Continuum of care in hospitalized patients with opioid or stimulant use disorder and infectious complications of drug use—substance use/infectious disease integrated clinic compared to treatment as usual to prevent infection-related readmission (CHOICE-STAR): a study protocol for an effectiveness-implementation randomized controlled trial

Abstract

Background

People who inject drugs (PWID) experience high rates of serious injection-related bacterial and fungal infections (SIRI), including cellulitis, osteomyelitis, and endocarditis. These infections often require prolonged antibiotic treatment and result in frequent rehospitalizations, with over 50% of patients readmitted within 1 year. Few evidence-based interventions exist to optimize continuity of care for addiction, management, and prevention of SIRI following hospitalization.

Methods

CHOICE-STAR is a hybrid type 1 randomized effectiveness-implementation trial, guided by the Exploration, Preparation, Implementation, and Sustainment Framework (EPIS), conducted at five hospitals across the USA. The study aims to assess the effectiveness of the integrated infectious diseases (ID) and substance use disorder (SUD) outpatient clinic on 6-month infection-related rehospitalization among people hospitalized with an infection related to injecting opioids or stimulants. The study also includes implementation outcomes guided by Proctor’s Implementation Outcomes taxonomy, as well as cost-effectiveness outcomes. The integrated clinic (IC) will offer facilitated linkage to a clinic providing medical care aimed at treating SUD and ID by completing treatment for the index infection, treating existing ID complications of SUD, and preventing subsequent infections by providing low barrier care for SUD including medication for OUD (MOUD) and harm reduction integrated into a single appointment and co-located at a single site for a minimum of monthly appointments over a 6 month time period. An additional 6 months’ follow-up will be included to assess outcomes following the completion of the intervention. The IC includes a weekly care coordination meeting between the ID and SUD providers. The study will enroll approximately 304 participants.

Discussion

This trial addresses a critical gap in post-hospitalization care for PWID with SIRI. If effective, the integrated care model could significantly reduce rehospitalizations, improve treatment completion, and provide a replicable framework for healthcare systems. The study’s implementation science components will inform the scalability and sustainability of this intervention. Results will inform evidence-based policy and practice recommendations for managing this high-risk population, potentially leading to improved patient health outcomes.

Trial registration

ClinicalTrials.gov NCT06513156. Registered on August 09, 2024.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13063-026-09550-5.

Administrative information

Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/).

Title {1}	Continuum of care in hospitalized patients with opioid or stimulant use disorder and infectious complications of drug use—substance use/infectious disease integrated clinic compared to treatment as usual to prevent infection-related readmission (CHOICE-STAR): a study protocol for an effectiveness-implementation randomized controlled trial
Trial registration {2a and 2b}	ClinicalTrials.Gov NCT06513156
Protocol version {3}	Version 4.0; April 28 2025
Funding {4}	NIH Helping to End Addiction Long-term Initiative (HEAL) Initiative (Contract #: 75N90023C0001 Funded by: NIH HEAL Initiative)
Author details {5a}	Elana Rosenthal:Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland; Marie-Claude Lavoie: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland, Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland; Edward Traver: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland; Jan Gryczynski: Friends Research Institute; Courtney Nordeck: Friends Research Institute; Joseph E. Carpenter: Department of Emergency Medicine, Emory University School of Medicine, Atlanta, Georgia, Grady Health System, Atlanta, Georgia; Rebecca Reece: Department of Medicine, West Virginia University School of Medicine, Morgantown, West Virginia; Irene Kuo: Department of Epidemiology, Milken Institute School of Public Health, The George Washington University, Washington, DC; Jillian S.Catalanotti: Department of Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC; Alaina R. Steck: Department of Emergency Medicine, Emory University School of Medicine, Atlanta, Georgia; Garrett Cooper: Department of Medicine, West Virginia University School of Medicine, Morgantown, West Virginia; Ayako Wendy Fujita: Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine; Sean M. Murphy: Department of Population Health Sciences, Weill Cornell Medical College, New York, New York State; Megan E. Mansfield: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland; Habib Omari Ramadhani: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland; Rachel Silk: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland; Henry Masur: National Institutes of Health, Bethesda, Maryland; Sarah Kattakuzhy: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland.
Name and contact information for the trial sponsor {5b}	Henry Masur, MD, hmasur@nih.gov Michelle Rankin, PhD, michele.rankin@nih.gov
Role of sponsor {5c}	This study is funded by the National Institutes of Health (NIH). NIH staff contributed to the study design and conceptualization. An NIH intramural investigator has collaborative and supervisory roles in study implementation, data collection, and data analysis. The intramural investigator will collaborate with investigators on the interpretation of study findings and the preparation of manuscripts for scientific publication.

Introduction

Background and rationale {6a}

People who inject drugs (PWID) are frequently hospitalized for serious injection-related bacterial and fungal infections (SIRI), such as cellulitis, osteomyelitis, and endocarditis. Hospitalizations for SIRI have increased sharply in recent years [1] driven by a threefold increase in rates of injection drug use (IDU) between 2011 and 2018 [2]. Over 2 million Americans are now estimated to inject drugs, and young people are especially vulnerable, with almost 1 out of every 50 young adults using injection drugs [3]. IDU-related infective endocarditis—a particularly severe type of infection—has increased over tenfold in the past decade [4, 5].

