Mobile Health Technology for Personalized Tobacco Cessation Support in Laos
Phase: PHASE2
Conditions: Cigarette Smoking
Sponsor: University of Oklahoma

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RESEARCH PROTOCOL 
 
 
(Last updated: July 15, 2020) 
 
Title of Project: Mobile Health Technology for Personalized Tobacco Cessation Support in 
Laos (Support Laos) 
 
Principal Investigator: 
Thanh Cong Bui; MD, DrPH 
Department of Family and Preventive Medicine, 
Stephenson Cancer Center 
 
Abstract 
Tobacco use remains the leading cause of preventable morbidity and mortality in Lao 
People's Democratic Republic (Lao PDR). This project adapts our theoretically and 
empirically based mobile health (mHealth) technology to help Lao people quit smoking 
cigarettes. This mHealth approach includes a fully automated, interactive, personalized, 
smartphone-delivered intervention for behavioral treatment, delivered through our 
Insight™ platform. The proposed project includes 2 main phases. In the R21 Phase, we 
will use formative research methods to adapt our intervention content to the sociocultural 
context, language, and communication styles of Laotians. In the subsequent R33 Phase, 
we will conduct a randomized controlled trial to evaluate the efficacy of our mHealth 
intervention and technology. In the trial, adult smokers of both sexes will be recruited 
through 2 large hospitals: Setthathirath Hospital in Vientiane and Champasak Hospital in 
Champasak Province. Participants (n=500) will be randomized to either Standard Care 
(SC; n=250) or Automated Treatment (AT; n=250) group. SC consists of brief advice to 
quit smoking delivered by research staff, self-help written materials, and a 2-week supply 
of nicotine replacement therapy (transdermal patches). AT consists of all SC components 
plus a fully automated smartphone-based treatment program that involves interactive and 
personalized proactive messages, images, or videos. 
 
Protection of Human Subjects: 
The study protocol and all related research materials (e.g., informed consent forms and 
assessments) will be reviewed and approved by the Institutional Review Boards (IRBs) of the 
Ministry of Health - Lao National Ethics Committee for Health Research (NECHR) IRB #1 
(IRB00006227) and of The University of Oklahoma Health Sciences Center (OUHSC). Our 
collaborative hospitals—Setthathirath Hospital and Champasak Hospital—are under 
supervision/management of the Ministry of Health of Lao PDR and have assurances relying 
upon the NECHR IRB#1 (FWA00026579 and FWA00028083, respectively). 
 
A. SPECIFIC AIMS 
The specific aims are to: 

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- 
Aim 1 (R21 Phase): Adapt the AT content to the Lao sociocultural context and 
communication styles. 
- 
Aim 2 (R33 Phase): Conduct a randomized trial to evaluate the efficacy of AT. 
Hypothesis: At the 12-month follow-up, 7-day point prevalence abstinence will be higher 
in the AT (vs. SC) group. 
- 
Aim 3 (capacity building): Advance mHealth research capacity in Lao PDR and sustain 
the US-Lao PDR research network by supporting Lao investigators through in-person 
workshops, in-service trainings, online trainings, manuscript preparation, and future 
mHealth research collaboration and grant applications. 
The US and Lao researchers are committed to a long-term partnership beyond this proposed 
project, with the goal of sustaining an affordable nationwide mHealth intervention for tobacco 
cessation and for other health promotion programs in Lao PDR. We have involved Lao 
stakeholders at national institutions, including national/regional hospitals, National Tobacco 
Control Committee (NTCC), and the Ministry of Health (MOH) in this project. If our findings 
indicate that AT is effective, this collaboration with influential Lao governmental agencies will 
facilitate wide-scale dissemination to other hospitals/clinics across the country. Thus, the project 
has the potential to transform healthcare services for tobacco treatment throughout the country 
and, ultimately, to significantly reduce tobacco-induced morbidity and mortality. The project will 
also contribute to creating a knowledge base for mHealth research applications in LMICs and 
advancing mHealth research capacity in Lao PDR (e.g., the use of mHealth tools for adaptive 
personalized interventions and analyzing ecological momentary assessment data). 
 
B1. BACKGROUND AND SIGNIFICANCE 
Globally, tobacco causes approximately 6 million deaths each year, of which 80% occur in 
low- and middle-income countries (LMICs).9,10 Tobacco use is the most important modifiable 
risk factor for cancer prevention and is a leading preventable cause of death9; smoking 
prevention and cessation are the most impactful and cost-effective interventions among the many 
recommended evidence-based preventive health services.11 Despite the need, cessation 
treatments in LMICs are often unavailable or unaffordable for most people.9 
Of 7 million citizens in Lao PDR, 51% of men and 7% of women smoke tobacco.1,12 
Although several tobacco control efforts have been implemented in Lao PDR (e.g., taxing 
tobacco products, expanding smoke-free environments, requiring health warnings on cigarette 
packaging, and comprehensive bans of tobacco advertising), no national tobacco treatment 
programs are available;12,13 we confirmed this in recent discussions with leaders of the National 
Tobacco Control Committee (NTCC) of Lao PDR. NTCC also described a pilot quitline with 
telephone counseling at the national Mahosot Hospital. However, funding limitations restrict 
NTCC’s ability to train more counselors and retain them for a nationwide implementation. Thus, 
there is a pressing need for evidence-based and highly scalable tobacco cessation treatment in 
Lao PDR to prevent smoking-related morbidity and mortality. Our project will address this 
unmet need. 
Potential of mHealth interventions. The World Health Organization (WHO) acknowledges 
that mHealth could transform the face of health service delivery across the globe, including in 
least-developed countries (LDCs).2 Data from the International Telecommunication Union, 

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which is the United Nation’s official source for global information technology statistics, show 
that mobile-cellular subscriptions now make up >98% of voice subscriptions in LDCs.14 Active 
mobile-broadband subscriptions grew extremely rapidly from 4% in 2007 to 56% in 2017, 
without signs of faltering.14 Mobile-phone prices in LDCs, including Lao PDR, decreased from 
29% of gross national income per capita in 2010 to 14% by the end of 2014, resulting in 
increased ownership rates.15 Worldwide, the Asia and Pacific regions have the lowest average 
prices of mobile phones and cellular service and the most aggressive competition in prepaid 
mobile-cellular service.15 In some LDCs in the region, including Lao PDR, prepaid handset- 
based mobile-broadband prices are less than 5% of gross national income per capita, making 
them outstanding examples for affordable mobile-broadband services in LDCs. In Lao PDR, 
there are 4 major mobile operators, 2 of which launched LTE in 2015.16 In recent years, mobile- 
cellular subscription rates in Lao PDR ranged from 56%–68%;15-17 half of these included mobile- 
broadband subscriptions.14 Although these subscription rates are moderate compared with the 
regional average, the most recent data indicate that Lao PDR was in the top 5 countries globally 
for increased mobile-broadband subscriptions from 2016–2017,14 suggesting substantial growth 
in mobile-broadband coverage and usage in the near future. Most smartphones (80%) in Lao 
PDR are Android-based (predominantly Samsung and Huawei)18 and can function in Lao script. 
In summary, smartphone ownership is clearly increasing in Lao PDR, providing an ideal yet 
largely untapped mechanism to deliver smoking cessation treatment. 
A small but growing body of research indicates that mHealth interventions are feasible in 
Lao PDR. For example, the Lao PDR Ministry of Health (MOH) supported the use of the Safe 
Delivery mobile app to provide midwives with direct and instant access to evidence-based and 
up-to-date clinical guidelines on basic emergency obstetric and neonatal care, making childbirth 
safer, especially in the most remote areas.19 Short message service (SMS) is also used in a real- 
time reporting system for vaccine administration and monitoring.20,21 The MOH’s receptiveness 
and support of mHealth solutions increase the potential for sustainability and widespread 
adoption of our proposed mHealth intervention approach. 
The effectiveness of smoking cessation interventions using text messaging, traditionally 
delivered via SMS, is shown in both randomized controlled trials (RCT) and a recent Cochrane 
review.3,4 A thorough economic analysis demonstrated that a mobile phone text messaging 
intervention for smoking cessation is cost-effective.5 Indeed, mobile phone-delivered text 
messaging has been identified as one of the most affordable interventions8 and has been endorsed 
and used by several international organizations, including the WHO, in their global tobacco 
control efforts.6,7 Development and evaluation of advanced smartphone-delivered interventions 
are ongoing. Leading app stores house >170 English-language apps designed to facilitate 
smoking cessation; however, only 6 of these are scientifically grounded, and only 3 of these have 
demonstrated a positive impact on abstinence compared to a control condition in pilot RCTs.22 
While the evidence base for these next generation interventions has not yet been established, 
many agencies such as the US National Cancer Institute have made scientifically-supported apps 
available for public use.23 
Summary. Cigarette smoking represents a major public health problem in LMICs including 
Lao PDR. However, both the literature and our discussions with key stakeholders in Lao PDR 
reveal a lack of national smoking cessation treatment programs. Our proposed study will 
evaluate our already developed cutting-edge mHealth intervention – Automated Treatment (AT) 
– for smoking cessation in Lao PDR. Given AT’s potential as a feasible, scalable, and highly 
affordable stand-alone intervention, our approach is appropriate for use in LMICs and could 

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substantially reduce smoking prevalence and smoking-related morbidities in the Lao 
population. The sustainability and potential for widespread adoption are enhanced by the direct 
involvement of Lao PDR governmental stakeholders at multiple institutes. Furthermore, it is 
largely unknown whether effective cessation interventions from high-income countries are 
transferable and applicable to LMICs;9 thus, our proposed work will address this gap in 
knowledge. Finally, the US-Lao collaborative work and capacity building activities in this 
project will advance mHealth research capacity and mHealth use in Lao PDR. Therefore, the 
proposed project is consistent with the objectives of this R21/R33 funding mechanism. 
 
