Clinical trial NCT04560868
Conditions: Tobacco Use Disorder Smoking Cessation Motivation Behavior, Smoking
Keywords: mHealth smoking smoking cessation motivation
Sponsor: Kaiser Permanente
Start date: 2020-12-16; Completion date: 2021-09-27
Enrollment: 57 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The current pilot study will assess the feasibility and acceptability of a novel mHealth app designed for people who are ambivalent about quitting smoking. Results will be used to refine the intervention and plan for a future randomized effectiveness trial.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Control mHealth program intervention 2: Experimental mHealth program intervention 3: Nicotine patch
Intervention descriptions: intervention 1: The intervention includes a mHealth intervention that is grounded in best practice recommendations for treatment of nicotine dependence. intervention 2: The intervention includes a mHealth intervention that is grounded in best practice recommendations for treatment of nicotine dependence. Experimental participants also receive additional content designed to motivate smoking reduction/quitting and provide skills training. intervention 3: Participants in both arms can earn the ability to request a 2-week supply of over-the-counter nicotine patches. Patches are earned through accumulated use of the assigned mHealth program.

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
 
 
Study Protocol and Statistical Analysis Plan 
 
Title 
Development of a mHealth Intervention for Ambivalent Smokers 
Principal Investigator 
Jennifer McClure, PhD 
Director of Investigative Science 
Kaiser Permanente Washington Health Research Institute 
Seattle, WA 
NCT Number 
NCT04560868    
Clinicaltrials.gov identifier 
1401452 
Version Date 
9/22/2022 for ClinicalTrials.gov  
 
 
 
 
 
 
 
 
 
 
 
 
 


2 
 
TABLE OF CONTENTS 
PAGE 
TABLE OF CONTENTS .............................................................................................................. 2 
LIST OF ABBREVIATIONS ......................................................................................................... 4 
PROTOCOL SUMMARY ............................................................................................................. 5 
1 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ......... 7 
1.1 
Background Information .......................................................................................... 7 
1.2 
Rationale ................................................................................................................ 7 
1.3 
Potential Risks and Benefits ................................................................................... 8 
1.3.1 
Potential Risks ............................................................................................ 8 
2 
OBJECTIVES ..................................................................................................................... 9 
2.1 
Study Objectives ..................................................................................................... 9 
2.2 
Study Outcome Measures ...................................................................................... 9 
2.2.1 
Primary ........................................................................................................ 9 
2.2.2 
Secondary ................................................................................................... 9 
2.2.3 
Other Secondary & Exploratory Outcomes ................................................ 10 
3 
STUDY ENROLLMENT AND WITHDRAWAL .................................................................. 11 
3.1 
Subject Inclusion Criteria ...................................................................................... 11 
3.2 
Subject Exclusion Criteria ..................................................................................... 11 
3.3 
Strategies for Recruitment and Retention ............................................................. 11 
3.4 
Treatment Assignment Procedures ....................................................................... 12 
3.4.1 
Randomization Procedures ....................................................................... 12 
3.4.2 
Masking Procedures .................................................................................. 12 
3.5 
Subject Withdrawal ............................................................................................... 12 
3.5.1 
Reasons for Withdrawal ............................................................................ 12 
3.5.2 
Handling of Subject Withdrawals or Subject Discontinuation of Study 
Intervention ............................................................................................... 13 
3.6 
Premature Termination or Suspension of Study .................................................... 13 
4 
STUDY INTERVENTION .................................................................................................. 14 
4.1 
Description ............................................................................................................ 14 
4.2 
Administration of Intervention ................................................................................ 14 
4.3 
Assessment of Subject Compliance with Study Intervention ................................. 14 
5 
STUDY SCHEDULE ......................................................................................................... 15 
5.1 
Screening and Enrollment ..................................................................................... 15 
5.2 
Baseline and Randomization ................................................................................ 15 
5.3 
1 and 3-month Follow-up Assessments ................................................................ 15 
5.4 
Biochemical Verification – In-Home Cotinine Saliva Test ...................................... 15 
6 
STUDY PROCEDURES /EVALUATIONS ........................................................................ 16 
7 
STUDY OVERSIGHT ....................................................................................................... 17 
8 
ASSESSMENT OF SAFETY ............................................................................................ 18 
8.1 
Specification of Safety Parameters ....................................................................... 18 
8.1.1 
Severity of Event ....................................................................................... 18 
8.1.2 
Non-serious Adverse Event Reporting ....................................................... 18 
8.1.3 
Serious Adverse Event Reporting .............................................................. 18 