IDU in the United States (US) has historically been mainly opioid use, with a shift over the past few decades from plant-derived heroin to cheaper, more potent synthetic fentanyl. Since 2010, overdose deaths have frequently involved opioids in combination with other drugs, particularly stimulants such as cocaine and methamphetamine [6]. Polysubstance use, particularly combinations of stimulants and opioids, may lead to higher rates of severe complications, including fatal overdose and SIRI [7]. The injection route of drug use may be a useful paradigm for risk classification and designing interventions, rather than focusing solely on the specific type of drug used.

Treatment of SIRI often requires prolonged courses of antibiotics, posing unique challenges for PWID. While hospitalized for SIRI, many PWID also confront addiction, withdrawal, unstable housing, insufficient social support, inadequate medical insurance, and stigma and discrimination related to substance use [8, 9]. These factors contribute to high rates of premature hospital discharge and low rates of antibiotic completion [10, 11]. Most PWID who are hospitalized with an acute infection are rehospitalized within 1 year [12].

Studies have identified various risk factors for poor outcomes after hospitalization with SIRI, including unaddressed addiction and withdrawal, unstable housing, and high rates of premature discharge [10, 12]. When antibiotic treatment is unnecessarily interrupted by premature discharge, readmission is more likely to occur [13]. Ongoing IDU can lead to new episodes of SIRI, suggesting a need to better address addiction and safer practices after hospitalization [14]. The provision of oral antibiotics alongside integrated outpatient infectious disease (ID) and addiction care shows promise as an effective intervention to improve antibiotic completion and treatment engagement [15, 16]. The effectiveness of these approaches in a prospective intervention is unknown.

In a large, multi-site retrospective cohort study of 1652 people hospitalized with infections due to injecting opioids, our group found that 53% were rehospitalized within 1 year, and most patients had a readmission due to SIRI [17]. Twenty-eight percent of the patients in this cohort were discharged prematurely, and the risk was higher for those with opioid withdrawal and those not treated with medication for opioid use disorder (MOUD) [18]. Sixty-five percent of patients with premature discharge required ongoing antibiotics but lacked a discharge plan for antibiotics. The risk of SIRI readmission was higher for those with unstable housing, premature discharge, and need for ongoing antibiotics. Readmissions related to the index SIRI occurred soon after discharge, while readmissions for a new SIRI occurred later (median 10 vs 126 days); readmission was even earlier if the index antibiotic regimen was interrupted. The study identified high rates of comorbid stimulant use, which lacks effective evidence-based treatments. The data from our retrospective cohort study demonstrated the potential impact of untreated opioid use disorders (OUD), premature discharge, and incomplete antibiotic therapy on readmission risk. The study also emphasized the need for distinct strategies to reduce early (index) SIRI readmissions and late (new) SIRI readmissions, and address infections resulting from the injection of stimulants.

Objectives {7}

In the Continuum of care in hospitalized patients with opioid or stimulant use disorder and infectious complications of drug use—substance use/infectious disease (ID) integrated clinic compared to treatment as usual (TAU) to prevent infection-related readmission (CHOICE-STAR) study, we aim to evaluate a low-barrier, harm reduction-focused integrated ID-substance use disorders (SUD) clinic for opioid use disorder (OUD) and stimulant use disorder (StUD). This intervention will be compared to treatment as usual, with the primary outcome being a reduction in rehospitalization at the end of the 6-month intervention period.

The CHOICE-STAR trial has three aims:

1. To assess the effects of the Integrated ID and SUD outpatient clinic (IC) on

   • i.
     Infection-related rehospitalization in the 6 months after discharge from the index hospitalization.
   • ii.
     Non-infection-related rehospitalizations, health service utilization, mortality, IDs acquisition and treatment, injection-related skin ulcers, outpatient linkage and retention in ID and SUD treatment, substance use and medication engagement, social determinants of health, stigma and coordination of care at 6 and 12 months after discharge from the index hospitalization.

2. To assess the effects of the IC compared to treatment as usual (TAU) on implementation outcomes.

3. To estimate the cost required to implement and sustain the IC intervention and evaluate its cost-effectiveness relative to TAU from the healthcare sector, state policymakers, and societal perspectives in the 12 months after discharge from index hospitalization.

We hypothesize that the IC intervention will result in a lower proportion of infection-related hospital readmissions at 6 months post-discharge compared to the TAU arm.

Trial design {8}

CHOICE-STAR, a hybrid type 1 randomized (1:1 ratio) effectiveness-implementation trial (superiority trial).

Conceptual framework

This study is grounded in the Exploration, Preparation, Implementation, and Sustainment (EPIS) framework [19]. EPIS is an implementation science framework characterized by four phases (exploration, preparation, implementation, and sustainment) and four constructs (outer context, inner context, innovation factors, and bridging factors). During the exploration phase, we consulted with partners across all sites to understand the enablers and barriers to care following hospitalization and their perceptions of proposed interventions (integrated care and linkage to care). In the preparation phase, the research team developed the study protocol, intervention manuals, training material, and fidelity assessments. The Implementation phase corresponds to the implementation of the study. For the sustainment phase, we adopted a dynamic approach, embedding sustainment throughout all phases.

