Incentives and Reminders to Improve Long-term Medication Adherence (INMIND): Protocol for a Pilot Randomized Controlled Trial

Background Nonadherence to antiretroviral therapy (ART) among people living with HIV is a crucial barrier to attaining viral suppression globally. Existing behavioral interventions have successfully increased ART adherence, but typically show only short-term impact that dissipates after the interventions are withdrawn. Objective This study aims to test the feasibility, acceptability, and preliminary efficacy of a novel intervention that uses SMS text messages and conditional incentives to support ART initiators in establishing pill-taking habits. Methods A sample of 150 participants aged ≥18 years who have initiated ART in the preceding 3 months will be recruited from Mildmay Uganda in Kampala, Uganda. All (150/150, 100%) participants will be educated on the anchoring strategy and will choose an existing routine to pair with their daily ART adherence from a set of 3 suggested routines: getting dressed in the morning, eating breakfast, or eating dinner. Then, participants will be randomized to receive either usual care (control group: 50/150, 33.3%) or 1 of the 2 interventions delivered over 3 months: daily SMS text message reminders to follow their chosen anchoring plan (messages group; treatment group 1: 50/150, 33.3%) or daily SMS text messages and incentives conditional on taking their ART medication around the time of their chosen anchor (incentives group; treatment group 2: 50/150, 33.3%). Long-term ART adherence will be evaluated for 6 months after the intervention, and survey assessments will be conducted at baseline, 3 months, and 9 months. Outcomes include feasibility and acceptability measures and intervention efficacy outcomes defined by electronically measured mean medication adherence during the intervention and during the 6 months after the intervention, along with a measure of routine ART adherence based on taking medications around the time of participants’ anchor during the intervention and during the 6 months after intervention. Results As of February 18, 2022, recruitment was completed. A total of 150 participants were recruited, and data collection is expected to end in December of 2022. Final results are expected to be submitted for publication by April 2023. Conclusions This study is the first to use behavioral economics–based interventions in combination with the anchoring strategy to improve long-term ART adherence among treatment initiators. We hypothesize that the combination of SMS text message reminders and incentives will increase participants’ use of their anchoring strategy, and thus medication adherence will be better maintained after the intervention ends in our intervention groups relative to the control group that uses only the anchoring strategy. Results of this pilot study will help to refine this combined intervention approach for testing at scale and broaden our understanding of the habit formation process. Trial Registration ClinicalTrials.gov NCT05131165; https://clinicaltrials.gov/ct2/show/NCT05131165 International Registered Report Identifier (IRRID) DERR1-10.2196/42216

HIBI LINNEMAYR, S 1R34MH122331-01A1 Linnemayr, Sebastian RESUME AND SUMMARY OF DISCUSSION: This application proposes to develop the "INcentives and ReMINDers to Improve Long-term Medication Adherence (INMIND)" intervention using the ADAPT-ITT framework and then assess the feasibility and acceptability of the intervention. The INMIND intervention will use small incentives and daily text messages to help study participants recruited from a Ugandan HIV clinic to anchor their pill taking to an existing routine. A small randomized trial will be performed to test the two elements of the intervention compared to a control group. All study participants will receive standard information on establishing behavioral routines and adherence counseling. One intervention group will receive daily text messages reminding them to stick to their pilltaking anchor plan for three months. The other intervention group will receive the same text messages plus conditional awards for three months. The study outcomes will be medication adherence, retention in care and viral load after 12 months. In addition, qualitative data about the intervention will be gathered from stakeholders and participants to prepare for a future R01 application. Maintaining mediation adherence over time is challenging for most people and interventions that improve ART adherence have the potential to have a significant public health impact. The applicant has been responsive to concerns raised in the prior review of this application. The study team was strengthened by the addition of Dr. Yvonne Karamagi, a clinician. The intervention was refocused around behavioral anchors and incentives which the committee felt was a much stronger approach. The applicant also clarified a number of other areas that had raised questions in the prior review. However, the committee was not convinced of the need for incentives, although the combination with anchoring was seen as a potentially useful approach. There was also an issue raised about whether the study's target population was young, male clients of the clinic. These remaining issues somewhat limited the committee's overall enthusiasm for this much improved resubmission.

