Design and methods of a multi-site randomized controlled trial of an integrated care model of long-acting injectable buprenorphine with infectious disease treatment among persons hospitalized with infections and opioid use disorder
Introduction
Almost a half million Americans have died from opioid overdose since the late 1990's, overtaking motor vehicle accidents as the leading cause of accidental death in the US and reducing overall life expectancy [1,2]. Associated with this staggering toll is a surge in life-threatening infectious diseases related to opioid and injection drug use (IDU), including bacterial and fungal infections [3,4], HIV [5], and HCV [6] that account for substantial healthcare utilization, morbidity, and mortality [7]. These intertwined epidemics of addiction and infection are typically managed separately.
Treatment of infectious disease (ID) in patients with opioid use disorder (OUD) is impeded by inadequate treatment of OUD. Hospitalized patients with infections often lack access to clinicians who are trained in medication treatment for OUD (MOUD) provision (e.g. buprenorphine, methadone, extended-release naltrexone) and standard of care typically consists of detoxification and/or referral to outpatient treatment. Detoxification from opioids, a historical standard of care, is associated with a high risk of relapse [8] and overdose [9,10]. In addition, patients may leave ‘against medical advice’ (AMA) before completion of antimicrobial therapy due to experiencing untreated opioid withdrawal symptoms [11], often leading to readmissions due to inadequate treatment of their infection [12]. Initiation of maintenance treatment with MOUD should be the standard of care as these medications are the most effective treatments for OUD, reducing opioid craving, opioid relapse, overdose and death [[13], [14], [15]]. Despite its extensive evidence base, MOUD are infrequently prescribed in the hospital setting or upon discharge from inpatient admission [16]. ID specialists and hospitalists are a logical resource to engage patients in treatments for both OUD and infections, building capacity and increasing access to MOUD.
Emerging evidence over the past two decades suggests that integration of OUD and infectious disease care improves outcomes [11,[17], [18], [19]]. MOUD improves HIV viral suppression and retention on antiretroviral therapy and reduces acquisition of HCV [[20], [21], [22]]. ID physicians may be first to engage patients with infections and OUD during hospitalization with the unique vantage point of providing inpatient to outpatient continuity of care [23]. Given the scarcity of MOUD providers, they are an efficient resource to provide integrated addiction and infection care while shepherding patients through the vulnerable acute care and post-discharge period [17].
A monthly injectable long-acting formulation of buprenorphine (LAB), recently approved by the FDA (Sublocade®), produces therapeutic blood levels for a month and has advantages for initiating inpatient OUD treatment including: 1) immediate and sustained treatment of opioid craving and withdrawal symptoms which frequently cause patients to leave the hospital prematurely; 2) allowing clinicians treating the infections to initiate early OUD treatment negating the wait for an addiction specialist consultation or deferring treatment to after discharge; and 3) providing a bridge to long-term OUD treatment, reducing relapse and optimizing antimicrobial treatment. LAB formulations have been found to be superior to placebo and non-inferior to SL buprenorphine for treatment of OUD [24,25], however available data for persons with concurrent infections and for patients hospitalized with co-occurring infections are scarce.
This study tests a new model of care (ID/LAB) in which OUD and infections are managed concurrently by ID specialists and hospitalists using LAB, followed by timely referral to community resources for long-term OUD treatment. We describe the design, protocol and outcomes measures in this on-going multi-site randomized controlled trial.
Section snippets
Study design
COMMIT (Coordinated Medical Treatment of Opioid Use Disorder and Infectious Disease) is a National Center For Advancing Translational Science (NCATS)- funded (U01 TR002763) multi-site randomized controlled trial of adult patients hospitalized with opioid use disorder and associated infections comparing integrated treatment of long-acting buprenorphine (LAB) with infectious disease care (ID/LAB) compared to treatment as usual (TAU). Adult patients (N = 200) hospitalized with severe bacterial or
Recruitment and screening
Recruitment began in August 2020 and will continue until mid-2022. All recruitment occurs in the inpatient hospital setting with referrals coming from inpatient providers from hospitalists, infectious diseases, addiction medicine, or the Emergency Department. A HIPAA waiver was obtained to allow for review of the electronic medical record for eligible participants.
Inclusion criteria are as follows:
1. Adult (age 18-65) volunteers able to provide written informed consent in English or Spanish; 2.
Screening and intervention measures
Screening and intervention measures to assess eligibility criteria are listed in Table 1 and described below. Upon obtaining consent, enrollment and baseline study procedures are conducted followed by randomization, with established study follow-up continuing at designated intervals for 6 months. Refer to Table 1 for the comprehensive study measures timeline.
Randomization and dispensing
Participants are randomized to one of the two study arms (ID/LAB vs TAU) using fixed permuted blocks of 4 and stratified by study site. The randomization was designed by the study statistician and integrated into the data system by the study data manager, who otherwise have no direct contact with study staff evaluating and managing the participants, and study staff have no access to the random sequence of treatment group assignments. Once a patient has consented and has been determined to be
Pre-discharge
After enrollment, baseline interview data is collected and then entered directly into the study database through a secure online platform. Study assessments are performed by research associates (RAs) and clinical researchers (CRs) (see Table 1). If not already available through the electronic health record, HIV, HCV and urine drug screen testing is performed. For those who had newly confirmed or previously known HIV and/or active HCV, viral load testing is obtained. Specific laboratory data is
Payments
Participants are compensated for donating their time to clinical research and not for receiving study medication as shown in Table 1. All payments are made in cash or gift card equivalent per site discretion. The study visits are compensated at a value of $50 for the baseline visit, week 12, and week 24 visits. Weeks 4 and 8 are compensated at $25. The non-study visit weekly Medical Management check-ins performed by the Nurse Care Managers are apportioned $5 per call with an opportunity for
Specific safety protocols
All participants are screened prior to enrollment by a clinical researcher and the local site investigator if needed to ensure appropriateness for the study. Those with severe medical or psychiatric comorbidity precluding safe participation are excluded. Buprenorphine products are not recommended for use in severe hepatic impairment – prior to enrollment all available clinical data is reviewed to assess for severe liver disease such as significant transaminitis or advanced cirrhosis. If any
Analytic plan
Below are brief descriptions of the planned analyses categorized by variable.
Implementation issues
There have been several implementation issues that were overcome prior to and during the conduct of this study, summarized below.
Summary
Medication treatment is recognized as the most effective treatment for OUD [65], and studies have shown that initiation of MOUD in hospital settings can improve OUD treatment outcomes [26,27]. Unfortunately, however, few persons are screened for OUD in hospital settings when admitted for infections or other medical comorbidities and few are offered maintenance MOUD to prevent opioid craving, manage opioid withdrawal symptoms or to reduce risk of relapse after discharge [66]. Without addressing
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
National Center For Advancing Translational Science (NCATS)U01 TR002763, Springer, Brady, Levin, Nunes; NIDA Independent Scientist Award K02DA032322, Springer. Sublocade® was donated in-kind by Indivior Inc. after an Investigator initiated Application was approved. The funders were not involved in the research design, analysis or interpretation of the data or the decision to publish the manuscript. We thank all study staff, and our participants for making this trial possible.
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