Evaluating the Efficacy of Automated Smoking Treatment for People With HIV: Protocol for a Randomized Controlled Trial

Background Smoking prevalence rates among people with HIV are nearly 3 times higher than those in the general population. Nevertheless, few smoking cessation trials targeting smokers with HIV have been reported in the literature. Efforts to develop and evaluate sustainable, low-cost, and evidence-based cessation interventions for people with HIV are needed. Given the widespread proliferation of mobile phones, the potential of using mobile health apps to improve the reach and efficacy of cessation interventions is promising, but evidence of efficacy is lacking, particularly among people with HIV. Objective This study will consist of a 2-group randomized controlled trial to evaluate a fully automated smartphone intervention for people with HIV seeking cessation treatment. Methods Participants (N=500) will be randomized to receive either standard treatment (ST; 250/500, 50%) or automated treatment (AT; 250/500, 50%). ST participants will be connected to the Florida Quitline and will receive nicotine replacement therapy in the form of transdermal patches and lozenges. This approach, referred to as Ask Advise Connect, was developed by our team and has been implemented in numerous health systems. ST will be compared with AT, a fully automated behavioral treatment approach. AT participants will receive nicotine replacement therapy and an interactive smartphone-based intervention that comprises individually tailored audiovisual and text content. The major goal is to determine whether AT performs better in terms of facilitating long-term smoking abstinence than the more resource-intensive ST approach. Our primary aim is to evaluate the efficacy of AT in facilitating smoking cessation among people with HIV. As a secondary aim, we will explore potential mediators and moderators and conduct economic evaluations to assess the cost and cost-effectiveness of AT compared with ST. Results The intervention content has been developed and finalized. Recruitment and enrollment will begin in the fall of 2021. Conclusions There is a critical need for efficacious, cost-effective, and sustainable cessation treatments for people with HIV who smoke. The AT intervention was designed to help fill this need. If efficacy is established, the AT approach will be readily adoptable by HIV clinics and community-based organizations, and it will offer an efficient way to allocate limited public health resources to tobacco control interventions. Trial Registration ClinicalTrials.gov NCT05014282; https://clinicaltrials.gov/ct2/show/NCT05014282 International Registered Report Identifier (IRRID) PRR1-10.2196/33183

1 R01 CA243552-01 3 ZCA1 RTRB-U (A1) VIDRINE, D ST approach. If efficacy is established, the AVAST approach will be readily adoptable by various HIV clinic and community-based organizations, and offer an efficient way to allocate limited public health resources to tobacco control interventions. The primary aim is to evaluate the efficacy of AVAST for facilitating smoking cessation among PLWH. Secondary aims include: 1) exploring potential mediators and moderators, and 2) conducting economic evaluations to assess the cost and cost-effectiveness of AVAST. In sum, there is a critical need for efficacious, cost-effective, and sustainable cessation treatments for PLWH who smoke tobacco. The proposed AVAST intervention has been designed to help fill this need.
PUBLIC HEALTH RELEVANCE: Given the extremely high rates of cigarette smoking among people living with HIV (PLWH) and the many health risks associated with smoking, developing smoking cessation treatments for PLWH is a pressing public health need. The overall purpose of this study is to evaluate a new, fully automated smartphone-delivered smoking cessation intervention for PLWH. The intervention is designed to be more effective than human-delivered counseling in helping people quit smoking, while being far less expensive.

CRITIQUE:
The written critiques of individual reviewers are provided in essentially unedited form in this section. Please note that critiques and criteria scores, prepared prior to the review meeting, may not have been revised following discussions at the meeting. The "Resume and Summary of Discussion" section summarizes the final opinions of the review committee.

CRITIQUE 1
Significance: 1 Investigator(s): 1 Innovation: 3 Approach: 3 Environment: 1 Overall Impact: This application proposes an N = 500 randomized trial comparing Standard Treatment (ST; NRT, SmokefreeTXT, and proactive quitline referral) to Automated Video-Assisted Smoking Treatment (AVAST; NRT, tailored texting via a smartphone app, and weekly tailored videos) for PLWH. Strengths are numerous, and include an exceptionally strong team with prior experience in smoking cessation with PLWH, as well as in other areas critical to the proposed study; access to two large infectious diseases clinics, at which the proposed team has a prior recruitment history; a strong theoretical basis; testing of a proactive, tailored, and highly pragmatic and scalable intervention approach against a credible control condition; and strong pilot data. Weaknesses are relatively minor and do not substantially decrease enthusiasm.

