An mHealth Mood Management Tool to Improve Population-Level Cessation
Phase: PHASE1
Conditions: Cigarette Smoking-Related Carcinoma
Sponsor: Fred Hutchinson Cancer Center

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NCT04525222 
An mHealth Mood Management Tool (Actify!) to Improve  
Population-level Cessation 
 
 

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FRED HUTCHINSON CANCER CENTER 
Current version: 6/13/2022 
 
Version 1 
6/11/2020 
Version 2 
10/14/2021 
Version 3 
1/25/2022 
Version 4 
6/13/2022 
 
 
Title of Protocol: 
An mHealth mood management tool to improve population-level cessation 
 
 
Investigators List: 
Jaimee Heffner, PhD 
Associate Member, FHCRC 
(206) 667-7314 
Edit Serfozo 
Project Manager, FHCRC  
(206) 667-2428 
Biostatistician: 
Kelsey Baker 
Cancer Center Biostatistical Shared Resource 
(206) 667-6655 
 
SPONSOR: National Institute on Drug Abuse, Grant Number: 1R34DA050967 
 
 

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PROTOCOL SYNOPSIS 
 
Protocol Title 
An mHealth mood management tool to improve population-level cessation 
Protocol Number 
 
Protocol Sponsor 
National Institute on Drug Abuse 
Trial Phase 
Phase 1 
Trial Type 
Pilot RCT 2 arm 
Clinical Indication 
Smoking cessation 
Study Objectives 
Conduct a pilot, randomized controlled trial (n=240) to test the 
primary outcome of treatment acceptability and secondary 
outcomes of efficacy and mechanism of change at 8-week follow-
up for two smartphone applications for smoking cessation: the 
novel Actify app, which integrates Behavioral Activation 
Treatment for Depression (BAT-D) with US Clinical Practice 
Guidelines (USCPG) vs. the National Cancer Institute’s QuitGuide 
app, which is based on USCPG. Specifically, we will: 
a) compare the treatment groups on user satisfaction and 
app utilization (treatment acceptability) 
b) preliminarily compare the effects of the interventions on 
30-day point prevalence smoking abstinence (efficacy) and 
behavioral activation (mechanism of change)c) determine 
whether there is evidence of differential efficacy in smokers 
with vs. without pre-quit depressive symptoms 
Study Design 
2-arm randomized controlled pilot trial with 1:1 parallel assignment 
Population 
Adult smokers with and without depressive symptoms 
Primary Endpoints 
Treatment acceptability: 
• 
Satisfaction (user satisfaction ratings of the assigned app at 8 weeks 
post-randomization)  
• 
Utilization (total number of log-ins to the assigned app at 8 weeks 
post-randomization) 
Secondary Endpoints 
Treatment efficacy (e.g., smoking abstinence), changes in theory-based 
mechanisms of change. 
 
Smoking abstinence outcomes:  
• 
Primary: Self-reported 30-day point prevalence abstinence (PPA) 
from smoking at 8 weeks post-randomization 
• 
Secondary: Self-reported 30-day PPA from smoking at 6 months 
post-randomization; Biochemically-confirmed 30-day PPA from 
smoking at 8 weeks and 6 months post-randomization; Self-
reported and biochemically confirmed 7-day PPA from smoking at 8 
weeks and 6 months post-randomization; Self-reported and 
biochemically confirmed 30-day PPA from cigarettes and other 
non-medicinal nicotine/tobacco products at 8 weeks and 6 months, 
including e-cigarettes 
 
 
 

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Mechanisms of change outcomes:  
• 
Change in behavioral activation from baseline to 8 weeks post-
randomization 
• 
Change in depressive symptoms from baseline to 8 weeks post-
randomization 
Type of control 
Standard-care smoking cessation app (QuitGuide) 
Treatment Groups  
2 arm; Actify vs QuitGuide 
Treatment Schedule 
The treatment period is 8 weeks. Participants will be encouraged to use 
their assigned app as desired during that time.  
Number of trial subjects 
N=240 
Estimated duration of 
trial 
21 months 
Duration of Participation 
6 months 
 
 
 
 

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ABBREVIATIONS 
 
BAT-D 
Behavioral activation therapy for depression 
PPA 
Point Prevalence Abstinence 
USCPG 
US Clinical Practice Guidelines 
 
 

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Table of Contents 
1.0 
GENERAL INFORMATION .................................................................................................................................... 9 
1.1 
Protocol Title: An mHealth mood management tool to improve population-level cessation ............... 9 
1.2 
Sponsor Information: National Institute on Drug Abuse, Grant Number: 1R34DA050967 ................... 9 
1.3 
Investigator Information: Jaimee Heffner, PhD, (206) 667-7314 .......................................................... 9 
1.4 
Contractors and Consultants for the Study (if applicable):.................................................................... 9 
2.0 
INTRODUCTION TO THE PROTOCOL ................................................................................................................. 10 
2.1 
Introduction ......................................................................................................................................... 10 
2.2 
Clinical Data to Date ............................................................................................................................ 13 
2.2.3. Preliminary studies of mHealth apps for smoking cessation. ..................................................................... 16 
2.3 
Risks/Benefits ...................................................................................................................................... 16 
3.0 
PRE-TRIAL INTERVENTION USABILITY TESTING ................................................................................................. 17 
3.1 
Objectives: ........................................................................................................................................... 17 
3.2 
Study Population: ................................................................................................................................ 17 
3.3 
Study Design: ....................................................................................................................................... 17 
3.4 
Estimated Accrual: ............................................................................................................................... 18 
3.5 
Eligibility: .............................................................................................................................................. 18 
3.6 
Registration .......................................................................................................................................... 18 
3.7 
Usability Testing Overview .................................................................................................................. 18 
3.8 
Participant Compensation ................................................................................................................... 19 
3.9 
Enrollment Procedures ........................................................................................................................ 19 
3.10 
Assessments/Evaluations .................................................................................................................... 20 
3.11 
Analytical methods .............................................................................................................................. 20 
3.12 
Objective .............................................................................................................................................. 20 
4.0 
OVERVIEW OF CLINICAL TRIAL .......................................................................................................................... 21 
4.1 
Study Objectives .................................................................................................................................. 21 
4.2 
Study Population: ................................................................................................................................ 21 
4.3 
Study Design ........................................................................................................................................ 21 
4.4 
Estimated Accrual: ............................................................................................................................... 22 
4.5 
Name of Sponsor/Funding Source: ...................................................................................................... 22 
5.0 
SUBJECT ELIGIBLITY ........................................................................................................................................... 22 
5.1 
Inclusion Criteria .................................................................................................................................. 22 
5.2 
Exclusion Criteria ................................................................................................................................. 23 
6.0 
SUBJECT REGISTRATION .................................................................................................................................... 23 
7.0 
TREATMENT PLAN ............................................................................................................................................. 23 
7.1 
Treatment Plan Overview .................................................................................................................... 23 
7.2 
Description of the interventions .......................................................................................................... 24 

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7.3 
Concomitant Medication ..................................................................................................................... 25 
7.4 
2 and 6-Month Follow-up Data Collection ........................................................................................... 25 
7.5 
Participant Compensation ................................................................................................................... 25 
8.0 
SUBJECT EVALUATION ...................................................................................................................................... 26 
8.1 
Data Collection Overview .................................................................................................................... 26 
8.2 
Enrollment Procedures. ....................................................................................................................... 26 
8.3 
Assessments/On-Study Clinical Evaluations ........................................................................................ 27 
9.0 
SUBJECT DISCONTINUATION OF ACTIVE TREATMENT ...................................................................................... 28 
10.0 
CONCOMITANT MEDICATIONS ......................................................................................................................... 29 
11.0 
ADVERSE EVENTS .............................................................................................................................................. 29 
11.1 
Adverse Events .................................................................................................................................... 29 
11.2 
Collection and reporting of AEs and SAEs ............................................................................................ 29 
12.0 
DATA AND SAFETY MONITORING PLAN ............................................................................................................ 30 
13.0 
DATA MANAGEMENT/CONFIDENTIALITY ......................................................................................................... 30 
14.0 
STATISTICAL CONSIDERATIONS ......................................................................................................................... 31 
14.1 
Study Design ........................................................................................................................................ 31 
 
Primary/Secondary Endpoints/Hypotheses and Analytical Methods .................................................. 31 
14.2 
31 
14.3 
Sample Size and Power ........................................................................................................................ 33 
14.4 
Randomization ..................................................................................................................................... 33 
14.5 
Ethnic and Gender Distribution Chart: Projected Target Accrual ........................................................ 33 
15.0 
INVESTIGATOR OBLIGATIONS ........................................................................................................................... 34 
16.0 
REFERENCES ...................................................................................................................................................... 34 
17.0 
APPENDICES ...................................................................................................................................................... 42 
Appendix A: .................................................................................................................................................................... 43 
Data & Safety Monitoring Plan ...................................................................................................................................... 43 
DSMP Contents .............................................................................................................................................................. 44 
1 
Summary of the protocol .................................................................................................................................. 45 
1.1 
Brief description of the protocol ......................................................................................................... 45 
1.2 
Primary and secondary outcome measures ........................................................................................ 45 
1.3 
Inclusion/exclusion criteria .................................................................................................................. 45 
1.4 
Power calculation and sample size ...................................................................................................... 46 
2 
Trial management ............................................................................................................................................. 47 
2.1 
List of participating enrolling clinics or data collection centers .......................................................... 47 
2.2 
Projected timetable for the pilot RCT .................................................................................................. 47 
2.3 
Target population distribution ............................................................................................................. 47 
3 
Data management and analysis ........................................................................................................................ 48 

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3.1 
Data acquisition and transmission ....................................................................................................... 48 
3.2 
Data entry methods ............................................................................................................................. 49 
3.3 
Data analysis plan ................................................................................................................................ 49 
4 
Quality assurance plan ...................................................................................................................................... 50 
4.1 
Procedures in place to ensure the validity and integrity of the data .................................................. 50 
4.2 
Procedures to guarantee the accuracy and completeness of the data ............................................... 50 
5 
Regulatory issues .............................................................................................................................................. 51 
5.1 
Reporting mechanisms of AEs/SAEs to the IRB and NIDA ................................................................... 51 
5.2 
Reporting mechanisms of IRB actions to NIDA .................................................................................... 51 
5.3 
Report of changes or amendments to the protocol ............................................................................ 51 
5.4 
Trial stopping rules .............................................................................................................................. 51 
5.5 
Disclosure of any conflict of interest ................................................................................................... 51 
6 
Trial safety ........................................................................................................................................................ 52 
6.1 
Potential risks and benefits for participants ........................................................................................ 52 
6.2 
Collection and reporting of AEs and SAEs ............................................................................................ 53 
6.3 
Management of SAEs or other study risks ........................................................................................... 54 
7 
Trial efficacy ...................................................................................................................................................... 55 
7.1 
Plans for interim analysis of efficacy data ........................................................................................... 55 
7.2 
Plans for final analysis .......................................................................................................................... 55 
8 
DSM plan administration .................................................................................................................................. 56 
8.1 
Responsibility for data and safety monitoring ..................................................................................... 56 
8.2 
Frequency of DSM reviews .................................................................................................................. 56 
8.3 
Content of DSM report ........................................................................................................................ 56 
9 
DSM Board Plan ................................................................................................................................................ 57 
Appendix B: Fraud Prevention Protocol ......................................................................................................................... 59 
 
 
 
 

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1.0 
GENERAL INFORMATION 
 
This document is a clinical research protocol for a randomized, controlled 2-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 Stage Model for 
Behavioral Intervention Development. We will use these pilot data to optimize the treatment and study 
design and to prepare for a rigorous test of the efficacy of Actify in a subsequent R01. 
 
Rationale. 
Cigarettes are the most deadly drug in the US. The number of deaths annually from cigarette 
smoking (~480,000) is over three times greater than the number of alcohol-related deaths 
(~88,000) and drug overdoses per year (~52,000) combined. Helping current smokers to quit is a 
public health priority. There are numerous forms of assistance available, yet they all have 
suboptimal outcomes for a large group of smokers: those who experience depressive symptoms 
before or during a quit attempt. Prior to making a quit attempt, 40- 55% of smokers report 
depressive symptoms. Because depressed mood and other forms of negative affect are also 
common nicotine withdrawal symptoms, mood management strategies have the potential to 
benefit a majority of treatment-seeking smokers. Indeed, our pilot data suggest that 83% of 
smokers interested in using a cessation app endorse mood difficulties as a barrier to quitting. 
Behavioral activation therapy for depression (BAT-D) is a novel addition to standard smoking 
cessation interventions that can address depressive symptoms as a risk factor for treatment 
failure. Scientific premise: Two pilot studies and one fully-powered randomized, controlled trial 
support the efficacy of BA-based treatments for smoking cessation delivered in face-to-face 
format. Delivery through an mHealth app would make this treatment widely disseminable as a 
standalone public health intervention. There are currently no BA- based mHealth treatments for 
smoking cessation with established efficacy. 
 
More detailed rationale can be found below in section 2.0.  
 
Overview of Study Design.  
This project involves conducting a pilot, randomized controlled trial (n=240) to test the primary outcome 
of treatment acceptability and secondary outcomes of efficacy and mechanism of change for the 
behavioral activation app (Actify) vs. the USCPG-based app for smoking cessation (QuitGuide). We will 
test the interventions using an 8-week treatment period, and, consistent with the evaluation period in 
our previous cessation app pilot study, our primary outcomes will be assessed at the 8-week end-of-
treatment mark. We will also collect 6-month follow-up data to assess long-term outcomes. 
 
1.1 
Protocol Title: An mHealth mood management tool to improve population-level cessation 
1.2 
Sponsor Information: National Institute on Drug Abuse, Grant Number: 1R34DA050967 
1.3 
Investigator Information: Jaimee Heffner, PhD, (206) 667-7314 
1.4 
Contractors and Consultants for the Study (if applicable):  
Jennifer McClure, PhD (Kaiser Permanente, Seattle);  
Stacey Daughters, PhD (University of North Carolina at Chapel Hill);  
Elisardo Becoňa Iglesias, PhD (University of Santiago de Compostela, Spain) 
 

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2.0 
INTRODUCTION TO THE PROTOCOL 
 
2.1 Introduction 
Cigarette smoking remains the leading preventable cause of death in the United States. The number of 
deaths annually from cigarette smoking (~480,000) [1] is over three times greater than the number of 
alcohol-related deaths (~88,000) [2] and drug overdoses per year (~52,000) [3] combined. Only 6% of 
smokers each year are able to successfully quit [4]. Novel interventions are needed to target the key 
factors that maintain smoking.  
 
2.1.1 Problem: Depression is prevalent and interferes with smoking cessation. Mood management 
treatments can help, but effective options accessible at the population level do not currently exist. 
 
