mHealth Intervention to Improve Treatment Outcomes Among People With HIV Who Use Cocaine: Protocol for a Pilot Randomized Controlled Trial

Background Antiretroviral therapy is effective in reducing HIV-related morbidity, mortality, and transmission among people with HIV. However, adherence and persistence to antiretroviral therapy are crucial for successful HIV treatment outcomes. People with HIV who use cocaine have poor access to HIV services and lower retention in care. Objective The primary goal of this paper is to provide a detailed description of a mobile health intervention. This study is designed to improve medication adherence among people with HIV who use cocaine. A secondary goal is to list the important challenges and adaptations incorporated in the study design. Methods This study, titled Project SMART, used a wireless technology–based intervention, including cellular-enabled electronic pillboxes called TowerView Health and smartphones, to provide reminders and feedback on adherence behavior. The intervention design was based on the theoretical frameworks provided by the self-determination theory and the Motivation Technology Model. The 12-week pilot randomized controlled trial with four arms provided three types of feedback: automated feedback, automated+clinician feedback, and automated feedback+social network feedback. Results The study was funded by the National Institute of Drug Abuse (R21DA039842) on August 1, 2016. The institutional review board for the study was approved by Yale University on March 21, 2017. Data collection lasted from June 2017 to January 2020. The final enrollment was 71 participants, of whom 57 (80%) completed the study. The data are currently undergoing analysis, and the manuscript is being developed for publication in early 2022. Conclusions Implementing complex mobile health interventions for high-risk and marginalized populations with multicomponent interventions poses certain challenges, such as finding companies with adequate technology for clients and financial stability and minimizing the research-related burden for the study population. Conducting feasibility studies is important to recognize these challenges and the opportunity to address these challenges with solutions while keeping the design of a randomized controlled trial as true as possible. Trial Registration Clinicaltrials.gov NCT04418076; https://clinicaltrials.gov/ct2/show/NCT04418076 International Registered Report Identifier (IRRID) DERR1-10.2196/28332

1 R21 DA039842-01A1 3 BSCH ALTICE, F PUBLIC HEALTH RELEVANCE: This project seeks to examine the impact of mHealth tools on ART adherence and persistence among HIV+ cocaine users through qualitative assessments and a 12-week pilot feasibility RCT. Qualitative assessments will consist of focus groups among cocaine users and healthcare providers that will evaluate the acceptability, feasibility, facilitators and barriers of implementing mHealth interventions. The pilot feasibility RCT will examine the impact of mHealth tools (cellular-enabled smart pill boxes and cell phones) and feedback (no feedback vs. automated feedback vs. automated + clinician feedback) on ART adherence and persistence, HIV viral suppression, cocaine use, and retention in HIV care.

CRITIQUE 1:
Significance: 2 Investigator(s): 1 Innovation: 1 Approach: 7 Environment: 2 Overall Impact: This is a moderately responsive revision of an application seeking support for a trial of a multi-component intervention to improve medication adherence in HIV-infected individuals with cocaine use disorders. While the problem to be addressed is highly significant, the study's underlying theoretical rationale is difficult to discern and important details about how the study intervention will be delivered are not clear, substantially reducing this study's likely overall impact.

Strengths
The study addresses adherence in an important population from a public health perspective.

Strengths
The investigative team is strong.

Strengths
The use of the MedSignals device in combination with IVR technology is innovative.

Weaknesses
Study design and implementation follows a standard approach.

Strengths
The proposed study will use the investigative team's well-established capabilities in developing an intervention that addresses adherence in an important groups and that has the potential to be cost-effective.

Weaknesses
Inclusion criteria state language may be either English or Spanish. It's not clear how persons whose preferred language is Spanish would participate in the planned focus groups or the intervention.
Focus groups will be completed with participants who report cocaine use in the past 30 days, while the intervention study will focus on those with cocaine use disorders. As it is possible that casual users may differ from those with more clear impairment, a better rationale for this strategy would strengthen the application.
It is still difficult to discern how the MedSignals device will provide individualized feedback to study participants on their level of adherence. The exact nature of clinician-provided feedback to individuals is not clearly explained beyond the investigators' suggestion that it would be related to the IMB model.
The investigators have been responsive to previous reviewers' concerns about the relevance of the proposed intervention to the IMB model, but it is still not evident how automated reminding maps onto IMB elements, beyond its ability to address a skill deficit (remembering to take medication). If, as the investigators suggest, the automated and clinician feedback will incrementally improve adherence skills then it would be useful to better understand how the intervention will do this.
Given the equivocal results of the LifeWindows study, it would be helpful to understand how the intervention will be made more effective by using its model. The relevance of the LifeWindows materials included in the Appendix to the planned Medsignals/IVR/clinician intervention is not clear.
How reminding is synergistic with the elements of the IMB model is not clear.
Given the extensive body of research on the influence of cognition on adherence, failing to take cognitive status into account is a significant weakness.

Strengths
The environment in which the study would be completed is excellent. Overall Impact: This experienced and highly productive team of investigators proposes to conduct qualitative research to assess the acceptability and feasibility of implementing mHealth interventions followed by a pilot feasibility study to examine the effect of mHealth tools on ART adherence in a population of HIV-positive individuals with cocaine use disordersa group with problematic ART adherence and persistence. The proposal was responsive to prior critiques regarding study design, measurement and analysis, and has high potential for a significant public health impact given the paucity of available adherence interventions for the marginalized population under study.

Strengths
Targeting HIV-positive individuals with cocaine use disorders is highly significant given the wellestablished challenges in ART adherence and persistence in this population, and paucity of established, efficacious interventions to improve HIV care outcomes.