3 
 
8.1.4 
Expected Adverse Reactions .................................................................... 18 
8.2 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 19 
8.3 
Characteristics of an Adverse Event ..................................................................... 19 
8.3.1 
Relationship to Study Intervention ............................................................. 19 
8.3.2 
Expectedness of SAEs .............................................................................. 19 
8.4 
Unanticipated Problem .......................................................................................... 19 
8.4.1 
Definition ................................................................................................... 19 
8.4.2 
Unanticipated Problems Reporting to IRB and NCI ................................... 20 
8.5 
Halting Rules ........................................................................................................ 20 
9 
CLINICAL SITE MONITORING ........................................................................................ 21 
10 
STATISTICAL CONSIDERATIONS .................................................................................. 22 
10.1 
Study Hypotheses ................................................................................................. 22 
10.2 
Sample Size Considerations ................................................................................. 22 
10.3 
Final Statistical Analysis Plan ............................................................................... 22 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .................. 24 
12 
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................. 25 
12.1 
Ethical Standard ................................................................................................... 25 
12.2 
Institutional Review Board .................................................................................... 25 
12.3 
Informed Consent Process ................................................................................... 25 
12.4 
Exclusion of Women, Minorities, and Children (Special Populations) .................... 25 
12.5 
Subject Confidentiality .......................................................................................... 25 
12.6 
Future Use of Identifiable Data ............................................................................. 26 
13 
DATA HANDLING AND RECORD KEEPING ................................................................... 27 
13.1 
Data Management Responsibilities ....................................................................... 27 
13.2 
Types of Data ....................................................................................................... 27 
13.3 
Data Capture Methods .......................................................................................... 27 
13.4 
Study Records Retention ...................................................................................... 27 
13.5 
Protocol Deviations and Violations ........................................................................ 27 
14 
RELEVANT LITERATURE ............................................................................................... 29 
 


4 
 
LIST OF ABBREVIATIONS 
ADL 
Activities of Daily Living 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
DHHS 
Department of Health and Human Services 
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NRT 
Nicotine Replacement Therapy 
OTC 
Over the Counter 
PPA 
Point Prevalence Abstinence 
SAE 
Serious Adverse Event/Serious Adverse Experience 
UC 
Usual Care 
UP 
Unanticipated Problem 
 
 
 


5 
 
PROTOCOL SUMMARY 
Title 
Development of a mHealth Intervention for Ambivalent Smokers: A 
Pilot Feasibility Study 
Précis 
Tobacco use remains the leading preventable cause of death and 
illness in our society. Despite this, 36.5 million US adults continue to 
smoke. Most of these people (70%) want to quit smoking someday 
but are not yet ready to quit or actively seeking treatment. That is, 
they are “ambivalent” about quitting. This project creates an 
innovative mobile health (mHealth) intervention targeted to 
ambivalent smokers.  
The trial uses a parallel, two-arm, randomized trial design. Ambivalent 
smokers will be randomized to receive either a control (“standard care”) 
version or an experimental version of the app and we will compare the 
two. 
Objective 
Conduct a randomized pilot study to assess the feasibility, 
acceptability, and potential impact of the experimental version of 
the app compared to the control version.  
Outcomes of Interest 
As a pilot study, we do not have a single “primary outcome” of 
interest.  Rather, we will examine a range of measures designed to 
inform our study objectives: assess the program’s feasibility 
(program engagement), acceptability (ratings of satisfaction and 
helpfulness), impact on cognitive mediators of change (self-efficacy, 
outcome expectations, and motivation) and impact on indicators of 
smoking behavior change (quit attempts, smoking reduction, and 
abstinence).  
Population 
Participants will be recruited nationwide via advertisements on 
online platforms. The team will also reach out to individuals who’d 
previously requested to be placed on the waiting list for tobacco 
studies at KPWHRI.  
The study will recruit smokers (18 and older) who want to quit 
smoking someday, but not in the next month, and who are not 
actively using or seeking treatment to quit; own and use a 
smartphone at least once a week and have (or are willing to upgrade 
to) a current iOS or Android operating system supported by the app; 
are willing to install and use the study program; are current smokers 
and smoke at least 10 cigarettes a day (as required for use of 
nicotine replacement therapy); speak/read English; and are willing 
to use birth control if they elect to use nicotine replacement therapy 


6 
 
(females). Only one member per household will be eligible.  Only 
those installing the app will be included in the final analytic sample. 
Number of Sites 
This pilot study includes 1 site (KPWHRI). 
Description of 
Intervention 
We have designed a mHealth app which blends sound scientific 
theory, evidence-based treatment, and best practice treatment 
guidelines for nicotine dependence with intervention content that is 
also responsive to the needs and preferences of ambivalent 
smokers.  
 
The experimental intervention combines the following components:  
• 
Best-practice self-help guidance for quitting based on the US PHS’ 
Clinical Practice Guidelines for treating nicotine dependence and 
best practice treatment recommendations (aka, Quit Guide) 
• 
A toolkit with other experimental features. 
• 
A referral to free local state tobacco quitline services . 
• 
The ability to earn and request a free 2-week starter kit of nicotine 
replacement patches 
• 
A series of 9 personal experiments, each designed to build 
motivation or teach the skills necessary to successfully cu-back or 
quit smoking.  
The control intervention also includes items 1-4 above.  
Study Duration 
The pilot will be carried out over a ~1 year period. 
Subject Participation 
Duration 
Each participant will be enrolled for a period of ~3 months. 
Estimated Time to 
Complete Enrollment 
Enrollment will occur over an ~8-month period. 
 