Significance Strengths
• This application directly addresses the important challenge of smoking cessation among PLWH, and does so in a creative and scalable way. • The proposed trial is well supported by preliminary data while also being a clearly needed next step for the proposed intervention/technology. Weaknesses • None noted.

Investigator(s) Strengths
• PI Dr. Damon Vidrine is a recognized tobacco cessation researcher with a strong record of productivity in that area, including significant work with PLWH. • Dr. Businelle is one of the key developers of the platform on which the proposed app is built.
The team also includes a statistician, health economist, three physicians, and two additional investigators with expertise related to the control intervention. • Dr. Drevets is Chief of the Infectious Diseases Section at one of the proposed recruitment sites. Weaknesses • The specific roles/duties of the large group of co-investigators are not clear in all cases. Some overlap appears to be present.

Innovation Strengths
• The proposed mobile phone app uses a unique process of weekly tailoring to produce video content that is appropriate to that participant's current status. The app itself is also used to provide tailored text messages, a process that can allow greater security than typical SMS messages.
• The proactive, brief nature of the weekly assessment and video content is an important feature given typical rates of patient-initiated use of similar technology.
• The use of tailored messages to refer back to/promote the use of the AVAST video content is also innovative.
• The weekly assessments with subsequent in-person follow-up will produce a great deal of useful data on within-individual and between-group change. Weaknesses • The proposed intervention content itself appears to be of high quality but not highly innovative.

Strengths
• The proposed intervention content and delivery approach are based have a strong theoretical basis, with hypothesized mechanisms that will be carefully measured as part of this trial.
• The control condition selected for this trial is highly credible, essentially being made up of the Ask, Advise, and Connect (to Quitline) model developed by this research team, plus NRT as well as SmokefreeTXT (to more accurately balance the text messages provided in the AVAST condition).
• The AVAST intervention will include attention to stress and negative affect, each of which are important in smoking cessation, particularly with PLWH.
• Pilot data are available suggesting good feasibility and acceptability of the AVAST app, as well as some early signal of efficacy.
• The AVAST app was originally developed-and will be further modified in the present studyusing a user-centered design process.
• The assessment schedule is strong, combining weekly (during treatment) as well as long-term follow-up (notably, designed to coincide with clinic visits).
• The analytic plan includes an adjustment for multiple comparisons, and the intent-to-treat analysis focuses on sensitivity analysis and imputation rather than the suboptimal assumption that any lost to follow-up are actively smoking. (Unfortunately, however, this strength is unclear, as the application later indicates that the investigators will, in fact, consider those lost to followup as positive.) Weaknesses • E-cigarettes are not sufficiently mentioned or measured, and breath CO will not adequately detect e-cigarette use.
• There does not appear to be a plan to seek access to Quitline data for participants, which could potentially provide important additional data.
• There does not appear to be an adequate plan to obtain data regarding HIV-or other healthrelated data from patient medical records.

Environment Strengths
• The investigators have access to two large infectious diseases clinics, at which the proposed team has a prior recruitment history.
• The University of Texas Health Sciences Center and the University of Oklahoma Health Sciences Center have adequate resources to support the proposed research. Weaknesses • None noted.

Study Timeline: Strengths
• The proposed timeline is feasible and includes attention to key aspects of the proposed trial.

Protections for Human Subjects: Acceptable Risks and/or Adequate Protections
• Adequate protections are in place for this generally low-risk study. Comment 1: additional discussion is needed regarding text messages and their security, particularly if any mention of HIV status or related issues will be included (there are no assurances that this information will not be included). Comment 2: the application indicates that it does not fall under the Single IRB rule and does not include a Single IRB plan. As a two-site study, it does appear to fall under that requirement.

Data and Safety Monitoring Plan (Applicable for Clinical Trials Only): Acceptable
• The PI will be responsible for monitoring and reporting of SAEs.