B2. INNOVATION 
Our mHealth Technology Shared Resource (Director: Dr. Businelle, co-I) has developed the 
novel HIPAA-compliant Insight™ mHealth platform (see Appendix). The Insight™ platform 
empowers researchers to build, test, and launch secure technology-based assessment and 
intervention tools for various health behaviors or issues. The versatile Insight™ platform enables 
researchers to track momentary changes in key variables from multiple data sources (i.e., phone- 
based surveys, sensor data, geolocation data) in near real-time and use this information to initiate 
interventions. The Insight™ platform has 2 primary components: a web-based Content 
Management System (Insight™ CMS) and an Insight™ app (a smartphone application shell). 
Once a project is created in the CMS, researchers can use the intuitive interface to select and use 
emerging approaches in research (e.g., ecological momentary assessments [EMA] or just-in-time 
adaptive intervention), features (e.g., facial recognition, activity monitoring, and remote carbon 
monoxide [CO] monitoring), assessment types, and intervention delivery options that are needed 
for the project. Currently, the Insight™ platform has been utilized in 40 projects focusing on 
diverse health behaviors, such as smoking cessation, alcohol cessation, sedentary behavior 
reduction, medication adherence, and linking homeless adults with case managers. Each project 
is firewalled from all other projects. 
In this project, US and Lao investigators will jointly use the Insight™ platform to deliver and 
manage AT. This use of Insight™ is innovative in several aspects. Insight™ allows our AT to 
function autonomously and minimizes human involvement, making the approach very 
affordable for large-scale implementation in LMICs. Using Insight™ CMS, investigators can 
easily load all intervention content and assessments and preschedule delivery dates and times. 
Through one-click buttons in the Insight™ app, participants can call or message project staff if 
they have questions or need assistance. During large-scale implementation of AT beyond this 
project, Lao researchers could also use the Insight™ CMS to modify the intervention (e.g., 
adding relevant treatment content in Lao or change assessment frequency). In other words, Lao 
researchers can directly manage AT whenever and however they wish without knowledge of 
programming languages. 
The use of Insight™ to deliver AT has several other advantages over the traditional SMS 
approach. While an SMS intervention would work on virtually all phones in Lao PDR, it requires 
an active cellular network connection. Our Insight™ app will automatically deliver all 
interventions and assessments as prescheduled, with or without an active connection, thus 
ensuring timely and reliable AT delivery throughout the 6-month treatment period. Similarly, 
Insight™ can deliver preloaded video content as needed while traditional SMS can only deliver a 
link and requires an active connection to view the media. Most importantly, Insight™ enables 
complex built-in algorithms and branching logic, allowing us to create and deliver dynamically 

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and individually tailored treatment content. Specifically, based on participant responses to 
baseline and in-clinic assessments, Insight™ will automatically select intervention content 
personalized to each individual’s characteristics, including biological sex and health conditions 
(e.g., lung or cardiovascular diseases). The weekly assessment will capture each individual’s 
thoughts, feelings, and behaviors (e.g., distress or self-efficacy) and behavioral phases (e.g., 
cessation vs. maintenance) following the Phase-Based Model.24,25 Utilizing these near real-time 
data, Insight™ will automatically select and schedule delivery of adaptive intervention content 
for the next week. Such a complex level of personalization and data-driven intervention is not 
possible with traditional SMS without intense human involvement. Because of the clear 
advantages, we propose to use the Insight™ app, although the Insight™ platform can deliver 
messages and links via SMS. While the use of Insight™ and smartphones may currently exclude 
some very low-income smokers, data shows that smartphone ownership is nearing ubiquity 
globally, including in Lao PDR (particularly, by the time the project is completed in 2025). Thus, 
our proposal to use Insight™ and smartphones for AT delivery represents an attempt to utilize 
powerful technology while maximizing reach and impact. 
In addition to addressing a critically important public health problem in Lao, the proposed 
project will allow our Lao-based investigators to become familiar with the Insight™ system and 
its capabilities. The Insight™ platform can be used to intervene upon health behaviors other than 
smoking cessation. In future collaborative studies, we envision evaluating advanced InsightTM 
features for other integrated healthcare services for Laotians (e.g., using facial recognition and a 
pillbox sensor to monitor medication adherence in smokers with tuberculosis). Lao researchers 
may also initiate Insight™-based intervention research tailored to the needs of their nation in 
collaboration with the US team. Our project will provide a strong foundation for future 
continued applications of mHealth intervention research in Lao PDR. 
Several other aspects of the proposed work are innovative. First, our AT is theoretically and 
empirically based. While several theory-based intervention studies (including our own) have 
been conducted in developed nations, efforts to adapt and disseminate these interventions to 
LMICs, such as Lao PDR, are lacking. In fact, there is no publication of theoretically based 
smoking cessation research in Lao PDR. Even in the US, where numerous smartphone apps for 
smoking cessation are available, only 4% of the top 50 apps in leading app stores have any 
scientific basis.22 Our proposed project is the first effort in Lao PDR to adapt a mHealth 
intervention for smoking cessation that is theoretically and empirically based and culturally 
tailored. Second, this project is a close collaboration between US investigators and Lao 
stakeholders at many institutions, including national/regional hospitals, the MOH, and the NTCC 
(see Research Team). The US and Lao researchers are committed to a long-term partnership to 
build and sustain a national mHealth treatment program for tobacco cessation in Lao PDR. 
This committed partnership will provide critical infrastructure to support the future widespread 
adoption and sustainability of AT in Lao. Finally, through collaboration and capacity building 
activities, this project will be the first to train Lao investigators in EMA methodology and will 
strengthen overall mHealth research competencies in Lao PDR. In summary, the project will lay 
the groundwork for a sustained US-Lao mHealth research network that will support future high 
quality mHealth research projects in Lao PDR. 
 
C1. RESEARCH TEAM 
A uniquely qualified multidisciplinary research team has been assembled for this project. Dr. 

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Bui (PI) has extensive experience conducting health promotion research in international settings 
and in mixed-methods studies.1,26-32 Other US co-investigators (co-I) bring valuable expertise in 
mHealth tobacco cessation for low-income and other underserved populations (Dr. D. Vidrine, 
Dr. Businelle),33-38 tobacco health risk communication (Dr. J. Vidrine),39-42 mHealth 
methodology (Dr. Businelle),43-46 and biostatistics (Dr. Frank-Pearce).44,45,47,48 Dr. Xangsayarath 
is the Vice Director of the National Center for Laboratory and Epidemiology (NCLE), a core unit 
of the Lao MOH that is responsible for a wide range of public health issues, including 
tuberculosis and other respiratory infections control. Dr. Xangsayarath was the PI of the National 
Adult Tobacco Survey (NATS) and has unique expertise regarding tobacco use in Lao PDR. Dr. 
Phandouangsy is the Deputy Head of the Secretariat of NTCC – an official inter-ministerial 
governmental authority responsible for tobacco control in Lao PDR, led by MOH. In this 
position, she provides technical support and oversight to several national tobacco control 
programs, including all 4 WHO-funded Global Youth Tobacco Surveys since 2003. Dr. Bui has 
worked with Drs. Xangsayarath and Phandouangsy since June 2017 to analyze the NATS data 
and prepare manuscripts.1 Drs. Keopaseuth and Keothongkou are Directors of the Setthathirath 
Hospital and Champasak Hospital, respectively, where the proposed R33 Phase will be 
implemented. 
 