 


7 
 
1 INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
1.1 
Background Information 
Fifteen percent of US adults smoke and tobacco use remains the leading preventable cause of 
death and illness in our society.1, 2  It kills an estimated 480,000 Americans annually and results 
in more than $300 billion in direct health care costs and lost productivity each year.3 Reducing 
smoking prevalence is a national priority and developing behavioral treatments which optimize 
treatment effectiveness by using scalable interventions to extend reach is a priority for NIH.4  
Most smokers (~70%) want to quit someday but are not yet ready to quit.5 These ‘ambivalent 
smokers’ are not actively seeking treatment, but many are receptive to treatment when 
offered. Prior research has shown that ambivalent smokers can reduce their smoking levels,6 
and in our prior work, we found ambivalent smokers are also willing to enroll in clinical trials 
when it is clear the goal is to help them explore their willingness to quit or to answer questions 
about the quitting process, as opposed to asking for a commitment to stop smoking, and many 
even successfully quit.7, 8 Others have shown that setting a goal of smoking reduction increases 
quit rates among ambivalent smokers, particularly when counseling is paired with a stop-
smoking medication.9-13 So there is good reason to expect interventions targeting ambivalent 
smokers can be effective, particularly if they are designed to be sensitive to smokers’ 
ambivalence, but the research with this population is relatively limited and insufficient to 
inform the design of interventions for ambivalent smokers beyond suggesting it is reasonable to 
encourage smoking reduction and provide pharmacotherapy. Thus, it is important to look to 
also look to theory to inform the content and design of these cognitive behavioral 
interventions. For example, Fagerstrom suggests ambivalent smokers require softer, more 
gradual intervention approaches, even if they contain much of the same basic behavioral and 
pharmacological strategies that are effective with smokers who are ready to quit.14 This 
recommendation is consistent with the evidence cited above7-13 and with West’s PRIME theory 
of motivation, which suggests motivation and stage of change are highly fluid and change 
quickly over time.15 As a result, West argues that rather than excluding these smokers from 
intervention, we need to modify interventions to be more engaging to ambivalent smokers. 
This perspective is a paradigm shift for some but could be an important tactic for helping 
reduce smoking prevalence. However, most available cessation treatments and most treatment 
development research target the minority of smokers who are ready to quit, not the majority 
who are not actively trying to quit. This results in critical gaps in both the evidence base and 
available treatment programs. The proposed study will address these gaps by pilot testing a 
theoretically-grounded intervention which combines cognitive behavioral principles with 
pharmaco-therapy for ambivalent smokers. 
1.2 
Rationale 
To date, no published trials have tested a mHealth intervention for ambivalent smokers, but 
there is strong rationale for doing so. 77% of US adults own a smartphone, including those with 
only a high school education (69%), who make $30,000-$49,999 a year (69%), and persons of 
color (Hispanics, 75%, black 72%)16—that is, demographic groups with high smoking rates.17  
We’ve also found that most ambivalent smokers who use smartphones are interested in 


8 
 
mHealth apps for smoking: 75% told us they would consider using a cessation app, 88% were 
interested in an app to help them reduce their smoking, and 91% were interested in an app that 
could help them decide “if , when, or how” to quit.18   
mHealth interventions are a reasonable strategy for reaching ambivalent smokers and research 
is needed to develop and evaluate interventions which can be broadly disseminated via 
mHealth platforms. The current study addresses this research gap. 
1.3 
Potential Risks and Benefits 
1.3.1 
Potential Risks 
The primary risks of participation include a breach of confidentiality and emotional upset 
or embarrassment due to assessment and intervention. If people quit smoking, they could 
experience nicotine withdrawal symptoms (such as irritability, cravings to smoke, difficulty 
concentrating, headache, constipation, trouble sleeping). Participants who “earn” and 
elect to use the free trial of over-the-counter (OTC) NRT patches could experience 
additional side-effects (most commonly, rash/skin irritation at patch site, headache, 
nausea, and indigestion).  Participants will be informed of all anticipated risks in the 
informed consent. 
Participants can choose not to participate in this trial. While no publicly available 
treatments currently exist for smokers who are not ready to stop smoking, those who elect 
to quit can purchase OTC NRT from their local pharmacy and can seek assistance quitting  
by calling 1-800-Quit-NOW to enroll in their local state tobacco quitline or by contacting 
their personal health care provider.  
        2.3.2 Potential Benefits 
All participants may receive some satisfaction or indirect benefit from contributing to this 
research.  People who quit smoking may experience positive gains such as improved health 
and well-being.  An additional benefit for all participants is receipt of free smoking 
cessation treatment via the mHealth app. 
 