Methods: participants, interventions, and outcomes

Study setting {9}

The study includes five sites: (1) University of Maryland Medical Center - Downtown Campus, Baltimore, Maryland; (2) George Washington University Hospital, Washington, District of Columbia (DC); (3) Emory University Hospital Midtown in Atlanta, GA (GA); (4) Grady Memorial Hospital, Atlanta, GA; and (5) West Virginia University J.W. Ruby Memorial Hospital, Morgantown, West Virginia.

Eligibility criteria {10}

The CHOICE-STAR trial includes three types of participants:

Participants randomized to the clinical trial. Inclusion criteria are as follows: (1) age ≥ 18 years; (2) admitted to the study hospital (defined as hospitalized with a primary team that is not emergency medicine); (3) injection opioid use and/or injection stimulant use (defined as cocaine or methamphetamine use) in the past 90 days—per patient self-report; (4) active suspected or confirmed qualifying infection (Supplemental Table 1) at the time of admission.

Exclusion criteria are as follows: (1) infection due to a cause other than injection drug use per determination of a site Principal Investigator (PI); (2) inability to provide consent due to circumstance (e.g., sedated, intubated), language, or cognitive impairment; (3) unwilling to provide informed consent; (4) unable to receive potential interventions due to geography; (5) on comfort measures or planned for discharge to hospice care; (6) incarcerated at the time of consent; (7) previously randomized in the CHOICE-STAR Study.

IC Intervention team. Inclusion criteria are as follows: (1) member of the IC Intervention team (see 11a under provider requirement for additional information) for at least 3 months.

Exclusion criteria are as follows: (1) unwilling to provide informed consent.

Healthcare leaders. Inclusion criteria are as follows: (1) being in a leadership position at the institution and can support future implementation of the intervention.

Exclusion criteria are as follows: (1) unwilling to provide informed consent.

Who will take informed consent? {26a}

The research team will provide participants with consent forms and explain the study’s objectives, procedures, duration, risks, benefits, and participants’ rights. For participants randomized to the clinical trial, a consent quiz will be administered to potential study participants up to three times until a score of 100% is achieved. Potential participants unable to score 100% on the quiz within three attempts will be ineligible for the study.

Additional consent provisions for collection and use of participant data and biological specimens {26b}

Urine specimens for urine drug screening will be collected.

Interventions

Explanation for the choice of comparators {6b}

The TAU will consist of the site’s standard practice following the discharge of hospitalized participants. Comparing the study intervention (IC) to TAU allows for assessing the added benefit of the intervention beyond what is currently available. This comparison is appropriate given the absence of structured discharge planning protocols presently used for this population.

Intervention description {11a}

The IC intervention will provide facilitated linkage to a clinic providing medical treatment aimed at treating OUD/StUD, resolving the sentinel infection, treating existing ID complications of OUD/StUD (HIV, Hepatitis C virus [HCV], wounds), and preventing subsequent infections by providing accessible care for IDs and OUD/StUD treatment that is integrated and delivered at a single appointment and co-located at a single site (either in person or via telemedicine) over 6 months (Table 1). We will include a follow-up period of 6 months to assess the medium-term effect of the intervention (total study timeline: 12 months). The IC will include weekly care coordination meetings between the ID and SUD providers. The dual goals of the IC intervention are to (1) facilitate access to ID and OUD/StUD care and (2) ensure care coordination between outpatient ID and SUD providers.

Table 1.

Overview of the IC intervention

Event (timing)	Services offered	Frequency	Person*	Type of visit	Mode of delivery
Enhanced linkage (within 14 days post-discharge)	Appointment scheduling and reminders Rescheduling appointments Coordination and payment for the transportation to/from the clinic for the intake visit	Ongoing until completion of the first visit	Study coordinator	NA	Calls Texts
Intake visit (within 14 days post-discharge)	Clinical services ID: Completion of treatment for index infection; HIV evaluation, treatment and prevention (PrEP); HCV treatment and evaluation; wound care provision or referral; and diagnosis and treatment of new infections hospitalization SUD: MOUD or MStUD prescribing, safe injection practice counseling, naloxone prescribing, referral to behavioral therapy as needed. For people already on MOUD at another site, MOUD adequacy/satisfaction/concerns will be discussed. The patient will be offered but is not obligated to, transition MOUD care to the integrated clinic	One-time	ID provider* and SUD providers*	Concurrent	In-person or telehealth or hybrid (one provider via telehealth and one provider in-person)
Follow-up visits (1–6 months)	ID and/or SUD services (see above)	Monthly (month 1, 2, 3, 4, and 5) and as needed	ID provider and SUD provider	Concurrent or sequential	In-person or telehealth or hybrid
Additional clinic visits (optional)	ID and/or SUD services as clinically needed	As clinically needed	ID provider and/or SUD provider	NA	In-person or telehealth or hybrid
Care coordination meeting	Review of patients actively on the IC arm and discuss management plans and care coordination needs	Weekly	ID provider(s) and SUD provider(s)	NA	In-person or virtual or hybrid

^*ID provider: Each site must have at least one physician board certified/board eligible in infectious diseases who must see patients, at least, until resolution of the index infection. Advanced practice providers within the division of infectious diseases can work in conjunction with the ID physician and take over ID care per the discretion of the ID physician after resolution of the index infection. MOUD/MStUD provider: Any prescriber of medication for SUD, who is familiar with guidelines for treatment of OUD and StUD. Board certification/eligibility in addiction medicine or addiction psychiatry is not required

Schedule

All participants in the IC arm will be scheduled for the first appointment within 14 days of discharge from index hospitalization and should subsequently be seen—at a minimum—at months 1, 2, 3, 4, and 5. Participants can have additional visits as many times as clinically indicated.

