The eligibility criteria to participate in this trial (Table 1) are deliberately broad to maximize the inclusion of Veterans in order to assess the co-primary outcomes (retention in MOUD and opioid abstinence) and to mirror ‘real world’ patients with OUD who present for MOUD in VHA clinical settings. Participants who have moderate-to-severe OUD [Diagnostic Statistical manual-5th Edition (DSM-5)] [31] who are entering a new episode of care and who are 18 years or older are eligible. This includes participants with psychiatric, substance use and medical comorbidities that are typical in the VHA OUD population. Participants previously maintained on buprenorphine or other forms of MOUD are permitted to participate, but in order to be eligible for this trial they must be initiating buprenorphine as a new episode of care at the time of study enrollment (< 30 consecutive days on MOUD treatment). As a real-world effectiveness trial, there are no restrictions in participation in psychosocial programs and other formal supports. Service utilization will be assessed as a secondary objective.

The exclusion criteria are also minimal to enhance generalizability, while maximizing patient safety. These include conditions (e.g., psychiatric conditions) requiring a higher level of care or medical conditions that preclude the use of buprenorphine. While participants are expected to have comorbid substance use disorders, whether to exclude participants using sedative hypnotics was carefully considered. Recent guidance from the American Society of Addiction Medicine (ASAM) [32] encourages treatment with buprenorphine even in those using sedative hypnotics since buprenorphine protects against risk of overdose from opioids. In this study, those participants at highest risk of combining medications, defined as those with a DSM-5 diagnosis of current sedative hypnotic use disorder are excluded.

Similarly, it is expected that participants will have medical comorbidities including hepatitis B and C and HIV. Only those participants for whom buprenorphine is medically contraindicated or who require intensive medical management (e.g., Childs-Pugh Class C cirrhosis) are excluded. Those with pending felony charges are also excluded due to likelihood of incarceration interfering with participation. In addition, in response to the COVID-19 pandemic, exclusion criteria exclude those with current moderate to severe COVID-19 symptoms who were at risk of intubation or critical illness. Those participants are able to join if they meet eligibility criteria after they recover from the acute phase of the infection.

Twenty geographically diverse sites were chosen across the United States with consideration for sites with facilities capable of supporting CSP research as well as those areas hard-hit by the opioid epidemic as shown in 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

This study is approved by the VA-Central Institutional Review Board (CIRB). Early identification, screening, and contact of patients seen by the medical center’s MOUD clinic and substance use disorder specialty clinics, mental health clinics, primary care and sub-specialty medical clinics and inpatient units responsible for the evaluation and treatment of patients with likely or confirmed diagnoses of OUD are key to the study’s success. CIRB-approved flyers and information sheets were developed to reach a broad and inclusive audience at local sites and result in patient-initiated contact with the local site study team.

Written consent for further screening and study participation is obtained in-person by an authorized member of the study team. Patients ineligible or unwilling to participate at any point in the recruitment process or who withdraw consent are referred for appropriate treatment via a warm handoff based upon consultation with the site study clinician.

The goal of CSP 2014, VA-BRAVE, is to evaluate whether the long acting injectable buprenorphine is more effective than the current standard of care, sublingual buprenorphine, and whether its cost effectiveness merits its adoption. One design challenge was to isolate the route of administration as the independent variable and, in order to satisfy equipoise, careful consideration was taken in terms of induction processes, dose, and frequency of medication prescription.

Participants who meet eligibility criteria are initiated on SL-BUP/NLX as soon as clinically possible in accordance with good clinical practice. Buprenorphine is prescribed during an induction phase with SL-BUP/NLX starting at a dose of 2 mg and then increased as needed for stabilization of opioid withdrawal symptoms. This induction procedure is consistent with clinical care as described in clinical practice guidelines [33] including SAMHSA TIP 63 practice guidelines [34]. The target maintenance dose is 16 mg to 24 mg titrated by day 3, with room for clinical flexibility defined as not more than 30 days from induction. This study allows for rapid initiation of INJ-BUP in the service of getting patients stabilized on treatment as soon as possible. Potential participants who are already taking a form of buprenorphine for less than 30 days or who are in the process of being clinically inducted are also eligible for the study and bypass protocolized induction procedures. As soon as a maintenance dose is identified, the participant is ready for randomization.