Inclusion of Women, Minorities and Children:
• Sex/Gender: Distribution justified scientifically • Race/Ethnicity: Distribution justified scientifically • For NIH-Defined Phase III trials, Plans for valid design and analysis: Not applicable • Inclusion/Exclusion of Children under 18: Excluding ages <18; justified scientifically • Children under the age of 18 will not be included due to the use of NRT and the need for alternate intervention approaches with adolescents. The investigators estimate that approximately 30% of participants will be women and 606 will be racial/ethnic minorities.

Resource Sharing Plans: Acceptable
• De-identified data will be shared in accordance with NIH requirements.

Budget and Period of Support: Recommend as Requested
• The need for three full-time coordinators/RAs and 8 Co-Investigators is not sufficiently justified.

CRITIQUE 2
Significance: 3 Investigator(s): 1 Innovation: 3 Approach: 3 Environment: 1 1 R01 CA243552-01 6 ZCA1 RTRB-U (A1) VIDRINE, D Overall Impact: The purpose of this project is to test an automated video-assisted smoking treatment (AVAST) compared to standard treatment (ST) among people living with HIV (PLWH) who are current smokers and interested in quitting. Smoking rates continue to be high in PLWH and, in turn, this population is at risk for significant negative health consequences. Low-cost, sustainable approaches to helping PLWH quit smoking could have a significant public health impact. This project is innovative in that it would be one of the first mHealth approaches to addressing smoking cessation in PLWH. The investigative team is excellent and demonstrates the necessary expertise to successfully complete this project. Specifically, the pilot work involving the developing and feasibility testing of the AVAST intervention was compelling, including its very promising smoking outcomes. The proposed trial is rigorously designed and includes many strengths including 2 different treatment sites, battery of assessments, long-term follow-ups, cost-effectiveness analysis, and tailored intervention content based on weekly assessments of relevant variables. Relative minor weaknesses include the need for a clearer understanding of how behavioral theories informed intervention development and intervention content is specifically hypothesized to change proposed mediators, and lack of assessment of other tobacco products. Overall, the strengths of this excellent application outweigh these relative weaknesses.

Strengths
• Persons living with HIV (PLWH) who smoke cigarettes are at increased risk of negative healthrelated consequences. • While general population rates of cigarette smoking have decreased, high rates of cigarette smoking continue in PLWH. • mHealth approaches for addressing smoking cessation may be cost-effective and reach a larger number of PLWH. • Rather than tailoring specific subsets of PLWH, the proposed AVAST intervention is designed to be relevant to the broader group of PLWH who smoke.

Weaknesses
• While the tailoring of video messages based on weekly assessments is a strength of the AVAST intervention, it is not clear how the algorithm would work. More specific information on how the AVAST intervention would influence the proposed mediators would have strengthened the significance. • Hypotheses related to the effect of the AVAST intervention on HIV-related outcomes were not adequately included.

Investigator(s) Strengths
• The principal investigator, Dr. Vidrine, is the Director of Intervention Research at the Oklahoma Tobacco Research Center at the Stephenson Cancer Center. Dr. Vidrine has a long history of NIH-funded research in the area of tobacco use in special populations including PLWH. • The rest of investigative team is impressive and has expertise in relevant areas including: intervention development and implementation (J. Vidrine, Gillapsy), HIV (Shahani, Drevets, Bui), mHealth (Businelle), and biostatistics (Frank-Pearce, Shih).

Innovation Strengths
• This would be one of the first self-contained, fully automated mHealth approach to addressing smoking cessation among PLWH.

Weaknesses
• A number of mHealth approaches for smoking cessation approaches already exists and it is not clear how AVAST would significantly differ from these, as it does not include any HIV-specific content.

Approach Strengths
• The pilot data was impressive. The investigator conducted an open pilot followed by a small RCT of the AVAST intervention. They demonstrated the feasibility and preliminary efficacy.
• The proposed trial will be conducted across 2 different treatment sites.
• The intervention periods extend to 6 months (greater than the more typical 12 weeks).
• Plans to promote NRT adherence as part of the AVAST intervention.
• The proposed assessment battery seems appropriate (though unrealistic to expect that it can be completed in 15 minutes).
• Intervention content in the AVAST intervention will be informed by the self-reported weekly responses to questions about affect, stress, and cravings.
• The proposed sample size is based on reasonable estimates of abstinence at 12-months.
• The inclusion of cost-effective analyses is a strength.
• Sex as a biological variable will be examined in relation to outcomes.
• Relevant variables will be considered during randomization to ensure equal representation across conditions.