DESCRIPTION (provided by applicant):
Recently the number of people initiating antiretroviral (ART) treatment ("treatment initiators") has increased but too many fail to achieve viral suppression. Healthy routines are key to achieving long-term behavioral change and healthy outcomes, but few people manage to form them on their own. Existing interventions typically suggest that people anchor the targeted behavior to an existing routine, but fail to support participants during the time it takes to turn the behavior into a routine, with the result that typically fewer than half end up carrying the targeted behavior out automatically. Behavioral economics (BE) points to two important biases preventing many people from translating their good intentions into successful routines; it also suggests two readily implementable approaches to counter these same biases: the bias of lack of salience of chronic treatment adherence (i.e. over time, the more pressing needs of daily life dominate good intentions) can be countered by low-cost reminder messages sent via mobile phone during the time it takes to turn pilltaking into a routine behavior. Present bias (i.e. giving in to short-term temptations, which can lead to skipping pill doses) explains why many people have trouble sticking to their good intentions. Using small, intermittent incentives until the behavior becomes a routine is a novel approach that has the potential to be a game changer for establishing the (currently elusive) goal of long-term high ART adherence. The proposed R34 study will be implemented in a Ugandan HIV clinic in a 12-month randomized controlled trial (RCT) among treatment initiators to establish feasibility, acceptability, and preliminary efficacy of the intervention. Following formative work in Phase 1, all study participants will be told about the importance of routine pill-taking and receive a leaflet with strategies for anchoring pilltaking to an existing routine. Participants in the first intervention group (n=50) will then receive daily text messages for 3 months to reinforce that information (Message group). Participants in the second intervention group (n=50) will receive the same messages, but will also have a chance of winning small rewards conditional on high and timely medication adherence (Incentive group). Participants in the Control group will receive the usual standard of care. Persistence of adherence (primary outcome) and timely pill-taking (secondary outcome) will be measured using MEMS caps for 9 months after the 3-HIBI LINNEMAYR, S months intervention, and retention in care as well as viral loads (secondary outcomes) will be assessed at month 12. Specific Aim 1 will be to evaluate the feasibility and acceptability of INMIND and develop the intervention using the ADAPT-ITT framework. Based on these insights, Specific Aims 2a and 2b will test the preliminary effectiveness of the intervention, including the relative effectiveness of two different implementation approaches (i.e. text messages alone vs. together with small BE-based incentives). Specific Aim 3 will collect data allowing adaptation of intervention parameters for a subsequent R01 application to test the intervention at scale.

PUBLIC HEALTH RELEVANCE:
For public health it is important to support the growing number of ART treatment-initiating clients who often fail to achieve viral suppression, with catastrophic consequences in particular in resource-constrained countries in which treatment options are limited. This study aims to increase ART adherence among treatment initiators by anchoring pill-taking to an existing routine behavior with the help of small incentives based on principles from behavioral economics in combination with text messages sent by mobile phone. The approach is particularly targeted at those with low motivation and cognitive problems, thereby reducing health inequality and facilitating high, long-term ART adherence for a particularly vulnerable group of HIV clients.

CRITIQUE 1
Significance: 3 Investigator(s): 2 Innovation: 3 Approach: 3 Environment: 2 Overall Impact: This is a revised application to adapt and pilot an intervention to support ART adherence. The proposal aims to promote anchoring as a way to establish sustainable adherence routines. Grounded in psychological and behavioral economic theory, the investigators argue that using incentives to routinize adherence among initiators early on can lead to sustained adherence over time. The proposed study could generate more evidence for the role of routinization and incentives. A piece that is missing, however, is recognition that non-adherence and treatment interruption could be caused by factors beyond individual level factors such as motivation and present bias. The fully individual-level focus raises concerns about how plausible it would be for this approach to lead to sustained adherence among individuals who experience external threats to their ability to adhere, despite being motivated to do so and having routines.

Strengths
• The need for innovation in the area of adherence support over time is a clear and compelling gap as this is a behavior that requires sustained maintenance over time.