C2. PRELIMINARY STUDIES 
Most relevant to this proposal is our most recent pilot work (with qualitative and quantitative 
components) at an HIV clinic in Phnom Penh, Cambodia.32,50 We linguistically and culturally 
adapted the intervention for Cambodian smokers, and then conducted a pilot RCT comparing SC 
(n=25) to AT (n=25) delivered by our Insight™ platform. Of all scheduled notifications and 
weekly assessments during the 2-month treatment period, 75% were delivered properly (i.e., the 
phones were properly charged, turned on, and not lost). Of all delivered messages and 
assessments, 81% were opened, as indicated by the digital date/time stamp. Retention through 
the end of the 2-month treatment period, as indicated by returning to the clinic for biochemical 
confirmation of smoking status (expired CO) was very promising – 100% in the AT group and 
92% in the SC group. The biochemically verified 7-day point prevalence abstinence rate at 2 
months was 40% in the AT group and 8% in the SC group (RR=5.0; 95% CI: 1.2–20.5). The 
AT group also scored significantly better (p=0.001) on knowledge items about smoking-related 
health risks and had a greater, but nonsignificant, change in cessation self-efficacy. Most 
participants agreed that the AT program was helpful in supporting smoking cessation (92%) and 
would recommend it to other smokers (88%). These data demonstrate the acceptability, 
feasibility, reliability, simplicity, and preliminary efficacy of our AT technology in LMICs. 
This success suggests that AT may be appropriate and efficacious in Lao PDR, a culture 
comparable to Cambodia. 
 
D. RESEARCH DESIGN AND METHODS 
D1. Overview 
This proposed project includes 2 main phases: the R21 and the R33. In the R21 Phase, we 
will use various formative research methods to validate and adapt our intervention content to the 
sociocultural context, language, and communication styles of Laotians. In the R33 Phase, we will 
conduct a 2-group RCT to compare the efficacy of 2 smoking cessation interventions: 
smartphone-delivered automated treatment (AT; n=250) versus standard care (SC; n=250). 

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D2. R21 Phase (2 years, July 2020 – June 2022): Adaption of the AT intervention content 
Because we will adapt an existing AT intervention that is theoretically-based and has 
demonstrated efficacy in our previous RCTs, we will use the cultural adaptation of evidence- 
based interventions approach.51,52 Although several models have been proposed to guide cultural 
adaptation, there is considerable consensus that cultural tailoring can be organized into 5 stages: 
information gathering, preliminary design, preliminary testing, refinement, and final trial.52 
Figure 1 summarizes our R21 research activities. 
In stage 1, formative research, including literature searches, quantitative results, and 
qualitative methods (e.g., key informant interviews) are often conducted to determine how well 
an original intervention will fit the needs and preferences of the target population. We have 
already partially completed this stage. Specifically, we have conducted literature searches, 
analyzed quantitative results of the NATS,1 and discussed our intervention approach with 5 key 
stakeholders (at the MOH, NTCC, and University of Health Sciences in Lao PDR). Information 
gathered from these activities helped us to shape this proposed project. For example, NATS data 
show that ~90% of male tobacco users smoke cigarettes;1 thus, we will adapt the AT intervention 
to target cigarette smokers first. MOH and NTCC stakeholders confirmed that the AT has great 
potential regarding scalability and sustainability. NTCC’s previously developed materials in Lao 
for smoking cessation support will be used for the SC group or to adapt our intervention content 
library. 

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Figure 1: Adaption of the AT intervention content 
In this project, we will 
conduct in-depth interviews 
with 30 healthcare providers 
at participating hospitals to 
learn more about how they 
typically motivate patients 
to quit smoking and stay 
abstinent. They can develop 
intervention messages if 
they wish or pinpoint the 
sources of treatment content 
that they use. We will use 
purposive sampling to select 
15 providers from each 
hospital, 15 of each sex, and 
ensure the sample is diverse 
with regard to age and 
specialty. Inclusion criteria 
for all healthcare providers 
in the R21 Phase include: 1) 
age ≥18 years; and 2) the 
ability to provide written 
informed consent to participate. Also, we will conduct 8 focus group discussions with 40–60 
patients who smoke (5–8 persons/group, 4 groups/hospital) to identify additional factors that 
motivate patients to quit smoking and stay abstinent, barriers to quitting, and strategies to 
overcome these barriers. We will use purposive sampling to select a diverse sample with regard 
to age, residence (urban vs. rural), disease type, and cessation phase, per the Phase-Based Model 
(PBM; see Conceptual Framework). Inclusion criteria for all patients in the R21 Phase (except 
in stage 5 below) include: 1) age ≥18 years; 2) self-reported current combustible cigarette 
smoking (smoked ≥100 cigarettes in lifetime and currently smoke ≥1 cigarette/day); 3) planning 
to quit in the next 6 months or having actually made a quit attempt; and 4) the ability to provide 
written informed consent to participate. We will conduct separate group discussions for men and 
women (2 groups for each sex at each hospital). For all qualitative components in the R21 Phase, 
we will use open-ended questions. All interviews/discussions will be recorded using a digital 
voice-recording app on an encrypted smartphone and will be transcribed verbatim. Qualitative 
data will be analyzed using thematic content analysis with the aid of the R-based Qualitative 
Data Analysis software package.53 Themes will be based on the purpose of each component and 
on theoretical constructs of the PBM. 
In stage 2, we will integrate information gathered in the first stage to modify the original 
intervention. For example, using literature search and qualitative findings from our Cambodian 
pilot study, we have expanded our treatment content library to include strategies for coping with 
craving/urges that are commonly used in Southeast Asian culture (e.g., chewing on 
ginger/lemon, chatting with friends via apps, or playing e-games on phones to keep hands busy). 
The original English treatment content library and NTCC’s available materials are mainly text 
based. For videos originating in the English library, US and Lao investigators will review, 
discuss, and select the ones that are culturally appropriate for use in Lao PDR (e.g., videos that 
Stage 1: 
Information 
gathering 
Stage 2: 
Prelimina 
ry design 
Stage 3: 
Prelimina 
ry testing 
Stage 4: 
Refine 
Stage 5: 
Pilot trial 
• Preliminarily modify the original intervention 
messages 
• Translate the intervention and assessments, 
including forward translation, editing, quality rating, 
• Literature search 
• Analyze available quantitative and qualitative data 
(completed) 
• Key informant interviews with 5 stakeholders 
(completed) 
• Preliminary test using Insight™ and REDCap with 20 
smokers 
• Continuous feedback from co-investigators and 
research staff 
• Refine the intervention based on the results and 
feedback from stage 3 
• Report errors using screenshots 
• Open-ended questions about usability & areas for 

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do not contain US-specific characters or contexts). Scripts of the selected videos will be 
translated as described below, and the videos will be dubbed by native-Lao speakers). 
Also at this stage, we will translate all English intervention materials and assessments that 
will be used in the R33 Phase to Lao, mirroring the WHO’s recommended methodology54,55 that 
we used in our pilot study in Cambodia. First, a health scientist, whose native language is Lao, 
will lead the forward translation process, focusing on conceptual (vs. literal) meaning and 
comprehensible language for the broadest audience. Second, a more senior bilingual health 
expert will review the translation, discuss disagreements with the forward translator, edit, and 
finalize the forward translation. Third, 2 other bilingual health professionals will independently 
rate the quality of the translation on 5 dimensions: conceptual equivalence, clarity in meaning, 
comprehensibility, use of common simple language, and cultural appropriateness. Any 
discrepancies will be discussed to reach consensus on translation or editing. Fourth, we will 
conduct 6 panel discussions (1 with female smokers, 1 with male smokers, and 1 with mixed-sex 
healthcare professionals at each participating hospital; 5-7 panelists per group). This step aims to 
evaluate material comprehensibility as well as linguistic and cultural appropriateness for the 
target populations, particularly to identify linguistic differences by regions (north vs. south) in 
Lao PDR and to find and use common words. Fifth, 2 other bilingual health professionals will 
independently backward translate the materials into English. Finally, the PI and site-PI will 
independently review and rate the backward-translations for conceptual equivalence with the 
original English versions. 
In stage 3, we will load the intervention content onto the Insight™ platform and assessments 
into REDCap and will preliminarily test them (on smartphones/ tablets) with 20 patients who 
smoke (10 male, 10 female). Additionally, we will systematically document continuous feedback 
from local investigators and staff members who implement stages 2 and 3 for adaption 
refinement. In stage 4, we will refine the intervention based on the results and feedback from 
stage 3. Critical changes at this stage (e.g., major deviations from the original intervention) will 
only be made in consultation with the leadership team. 
Stage 5 will be a 3-month pilot efficacy trial with 50 patients. Activities at this stage will 
mirror the full efficacy trial in the R33 Phase, except that only 50 patients will be recruited and 
treatment will last 3 months. In addition to the efficacy outcomes, we will collect data for further 
adaption and refinement. Specifically, at the baseline, we will instruct participants to take 
screenshots of the phones and ask them to do so whenever they see a message that they do not 
understand, that has an error, or that needs revision. We will ask participants to send us these 
screenshots together with descriptions of issues via Insight™ or e-mails. At the follow-up, we 
will check for and discuss all stored screenshots with participants to elicit their suggestions for 
revision, and we will ask AT participants open-ended questions regarding usability and areas for 
improvement in the AT. 
D3. R33 Phase (3 years, July 2022 – June 2025): Conduct a RCT to evaluate the efficacy of 
AT 
Overview. Participants will be patients recruited through 2 large hospitals in Lao PDR. 
Consenting participants will be randomized to one of the 2 study groups: Automated Treatment 
(AT; n=250) and Standard Care (SC; n=250). Participants will complete in-clinic assessments at 
baseline, and at 3, 6, and 12 months following study enrollment (Figure 2). Participants will also 
complete brief weekly assessments via smartphone. 
Design considerations. Several aspects of the project, as described below, were carefully 