Weaknesses
• The conceptual framework for the proposed intervention development was non-specific. It would have been helpful to understand which theories the investigative team utilized to help inform their conceptual model.
• If the proposed mediators for the 2 interventions are the same and it is expected that the effects of the intervention on the mediators (and on outcomes) will be larger for the AVAST condition. However, it is not clear WHY the investigators expect AVAST to do better (i.e., have larger effects) if the proposed mechanisms are the same between the 2 conditions. For example, what it is about AVAST that would decrease stress more than ST?
• It does not appear that other tobacco products will be examined.

Strengths
• The environment is excellent and sufficiently resourced to allow for the successful completion of the proposed project.

Study Timeline: Strengths
• The Timeline appears to be appropriate.

Weaknesses
• None. Overall Impact: This application proposes to further develop and test the impact of an innovative fully automatic smart phone-based smoking cessation intervention featuring tailored video messages, among other elements. The intervention methods and, to some extent, specific content could be widely generalizable at low cost to other locations. The well-balanced research team is experienced in smoking cessation interventions designed for disadvantaged populations, including PLWH. They have conducted a series of relevant studies, including pilot studies of the proposed intervention that yielded promising results. These pilots demonstrated the feasibility, acceptability, and potential impact of the proposed intervention on smoking behaviors. The conceptual approach is well-defined and incorporated into plans for intervention content and assessments. This framework provides testable hypotheses concerning the possible mechanisms of intervention effects. Strengths of the main trial design include a relatively strong standard treatment control and a long-term 12 month follow-up period for sustained cessation and other primary outcomes. Statistical power, data analysis, and other elements of the trial design appear to be appropriate. An economic analysis is well-developed and adequately supported. Limitations of the application plans included a decision to distribute cell phones to potential participants lacking an appropriate phone. Information about the development and specific content of the video library was limited. These limitations do not substantially diminish enthusiasm for the overall approach. On balance, this is a promising intervention that is at a relatively high level of development and well-suited for testing in a larger-scale clinical trial with potential for high impact.

Strengths
• Cigarette smoking cessation is a high priority for improving life expectancy among PLWH.
• Evidence is lacking for effective, sustainable and generalizable interventions to address this issue.
1 R01 CA243552-01 9 ZCA1 RTRB-U (A1) VIDRINE, D • Smart phone-based interventions, such as text systems, are promising. There is an opportunity to advance the impact of low-cost, generalizable phone-based cessation systems through capabilities such as tailored video messages.
• The reach and population impact would be high for a successful intervention that connected smokers with an attractive and effective automated phone-based system.

Weaknesses
• Although smart phone ownership is widespread, it is less accessible to disadvantaged populations among whom smoking rates are higher. The projected smartphone ubiquity may not be realized. and some PLWH who smoke may be logistically excluded from cessation services if an automated phone service is the only option.
• Creation of a single set of video messages that are attractive to many audiences may be more challenging than creation of widely attractive text messages. Visual and audio style elements may have strong effects on message recipient responses across target population subgroups.

Investigator(s) Strengths
• The Principal Investigator is experienced in design and evaluation of tobacco cessation interventions for underserved and disadvantaged populations, including PLWH, and with mobile phone tobacco cessation interventions and assessments. He has substantial experience in leading externally funded projects in these areas. He is very well qualified for his role.
• The Co-Investigators have strong qualifications and are appropriately funded for their roles in the project focused on intervention design and implementation, participant recruitment and retention, clinical issues, and evaluation.
• The Co-I located at the secondary recruitment site and the investigator focused on economic evaluation of the intervention are well-qualified.
• This is a balanced and experienced team, many of whom have collaborated on previous related work.

Innovation Strengths
• The tailored video components of the phone-based intervention will be innovative. • The proactive and user imitated features also may be innovative.

Weaknesses
• This is an incremental advance based on substantial prior research and experience for most elements of the proposed intervention.