Weaknesses
• While the investigators provide a compelling hypothesis regarding using incentives to establish routines early on, the exclusive focus on individual level determinants of non-adherence (present bias, motivation, forgetfulness) does not account for other social and structural determinants of adherence. HIBI LINNEMAYR, S • The relevance of the work for other chronic conditions is mentioned in the aims and the proposal but this idea is not developed at all. It would be helpful to have more consideration of this as applicability to other chronic diseases would make this more significant.

Strengths
• The PI has extensive experience leading intervention studies in this setting and the proposed study represents an effort to extend that work. The team has worked together in the past and has demonstrated productivity. The roles of each investigator are well defined.
• The discussion of capacity building and career development is appreciated. It is notable that there is a named study coordinator, reflecting the strong existing research collaboration between the teams at RAND and Mildmay clinic.

Weaknesses
• none

Strengths
• There is innovation in the premise of the study, focused on testing the theory that anchoring and promoting the establishment of routines could promote sustained adherence.

Weaknesses
• The use of incentives itself is not innovative and the investigator team has already conducted extensive research in this area in this setting.

Strengths
• Integration of qualitative and quantitative methods is appropriate for the study purpose and scope and will provide holistic information.
• Use of surveys at both 3 and 12 months will give some sense of sustained adherence. While the real gap is sustaining adherence consistently over longer periods, this will give some indication of the feasibility and effectiveness of this approach.
• Use of FGDs in Aim 3 is appropriate and could provide important data for understanding the intervention experience and processes.

Weaknesses
• Time allocated for ADAPT-ITT process (6 months) is short and may not facilitate meaningful engagement with the full range of steps and rich analysis of data. The investigators indicate having added more detail to Phase 1 description, but the current presentation is disproportionately focused on the content of the interview guide, with very little discussion of the steps in the ADAPT-ITT process.
• There is also disconnect between the Aim 1 analysis and the steps of the ADAPT-ITT process.
Description of analysis stops at code reports and does not describe how they will be used to adapt the intervention. HIBI LINNEMAYR, S • Who will conduct qualitative interviews? No detail provided on the "facilitators".
• The investigators mention documenting both themes that are commonly discussed as well as those that are not in the aim 1 qual analysis. However, there is no discussion of how these data will be handled -less commonly discussed themes could be reflective of critical inductive findings that certain participants bring up despite not being a focus of the study guide and that the authors had not considered beforehand.
• For Aim 3, analysis of FGDs is described as the same as the approach for IDIs, which fails to account for the group dynamics, which can be a critical part of the production of data in FGDs. Again, how code reports will be interpreted and used to generate findings is not clear.

Strengths
• The Mildmay clinic offers the potential study population and has an established history of collaboration.

Weaknesses
• none Study Timeline:

Strengths
• None noted by reviewer.

Weaknesses
• Adapt component condenses many steps into a very short time period with limited discussion of the details involved in this process. • The investigators provided a detailed response and made critical revisions. The revisions to the phase 1 qualitative section place disproportionate emphasis on the initial in-depth interviews and not enough detail on the adaptation process.

Applications from Foreign Organizations:
• Mildmay and RAND have a longstanding collaboration that will facilitate the proposed study.

Resource Sharing Plans:
Acceptable Budget and Period of Support: Budget Modifications Recommended (in amount/time) Recommended budget modifications or possible overlap identified: • It is noted that travel to Uganda does not appear to be included in the budget.

CRITIQUE 2
Significance: 3 Investigator(s): 1 Innovation: 2 Approach: 3 Environment: 1 Overall Impact: This application will develop, pilot test, and refine an intervention to facilitate pill-taking routines to improve HIV treatment adherence among PLHIV in Kampala, Uganda. Interventions to promote habit development are essential for adherence to ART regimes and adherence to other health behaviors. The hypothesis that providing incentives for taking the medication in combination with established routines (rather than providing incentives for just taking the medication) may help to consolidate pill-taking habits, is innovative. The approach involves 4 well-developed phases including formative interviews, systematic intervention adaptation process, pilot trial of the adapted intervention, and focus groups to assess acceptability and implementation issues. Overall, this is very good application. The scientific premise is clear and decisions are well-thought and justified. The intervention will not certainly address all factors that disrupt adherence (e.g., mental health, substance use, homelessness). However, this proof-of-concept study may result in a scalable intervention to promote adherence in low resource settings, in addition to providing further information about developing healthy habits. Remaining concerns are the assessment of adherence by averaging 9 months of MEMS cap data and questions about the significance of the preliminary data in Figure 2.

