A study protocol for Project I-Test: a cluster randomized controlled trial of a practice coaching intervention to increase HIV testing in substance use treatment programs

In its ongoing recognition of HIV testing as a fundamental component of HIV treatment and prevention, the latest 2022 National HIV/AIDS Strategy (NHAS) continues to encourage the expansion of HIV testing to nonclinical and nontraditional settings throughout the United States (U.S.), emphasizing the public health significance of all people with HIV (PWH) knowing their status [1]. Despite recommendations from the US Preventive Services Task Force (USPSTF) that all adolescents and adults be screened for HIV in health care settings [2], less than half (43%) of U.S. adults have ever been tested for HIV [3]. In addition, of the estimated 1.2 million PWH in the U.S., approximately 13% are unaware of their HIV status [4]; individuals unaware of their infection status are estimated to contribute to over one-third (35%) of new HIV transmissions [5, 6].

Lack of testing is considered one of the main reasons that annual HIV incidence in the U.S. has remained steady at more than 30,000 cases over the last decade [7]. The COVID pandemic exacerbated already suboptimal HIV testing efforts and led to a massive hindrance of HIV testing efforts. Over the first 1-year period of the pandemic alone (2019–2020), the Centers for Disease Control and Prevention (CDC) reported a significantly sharp decrease in testing in both healthcare (43%) and non-healthcare settings (50%) [8]. The CDC and World Health Organization (WHO) have continued to call for expanding HIV testing in settings where persons vulnerable to HIV infection receive health services, including opioid treatment programs (OTP). In addition, the 2022 NHAS called for targeted HIV efforts and resources that specifically prioritize five populations that bear disproportionately higher HIV burden, one of which is persons who inject drugs (PWID) [1]. PWID accounts for approximately one in ten incident HIV cases [9], with many citing socioeconomic barriers (e.g., homelessness, incarceration) hindering the ability of PWID to access prevention and treatment services for both HIV as well as substance use [10].

Given the populations of people who are vulnerable to HIV due to injection and non-injection use of drugs, outpatient substance use disorder (SUD) treatment centers and OTPs are well-positioned to implement routine HIV testing and diagnose incident cases early in the infection trajectory. In addition, prior research has shown both the feasibility (e.g., improvements in testing rates and receipt of test results compared to off-site referrals) and economic value of on-site HIV testing in SUD treatment programs [11‐13]. Yet, despite the need, feasibility and value of on-site HIV testing in these viable settings, most programs do not offer testing, with less than half of U.S. SUD programs and less than one-third of OTPs offering on-site HIV testing [14]. Prior research has noted many significant organizational-level and client-level barriers preventing widespread HIV testing uptake in these treatment settings, including lack of reimbursement and insufficient billing systems, constraints surrounding staffing, resources, training and workflow, and concerns about delivering HIV test results and linkage to care [14‐16]. In addition, research has shown greater prioritization and perceived need for hepatitis C virus (HCV) testing compared to HIV testing, given the higher prevalence of HCV compared to HIV within this population [17, 18]. Additionally, the percentage of individuals with chronic HCV infection who are unaware of their infection (approximately 40%) is higher than those with undiagnosed HIV [19]. Despite the availability of better-tolerated, shorter-duration HCV curative treatments, recent CDC data in the U.S. has shown that the number of people with HCV who have initiated treatment has declined over the past few years [19]. Therefore, offering on-site testing services for HCV and HIV has been touted as being more relevant to OTPs than offering on-site testing services for HIV alone. The joint offer of HIV and HCV testing in OTPs [20] is particularly salient, considering that approximately 90% of PWID who seek care in traditional healthcare settings, i.e., non-substance use-related treatment, do not receive any HIV/HCV testing at their clinical visit [21]. As such, more integrated approaches in OTPs may enhance key testing opportunities for high-risk populations to improve the identification of HIV and/or HCV and subsequent active referral for care.