2.1.1.a. Prevalence of depressive symptoms among smokers. The estimated prevalence of 
current (past 12 months) major depressive disorder among smokers is 11% [5]. Depressive symptoms 
that do not meet full criteria for a mood disorder are even more prevalent, particularly among 
treatment-seeking smokers. Among callers to a state tobacco quitline, 41% reported current depressive 
symptoms on the Patient Health Questionnaire-9 (PHQ-9) [6]: 25% met criteria for a major depressive 
episode and an additional 16% reported depressive symptoms that fell below the diagnostic threshold 
[7]. We have found similarly high rates of depression among smokers enrolled in our trials of 
technology-delivered cessation treatments. In a recent trial of web-based Acceptance and Commitment 
Therapy (ACT) for smoking cessation [8], over half (56%) of the 2637 study participants screened positive 
for depression on the Center for Epidemiological Studies Depression (CES-D) [9] scale. Approximately 
40% of participants in a pilot trial of smartphone-delivered ACT [10] screened positive for depression. 
This high prevalence of depressive disorders and symptoms observed among treatment-seeking 
smokers (i.e., 40-55%) in both clinical and research settings likely reflects the greater difficulty of 
quitting for these smokers and consequently greater need for assistance. 
 
2.1.1.b. Evidence that depressive symptoms have a negative impact on quitting is robust. 
Observational population [11, 12] and clinical studies [13] have shown that both mood disorder 
diagnoses and depressive symptoms predict a lower likelihood of long-term cessation. Quit rates for 
people with mood disorders are between 17% (for major depressive disorder) and 60% (for bipolar 
disorder) lower than for people without mood disorders [14-17]. In smoking cessation trials, depressed 
mood at the time of a quit attempt predicts failure to quit smoking [7, 18-21], as does emergence of 
depression and other forms of negative affect during the post quit period [22]. Data from our trial of 
group-delivered cessation therapy suggested that the odds of quitting are reduced by 50% among 
smokers with depressive symptoms at the time of a quit attempt, even when they receive gold-standard 
treatment combining pharmacotherapy with intensive smoking cessation counseling [23]. Furthermore, 
a majority of treatment-seeking smokers express concern about the impact of mood on their likelihood 
of quitting. Illustrating the pervasiveness of this concern among users of mHealth interventions, data 
from the first 1100 users of our SmartQuit smoking cessation app indicated that 83% of the users 
endorsed mood difficulties as an anticipated barrier to quitting [24]. A problem with the current 
standard treatment approach, as outlined in the US Clinical Practice Guidelines (USCPG) [25], is that it 
does not address depressive symptoms as a mechanism that maintains smoking. 
 
2.1.2. Solution: A readily accessible mHealth app for smoking cessation grounded in evidence-based 
behavioral activation therapy for depression (BAT-D).  

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2.1.2.a. mHealth apps for cessation are readily accessible and can be effective. Currently, 77% 
of US adults own smartphones [26], and ownership rates among smokers mirror those of the general 
population [27]. The proportion of smartphone owners using mHealth applications is steadily increasing 
[27], broadening potential reach of mHealth apps for smoking cessation. From 2012-2014, smoking 
cessation apps were downloaded to smartphones in the US over 3.2 million times [28, 29], which is 
substantially greater than enrollment in text messaging programs for smoking cessation (i.e., 140,000 
subscriptions/year [30]). In a 2014 survey, 15% of US smokers said that had previously downloaded an 
app for smoking cessation, and 43% indicated an intent to use a cessation app in the future [31]. Given 
the fast pace at which uptake of technology and technology-delivered interventions occurs, it is likely 
that these 2014 data underestimate current use of and interest in mHealth apps for smoking cessation.  
mHealth apps could make cessation treatment more accessible at the population level, 
particularly to low-income, uninsured smokers. Even at the lowest level of income ($0-$14,999/year), 
almost half (45%) of US smokers own smartphones [27], and evidence suggests that similar proportions 
of smokers across the socioeconomic spectrum use smartphone apps for smoking cessation [32]. 
Additionally, smartphone ownership is not associated with race or ethnicity either in the broader US 
population [26] or among cigarette smokers [27] and, as such, does not perpetuate racial/ethnic 
disparities in access to interventions delivered in this new modality (as opposed to healthcare settings, 
where there are racial ethnic disparities in access to care). An increasing number of Americans—
particularly racial/ethnic minorities and low-income adults—are now relying exclusively on smartphones 
for Internet access (~20% of each group) [26], meaning that traditional web-based interventions for 
smoking cessation that are not optimized for small screens or repackaged as mHealth apps will become 
virtually unusable for large segments of the population. As such, mHealth apps may have greater 
potential reach—including reach into tobacco-related health disparities groups—than both text message 
and web-based interventions as smartphones become an increasingly ubiquitous technology. 
Although a fully-powered effectiveness trial has yet to be completed, mHealth apps for smoking 
cessation have been evaluated in a number of pilot studies, demonstrating promising results for 
acceptability and quit rates as high as 45% [10, 33-38]. However, the literature base to support apps for 
smoking cessation is still emerging and currently includes only two randomized, controlled trials [10, 
34]—both of which are pilot trials with wide confidence intervals for the point estimates of cessation 
and, as expected for a pilot study, lack of a statistically significant difference between treatment groups, 
even where differences in quit rates would be clinically meaningful if replicated in a larger trial [10]. 
While the early results are promising, published pilot studies of mHealth apps for smoking cessation 
have a number of methodological limitations including lack of biochemical verification, few studies with 
active control groups, and no assessment of long-term outcome data. In the design of the proposed 
project, we address all of these methodological limitations of prior app studies. 
Although the literature on mHealth apps for smoking cessation are still in nascent stage, there is 
ample evidence from the broader literature on mHealth interventions for behavior change that apps can 
be effective for supporting improved health behaviors. Results of the most comprehensive review to 
date of mHealth interventions for health behavior change showed that the majority (17 of 23 studies 
meeting inclusion criteria) showed statistically significant effects of the mHealth app on the targeted 
health behavior [39]. 
 
2.1.2.b. BAT-D is an efficacious, theory-based treatment for depression. Content analyses of 
mHealth apps that are currently available for a variety of conditions (including over 400 for smoking 
cessation) have been repeatedly shown to adhere poorly to behavioral theory and evidence-based 
behavior change techniques [40-43]. BAT-D is based on a well-supported behavioral conceptualization of 
depression as resulting from inadequate positive reinforcement obtained from one’s environment for 
non-depressed behaviors [44, 45]. The primary goal of BAT-D is to increase engagement in positively 

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reinforcing activities consistent with one’s values. These, in turn, are expected to increase positive affect 
and to reduce negative moods and avoidance behaviors [45]. Behavioral activation (BA) is a component 
of cognitive behavioral therapy (CBT), demonstrated in a seminal dismantling study by Jacobson and 
colleagues to have similar efficacy to the full CBT package for treating depression [46]. Given that BA is 
less complex than CBT, it is more disseminable at the population level. BAT-D’s disseminability is even 
greater given that it is a briefer form of the treatment that, like BA [47], has demonstrated effectiveness 
as a treatment for depression [48, 49]. 
 
2.1.2.c. Application of BA to smoking cessation improves quit rates. Although the origins of BA 
are as a treatment for depression, this approach has particular relevance for cigarette smoking and its 
co- occurrence with depressive symptomatology. In accordance with reinforcement theory, 
maintenance of smoking as well as depressed behaviors results in part from a lack of reinforcement for 
healthy, alternative behaviors [44]. In support of the theory, preliminary outcomes from an adult 
smoking cessation trial of combined counseling and pharmacotherapy indicated that participants who 
were abstinent at the end of an eight-week treatment demonstrated an increase in the level of 
alternative, smoke-free, rewarding activities during the course of treatment and evidenced a reduction 
in depressive symptoms [50].  
Evidence to date suggests that the integration of BA principles more broadly, and BAT-D 
specifically, into standard cessation counseling can significantly improve quit rates for (1) the general 
population of smokers (of whom an estimated 40-55% will have depressive symptoms) [51], (2) smokers 
with depression [52], and, (3) smokers at high risk of either having or developing depression [53]. 
Evidence from a fully- powered, randomized, controlled trial [51] of a face-to-face, BA-based cessation 
intervention (n=110) compared with standard cessation (n=109) and a waitlist control group (n=56) for 
general population smokers (of which 40% had a history of depression treatment) provides evidence to 
support integrating BA with standard cessation treatments for improved cessation. In this trial, recently 
completed by our consultant, Dr. Becoňa and colleagues, the two active treatment groups received 8 
weeks of hour-long group counseling. At end of treatment, biochemically-confirmed quit rates were 
superior in the BA condition (64.7%) relative to the standard counseling condition (45.9%, p=.008) and 
the waitlist control condition (5.4%. p=.001). The higher quit rates in the BA condition relative to 
standard counseling persisted across the 3-month (38.2% vs. 22.9%, p=.045), 6-month (30% vs. 18.3%, 
p=.273), and 12-month follow-ups (30.0% vs. 18.3%, p=.302), albeit with some attenuation of the effect 
over time. A limitation of this study was that it was underpowered to detect smaller but still clinically 
meaningful effects (e.g., absolute difference of 12 percentage points between two behavioral 
interventions at long-term follow-up could readily be considered a meaningful difference [54]). 
In a proof-of-concept study conducted by our consultant, Dr. MacPherson, smokers with 
depressive symptoms were assigned to receive either the BAT-D-based Behavioral Activation Treatment 
for Smoking (BATS; n= 35) or standard cessation treatment (ST; n=33), and both groups received 
nicotine patches. Participants were assessed at baseline, throughout treatment, and at 4, 16, and 26-
week follow-ups for depressive symptoms and carbon-monoxide (CO)-verified 7-day point prevalence 
abstinence. At the end of treatment, BATS participants were 2.1 times more likely to be abstinent (p< 
0.05) than ST participants (17.1% vs. 9.1%). As expected, abstinence rates declined over time in both 
groups, yet there remained a significant effect of BATS treatment at the 26-week follow-up (14.3% vs. 
0.0%; p < 0.05). Participants receiving BATS also evidenced greater improvements in depressive 
symptoms across the 26-week follow-up period. 
Another pilot study [53] showed promising results of a BATS-based cessation treatment for 
smokers recently hospitalized with acute coronary syndrome (CS)—a population with a high prevalence 
of depression. Participants received either the BATS-CS intervention (n=28) or an intervention using 
standard cessation counseling content (standard of care, or SC; n=31). Results of this feasibility trial 

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indicated that BATS-CS was highly acceptable to participants and also produced greater improvements 
in positive affect, negative affect, and stress than SC at 24-week follow-up. Additionally, the effect size 
for BATS-CS on smoking cessation was promising: OR=1.27 (95% CI=0.41-3.93) for 7-day point 
prevalence abstinence at 24 weeks. The study was not powered to detect statistically significant effects, 
but cessation and mood outcomes were all in the hypothesized direction, favoring BATS-CS over SC. 
 
2.1.2.d. Evidence that BAT-D is efficacious as a treatment for non-nicotine substance use 
disorders. The first fully-powered trial of BAT-D for non-nicotine substance use disorders was published 
in 2018, adding further support for the scientific premise of the proposed study. In a large, 
methodologically rigorous trial, our consultant, Dr. Daughters, and colleagues found that the BAT-D in-
person intervention resulted in superior biochemically-verified abstinence rates at 3- (42% vs. 25%, 
OR=2.2, 95% CI=1.3-3.7), 6- (27% vs. 12%, OR=2.6, 95% CI=1.3-5.0), and 12-month (20% vs. 8%, OR=2.9, 
95% CI=1.3-6.1) follow-ups relative to a contact-matched control condition [55]. While not necessarily 
generalizable to smoking cessation, these findings suggest that BAT-D can be an effective treatment for 
substance use disorders that share common causal and maintenance factors with nicotine dependence, 
including lack of reinforcement of alternative behaviors to substance use. 
 
2.1.3. Summary of significance. Symptoms of depression, which are common among smokers, decrease 
the odds of quitting by 50%. This study addresses the important public health problem of low quit rates 
and resultant tobacco-related health disparities among smokers experiencing mood dysregulation. The 
proposed project builds off of a growing body of literature supporting the value of behavioral activation 
as a component of cessation counseling.  Behavioral activation is a promising treatment approach for an 
mHealth cessation intervention because: (1) it has demonstrated long-term efficacy for promoting 
abstinence from tobacco and other substance use and shown promise for smoking cessation in the face-
to-face format [52, 53, 55], (2) its rationale, principles, and components are well-suited to translation 
into an app (e.g., scheduling valued activities and tracking their completion), and, (3) it is theory-based 
[44]. A BAT-D-based treatment accessed through smartphones–where there have been steady increases 
in ownership rates among adults–represents a new opportunity for increasing the accessibility of 
evidence-based smoking cessation interventions. This work fits with NIDA Behavioral & Integrative 
Treatment research priorities: developing interventions that are designed for dissemination, guided by 
theory-based mechanisms of change, and with a focus on co-occurring psychiatric symptoms and 
disorders. At present, randomized controlled trials of BAT-D-based cessation interventions have relied 
on face-to-face treatment, which would reach only 4-6% of the 42 million smokers in the US based on 
current utilization of the traditional treatment modalities of individual and group counseling [1, 4, 56]. 
To extend the reach of this promising new intervention to the estimated 32 million smokers with 
smartphones [1, 57, 58], the vast majority of whom will not seek formal treatment, we propose to 
develop a BAT-D app for smoking cessation to provide smokers with an effective method of addressing 
depressive symptoms as a barrier to quitting. 
 
 
2.2 Clinical Data to Date 
 
2.2.1. Development of the Actify app. With the support of a pilot grant from the Fred Hutchinson 
Cancer Research Center (PI: Heffner), we developed a working prototype of a smartphone app, Actify, 
that delivers BAT-D as part of a smoking cessation intervention. The app was created following user-
centered design processes, including competitive analysis, focus groups, and usability testing of early 
and late prototypes, followed by a single-arm pilot trial. 
 

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2.2.1.a. Competitive analysis. We first reviewed depression apps currently on the market to 
generate (via personal experience) and assess (via user comments in app stores) user sentiment toward 
them in relation to their design and functionality. Such information is useful for understanding desirable 
features for a new app as well as “pain points” that a user may experience if Actify contained similar 
features. Example desirable features included a user interface that is easy to navigate, personalized, and 
with clear presentation of accessible community or national resources for assistance with depression. 
Example pain points included multi-screen data input, incoherent gamification, and unclear indication of 
progress. 
 