9 
 
2 OBJECTIVES 
2.1 
Study Objectives 
The primary objective of this pilot study is to evaluate the feasibility, acceptability, and 
potential effectiveness of a scalable mHealth intervention targeted to ambivalent smokers. 
The secondary objective of this study is to plan for a future randomized efficacy trial to test the 
program. 
2.2 
Study Outcome Measures 
As a pilot study, we do not have a single “primary outcome” of interest.  Rather, we will 
examine a range of measures designed to inform our study objectives: assess the program’s 
feasibility (program engagement), acceptability (ratings of satisfaction and helpfulness), impact 
on cognitive mediators of change (self-efficacy, outcome expectations, and motivation) and 
impact on indicators of smoking behavior change (quit attempts, smoking reduction, and 
abstinence).  
Outcomes will be used to assess whether the intervention warrants further refinement and 
whether a future randomized efficacy trial is warranted.  
2.2.1 
Primary  
The primary outcomes of interest that will be explored are: 
• Seven-day point prevalence abstinence (PPA) at 3-month follow up; 
• Total program log-ins to the assigned program during the study period at 3 months 
post-enrollment;  
• Self-reported presence of an intentional quit attempt lasting at least 24 hours since 
study enrollment by 3-month follow up. 
2.2.2 
Secondary 
Key secondary outcomes that will be explored at the 1-month follow up only: 
• Self-report of no smoking in the past 7 days. 
Key secondary outcomes to be explored at both the 1 and 3-month follow up include: 
• Overall satisfaction with assigned program;  
• Helpfulness ratings for each personal experiment, as well as satisfaction ratings of 
the associated experimental program features; 
• Self-report rating of motivation for quitting; 
• Self-report ratings of self-efficacy for quitting smoking; 
Secondary outcomes to be explored at the 3-month follow up only: 
• Cumulative duration of assigned program utilization in minutes, based on 
automated program tracking data. 


10 
 
2.2.3 
Other Secondary & Exploratory Outcomes 
Given the exploratory nature of this pilot study we will also examine a range of other 
potential secondary outcomes to include: program duration days, number of days quit 
attempts were maintained, any quit attempt, NRT earned, NRT requested, NRT used, 
program component contact time, use of each intervention component, number of 
personal experiments completed, stage of change, utilization badges earned, change in 
smoking rate, and self-reported outcome expectations, motivation and self-efficacy for 
staying quit; self-efficacy for enacting related behavioral skills targeted in the experimental 
intervention. 


11 
 
3 STUDY ENROLLMENT AND WITHDRAWAL 
3.1 
Subject Inclusion Criteria 
In order to be eligible to participate in this study, a participant must meet all of the following 
criteria (see also Eligibility Screen in Appendix D): 
• 18 years of age or older; 
• Speak/read English; 
• Want to quit smoking someday, but not planning to quit in the next month; 
• Are not actively using or seeking treatment to quit;  
• Smoked at least 100 cigarettes in their lifetime and smoked in the last 7 days; 
• Own and use a smartphone and use it at least weekly; 
• Are comfortable reading text on the screen or in text messages; 
• Willing to install the study app on their smart phone and use it; 
• Have a current iOS or Android operating system or are willing to update to one; 
• Are willing to use birth control if elect to use NRT during the study (females). 
3.2 
Subject Exclusion Criteria 
Individuals will be excluded if they: 
• Smoke less than 10 cigarettes per day 
• Self-report a lifetime history of dementia, manic depression, bipolar disorder, or 
schizophrenia;  
• Have medical contraindications for NRT (i.e., recent heart attack, an arrythmia, or 
currently pregnant);  
• Another household member is enrolled in the pilot study (based on self-report or 
mailing addresses on file for participants) 
• Study staff are unable to verify the phone number or email address provided (i.e., 
unable to complete the enrollment process) 
• Do not install the app during the study period 
 
3.3 
Strategies for Recruitment and Retention 
Recruitment:  
Our primary strategy will be to recruit a nationwide sample of smokers using online postings, 
ads and message boards (e.g., Craigslist, Facebook, online newspapers). 


12 
 
If recruitment lags, we will seek IRB approval to expand enrollment to smokers enrolled in 
Kaiser Permanente Washington or recruit via community flyers.  
Interested smokers will be directed to call the toll free study number at KPWHRI to learn more 
about the study and be screened for eligibility. We will adjust our recruitment posting, as 
needed, to ensure we meet our recruitment goal. Each participant will then be followed for ~3 
months post-enrollment. 
Retention:   
Several steps will be taken to ensure participant retention, as follows:  
• Participants will be compensated a $25 e-gift card for completing the baseline and each 
follow-up survey, for $75 total compensation.  
• Participants will receive an additional $20 e-gift card for providing timely biochemical 
confirmation of their smoking status via saliva testing following the 3-month survey. 
• Assessments will be kept brief and will be available for completion online.  If not 
completed online within 2 weeks, they will be offered by phone. 
• We will collect multiple forms of contact information in order to track participants, 
including: mailing address, email address, and phone number(s). 
3.4 
Treatment Assignment Procedures 
3.4.1 
Randomization Procedures  
Randomization will be automated using a stratified block randomization scheme. Participants 
will be randomized following completion of the online baseline survey. We will stratify by 
cigarettes per day (>15 vs. <15) and frequency of smartphone use (daily vs. non-daily) since 
these factors might influence quitting smoking and program participation.  Half will be 
randomized to each of the two study arms (control vs. experimental). Following randomization, 
participants will receive instructions on how to download and set up and access their assigned 
program on their smart phone. 
3.4.2 
Masking Procedures 
Participants will be blinded to their study arm. 
Staff completing follow-up surveys by phone will be blinded to participants’ treatment arm until 
the last section of the survey, which will contain additional satisfaction questions for the 
experimental arm. 
Staff who interpret the saliva test results will be blinded to participants’ study arm. 
3.5 
Subject Withdrawal 
3.5.1 
Reasons for Withdrawal 
Participants are free to withdraw from participation in the study at any time upon request. 
Individuals will be asked their reason for drop out and may be asked to provide information on 
the primary outcome variables if drop out occurs within ~ one month of a scheduled follow-up 
assessment.   