Within this context, the objective of our 3-arm randomized controlled trial (RCT) “Project I Test: Implementing HIV Testing in Opioid Treatment Programs” is to focus on addressing commonly cited organizational-level barriers to widespread HIV testing in OTP settings, as well as examine whether the offer of HCV testing in conjunction with HIV testing serves as a motivator for implementation of HIV testing. These goals align with the current NHAS strategy to develop new and expanded implementation of effective, evidence-based, or evidence-informed models for HIV testing that improve convenience and access [1]. The approach we adapted, implemented, and are currently assessing through this RCT utilizes “Practice coaching” (PC), a low-intensity, evidence-based, hands-on approach used to guide implementation of a change initiative, with the change initiative in this study being increased on-site HIV testing in OTPs. PC has been used to implement change in healthcare practices that improve client outcomes, largely through care delivery in primary care settings including increasing preventive service delivery rates, assisting with chronic disease management, and implementing system-level improvements within practice settings [22‐26]. The two active PC intervention approaches in this RCT were designed to improve the initial and sustained implementation of on-site HIV testing and linkage to care among OTP clients either alone or in conjunction with HCV testing; rates of HIV testing and linkage to care (as well as their associated cost-effectiveness) of the two PC interventions can then eventually be compared incrementally to one another as well as to an information-only control condition. The purpose of this paper is to discuss these approaches, as well as outline the overall protocol of our Project I Test study, which to our knowledge is the first study to test organizational approaches to increase uptake of HIV and HIV/HCV testing and linkage to care within community-based outpatient programs that provide opioid use disorder (OUD) treatment. Therefore, this study has critical public health implications for understanding how OTP settings can best be supported in the implementation of our innovation of interest (i.e., offering HIV testing on-site and linking PWH to care) and in their sustainment of these improvements, with the ultimate goal of improving HIV-related health outcomes for clients receiving opioid treatment.

The primary objective of the study (Project I Test) is to evaluate the uptake of HIV testing at OTPs, following the implementation of interventions that include practice coach facilitated structured conversations around implementing change, along with provision of relevant resources and documents to support the implementation of (1) HIV testing only, or (2) HIV/HCV testing, and (3) a control condition that provides a package with information only. The secondary objectives of the Project I Test study are to evaluate the following: the incremental impact of the HIV/HCV intervention (e.g., proportion of OTP clients tested) on the implementation of HIV testing, compared with the HIV only intervention, and during the initial impact period; the effectiveness of the interventions relative to the control condition, on the sustained impact of HIV testing; and initial impact of HCV testing and sustained impact of HCV testing. The tertiary objectives of the Project I Test study are to evaluate the effectiveness of the interventions relative to the control condition on linkage to HIV care among OTP clients who test positive for HIV; linkage to HCV care among OTP clients who test positive for HCV; change in perceived barriers/facilitators to HIV testing; and intervention impact mediated by change in perceived barriers/facilitators. Additional tertiary objectives include evaluating the organizational and environmental characteristics of OTPs that serve as facilitators and barriers to the provision of HIV testing, the sustained implementation of HIV testing, the uptake of testing by OTP clients, and providing timely linkage to care for persons who test positive. The quaternary objective is to assess the health outcomes, health care utilization, and cost-effectiveness of the PC interventions compared incrementally to one another and to the control condition. This will allow for assessing the budget required to implement (scale up and sustain) the PC interventions nationally.

The two PC interventions are manualized and training of Practice Coaches (PCs) emphasizes the importance of adhering to the manual that corresponds to a site’s assigned intervention condition (i.e., preventing drift). To ensure consistency of intervention delivery across all PCs, the PCs co-facilitated the first few intervention sessions. PCs also co-facilitate some intervention sessions later in the study to ensure that they are still delivering the intervention in the same manner and adhering to the manuals. Additionally, the Intervention Director conducts regularly scheduled “peer to peer” conference calls to discuss difficulties and successes in conducting the PC interventions; to facilitate the PCs learning from and supporting each other; and to facilitate receiving support and feedback from the Intervention Director.

All participants are provided with information and resources, per their intervention allocation. Programs are discouraged from additional treatments that are not according to the study protocol, during the intervention period. Participants will be required to report all treatments that are not according to the treatment protocol, i.e., an initiative that supports the adoption of HIV or HCV testing delivered by a coach.