2.2.1.b. Focus groups. Two focus groups were conducted in October 2016 to assess potential 
users’ previous experience using depression apps (e.g., likes/dislikes); to develop user personas, the 
embodiment of a “typical” user or users, which is a common user-centered design strategy; to elicit 
ideas for valued activities in several life domains (e.g., relationships, health, leisure) that the app could 
suggest to the user; and to understand users’ associations between emotions and colors that might 
appear in the app. Participants expressed a desire for a flexible, customizable program that took into 
account the uncertainties of daily life and provided relevant mood-related suggestions, tracking of no 
more than 5-10 basic emotions, and feedback on progress. Participants described mood apps they used 
previously as “boring” and noted that addition of some humor or excitement would help keep them 
engaged, as would a light color palette that had positive, uplifting associations. Two distinct user 
personas were developed (one primary, one secondary) to guide design decisions, and lists of common 
values and valued activities were generated for inclusion in the app.  
 
2.2.1.c. Late prototype usability testing.  Based on users’ reactions to early prototypes, the 
study team decided to continue developing Prototype B, the first version of Actify. The user experience 
(UX) design team, consisting of a UX researcher and two UX design interns, developed several iterations 
of Actify features revised on the basis of early prototype testing. The revised version underwent three 
rounds of user testing between Jan 2017 and March 2017. In each round, users were given 4-5 tasks to 
complete to test their ability to navigate the major app components of onboarding, values identification, 
activity scheduling, activity tracking, calendar, progress, and resources as well as to assess user 
expectations and desires for app functionality. The programmed version of the app was completed by 
the study team’s long-time partner, 2Morrow, in July 2017. For evaluation purposes, Actify was 
developed as a native app for Apple’s iOS. 
 
2.2.1.d. Single-arm trial of a limited Actify app. Between November 2017 and June 2018 we 
conducted a single-arm pilot trial of an Actify app with functionality limited to the BAT-D component. 
Because the planned notifications and other components to support smoking cessation were not 
included in this early development phase due to budgetary constraints, participants used NCI’s 
SmokefreeTXT text messaging program alongside Actify to provide content similar to what would be 
included in the final app. Primary aims were to (1) obtain preliminary data on user engagement and 
satisfaction, and (2) evaluate effects on the target behavior of increased engagement in valued activities 
as well as smoking cessation and improved mood. To achieve these aims, we used a 6-week evaluation 
period to evaluate both engagement and short-term efficacy.  
Major inclusion criteria were: (1) age 18 or older, (2) current smoker, averaging at least 5 
cigarettes/day for the last 30 days, (3) interested in quitting smoking in the next 30 days, (4) own an 
iPhone version 5 or higher, which is necessary to run the current version of the Actify app without 
technical problems, (5) experience downloading and using one or more apps on their iPhone, (6) screens 
positive for mild to moderate current depressive symptoms (PHQ-9 score 5-19). Exclusion criteria were: 
(1) currently receiving other treatment for depression, including psychotherapy or medication, (2) 

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current use of another depression app, (3) severe depression (PHQ-9 ≥ 20) (3) current suicidal ideation 
(PHQ-9 item 9 score > 1), (4) receiving other treatment for smoking cessation, and (5) previous use of 
the SmokefreeTXT program. 
Participants were recruited from the Seattle area primarily via no-cost Craigslist ads (59% of 
sample) and paid Facebook advertisements (41% of sample). We screened 72 individuals to enroll 17 
participants in the single-arm trial, of whom 16 (94%) completed the in-person, 6-week follow-up visit 
and are included in the subsequent complete-case results. These participants were 56% men, 38% racial 
minority, and 25% Hispanic, with mean age of 36 (SD=10). There was strong engagement with the app: 
average number of logins per participant was 20 (SD=16). Average change in depression on the PHQ-9 
was a 5-point decrease from baseline (SD=6), which was a statistically significant improvement in 
symptoms (p=.009). Average change in Behavioral Activation for Depression Scale (BADS) overall scale 
scores and activation subscale scores (Bat-D’s theory-based change mechanism) were not statistically 
significant but were in the hypothesized direction: BADS total scores increased by 14 points, on average 
(SD=32; p=.09) and activation subscale scores increased by 4 points (SD=10; p=.17). The 7-day point 
prevalence abstinence rate at follow-up was 31% (5/16), and the 30-day PPA was 19% (3/16).  
Collectively, these results demonstrate (1) our ability to recruit and retain participants, (2) high 
engagement with the app, and (3) a promising signal for impact on theory-based change processes and 
cessation outcomes, which were descriptively higher for Actify than for our ACT SmartQuit app among 
the subgroup of depressed smokers (31% vs. 23% for complete-case 7-day PPA and 19% vs. 6% for 30-
day PPA at short-term follow-up) and better than published quit rates of 7% for SmokefreeTXT alone 
[60]. Engagement was also higher for Actify than SmartQuit (average of 20 logins over 6 weeks for Actify 
vs. 12 logins over 2 months for SmartQuit). Preliminary quit rates also compare favorably to the previous 
trial of face-to-face BAT-D for depressed smokers (i.e., CO-confirmed, 7-day PPA rate of 17% at end of 
treatment vs. 31% for Actify) conducted by our consultant, Dr. MacPherson [52]. These promising 
findings warrant completing development of the Actify app, modifying it to improve usability, and 
evaluating the complete product in a controlled pilot trial. 
 
2.2.2. Next steps.  
Following our extensive development work to translate BAT-D into an engaging mHealth app format, the 
next step is to complete the development of Actify by incorporating the smoking cessation content into 
the established structure of the app. After completion of this next stage of work, the fully developed 
Actify app will be ready for pilot randomized trial to obtain a preliminary estimate of its acceptability, 
efficacy, and effects on behavioral activation and depressive symptoms as the theory-based mechanisms 
of change for smoking cessation (see Figure 1 for development timeline). This plan is consistent with 
Stage Ia and Ib of the NIDA Behavioral Therapies Development Model [61] and with the aims of the 
NIDA R34 mechanism to support behavioral and integrative treatment development. 
 
Figure 1. Progress to date toward development of a complete version of the Actify app and launch of a 
pilot trial. 
 
 
 
 

OnCore # RG1121054 
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2.2.3. Preliminary studies of mHealth apps for smoking cessation. 
Our research team developed the first mHealth app for smoking cessation based on ACT—called 
SmartQuit—in 2013 (PI: Bricker, Fred Hutchinson Cancer Research Center Hartwell Innovation Fund). We 
then conducted the first RCT comparing two smartphone apps for smoking cessation—SmartQuit vs. 
NCI’s QuitGuide. Based on previously successful methods for national recruitment in our trial of web-
based ACT [62], we recruited via Facebook ads, Google ads, and a press release developed by the FHCRC 
communications department. These efforts yielded 738 participants screened, 400 eligible, 340 
consented, and 196 randomized (98 per arm). The recruitment sources were: 39% from Facebook ads, 
38% from press-release generated media, and 23% from other sources. To maximize outcome data 
survey completion, we followed a protocol that sequentially timed the administration of separate survey 
modalities until the survey was completed: first via the web, then by telephone, and then by mail. 
Participants were compensated $25 for completing the survey. The achieved outcome survey 
completion rate of 84%, much higher than the 54% typically obtained in web- based cessation trials [63-
68], provided confidence in the effectiveness of our follow-up survey methods for maximizing data 
retention. Retention did not differ between arms. SmartQuit participants had higher engagement with 
their assigned app (p <.0001) and a descriptively higher quit rate than the QuitGuide app at 2 months 
post-randomization:13% (95% CI: 6%-22%) in SmartQuit vs. 8% (95% CI: 3%-16%) in QuitGuide. 
We developed the second version of the app (SmartQuit 2.0) in 2014 (PI: Bricker, Washington 
State Life Sciences Development Fund). Using data from the trial of SmartQuit 1.0, we evaluated which 
features of the app were most used and how feature usage was associated with quitting. Based on that 
analysis [69], the app was restructured to funnel users to the features that showed the strongest 
relationships with quitting. This method yielded an 8-exercise program with a core feature that 
prompted users to track when they let an urge pass—a major focus of the ACT exercises and a strong 
correlate of quitting in the SmartQuit 1.0 trial [69]. Relative to SmartQuit 1.0, we found that SmartQuit 
2.0 had better user satisfaction (84% vs. 59%), although the estimated quit rate was similar (11% vs.13% 
achieved 30-day PPA at 2 months). 
In 2016, we completed a major redesign of SmartQuit, now called iCanQuit, which is currently 
being evaluated in a large (n=2500) RCT (PI: Bricker, R01CA192849). Development of iCanQuit 
incorporated lessons learned from building SmartQuit 1.0 and 2.0, with additional user research 
conducted to understand how to best incorporate game elements into the app. With the guidance of 
our design vendor Ayogo Health, which specializes in patient engagement in digital health interventions, 
the app now incorporates a level system and badges to increase engagement with the ACT content. 
Recently, our team developed and began pilot testing a targeted version of iCanQuit for cancer patients 
who smoke (PI: Bricker, CVS Moonshot Award). 
This preliminary work demonstrates that (1) we have acquired considerable experience 
developing apps for smoking cessation over the past six years, including formative research to 
understand user needs and desires and on methods to increase engagement (e.g., gamification), (2) our 
iterative development process has proven effective for improving user satisfaction across app versions, 
and (3) our methods for conducting nationally-recruiting mHealth trials yield strong recruitment and 
retention outcomes. 
 
2.3 Risks/Benefits 
 
Potential Risks. Participants will be told that the study may involve the following risks and/or 
discomforts: 
 
Therapeutic risks include: (1) physical and psychological consequences of smoking abstinence, 
including nicotine withdrawal, and (2) the possibility that the intervention may not help the 

OnCore # RG1121054 
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participant manage depressive symptoms and/or quit smoking. 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). 
 
Research-related risks: (1) the possibility that answering some questions may be emotionally 
upsetting, and (2) the possibility of breach of confidentiality. It is possible that some of the 
questions asked of participants may cause some emotional discomfort. For example, assessment 
of symptoms of depression may result in feelings of shame due to the stigma associated with 
mental health conditions. There is also a small risk of breach of confidentiality if participant 
data, either in electronic or hard copy form, were to be accessed by an unauthorized person. 
 
Potential Benefits of the Proposed Research to the Subjects and Others 
Subjects will be provided with information regarding potential benefits of participation in the study, 
including: 1) the possibility that the study interventions might help them to quit smoking and manage 
their depressive symptoms, 2) access to a smoking cessation smartphone application at no cost. 
 
Importance of the Knowledge to be Gained 
This study involves pilot testing of an intervention that, if found to be effective in a larger trial that 
would be informed by this pilot trial, could have an enduring, positive impact on the low quit rates 
among smokers experiencing depressive symptoms. As such, the minimal risks associated with 
participation in the proposed study are exceeded by the potential benefits of completing this research. 
 
3.0 
PRE-TRIAL INTERVENTION USABILITY TESTING 
3.1 Objectives: 
3.1.1 
Add smoking cessation content to Actify, refine app structure, and conduct a ~9-
day diary study to assess user satisfaction with the updated app and its 
components as well as program utilization (n=10). 
 
3.2 Study Population:  
We will recruit 10 adult smokers, age 18 or older with two levels of depressive symptom severity based 
on PHQ-8 score--none/minimal symptoms of depression (scores of 0-4: n=5) and mild/moderate 
symptoms of depression (scores of 5-19; n=5)--who are interested in quitting smoking. Participants will 
be recruited nationally via one or more recruitment strategies used successfully in our previous studies: 
targeted Facebook ads, Craigslist ads in states with a high prevalence of smoking or racial/ethnic 
minority residence (to achieve the target 25% racial/ethnic minority representation in the sample), 
other free methods of advertising on the Internet (e.g., Reddit, Twitter), ResearchMatch.org, and earned 
media generated by press releases from the Fred Hutch media team. 
3.3 Study Design: 
When a prototype of the complete Actify app is ready, we will conduct a diary study as a field-based 
evaluation of its usability. Usability is the extent to which an app can be easily navigated and understood 
by the user. Usability is a critical outcome of the Stage I intervention development process, as low 
usability can undermine engagement with the intervention [70] as well as its potential efficacy for 
smoking cessation [71]. 

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3.3.1 
Primary Objective: Completed development of an smartphone application for smoking 
cessation based on BAT-D. The Actify! app will be easily navigated and understood by 
the user and free from any technical difficulties. 
3.4 Estimated Accrual: 
We estimate that our recruitment efforts will lead to 120 screened, 40 eligible and 10 enrolled. We 
estimate recruitment to take 3 weeks. 
 
3.5 Eligibility: 
3.5.1 
Inclusion Criteria  
• 
age 18 or older 
• 
current smoker, averaging at least 5 cigarettes/day for the last 30 days 
• 
interested in quitting smoking in the next 30 days 
• 
experience downloading and using one or more apps on their smartphone 
• 
either screens negative (PHQ-8 score 0-4) for depression ( n=5) or screens 
positive for mild to moderate current depressive symptoms (PHQ-8 score 5-19; 
n=5) 
• 
willing and able to complete all study activities and to receive compensation by 
mail 
• 
comfortable reading and writing in English 
• 
have a mobile data plan and/or access to WiFi to support the use of the Actify 
app 
• 
reside in the US 
 
3.5.2 
Exclusion Criteria  
• 
severe depression (PHQ-8 ≥ 20) 
• 
receiving other treatment for smoking cessation 
• 
employees/family of investigator or study center 
• 
member of the same household as another participant 
• 
woman who is pregnant or breastfeeding, or planning to become pregnant 
• 
having a Google voice number as their primary phone number (due to 
association with fraudulent study entry attempts in our previous work) 
• 
currently incarcerated 
• 
participated in earlier studies to develop the Actify app  
3.6 Registration 
Potential participants will be recruited via Craigslist, Facebook, Twitter, and Reddit. Initial screening for 
participation will be conducted via web-based survey in MS Forms. Individuals deemed eligible will be 
contacted by phone to ensure eligibility and discuss study procedures; individuals remaining eligible and 
interested will be invited to attend an online, video-based onboarding visit.  
3.7 Usability Testing Overview  
 
Figure 1. Usability Testing Study Flow Chart 
 
 
 
 
Onbording 
online video 
meeting & 
Verbal 
consent 
Access to 
Actify! 
Intervention  
Brief check-in 
call at 
midpoint of 
the daily diary 
entries 
Daily Diary 
entry for 7 
days, via MS 
Forms 
Final exit 
interview  

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During the online, video-based onboarding visit, participants will be provided with information about 
the study and provide verbal informed consent to participate. During that visit, study staff will assist 
enrolled participants in downloading Actify to their personal phone. Participants will be instructed to 
use Actify for one week and to keep a daily diary to report on their usage of and satisfaction with the 
program. Daily diaries will follow a semi-structured format, including assessments of when they used the 
app, what prompted them to open it, what features they accessed, and what their overall experience 
was like. They will also be asked about any technical difficulties encountered and about ease of 
navigation.  Following completion of the diary entries, they will be asked to attend a final debriefing 
session which will include a semi-structured exit interview to assess (a) usage and satisfaction with the 
app, and (b) the impact of Actify on their smoking, mood, and engagement in valued activities. 
Participants will also complete the 10-item System Usability Scale [72], a common method of evaluating 
the usability of software. The User Experience (UX) researcher will be responsible for conducting the 
diary study. Full length of study participation will be ~9 days. 
 