IC elements

1. Enhanced linkage: The study team will coordinate with the participants (during or post-hospitalization) to link them to the first IC visit (intake visit) only. Enhanced linkage may include the following: (1) appointment scheduling; (2) phone and/or text message appointment reminders; (3) transportation assistance (to/from) for the first IC visit; and (4) rescheduling as needed until the first visit is completed.

2. IC visits: An integrated ID-SUD visit consists of a single appointment where a patient is seen by both ID and SUD providers.

   • ◦
     Provider requirements:

     • ID: Each site must have at least one physician board-certified/board-eligible in ID who must see participants at least until the index infection is resolved. Advanced practice providers within the division of ID can work with the ID physician and assume ID care at the discretion of the ID physician after the resolution of the index infection.
     • MOUD/medication for stimulant use disorder (MStUD): Any prescriber of medication for SUD, who is familiar with the guidelines for the treatment of OUD and StUD. Board certification or eligibility in addiction medicine or addiction psychiatry is not required.
     • Clinical services: These services will be provided at each visit: (1) ID: Completion of treatment for index infection, HIV treatment and prevention (pre-exposure prophylaxis [PrEP]), HCV treatment, evaluation and treatment of wound infections and/or referral for wound care, diagnosis, and treatment of new infections not requiring hospitalization. (2) SUD: MOUD or MStUD prescribing, safe injection practice counseling, naloxone prescribing, and referral to behavioral therapy as needed. For participants already on MOUD at another site, adequacy, satisfaction, and concerns related to MOUD will be discussed. The participant will be offered the option to transition MOUD care to the integrated clinic (optional).
   • ◦
     Integration of care: An integrated visit is defined as care provided during the same visit and at the same site. Integrated visits can occur either concurrently (with both providers present for the entire visit) or sequentially (successive consultations). The first IC visit must be concurrent, and subsequent visits may be concurrent or sequential. During sequential visits, providers will engage with the patient independently, but in a sequential manner, as part of a single clinical visit.
   • ◦
     Site: Participants will remain in the same location throughout the IC visit, which can be delivered in person, via telemedicine, or as a combination of both.

3. Weekly care coordination meetings: The IC provider team will meet weekly (in-person, remote, or hybrid) to review participants’ active in the IC intervention and discuss management plans and care coordination needs.

Criteria for discontinuing or modifying allocated interventions {11b}

Participants may choose not to engage in the study intervention at any point and can continue to remain in the study. The PI or site PIs may withdraw a participant from the study intervention at any time if they assess that the intervention is a risk to the participant or the intervention team.

Strategies to improve adherence to interventions {11c}

Adherence to IC visits and fidelity to the components of the IC visits will be determined based on the review and abstraction of information from the electronic medical record (EMR). Adherence to the weekly care coordination meetings will be assessed in real-time and documented in Research Electronic Data Capture (REDCap) [20, 21] by a study team member participating in the weekly meetings. IC visits will be further characterized by the degree of integration, the site(s) of the visit, and the use of checklists and documentation templates.

Relevant concomitant care permitted or prohibited during the trial {11d}

There are no restrictions on medications.

Provisions for post-trial care {30}

The IC intervention will last 6 months. After the intervention ends, participants may receive care with the same providers and/or clinics per the site’s TAU. There is no post-trial care or compensation for harm from the trial.

Outcomes {12}

The primary outcome is the proportion of participants with new hospitalizations due to infection 6 months after the index hospitalization. The secondary outcomes will be measured at 6 and 12 months: emergency Department (ED) visits; all-cause hospital readmission; mortality; completion of antibiotics; resolution of index infection; discharge type (planned, patient directed); HCV and HIV testing; PrEP use; new infections requiring hospitalization, including injection-related skin ulcers; linkage to care for ID; MOUD linkage and initiation; substance use (opioid, stimulant use, other drug, alcohol, tobacco); overdose; social determinants of health; perceptions of the coordination of care; and medical stigma. We will report on implementation outcomes, including reach/penetration, adoption, acceptability, appropriateness, feasibility, and sustainability. The primary economic outcome will be the incremental cost-effectiveness ratio (ICER), which will be reported for each perspective.

Participant timeline {13}

Participants will be enrolled during hospitalization for an infection (see Supplemental Table 1). Following discharge from the index admission, participants will receive 6 months of intervention (at a minimum- at months 1, 2, 3, 4, and 5), followed by an additional 6 months of follow-up; therefore, the total participant timeline is 12 months (Fig. 1). We included a 6-month assessment to assess whether the effects of the intervention are sustained after its cessation. The study outcomes visits will occur after discharge from index admission at the following times (− 7 days/+ 7 days): 14 days, at 1, 3, 6, 9, and 12 months (Fig. 2). We defined a month as 28 days.

Fig. 1.

Study schema

Fig. 2.

