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.

Keywords: Buprenorphine; Comparative effectiveness trial; Injectable; Opioid use disorder; Veterans.

Fig. 1

CSP2014: VA-BRAVE study design. OUD opioid use disorder, MOUD medication treatment for OUD, MOUD medication for opioid use disorder, TLFB timeline follow-back

Fig. 2

CSP2014: VA-BRAVE map of study sites. Original active sites: Bay Pines, FL; Boston, MA; Cleveland, OH; Dallas, TX; Dayton, OH; Gainesville, FL; Hampton, VA; Long Beach, CA; Milwaukee, WI; Palo Alto, CA; Philadelphia, PA; Pittsburgh, PA; Providence, RI; Salem, VA; Salt Lake City, UT; San Francisco, CA; West Haven, CT; Seattle, WA; White River Junction, VT. Back-up sites: Bedford, MA; Detroit, MI; Huntington, WV; Phoenix, AZ; San Diego, CA; Tuscaloosa, AL

Fig. 3

CSP2014: VA-BRAVE timeline. PRN: as needed; WK: week; RES/Med VISIT: Research/Medication Administration Visit; 30 Day POST: 30 day post study safety monitoring period. *At each visit, research assessments are collected. For more information on the schedule of assessments, refer to Table 1