Study Design
The study is a four-arm, 1:1:1:1 randomized controlled trial (RCT). We will recruit participants and monitor their ART adherence using Wisepill devices to measure pill container openings remotely for three months. After this period (henceforth `observation period’), we will identify clients exhibiting low adherence, the target population for our intervention. All clients who adhere to less than 90% of their medication in the month before their baseline visit will be recruited for the intervention phase, and randomly assigned to one the GOALS study arms, and those with adherence higher than 90% will be unenrolled.
We will randomize these participants with low adherence into one of four equal-sized study arms for the first year of the intervention (‘Improvement phase’). In the three treatment arms, participants will be eligible for a prize drawing to win small amounts of mobile airtime of either 500, 5,000 or 10,000 Ugandan Shillings (approximately $0.15, $1.50, and $3, respectively) if they reach the adherence goal required in the respective treatment arm. Those randomized to the fourth group will receive usual care as well as weekly text messages, but no incentives. The goals will be set as follows for the different study arms:
- Assigned subgoals (T1): in this group, the study coordinator will choose the ART adherence target for the participant. This will be done as follows: given an expected four prize drawings during the first year of the intervention, the study coordinator will measure the participant’s baseline adherence and gradually increase the target every three months by equal amounts, working towards 90% adherence at the end of year 1. For example, for someone with 50% baseline adherence, the study coordinator would calculate (90%-50%=40%; 40%/4=10%), and set the adherence targets at the four study visits equal to 60% at month 3, 70% at month 6, 80% at month 9, and 90% at month 12.
- Participatory subgoals (T2): the participant will choose their own adherence target every three months, working towards 90% adherence at the end of year 1. Each target chosen must be higher than the highest adherence ever achieved. For example, someone selected their adherence target in three months to be 70%, but they actually achieve 75%. The next target they choose must then be 75% or higher. If a given target was not achieved, the participant can then choose one that is equal or higher to the one chosen previously.
- Fixed goal (T3): the study participant must reach a fixed (i.e. non-varying) target adherence level of 90% at each study visit; this arm corresponds to how adherence interventions typically are implemented.
- Control group (T4): will receive the usual standard of care offered at Mildmay Uganda.
The three treatment groups will receive weekly motivational messages and a reminder of their upcoming prize drawing. Weekly SMS messages will help maintain contact with study participants and enable them to become accustomed to receiving messages from the study for potential remote prize drawings (given the evolving COVID situation and corresponding clinic changes towards visits that are more spaced out, we expect some prize drawings to be done in person, and others remotely as further detailed below). In contrast, the control group will only receive the motivational portion of the text messages (without the reminders of the possibility of winning prizes) as an attention control due to the potential beneficial effects of text messages.
After the first year of the study, we will evaluate participants in the treatment groups to determine those who achieved high adherence of at least 90% (high adherers) and those who did not (low adherers).
Figure 1 below shows that in year 2, high adherers will progress to the `Maintenance phase’ between months 12-24 where we will assess the intervention's effectiveness in maintaining at least 90% adherence. They will have the chance to win prizes every three months if they maintain their adherence at or above 90% throughout this phase. They will then move to the `Persistence phase’ between months 25-36 to assess the treatment arms' impact on long-term adherence once incentives are removed.
Low adherers will be given an additional six months in the `Improvement phase’ between months 12-18. During this time, low adherers in the participatory subgoals group will have one more opportunity to set their personal target; they will be encouraged to set a target at month 15 such that they would achieve 90% by month 18. Low adherers in the assigned subgoals group will receive two more pre-chosen targets starting from their adherence at month 12 in equal increments up to 90% (e.g. if month 12 adherence is 80, their target is 85 for month 15 and 90 for month 18). The maintenance phase for the low adherers in the assigned goal and participatory goal groups will begin at month 18 for 12 months.
Low adherers in the fixed goal group will maintain their target of 90%. At Month 18, we will identify the treatment arm with the highest effectiveness and move low adherence participants in the fixed goal arm to that arm to give them an opportunity to also benefit from the intervention. These participants will continue in the improvement phase between months 18-30, while assigned subgoals and participatory subgoals participants move to the maintenance phase. Low adherers across in the participatory and assigned goals group will complete their `Persistence phase’ of the study in months 30-36.