Once reaching the target dose, eligible participants are randomized 1:1 to receive either continued daily SL-BUP/NLX at the dose identified in the induction period or to receive monthly subcutaneous abdominal INJ-BUP with a target dose of 300 mg, with the option to use 100 mg dose. Randomization is performed centrally by the CSP Clinical Research Pharmacy Coordinating Center (CSPCC) using an interactive web-based randomization program that allows for randomization of participants in real time by authorized study team members at each site who submit a randomization request form. The study participant is allocated to the appropriate treatment arm according to the randomization schema and a certificate is generated. The certificate is used by the local site investigator and research pharmacist to direct study drug dispensing. Participants are informed of their randomized treatment assignment during their visit, and prior to initiation of either SL-BUP/NLX or INJ-BUP.

This is an open label comparative effectiveness study so neither staff nor participants are blinded to treatment assignment.

Study drug is prescribed for a treatment course totaling 52 weeks in either 28-day prescriptions of daily SL-BUP/NLX (target dose 16–24 mg) or 28-day INJ-BUP (target dose 300 mg) injections, a formulation which provides steady blood level over 28–30 days. While two doses of INJ-BUP are available, 100 mg and 300 mg, the 300 mg dose was chosen as a target dose as it delivers a far more adequate steady state mean blood level and has been associated with better opioid abstinence outcomes than the 100 mg dose for those who inject heroin [35]. The SL-BUP/NLX formulation used in this study is a sublingual film formulation across all sites. The dose range of 16–24 mg is the standard dose recommended for clinical practice. The prescribing physician can make adjustments in dose for the SL-BUP/NLX following standard clinical practice. For those randomized to INJ-BUP, the 300 mg dose is the target dose; however, the prescribing physician can lower the dose to 100 mg after the first injection depending on patient preference or if clinically indicated (e.g., opioid agonist side effects). In order to satisfy equipoise, participants randomized to the SL-BUP/NLX arm receive a 28-day take-home supply; while those in the INJ-BUP arm receive monthly INJ-BUP administered in the clinic at 28-day intervals. The study visits as depicted in Fig. 3 are identical between groups, and all participants regardless of their assigned treatment arm, receive a Medication Management (MM) session at each 28-day study visit (described below). Each site has a local site investigator and a study team; all study-related drugs are prescribed and administered by a clinician(s) (e.g., MD, NP, DO, PA, RN). Site investigators are mostly psychiatrists but also include primary care physicians; all are clinicians working in substance abuse clinics or in settings in which they are treating patients with opioid use disorder. Site investigators were chosen based on their experience with the patient population and with research (or with the availability of local research mentorship).

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

VA-BRAVE is a 52-week study that includes scheduled receipt of study medication and active follow-up. Many studies of OUD are limited to 12 or 24 weeks of active treatment; given that OUD can be chronic and relapsing, longer studies are needed to understand the clinical benefit of buprenorphine over time. This 52-week study will be better able to evaluate retention on study drug and opioid abstinence. In addition, there is an additional passive follow-up period, using the electronic medical record of up to 10 years (from date of first participant randomized), to assess longer-term patterns of service use including medications and hospitalizations.

Local staff will maintain participant engagement via periodic phone calls to remind them about visits, for check-ins between visits, to follow-up on missed visits, and to obtain relevant study data if necessary. Participant-provided contact forms facilitate this outreach. Participants will be notified that those listed may be contacted but information regarding study participation will not be disclosed. Local staff will update this form as needed throughout the study. Participants will not be considered “lost to follow-up” until their week 52 visit, so there is always the opportunity to re-engage with the study after a lapse.