13 
 
An investigator may terminate a study subject’s participation in the study if: 
• Any adverse event (AE) or other medical condition or situation occurs such that 
continued participation in the study would not be in the best interest of the subject. 
• The subject meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation. For example, the participant is 
found to be ineligible after enrollment (e.g., prior household member enrolled). 
3.5.2 
Handling of Subject Withdrawals or Subject Discontinuation of Study 
Intervention 
Participants who request to drop out will be given the option to withdraw from participation in 
the intervention only, but to still participate in the follow-up evaluations.  Participants who 
refuse this offer and request to completely withdraw from the study will no longer be 
contacted. However, previously obtained data will be retained with subject consent. 
Budget permitting, we may attempt to recruit replacement participants for drop-outs. Persons 
who withdraw as a result of an adverse event will be referred for appropriate care. 
3.6 
Premature Termination or Suspension of Study 
This study may be prematurely terminated if, in the opinion of the investigator, the sponsor, or 
the IRB there is sufficient reasonable cause. Written notification, documenting the reason for 
study termination, will be provided to the investigator and/or sponsor by the terminating party. 
Circumstances that may warrant termination include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to subjects.  
If the study is prematurely terminated or suspended, the sponsor will promptly inform the 
investigators/institutions, and the regulatory authority(ies) of the termination or suspension 
and the reason(s) for the termination or suspension. The IRB will also be informed promptly 
and provided the reason(s) for the termination or suspension by the sponsor or by the 
investigator/institution, as specified by the applicable regulatory requirement(s). 
 


14 
 
4 STUDY INTERVENTION 
The study uses a parallel, two-arm, randomized trial design. Ambivalent smokers will be 
randomized to either an experimental or control intervention.   
4.1 
Description 
Both arms will receive an mHealth intervention consisting of:  
• 
Best-practice self-help guidance for quitting based on the US PHS’ Clinical Practice Guidelines for 
treating nicotine dependence and best practice treatment recommendations (aka, Quit Guide) 
• 
Ability to track how many cigarettes they smoke a day, calculate what they would save if they 
stopped smoking, read motivational testimonials from others, and take notes within the app on 
things they’ve learned. 
• 
A referral to their local state tobacco quitline. 
• 
The ability to earn and request a free 2-week starter kit of nicotine replacement patches. 
 
Experimental participants will also receive: 
• 
A series of 9 personal experiments, each designed to build motivation or teach the skills 
necessary to successfully cut-back or quit smoking. They may also receive reminder prompts to 
complete experiments which are not initiated or started. 
                                              -Proprietary Intervention Detail Redacted- 
 
4.2 
Administration of Intervention 
Subjects will download the app to their smart phone using instructions emailed to them and 
have access to the intervention for the full study period.  
Experimental participants will earn badges for each experiment they attempt (whether they 
succeed or not). Participants in both arms can earn badges for viewing/using other program 
content. 
4.3 
Assessment of Subject Compliance with Study Intervention 
System-generated program utilization data will be tracked during participants’ study 
enrollment. This will include the total number of program log-ins (both arms), features used, 
duration of time engaging with the program. Participant use of the program will also be 
assessed via self-report. 
 
 


15 
 
5 STUDY SCHEDULE 
5.1 
Screening and Enrollment  
Interested smokers will phone the study toll free number to request a call back in response to 
ads placed online. Smokers currently on KPWHRI’s wait list for smoking-related research studies 
may also be contacted and invited to be screened.  
Study staff will administer an eligibility screening questionnaire to interested smokers by 
phone. Those found to be eligible will be read an informed consent script and then emailed a 
link to the study information sheet to read. The study team may email a PDF as a back-up 
method if a participant is unable to open the information sheet using the link provided.  
If after reviewing the information sheet they elect to join the study, they will be instructed to 
complete the online baseline survey within the next 7 days. The study will consider an eligibility 
screening to ‘expire’ after 14 days of non-response and a new eligibility screening questionnaire 
will be required. 
5.2 
Baseline and Randomization 
Consenting participants will be emailed a link to complete the online baseline survey. Following 
completion of the baseline survey, they will be automatically randomized and provided 
instructions for accessing their assigned version of the app on their smartphone. Staff will be 
available to assist with this, as needed. Randomization date is Day 0. 
5.3 
1 and 3-month Follow-up Assessments 
Self-reported follow-up data will be assessed at 1 and 3-months post-enrollment using an 
online survey with phone follow-up.   
Following completion of all study activities (3 month assessment and cotinine verification, if 
applicable, or a failure to complete the 3 month survey in the allowed timeframe), staff will 
turn off participant’s access to the app from the back-end administrative dashboard. 
5.4 
Biochemical Verification – In-Home Cotinine Saliva Test 
The original study plan included biochemical confirmation of abstinence at 3 month follow-up. 
Due to a programming error, not all non-smokers were identified and flagged for this 
assessment, so this was dropped in the final plan. 
 