Participant timeline: schedule of enrollment, interventions, and assessments. ^a At a minimum, IC visits will occur at months 1, 2, 3, 4, and 5. Participants can receive additional IC visits as needed. ^b Semi-structured interviews will be conducted with a sample of participants randomized to the intervention to explore implementation outcomes and determinants. ^c Data collected during the IC Integrated visit. ASM, alcohol and substance use-modified; BARC10, Brief Assessment of Recovery Capital-10; CLAF, Criminal and Legal Activities Form; CPCQ, Client Perceptions of Coordination Questionnaire; D, days; DAST-10, Drug Abuse Screening Test-10; HIS, Heaviness of Smoking Index; IC, integrated ID and SUD outpatient clinic; IRSU, injection-related skin ulcers form; M, months; MPS-PWUD, Medical Provider Stigma Experienced by People who Inject Drugs; NMOS, Non-Study Medical and Other Services Form; OCS, Opioid Craving Scale; ODI, overdose information; PROMIS-16 modified, Patient-Reported Outcomes Measurement Information System 16 modified; RAN, risk assessment battery–needle use-modified; TAU, treatment as usual

Sample size {14}

Participants randomized to the clinical trial

The proposed RCT has two arms (i) IC and (ii) TAU. We hypothesize that the IC intervention will result in a lower proportion of infection-related hospital readmissions at 6 months post-discharge compared to the TAU arm. Hospital readmission among patients with SUD from the prior study was 45% [22]. Assuming 40% and 25% of people will be readmitted under the TAU and IC arms, respectively, 304 is sufficient to detect a 15% absolute difference in the proportion of hospital readmissions at a power of 80% and a two-sided p-value of 0.05. Sample size estimation was performed using SAS PROC POWER for the difference between proportions.

Semi-structured interviews (SSI). At month 3, we will recruit 20–40 participants for SSI with 5–10 participants per site. At month 6, we will attempt to follow up with the participants. We anticipate a high rate of attrition, specifically 50% per follow-up. Therefore, we anticipate retaining 10–20 participants at month 6. We will recruit additional participants for SSI as needed until saturation is reached.

IC intervention team

We will invite the site’s intervention teams to participate (n = 2–6) in the focus group discussions (FGDs), periodic reflections, and the survey.

Healthcare leaders

We will purposively select one to two eligible individuals in leadership positions at each facility.

Recruitment {15}

Participants randomized to the clinical trial

The study team will pre-screen hospitalized patients receiving antibiotics through EMR review. Eligible participants will complete informed consent, Health Insurance Portability and Accountability Act (HIPAA) authorization, and screening forms while hospitalized.

IC Intervention team

The study coordination team will contact the site’s intervention team to invite them to participate in the study.

Healthcare leaders

We will purposively sample healthcare leaders within the participating site. The site PIs will contact the site healthcare leaders to invite them to participate in the study.

Assignment of interventions: allocation

Sequence generation {16a}

Participants will be randomly assigned to the IC intervention or TAU in a 1:1 ratio. Participants will be stratified by site and baseline MOUD status. To avoid predicting the assignment of the last participant from the block, we will vary block size by including 2, 4, and 6 participants per block. The random allocation sequence will be performed after confirming the participant’s eligibility and obtaining their signed consent form. The research team will inform participants of their group assignment.

Concealment mechanism {16b}

The personnel who enrolled and those who assigned participants to the interventions will not have access to the random allocation sequence.

Implementation {16c}

The allocation sequence will be determined by a computer program using SAS software to generate a randomization table [23]. The research team will enroll participants after completing the informed consent form and ensuring eligibility, which will be confirmed by a site PI. Randomization will be determined by a centralized computer-generated random assignment with REDCap and must occur while the patient is hospitalized [20, 21]. A computer-generated randomization sequence will be created by the study statistician who has no involvement in participant recruitment.

Assignment of interventions: blinding

Who will be blinded {17a}

Neither the participants nor the research team will be blinded to the group assignment.

Procedure for unblinding if needed {17b}

Not applicable as not possible to blind participants, and the study biostatistician will not be blinded.

Data collection and management

Plans for assessment and collection of outcomes {18a}

Questionnaires

Participants randomized to the clinical trial

Screening only

• Pre-screening form: EMR-based assessment of potentially eligible patients.

• Screening form: Assessment of which patients are eligible for inclusion in the study.

Baseline and follow-up

We will use the Locator Form (see 18b); epidemiologic survey (socio-demographic characteristics); Non-study Medical and Other Services (NMOS) [24]; Alcohol and Substance Use- modified (ASM) [25, 26]; Opioid Craving Scale (OCS) [27]; Cocaine Craving Scale (CCS) [28]; Methamphetamine Craving Scale (MCS) [27]; Overdose Information (ODI); Drug Abuse Screening Test (DAST-10) [29, 30]; Brief Assessment of Recovery Capital (BARC-10) [31]; Heaviness of Smoking Index (HSI) [32]; Injection Related Skin Ulcers form (IRSU); Criminal and Legal Activities Form (CLAF); Drug Abuse Treatment Cost Analysis Program (DATCAP) [33]; Patient-Reported Outcomes Measurement Information System (PROMIS) Preference (PROPr) [34, 35]; Medical Provider Stigma Experienced by People who Inject Drugs (MPS-PWUD) [36], and the Client Perceptions of Coordination Questionnaire (CPCQ) [37].

Follow-up only

We will use the Index Infection Outcomes (IIO); other ID outcomes, and the Acceptability of Intervention Measure (AIM) [38].