Phase 1 includes five steps: Step 1 is a teleconference call between the PC and the site’s Leader, including advice to select a champion, with appropriate interest, knowledge base, skill set, and leadership capacity. Step 2 is a teleconference call between the PC and the site’s designated champion. Step 3 involves the PC’s comprehensive assessment of barriers and facilitators to the provision, client uptake, and reimbursement of HIV testing services. This assessment is based on a structured interview conducted by the PC. Step 4 is a concentrated in-person or virtual workshop and with the champion and key staff from the site. PCs review the goals and objectives of practice coaching, knowledge-based HIV information, the provision of HIV testing services, quality improvement, monitoring and evaluation tools, billing and reimbursement for HIV testing (including alternatives such as securing free test kits from the local health department and/or establishing Memoranda of Understanding / Agreement (MOU/ MOAs) with the health department and/or other community-based organizations to provide HIV testing services within the site), introduction to evidence-based linkage to care strategies as well as a review of roles/responsibilities and data capture forms. One purpose of the workshop is for the PC to synthesize results of the site’s comprehensive barriers/facilitators assessment and pre-intervention performance data and present these results to the site’s champion(s) and key staff, providing constructive feedback on identified barriers and potential solutions. Another key purpose of the visit is creating an action plan that is tailored to the OTP’s context and culture and that addresses identifying/securing resources needed to initiate or increase on-site testing. Step 5 is a debrief phone call with site Champion and Change Team to review and discuss the action plan for testing. This interaction with the PC also presents opportunities for sites to ask additional questions.

Each site is given access to self-management tools as well as national and state resource guides accessible via study-managed folders in Box.com, which include online links to organizations such as the CDC, Health Resources and Services Administration (HRSA) and SAMHSA, the site’s state health department, and a repository of guidelines and updated information on HIV testing and linkage to care practices. Sites are also provided with support tools, such as flowcharts and spreadsheets to track clients across the HIV care continuum. Additionally, sites have the opportunity to share other state and national resources pertinent to testing and linkage to care with each other (if they wish) by posting these resources to a shared space in Box.com. As appropriate, PCs serve as liaisons, connecting staff at each site with resources in their community to support testing and linkage to care for clients who test positive. PCs meet with program teams regularly (via video conference or telephone) to support the tailoring and implementation of their action plan and system-wide changes to achieve their stated goals. While PCs guide and support the initiation, sustained implementation, and measuring of changes to HIV testing practices, PCs do not lead the actual implementation of the proposed changes.

To facilitate inter-organizational learning during the Implementation Phase, PCs consider ways to connect sites willing to share their learning experiences with their OTP peers. Conference calls between sites within the same intervention condition are encouraged and arranged by PCs when sites are willing to participate in this activity. The calls allow participating programs to learn about various implementation strategies and seek guidance from colleagues on strategies to overcome different barriers. The calls also serve as a uniquely informative place for sites to learn about “late breaking,” on-the-ground changes in policies affecting services, funding, and organization, and what may (or may not) be relevant from one region to another. Attending sites set the agenda for (and facilitate) the interactive calls (not the PC). However, the PC may attend the call and provide input at the sites’ request.

Substantial organizational change literature shows that once adopted and successfully implemented, practices or innovations are often maintained over time without the need for continuing intervention. The sustainability of organizational-level changes is often associated with changes in organizational practices rather than the behavior of individuals. Changes to organizational practices may, however, have a direct beneficial impact on individual behavior. Additionally, interventions are considered sustainable when implementation strategies are maintained, and relevant activities (i.e., as described in Phases 1–3) and resources are allocated in-line with stated goals. Therefore, PCs will focus on five main activities to enable sustainability:

Three types of data are collected, client data, site data, and state data. The assessments used in the study consist of three quantitative surveys with treatment program staff (i.e., treatment program administrators, treatment program clinical staff), and state administrators; and qualitative interviews with treatment program directors and study champions (see Table 2). The treatment program administrator survey measures structure and service setting, client characteristics, staffing characteristics, program guidelines, barriers to care, and perceptions. The treatment program clinician survey measures training, knowledge, experience, barriers, and perceptions. The state administrator survey covers policies/regulations, reimbursement, and prioritization of testing services. The qualitative interviews address in-depth discussion about testing services offered at the site, barriers and facilitators to offering HIV/HCV testing services and linkage to care, attitudes towards services and training at the site, and organizational readiness for change.