All participants in the treatment groups will be eligible for a larger prize drawing at the end of their maintenance phase if they achieve viral suppression, defined as a viral load of 200 copies/mL or less.
Follow-up surveys will be conducted every six months for 24 months, and a cost-effectiveness analysis will also be performed after 36 months to help determine the intervention design's potential for sustainability and scale-up.
Study Sites
The study will be conducted at Mildmay Uganda, an NGO with headquarters in Uganda’s capital, Kampala. Mildmay Uganda specializes in the provision of comprehensive HIV and AIDS prevention, care, and treatment services. Mildmay Uganda provides quality outpatient and inpatient HIV care and trains health care workers throughout Uganda and the region in the provision of such care. Mildmay serves over 105,000 patients (15, 000 at the Main Site in Lweza and over 95,000 at supported health facilities in 8 districts in Central Region of Uganda). The main-site facility has a well-trained, experienced team of clinicians and health workers, and modern laboratory infrastructure with ability to do virology and other tests. The Mildmay Uganda laboratory is accredited by the South African National Accreditation System (SANAS) for International Organization for Standardization (ISO) 15189:2012 for medical laboratories and also acts as a national back up laboratory for the government of Uganda Central Public Health Laboratories. Some of the services provided include: HIV counseling and testing; pediatric and adult HIV prevention, treatment and care services; sexual and reproductive health services; diagnostic (laboratory) services and radiology; rehabilitative services (nutrition, physiotherapy, occupational therapy); safe male circumcision (SMC); ophthalmic; and dental care. Of the 15,000 patients served at the main-site in Lweza 11% are children below 18 years, 65% are female and 100% of all clients in care are on ART. Mildmay is one of a growing number of facilities with a well-established electronic medical records system in Uganda.
Sampling and Participants
We expect to enroll 1,256 individuals for the observation phase of the study that serves to measure baseline adherence. Monitoring baseline adherence will ensure that individuals being randomized to the interventions are indeed those in need of adherence support, i.e. have relatively low baseline mean adherence of less than 90%.
We arrived at this starting sample size in the following way. For the primary outcome of adherence, a sample size of 140 participants in each arm (n=560 total) will be able to detect an 8 percentage point (pp) difference in mean adherence between each treatment arm and control, and compared to each other. The corresponding difference at month 24 is 9pp. This assumes mean control group adherence of 62%. In order to reach this required sample size at year 3, we assume 6% attrition per year over 2 years of the study (1.06^2 = 1.1236) which results in a sample size for the beginning of GOALS recruitment to be 629 (560*1.1236). To ensure an even number across the four study arms, we reduce this target from 629 to 628. We then assume that 50% of those who complete the adherence observation phase are eligible for the GOALs intervention. We therefore need a starting sample size of 1,256 ((628/50) *100). All assumptions surrounding attrition rates and rates of adherence are based on data from PI Linnemayr’s previous study at the same site.
Inclusion Criteria
For a participant to be eligible for the 3-month observation period preceding the GOALs intervention they must meet the following requirements:
- Aged 15-30 inclusive
- Receiving ART medication from Mildmay for more than 3 months
- Has regular access to a mobile phone (less than 5 out of 7 days)
In order for participants to be eligible for the GOALS intervention after the observation period, the participant must meet the following additional requirement:
- Have a mean adherence below 90% in the last month of the observation period
Exclusion Criteria
Exclusion criteria for the 3-month observation period preceding the GOALs intervention and for the GOALs intervention:
- Is not willing or able to use the Wisepill device when taking ART medication
- Has mental health problems that require immediate treatment (e.g., psychotic symptoms), a diagnosed mental disorder that would limit the ability to participate (e.g., dementia), or cognitive impairments that result in a limited ability to provide informed consent.