16 
 
6 STUDY PROCEDURES /EVALUATIONS 
Standard operating procedures for the study will be detailed in the Manual of Procedures 
(MOP), which will be provided to study staff prior to study start-up. Overviews of the 
procedures are provided here. Data collected will be directly entered into our electronic data 
collection system.  


17 
 
7 STUDY OVERSIGHT 
According to NCI’s Policy for Data and Safety Monitoring of Clinical Trials 
(http://deainfo.nci.nih.gov/grantspolicies/datasafety.pdf), the method for monitoring patient 
safety should be commensurate with the level of risk.  For Phase I and II trials, a DSMB is not 
required and data safety can be monitored by the study PI and/or project manager. 
For the current low risk pilot study, the study PI will be responsible for monitoring the data 
integrity and patient safety as outlined above.  


18 
 
8 ASSESSMENT OF SAFETY 
8.1 
Specification of Safety Parameters 
This is a minimal risk behavioral intervention.  Nevertheless, adverse events (AEs) and serious 
adverse events (SAEs) will be recorded and reported over the course of the study. 
An adverse event is any untoward or unfavorable medical occurrence in a human subject, 
including any abnormal sign (for example, abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with the subject’s participation in the research, 
whether or not considered related to the subject’s participation in the research. 
Project staff with participant contact will be trained to identify potential AEs and SAEs and 
instructed to report them immediately to the study PI and the project manager.   
8.1.1 
Severity of Event 
The following scale will be used to grade the severity of adverse events: 
1) Asymptomatic or mild symptoms; no intervention needed (non-serious); 
2) Moderate: minimal, local, or non-invasive intervention indicated; limiting on ADL (non-
serious); 
3) Severe or medically significant but not immediately life threatening; hospitalization or 
prolonged hospitalization needed; disabling; limited self-care ADL (serious); 
4) Life-threatening; urgent intervention required (serious); 
5) Death related to AE (serious).  
8.1.2 
Non-serious Adverse Event Reporting 
Non-serious AEs will be reported annually to the IRB. 
8.1.3 
Serious Adverse Event Reporting 
All serious AEs will be reported within 48 hours, consistent with KPWHRI IRB policy and NIH 
guidelines.  All participants learned to be deceased, regardless of the cause of death or 
relatedness to the program, will be reported to the IRB.  The IRB will work with the PI to ensure 
additional agencies (e.g., NIH, etc.) are notified as required. All SAEs will be followed until 
satisfactory resolution or until the PI deems the event to be chronic or the patient to be stable. 
8.1.4 
Expected Adverse Reactions 
Expected adverse events include: 
• Upset due to participation in research assessments.  Such reactions are expected to be 
mild and transient.   
• Nicotine withdrawal. Participants who chose to quit smoking may experience nicotine 
withdrawal symptoms such as irritability, cravings to smoke, difficulty concentrating, 
headache, constipation, and trouble sleeping. 


19 
 
• NRT side-effects.  Participants who chose to use the optional OTC NRT patches may 
experience side-effects such as rash/skin irritation at patch site, headache, nausea, and 
indigestion. These adverse events are expected, transient, and generally mild to 
moderate intensity. While NRT use is considered safer than smoking, female 
participants will be advised to use birth control while using NRT. 
8.2 
Time Period and Frequency for Event Assessment and Follow-Up 
Reportable events will be recorded in the data collection system throughout the study. Events 
will be followed for outcome information until resolution or stabilization.   
The PI will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study 
participation.   
8.3 
Characteristics of an Adverse Event 
8.3.1 
Relationship to Study Intervention 
The Study PI will determine is AE’s are deemed possibly related to the individual’s study 
involvement.  The following guidelines will be used.   
• Associated – The event is temporally related to the study participation and no other 
etiology explains the event.  
• Not Associated – The event is temporally independent of study participation and/or the 
event appears to be explained by another etiology 
8.3.2 
Expectedness of SAEs 
The Study PI will be responsible for determining whether an SAE is expected or unexpected.  An 
adverse event will be considered unexpected if the nature, severity, or frequency of the event is 
not consistent with the risk information previously described for the intervention. 
8.4 
Unanticipated Problem  
8.4.1 
Definition 
The Office for Human Research Protections (OHRP) considers unanticipated problems (UP) 
involving risks to subjects or others to include, in general, any incident, experience, or outcome 
that meets all of the following criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved 
research protocol and informed consent document; and (b) the characteristics of the 
subject population being studied; 
• Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 


20 
 
• Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
8.4.2 
Unanticipated Problems Reporting to IRB and NCI 
Incidents or events that meet the OHRP criteria for unanticipated problems will be reported to 
the IRB within 48 hours of when the team is made aware of the event. 
Unanticipated problem reports will include: 
• Appropriate identifying information for the research protocol, such as the title, 
investigator’s name, and the IRB project number;  
• A detailed description of the adverse event, incident, experience, or outcome;  
• An explanation of the basis for determining that the adverse event, incident, 
experience, or outcome represents an unanticipated problem;  
• A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the unanticipated problem 
The IRB will determine if other immediate action is required (e.g., suspension of recruitment, 
protocol closure, etc.).  Temporary or permanent suspension of an NIH-funded protocol will be 
reported to the NCI Program Official responsible for the grant. 
8.5 
Halting Rules 
Study halting may occur as required by the IRB or NCI.  The study PI may temporarily suspend 
enrollment pending review by these authorities if warranted based on the presence, type, or 
frequency of SAE’s or other changes in the study protocol which may place participants at 
greater than anticipated risk. 