Weaknesses
None noted.

Investigator(s):
Strengths PI Frederik Altice has considerable experience on -development and evaluation of innovative strategies to identify, link, treat and retain HIV-infected individuals in care who have underlying 1 R21 DA039842-01A1 6 BSCH ALTICE, F substance use‖-this is evidenced by his involvement with a number of RCTs to evaluate interventions to improve ARV adherence among HIV+ people who use drugs Substantial experience among other applicants (Krishnan; Copenhaver) in RCTs of interventions to improve adherence and other outcomes among substance users. The PI has experience in qualitative research, demonstrate by his role as PI on the project -Expanding Medication Assisted Therapies in Ukraine‖ History of previous collaboration between Atice, Copenhaver and Krishnan.

Weaknesses
Given that 25% of the effort for this project comes from Dr. Shan-Estelle Brown (other personnel), a bit more detail about her research experience was expected. However, from what is provided, she seems to be well-suited to lead the qualitative component of this study given her background in Medical Anthropology and research focus on substance users' attitudes toward medical technologies.

Strengths
While an mHealth initiative such as the one proposed is not necessarily innovative in and of itself, its application to a population with cocaine use disorders is unique, and may result in valuable guidance on future HIV care interventions in this population regardless of the outcome of the trial.

Weaknesses
None noted.

Strengths
The scope, content and context of the proposal is an excellent fit with the R21 funding mechanism. Given the novelty of the intervention, it is absolutely appropriate and prudent to pilot test this form of intervention in the targeted patient population.
The acknowledgement and inclusion of persistence as well as adherence as outcomes is a strength Acknowledgement of cost considerations -and the impact of these considerations on the scalability of any such interventionsis also a strength The investigators have provided a wealth of detail regarding study instruments and procedures thus addressing the key weaknesses identified in prior submission The analysis plan for the pilot has now been sufficiently developed.

Weaknesses
Given the emphasis on efficiency in the significance section, it is somewhat surprising that the investigators have not proposed a basic analysis to estimate the costs of delivering each intervention, or otherwise used the pilot to determine whether health care cost data collection is feasible in this population.

Strengths
This study is ideally situated. The environment is very strong and well suited to carry out the proposed study.

Weaknesses
None noted.

Resubmission:
This proposal was highly responsive to prior critiques, resulting in a very strong proposal.

CRITIQUE 3:
Significance: 1 Investigator(s): 1 Innovation: 2 Approach: 3 Environment: 1 Overall Impact: This resubmission of an R21 application proposes to determine the acceptability, study design, and implementation procedures for carrying out an RCT built upon patient-mHealthclinician relationship for improving ART adherence and persistence among PLH with cocaine use 1 R21 DA039842-01A1 8 BSCH ALTICE, F disorders (CUDs). Qualitative assessment phase utilizing feedback from patients with CUDs and healthcare providers will inform the pilot trial and feedback elements. Use of mHealth devices and realtime feedbackmapped onto the IMB modelare proposed as the primary tools of the intervention. The investigative team is strong, methods are clear, and the environment is well suited to conduct the study. Minor issues remain in the approach but are quite addressable.

Strengths
Persons with cocaine use disorders continue to be at high risk for poor medication adherence; approaches to reduce their risk has implications for their own health as well as reducing HIV transmission.
Interventions that can communicate in -real time‖ may hold promise for high risk groups.

Weaknesses
None noted.

Strengths
The investigative team is strong and has relevant expertise in the various components of the study.

Weaknesses
None noted.

Strengths
Although the IMB itself is not innovative, its application to mHealth interventions and the substance using population is an innovative use of the model.

Weaknesses
None noted.

Strengths
Qualitative methods are well defined.
The intervention elements are mapped on to the theoretical framework.

The inclusion of the MacArthur Competence Assessment Tool is a strength
Use of the focus groups to identify how messages should be tailored will improve the relevance of messages.
Prior experience and data showing that unstably housed individuals can participate in mHealthtype intervention studies supports the methods proposed herein.

Weaknesses
Study timeline for both qualitative and pilot feasibility elements may be ambitious. 1 R21 DA039842-01A1 9 BSCH ALTICE, F A feasibility study does not require sophisticated analysis plan (although it is assumed that the proposed models are to generate effect sizes for the future R01).
Prior review noted that the study population is at risk for cognitive impairment. This resubmission attempts to address this concern via stratification of an Axis I Depressive Disorders. Although an important variable, this does not account for the presence of cognitive impairment that may dilute intervention effectiveness.

Strengths
The environment is excellent and well-suited to support the proposed study.

Weaknesses
None noted.

Acceptable Risks and/or Adequate Protections
Use of the MacArthur measure for competence is a particular strength as is inclusion of a psychiatrist and clear plan for referring persons with clinically significant depressive symptoms.

Inclusion of Women, Minorities and Children:
Sex/Gender: Distribution justified scientifically Race/Ethnicity: Distribution justified scientifically Inclusion/Exclusion of Children under 21: Including ages < 21 justified scientifically Vertebrate Animals:

Not Applicable (No Vertebrate Animals)
Biohazards:

Resubmission:
Applicants were mostly responsive to reviewer comments and have made important adjustments, justification, and clarifications.

Budget and Period of Support:
Recommend as Requested 1 R21 DA039842-01A1 10 BSCH ALTICE, F 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. Consultants are required to absent themselves from the room during the review of any application if their presence would constitute or appear to constitute a conflict of interest.