- No longer has access to a phone (less than 5 out of 7 days), if phone access changed over the course of the 3-month observation period
- Participating in another study
- Unable to read
Randomization
Random treatment assignment will occur after participants are recruited, and before they complete a baseline survey using a 1:1:1:1 ratio. Randomization will be done using sequential assignment while stratifying by baseline adherence measured during the observation period (0 -54%, 55 – 71%, 72 – 82%, 83 – 89%). Stratification will be performed to increase power and achieve better balance than in a simple random draw. A randomization schedule will be established ex-ante and sequential participants within a stratum randomized accordingly. The randomization schedule will contain blocks of four possible randomizations to the three treatment arms or the control group, with the order of the four possibilities randomized each time a new block begins. We will use the ralloc function in Stata 17 to generate the randomization lists, which will be uploaded to SurveyCTO and programmed to randomize participants on the spot.
The observation phase lasts approximately three months, after which adherence-based eligibility is determined, and all recruited participants will complete a baseline survey. They will be informed of their assignment to either one of the three intervention arms or the control group after completing the baseline survey. Participants who provide informed consent will be asked to participate in the baseline survey before the treatment assignment is revealed to make sure group assignment does not influence the answers given.
Participants cannot be blinded to their treatment status and neither can interviewers. The data analyst who will conduct the impact analysis will be blinded to treatment assignment.
As the only blinded party is the analyst, and the blinding occurs to avoid any bias of the analyst to find a statistically significant effect for the intervention group(s), we cannot think of a justified reason for unblinding the analyst.
Design
The study will use three intervention arms and a control arm. The intervention arms will all provide mobile airtime as incentives, but the incentives will be based on different eligibility criteria in the different arms. We will collect ART adherence data continuously for three months prior to the intervention, for 24 months after the intervention begins, and for 12 months after the intervention ends for all participants using Wisepill devices. We will acquire routine viral load measures for all participants throughout the study, which will be performed roughly every 12 months as per clinic and Uganda Ministry of Health guidelines. We will also conduct a baseline survey, and then surveys every 6 months for 24 months for all participants. See the SPIRIT Figure for a detailed description of the timing of study activities.
This study protocol uses the SPIRIT reporting guidelines. 37
Procedures
Intervention components
All participants in the treatment arms will be eligible for a quarterly prize drawing if they meet the goal that corresponds to their treatment assignment, and for an annual prize drawing if they show 90% adherence by the time they reach month 12 (as measured by reaching 90% in the last 3 months of month 12).
Quarterly Prize Drawings
Participants in the three treatment arms will be eligible to enter an in-person or remote prize drawing for a mobile airtime reward every three months if they meet their target adherence. In-person prize drawings will be done if the date of the drawing coincides with the participants' regularly scheduled clinic visits; otherwise, they will be done remotely. Wisepill records adherence remotely, so the study team can monitor adherence without an in-person visit. Remote prize drawings will be conducted automatically by the computer, and the results and airtime reward texted to the participant over the phone.
Assigned sub-goal eligibility: Participants in the assigned subgoals arm will be eligible for the quarterly prize drawing if they reach their assigned sub goal in the respective quarter. The goal will be assigned based on observed baseline adherence, which will be deducted from 90%, and divided by four to get at 4 equal, relatively small, increasing steps. For example, someone with 50% baseline adherence would be asked to reach 60% at month 3, 70% at month 6, 80% at month 9, and 90% at the end of the first intervention year.
Participatory sub-goal eligibility: Participants in the participatory subgoals arm will be eligible for the quarterly prize drawing if they reach the goal they choose for themselves in the respective quarter. The only restrictions are that each goal has to be equal to or higher than the previous one, and that at month 12 90% adherence is reached.
Fixed-goal eligibility: Participants in the fixed-goal arm will be eligible for the quarterly prize drawing if they reach 90% adherence in the respective quarter.
Patients scheduled for the in-person prize drawing will also be required to complete a prize drawing survey after they participate in a prize drawing. This survey will measure how feedback given on the achieved versus planned ART adherence influences motivation for future performance and perceived attainability of the next goal. Target, distance, and valence influence attitudes and motivation towards future goals.
Annual Prize Drawings
Participants in all three treatment arms will be eligible to enter a larger prize drawing at the end of year 1 if they reach 90% adherence over the course of 12 months.