21 
 
9 CLINICAL SITE MONITORING 
Clinical site monitoring will not be done for this study; however, the NCI reserves the right to 
conduct independent audits or clinical monitoring as necessary. 
 


22 
 
10 STATISTICAL CONSIDERATIONS 
10.1 
Study Hypotheses 
We hypothesize that by engaging in the experiments, ambivalent smokers in the intervention 
arm will have successive mastery experiences which will build their confidence and positive 
outcome expectations (i.e., belief that I can control my smoking or I can quit when I am ready) 
and, in turn, will better motivate them to change their smoking behavior, including making a 
successful quit attempt and, possibly, quitting smoking. We also expect that experimental 
participants will be more likely to use the provided nicotine replacement patches and tobacco 
quitline referral than are control participants. 
 
10.2 
Sample Size Considerations 
The primary analytic goals of this pilot study are to assess feasibility and to estimate the 
magnitude of intervention effects on study outcomes.  The target sample size (n = 60) for this 
pilot is based on recommended guidelines for estimating effect sizes in behavioral treatment 
development research22 and not on our anticipated intervention effect size. By design, the pilot 
trial is not powered to evaluate efficacy or to test for statistically significant differences 
between intervention groups. 
 
10.3 
Final Statistical Analysis Plan 
All summaries and analyses will be limited to randomized individuals who installed the app 
using a modified intent-to-treat approach, whereby participants are labeled by their 
randomization group regardless of app usage. However, when assessing self-reported 
satisfaction with specific app features, analyses will be restricted to participants who both self-
report use of the feature and whose automated data confirm this use. This is done to eliminate 
ratings from people who either did not use each feature or recall its use, both of which could 
invalidate users’ ratings. 
 
First, descriptive statistics will be used to characterize the baseline sample. Summaries across 
arms for outcomes of interest 1- and/or 3-months post-baseline will be conducted in addition 
to counts of Experiments completed in the experimental arm.  
 
Similar statistical methodology will be used to conduct inference for all outcomes. Regression 
models will be fit using generalized estimating equations with robust standard errors and an 
exchangeable working correlation. When applicable for a given outcome, the regression model 
will be fit to outcomes collected at both time points simultaneously, even if reported 
separately. For each binary outcome of interest—such as 7-day PPA and having a successful 24-
hour smoking quit attempt—we will initially attempt to estimate relative risks (RR) of the 
outcome in the experimental app relative to the control app using a Poisson regression model. 
When outcomes are too rare to obtain estimates of relative risks, we will fit linear regression 
models to binary outcomes and estimate risk differences (RD) of the outcome instead. Linear 


23 
 
regression models will be fit to continuous outcome data—including number of program log-
ins, Likert scales for self-efficacy and satisfaction and average number of cigarettes smoked per 
day—to estimate mean differences in the outcome across app versions.  All point estimates will 
be accompanied by 95% confidence intervals and P-values from two-sided Wald tests.  
 
All app comparisons will adjust for the assigned app, number of cigarettes smoked at baseline, 
and when applicable, the time of survey collection and interaction between follow-up time and 
assigned app. The latter interaction allows for results to be presented separately at one and 3-
months post-baseline. If the outcome measure is collected at baseline and not identical across 
all participants at baseline, we will additionally adjust for the outcome measure at baseline. 
With this adjustment, the estimated average difference across study arms may also be 
interpreted as the average difference in change from baseline across arms. Depending on 
differences identified between arms at baseline that were not avoided despite randomization 
by chance, additional potential confounders may be adjusted for.  
 
Outcomes collected via follow-up surveys are subject to missingness; however, per convention, 
missing data for smoking cessation outcomes will be imputed as smoking or failing to 
successfully quit smoking for at least 24 hours. For these outcomes, additional sensitivity 
analyses will be conducted using (1) complete cases only and (2) completed assessments using 
multiple imputation by chained equation24 with 10 imputed data sets created with logistic 
regression imputation using Barnard-Rubin adjusted degrees of freedom25. For all other 
outcomes, analyses will use complete cases only. Further sensitivity analyses may consider 
modification of the effect of intervention on the primary outcomes by gender. 
 
 


24 
 
11 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
Study staff will maintain appropriate treatment and research records for this study, in 
compliance with ICH E6, Section 4.9 and regulatory and institutional requirements for the 
protection of confidentiality of subjects.  Study staff will permit authorized representatives of 
NCI and regulatory agencies to examine (and when required by applicable law, to copy) 
research records for the purposes of quality assurance reviews, audits, and evaluation of the 
study safety, progress and data validity.   
 
