pilot data to optimize the treatment and study 
design and prepare for a rigorous test of the efficacy of Vet Flexiquit in a subsequent R01. We plan to accrue a 
total of 50 patients in the pilot trial for a balanced design.  
13.4 Randomization 
Eligible participants will be randomized via a web-based system at the baseline  visit using an automated 
algorithm. A permuted block design with random blocks of size 2 and 4 will be used to balance randomization on 
the stratification variable: high (>5) or low (5 or less) readiness to quit on the Contemplation Ladder [39]. 
Participants will receive an email with a link to their assigned web site. Investigators and participants will be 
blinded to both allocation sequence and random intervention assignment.  This same procedure has been used 
in 3 prior Fred Hutch studies of technology-delivered interventions for smoking cessation. 
 
13.5 Ethnic and Gender Distribution Chart 
Projected Target Accrual 
ETHNIC AND GENDER DISTRIBUTION CHART 
Planned 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American 
Indian/ Alaska 
Native 
1 
0 
0 
0 
1 
Asian 
0 
3 
0 
0 
3 
Native Hawaiian or 
Other Pacific 
Islander 
1 
0 
0 
0 
1 

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21 
 
 
Black or 
African 
American 
3 
3 
1 
0 
7 
White 
5 
29 
1 
2 
37 
More than One 
Race 
1 
0 
0 
0 
1 
Total 
11 
35 
2 
2 
50 
 
 
14.0 INVESTIGATOR OBLIGATIONS 
 
The PI is responsible for the conduct of the clinical trial at the site and is responsible for personally overseeing 
the treatment of all study subjects. The PI must assure that all study site personnel, including sub-Investigators 
and other study staff members, adhere to the study protocol and to all applicable regulations and guidelines 
regarding clinical trials both during and after study completion. 
 
All subjects are informed of the nature of the program, its possible hazards, and their right to withdraw at any 
time, and each subject signs a form indicating their consent to participate prior to receiving any study-related 
procedures. 
 
15.0 REFERENCES 
 
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Bridgette EG, Shanta RD, Angela T, Ralph SC, Terry FP, Centers for Disease C, et al. Cigarette 
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