Wisepill procedures
All participants will be given a Wisepill device upon recruitment into the observation period of the study. At the time they receive the device they will be instructed in how to refill the pill box. The team will only monitor adherence to one antiretroviral as studies show that rates of adherence do not differ significantly across a patient’s medications.
Participants will be asked to use the Wisepill device continuously throughout the study and to notify the study coordinator if their provider changes their regimen during the study (which may be a real possibility, in particular for the youths on prophylaxis). They will be asked to remove only one dose at the time of ingestion and will also be informed that the data recorded will not be shared with clinicians. The team will carefully discuss the restrictions associated with the device with the patient and solutions to potential concerns that are acceptable to both the patient and the project will be generated. We will review the instructions and restrictions with the participant at each successive clinic visit.
The three-month period will also allow individuals to incorporate the device into their daily life and to test and troubleshoot its use prior to beginning the intervention. During this time, we will monitor their adherence. Participants who are unable to use the device consistently will be excluded from the study after careful discussion of the reason for the low observed adherence with the patient (to avoid excluding participants with truly low adherence that is not related to an inability or unwillingness to use the Wisepill device). We will also exclude participants who have adherence above 90% during this period to target the intervention at those with low wisepill-measured adherence (as those over 90% adherence have little room and/or need for improvement).
Intervention modifications
Participants will be discontinued from the study if they experience serious adverse events related to the intervention. Participants will also be discontinued from the study at their own request, if they are not in a position to adhere to study protocols which include the use of wisepill devices to monitor their medication intake.
Strategies to improve adherence to intervention protocols
Intervention implementation will be closely monitored via inspecting routine data collected through surveyCTO, conducting regular data quality checks, and providing the study team up to date data to facilitate implementation. Progress trackers are based on incoming data, which tracks the number of people who have begun each phase of the intervention, those randomized to each group, and those who completed each study activity. Study coordinators are provided a study activity tracker, which updates weekly, to inform them of upcoming in-person prize drawings that coincide with clinic visits. Remote prize drawings are conducted via the Telerivet SMS platform. For both prize drawing messages and weekly SMS messages, the study team tracks message sending success rate on a weekly basis, and resends messages that were not successful the first time. Weekly team calls are also conducted across SCs and PIs to debrief progress and challenges. Site investigator MO monitors implementation fidelity regularly; in addition, PIs Huang and Linnemayr visit several times a year to observe study activities and troubleshoot issues.
Study Timeline
The SPIRIT figure above shows the study timeline.
Recruitment
During recruitment for the observation phase, the client will be given a Wisepill device. During this recruitment visit the study coordinator will consent the participant and explain the reason for and conditions of using the Wisepill device. Participants will be compensated 10,000 USh for their time.
As dates of the next appointment are readily available from the electronic medical records system, the clinic system will allow us to print out weekly lists of eligible clients together with the date they are expected at the clinic, and the date they are scheduled for their next viral load test.
We will consent and enroll 4-6 clients per day (some clients may refuse participation, though this has been rare in our previous studies) during the 9- to 12-month recruitment period. Based on the large clinic population and our previous experience, we expect to easily recruit the 1,256 clients within a 12-month period but allow for sufficient extra time to accommodate any delays due to public holidays and other reasons for clinic closures or other delays.
Baseline Survey and Randomization
When the client returns for their next scheduled clinic visit after the observation period (after about three months) and is eligible based on their observed adherence, we will conduct the baseline survey, reveal treatment assignment to either the control or one of the three intervention groups, and begin the intervention. In scheduling these return visits, we will aim to schedule them to coincide with a scheduled clinic visit so that participants do not have to come to the clinic for the sole purpose of study activities. However, participants with next scheduled visits longer than three months will be messaged or called to come back at the three-month mark.