Significance:
Strengths HIBI LINNEMAYR, S • High ART adherence is needed to achieve viral suppression and control the HIV epidemic.
• Understanding adherence behaviors is significant for multiple medical conditions. • Simple, low-cost, scalable interventions can have significant public health impact.
• Integration of the intervention within the clinic procedures can help identify implementation challenges and opportunities, which will facilitate dissemination and scalability.
• The intervention can easily be adapted to other clinical and nonclinical settings.

Weaknesses
• Individuals who experience psychosocial and structural barriers to adherence are less likely to sustain other habits, comply with healthcare visits, follow instructions (such as bringing the MEMs cap to clinic visits), and remain in care.
• Figure 2 suggests that, among participants who did not associate pill-taking with other routines, the effect of removing incentives on adherence was only 3%.

Strengths
• The PI has expertise in behavioral economics which provides the theoretical underpinning for the proposed intervention.
• The PI has 10 years of experience working in Uganda and with the Mildmay Clinic.

Weaknesses
• Unclear if the team has expertise in longitudinal and time series analyses.

Strengths
• Linking pill-taking to other routines is the main innovation of the study.
• The combination of developing personalized action plans, reminder messages with information, and incentives is innovative.
• Using reminder messages that include procedural information is innovative as is assessing routinization through MEMs cap. Weaknesses • Incentives and reminder messaging are not novel interventions

Strengths
• A strong conceptual framework guides all aspects of the design and intervention. • The sequence of formative work, ADAPT-ITT, feasibility/acceptance/efficacy pilot trial, and qualitative interviews to address implementation issues is a strength.
• Using MEMS cap to measure routinization is a strength.
• Using multiple complementary measures of adherence (MEMS cap, self-report, viral load) is also a strength. Weaknesses HIBI LINNEMAYR, S • There are remaining concerns about how MEMS cap data will be analyzed and about using 9month average measures of adherence, as this will not capture changes or trends following the intervention.
• Collecting process information may be beneficial to assess acceptability and adapt the intervention, for example, to determine whether participants become desensitized to the text messages or whether they read them and remember the content.
• As the time needed for habit development has not been studied in health settings, following more closely pill-taking routinization can provide information about how habits are consolidated. • Generally responsive to critiques. Some of the responses are clarifications rather than changes.

Environment
The 9-month average measure of adherence remains a concern.
Resource Sharing Plans:

CRITIQUE 3
Significance: 3 Investigator(s): 3 Innovation: 4 Approach: 4 Environment: 2 Overall Impact: This application proposes to develop a medication adherence intervention in collaboration with a Ugandan HIV clinic. The intervention, named INMIND, proposes to use small incentives and daily text messages to support treatment initiators anchoring ART pill-taking to an existing routine with the goal of establishing persistent ART adherence. The investigators propose 3 phases including a formative phase that will evaluate the feasibility and acceptability of INMIND, an intervention phase that will test for preliminary effectiveness (actually efficacy), and an adaptation phase based on that will inform a subsequent R01 larger study. The proposal is largely responsive to previous critique and has the potential to be successful. Enthusiasm for the proposal was limited by having many Approach concerns including that there was a lack of certainty about who the target population will be.

Strengths
• ART medication adherence is a significant public health problem.
• The intervention is in reaction to a common reason for non-adherence -forgetting.
• Supporting/influencing patients when they initiate medication taking might influence long term behavior.
Weaknesses HIBI LINNEMAYR, S • As the intervention relies on having funds for rewards, and many clinics may struggle with having discretionary money, it is not clear how scalable this approach could be. However, this is relatively low cost.

Strengths
• The PI has worked with this clinic on several NIH projects.
• Many experienced investigators with background in behavioral economics.

Weaknesses
• A prior critique stated, "The administrative contribution of Mukasa (8-10%) appears to be clear.
However, her scientific contribution is unclear. She would be more suited for a Project Manager or Project Coordinator roles rather than as a Co-Investigator." However, as per her biosketch, she says, "I will support the research team to provide administrative and programmatic oversight for implementation of the proposed research." This critique is not addressed as she is still a co-I without her providing a statement of her scientific contribution.