These procedures are consistent with best practices and usability testing of government funded 
cessation programs [73] and have been successfully implemented previously in our treatment 
development work. After the diary study, the UX Researcher and the UX Designer will work with the PI 
(Heffner) and consultants (Becoňa, McClure, and Daughters) to use data gleaned from the diary study to 
inform any needed changes to Actify’s content and structure as well as to address any technical 
difficulties experienced by the users. Based on prior work, the types of changes needed at this stage of 
development are typically smaller adjustments such as changes to increase readability of text on 
different devices (e.g., font size, color), changes to the wording of specific messages, or de-bugging new 
features (e.g., inactive buttons). The Moby Inc. programming team will then make changes needed to 
improve the usability and/or content of the app. The final version of Actify, which will be developed 
after the diary study, and will be used in the pilot RCT. 
3.8 Participant Compensation  
 
Participants will receive up to $150. Compensation will be pro-rated and dispersed as follows: 
 
• 
$10 for the baseline visit 
• 
$10 for mid-point check in 
• 
$40 for the final debriefing visit 
• 
$10 for each daily diary entry, up to $70 (for 7 days)  
• 
$20 bonus for completing all 7 diary entries  
 
3.9 Enrollment Procedures  
 
Participants will be recruited nationally through online services (e.g., Facebook, Twitter, Craigslist and 
Reddit advertisements). Recruitment materials will direct potential participants to a web-based 
screening survey on Microsoft Forms. The survey provides basic information about the study to allow 
individuals to choose whether or not to proceed, then assess basic eligibility criteria. Individuals who do 
not meet eligibility criteria will be provided with the following quit-smoking resources via e-mail; the 
QuitGuide app and the 800-QUIT-NOW phone number to reach their state’s quitline.  
 
Phone screening & informed consent. Study staff will call individuals who are deemed potentially eligible 
based on the initial online screening. During this call, the purpose and procedures of the study will be 

OnCore # RG1121054 
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explained in further detail and key eligibility criteria will be re-assessed to ensure consistency of 
answers. Those who remain eligible will be invited to participate in the diary study. Individuals who 
remain interested will be scheduled for their onboarding meeting and study staff will email the study 
information sheet to the individual to review before the onboarding meeting.  
 
Onboarding video meeting. We will email participants the information needed to access the online 
meeting, which will be conducted and recorded via video conference. The onboarding meeting will be 
conducted by the UX researcher and will last approximately 30 minutes. The study information sheet 
will be discussed first, and participants will be asked to provide verbal consent before proceeding. 
During the onboarding meeting, participants will be given password-protected access to the Actify! app 
and will receive assistance with downloading the app. During this meeting, participants will also be 
asked about their motivation to quit smoking. The brief (10-15 minutes) mid-study session call and the 
final exit interview will also be scheduled. After the onboarding meeting, study staff will email 
participants their log-in credentials for the Actify app as well as the date and time of their mid-study 
feedback call and their final exit interview. 
 
3.10 Assessments/Evaluations 
 
Onboarding video call (Day 1):  Smoking level, motivation (importance and confidence) to change 
smoking habits and cost of smoking will be assessed. 
 
Daily diary entry (Days 2-8): Participants will be instructed to use Actify for one week and to submit a 
daily diary to report on their usage of and satisfaction with the program. Daily diaries will follow a semi-
structured format, including assessments of when they used the app, what prompted them to open it, 
what features they accessed, and what their overall experience was like. They will also be asked about 
the specific device and operating system they used to access the app, any technical difficulties 
encountered and about ease of navigation.  
 
Mid-study check in call (Day 4-5): the UX Researcher will connect briefly with each participant for a 10–
15-minute check in about their experience and engagement with the Actify! app. Qualitative research 
notes will be taken during this call.  
 
Final exit interview (Day 9-10): Following completion of the diary study, participants will be asked to 
attend an online video meeting for a final debriefing session which will include a semi-structured exit 
interview to assess (a) usage and satisfaction with the app, and (b) the impact of Actify on their smoking, 
mood, and engagement in valued activities. As part of the final exit interview, participants will complete 
the 10-item System Usability Scale [72], a common method of evaluating the usability of software. 
Participants will also be asked to report any technical difficulties they may have experienced.   
 
3.11 Analytical methods 
 
Qualitative data from diary entries and exit interviews will be coded and analyzed using inductive 
content analysis to extract themes. Usability data from the SUS will be reported using descriptive 
statistics and compared against the benchmark score of 68, which represents average usability. 
 
3.12 Objective 
 
The Acitfy! App will be developed that can be easily navigated and understood by the user. 

OnCore # RG1121054 
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4.0 
OVERVIEW OF CLINICAL TRIAL 
 
4.1 Study Objectives 
 
4.1.1 
Primary Objectives:  Assess and compare treatment acceptability across treatment 
arms.  
4.1.2 
Secondary Objectives: Preliminarily assess efficacy and mechanism of change for 
the behavioral activation app (Actify) vs. the USCPG app (QuitGuide) for smoking 
cessation. 
4.1.3 
Tertiary Objectives:  Determine whether there is evidence of differential efficacy in 
smokers with vs. without pre-quit depressive symptoms 
 
4.2 Study Population:  
We will recruit 240 adult smokers, both with (PHQ=8 score 5-19; n=120) and without (PHQ-8 score 0-4; 
n=120) depressive symptoms, who are interested in quitting smoking. Participants will be recruited 
nationally via recruitment strategies used successfully in our previous studies: targeted Facebook ads, 
Craigslist ads in states with a high prevalence of smoking or racial/ethnic minority residence (to achieve 
the target 25% racial/ethnic minority representation in the sample), other free methods of advertising 
on the Internet (e.g., Reddit, Twitter), ResearchMatch.org, and earned media generated by press 
releases from the Fred Hutch media team. 
 
Inclusion of Women & Minorities.  
Our previous trials suggest that, without intervention to diversify the sample, the vast majority of 
participants would be Caucasian and female. To attain adequate representation of racial/ethnic 
minorities and men, we will cap enrollment of Caucasians and women at 75% of the sample via our 
online screening and enrollment process for the pilot trial. We anticipate that these caps will be 
necessary and that the resulting sample will be 25% male and 25% racial/ethnic minority. If needed, we 
will use targeted Facebook and Twitter campaigns specifically to recruit men and/or people with 
racial/ethnic minority affiliations (the ad platform’s proxy for race/ethnicity). Based on demographic 
data from our recent trial of a technology-delivered cessation intervention using similar recruitment 
procedures [8], we expect the following percentages of racial minority participants: African American 
(10%), Native American or Alaska Native (2%), Native Hawaiian or Pacific Islander, Asian (2%), or 
other/multiple races (5%). In terms of ethnicity, we expect 8% to identify as Hispanic or Latino. 
 
4.3 Study Design 
 
This is a pilot, randomized controlled trial (n=240) to test the primary outcome of treatment 
acceptability and secondary outcomes of efficacy and mechanism of change for the Actify app vs. the 
active control app (the National Cancer Institute’s QuitGuide app). We will test the interventions using 
an 8-week treatment period, and, consistent with the evaluation period in our previous cessation app 
pilot study, our primary outcomes will be assessed at the 8-week end-of-treatment mark. We will also 
collect 6-month follow-up data to assess long-term outcomes. 
 
4.3.1 
Primary Endpoints: Treatment acceptability as indicated by user satisfaction with 
assigned treatment (user satisfaction ratings of the assigned app at 8 weeks post-

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randomization) and app utilization (total number of app server-recorded openings 
of the assigned intervention) 
 
4.3.2 
Secondary Endpoints: Treatment efficacy (smoking cessation) and changes to 
theory-based mechanisms of change (behavioral activation).  
 
• 
Treatment efficacy: 
o Self-reported 30-day point prevalence abstinence (PPA) from 
smoking at 8 weeks post-randomization 
o Self-reported 30-day PPA from smoking at 6 months post-
randomization; Biochemically-confirmed 30-day PPA from smoking 
at 8 weeks and 6 months post-randomization; Self-reported and 
biochemically confirmed 7-day PPA from smoking at 8 weeks and 6 
months post-randomization; Self-reported and biochemically 
confirmed 30-day PPA from cigarettes and other non-medicinal 
nicotine/tobacco products at 8 weeks and 6 months, including e-
cigarettes 
• 
Mechanisms of change: 
o Change in behavioral activation from baseline to 8 weeks post-
randomization 
o Change in depressive symptoms from baseline to 8 weeks post-
randomization 
 
4.3.3 
Exploratory Endpoints: Differences in treatment effects by pre-quit depression 
(depressed vs. not depressed) 
4.4 Estimated Accrual:  
We estimate that our recruitments efforts will yield 904 screened, 490 eligible, 416 consented, and 240 
randomized into the trial (120 per arm). We conservatively allotted 9 months for recruitment (26 
enrolled/month). 
 
4.5 Name of Sponsor/Funding Source:  
National Institute on Drug Abuse, Grant Number: 1R34DA050967 
 
5.0 
SUBJECT ELIGIBLITY 
 
5.1 Inclusion Criteria  
• 
age 18 or older 
• 
current smoker, averaging at least 5 cigarettes/day for the last 30 days 
• 
interested in quitting smoking in the next 30 days 
• 
experience downloading and using one or more apps on their smartphone 
• 
either screens negative (PHQ-8 score 0-4) for depression (n=120) or screens positive for 
mild to moderate current depressive symptoms (PHQ-8 score 5-19; n=120) 
• 
willing and able to complete all study activities including willing to receive study 
compensation by mail  
• 
comfortable reading and writing in English 
• 
have a mobile data plan and/or access to WiFi to support the use of the Actify app 
• 
reside in the US 

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• 
have a smartphone either an iPhone (running iOS version 11 or higher) or an Android 
phone (running version 5.0 or higher) 
 
5.2 Exclusion Criteria  
• 
currently receiving behavioral treatment for depression (e.g., psychotherapy) 
• 
current use of a depression app 
• 
severe depression (PHQ-8 ≥ 20) 
• 
receiving other treatment for smoking cessation 
• 
previous use of the QuitGuide program 
• 
current or recent (within the past year) enrollment in a Fred Hutch smoking cessation 
study 
• 
employees/family of investigator or study center 
• 
member of the same household as another participant 
• 
woman who is pregnant or breastfeeding, or planning to become pregnant 
• 
currently incarcerated  
• 
Is ineligible per fraud prevention protocol 
 
6.0 
SUBJECT REGISTRATION 
 
Recruitment materials will direct potential participants to a recruitment website, which provides basic 
information about the study and a portal to the informed consent form, screening, and baseline surveys. 
 
For participants who screen eligible on the recruitment website and provide their email address, we will 
instantly send them an email (and two reminders over a 14-day period) inviting them to complete a 
secured online survey to provide informed consent and complete the baseline assessment. Those not 
consenting and completing the online enrollment process within 14 days will be sent an email notifying 
them that they were not enrolled and providing both the QuitGuide app and the 1-800-QUIT-NOW 
phone number to reach their state’s quitline. Both arms will be described as smartphone apps designed 
to assist with quitting and containing tools to improve mood. 
 
To address potential fraudulent responses to web-based screening surveys with compensation for 
participation, we will use the same methods used in our previous studies: CAPTCHA verification, 
ineligibility if the IP address was previously used or suspicious, and telephone contact by research staff if 
any aspect of automated data collection revealed suspicious activity (e.g., very brief survey completion 
times or unusual patterns in email addresses). To further deter fraudulent attempts to enter the study, 
no compensation will be provided for completion of the  screening and baseline surveys. 
 
Participants completing this process will be enrolled in the study. This information will be stored in a 
secure research database behind FHCRC firewall. See section 7.2 Enrollment Procedures for more 
details.  
7.0 
TREATMENT PLAN 
 
7.1 Treatment Plan Overview 
 
 
 
 

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Figure 2. Study Flow Chart 
 
 
 
 
 
 
 
 
 
 
7.2 Description of the interventions  
 
QuitGuide app. QuitGuide was created by the NCI’s Smokefree team. It contains brief quit advice; a tool 
for tracking smokefree days and a statistics menu for viewing progress; a tool for tracking cravings and 
receiving a brief, related tip in response; a “Learn to Quit” feature with information on steps to prepare, 
cravings, withdrawal, slips, and staying smokefree. QuitGuide also has a “Manage My Mood” feature on 
the main page that gives it credibility as an intervention for smokers with depression, but with minimal 
expected efficacy due to the limited nature of the feature—i.e., recording a mood state and having the 
option to journal, call a friend, view photos and notes, or view a tip or distraction for handling difficult 
mood states. An example tip offered for handling negative affective states: “Distract. Do a crossword 
puzzle, play a game, or start a book that’s been gathering dust.” 
 