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considered prior to deciding on the proposed design. 
Provision of NRT. We considered a 2X2 fully crossed randomized design to differentiate 
the effects of pharmacological support (NRT) versus behavioral treatment (AT). However, NRT 
helps address nicotine withdrawal/craving25,56 and the US Public Health Service Guidelines state 
that NRT should be considered the minimal standard of care.57 Thus, it would be unethical to 
have a study group without NRT in a large trial. On the other hand, providing too much NRT 
may mask the effect of AT and affect the sustainability of the program. Most quitlines in the US 
provide a minimum of a free 2-week starter kit of NRT and we will follow this practice. 
Provision of smartphones. We considered using a more real-world approach, in which 
only individuals who already owned smartphones would be eligible for study entry. However, 
we decided that loaning smartphones to those who either do not own or own an incompatible 
smartphone would actually provide a more thorough and realistic estimate of AT’s potential. 
This is especially true given the trend in Lao smartphone ownership over the past few years 
which indicates that ownership will be nearly ubiquitous in the near future. In our Cambodian 
pilot study, 88% returned the project phones after 2 months. 
Figure 2: Trial schema 
 
 
 
Participants complete baseline assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-month follow-up: in-clinic assessment, breath CO measured 
Oversampling female 
smokers. We acknowledge the 
importance of ensuring that our 
mHealth-based AT program 
works well for women. Thus, in 
the R21 Phase, we will recruit 
equivalent numbers of male and 
female smokers for qualitative 
interviews/discussions. 
However, given the limited 
timeframe and budget of the 
R33 Phase, we must guarantee a 
sufficient sample size to 
demonstrate the efficacy of AT 
in at least the majority group of 
smokers (i.e., males) if 
subgroup analysis is needed. 
Thus, we cannot oversample 
female smokers but we will 
ensure that female smokers are 
represented in a manner that 
aligns with smoking prevalence 
in the real-world. Specifically, 
because the male to female 
smoking prevalence ratio in the general population is ~7 (51%:7%),1 we propose to recruit a 
sample that includes 15% (n=75) females. By doing so, we recognize that we may not have 
sufficient power to detect a difference in the primary outcome in the female subsample. 
However, given that little is known about the factors associated with smoking cessation in 
Laotian females, this proposal will provide valuable information that may inform future research 
efforts. 
Conceptual Framework for AT. Our AT intervention is based on Phase-Based Model 
Patients who smoke recruited from 2 hospitals (N=500) 
  
 
Randomization (N=250 in each arm) 
Standard Care (SC): 
• Brief advice to quit 
• Nicotine patches 
• Self-help materials 
• Weekly diet 
assessments via 
Insight™ app 
Automated Treatment (AT) 
• Brief advice to quit 
• Nicotine patches 
• Self-help materials 
• Weekly smoking-related assessments 
to drive treatment via Insight™ app 
• Interactive personalized treatment 
3-month follow-up: in-clinic assessment, breath CO measured 
6-month follow-up: in-clinic assessment, breath CO measured, 
weekly assessments via Insight™ app and AT end 
  
 

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(PBM), a theoretical framework that is specific to smoking cessation.24,25 PBM partitions the 
cessation process into 4 phases: motivation, preparation (pre-cessation), cessation (quit date to 4 
weeks post-quit), and maintenance (up to 6 months post-quit); this RCT focuses on the latter 3 
phases. PBM helps identify challenges/opportunities that smokers face at each phase, explains 
underlying phase-specific mechanisms, and facilitates selection of intervention components and 
measures. Using data from weekly assessments, the proposed AT intervention will dynamically 
target several putative mechanisms, mainly those that are relevant across phases and have been 
reliably associated with long-term abstinence in previous studies: withdrawal/craving, motivation 
to quit, positive/negative affect, coping with stress and urges, and self-efficacy.25,58-61 
Withdrawal/Craving. As explained above, NRT provision helps address nicotine 
withdrawal/craving,25,56 and increases quit rates.57 AT will also promote skills to further reduce 
and cope with withdrawal and craving. 
Motivation to Quit. Substantial evidence underscores the critical role of motivation in 
initiating and successfully maintaining change.62-65 Evidence also demonstrates that motivation 
for change can fluctuate rapidly.66 For example, 41% of US smokers report that their motivation 
to quit smoking changes daily,67 and half or more quit attempts are unplanned versus 
planned,68,69 consistent with the PBM’s tenet that motivation is dynamic. Empirical data indicate 
that higher levels of intrinsic motivation were associated with readiness to quit and the 
maintenance of abstinence at 12-month follow-up.65,70 
Stress, Negative/Positive Affect. These are important mechanisms to target in the 
preparation and cessation phases.25,58 Stress and negative affect, measured in different ways, 
have a strong dose-response relationship with smoking-related acute events.71 The magnitude 
and trajectory of stress/negative affect over time are powerful predictors of cessation,58,72,73 as 
are individual differences in affective vulnerability.74,75 Stress/negative affect are associated with 
relapse and poor treatment outcomes in numerous studies.76-79 
Self-efficacy. Self-efficacy is a form of agency that is context and behavior dependent. In 
the context of smoking, self-efficacy is reflected in one’s confidence to not smoke in different 
challenging situations80 and is among the best predictors of smoking treatment outcomes60,77,81-83 
and relapse.84 Therefore, the PBM posits self-efficacy as a key mechanism in cessation and 
maintenance phases. 
Sites and participant recruitment. Participants 
(n=500) will be recruited from the patient populations at 
Setthathirath Hospital (SH) in Vientiane and Champasak 
Hospital (CH) in Champasak Province. Vientiane is the 
capital and the largest city of Lao PDR, while 
Champasak is the most southwestern province and 
borders Thailand and Cambodia (Figure 3). SH and CH 
are public general hospitals under Lao MOH supervision. 
In 2018, the Lao MOH and Japan International 
Cooperation Agency selected SH and CH to receive 
grant aid of approximately 1.7 million USD from the 
Government of Japan to increase their capacities in 
providing high-quality medical care and services.85 The 
grant supports improved facilities (e.g., construction of 
new buildings/rooms) and equipment (e.g., computed 
Figure 3. Location of recruitment sites 

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tomography scan and computers) to help the hospitals serve more patients in the region. The goal 
of this capacity enhancement is to achieve universal health coverage, defined as coverage such 
that all people receive appropriate health promotion, and preventive, curative, and rehabilitative 
health services at affordable costs.85 SH and CH are also among major implementation sites for 
several national disease control programs, including HIV, tuberculosis, and severe acute 
respiratory syndrome. These missions position the 2 hospitals as ideal venues to offer smoking 
cessation treatment, and the improved facilities and resources afford a solid foundation for AT 
adoption and implementation. 
SH is a national hospital (i.e., at the top/central level in Lao PDR health system). Each year, 
SH serves approximately 20,000 inpatients and 90,000 outpatients from all over Lao PDR, 
mostly from the north and central regions. CH is the largest and the top-referral hospital in the 
southern region. CH serves patients from all nearby provinces, of which the total population is 
approximately 1.5 million people. 
All non-emergency patients coming to SH and CH first go to a reception desk to receive a 
queue number and a basic medical form. A flyer that introduces this study will be attached to the 
basic medical form. Additionally, we will proactively recruit patients at the Respiratory Disease 
Screening Units (RDSU) and departments/clinics specializing in women’s health (e.g., 
Gynecology, and Breast and Gynecologic Cancer). Due to the national organization and 
implementation of NCLE’s disease control programs, all patients visiting SH or CH with 
respiratory symptoms are first examined at the RDSU for type of disease, severity, and whether 
the disease is included in a national disease control program (e.g., tuberculosis or severe acute 
respiratory syndrome). Patients are then referred to appropriate departments/clinics or disease 
control units. The RDSUs at SH and CH see about 40 and 20 patients daily, respectively. Of 
these, 70% are men; 60%–70% of male patients smoke cigarettes (no estimate available for 
women).86,87 Research staff will proactively screen as many patients visiting the RDSU as 
possible for eligibility and invite eligible individuals to participate. Research staff will also 
proactively screen as many women visiting the women’s health clinics as possible to enroll the 
target number of female smokers (n=75). Study protocols and procedures will be developed in 
Lao to standardize all research activities across sites. 
Trial inclusion criteria include patients who are 1) aged ≥18 years; 2) self-reported current 
combustible cigarette smokers (smoked at least 100 cigarettes in lifetime and currently smoke ≥1 
cigarette/day); 3) willing to set a quit date within 2 weeks of study enrollment; 4) able to provide 
written informed consent to participate; and 5) able to read Lao (score ≥4 points on the Rapid 
Estimate of Adult Literacy in Medicine—Short Form88). Exclusion criteria include 1) history of 
a medical condition that precludes use of NRT; 2) ineligibility to participate based on medical or 
psychiatric conditions diagnosed by a physician/clinician; and 3) enrollment in another cessation 
program or current use of other cessation medications. In our Cambodian pilot study at a clinic 
with fewer patients, 86% of identified eligible smokers consented to participate, and we recruited 
2–5 participants per day; we expect a similarly high consent rate for this study. Together, SH and 
CH see >160,000 unique patients each year. Based on the smoking prevalence in the general 
population (51% in men and 7% in women), we estimate that approximately 40,000 male 
patients and 5,600 female patients at SH and CH will be current smokers. Assuming, 
conservatively, that only half of these smokers are eligible for the study and even if only half of 
eligible smokers want to participate, there will be 10,000 available male and 1,400 available 
female smokers in a one-year recruitment period. Thus, our goal to enroll 500 participants (<5% 
of eligible smokers) at SH and CH is highly feasible. 