IC intervention team

End of the study

We will use the Appropriateness of Intervention Measure (IAM) and Feasibility of Intervention Measure (FIM) [38], and the Clinical Sustainability Assessment Tool (CSAT) [39].

Laboratory assessments

Urine drug screens (UDS) will be collected to assess for the presence of cocaine, amphetamines, methamphetamine, marijuana, methadone, methadone metabolite (EDDP), opiates, oxycodone, phencyclidine, barbiturates, benzodiazepines, ecstasy, morphine, buprenorphine, ethyl glucuronide (alcohol), and fentanyl. If a urine drug screen is not collected during the study window, a UDS collected clinically during the study window can be used at that time point.

EMR/HIE (Health Information Exchange) abstraction

EMR/HIE abstraction will occur as needed throughout the study to verify and collect details of the index hospitalization, readmissions, and deaths.

• Index hospitalization: This form will collect data from the EMR about the index hospitalization, including index infection, treatment plan, specialty consultations, SUD treatment, and discharge plan.

• Readmission: This form will collect data from the EMR about the hospitalizations in the year following the index hospitalization, including the reason for admission, the status of the index infection, the treatment plan, specialty consultations, OUD treatment, and the discharge plan.

• Death: The death form will be completed for those who die during the study, based on reports or EMR/HIE abstraction, and validated by vital records when possible.

Plans to promote participant retention and complete follow-up {18b}

Sites will conduct outreach to promote retention in the months without a study outcomes visit (months 2, 4, 5, 7, 8, 10, 11). This outreach will involve the study team attempting to contact participants to update the Locator Form information (see 18b).

Data management {19}

Quantitative data

Clinical providers will record visit data in the site-specific EMR per standard of care. Data will be abstracted and summarized from the clinical record by the research team. There is a risk of potential loss of privacy and confidentiality. This risk will be minimized by providing privacy during study visits. We will use de-identified data for analysis. All research records will be coded with a number. All paper records will be kept in a locked location with limited access. Research data (from surveys and UDS) and a log of the IC weekly case review will be recorded in REDCap. REDCap will be securely hosted on the UMB server and will be password protected. Data entry fields will include validation by range or type. Mandatory data fields will be used to minimize missing data.

Qualitative data

Each FGD and SSI will be audio-recorded and then transcribed verbatim. The transcripts will be reviewed by the study team for quality of transcription and any cleaning necessary to maintain participant confidentiality (e.g., removal of names). The periodic reflections will be audio-recorded, and summary notes will be taken. The study analysts will engage in a multi-stage coding and analysis procedure using ATLAS.ti software, beginning with data familiarization—which involves the analysts getting acquainted with the scope and depth of the transcripts’ content. Stage 1 results with an initial codebook that is piloted in Stage 2 by analysts independently coding a subset of transcripts. Analysts will continue to adapt the codebook and pilot it until they are calibrated (i.e., using the codebook consistently). During Stage 3, each transcript will be coded independently by two different analysts who will meet to discuss any disagreements they have in their coding. For Stage 4, all coded extracts will be exported, which the analysts will use to identify, define, and organize themes. If possible, a brief report describing the themes will be shared with participants to validate analysts' interpretation of their data.

Confidentiality {27}

The study participant’s contact information will be securely stored at each site for internal use. Each participant will be assigned a unique study ID. The study data entry and study management systems used by clinical sites and research staff will be secured and password-protected. The PI and study team will have access to the password-protected database. At the end of the study, all study databases will be de-identified and archived at the University of Maryland School of Medicine.

Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}

N/A, as these activities will not be performed as part of this study.

Statistical methods

Statistical methods for primary and secondary outcomes {20a}

We will examine the balance between study arms by comparing participants in the IC intervention vs. TAU on different baseline characteristics, including gender, age, race, employment, socioeconomic status, incarceration, and housing. Chi-square/Fisher’s exact tests for categorical variables or t-tests for continuous variables will be used to assess balance across study arms. Additional preliminary analyses will be conducted to assess distributional assumptions of other important characteristics. Analysis will be performed on an intention-to-treat basis.

Primary objective

We hypothesize that the IC intervention will result in a lower proportion of infection-related hospital readmissions at 6 months post-discharge compared to the TAU arm. The impact of study arms on reducing infection-related rehospitalization will be assessed in two ways. First, we will assess the proportion of infection-related hospitalization by comparing the two study arms. Secondly, we will treat rehospitalizations as counts as well as assess time to first rehospitalization. For time to first rehospitalization, Cox proportional hazard regression models will be used to estimate the hazard ratios and corresponding 95% confidence intervals. Kaplan–Meier curves will be used to assess the survival distributions of participants within study arms, and log-rank tests will be used to compare the hazard functions across study arms. For the number of rehospitalizations, Poisson regression models will be used to compute incidence rates, incidence rate ratios, and the corresponding 95% confidence intervals. SAS PROC PHREG will be used to fit Cox proportional hazard regression models while SAS PROC GENMOD will be used to fit Poisson regression models. Using standard model-building procedures, study arm will be entered as the primary predictor in each model. Based on the results of our preliminary analysis, additional covariates will be entered into the multivariable regression models.