Actify. Consistent with the BAT-D treatment model, the core functions of the current version of Actify 
are: (1) introducing the user to the program by describing the rationale for behavioral activation as an 
intervention for both depressive symptoms and smoking cessation, (2) helping the user to identify 
personal values, important life areas and meaningful activities associated with their values that will 
replace smoking habits (e.g., reading to my children), (3) prompting the user to schedule meaningful 
activities and providing reminders to complete them and, (4) visualizing overall progress toward meeting 
activity goals as well as the relationship between activities completed and mood. The app also contains  
tailored messages for smoking status and activity completion and resource sections with guidance for 
starting and maintaining a smoke free life. To increase engagement, the user receives daily tips, 
personalized feedback on money saved by cutting down/quitting smoking, feedback on activities 
completed, inspirational messages, user stories and quotes of ex-smokers overcoming challenges, 
noticing the benefits of quitting and how behavioral activation helped them to improve their mood and 
quit smoking. User stories illustrating how values can be translated into actions were associated with 
cessation in our prior work [69]. To acknowledge and motivate continued progress, the user is able to 
earn badges for smoke free streaks, usage of the app, and activity completion. 
In-app notifications will be used to provide reminders to use the program, to track daily smoking 
and activity completion, and to remind users of upcoming scheduled activities. We added a Quit Guide 
section to the app, similar to QuitGuide’s “Learn to Quit” menu, that it is available for reference if users 
need on-demand assistance. Portions of the QuitGuide are also presented as suggested reading on the 
users’ dashboard. Content for the new Quit Guide feature supports users with setting and preparing for 
a quit date, learning about medications to assist with quitting, managing cravings and other withdrawal 
symptoms, handling high-risk situations, staying motivated, and recovering from lapses. The addition of 
the Quit Guide section matches Actify to the NCI QuitGuide app on the cessation content, allowing for 
stronger inferences about the specific effects of Actify’s BAT-D components 
 
Informed  
Consent &  
Baseline 
Assessment 
Access to Actify intervention & 
associated text messages 
2-month 
Follow-up 
Assessment 
Enrollment/ 
Randomization 
Access to QuitGuide intervention 
& associated text messages 
6-month 
Follow-up 
Assessment 

OnCore # RG1121054 
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Comparison of Actify and QuitGuide. 
Actify 
QuitGuide 
Treatment approach 
Behavioral activation + USCPG 
USCPG 
Cessation content description 
Static quit guide, push notifications 
with reminders to track activities and 
smoking 
Static quit guide, push notifications 
with tips for quitting 
Targeting (mood management) 
In-depth, personalized based on user 
input into the in app tracking system; 
core function of app 
Superficial, “manage my mood” 
feature 
Interactive tracking/progress features Mood, activities, smoking level 
Mood, craving 
Game elements for engagement 
Badges (trophies) for progress 
Badges (trophies) for progress 
 
7.3 Concomitant Medication 
Use of concomitant treatments for both tobacco cessation and depression will be assessed at each time 
point. Individuals who report using self-report 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 study. At the 2 and 6-month follow-up assessment, 
participants will be asked about their use of FDA-approved quit-smoking and pharmacotherapy for 
depression. Initiating use of FDA-approved quit-smoking medications during the study is allowed.  
 
7.4 2 and 6-Month Follow-up Data Collection 
At baseline, we will collect email, phone, and mailing address information as well as optional contact 
information on up to two collateral contacts.  At each follow-up, we will send reminder letters. The data 
collection protocol is as follows: Day -14: mail a $2 pre-incentive letter (non-contingent incentives 
increase retention [86]) two weeks before the first online survey invitation; Day 0: First email invitation 
with link to online version of survey, with offer of $10 bonus for completing the survey within 24 hours; 
Day 7: Second email invitation with link to online version of the survey; Days 10 to 18: Eight attempts to 
complete telephone version of survey (one call per day); Day 19: Send mailed version of the survey. 
Based on our WebQuit RCT trial experience (n=2,637), we estimate that this protocol will yield 89% data 
retention, and that 92% of respondents will complete the web-based version of the survey (68% within 
24 hours and 32% after 24 hours).  
 
7.5 Participant Compensation 
 
Participants will receive up to $124 for participating in this study. Specifically, at 2- and 6-month follow-
ups, participants will receive compensation based on the following structure:  
• 
$2 in a pre-incentive letter for each follow-up (for a total of $4) 
• 
$25 for each follow-up survey completed in any modality (for a total of up to $50) 
• 
$10 bonus for completing the follow-survey within 24 hours of the initial email invitation (for a 
total of up to $20) 
• 
$25 for completing saliva cotinine and smartphone application-based carbon monoxide testing, 
if asked, after the 2-month and the 6-month follow-up study survey (for a total of up to $50) 
Participants whose data are flagged for potential deception related to study eligibility criteria (e.g., age, 
US residence) will be contacted prior to compensation being provided in order to confirm eligibility.  If 
eligibility cannot be confirmed, participants will not be compensated. 
 

OnCore # RG1121054 
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8.0 
SUBJECT EVALUATION 
 
8.1 Data Collection Overview 
 
Table 1. Phase II Pilot Study Data Collection Overview 
 
Measure 
Screening 
Baseline 
8-week 
follow-up 
6-month 
follow-up 
Purpose 
PHQ-8 (8 items) 
X 
X 
X 
X 
Eligibility, 
mechanism of 
change 
Other eligibility criteria (~11 
items) 
X 
Eligibility 
Demographics (~10 items) 
X 
Sample 
Description 
FTND (6 items) 
X 
Sample 
Description 
Treatment satisfaction (~8 items) 
X 
Acceptability 
Treatment preferences (~5 
items) 
X 
 
 
Tobacco/Nicotine use (~12 
items) 
X 
X 
X 
Efficacy 
Behavioral Activation for 
Depression Scale (25 
items) 
X 
X 
X 
Mechanism of 
change 
Concomitant treatment (2 items) 
X 
X 
X 
X 
Stratification, 
sensitivity 
analysis 
Total number of items 
36 items 
70 items 
53 items 
45 items 
Estimated duration 
~5-8 min 
~10-15 min 
~15-20min 
~10-15 min 
 
8.2 Enrollment Procedures.  
 
The study recruitment website provides basic information about the study, FAQ, information about the 
study team and Fred Hutchinson Cancer Research Center (FHCRC), and a portal to the informed consent 
form, screening, and baseline surveys. 
 
We will use the identical enrollment method proven successful in our previous, remotely-conducted 
RCTs. Specifically, for participants who screen eligible on the recruitment website and provide their 
email address, we will instantly send them an email (and two reminders over a 14-day period) inviting 
them to complete a secured online survey to provide informed consent and complete the baseline 
assessment. Those not consenting and completing the online enrollment process within 14 days will be 
sent an email notifying them that they were not enrolled and provide both the QuitGuide app and the 
800-QUIT-NOW phone number to reach their state’s quitline.  
 
To address potential fraudulent responses to web-based screening surveys, we will use the same 
methods used in our previous studies: CAPTCHA verification, ineligibility if the IP address was previously 
used or suspicious, and telephone contact by research staff if any aspect of automated data collection 
revealed suspicious activity (e.g., very brief survey completion times or unusual patterns in email 
addresses). To further deter fraudulent attempts to enter the study, no compensation will be provided 
for completion of the screening and baseline surveys. 
 

OnCore # RG1121054 
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Informed Consent. Participants will be asked to review and sign the online informed consent before 
completing the baseline assessment. The informed consent will encourage individuals to contact either 
Dr. Heffner or the project manager (Edit Serfozo) with questions about the study (contact information 
will be provided). The informed consent will be collected and stored in the secure database behind 
FHCRC firewall. Participants who complete the enrollment process will receive a copy of the informed 
consent via email for future reference.  
 
Baseline Assessment. The baseline survey assesses demographics, smoking history and current smoking 
behaviors the use electronic cigarettes, mechanisms of change, and potential treatment moderators. 
More details below in section 7.3. The baseline survey data will be collected and stored in a research 
database behind FHCRC firewall.  
 
After completing the baseline assessment, and first log-in, the participants will be randomized to receive 
either Actify or QuitGuide intervention. Randomization will be stratified based on sex assigned at birth, 
level of smoking and the presence of pre-treatment depressive symptoms. 
 
Following the completion of the baseline and contact information survey the participant will receive a 
text message with a link to their phone. Once this link is clicked the study team will send an email and a 
text message indicating that they are enrolled in the study. This email and text message will provide 
them with a link to the randomly assigned intervention and login credentials. If in 3 days the participant 
has not opened the app, they will receive a text message reminder. If in 3 more days the participant has 
still not opened the app, study staff will reach out by phone and offer technical assistance.  
 
8.3 Assessments/On-Study Clinical Evaluations 
 
A complete schedule of assessments is provided in the table 1 above. All data from these assessments 
will be collected via web- based, telephone, or mailed surveys.  
 
Eligibility and sample description. Demographic items assessed at baseline will include age, gender, sex 
assigned at birth, education, employment, income, and marital status. The 6-item Fagerström Test for 
Nicotine Dependence (FTND) [75] will be administered to assess degree of physical dependence on 
nicotine. Living with a smoker and quit attempts in the last 12 months will also be assessed. The Patient 
Health Questionnaire-8 (PHQ-8) is a widely-used assessment of depressive symptoms that has 
demonstrated ability to detect symptom changes over time as a result of treatment [91]. The scale 
scores range from 1 to 24, with severity thresholds as follows: 5-9=mild, 10-14=moderate, 15-
19=moderately severe, 20-24=severe. A score of 10 has 88% sensitivity and 88% specificity for a 
diagnosis of major depression [6]. We elected to use the PHQ-8 rather than the PHQ-9 because (a) the 
suicidal ideation item on the PHQ-9, which is omitted from the PHQ-8, does not have a significant 
impact on the evaluation of depression severity, as the cut-off scores are the same for both versions, (b) 
because it would be impractical to conduct follow-up suicidality assessments and referrals for all 
screening completers who endorse any suicidal thoughts, and (c) because there is no reason to believe 
that behavioral interventions for tobacco cessation would increase the risk of suicidality and therefore 
require ongoing monitoring of suicidality as a safety assessment. 
 
Treatment acceptability will be assessed at the 8-week end-of-treatment follow-up using measures of 
treatment utilization and satisfaction. Treatment utilization will include number of logins to the assigned 
application, determined objectively using custom web site analytics data. Consistent with our prior 
studies, treatment satisfaction will be assessed with 8 items on the 8-week outcome survey. Example 

OnCore # RG1121054 
28 
 
items include, “Overall, how satisfied are you with your assigned program?”; and “How useful was your 
assigned program?” Follow-up questions will probe satisfaction with specific components of the 
program (e.g. app content, app organization, push notification content, push notification frequency). 
These data are critical for making iterative improvements of the content and functionality of the app as 
it progresses through the development cycle.  
 
Efficacy for smoking cessation will be self-reported 30-day point prevalence abstinence (PPA) at 8 
weeks post-randomization (“Have you smoked at all, even a puff, in the last 30 days?”), consistent our 
previous RCT of SmartQuit vs. QuitGuide for smoking cessation [10]. Secondary efficacy endpoints 
include: (1) 30-day PPA at 6-months post-randomization, (2) 7-day PPA at 8 weeks and 6 months, and (3) 
no use of cigarettes and other non-medicinal nicotine/tobacco products at 8 weeks and 6 months, 
including e-cigarettes. Use of these products will be measured at baseline and at 8-week and 6-month 
follow-up. Generally, biochemical verification of smoking abstinence is considered unnecessary in 
population-level interventions with no face-to-face contact [77]. However, we will confirm self-reported 
abstinence among those who report 30-day PPA at 8 weeks and at 6 months using saliva cotinine and 
expired carbon monoxide. Based on the just-published expert recommendations on biochemical 
confirmation of tobacco use and abstinence [90], our biochemical verification procedures will include 
both saliva cotinine testing as well as remote carbon monoxide (CO) monitoring using iCO Smokerlyzers.  
Both the cotinine tests and the Smokerlyzers will be sent to participants by mail.  Participants will 
complete the CO testing on their smartphones using the iCO app and send results to the study team via 
email, using a function available within the app. We will also ask them to take a photo of the cotinine 
test results and return it via email. Aside from analysis of minor tobacco alkaloids (anabasine/anatabine, 
which require a urine sample and laboratory testing that would not be feasible in a remotely-conducted 
trial), this combination of methods is the best available approach that is feasible in a trial of this nature 
for differentiating distinct forms of nicotine and tobacco use. In order to meet the definition of 
biochemically-confirmed smoking abstinence, only the CO testing must be negative (<6 ppm for CO[1]). 
For analysis of abstinence from all forms of nicotine and tobacco, the CO test must be negative and the 
saliva cotinine must be negative for all abstainers who do not report recent (past 72 hours) use of 
nicotine replacement therapies. For those who report recent use of NRT, there is no feasible method of 
differentiating therapeutic use of nicotine from other forms of nicotine intake in this trial. We will report 
both self-reported abstinence and biochemically confirmed abstinence in all reports of study outcomes. 
 
Mechanisms of change will be assessed using the PHQ-8 for depression and the 25-item Behavioral 
Activation for Depression Scale (BADS) [82], which was designed to assess activation as a treatment 
process targeted by BAT-D. Example items from the BADS scale include “I did something that was hard 
to do but it was worth it,” and “I made good decisions about what type of activities and/or situations I 
put myself in.” 
 
Other assessments. Use of concomitant treatments for both tobacco cessation and depression will be 
assessed at each time point. Treatment preferences will be assessed with a single question and alcohol 
(AUDIT-C) will be assessed at baseline.  
 
9.0 
SUBJECT DISCONTINUATION OF ACTIVE TREATMENT 
Participants can choose to discontinue their participation in this study at any time for any reason.  
 

OnCore # RG1121054 
29 
 
10.0 CONCOMITANT MEDICATIONS 
Use of concomitant treatments for both tobacco cessation and depression will be assessed at each time 
point. Individuals who report using self-report 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 study. At the 2 and 6-month follow-up assessment, 
participants will be asked about their use of FDA-approved quit-smoking and pharmacotherapy for 
depression. Initiating use of FDA-approved quit-smoking medications during the study is allowed.  
 
11.0 ADVERSE EVENTS 
 
11.1 Adverse 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. 
11.2 Collection and reporting of AEs and SAEs 
Any adverse events detected during this study will be recorded in the Adverse Event Summary Form and 
reported as follows.  
 
Monitoring. 
Throughout the study, the project manager and outcome assessors will monitor participants’ progress 
and responses to surveys for adverse events and protocol compliance. The study manager will complete 
quarterly reports on participant progress and status, any adverse events, and any protocol deviations.  
 
Reporting. 
All study staff working on the trial will be trained and required to report all unexpected and adverse 
events to the project manager and the Principal Investigator. A form will be available for this purpose. 
Adverse events beyond what would be expected in the course of smoking cessation will be reported to 
the Fred Hutch’s IRB in accordance with Fred Hutch policy.  
 
Reporting SAEs. For AEs meeting the criteria for an SAE, regardless of attribution, the study 
coordinator will inform the Fred Hutch IRB per their reporting guidelines and will complete and 
submit a NIDA SAE report form within 72 hours of the reported event. Should additional 
information become available after the initial report, a revised report will be submitted as soon 
as possible. 
Reporting AEs that do not meet the criteria for SAE. All reported AEs will be collected and 
reported via the study’s electronic database. AEs that are expected will be summarized at the 
time of continuation review.  
Reporting UEs that do not meet the criteria for AEs. The study team will report any UEs to the 
Fred Hutch IRB per their reporting guidelines.  Fred Hutch will report the UE to the sponsor in 
accordance with the protocol. 
 

OnCore # RG1121054 
30 
 
Definitions  
In general, unexpected events (UEs) include any event, adverse or otherwise, that was not described as 
part of the study risks. For this trial, an example of an unexpected event that is not adverse is a 
participant who has become very unhappy with trial procedures. Adverse events (AEs) are any untoward 
occurrence with a trial participant whether or not it can be considered to be related to their smoking 
cessation intervention. Examples of adverse events in this trial could include development or worsening 
of depression symptoms. Serious adverse events (SAEs) include any AE that results in death, a real risk of 
dying, inpatient hospitalization, persistent or significant disability/incapacity, or AEs that require 
intervention to prevent permanent impairment or damage. In this trial, an example of a serious adverse 
event would be a suicide attempt.  
 