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Baseline assessment. Enrolled participants will complete a 45-minute tablet-delivered 
baseline audio computer-assisted self-interview, managed and delivered by REDCap.89,90 The 
use of REDCap will enhance both accurate data collection across sites and timely and secure 
data transmission. Research staff will assist participants complete the assessment if needed. 
Participants will be assigned to a treatment group using a form of adaptive randomization called 
minimization,91-93 this ensures better group balance regarding participant characteristics and does 
not impose limitations such as empty or near-empty strata. Randomization variables include 
biological sex, nicotine dependence, and reading level. All participants will complete a brief 
training session on smartphone use and the Insight™ app. Smartphones will be loaned to 
participants who need them. 
Treatment groups. 
Standard Care (SC). Participants randomized to SC will receive brief advice to quit 
smoking delivered by research staff, NTCC’s self-help materials (developed based on the 
WHO’s “A guide for tobacco users to quit”94), and a 2-week supply of NRT (patches). SC 
participants will be asked to complete weekly 4-item smartphone-delivered assessments about 
their diet (see explanation in Measures) for a 6-month period. 
Automated Treatment (AT). Participants in the AT group will receive the SC components 
(except the dietary assessments) plus proactive personalized messages/images/videos for 
smoking cessation. The AT content is adapted from the team’s previous efforts (see Preliminary 
Studies), is informed by the R21 phase outcomes, and is designed to tap the theoretical 
mechanisms described in the PBM. That is, AT content is designed to increase motivation, self- 
efficacy, and use of coping skills, while reducing nicotine withdrawal symptoms and stress. AT 
will begin immediately after enrollment and continue for a 26-week period (about 2 
messages/images/videos per day). The AT approach allows for several levels of personalization 
for each participant. First, at baseline, participants will be asked several questions about past quit 
attempts, preferred coping skills, and the presence or fear of 
specific health conditions. Treatment content tailored to these 
responses will be automatically delivered throughout the 
treatment period. Second, there will be different bins of treatment 
content for different cessation phases to ensure that AT targets 
critical mechanisms of each participant’s PBM phase, which may 
dynamically change during treatment. Third, participants will be 
asked to complete brief (4 items) smartphone-delivered 
assessments during each week of the AT course. These questions 
will vary depending on each participant’s phase (e.g., current 
level of intrinsic motivation for preparation or maintenance 
phases or smoking status in the past week and self-efficacy level for all phases). Treatment 
content (e.g., types and frequencies of messages) for the following week will be based on 
responses to these weekly assessments and participant phases (e.g., level of self-efficacy or past- 
week smoking status). Our team’s previous work with disadvantaged populations has observed 
high adherence (76%) with weekly smartphone assessments across a 6-month timeframe. 
The Insight™ platform will be used to manage and deliver AT. Our pilot results in Cambodia 
demonstrate that Insight™ works very well in Southeast Asia; it is compatible with the GSM and 
4G data networks, properly delivers messages and weekly assessments, and reliably collects and 
transfers data to our encrypted server. Our preliminary work also shows that the Insight™ 
platform and app work well with Lao script (Figure 4). 
Figure 4. 

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Measures and assessment strategy. 
Table 2: Study Assessments 
Variable 
Type 
Measure 
Baseline Weekly* 
In-clinic Follow- 
up 
(3-, 6-, & 12- 
mth) 
Descriptors 
/ potential 
moderators 
Demographics; Health literacy95 
Health conditions and comorbidities; Substance 
use96,97 
Dependence – Heaviness of Smoking Index98 
X 
X 
X 
X 
Adherence 
to 
treatment 
Duration of phone on/off; numbers of 
messages/images/videos delivered, opened, and 
marked as viewed; numbers of weekly assessments 
opened and completed; data syncing frequencies 
(manual and automatic) 
Documented by digital date/time 
stamps in the Insight™’s activity 
log. 
app 
Wisconsin Smoking Withdrawal Scale99 
X 
X 
Phase- 
Based 
Model 
mechanism 
s 
Reasons for quitting (intrinsic, extrinsic)65 
Contemplation Ladder62,63 
Kessler Psychological Distress Scale (K10)100 
Positive and Negative Affect Schedule101 
X 
X 
X 
X 
X** 
X** 
X 
X 
X 
X 
Self-efficacy (related to smoking cessation)84 
X 
X** 
X 
Primary 
outcome 
Smoking status (includes number of quit attempts, and 
days abstinent)102 
Expired CO102 
X 
X 
X** 
X 
X 
* Delivered via Insight™ app on smartphone; ** Brief versions of the scales. 
 
In-clinic assessments at baseline and at 3-, 6-, and 12-month follow-ups. Three types of 
data will be collected at each visit: ACASI data (Table 2) collected by the HIPAA-compliant 
REDCap program on a tablet, expired air CO assessed with a CO monitor (Vitalograph 
BreathCO) to verify smoking status biochemically, and medical record data (to collect clinical 
information, such as current diagnosed health conditions for AT personalization). The REDCap 
assessment will be administered at baseline (~45 minutes to complete) and at each follow-up in- 
clinic visit (~20 minutes). For measures that have not been validated in Lao, we will adapt them 
as described in the R21 Phase. Participants will be compensated $15 USD for each in-clinic visit. 
Brief weekly smartphone assessments. Participants will be asked to complete weekly 4- 
item assessments via smartphone for 6 months, delivered by the Insight™ app. Participants in the 
AT group will receive 4 smoking-related questions (Table 2). Although these treatment-driving 
questions can be considered part of the AT, we will attempt to balance the effects of these 
weekly contacts between the treatment groups; SC participants will also be asked to complete a 
weekly 4-item assessment via Insight™ app with questions about diet. Responses will be 
temporarily stored on smartphones and will sync to our secure server whenever a connection is 
active; thus, we will have near real time access to the data. To carefully track participants’ 
completion of weekly assessments and adherence, data plans will be provided for 6 months for 
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Primary outcome. The primary outcome is smoking status at 12 months post-enrollment. 
Abstinence will be defined as biochemically confirmed self-reported 7-day point prevalence 
abstinence with expired CO <6 ppm.102 Secondary outcomes include 3- and 6-month abstinence. 
We will consider several other common outcomes, such as continuous and sustained abstinence, 
number of quit attempts, and length of abstinence. 
Participant tracking and retention procedures. We will use various approaches to 
maximize our follow-up rate. These include: 1) reminders via phone calls, messages through the 
Insight™ home screen, and Insight™ push notifications before the follow-up visit; 2) offering 
follow-up assessments on different days/times to accommodate schedules; 3) collecting other 
phone numbers and home addresses of participants; 4) obtaining the names and phone numbers 
of at least 3 collaterals (e.g., relatives/friends) who can help locate the participant should the 
participant move or otherwise lose contact during the study; and 5) financially compensating 
participants for the time and costs associated with study participation (e.g., transportation, child- 
care). With these procedures applied in our Cambodian study, retention rates at 2 months were 
100% for the AT group and 92% for the SC group. Thus, we expect a high retention rate for this 
proposed project. 
 
E. CHART REVIEW 
As described above, at the in-clinic assessments at baseline and at 3-, 6-, and 12-month follow- 
ups, the Lao research team will also collect data from participants’ medical records (in addition 
to interview data and expired air CO assessment). Medical records will be used to collect clinical 
information, such as comorbidities, recent/current diagnosed health conditions, and current use 
of medications for AT personalization. In Lao PDR, most of these medical records/data are in 
paper form; thus, the Lao research staff will review the records/forms and will enter data into the 
standardized sections/questions in REDCap Mobile app. The tablets that contain the REDCap 
app are password protected, encrypted, and can be remotely wiped if lost. 
 