Secondary objectives

We will also assess the impact of study arms on several secondary outcomes, including ED visits, all-cause rehospitalization, and mortality. ED visitations and all-cause rehospitalization will be analyzed as time to first occurrence of event and as counts. For time to death, first occurrence of ED visit and all-cause rehospitalization, Cox proportional hazard regression models will be used to estimate the hazard ratios and corresponding 95% confidence intervals. For the number of ED visits and all-cause rehospitalizations, Poisson regression models will be used to compute incidence rates, incidence rate ratios, and the corresponding 95% confidence intervals for the association between treatment arms and these outcomes. We will integrate qualitative and quantitative data using a convergent, mixed methods design in which we will merge the quantitative and qualitative data to understand comprehensively the implementation and outcomes associated with the CHOICE-STAR study. We will organize the joint display using the EPIS framework [19] and the Proctor Implementation Outcomes [40] to include illustrative quotes and quantitative summary data. The qualitative data will enable us to contextualize these findings, thereby providing a better understanding of the quantitative data. The inclusion of semi-structured interviews, focus group discussions, and periodic reflections with different key partners will enhance our understanding of quantitative findings.

Economic evaluation analysis

Economic analyses will follow established guidelines and be conducted from the healthcare sector, state policymakers, and societal perspectives [41–43]. Intervention costs will be estimated using microcosting analysis. Adjusted-mean costs and effectiveness measures—quality adjusted life years (QALYs), opioid-free years (OFY), and infection-free years (IFYs)—will be estimated using multivariable generalized linear mixed models. QALYs will be calculated via area under the curve methods using PROPr-derived health utility values, while OfYs and IfYs represent predicted time free from opioids and serious infections, respectively. Standard errors will be estimated via nonparametric bootstrapping. ICERs will be calculated at 6 and 12 months for each perspective by dividing relevant mean cost differentials by mean effectiveness differentials. Uncertainty around ICERs will be assessed using cost-effectiveness acceptability curves, which will display the probability that IC is cost-effective relative to TAU across a range of value thresholds. Sensitivity analyses will test the robustness of results to variations in assumptions and parameter estimates.

Interim analyses {21b}

As we do not anticipate more targeted safety events in one trial arm over the other, if deemed necessary, a single interim analysis will be performed by the project statistician when 25% to 50% of study participants have completed 6 months of follow-up to determine effectiveness. If an interim analysis is performed, we will adjust the type I error rate to declare the treatment effect of the IC intervention over TAU. Along with other relevant trial-related supportive evidence, if the result of the planned interim analysis provides evidence of superior effectiveness of the intervention over TAU, the medical monitor may recommend early termination of the trial.

Methods for additional analyses (e.g., subgroup analyses) {20b}

We will assess the effect measure modification of the potential interaction between categorical variables (such as age group, race) and study arm by generating an interaction term of categorical variables X study arm. Statistically significant results of the interaction term suggest that the effect of the study arm varies at different levels of categorical variables.

Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}

Throughout the study, data quality control checks will be conducted on the database. Any missing data or data anomalies will be reviewed by the study PI and site PIs for clarification or resolution. During the analysis, for observed missing data, we will follow guidelines for handling clinical trial missing data. Specifically, data are assumed to be missing at random (MAR) for the intention to treat analysis, with the possibility of using multiple imputation methods for missing data. Sensitivity analyses to examine patterns of missingness across treatment groups will be conducted to assess the robustness of the MAR assumptions.

Plans to give access to the full protocol, participant-level data, and statistical code {31c}

Following the completion of the trial, upon written request, a de-identified dataset can be provided to other researchers.

Oversight and monitoring

Composition of the coordinating center and trial steering committee {5d}

The PI will be responsible for the overall conduct of the study. At each site, study PIs will oversee the recruitment, implementation of the intervention arms, follow-up of the participants, and quality of the data.

Composition of the data monitoring committee, its role, and reporting structure {21a}

We have external clinical monitoring by a Clinical Research Organization and the Medical Monitor (MM).

Adverse event reporting and harms {22}

This study will not involve any investigational drugs or devices therefore this study is considered minimal risk. No causally related adverse events (AE) and/or serious adverse event (SAE) are anticipated and will not be monitored. Safety oversight for this study will be done by the PIs and an independent MM who is not involved in the study. Safety reporting will focus on targeted safety events (TSE) that include the following events: ED visits, hospitalizations, overdose events, and deaths. A meeting will be scheduled after the first 6 months and annually thereafter. During these meetings, the PI and MM will review all cumulative TSE irrespective of the site PI's attribution of causality. All TSEs will be reported during the continuing review and medical monitor meetings. Unresolved differences regarding attribution of causality, event reporting, event management, or stopping criteria will be submitted for appropriate adjudication and reported promptly to the Institutional Review Board (IRB). The MM will document its meetings in writing and submit them to the IRB at Continuing Review, or sooner if the findings warrant earlier reporting.

Frequency and plans for auditing trial conduct {23}

An independent clinical research organization will provide outside study monitoring at all four sites. Monitoring will occur at 3, 6, 12, 18, and 36 months. The plan includes monitoring of consents, eligibility, electronic data/source, regulatory documents, and recruitment.

Plans for communicating important protocol amendments to relevant parties (e.g., trial participants, ethical committees) {25}

The study PI will submit protocol modifications to the central IRB. The PI will notify the study sites’ PIs about modifications. Site PIs will acknowledge receipt and review of each new protocol version. When needed, the research team will notify participants about the modifications and re-consent participants.