Management of SAEs or other study risks 
UEs, AEs, and SAEs will be reported to the Principal Investigator as soon as staff members are aware of 
them. If there is any doubt as to whether an event qualifies as a UE, AE, or SAE, staff members will be 
trained and encouraged to err on the side of caution – and to bring the event to the Principal 
Investigator’s attention for review. The PI will be responsible for managing UEs, AEs, and SAEs. 
 
Attribution 
The Principal Investigator will decide if a UE should be classified as an AE. If an event is classified as an 
AE, further attribution will be determined, as follows: 
• Related – AEs that are definitely, probably, or possibly related to the intervention. 
• Not Related – AEs that are doubtfully related or clearly not related to the intervention. 
 
12.0 DATA AND SAFETY MONITORING PLAN 
This study is a low-risk, single-site, randomized 2-arm pilot trial of a behavioral intervention for smoking 
cessation, monitoring of participant safety and data quality will be overseen by the PI, who will have 
weekly meetings with the study team to discuss study progress, including recruitment and retention, 
adverse events, and protocol adherence. Detailed DSMP in included in Appendix A. 
 
13.0 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 Fred Hutch 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 project staff. All workstations and servers are physically 
secured in locked offices, reside behind the Fred Hutch 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 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 Fred Hutch 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 Fred 

OnCore # RG1121054 
31 
 
Hutch IRB policy (7 years after the end of the study). 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 Fred Hutch Information Security Officer of such action. 
 
Online Surveys. The study database will be designed and maintained by Datatope, kept behind FHCRC 
firewall. Only key study staff will have access to the study database system. All staff have received 
Human Subject Research and HIPAA training. All data will be stored in a secure password protected 
computer folder, which only authorized research staff will have access to. 
Mailed Surveys. Numerous safeguards will keep hard copy data secure. All hard copy data will be kept in 
a locked file cabinet accessible only by authorized research staff.  
 
Actify and QuitGuide app-based Intervention. Numerous safeguards will keep electronic data secure. A 
secure password is required to access computers at our site, and computer networks are on secured 
servers that meet or exceed federal confidentiality standards. Each participant will have access to their 
website protected with a login. All connections to this website will be made using the secure sockets 
layer (SSL). Participant data are maintained on a server in a locked server room at Fred Hutch. Full access 
to the server is restricted to two staff members of the Fred Hutch Public Health Sciences Information 
Technology (PHS-IT) group and the two staff members of Datatope Inc. Participants access their 
intervention app by providing login credentials on the app, which is hosted on a secure server. The Login 
server has no access to the study database. It can send login credentials and, upon successful login, it 
can receive the participant’s responses provided in the intervention app to questions related to smoking 
and values. No potentially identifying information is entered into the app by the participant. All 
communication with the Actify and the QuitGuide app occurs over Secure Sockets Layer (SSL). The 
intervention app stores participant usage data. The only participant identifier that will be transmitted to 
this database server will be their login id. The site only stores data related to site usage. 
 
 
14.0 STATISTICAL CONSIDERATIONS 
14.1 Study Design  
 
Randomized controlled 2-arm pilot trial 
14.2 Primary/Secondary Endpoints/Hypotheses and Analytical Methods 
 
Data analyses will be conducted using the intent-to-treat approach, except where otherwise indicated.  
 
Aim 1. Conduct a pilot, randomized controlled trial (n=240) to test the primary outcome of treatment 
acceptability and secondary outcomes of efficacy and mechanism of change for the two treatment 
groups: Actify vs. QuitGuide.  
 
 
ENDPOINTS 
• 
The primary acceptability endpoints are number of app openings and overall satisfaction 
ratings.  
 

OnCore # RG1121054 
32 
 
• 
For smoking cessation: 
o The primary endpoint is the 30-day point prevalence abstinence (PPA) at 8 weeks 
post-randomization, which is comparable to the primary endpoints of the two 
extant trials of smartphone apps for smoking cessation [10, 34].  
o The secondary endpoints are 7- and 30-day PPA at 6 months, 7-day PPA at 8 weeks, 
and biochemically-confirmed abstinence from any nicotine/tobacco product (other 
than FDA-approved cessation medications) between baseline and 8-week and 6-
month follow-ups.  
 
• 
For mechanism of change,  
o The primary endpoint is the change in BADS scores between baseline and the 8-
week follow-up  
o The secondary endpoint is the change in depressive symptoms over the same time 
period.  
 
ANALYTICAL METHODS 
Linear regression will be used to evaluate treatment effects between the two arms for 
continuous endpoints. This model will adjust for any demographic or other variables that differ 
between study arms at baseline and are related to outcome as well as the stratification factors 
(depression severity, sex assigned at birth, and level of smoking). To compare binary endpoints 
between two arms (e.g. smoking abstinence), a logistic regression model will be conducted with 
control for potential confounding variables and the stratification variable. Sensitivity analyses 
excluding participants using concomitant treatment for smoking cessation and/or depression 
will also be conducted. 
 
Additional exploratory analyses will be conducted. To explore differential treatment effects by 
pre-quit depression, we will preliminarily test the interaction of treatment group assignment 
and pre-quit depression and present descriptive data on quit rates for the four subgroups 
(Actify, depressed; Actify non-depressed; QuitGuide, depressed; QuitGuide non-depressed). To 
evaluate the theory underlying BAT-D for smoking cessation, we will examine change in BADS 
scores between baseline and 8-week follow-up as a predictor of 30-day PPA at 6-month follow-
up using a logistic regression model. To generate empirical evidence to set usage benchmarks 
for the Actify app, we will evaluate the relationship between app “dosage” and cessation 
outcomes by regressing 30-day PPA at 8 weeks on objective measures of app utilization (e.g., 
number of app logins, total duration of use) using logistic regression. Similar to our feature 
analysis of SmartQuit that guided future app development [69], we will also regress 30-day PPA 
at 8 weeks on utilization of specific app components (e.g., scheduling, mood tracking) to 
determine “active ingredients.” To evaluate the relationship between user characteristics and 
treatment utilization and outcomes, we will use logistic (for cessation outcomes) or negative 
binomial (for login count data) models and baseline data as predictors. To examine sex as a 
biological variable, we will preliminarily test for sex differences in treatment response by 
descriptively examining results separately by sex. 
 
Missing data: Consistent with prevailing standards for smoking cessation trials [88], participants 
with missing smoking data will be considered non-abstinent in the primary analysis. As a 
sensitivity analysis, we will also report abstinence rates from complete case analyses and 
multiple imputation. Treatment acceptability and mechanism of change (i.e., behavioral 
activation [BADS] and depression [PHQ-8] scores) will be analyzed using complete case analysis. 

OnCore # RG1121054 
33 
 
 
Modified intent-to-treat approach. Because treatment acceptability is the primary outcome of 
this pilot trial, and because a valid assessment of acceptability is not possible in cases where 
there is pre-intervention attrition (i.e., never downloading or opening the assigned app), we will 
use a modified intent-to-treat approach in which only those participants who open their 
assigned app at least once will be included in the outcome analyses. 
14.3 Sample Size and Power 
As a pilot treatment development project, this study is not powered 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 to prepare for a rigorous test of the efficacy of Actify in a subsequent R01. We plan to 
accrue a total of 240 patients in the pilot RCT for a balanced design. The NIDA Stage Model of behavioral 
treatment development suggests that pilot treatment development trials should include approximately 
15-30 participants per arm to test feasibility [61]. However, as demonstrated in a recent simulation 
focused on sample size for pilot studies [87], binary outcomes (e.g., smoking abstinence) require higher 
sample sizes for reasonable precision of the effect size estimate than do continuous outcomes. To be 
conservative, and in consideration of the higher recruitment capacity in remotely conducted studies 
involving standalone mHealth interventions, we chose to include 60 subjects per arm within each 
stratum (depressed vs. non-depressed), as a sample size of 60 is a point of diminishing returns in terms 
of precision of effect size estimates for binary outcomes [87]. Thus, each arm will have 120 participants, 
of which 60 will meet criteria for mild to moderate depression. 
14.4 Randomization 
 
Following completion of the baseline survey, the web-based program will randomize participants to 
receive either Actify or QuitGuide with a 1:1 allocation ratio. The randomization algorithm will be 
developed by the study biostatistician, with stratification by presence of mild to moderate depressive 
symptoms (PHQ-8 < 5 or PHQ-8 ≥ 5), sex assigned at birth (2 levels: male or female) and level of smoking 
(2 levels: 20 or more cigarettes per day vs. < 20). Randomized participants will be emailed a secured link 
to download their assigned app. All participants will be emailed identical once-weekly reminders to use 
their assigned intervention. Although we project, based on recent data from our trial of web-based 
interventions [8], that the vast majority (92%) of outcome assessments will be completed via web-based 
survey, any outcome evaluator who has direct contact with participants will be blinded to treatment 
group assignment. 
 
 
 
14.5 Ethnic and Gender Distribution Chart: Projected Target Accrual 
Planned 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ 
Alaska Native 
 
2 
0 
0 
6 
Asian 
4 
2 
0 
0 
6 

OnCore # RG1121054 
34 
 
Native Hawaiian or 
Other Pacific Islander 
2 
0 
0 
0 
2 
Black or African 
American 
17 
8 
2 
0 
27 
White 
139 
47 
12 
4 
202 
More than One Race 
10 
2 
0 
0 
12 
Total 
176 
61 
14 
4 
255 
 
 
15.0 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. 
 
 
16.0 REFERENCES 
 
1. US Department of Health and Human Services. The health consequences of smoking--50 years of 
progress. A report of the Surgeon General. US Department of Health and Human Services 
CfDCaP, National Center for Chronic Disease Control and Prevention, Office on Smoking and 
Health., editor. Atlanta, GA.2014. 
2. Centers for Disease Control and Prevention. Alcohol and public health: Alcohol-related disease 
impact (ARDI). Average for United States 2006-2010 alcohol-attributable deaths due to 
excessive alcohol use. [cited 2017 September 30]. Available from: 
https://nccd.cdc.gov/DPH_ARDI/Default/Report.aspx?T=AAM&P=f6d7eda7-036e-4553-9968- 
9b17ffad620e&R=d7a9b303-48e9-4440-bf47-070a4827e1fd&M=8E1C5233-5640-4EE8-9247- 
1ECA7DA325B9&F=&D. 
3. Rudd RA, Seth P, David F, Scholl L. Increases in Drug and Opioid-Involved Overdose Deaths - 
United States, 2010-2015. MMWR Morb Mortal Wkly Rep. 2016;65(5051):1445-52. Epub 
2016/12/30. doi: 10.15585/mmwr.mm655051e1. PubMed PMID: 28033313. 
4. Centers for Disease Control and Prevention. Quitting smoking among adults--United States, 
2001- 2010. MMWR Morb Mortal Wkly Rep. 2011;60(44):1513-9. Epub 2011/11/11. PubMed 
PMID: 22071589. 
5. Weinberger AH, Gbedemah M, Wall MM, Hasin DS, Zvolensky MJ, Chaiton M, et al. Depression 
Among Non-Daily Smokers Compared to Daily Smokers and Never-Smokers in the United States: 
An Emerging Problem. Nicotine Tob Res. 2017. Epub 2017/03/25. doi: 10.1093/ntr/ntx009. 
PubMed PMID: 28339571. 

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6. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J 
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17.0 APPENDICES 
 
Appendix A: 
Data & Safety Monitoring Plan 
 
Appendix B: 
Fraud Prevention Protocol for Pilot Trial 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Included in this protocol document for Scientific Review Committee, all other appendices will be 
provided for IRB submission  
 
 
 
 
 

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Appendix A: Data & Safety Monitoring Plan 
Version 2, 1/25/2022 
 
R34 DA050967 
 
“An mHealth mood management tool to improve population-level tobacco cessation” 
 
PI: Heffner, Jaimee L. 

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DSMP Contents 
1 
Summary of the protocol 3 
1.1 
Brief description of the protocol 
3 
1.2 
Primary and secondary outcome measures 3 
1.3 
Inclusion/exclusion criteria 4 
1.4 
Power calculation and sample size 4 
2 
Trial management 5 
2.1 
List of participating enrolling clinics or data collection centers 
5 
2.2 
Projected timetable 
5 
2.3 
Target population distribution 
5 
3 
Data management and analysis 
6 
3.1 
Data acquisition and transmission 6 
3.2 
Data entry methods 
7 
3.3 
Data analysis plan 7 
4 
Quality assurance plan 
8 
4.1 
Procedures in place to ensure the validity and integrity of the data 8 
4.2 
Procedures to guarantee the accuracy and completeness of the data…8    
5 
Regulatory issues 10 
5.1 
Reporting mechanisms of AEs/SAEs to the IRB and NIDA 10 
5.2 
Reporting mechanisms of IRB actions to NIDA 
10 
5.3 
Report of changes or amendments to the protocol 10 
5.4 
Trial stopping rules 
11 
5.5 
Disclosure of any conflict of interest 
11 
6 
Trial safety 
12 
6.1 
Potential risks and benefits for participants 12 
6.2 
Collection and reporting of AEs and SAEs 13 
6.3 
Management of SAEs or other study risks 14 
7 
Trial efficacy 
15 
7.1 
Plans for Interim Analysis of efficacy data 15 
8 
DSM plan administration 16 
8.1 
Responsibility for data and safety monitoring 
16 
8.2 
Frequency of DSM reviews 
16 
8.3 
Content of DSM report 
16 
9 
DSM Board Plan 17 

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1 
Summary of the protocol 
1.1 Brief description of the protocol 
 
This study aims to inform the development of an app (Actify!) for smoking cessation that is grounded in 
behavioral activation therapy for depression (BAT-D). The primary aims are to (1) complete development 
of the new app by adding cessation content, improving the app structure, conducting a 1-week diary study 
to evaluate the app’s usability, and refining the app, and (2) conduct a pilot, randomized controlled trial 
(n=240) to test the primary outcome of treatment acceptability and secondary outcomes of efficacy and 
mechanism of change for the Actify app vs. the active control app (the National Cancer Insitute’s 
QuitGuide app). We will test the interventions using an 8-week treatment period, and, consistent with the 
evaluation period in our previous cessation app pilot study, our primary outcomes will be assessed at the 
8-week end-of-treatment mark.  We will also collect 6-month follow-up data to assess long-term 
outcomes. 
1.2 Primary and secondary outcome measures 
 