F. BIOSPECIMEN 
This project does not collect biospecimen. 
 
G. BANKING/REPOSITORY/DATABASE 
This project does not bank or store data for future use in other projects. 
 
H. INCLUSION/EXCLUSION CRITERIA 
Inclusion criteria (R21 Phase): 
- 
Inclusion criteria for all healthcare providers in the R21 Phase are: 1) age ≥18 years; 
and 2) the ability to provide written informed consent to participate. 
- 
Inclusion criteria for all patients in the R21 Phase, except the pilot trial at stage 5, are: 
1) age ≥18 years; 2) self-reported current combustible cigarette smoking (smoked 
≥100 cigarettes in lifetime and currently smoke ≥1 cigarette/day); 3) planning to quit 
in the next 6 months or having actually made a quit attempt; and 4) the ability to 
provide written informed consent to participate. 

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- 
Inclusion criteria in the pilot trial at stage 5 include patients who are: 1) aged ≥18 
years; 2) self-reported current combustible cigarette smokers (smoked at least 100 
cigarettes in lifetime and currently smoke ≥1 cigarette/day); 3) willing to set a quit 
date within 2 weeks of study enrollment; 4) able to provide written informed consent 
to participate; and 5) able to read Lao (score ≥4 points on the Rapid Estimate of Adult 
Literacy in Medicine—Short Form88). 
Inclusion criteria (R33 Phase): All participants must be patients who are: 1) aged ≥18 years; 2) 
self-reported current combustible cigarette smokers (smoked at least 100 cigarettes in lifetime 
and currently smoke ≥1 cigarette/day); 3) willing to set a quit date within 2 weeks of study 
enrollment; 4) able to provide written informed consent to participate; and 5) able to read Lao 
(score ≥4 points on the Rapid Estimate of Adult Literacy in Medicine—Short Form88). 
Exclusion criteria (R33 Phase): 1) history of a medical condition that precludes use of NRT; 2) 
ineligibility to participate based on medical or psychiatric conditions diagnosed by a 
physician/clinician; and 3) enrollment in another cessation program or current use of other 
cessation medications. 
 
I. GENDER/MINORITY/PEDIATRIC INCLUSION FOR RESEARCH 
I1. Inclusion of Women 
This project includes 2 main phases: the R21 Phase and the R33 Phase. In the R21 Phase, 
we will use qualitative methods (e.g., in-depth interviews and focus group discussions) to 
validate our intervention content to the sociocultural context, language, and communication 
styles of Laotians. We plan to recruit up to 110 participants for these qualitative components, 
with equivalent numbers of men and women. Then, we will conduct a pilot trial with 50 patients 
who smoke. We will recruit a pilot sample that mirrors the sample proposed in the main trial 
(R33 Phase). Specifically, we will ensure that female smokers are represented in our sample in a 
manner that aligns with the smoking prevalence by sexes in the real-world. Thus, we propose to 
recruit a sample that includes 15% (n=8) female smokers and 85% (n=42) male smokers in the 
pilot trial. 
In the R33 Phase, we will conduct a full efficacy trial with 500 patients who smoke. We 
will ensure that female smokers are represented in our sample in a manner that aligns with the 
smoking prevalence by sexes in the real-world. Thus, we propose to recruit a sample that 
includes 15% (n=75) female smokers and 85% (n=425) male smokers. All participants, including 
men and women, will be encouraged to continue their participation in the study. 
 
I2. Inclusion of Minorities 
An attempt to enroll all eligible participants will be made without regard to race/ethnicity. 
Because this project will take place in Lao PDR, we expect that all participants will be Asian. 
Among these, approximately 90% will be of Lao ethnicity, 5% will be of other ethnicities (e.g., 
Chinese, Vietnamese, Thailand), and 5% will be multi-ethnicity. As with all participants, the 
recruited minority participants will be encouraged to continue their participation in the study. 
 
I3. Inclusion of Children 
We have excluded children under the age 18 from the proposed study. In Lao PDR, 18 is 
the age of majority and, therefore, participants aged ≥ 18 years can consent. We excluded 

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smokers under the age of 18 because the safety of nicotine replacement therapy (NRT) has not 
been determined for this population. The US Food and Drug Administration has not approved 
the use of NRT for smoking cessation for children and adolescents. 
 
J. RECRUITMENT AND ENROLLMENT 
We will recruit up to 110 participants for qualitative components in the R21 Phase, 50 
participants for the pilot trial in the R21 Phase, and 500 participants for the main trial in the R33 
Phase. All participants will be recruited from the SH and CH in Lao PDR. All participants will 
undergo an informed consent process. Participants will be informed of the nature of the 
investigation, the steps that they will complete, and the types of interventions involved. 
In the R21 Phase, the Lao research team will use purposive sampling to select potential 
participants (i.e., healthcare providers and patients) from the participating hospitals as described 
in the section D2 above. The Lao research team will directly contact potential participants and 
invite them to participate. The whole informed consent process and interviews or focus group 
discussions will be conducted in Lao by local research staff and will take place in a quiet, private 
location (e.g., an empty room) at the participating hospitals. 
Specifically for the pilot and the main trial (R33 Phase), during the consent process, 
potential participants will be made aware that: (1) they are participating in a research study, (2) 
they will be asked to complete assessments according to research protocols, (3) they have a 
chance of being randomized to either the SC or AT arm of the study, and (4) their study data, 
without any identifiers, will be posted on the US ClinicalTrials.gov website. Participants will 
receive explanations about the potential risks of participation, measures to protect against risks, 
and the alternative option of not participating. In addition, research staff will explain how 
information related to study participation will be handled, including data management and plans 
to publish data in group format without identifying information. The whole informed consent 
process will be conducted in Lao by local research staff and will take place in a quiet, private 
location at the participating hospitals. Participants will be given up to one month to discuss the 
study participation with their families and to consider participating. Individuals wishing to enroll 
will be asked to sign an IRB-approved informed consent form. 
 
K. RISKS AND BENEFITS 
K1. Potential Risks 
The risks to participants are generally minimal and include breach of confidentiality, 
emotional distress (due to the nature of the assessment questions), and side effects associated 
with NRT patch use. 
There are minimal potential risks to participants from the personal nature of the questions 
asked regarding health behaviors and health status. Answering the questions may cause 
participants to feel uncomfortable and/or upset. 
Problems associated with the use of nicotine patches include local skin irritation at the 
site of application, nausea (if the dose of the patch is too high or if high levels of smoking are 
continued while using the patch), and distressing dreams. Skin allergic reactions have been less 
commonly reported. Participants may experience unpleasant withdrawal symptoms following 
smoking cessation. These symptoms include anxiety, restlessness, anger, irritability, sadness, 
difficulty concentrating, change in appetite, weight gain, insomnia, and decreased heart rate. 

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K2. Protection against Risks 
Protection against Confidentiality Breach: Confidentiality will be maintained for all data and 
contact information. To protect against the risk of a confidentiality breach, the following steps 
will be taken: 
- 
REDCap will be used to collect and manage information for most procedures, including 
screening eligible participants, administering in-clinic assessments at baseline and 
follow-ups, and capturing participants’ information from medical records. REDCap is a 
secure web-based application designed to comply with all HIPAA regulations. Data will 
be collected by participants (e.g., self-interviews for baseline assessment) or by research 
staff (e.g., screening or reviewing medical records) on tablets using the REDCap Mobile 
App. Each participant will be given a unique identification number (UIN) in this study, 
and the UIN will be used in all data collection procedures that are managed by REDCap. 
The REDCap Mobile App employs encryption at-rest on the mobile device’s hard drive 
so that all important data and information stored on the device are properly protected 
from unauthorized or malicious users. All data are transmitted between the app and the 
OUHSC secure REDCap server using a secure, encrypted transmission (SSL/HTTPS). 
REDCap has been used by several institutions in Lao. The tablets are password protected, 
encrypted, and can be remotely wiped if lost. 
- 
All data related to participants will be identified only by the UIN. A master list of 
participant UINs linked to participant names will be stored in locked file cabinets in 
locked study offices at SH or CH. Access to the master list will be limited to those with 
privileges. After completion of the study and data analysis, the identification file will be 
destroyed. 
- 
To minimize the risk of participant information being disclosed via IDIs or FGDs in 
Phase 1, participants will be instructed to use initials to refer to themselves. Participants 
will also be advised not to use their names or mention another’s name during discussions. 
Any names accidentally mentioned during group discussions will be replaced with the 
initial of the first name or with a random initial when transcribed. 
- 
Participants will not be identified in any public reports or documents. In qualitative 
component reports, if any, only participant initials or random initials will be used for 
quotations. In the trials, only aggregate data will be reported and released. At no time will 
individual names appear in any report, article, or manuscript related to the study. 
- 
To minimize risks related to participant information potentially being disclosed via the 
use of smartphones, the following features are designed to ensure the security of the 
assessment data: 
o The data stored on the smartphone device is in a SQLite database in a sandbox 
environment, where read/write operations are only available through the 
programming application (i.e., no file or output is readable to end users). 
o A 10-character password (only known to researchers) is required to authenticate 
the current user before data can be manually accessed on the smartphone. 
o Encrypted smartphone data will be automatically sent to our OUHSC mHealth 
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o The web browser application linking the investigator’s computer to the database 
uses HTTPS protocol (SSL certificate with encryption), which will guarantee the 
protection of data transferred from the web browser to the backend database. 
o The backend database is hosted by the OUHSC mHealth Shared Resource in a 
secure setup. 
o Software will be downloaded onto each study phone so that phones can be 
remotely wiped if lost. 
- 
During the consent process, participants will be informed of the potential for 
psychological distress or discomfort associated with unintentional disclosure of personal 
information to non-study staff, and the nature of the questions to be asked will be made 
clear. 
- 
Participants will be informed of the safeguards in place and encouraged to contact 
investigators at any time to discuss any confidentiality concerns that arise. 
Protection against Coercion: All recruitment contacts will emphasize the voluntary nature of 
participation. Consent materials will clearly state that participants recruited for the trial will be 
randomly assigned to 1 of 2 groups and that participation in the study may not be personally 
beneficial. 
Protection against Assessment-Related or Intervention-Related Discomfort: 
The potential for discomfort associated with being asked personal questions regarding sensitive 
topics will be minimized in the following ways: 
- 
Participants will be informed of the nature of questions to be asked and topics covered; 
participants can decline participation if such topic areas are known to be personally 
uncomfortable. 
- 
Only measures that have been validated or used in prior studies will be used or will be 
adapted for use in this study. None of the proposed instruments have been known to 
evoke serious emotional reactivity. 
- 
In the pilot and main trials, the use of self-administration for the assessments on a tablet 
or phone may help participants feel more comfortable in answering sensitive questions. 
- 
Participants can refuse to answer any questions that they do not wish to answer. 
- 
Participants who become distressed by answering questions will be given resources to 
access help. 
- 
Participants will be reminded during the consent process that they may contact the 
research staff with any questions or concerns that arise during their participation. 
- 
Participants may choose to discontinue participation at any time. 
 