 
 


25 
 
12 ETHICS/PROTECTION OF HUMAN SUBJECTS 
12.1 
Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with the principles 
set forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research, as drafted by the US National Commission for the Protection of Human 
Subjects of Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR Part 46 
and/or the ICH E6.  
12.2 
Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IRB for review and approval.  IRB approval of the protocol and consent 
processes must be obtained before any subject is enrolled.  Any amendment to approved study 
materials will require re-review and approval by the IRB before the changes are implemented in 
the study.   
12.3 
Informed Consent Process 
Each person will provide consent to be screened for eligibility by phone.  If screened eligible, 
they will provide verbal consent and be emailed a link to a study information sheet for their 
records. The study team may email a PDF as a back-up method if a participant is unable to open 
the study information sheet using the link. 
Informed consent will include permission for contacting participants by push 
notification/mail/email/text to remind them of follow-up surveys and other study events and 
permission to collect all study data and track their use of the program. It will also include 
permission to order a 2-weekly supply of NRT patches from an online pharmacy and have it 
sent to participants’ homes, for those participants meet the study requirements to receive the 
NRT and also specifically request for it to be mailed to them. (Note: receipt of the NRT is 
optional for participants.)  
Participants are free to refuse to answer any survey questions or drop out of the study at any 
time.  Participants will be instructed how to discontinue involvement in the intervention or 
drop out of the study as part of the consent process.     
 
12.4 
Exclusion of Women, Minorities, and Children (Special Populations) 
Individuals of any gender or racial/ethnic group may participate. Children under the age of 18 
years will be excluded. 
12.5 
Subject Confidentiality 
Appropriate steps will be taken to safeguard participant confidentiality.  This includes the 
following: 
• KPWA is a HIPAA covered entity and complies with all HIPAA regulations regarding data 
security. All study files will be maintained in a centralized location on the KPWHRI 


26 
 
departmental server. Access to this data is password protected and subject to the same 
security protections as other confidential health plan data. Access will be limited to staff 
working on this study and require access to these files. All staff are trained in 
appropriate security protections, computer passwords are changed on a regular basis, 
and all staff sign annual confidentiality agreements. 
• Participants’ identities will not be shared with anyone other than relevant team 
members at KPWHRI as needed to perform their study roles. 
• Electronic communications we send will not contain personal health information (PHI) 
other than references to smoking and participant first names. 
• Biochemical confirmation of smoking abstinence will be remotely monitored using a 
secure video conference software for Apple and Android devices. The software does not 
store or access PHI, uses encrypted video streaming to protect confidentiality, and does 
not allow video sessions to be recorded, to further protect patient confidentiality. 
• Participant information will not be stored on their phones. Data generated by the app 
will be encrypted when transmitted and then securely stored in a back-end database 
behind the KP firewall. Access will be limited to staff who need it, who will log-in using 
their NUID or other secure password (as recommended by KP). 
• Data exported from the backend database will be stripped of identifiers before being 
stored or analyzed. 
• Data from study surveys (collected in REDCap) will not be tied to personal identifiers. 
12.6 
Future Use of Identifiable Data 
Identifiable information will be destroyed within 5 years of the end of the study, consistent 
with HIPAA and our IRB requirements. 
We have no plans to retain identifiable information beyond this period.  If this plan changes, we 
will obtain appropriate IRB approval and participant consent. 
 


27 
 
13 DATA HANDLING AND RECORD KEEPING 
13.1 
Data Management Responsibilities 
Data collected will be captured in electronic records (e.g., REDcap).   
Final datasets will be saved electronically, clearly labeled and stored in a secure project folder 
on the KPWHRI server accessible only to study staff.   
No electronic participant data shall be overwritten by study staff.  As necessary, variables may 
be recoded into new variables for analyses, but will done in a way to preserve the original 
record. All changes will be documented. 
13.2 
Types of Data 
Data for this study will include eligibility screening, baseline and follow-up assessments, web 
analytics monitoring the program use, confirmation of smoking abstinence, and safety data. 
13.3 
Data Capture Methods 
• Eligibility screening and consent will be completed by telephone and documented in 
REDCap. 
• The baseline assessment will be completed by participants online in REDCap.  
• Participants will be sent a link to complete the 1 and 3-month follow-up surveys online 
in REDCap. If unresponsive to the online survey, study staff may attempt to administer 
the assessment by phone. 
• Video-based confirmation of smoking abstinence will be conducted using a secure 
telemedicine program. Participants will use saliva test kits mailed to them by the study. 
Results of biochemical confirmation of abstinence will be recorded in REDCap by study 
staff and a photo of the de-identified saliva test securely saved to the study files. 
• Adverse events may be self-reported to study staff via email or by phone. Events will be 
documented in study records and followed up for resolution and stabilization, as 
appropriate. Adverse events will not be reported or tracked through the 
intervention/app. 
• All electronic records will be kept in a 21 CFR Part-11 compliant data capture system, 
which includes password protection. 
13.4 
Study Records Retention 
All study data will be maintained for at least 5 years after the conclusion of the study.  At that 
time, consistent with HIPAA guidelines, identifying information and linking files will be 
destroyed unless consent to retain these files is granted by study participants or the IRB. 
13.5 
Protocol Deviations and Violations 
All staff will immediately report protocol deviations and violations to the KPWHRI Project 
Manager, who will inform the PI.  Deviations will be considered any noncompliance with this 
clinical trial protocol, Good Clinical Practice, or the Manual of Procedures.   


28 
 
Protocol deviations will be reported annually to the IRB. Protocol violations will be reported to 
the IRB in a timely manner.   
 


29 
 
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