Rationale, design and methods of VA-BRAVE: a randomized comparative effectiveness trial of two formulations of buprenorphine for treatment of opioid use disorder in veterans

Abstract

Background To address the US opioid epidemic, there is an urgent clinical need to provide persons with opioid use disorder (OUD) with effective medication treatments for OUD (MOUD). Formulations of sublingual buprenorphine/naloxone (SL-BUP/NLX) are considered the standard of care for OUD including within the Veterans Healthcare Administration (VHA). However, poor retention on MOUD undermines its effectiveness. Long-acting injectable monthly buprenorphine (INJ-BUP) (e.g., Sublocade®) has the potential to improve retention and therefore reduce opioid use and overdose. Designing and conducting studies for OUD pose unique challenges. The strategies and solutions to some of these considerations in designing Cooperative Studies Program (CSP) 2014, Buprenorphine for Treating Opioid Use Disorder in Veterans (VA-BRAVE), a randomized, 20-site, clinical effectiveness trial comparing INJ-BUP to SL-BUP/NLX conducted within the VHA may provide valuable guidance for others confronted with similar investigation challenges. Methods This 52-week, parallel group, open-label, randomized controlled trial (RCT) evaluates the comparative effectiveness of two current FDA-approved formulations of buprenorphine: (1) daily SL-BUP/NLX vs. (2) monthly (28-day) INJ-BUP for Veterans with moderate to severe OUD (n = 952). The primary outcomes are (1) retention in MOUD and (2) opioid abstinence. Secondary outcomes include measures of other drug use, psychiatric symptoms, medical outcomes including prevalence rates of HIV, hepatitis B and C as well as social outcomes (housing instability, criminal justice involvement), service utilization and cost-effectiveness. Special considerations in conducting a comparative effectiveness trial with this population and during COVID-19 pandemic were also included. Discussion The evaluation of the extended-release formulation of buprenorphine compared to the standard sublingual formulation in real-world VHA settings is of paramount importance in addressing the opioid epidemic. The extent to which this new treatment facilitates retention, decreases opioid use, and prevents severe sequelae of OUD has not been studied in any long-term trial to date. Positive findings in this trial could lead to widespread adoption of MOUD, and, if proven superior INJ-BUP, by clinicians throughout the VHA and beyond. This treatment has the potential to reduce opioid use among Veterans, improve medical, psychological, and social outcomes, and save lives at justifiable cost. Trial registration Registered at Clinicaltrials.gov NCT04375033

Real-world Evidence for Impact of Opioid Agonist Therapy on Nonfatal Overdose in Patients with Opioid Use Disorder during the COVID-19 Pandemic

“…Available data examining OD risk in patients treated with MET or BUP-SL who continue to use fentanyl supports a protective effect for both options compared to no treatment 15 . To our knowledge, this is the first examination of the potential benefit of BUP-XR in reducing risk of OD, although additional studies are being conducted that may further extend our knowledge on this important question 16–18 …”

“…15 To our knowledge, this is the first examination of the potential benefit of BUP-XR in reducing risk of OD, although additional studies are being conducted that may further extend our knowledge on this important question. [16][17][18] The parsimonious model, selected using a backward algorithm with P > 0.15 as the exclusion criterion, was used for risk adjustment. The outcome variable for the logistic regression model was the occurrence of at least 1 NF-OD event during the study.…”

The FASTER-BUP Study, Extended-Release Injectable Buprenorphine for the Treatment of Opioid Use Disorder Among Individuals at High Risk of Overdose: Protocol for an Observational Prospective Study

“…10 Another non-randomized trial in Australia investigating XR-BUP in custodial settings showed treatment retention and outcomes were comparable to those observed in community settings and other MOUD (ie, methadone). 11 Clinical trials comparing XR-BUP and SL-BUP in other populations with OUD, such as pregnant persons 12 and veterans, 13 are underway in the United States. Additionally, an ongoing clinical trial is testing different doses and formulations of buprenorphine (ie, standard dose SL-BUP, high dose SL-BUP, and XR-BUP) as well as tapering strategies.…”