Dissemination plans {31a}

The study’s findings will be disseminated through different mechanisms, including (1) peer-reviewed journals, (2) national and global conferences, (3) webinars, and (4) local level at participating sites. Only de-identified data will be shared.

Discussion

This randomized effectiveness-implementation trial is designed to assess the effectiveness of the IC intervention compared to treatment as usual on hospital readmission (primary outcome) and secondary outcomes (clinical, mortality, implementation outcomes, cost-effectiveness, and other health-related outcomes). Limited evidence is available on the effectiveness of models of care post-hospitalization among PWID admitted with an infection. The study aims to fill this knowledge and practice gap.

Trial status

The current protocol is V4, dated April 28, 2025. Recruitment started at the University of Maryland Medical Center site on October 30, 2024, at Emory University on December 3, 2024, at George Washington University on February 19, 2025, and at West Virginia University on February 21, 2025. Recruitment is expected to be completed in June 2026.

Abbreviations

AE

Adverse event

AIM

Acceptability of Intervention Measure

ASM

Alcohol and Substance use Modified

BARC-10

Brief Assessment of Recovery Capital-10

EMR

Electronic medical records

CCS

Cocaine Craving Scale

CHOICE-STAR

Continuum of care in hospitalized patients with opioid or stimulant use disorder and infectious complications of drug use—substance use/ID integrated clinic vs. TAU to prevent infection-related readmission

CLAF

Criminal and Legal Activities Form

CPCQ

Client’s Perceptions of the Coordination Questionnaire

DAST-10

Drug Abuse Screening Test-10

DATCAP

Drug Abuse Treatment Cost Analysis Program

DC

District of Columbia

EDDP

Methadone metabolite

EPIS

Exploration, Preparation, Implementation, and Sustainment

EQ-5D-5L

EuroQol 5 Dimensions 5 level

FGD

Focus group discussions

GA

Georgia

HCV

Hepatitis C virus

HEAL

Helping to End Addiction Long-term Initiative

HIE

Health Information Exchange

HIPAA

Health Insurance Portability and Accountability Act (HIPAA)

HSI

Heaviness of Smoking Index

IC

Integrated ID and SUD outpatient clinic

ID

Infectious diseases

IDU

Injection drug use

IFYs

Infection-free years

IIO

Index Infection Outcomes

IRB

Institutional Review Board

IRSU

Injection-related skin ulcers

MCS

Methamphetamine Craving Scale

MPS

Medical Provider Stigma Experienced by People who Inject Drugs

MStUD

Medication for stimulant use disorder

MOUD

Medication for opioid use disorder

NMOS

Non-study Medical and Other Services

NY

New York

OCS

Opioid Craving Scale

ODI

Overdose information

OFY

Opioid-free years

OUD

Opioid use disorder

PI

Principal Investigator

PrEP

Pre-exposure prophylaxis

PROMIS

Patient-Reported Outcomes Measurement Information System

PROPr

PROMIS-Preference score

PWID

People who inject drugs

QALYs

Quality-adjusted life-year

RAN

Risk assessment battery–needle use-modified

REDCap

Research Electronic Data Capture

SAE

Serious adverse events

SIRI

Serious injection-related bacterial and fungal infections

StUD

Stimulant use disorders

SUD

Substance use disorders

TAU

Treatment as usual

TSE

Targeted safety events

UDS

Urine drug screens

UMB

University of Maryland Baltimore

US

United States

Authors’ contributions {31b}

ER is the Principal Investigator of the study; she conceived the study, led the proposal and protocol development. MCL is the lead implementation scientist of the study; she conceived of the implementation science elements and analysis for the study and protocol. ET is the UMB site PI; he helped conceive the study and protocol development. JG and CN helped conceive of the study intervention and protocol development. ET, JEC, RR, IK. JSC, ARS, and GC are site Co-PI and helped conceive the study and protocol development. AWF contributed to the study protocol development. SMM is the lead health economist; he conceived of the cost-effectiveness elements and analysis for the study and protocol. MM helped develop the implementation science elements of the protocol. HOR is the lead trial statistician. He developed the sample size and statistical analysis plan. RS and HM helped conceive the study, proposal and protocol development. SK is lead associate investigator for the study; she helped conceive the study, the proposal and protocol development. All authors read and approved the final protocol.

Funding {4}

This clinical trial is funded by the National Institute of Health’s Helping to End Addiction Long-term Initiative (NIH HEAL) Contract #: 75N90023C00013.

Data availability {29}

The final trial de-identified dataset and related study relevant study materials will be available from the study PI (ER) upon reasonable request.

Declarations

Ethics approval and consent to participate {24}

This study was initially approved by the WCG IRB on August 9, 2024. The study is registered in ClinicalTrials.gov NCT06513156 (https://clinicaltrials.gov/study/NCT06513156). The consent form for the trial participants is included in Supplement 1.

Consent for publication {32}

Willing to provide a participant model consent form on request.

Competing interests {28}

JG—no financial or competing interests to report; unrelated to the present study: part owner of COG Analytics, LLC; MPI on a NIDA-funded study that received in-kind medication from Indivior and Alkermes. All remaining authors declare that they have no competing interests.