Approach Strengths
• Study sites likely have sufficient numbers of potential participants. • The research group has established a working relationship with the proposed sites.
• The team has conducted a substantial amount of preliminary research directly related to the proposed study.
• Preliminary studies comparing various cessation modalities to a pilot version of the proposed intervention suggest that this approach is technically feasible, acceptable and possibly more efficacious than a standard treatment. 1 R01 CA243552-01 10 ZCA1 RTRB-U (A1) VIDRINE, D • The conceptual approach is well-developed and details hypothesized testable mechanisms of action for the interventions.
• Recruitment, enrollment, randomization, and participant retention procedures follow established protocols that have been implemented previously at these sites or are documented in the clinical trials literature.
• An adaptive randomization procedure will contribute to balance between study groups. • The design will compare the new treatment to a standard treatment to assess the possible advantage of the new treatment over a standard.
• The standard treatment will be delivered by the same contractor at both sites, ensuring reasonably identical treatment for participants from both sites in this study arm.
• The standard treatment will be relatively powerful.
• The underlying technology infrastructure for the tailored content interventions appears to be well-developed.
• The intervention will undergo an additional intensive pilot/feedback procedure to refine components and processes prior to the main study.
• The major outcome is verified abstinence at 12 months, a relatively strong test of sustained intervention impact.
• Statistical design and statistical power considerations are thoroughly described and appropriate.
The sample size is adequate to detect a clinically relevant effect size for the major outcomes.
• The economic analysis of results will contribute to understanding of dissemination potential.

Weaknesses
• Description of the video library messages is limited, including methods used to develop or acquire them, numbers of messages available, and prior audience testing of these messages.
• Distribution of cell phones to potential participants without an appropriate phone for the interventions is unrealistic if such an automated intervention is disseminated. This feature is a limitation of generalizability.
• Respondent burden for the assessments may be high and could negatively affect participant retention.

Strengths
• The primary research home at Oklahoma University Health Sciences Center has a strong set of resources relevant to the proposed project and is a supportive environment for this type of research. Existing facilities and personnel for mHealth applications are a particularly important resource.
• The secondary clinical site in Houston has resources appropriate to its role in the project.
• Economic analyses will be done at M.D. Anderson Cancer Center, a research-supportive organization.

Study Timeline: Strengths
• Adequate time allowed for the major study phases.

Inclusion of Women, Minorities and Children:
• Sex/Gender: Distribution justified scientifically • Race/Ethnicity: Distribution justified scientifically • For NIH-Defined Phase III trials, Plans for valid design and analysis: • Inclusion/Exclusion of Children under 18: Excluding ages <18; justified scientifically • Issues are discussed in detail and decisions are well justified.

Resource Sharing Plans: Acceptable
Budget and Period of Support: Recommend as Requested Footnotes for 1 R01 CA243552-01; PI Name: Vidrine, Damon J.

THE FOLLOWING SECTIONS WERE PREPARED BY THE SCIENTIFIC REVIEW OFFICER TO SUMMARIZE THE OUTCOME OF DISCUSSIONS OF THE REVIEW COMMITTEE, OR REVIEWERS' WRITTEN CRITIQUES, ON THE FOLLOWING ISSUES
NIH has modified its policy regarding the receipt of resubmissions (amended applications). See Guide Notice NOT-OD-14-074 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-14-074.html. The impact/priority score is calculated after discussion of an application by averaging the overall scores (1-9) given by all voting reviewers on the committee and multiplying by 10. The criterion scores are submitted prior to the meeting by the individual reviewers assigned to an application, and are not discussed specifically at the review meeting or calculated into the overall impact score. Some applications also receive a percentile ranking. For details on the review process, see http://grants.nih.gov/grants/peer_review_process.htm#scoring.

National Cancer Institute Special Emphasis Panel NATIONAL CANCER INSTITUTE Improving Smoking Cessation Interventions Among Pople Living with HIV (R01 & R21)
ZCA1 RTRB-U (A1) 06/06/2019 Notice of NIH Policy to All Applicants: Meeting rosters are provided for information purposes only. Applicant investigators and institutional officials must not communicate directly with study section members about an application before or after the review. Failure to observe this policy will create a serious breach of integrity in the peer review process, and may lead to actions outlined in NOT-OD-14-073 at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-14-073.html and NOT-OD-15-106 at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-106.html, including removal of the application from immediate review.