We use various approaches to collect data to measure outcomes and covariates (see Table 3). Study sites, upon enrollment in the study, are provided with a spreadsheet which they may use to assist in compiling aggregate de-identified data summaries, including HIV/HCV testing data. These data are transferred from sites at 6-month intervals and are checked for consistency. We use REDCap Survey data capture tools, with automatic range and consistency checks for quantitative survey data collection. PCs track the intervention process and record these data in structured forms, i.e., Practice Coach Interaction Form (PCIF). Some of the intervention process data are collected and managed using REDCap, and other intervention process data are collected using electronic collection forms. Qualitative interview data, including audio recordings and transcriptions, are collected via digital audio recorders. All data are stored securely on an encrypted and password-protected server. All personal data of participants, both program and staff, are assigned a unique identifier that is stored on a secure server available only to data analysts and researchers with approved access to the database. Data analysis will only include non-identifiable data. Prior to analyses of the site surveys, factor structure and reliability of scales will be documented and all variables will be assessed for appropriate statistical distributions for analysis. Any missing data will be accommodated using multiple imputation.

To ensure monitoring of other study-related participant safety events or incidents, procedures regarding confidentiality and data integrity are continually monitored and regularly audited. Members of the PI team meet regularly (e.g., biweekly) during the study period to review trial progress.

Developed and implemented by the PIs, who constitute the data safety and monitoring board (DSMB), the data and safety monitoring plan (DSMP) assures minimal risk and data integrity in this study. The plan assures that all data collection procedures concur with all local, state, and federal guidelines. To assure integrity of data and safety, all aspects of the program are monitored, including informed consent procedures, data collection and quality (i.e., review for statistical anomalies), fidelity of the practice coaching intervention to the intervention manual, and adherence of the qualitative interviews to the interview guide. The data monitoring center, as well as DSMB, examines accumulating data to assure protection of participants’ safety while the study’s scientific goals are being met. The DSMB conducts periodic reviews of accumulating safety and effectiveness data and determines whether there is support for continuation of the study, or evidence that study procedures should be changed, or if the study should be halted for reasons relating to the safety of the study participants, the effectiveness of the treatment under study, or inadequate study progress. Because the study supports the implementation of HIV testing based on a practice coaching intervention, adverse events related to the intervention are not expected. However, unintended adverse events may include unauthorized disclosure of confidential information and potential discomfort/embarrassment related to answering quantitative and/or qualitative questions concerning clinical and organizational practices, perceptions, and attitudes about HIV/HCV testing; and potential violations of confidentiality. In the event that an adverse event or otherwise untoward incident occurs as a direct result of or in the context of the project, we closely follow IRB directives and reporting policies. Specifically, we report to the appropriate IRBs within 10 working days, in writing, all serious adverse or otherwise untoward events associated with procedures. To ensure monitoring of other study-related participant safety events or incidents, procedures regarding confidentiality and data integrity are continually monitored and regularly audited. The PIs promptly inform other Co-Is and NIDA staff of any proposed changes in site enrollment, intervention implementation, or in the protocol that are relevant to safety, as well as any actions taken by the IRBs as a result of their continuing review of the project. In the event of any major changes in the status of an ongoing protocol (which occurs only with IRB approval), the PIs inform NIDA’s program officer and the DSMB immediately. Such changes would include, but are not limited to protocol amendments, temporary suspension of site initiation/commencement, changes in informed consent or IRB approval status, termination of participation by the site and/or site personnel, or other problems or issues that could affect the human subjects in the study.

Statistical power and sample size were determined using a simulation programmed in SAS 9.3. The simulation generated data with a range of intra-class correlations (ICC) from 0.04 to 0.08, and an information control condition with a proportion of clients’ HIV testing of 20% as found in the control condition in CTN0032, a study assessing the relative effectiveness of three HIV testing strategies on increasing receipt of test results and reducing HIV risk behaviors among patients seen at drug use treatment centers [13]. A sample size of 51 OTPs and an average of about 100 clients per site per 6-month period provides over 95% power for the primary outcome and 85% power for the secondary outcome if the proportion of clients’ HIV testing in the HIV PC condition is 30% (absolute difference of 10% from control condition) and the proportion of clients’ HIV testing in the HIV/HCV PC condition is 41% (absolute difference of 11% from the HIV PC condition) for all expected levels of ICC (0.04 to 0.08). Should some sites drop out, there is still over 95% power for the primary and 83% power for the secondary, as long as 45 sites remain in the study. For the quasi-experimental evaluation of the blending product, the study will have over 80% power to uncover an absolute change in proportion testing for HIV of 6 to 7%. For analysis of change in proportion of facilitators/barriers, the study will have over 80% power to uncover a significant difference in change if the difference in change is 0.5 to 0.65 of a standard deviation, a medium effect size.