In the pilot and main trials, those who experience a skin reaction from nicotine patch use 
will be instructed to move the site of the nicotine patch each day. Additionally, participants will 
be instructed to wait at least 7 days before using the same site for patch placement. To minimize 
nausea, participants will be instructed not to smoke while using the patch. If smoking relapse 
occurs, the participant will be instructed to stop using the patch. Participants experiencing 
distressing dreams or other sleep interference will be instructed to remove the patch before 
bedtime. If a severe skin reaction develops, the participant will be instructed to discontinue patch 
use. Use of the patch should reduce the severity of withdrawal-related symptoms. Withdrawal 

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symptoms are generally short-lived and typically last no more than 2 weeks after smoking 
cessation. Patches will be dispensed under the supervision of a health care provider. 
K3. Potential Benefits of the Proposed Research to Human Subjects and Others 
Tobacco smoking is among the leading causes of morbidity and mortality in low- and 
middle-income countries. Smoking cessation treatment offers tremendous potential to prevent 
smoking-related morbidity and to reduce overall mortality in this population. The risks to 
participants are small, and the health benefits of quitting smoking at the individual level are 
appreciable and well documented. 
To our knowledge, no theoretically based tobacco treatment program is available in 
national public hospitals in Lao PDR. It is also unknown whether mHealth-based smoking 
cessation approaches that have efficacy in developed countries would be effective in low- and 
middle-income countries. The results of this study will help Lao governmental health officials 
implement a potential affordable and sustainable approach for smoking cessation for Laotians 
that may lead to widespread adoption and also be applicable to other health issues. Thus, this 
research has the potential to transform healthcare delivery throughout the country. 
 
L. MULTIPLE SITES 
Not applicable. 
 
M. STATISTICAL METHODS 
Hypothesis: At the 12-month follow-up, 7-day point prevalence biochemically confirmed 
abstinence (primary outcome) will be higher in the AT (vs. SC) group. 
The primary abstinence analysis will be intention-to-treat; patients not completing 
follow-up assessments will be considered smokers. However, we will explore other ways of 
dealing with missing data (see below). Based on our previous work and assuming attenuation of 
abstinence rates across the follow-up visits, we anticipate that the 7-day point prevalence 
abstinence at the 12-month follow-up will be 8% in the SC group and 17% in the AT group. 
With 250 participants in each group and assuming a two-sided alpha of 0.05, we will have 86% 
power to detect a difference of 9% in 12-month 7-day point prevalence abstinence in the overall 
sample. It is unknown whether factors associated with smoking cessation differ by sex; it seems 
likely given the variation in smoking prevalence between sexes. Thus, we chose a sample size 
that gives 80% power to detect this difference in a subgroup analysis of only males (n=425, 85% 
of the sample). The sub-sample of females (n=75) gives 80% power to detect a 25% difference in 
12-month 7-day point prevalence abstinence. 
To estimate the effect of AT on abstinence rates while accounting for the potential 
clustering of participants recruited from the 2 clinic sites, we will use generalized linear mixed 
models (GLMM) analysis in which intervention groups (AT vs. SC) will be estimated as a fixed 
effect while the clinic will be modeled as a random effect nested within treatment condition. Sex 
can also be modeled as a random effect nested within clinic and treatment condition. 
Specifically, log binomial mixed models will be used to estimate the relative risk of quitting in 
the AT (vs. SC) group. Although groups should be similar in baseline characteristics due to 
randomization, we will explore models that control for any demographic or clinical variables that 
differ between treatment groups at baseline. We will also use GLMM models to examine 
changes in abstinence rates over time, while accounting for relevant baseline covariates. Similar 

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GLMM or linear mixed model (LMM) methodology, as appropriate for each outcome variable, 
will be used to examine other smoking-related variables, such as continuous abstinence, 
prolonged abstinence, and quit attempts. This project focuses on the latter 3 PBM phases, and 
thus we will explore phase-specific outcomes such as abstinence attainment and number of days 
smoking/abstinent. Statistical analyses will be performed using SAS 9.4 (SAS Institute, Inc.). 
Potential treatment mechanisms will be examined via mediation analyses with 
intervention group (AT vs. SC) being the independent variable, abstinence at 12 months being 
the outcome variable, and the hypothesized mechanisms (motivation, self-efficacy, 
stress/negative affect) being potential mediators. The PROCESS macro for SPSS/SAS103,104 will 
be used to identify variables (e.g., motivation, self-efficacy) that mediate the relationship 
between treatment condition and smoking cessation outcomes. This method uses an ordinary 
least squares path analytic framework to estimate direct and indirect effects in single and 
multiple mediation models, and bootstrapping methods are incorporated to generate confidence 
intervals. 
Missing data and dropouts. Although treating participants lost to follow-up as smoking is 
a widely used strategy in smoking cessation studies, some researchers point to problems with this 
approach, especially when comparing treatment arms with differential dropout rates.105 Thus, we 
will conduct sensitivity analyses to test for treatment differences assuming different missing data 
mechanisms. For example, we will consider a multiple imputation approach based on smoking- 
related patient characteristics at baseline, as well as demographics to account for potential 
missing-at-random mechanisms. We will also explore pattern-mixture and selection models to 
account for potential (and likely) missing-not-at-random mechanisms.106 Similar findings based 
on these analyses will strengthen our study conclusions. 
 
N. DATA AND SAFETY MONITORING PLAN 
The PI (Dr. Bui) and site PI (Dr. Xangsayarath) will be responsible for all data 
monitoring and for compliance with all federal, OUHSC IRB, and Lao IRB policies and 
procedures regarding monitoring progress, safety, reporting of unanticipated problems or adverse 
events, and assuring that actions resulting in suspension of the study are reported. 
Stages 1–4 of the R21 Phase have minimal risk. The research team will protect 
participants’ privacy and confidentiality as described in section P below. 
In Stage 5 (pilot trial) and R33 Phase (main trial), we will consult the Lao IRB to see if 
and how a Data Safety and Monitoring Board (DSMB) should be established. The DSMB will be 
responsible for monitoring rates of enrollment and for reviewing patient safety, risks of 
participation, protocol adherence by the research team, safety and confidentiality of data 
collection, data entry, and statistical issues. The DSMB may consist of five members, from both 
OUHSC and Lao institutions, who will oversee safety issues and overall conduct of the study. 
The DSMB will decide their meeting frequency for the specific purposes of data and safety 
monitoring. Relevant unanticipated problems, adverse events, or participants’ concerns will be 
reviewed at these meetings. Summaries of all relevant discussions will be promptly disseminated 
to study personnel via e-mail, and retraining procedures will be implemented as needed. 
Appropriate modifications will be made in consultation with the OUHSC IRB and the designated 
program person at the NCI if necessary. 
Unanticipated problems 