Acceptability outcomes: 
• 
Co-primary: User satisfaction ratings of the assigned app at 8 weeks post-randomization 
• 
Co-primary: Total number of log-ins to the assigned app at 8 weeks post-randomization 
Smoking abstinence outcomes 
• 
Primary: Self-reported 30-day point prevalence abstinence (PPA) from smoking at 8 weeks post-
randomization 
• 
Secondary:  
▪ 
Self-reported 30-day PPA from smoking at 6 months post-randomization 
▪ 
Biochemically-confirmed 30-day PPA from smoking at 8 weeks and 6 months post-
randomization 
▪ 
Self-reported and biochemically confirmed 7-day PPA from smoking at 8 weeks and 6 
months post-randomization 
▪ 
Self-reported and biochemically confirmed 30-day PPA from cigarettes and other non-
medicinal nicotine/tobacco products at 8 weeks and 6 months, including e-cigarettes 
Mechanisms of change 
• 
Co-primary: Change in behavioral activation from baseline to at 8 weeks post-randomization 
• 
Co-primary: Change in depressive symptoms from baseline to 8 weeks post-randomization 
1.3 Inclusion/exclusion criteria 
 
Inclusion criteria:  
• 
age 18 or older  
• 
current smoker, averaging at least 5 cigarettes/day for the last 30 days  
• 
interested in quitting smoking in the next 30 days 
• 
experience downloading and using one or more apps on their smartphone  
• 
either screens negative (PHQ-8 score 0-4) for depression (Phase I n=5, Phase II n=120) or 
screens positive for mild to moderate current depressive symptoms (PHQ-8 score 5-19; Phase I 
n=5, Phase II n=120)  
• 
willing and able to complete all study activities and willing to receive study compensation by US 
mail 
• 
comfortable reading and writing in English 
• 
have a mobile data plan and/or access to WiFi to support the use of the Actify app 

OnCore # RG1121054 
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• 
reside in the US 
• 
have a smartphone either an iPhone (running iOS version 11 or higher) or an Android phone 
(running version 5.0 or higher) 
 
Exclusion criteria:  
• 
currently receiving behavioral treatment for depression (e.g., psychotherapy) 
• 
current use of a depression app 
• 
severe depression (PHQ-8 ≥ 20) 
• 
receiving other treatment for smoking cessation 
• 
previous use of the QuitGuide program 
• 
current or recent (within the past year) enrollment in a Fred Hutch smoking cessation study 
• 
employees/family of investigator or study center 
• 
member of the same household as another participant 
• 
woman who is pregnant or breastfeeding, or planning to become pregnant 
• 
currently incarcerated  
• 
is ineligible per fraud prevention protocol 
1.4 Power calculation and sample size 
 
As a pilot treatment development project, this study is not powered 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 to prepare for a rigorous test of the efficacy of Actify in a subsequent R01. We plan to 
accrue a total of 240 patients in the pilot RCT for a balanced design. The NIDA Stage Model of behavioral 
treatment development suggests that pilot treatment development trials should include approximately 15-
30 participants per arm to test feasibility 1. However, as demonstrated in a recent simulation focused on 
sample size for pilot studies 2, binary outcomes (e.g., smoking abstinence) require higher sample sizes for 
reasonable precision of the effect size estimate than do continuous outcomes. To be conservative, and in 
consideration of the higher recruitment capacity in remotely conducted studies involving standalone 
mHealth interventions, we chose to include 60 subjects per arm within each stratum (depressed vs. non-
depressed), as a sample size of 60 is a point of diminishing returns in terms of precision of effect size 
estimates for binary outcomes 2. Thus, each arm will have 120 participants, of which 60 will meet criteria 
for mild to moderate depression. 

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2 
Trial management 
2.1 List of participating enrolling clinics or data collection centers 
 
Fred Hutchinson Cancer Research Center, Seattle, WA 
2.2 Projected timetable for the pilot RCT 
 
Task 
Year 1 
Year 2 
Year 3 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Q1 
Q2 
Q3 
Q4 
Complete app development  
 
 
 
 
 
 
 
 
 
 
 
 
Diary study 
 
 
 
 
 
 
 
 
 
 
 
 
Pilot RCT preparationa 
 
 
 
 
 
 
 
 
 
 
 
 
Recruitment for pilot RCT 
 
 
 
 
 
 
 
 
 
 
 
 
Intervention 
 
 
 
 
 
 
 
 
 
 
 
 
Outcome assessment 
 
 
 
 
 
 
 
 
 
 
 
 
Data entry & quality control 
 
 
 
 
 
 
 
 
 
 
 
 
Data analysis 
 
 
 
 
 
 
 
 
 
 
 
 
Grant & manuscript 
preparation 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Recruitment rate (~26 randomized/month) is feasible based on prior work and will prevent pilot RCT activities 
from being delayed. 
a Finalize survey instruments and recruitment materials; IRB application and approval; build web-based study 
management system. 
2.3 Target population distribution 
 
Broadly, this study targets adult smokers with no more than mild to moderate symptoms of 
depression. Our previous trials suggest that, without intervention to diversify the sample, the vast majority 
of participants would be Caucasian and female. To attain adequate representation of racial/ethnic 
minorities and men, we will cap enrollment of Caucasians and women at 75% of the sample via our online 
screening and enrollment process for the pilot RCT. We anticipate that these caps will be necessary and 
that the resulting sample will be 25% male and 25% racial/ethnic minority. Based on demographic data 
from our recent trial of a technology-delivered cessation intervention, we expect the following percentages 
of racial minority participants: African American (10%), Native American or Alaska Native (2%), Native 
Hawaiian or Pacific Islander, Asian (2%), or other/multiple races (5%).  In terms of ethnicity, we expect 
8% to identify as Hispanic or Latino. 
 

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3 
Data management and analysis 
3.1 Data acquisition and transmission 
3.1.1 Consent and enrollment 
Participants will be recruited nationally via recruitment strategies used successfully in previous 
technology-delivered cessation intervention studies conducted by our group. This includes targeted 
Facebook and Twitter advertisements, Craigslist advertisements in states with a high prevalence of 
smoking or racial/ethnic minority residence (to achieve the target 25% racial/ethnic minority 
representation in the sample), other free methods of advertising on the Internet (e.g., Reddit, Twitter), 
ResearchMatch.org, and earned media generated by press releases from the Fred Hutch media team. If 
needed, we will use targeted Facebook and Twitter ad campaigns specifically to recruit men and/or 
people with racial/ethnic minority affiliations (the ad platform’s proxy for race/ethnicity). 
Our recruitment materials, which have now been used in two nationally-recruiting trials of web- 
and smartphone-delivered smoking cessation interventions (R01CA166646, R01CA192849), were 
developed in partnership with the Dana Farber/Harvard University Health Communications Core, which 
specializes in participant recruitment. They designed our recruitment website, which provides basic 
information about the study, FAQ, information about the study team and Fred Hutchinson Cancer 
Research Center (FHCRC), and a portal to the informed consent form, screening, and baseline surveys. 
They also assisted with the design and optimization of online ads (e.g., Facebook and Twitter ads) for 
referring potential participants to the recruitment website and worked with the FHCRC communications 
department on the design of press releases to be distributed over the course of the recruitment period. All 
of these recruitment procedures and materials will be adapted for this trial. Similar to our other trials, we 
will program the recruitment website to limit non-minority recruitment to 75% and continue recruitment 
until the minority recruitment goal of at least 25% is reached.  
We will use the identical enrollment method proven successful in our previous, remotely-
conducted RCTs. Specifically, for participants who screen eligible on the recruitment website and provide 
their email address, we will instantly send them an email (and two reminders over a 14-day period) 
inviting them to complete a secured online survey to provide informed consent and complete the baseline 
assessment. Those not consenting and completing the online enrollment process within 14 days will be 
sent an email notifying them that they were not enrolled and provide both the QuitGuide app and the 800-
QUIT-NOW phone number to reach their state’s quitline.  
To address potential fraudulent responses to web-based screening surveys, we will use the same 
methods used in our previous studies: CAPTCHA verification, ineligibility if the IP address was previously 
used or suspicious, and telephone contact by research staff if any aspect of automated data collection 
revealed suspicious activity (e.g., very brief survey completion times or unusual patterns in email 
addresses). To further deter fraudulent attempts to enter the study, no compensation will be provided for 
completion of the screening and baseline surveys. 
 
3.1.2 Smartphone app utilization data 
Web site analytics data will be used to determine the number of times participants log into their assigned 
smartphone apps. 
3.1.3 Outcome data collection 
At baseline, we will collect email, phone, and mailing address information. At each follow-up, we will send 
reminder letters. The data collection protocol is as follows: Day -14: mail a $2 pre-incentive letter (non-
contingent incentives increase retention 3) two weeks before the first online survey invitation; Day 0: First 
email invitation with link to online version of survey, with offer of $10 bonus for completing the survey 
within 24 hours; Day 7: Second email invitation with link to online version of the survey; Days 10 to 18: 
Eight attempts to complete telephone version of survey (one call per day); Day 19: Send mailed version 
of the survey. Based on our WebQuit RCT trial experience (n=2,637), we estimate that this protocol will 

OnCore # RG1121054 
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yield 89% data retention, and that 92% of respondents will complete the web-based version of the survey 
(68% within 24 hours and 32% after 24 hours). Participants will be compensated $25 for each follow-up 
survey completed. 
3.2 Data entry methods 
All screening, baseline, and outcome survey data will be entered either directly by study participants who 
complete the online surveys or study staff (for participants who complete the surveys by phone or mail) 
into a study database managed by Datatope, Inc.  
3.3 Data analysis plan 
Primary statistical review of the study will be conducted by the study statistician at the end of the study, 
guided by the Principal Investigator. (See section 7 for detailed analysis plan).  
 

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4 
Quality assurance plan 
4.1 Procedures in place to ensure the validity and integrity of the data 
 
Numerous safeguards will keep data secure. Each subject will be assigned a code number so that, 
should any non-study personnel gain access to the data, they will not know to whom they belong.  Any 
hard copy data will be kept in a locked file cabinet accessible only by authorized research staff. A secure 
password is required to access computers at each site, and computer networks are on secured servers 
that meet or exceed federal confidentiality standards. Once randomized, each participant will have access 
to their assigned app protected with a login. All connections will be made using the secure sockets layer 
(SSL).  
 
Participant data are maintained on a server in a locked server room at Fred Hutch. Full access to the 
server is restricted to two staff members of the Fred Hutch Public Health Sciences Information 
Technology (PHS-IT) group and the two developers of the study management system. 
4.2 Procedures to guarantee the accuracy and completeness of the data 
Data accuracy has two aspects in this trial: (1) accuracy of self-reported data by trial participants, and (2) 
accuracy of data management. The trial has procedures for both, which will be reviewed annually by the 
project manager and approved by the Principal Investigator. 
4.2.1 Procedures during data entry 
 
Both participants and site personnel will enter study data into the study database managed by Datatope, 
Inc. The project manager will monitor completeness of data submitted by participants and staff and 
accuracy of data entered by staff from phone or mailed surveys. Missing data and data flagged for 
indication of inaccuracy (e.g., inconsistent dates of birth across surveys) will be reviewed regularly and 
flagged for follow-up with study participants.  
4.2.2 Procedures during data transmission 
Forms used by participants and staff will be web-based forms. Data are maintained on a server in a 
locked server room at Fred Hutch. Full access to the server is restricted to two staff members of the Fred 
Hutch Public Health Sciences Information Technology (PHS-IT) group and the two developers of the 
study management system. 
 
Project staff access the study database via the Study Management (SM) Web site. The SM Web site is 
only accessible from specific Internet Protocol (IP) addresses used by study staff. All communication with 
the SM Web site occurs over Secure Sockets Layer (SSL). Both intervention arms will store participant 
usage data.  
4.2.3 Procedures during data analysis 
When data collection is complete, the study statistician will lock the database and conduct quality checks. 
Data quality will be assessed through a number of analytic methods. The study statistician will tabulate 
categorical variables with frequency counts, and for continuous variables we will examine descriptive 
statistics (mean, standard deviation, median, interquartile range, minimum, maximum), distributional 
characteristics (skewness, kurtosis, frequency histograms, normal probability plots), and associations 
(correlations, scatter plots).  Any free text or numeric values will be checked for accuracy, range 
consistency, and outlying values. We will examine all missing response data to determine whether or not 
there are predictive characteristics that suggest the values are not missing at random and to determine 
whether imputation may be needed. Data determined to be invalid based on apparent inaccuracies (e.g, 
two different dates of birth provided at different survey time points) that cannot be resolved via follow-up 
with participants will be excluded from the final dataset. 

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5 
Regulatory issues 
5.1 Reporting mechanisms of AEs/SAEs to the IRB and NIDA 
5.1.1 Reporting SAEs 
For AEs meeting the criteria for an SAE, regardless of attribution, the study coordinator will inform the 
Fred Hutch IRB per their reporting guidelines and will complete and submit a NIDA SAE report form within 
72 hours of the reported event.  Should additional information become available after the initial report, a 
revised report will be submitted as soon as possible.  
5.1.2 Reporting AEs that do not meet the criteria for SAE 
All reported AEs will be collected and reported via the study’s electronic database. AEs that are expected 
will be summarized at the time of continuation review.  
5.1.3 Reporting UEs that do not meet the criteria for AEs 
The study team will report any UEs to the Fred Hutch IRB per their reporting guidelines.  Fred Hutch will 
report the UE to the sponsor in accordance with the protocol. 
5.2 Reporting mechanisms of IRB actions to NIDA 
Within one business day of IRB actions on SAE, the PI will be responsible for reporting to the NIDA 
Project Officer of said action. 
5.3 Report of changes or amendments to the protocol 
The PI will apply to the Fred Hutch IRB for a modification to request changes or amendments to the 
protocol. When approved, the modification will serve as the official report of the changes or amendment. 
Major changes to the protocol will be pre-approved by the NIDA project officer. 
5.4 Trial stopping rules 
5.4.1 Complying with trial suspension reporting requirements 
Were the IRB or Clinical Trials Office to issue a temporary or permanent suspension of the trial, the trial’s 
Principal Investigators will immediately contact the trial’s project officer, Will Aklin, Ph.D., National Institute 
on Drug Abuse, Division of Clinical Neuroscience & Behavioral Research, Behavioral and Integrative 
Treatment Branch, 6001 Executive Boulevard, Room 3182 Bethesda, Maryland 20892-9551. Phone: 301-
443-4877, Email: aklinwm@mail.nih.gov. 
5.5 Disclosure of any conflict of interest  
None of the investigators have a conflict of interest. If one arises, it will immediately be reported to the 
Fred Hutch IRB and NIDA Project Officer. The PI will request guidance from the IRB and the NIDA Project 
Officer on how to proceed with the DSMP given the conflict of interest.  
 