The primary outcome analysis will test the hypothesis that the two PC interventions will result in significantly higher proportions of clients tested for HIV than the control condition during the “initial impact” period (7–12 months post-randomization or T3), controlling for the proportion of clients tested during the baseline period (T1). We will use a generalized estimating equation (GEE) model with a binary distribution and logit link. The model will include four 6-month periods: T1 (months − 6 to − 1)—prior to randomization, T2 (months 1–6)—during intervention/control period, T3 (months 7–12)—initial impact, and T4 (months 13–18)—sustained impact. Time and participants are both nested within site. However, time is not nested within participants in the primary analysis. Individuals within a site may be more alike (correlated) than are individuals between sites, which will be accounted for in the GEE by inclusion of the working correlation matrix within site and the sandwich estimator for standard errors. The model will include gender and race/ethnicity, and geographic region as control variables. The primary tests of H1 will be done using a contrast of testing differences across conditions in the proportion of clients tested during T3, controlling for the proportion of clients tested pre-randomization (T1). All hypotheses will use the intention-to-treat approach and include all available data for the sites that are randomized.

The secondary and tertiary outcome analyses will use similar GEE methods as described for the primary outcome measure. The secondary outcome will test the hypothesis that the HIV/HCV PC intervention will result in significantly higher proportions of clients tested for HIV than the HIV PC intervention during the initial impact period (7–12 months post-randomization or T3), controlling for the proportion of clients tested during the baseline period (T1). Of note, the design of the primary outcome and the secondary outcome comparing the HIV/HCV intervention to the HIV intervention are an orthogonal decomposition of the 2-degree of freedom test of whether the 3 interventions are significantly different from each other. As such, there is still a type I error of 0.05 for these two hypotheses jointly and there is no reason for error correction for using 2 tests to determine differences among the interventions.

Other secondary measures will examine, for example, the impact of the PC interventions on the provision and sustainability of HIV testing (T4), the impact of the PC interventions on initial impact of HCV testing (T3). The tertiary outcome analysis related to linkage to care will evaluate the effectiveness of the interventions relative to the control condition on linkage to HIV care among OTP clients who tested positive for HIV, or for HCV, as well as change in perceived barriers/facilitators to HIV testing.

We will use mixed methods to evaluate the impact of the PC interventions and the OTPs’ organizational and environmental characteristics that serve as facilitators and barriers to the provision and uptake of HIV testing (T3), sustained implementation of HIV testing (T4), and improving timely linkage to care for persons who test positive. We will use a multilevel GEE model to examine whether change in perceived barrier/facilitators mediates intervention impact on HIV testing (T4). Mediation will be assessed by the product of coefficients method.

The quaternary outcome includes determining the costs associated with health outcomes and evaluating the cost-effectiveness of the interventions. We plan to complete a cost-effectiveness analysis, using data from the I Test trial to populate a simulation model, the Hepatitis C Cost-Effectiveness model (HEP-CE). HEP-CE is a microsimulation of HCV disease progression, screening, and treatment. The cost-effectiveness analysis will assume a health sector cost perspective and a lifetime horizon. We will test the hypothesis that the incremental cost-effectiveness ratio (ICER) for the HIV PC intervention will be below a commonly cited US willingness-to-pay threshold (< $100,000/quality-adjusted life years (QALY)) and therefore more economically attractive than the control condition. That is I Test will be cost-effective assuming a societal willingness to pay of $100,000 per QALY gained. Our other hypothesis is that the ICER for the HIV/HCV PC intervention will be more economically attractive than the HIV PC intervention. The study will follow a proven model of effective collaboration among the intervention team and computer simulation modelers to evaluate the health outcomes, health care utilization, and cost-effectiveness of the PC interventions [11]. We will use I Test data to inform key model parameters, such as rates of linkage to care with and without the I Test intervention, as well as the cost of the intervention. The established micro-costing techniques will be used to identify the costs of delivering the PC interventions, including personnel and non-personnel costs incurred centrally to deliver the intervention and incurred at the OTPs to participate in the intervention and conduct follow-up activities (excluding time required for research activities). Model outputs include cases identified, linked to care, and treated, as well as life expectancy, quality-adjusted life expectancy, costs, and cost-effectiveness.