The study design has particular strengths that contribute to its scientific value and ensure ethical care. The choice of primary and secondary outcomes provides broad, patient-centered results, critical to the lives of Veterans seeking medication treatment for OUD. The study’s exclusion criteria are minimal in order to make the results generalizable to a wide spectrum of Veterans seeking medication treatment for OUD (Table 1). Additionally, the induction phase preceding randomization follows established guidelines to engage participants in MOUD as early in treatment as possible.

Participants with OUD are at risk for opioid overdose. To mitigate this risk, study procedures ensure all participants receive Overdose Education and Naloxone Distribution (OEND) consistent with usual good clinical care practices for Veterans with OUD. In addition, all participants are provided Medication Management, a 15-min counseling session that recommends opioid and other substance use abstinence and adherence to MOUD.

One strength of this study is its use of two co-primary outcomes, retention and opioid abstinence, chosen because they are clinically meaningful, practical, patient-centered, and appropriate for a 52-week, large-scale comparative effectiveness trial.

Retention on treatment Retention on MOUD is a highly sensitive indicator of effective treatment, as discontinuation is strongly associated with recurrence to use of opioids, risk for overdose, transmission of bloodborne infectious diseases, and incarceration. Retention is defined as time from randomization to the first period of missed study-prescribed drug coverage lasting at least 4 weeks. This outcome is accurately measurable, unaffected by loss to follow-up, and highly indicative of clinical benefit.

Opioid abstinence reflects direct opioid use and will be indicated by self-report opioid abstinence using the systematic timeline follow-back (TLFB) [36] method and urine toxicology (UTOX) negative for opioids across 28 timepoints. The National Institute on Drug Abuse (NIDA)-funded Clinical Trials Network investigators have recommended using the method of self-report plus toxicology as a standard in substance use disorder trials.

Self-reported drug use is collected using the TLFB calendar method, in which study personnel record the participants’ reported opioid use for each day since the last study visit. The TLFB is reliable and valid when used by trained interviewers and when there is no penalty for reporting use of drugs. The advantage to this method is that data are collected retrospectively to the last visit, so a missed appointment does not necessarily result in missing self-report data; limitations include reliance on self-report and lack of objective measurement. For that reason, a biological measure, with UTOX as standard, is also collected as an indicator of opioid abstinence. UTOX for this study is a UTOX-13 panel from a centralized lab, Redwood Toxicology, and collected at each study visit as indicated in Fig. 3 and the Schedule of Assessments in Table 2 and measures opioid drug use including oxycodone/noroxycodone, benzodiazepines, ethyl glucuronide, methadone, fentanyl, buprenorphine, tramadol, methylene-dioxy-methamphetamine (MDMA), amphetamines, cocaine metabolite, opiates, cannabinoids, and THC/creatinine ratio. UTOX screening is a routine part of buprenorphine maintenance treatment. UTOX screening methods have the issue of how to handle missing data [37]. For this trial, the conservative method that assumes missing UTOX is indicative of use is used (although participants may miss appointments for other reasons) and is consistent with most published research. Both the TLFB and UTOX data must be negative for opioid use to deem a participant abstinent.

Secondary objectives include determining whether the use of INJ-BUP is associated with better outcomes than SL-BUP/NLX in: opioid craving; use of other illicit substances and alcohol; preventing opioid overdose; reducing mental health symptoms (including depression, PTSD, and suicidality; homelessness); incarceration and criminal legal involvement; self-reported risky sexual and injection drug use behaviors and the incidence of new cases of HIV, HBV, and HCV. In addition, the total cost impact of INJ-BUP and cost-effectiveness from the perspective of VHA and of society will be evaluated. We will thus also assess non-VA service utilization, especially since the MISSION ACT [38], allows a Veteran to receive care from a community provider paid for by the VA. Table 2 summarizes the Schedule of Assessments including self-report and biological measures and their administration times. Data will also be captured to identify reasons for missed study injections as well as overall study visits.