The baseline survey contains the following information:
- Demographics and socioeconomic status, including age, gender, education, relationship status, employment type and status, income, housing, economic shocks, and household composition;
- HIV Status and Clinic Visits e.g., respondents will be asked whether they have disclosed their status to members they live with and the number of those who have HIV/AIDS, their primary caregiver, the person that ensures they take their ART medication and their clinic visit habits and expenses;
- Adherence self-efficacy i.e. reasons for non-adherence or failure to seek care (we will use an 11-item modification developed by the ACTG, that asks participants to indicate whether listed items were reasons for their not taking medication in the previous month or seeking care, such as “when the drugs make you feel bad,” or “when your daily routine is interrupted.”, or “lacked resources).
- Participants’ subjective experiences related to taking medications38 using the Intrinsic Motivation Inventory. The survey will also collect information related to behavioral economics biases such as present bias or risk preferences.
Follow-up Surveys
Follow-up surveys will be conducted at month 6, 12, 18 and 24 post baseline. These assessments will allow us to collect several data points for each participant on mediators or moderators that we believe may be influenced by the intervention (e.g., cognitive and motivational factors). Participants will be compensated 30,000 UGX for their time every time they complete a survey questionnaire.
Retention
To promote participant retention and complete follow-up, the study has aligned its activities with the participants' clinic visit dates. By doing this, the study aims to ensure that participants are not only coming to the clinic for study-related activities but also for their routine clinical visits. This approach is expected to reduce the burden on participants, minimize missed appointments, and increase compliance with the study protocol. Participants who discontinue the study will return their Wisepill devices and we will not be collecting outcomes data.
Outcomes
Primary Outcome
Outcome 1: Mean adherence to ART (Time Frame: adherence over a 12-months period continuously tracked remotely): Wisepill devices monitor the date and time of all device openings to retrieve ART medication, allowing ART adherence to be tracked continuously on the Wisepill server. Mean adherence will be coded as the number of ART doses taken / number of doses prescribed, with adherence being capped at 100% each day to avoid multiple openings on a given day artificially inflating mean adherence.
Outcome 2: The fraction of clients with adherence of 90% or more (Time Frame: continuously tracked remotely).
Outcome 3: Probability of reaching adherence target (Time Frame: tracked every 3 months corresponding to routine prize drawing opportunities). Probability that participants in the treatment groups reach their assigned target (T1), self-selected target (T2), or high fixed target of 90% (T3).
Secondary Outcomes
Outcome 1: Fraction of clients with treatment interruptions of more than 48 hours (Time Frame: Continuously tracked remotely).
Outcome 2: Suppressed viral load (viral load <=200 copies/ML) amongst participants (Time Frame: At baseline and month 24): Viral load will be chart abstracted from clinic data. They are typically done once a year as part of routine clinical care.
Outcome 3: Retention in Care, chart abstracted from clinic data. First, we will use the binary definition of retention from the Health Resources and Services Administration HIV/AIDS Bureau as at least 2 clinic visits separated by 90 days in the previous 12 months. Second, we will use the more detailed measure outlined by Lee et al. (2018) to create a variable that categorizes clients as having different levels of retention in care that provides more granular information about retention. We will define a client as fully retained in care if they attended all scheduled appointments over the previous 12 months (usually 4 or 5 total appointments). We will then create three different levels of care disengagement: missed one appointment but not more than 6 months without a visit, missed 2 appointments or 6-9 months without a visit, and missed 3 or more appointments or 9-12 months without a visit.
Sample Size and Power
We have calculated the size of effects that our sample will be able to detect with 80% power (2-tailed test) with regard to outcomes at month 12 and 24, and assuming 10% attrition every year (we observed 8% attrition for our pilot study, so this is a conservative estimate). For the primary outcome of adherence, a sample size of 140 participants in each arm (n=560 total) will be able to detect an 8-percentage point (pp) difference in mean adherence between each treatment arm and control, and compared to each other. The corresponding difference at month 24 is 9pp. This assumes mean control group adherence of 62%, based on our pilot data. For the secondary outcome of viral suppression, we use a conservative estimate of about 70% of clients in the control group showing suppression based on discussions with the Mildmay team. Our sample size of 140 participants in each of the three arms will be able to detect about a 10pp difference at month 12, and 11pp at month 24. These represent conservative estimates of minimum detectable effect size that do not account for stratified randomization that we will perform to increase power, and to achieve better balance compared to a simple random draw.39
Data Analysis
Our primary analyses will be intention-to-treat analyses, with secondary analyses involving study completers only.