The micro-costing results and data on the characteristics of clients at each of the OTPs will be used as inputs to analyses conducted using the HEP-CE microsimulation model of HIV and HCV infections [33, 34]. These analyses will evaluate the incremental health outcomes, healthcare utilization, and cost-effectiveness of the PC interventions, considering the lifetime benefits and costs of linking to treatment clients newly identified as HIV-infected and as HCV-infected. The HEP-CE model will be used to conduct sensitivity analyses that consider a range of assumptions about key model parameters such as prevalence of undiagnosed HIV and HCV infection, effectiveness of linkage to care, likelihood of treatment initiation once linked, and likelihood of screening and linkage in the absence of the intervention. Separately, micro-costing data will be used to explore the budgetary requirements to scale up the PC interventions nationally, including the budget implications for participating OTPs. Sensitivity analyses will consider different scenarios for the sustainability of the interventions depending on level of success at institutionalizing testing practices.

The development and application of a multilevel coding scheme is an integral component of the data analysis process. At the highest level of the coding hierarchy are the primary analytic foci, coded as headings. Specific dimensions of the headings are assigned core codes, while dimensions of the core codes are assigned sub-codes. We will use ATLAS.ti, a software program for qualitative analysis, to facilitate the analysis. Seven steps will be used to develop the coding scheme: (1) identify the principal issues discussed by participants; (2) construct definitions of the primary analytic themes; (3) develop and apply core codes (themes) and sub-codes (sub-themes) to the initial set of interviews; (4) develop a provisional coding scheme; (5) test the coding scheme by applying it to a subsample (n = 15) of interviews, (6) refine the provisional coding scheme; (7) have two research team members independently apply the coding scheme to a new subsample (n = 15) of interviews; (8) have them meet to reconcile differences in their application of the codes; (9) Refine the coding scheme as needed and finalize it; and (10) apply the finalized coding scheme to the full data set. Inter-coder reliability will be assessed with kappa statistic.

Our PC interventions, if shown to be effective and cost-effective, could be used at multiple levels to provide ongoing support to OTPs in delivering HIV/HCV testing. This promising approach should be adaptable to address HIV testing in other settings, including pharmacies, dental care settings, and community centers. To our knowledge, this study is the first to test organizational approaches to increase HIV and HIV/HCV testing strategies in OTPs. If successful, SAMHSA, HRSA, the AIDS Education and Training Center, the Addiction Technology Transfer Centers and other community-based agencies at the national, state, and local levels could use our organizational support approaches to provide ongoing support to SUD treatment programs in delivering HIV and HCV testing. This proposal is also well-aligned with the new National Institutes of Health (NIH)-wide guidelines for priorities for HIV/AIDS grants. The first priority is to reduce the incidence of HIV/AIDS and one of the main goals is to develop, test, and implement strategies to improve HIV testing and entry into prevention services.

Despite evidence highlighting the effectiveness and economic value in on-site HIV testing in SUD treatment programs, current testing practices are inadequate. There is an overall need for expanded HIV testing among persons who use substances, particularly in underutilized settings where high-risk persons receive health services. The I Test project is one of the first comprehensive studies to develop and test a PC intervention to support the adoption and implementation of HIV and HIV testing in opioid treatment programs. It is also novel in that it employs a study design that accounts for the integration of HIV and HCV testing in treatment programs, with a focus on linkage to care [35]. Additionally, the translation of findings from this study is central and is supported by the cost analysis. In light of the Affordable Care Act (ACA) facilitating initiatives to increase the provision and sustainability of HIV testing, therein lies a pivotal opportunity for OTP treatment sites to increase their continuous implementation of HIV testing and timely linkage to care. With cost barriers being largely negated, organizational barriers remain the predominant limiting factor in OTP sites’ uptake of testing; as such, our study is among the first to systematically test implementation strategies at the organizational level to promote the delivery of HIV testing in OTPs. By introducing a PC approach shown to be effective in primary care settings into OTP sites, our study aims to help sites navigate their reimbursement systems and mitigate staff-related barriers with the ultimate goal of bolstering timely HIV testing and linkage to care for those most in need.

The trial is in the data collection stage, with the recruitment and randomization process nearly completed. Recruitment began 6/14/2017 and is expected to continue until late 2023. The protocol version number is 7.0, with date of 4/7/2021.