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The PI will inform the OUHSC and Lao IRB within five (5) business days of discovering 
any unanticipated problems (both internal and external) involving risks to participants and 
others. 
Serious adverse events 
A serious adverse event is defined as follows: death, a life-threatening adverse event, 
inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, a congenital anomaly/birth defect, or a medically significant event. Risks of 
participation will be continually monitored and appropriate measures implemented in cases of 
unforeseen adverse events. If a serious adverse event occurs, the PI will notify the IRB and the 
designated program person at the NCI in writing. These events will be reported regardless of 
whether they appear to be related to study procedures. 
Given the non-invasive, minimal risk nature of the proposed research, we anticipate no 
serious adverse events related to the interventions or the study procedures. The types of adverse 
experiences that may occur, if any, will focus on the possible distress associated with self- 
interviews during data collection or on the use of nicotine patches. We have included procedures 
to minimize these risks (see section K above). 
Adverse Experiences Associated with Self-Report 
The trials will involve the use of assessments that could reveal sensitive information (e.g., 
mood disturbance, substance use). The instruments are not used to communicate psychiatric 
diagnosis to the participant and procedures are in place to protect participant confidentiality. 
Possible resolutions for this type of adverse experience include referring participants to their 
primary care physicians, and/or other physicians, and/or other mental health providers. Other 
procedures to minimize this type of adverse experience are described in the section K above. 
Adverse Experiences Associated with the Nicotine Patch 
Adverse experiences associated with the nicotine patch are almost always of a mild 
nature. Potential risks arising from use of nicotine patch therapy are mostly limited to nausea, 
erythema, and other dermatologic reactions. Procedures to minimize this type of adverse 
experience are described in the section K above. The incidence of side effects with the patch is 
small and can be locally treated or reversed with discontinuation of the patch. The risk of 
nicotine toxicity is extremely low. Appropriate warnings about not smoking while using the 
patch will be issued each time patches are dispensed. Management of AE’s are done in 
accordance with standards of clinical practice and almost always are relieved by a reduction in 
dose, or although rarely necessary, discontinuation of patch use. 
Adverse Experiences Associated with Nicotine Abstinence/Withdrawal 
Participants may also experience nicotine abstinence/withdrawal effects. These effects 
may include irritability, difficulty concentrating, insomnia, anxiety, dysphoria, and increased 
hunger. None of these effects results in serious adverse events. 
COVID-19 Risk Mitigation Plan for Interviews and Focus Group Discussions (FGDs) 
The below actions will be implemented to mitigate the risk of COVID-19 transmission 
and acquisition: 
- 
In general, the Lao research team and US investigators in Lao PDR will follow COVID-19 
prevention plan/guidance of the Ministry of Health of Lao PDR. 

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- 
Online meeting option for FGDs: Research staff will set up a Zoom meeting for all FGDs. FGD 
participants will be given the option to participate online via Zoom. In-person attendance of 
FGDs will be limited to 10 persons, including research staff. 
- 
Body temperature check: Before in-person interviews or FGDs, body temperature of research 
staff and participants will be measured using a portable non-contact infrared digital thermometer. 
Research staff’s body temperature will be measured once per day before the first interview/FGD. 
Persons with a temperature >38.5oC will not be allowed to participate in the interviews/FGDs and 
will be advised to seek further health care. 
- 
Masking: All research staff and participants will be provided surgical-style masks and will be 
required to wear masks during in-person interviews/FGDs. 
- 
Hand washing: Research staff and participants will be asked to wash their hands before and after 
the interviews/FGDs. 
- 
Wearing gloves: Research staff will be required to wear gloves when direct physical contact with 
research participants is needed, discard gloves after contact appropriately, and wash hands. 
- 
Social distancing: Research staff and participants will be required to maintain social distancing of 
6-feet (2 meters) in all directions unless necessary to conduct intervention or measures. 
- 
Disinfection: 
Research areas and tools, including rooms, tables, chairs, and tablets will be 
appropriately disinfected as recommended by the Ministry of Health of Lao PDR. Disinfecting 
will take place before the first participant, between participants, and after the last participant. 
Inexpensive supplies such as pens, small notebooks, or participants’ folders will be given to 
participants without reuse/recycling. 
- 
The Directors of the participating hospitals and of the NCLE (i.e., site PI) will be informed if the 
research staff becomes aware of a team member or a participant who tests positive for COVID- 
19. 
- 
As the nature of COVID-19 remains dynamic, the NCLE will regularly evaluate this COVID-19 
prevention plan and revise the plan if necessary. 
 
O. DATA SHARING 
The US and Lao investigators have equal rights to access to study data. 
All qualitative data will be deidentified during the verbatim transcribing process and 
translation to English. Deidentified data will be transferred to the PI in encrypted files. 
Quantitative data collected by REDCap program will be transmitted between the 
REDCap app and the OUHSC secure REDCap server on a daily basis using a secure, encrypted 
transmission (SSL/HTTPS). REDCap has been used by several institutions in Lao. The tablets 
with REDCap mobile app are password protected, encrypted, and can be remotely wiped if lost. 
Quantitative data collected by our Insight app on smartphones will be automatically 
encrypted and will be automatically sent to our OUHSC mHealth Shared Resource secure 
servers whenever there is active internet (4G) connection. The web browser application linking 
the investigator’s computer to the database uses HTTPS protocol (SSL certificate with 
encryption), which will guarantee the protection of data transferred from the web browser to the 
backend database. The backend database is hosted by the OUHSC mHealth Shared Resource in a 
secure setup. 

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Data storage, or data transfer if there is a request, will follow all OUHSC’s requirements 
for data security. In all components of the research project, participants will be assigned unique 
identification numbers, and this identification numbers will be used in all data transfer and data 
analysis. When data sharing is requested, de-identified data files will be transferred on a 
password-protected and encrypted drive and will be maintained on institutional servers with 
appropriate antivirus software. Final de-identified data files will be maintained by the PI at 
OUHSC, and all other copies of data files will be deleted after the publication of outcome papers. 
 
P. CONFIDENTIALITY 
Protection against Confidentiality Breach: Confidentiality will be maintained for all data and 
contact information. To protect against the risk of a confidentiality breach, the following steps 
will be taken: 
- 
REDCap will be used to collect and manage information for most procedures, including 
screening eligible participants, administering in-clinic assessments at baseline and 
follow-ups, and capturing participants’ information from medical records. REDCap is a 
secure web-based application designed to comply with all HIPAA regulations. Data will 
be collected by participants (e.g., self-interviews for baseline assessment) or by research 
staff (e.g., screening or reviewing medical records) on tablets using the REDCap Mobile 
App. Each participant will be given a unique identification number (UIN) in this study, 
and the UIN will be used in all data collection procedures that are managed by REDCap. 
The REDCap Mobile App employs encryption at-rest on the mobile device’s hard drive 
so that all important data and information stored on the device are properly protected 
from unauthorized or malicious users. All data are transmitted between the app and the 
OUHSC secure REDCap server using a secure, encrypted transmission (SSL/HTTPS). 
REDCap has been used by several institutions in Lao. The tablets are password protected, 
encrypted, and can be remotely wiped if lost. 
- 
All data related to participants will be identified only by the UIN. A master list of 
participant UINs linked to participant names will be stored in locked file cabinets in 
locked study offices at SH or CH. Access to the master list will be limited to those with 
privileges. After completion of the study and data analysis, the identification file will be 
destroyed. 
- 
To minimize the risk of participant information being disclosed via IDIs or FGDs in 
Phase 1, participants will be instructed to use initials to refer to themselves. Participants 
will also be advised not to use their names or mention another’s name during discussions. 
Any names accidentally mentioned during group discussions will be replaced with the 
initial of the first name or with a random initial when transcribed. 
- 
Participants will not be identified in any public reports or documents. In qualitative 
component reports, if any, only participant initials or random initials will be used for 
quotations. In the trials, only aggregate data will be reported and released. At no time will 
individual names appear in any report, article, or manuscript related to the study. 
- 
To minimize risks related to participant information potentially being disclosed via the 
use of smartphones, the following features are designed to ensure the security of the 
assessment data: 

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o The data stored on the smartphone device is in a SQLite database in a sandbox 
environment, where read/write operations are only available through the 
programming application (i.e., no file or output is readable to end users). 
o A 10-character password (only known to researchers) is required to authenticate 
the current user before data can be manually accessed on the smartphone. 
o Encrypted smartphone data will be automatically sent to our OUHSC mHealth 
Shared Resource secure servers multiple times per day. 
o The web browser application linking the investigator’s computer to the database 
uses HTTPS protocol (SSL certificate with encryption), which will guarantee the 
protection of data transferred from the web browser to the backend database. 
o The backend database is hosted by the OUHSC mHealth Shared Resource in a 
secure setup. 
o Software will be downloaded onto each study phone so that phones can be 
remotely wiped if lost. 
- 
During the consent process, participants will be informed of the potential for 
psychological distress or discomfort associated with unintentional disclosure of personal 
information to non-study staff, and the nature of the questions to be asked will be made 
clear. 
- 
Participants will be informed of the safeguards in place and encouraged to contact 
investigators at any time to discuss any confidentiality concerns that arise. 

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