Estimating impact on primary outcomes
To estimate the impact of our interventions on primary outcomes, we will use an ordinary least squares Linear Probability Model. In the context of experimental evaluations, linear probability models provide unbiased estimates of program impact and correctly estimate standard errors (Gomila, 2020; Deke, 2014) 40. We will estimate an unadjusted model and a model that includes the following prespecified covariates to adjust for baseline characteristics and improve precision: age, education, sex, strata fixe, baseline WHO disease stage, baseline viral suppression, duration on ART, socio-economic status as measured by the Poverty Probability Index for Uganda, and HIV disclosure status.
Mean adherence to ART and the fraction of clients with adherence of 90% or more will be analyzed with the following adjusted and unadjusted models:
Unadjusted:
The `Maintenance’, and `Persistence’ phases of the study will be analyzed for the number of months the participant spends in each phase. For the improvement phase, we will focus only on the month preceding month 12, as for that phase each participant in the participatory and assigned subgoals groups will display a different subgoaling path, and the only goal they share is to reach 90% adherence by month 12 (and eligibility for the prize drawing is measured for the 30 days preceding the month 12 visit).
Subgroup Analysis
We will also do some exploratory subgroup analyses based on the following characteristics:
- High vs. low baseline adherence
- High vs. low baseline intrinsic motivation to take treatment
- High vs. low baseline self-efficacy
- High vs. low frequency in usage of sending and receiving messages through their mobile phone
Standard Errors
We will estimate Huber-White robust standard errors in all analyses. All standard errors will be clustered at the individual level.
Adjusting for multiple hypotheses
P-values will be adjusted for multiple hypothesis testing for all secondary outcomes by applying a false discovery rate adjustment (FDR) following Benjamini et al. (2006). In particular, we will use the sharpened q-values discussed in Anderson (2008). This correction will control for the expected proportion of Type 1 errors.
Data Management
Existing clinic identifiers will be used as unique study identification numbers during data collection. Consent forms will bear the name and signatures of study participants, but all other information (such as viral load tests, Wisepill measurements etc.) will be collected using these unique clinic identifiers. The study team in Uganda (one team leader, two lead interviews, and three supporting team members) will be in charge of collecting all of the data and carrying out the in-person intervention. All survey data will be collected with computer-assisted software (SurveyCTO) using a tablet. The survey data will be uploaded to the password protected study computer at the end of each day (at which point they are then automatically deleted from the device) and saved in an encrypted folder on that computer.
All datasets and files with identifiers will always remain encrypted through a zipped folder or by using BoxCryptor within DropBox, an online data portal that can only be accessed using a secure password. Adherence to HIV antiretrovirals will be monitored using a Wisepill device. Data from these devices will be uploaded remotely to an encrypted server using a sim card embedded in the Wisepill device in real time. Participant adherence data will then be downloaded and stored securely via BoxCryptor and will only be identified via an alpha-numeric clinic ID. SMS messaging data will be downloaded from the messaging platform, Telerivet. Text messaging data will not include sensitive or private information, such as the participant's name or current HIV status at any point. Downloaded datasets will include text messages sent and received, time and date of messages. For any data exports containing participant's phone number we will ensure this always remains in an encrypted folder using BoxCryptor within DropBox.
Paper copies of consent forms will be stored and locked at the Mildmay RAND office in Kampala, and access will only be granted to key personnel and the study PIs. Any published material will not contain participants’ identifying information. There is no formal data monitoring committee since the trial was deemed minimal risk, but data monitoring will occur through weekly checks by the study team in the US, and an independent study monitor.
Handling missing data and attrition
Missing data have been a minor issue in our previous studies with the same study population and outcomes. Attrition has been well under 10% per year. However, when subjects drop out, we will fit multiple logistic regression models to assess whether this dropout is random. If it is not, we will construct “nonresponse” weights using logistic regression that correct for dropout by assigning weights to continuing subjects that are inversely proportional to the predicted probability of the subjects’ continuing to the time period in question. Analyses will incorporate design effects from this weighting in the calculation of standard errors and tests of significance. In addition, we will present sensitivity tests regarding changes in outcomes when excluding those with missing observations to give a fully transparent picture of the data.