Strengths
• Intervening specifically at initiation is innovative.
• A novel measure of behavior routinization is proposed.

Weaknesses
• Targeting forgetfulness is not an innovative strategy.
• The approach is appropriate for an R34 (formative work, test with pilot, refine intervention).
• The involvement of the community advisory board is a strength.
• The application of the ADAPT-ITT framework looks appropriate.
• The intervention is performed for 3 months followed by 9 months of observation to evaluate behavioral persistence. The 9 months is a good period of time for an R34 to observe after intervention.
• Evidence was given that they can recruit the number of proposed initiators.
• The plan to prevent attrition is well described.

Weaknesses
• Small rewards may overcome lack of motivation and help establish adherence as a routine. But it is not clear that for medication adherence this will be sustainable. This proposal will test that for 9 months beyond the intervention but medication adherence is a high hurdle for those challenged with it. HIBI LINNEMAYR, S • The proposal states that "existing anchoring interventions have not been successful at supporting routine creation during" the relatively long time of 3 months. So it sounds like they are modifying a failed approach with an incentive. If that is so, it seems it is going to have to be highly effective in order to make a difference.
• A "major concern" is to ensure participants are not denied prize drawings due to circumstances beyond their control. The investigators will "ask participants about such obstacles and find solutions with clinic staff" but it is not clear how they know they will be able to find solutions. Also, this would have been a good thing to explore when drafting this proposal given the ongoing relations the investigators have with this clinic rather than have it occur only after funded given that it is a major concern.
• The proposal appropriately states that "An important issue will be integrating the intervention in the routine clinic flow to avoid burdening either participants or providers and to confirm the feasibility of intervention procedures." However what evidence is there that this is likely not to burden them and thus be a problem with feasibility and sustainability?
• The population for this study has not been determined. The proposal says they will launch it in the HIV clinic population but then also says "We will discuss with the medical staff and Mildmay's CAB whether to limit recruitment to young, male clients with less than primary education. If they are considering a targeted subpopulation, there should be a background section about this earlier in the grant. It also seems odd to say that the population for the study may be this or that rather than a clear approach. Additionally, why were these discussions not had in the preparation of the grant to make the decision? Additionally, it seems the greatest impact is expected in this small group but it is not clear from the grant how small is this group.
• The proposal states that they will "assess program dynamics over the 12-month study period" but it was not clear what this meant or how it would be done.
• At recruitment, participants are given an explanation and a one page leaflet laying out the strategy for anchoring to an existing routine. However, they stated that they might target young males with less than primary education. So it is not clear how they would be able to read even a simple language leaflet.
• Again, with text messages planned, if they are targeting young males who have little to no education, what evidence is there that they read and use text messages.
• Mention was made in the message group that they will receive daily text messages reminding them of their personalized action plans. However, it was not clear where or how these "personalized action plans" were created.
• Participants are asked to get an extra viral load test if there is none routinely collected within three months of the baseline visit or the month 12 study visit. It was not clear if they provide an incentive for this or just expect the participant to do it when told.
• The analysis should explore if young low education males are more likely to have present bias.
• The description of the post-intervention focus groups was only one paragraph and used vague language rather than described methods: "We will also talk with clinic staff to gauge their perception of intervention feasibility, limitations, and sustainability…" • It was surprising to see a limitations section that describes no expected limitations.
• Minor -In response to a critique, the investigators increased the incentive frequency to monthly rather than only once after three months. While this may increase the efficacy, it also modestly decreases the feasibility by increasing the cost. HIBI LINNEMAYR, S

Strengths
• RAND Corporation is an excellent environment for research.
• There is a successful track record of working with Mildmay Clinic in Uganda.

Strengths
• The timeline seems adequate.

Weaknesses
• None noted. • If they are going to select only young males as they said they might, they did not adequately justify that.

Vertebrate Animals:
Not Applicable (No Vertebrate Animals)

Resubmission:
• The resubmission is mostly responsive. The issue noted above is whether or not Dr. Mukasa contributes scientifically.