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6 
Trial safety 
6.1 Potential risks and benefits for participants 
6.1.1 Risks of intervention and mitigation plan 
 
Therapeutic risks include: (1) physical and psychological consequences of smoking abstinence, including 
nicotine withdrawal, and (2) the possibility that the intervention may not help the participant quit smoking.  
Participants will be informed of the discomfort associated with nicotine withdrawal, including common 
withdrawal symptoms, and that nicotine withdrawal may temporarily exacerbate some psychiatric 
symptoms (e.g., depressive symptoms, which are part of nicotine withdrawal) even though mental health 
has been extensively demonstrated to either remain unchanged or to improve by end of treatment and 
follow-up [4].   
 
Physical and psychological consequences of smoking abstinence, including nicotine withdrawal.  
Participants will be informed about potential nicotine withdrawal symptoms. A rating scale for depression 
(PHQ-8) will be administered at screening to assess eligibility and follow-up to assess intervention effects. 
Study staff completing telephone assessments and processing questionnaires returned by mail will be 
trained to alert the study coordinator immediately if any suicidal ideation is spontaneously reported by 
participants. All non-eligible individuals who complete the screening survey will receive an email 
containing other resources for depression assistance (including crisis line numbers) and cessation 
assistance. Enrolled participants will receive crisis line information as part of their weekly emails with 
reminders to use their assigned program. Additionally, if a participant reports suicidal ideation at any time 
point, the participant will be evaluated by the PI using the Suicidal Ideation Action Tree that we have used 
in previous studies of remotely delivered cessation interventions with national recruitment. Participants 
will be told, as part of the informed consent process, that study staff will not be monitoring self-report data 
in real time and that, should they experience suicidal thoughts during the study, they should seek 
assistance from a healthcare provider or crisis line. 
 
Possibility that the study interventions may not help the participant to quit smoking.  Participants 
will receive information about the availability of alternative treatments to facilitate smoking cessation, 
including pharmacotherapies such as nicotine replacement, bupropion, or varenicline; and 
counseling/support through telephone quitlines (1-800-QUIT-NOW) or web sites like Smokefree.gov.  
6.1.2 Risks related to research procedures and risk mitigation plan 
Participants will be informed of the following research-related risks: (1) the possibility that answering 
some questions may be emotionally upsetting, and (2) the possibility of breach of confidentiality.  It is 
possible that some of the questions asked of participants may cause some emotional discomfort.  For 
example, assessment of symptoms of depression may result in feelings of shame due to the stigma 
associated with mental health conditions. There is also a small risk of breach of confidentiality if 
participant data, either in electronic or hard copy form, were to be accessed by an unauthorized person. 
 
All study personnel will receive required training in protection of human subjects in research as well as 
Good Clinical Practice training. Participants will be informed of therapeutic and research related risks as 
well as the safeguards and/or precautions taken to reduce these risks. The following procedures will be 
implemented to protect against the risks outlined above. 
 
Informed consent.  At the outset of the study, participants will be provided with detailed information 
about the study and provided with the opportunity to ask questions about study participation. Informed 
consent will be obtained following the guidelines of the Fred Hutch Institutional Review Board. 
Participants will be reminded that they are free to withdraw from the study at any point. 
 

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Emotional upset.  Prior to administration of study assessments, participants will be reminded that they 
have the choice to not answer any question that makes them uncomfortable. Participants who report 
feeling upset as a result of responding to study assessment items will be given the option to speak with 
the PI. Dr. Heffner is a clinical psychologist who has experience working with smokers with mood 
disorders in a research context.  
 
Breach of confidentiality. Numerous safeguards will keep electronic and hard copy data secure. Each 
subject will be assigned a code number so that, should any non-study personnel gain access to the data, 
they will not know to whom they belong.  All hard copy data will be kept in a locked file cabinet accessible 
only by authorized research staff. A secure password is required to access computers, and computer 
networks are on secured servers that meet or exceed federal confidentiality standards. Once randomized, 
each participant will have access to the assigned apps protected with a login.  To address the possibility 
that individuals other than the participant might gain access to the participant’s phone, we will suggest 
that each participant password protect their phone to prevent unauthorized access. 
 
The study will be covered by a Certificate of Confidentiality from the National Institutes of Health to 
protect participants from involuntary disclosure of information collected as part of the study. Participants 
will be informed both verbally and in writing that the Certificate of Confidentiality does not supersede 
federal and/or state laws governing exceptions to confidentiality (e.g., danger to self or others, mandated 
reporting of child or elder abuse/neglect). Similarly, participants will be notified that agents of the Fred 
Hutchinson Cancer Research Center Institutional Review Board and the National Institutes of Health will 
be allowed to inspect sections of their study records, if requested. Otherwise, no information will be 
released to any individual or organization without their prior written authorization. Subjects will be 
informed that the data from the study may be published; however, they will not be identified by name. 
Subjects will be informed that their identity will remain confidential unless law requires such disclosure.  
6.1.3 Benefits of intervention 
It is possible that trial participants could quit smoking as a result of their participation. If so, the benefit to 
their short and long-term health would be significant.  
6.1.4 Benefits of research procedures  
Participation in the trial’s surveys will not offer any direct benefits, but will advance knowledge in many 
important areas of adult smoking and smoking cessation. Participants may have a positive feeling about 
participating in this effort by completing the trial’s surveys.  
6.1.5 Other information 
Token monetary incentives are offered for completion of the study assessments. Although not the 
purpose of these token electronic gift cards, they may be perceived by some participants as a benefit to 
participation. 
6.2 Collection and reporting of AEs and SAEs 
6.2.1 Monitoring 
Throughout the study, the project manager and outcome assessors will monitor participants’ progress and 
responses to surveys for adverse events and protocol compliance. The project manager will complete 
quarterly reports on participant progress and status, any adverse events, and any protocol deviations. 
Protocol adherence will be monitored by the Principal Investigator.  
6.2.2 Reporting 
All study staff working on the trial will be trained and required to report all unexpected and adverse events 
to the project coordinator and the Principal Investigator. A form will be available for this purpose. Adverse 
events beyond what would be expected in the course of smoking cessation will be reported to the Fred 
Hutch’s IRB in accordance with Fred Hutch policy. 

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6.2.3 Definitions  
In general, unexpected events (UEs) include any event, adverse or otherwise, that was not described as 
part of the study risks. For this trial, an example of an unexpected event that is not adverse is a 
participant who has become very unhappy with trial procedures. Adverse events (AEs) are any untoward 
occurrence with a trial participant whether or not it can be considered to be related to their smoking 
cessation intervention/NRT therapy. Examples of adverse events in this trial could include development 
or worsening of depression symptoms. Serious adverse events (SAEs) include any AE that results in 
death, a real risk of dying, inpatient hospitalization, persistent or significant disability/incapacity, or AEs 
that require intervention to prevent permanent impairment or damage. In this trial, an example of a 
serious adverse event would be a suicide attempt.  
6.3 Management of SAEs or other study risks 
UEs, AEs, and SAEs will be reported to the Principal Investigator as soon as staff members are aware of 
them. If there is any doubt as to whether an event qualifies as a UE, AE, or SAE, staff members will be 
trained and encouraged to err on the side of caution – and to bring the event to the Principal 
Investigator’s attention for review. The PI will be responsible for managing UEs, AEs, and SAEs. 
6.3.1 Attribution 
The Principal Investigator will decide if a UE should be classified as an AE. If an event is classified as an 
AE, further attribution will be determined, as follows: 
• 
Related – AEs that are definitely, probably, or possibly related to the intervention. 
• 
Not Related – AEs that are doubtfully related or clearly not related to the intervention. 
 

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7 
Trial efficacy 
 
7.1 Plans for interim analysis of efficacy data 
As this is a pilot study, no interim efficacy analyses will be conducted. 
 
7.2 Plans for final analysis  
Data analyses will be conducted using the intent-to-treat approach, except where otherwise indicated.  
Analyses will consist of a comparison between two arms on three outcomes: acceptability, efficacy for 
smoking cessation, and effect on BAT-D theory-based mechanisms of change. The primary acceptability 
outcomes are number of app openings and overall satisfaction ratings.  For smoking cessation, the 
primary endpoint is self-reported 30-day point prevalence abstinence (PPA) at 8 weeks post-
randomization, which is comparable to the primary endpoints of the two extant trials of smartphone apps 
for smoking cessation [10, 34]. The secondary endpoints are self-reported and biochemically confirmed 7- 
and 30-day PPA at 6 months, 7-day PPA at 8 weeks, and biochemically-confirmed abstinence from any 
nicotine/tobacco product (other than FDA-approved cessation medications) between baseline and 8-week 
and 6-month follow-ups. For mechanism of change, the primary endpoint is the change in BADS scores 
between baseline and the 8-week follow-up and the secondary endpoint is the change in depressive 
symptoms over the same time period.  
 
Linear regression will be used to evaluate treatment effects between the two arms for continuous 
endpoints (e.g, treatment satisfaction ratings). This model will adjust for any demographic or other 
variables that differ between study arms at baseline and are related to outcome as well as the 
stratification factors (depression severity, sex assigned at birth, and heaviness of smoking). To compare 
binary endpoints between two arms (e.g. smoking abstinence), a logistic regression model will be 
conducted with control for potential confounding variables and the stratification variable. Sensitivity 
analyses excluding participants using concomitant treatment for smoking cessation and/or depression will 
also be conducted. 
 
Additional exploratory analyses will be conducted. To explore differential treatment effects by pre-quit 
depression, we will preliminarily test the interaction of treatment group assignment and pre-quit 
depression and present descriptive data on quit rates for the four subgroups (Actify, depressed; Actify 
non-depressed; QuitGuide, depressed; QuitGuide non-depressed). To evaluate the theory underlying 
BAT-D for smoking cessation, we will examine change in BADS scores between baseline and 8-week 
follow-up as a predictor of 30-day PPA at 6-month follow-up using a logistic regression model. To 
generate empirical evidence to set usage benchmarks for the Actify app, we will evaluate the relationship 
between app “dosage” and cessation outcomes by regressing 30-day PPA at 8 weeks on objective 
measures of app utilization (e.g., number of app logins, total duration of use) using logistic regression. 
Similar to our feature analysis of SmartQuit that guided future app development [69], we will also regress 
30-day PPA at 8 weeks on utilization of specific app components (e.g., scheduling, mood tracking) to 
determine “active ingredients.” To evaluate the relationship between user characteristics and treatment 
utilization and cessation outcomes, we will use logistic (for cessation outcomes) or negative binomial (for 
login count data) models and baseline data as predictors. To examine sex as a biological variable, we will 
preliminarily test for sex differences in treatment response by descriptively examining results separately 
by sex. 
 
Missing data: Consistent with prevailing standards for smoking cessation trials [88], participants with 
missing smoking data will be considered non-abstinent in the primary analysis. As a sensitivity analysis, 
we will also report abstinence rates from complete case analyses and multiple imputation. Treatment 
acceptability and mechanism of change (i.e., behavioral activation [BADS] and depression [PHQ-8] 
scores) will be analyzed using complete case analysis. 

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8 
DSM plan administration 
8.1 Responsibility for data and safety monitoring 
Dr. Heffner will be responsible for monitoring the trial. 
8.2 Frequency of DSM reviews 
Data will be reviewed in the course of the trial on a quarterly basis. A full DSM report will be generated 
annually. 
8.3 Content of DSM report 
The content of the annual DSM report will follow this structure: (1) Brief description of the trial, (2) 
Baseline sociodemographic characteristics, (3) Retention and disposition of study participants, (4) Q.A. 
issues, (5) Regulatory issues, (6) AEs, (7) SAEs, (8) Efficacy. A copy of this report will be provided to the 
NIDA project officer annually. 

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9 
DSM Board Plan 
A DSMB is not needed for this low-risk, single-site trial of two behavioral interventions for smoking 
cessation. 

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References 
 
1. 
Rounsaville BJ, Carroll KM, Onken LS. A stage model of behavioral therapies research: Getting 
started and moving on from stage I. Clinical Psychology: Science and Practice. 2001;8(2):133-
142. 
2. 
Teare D, Dimairo M, Hayman A, Shephard N, Whitehead A, Walters S. Sample size requirements 
for pilot randomised controlled trials with binary outcomes: a simulation study. Trials. 
2013;14(S1):O21. 
3. 
Dillman DA. Mail and Internet Surveys: The Tailored Design Method. 2nd ed. Hoboken, NH: John 
Wiley & Sons, Inc.; 2007. 
4.  
Taylor G, McNeill A, Girling A, Farley A, Lindson-Hawley N, Aveyard P et al. Change in mental 
 
health after smoking cessation: systematic review and meta-analysis BMJ 2014; 348 :g1151 
 
doi:10.1136/bmj.g1151 
 
 

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Appendix B: Fraud Prevention Protocol 
 
ANTI-FRAUD PROCEDURES FOR STUDY ENTRY 
 

OnCore # RG1121054 
60 
 
 

OnCore # RG1121054 
61 
 
 
 
  
 
ANTI-FRAUD PROCEDURES FOR POST-ENROLLMENT DATA CLEANING 
 
Procedure for project manager to validate eligibility post-enrollment: 
 
1. Datatope will create post-enrollment flags on data validity, including (a) inconsistency between 
outcome surveys and screening/baseline surveys in date of birth,  (b) multiple IP addresses/non-
US IP addresses detected post-enrollment  
2. Post-baseline manual checks for address and IP address. 
3. Depending on level of evidence for fraud a participant could beflagged  and contacted by 
telephone. Let them know that, before they can be compensated for their participation, we 
need to verify that some the information that they provided is correct. 
4. Ask for full name and address.  If different than what they provided previously, ask if they may 
have provided any other name or address and the reason for the change.   
5. Ask for their date of birth, current age, gender, and race and ethnicity. If gender or 
race/ethnicity are different than what they provided previously, ask if they may have provided 
any different response on a survey. 
6. After completing the call, check information provided against survey data. If there is clear 
evidence of deception (e.g, different dates of birth provided, non-matching age and DOB, 
different first and last name provided across surveys, with no explanation), note in their study 
record that they should be excluded from outcome analyses.  Do not mail compensation for 
survey completion if they can’t be reached for verification.  
7. After final dataset is received from Datatope, review all records for incoherent responses to 
open-ended questions on baseline & follow-up surveys. Flag these records for manual review to 
check for data quality (e.g, evidence of straightlining, unusual responses). 
8. In cases where deception is suspected but cannot be confirmed, add participant ID to database 
of participants whose inclusion will be adjudicated by the study team prior to analyzing outcome 
data.  Include note providing all reasons why deception is suspected, along with any evidence 
that might indicate that the participant’s data are valid.