OVERSIGHT AND MONITORING
Data monitoring formal committee
The study is a clinical trial with a low risk of harm. Therefore, we appointed a single independent clinical psychologist who is an expert in treating depression in people with HIV as the monitor instead of using a Data Monitoring Committee (DMC). The monitor will receive reports every six months on subject enrollment, retention, adverse events, and reasons for dropouts and will review the reports and make recommendations regarding the study's continuation, modification, or termination. All the communication from the independent monitor will be shared with the institutional review boards and NIH. The monitor is independent of the sponsor and has no competing interests.
Interim analysis
As described in the Methods – Study Design section, interim analysis will be conducted at Month 12 to classify participants into those who have reached 90% and those who have not. At 18 months, we will analyze impact results across study participants to determine the treatment arm with the highest effectiveness; participants in the fixed arm who have not reached 90% adherence will then be moved to this arm.
Adverse event reporting and harms
While we are doing everything to avoid that a study participant is at increased risk because of any study-related activity, we will be very careful in tracking any potential negative events experienced by all study participants. Adverse events relating to ancillary and post-trial care may encompass both physical and psychological harms. The study coordinator will be experienced and trained to recognize risks or crises that require referrals. Team members have established procedures and guidelines to respond to risk disclosures and crisis situations among participants. If there are indications during the study visits that a participant poses a risk of suicide or to harm him/herself, the interviewer will stop the session and explain to the participant that they would like an on-site Mildmay mental health counselor to speak with the participant about the situation. The counselor would then assess the risk for potential harm and the appropriate action in terms of evaluating the client’s need for mental health services and notifying appropriate authorities. This assessment would be done as soon as possible and before the client leaves the premises to the extent possible. A serious adverse event report will be filed, if necessary. This will all be done immediately if possible and certainly within 24 hours.
Anything that looks like it could be an Adverse Event will be brought to the attention of the local and study PI as each case needs to be investigated. Any unexpected, serious adverse events that occur during the course of this investigation and follow-up period will be reported by telephone by one of the PIs, Dr. Linnemayr or Dr. Huang, within the next business day to the study IRBs and the independent study monitor. The telephone report will be followed within 3 business days by a written report, which will contain: subject’s ID#, the title and date of serious adverse event, and narrative explanation (e.g., how the research staff was notified of the event, dates of consent, study screening for inclusion/exclusion, whether the participant participated in the intervention or was in the control condition, dates and circumstances of the hospitalization/death, and participant status at last clinical or research contact). In consultation with the IRBs, the PI will address whether there is a need to redesign or amend the protocol, and/or to inform current and future subjects of a change in description of risk (e.g., in consent form and protocol).
Except for adverse events, we do not expect any reasons for discontinuing the intervention. As per our IRB protocol, participants are free to discontinue the study at their own discretion. Due to the low-risk nature of the intervention, there will be no interim analyses, or stopping rules.
Auditing
The Mildmay Uganda Research Ethics Committee and the Uganda National Council for Science and Technology will conduct an independent audit of the study once every year. The procedures for audit will include a site visit, document reviews, participant record reviews, and interviews with study coordinators. The auditors will also review compliance with regulatory requirements and ethical principles, as well as the accuracy and completeness of data collection and reporting.
Dissemination of Results
Study findings will be disseminated to researchers and clinicians via peer-reviewed publications and sharing of findings at conference presentations. Authorship of published papers will follow established guidelines for defining the level of contributions that warrant authorship. These findings will also be relevant to local Ugandan and global communities with an interest in understanding underlying behavioral mechanisms that affect HIV treatment adherence. We will share these findings with senior level officials at the Ministry of Health and at Mildmay Uganda, so they can formulate appropriate policy in line with the national recommendations on annual viral load screenings for HIV-positive patients.
The full protocol will be made publicly available. Participant-level dataset and statistical code will also be made available upon publication of the impact results.