The efficacy and safety of BRIXADI for the treatment of opioid use disorder was evaluated in a Phase 3, 24-Week, randomized, double-blind, double-dummy, active controlled, multicenter study in patients who met the DSM-5 criteria for moderate or severe opioid use disorder and who were actively seeking but not currently receiving buprenorphine treatment. Patients were randomized to receive either BRIXADI injections with placebo sublingual tablets or sublingual buprenorphine/naloxone (SL BPN/NX) tablets with placebo injections. All patients received individual drug counseling for the duration of the study. 

On the first day of treatment patients received an open-label 4 mg test dose of sublingual buprenorphine. Patients who tolerated the test dose (two patients did not tolerate the test dose) were randomized and given a 16 mg injection of BRIXADI (weekly) or matched placebo. During the next 6 days patients were allowed up to two further 8 mg injections as needed. Patients received an injection of 16, 24, or 32 mg on Day 8 matched to the dose they received in the previous seven days. Patients received injections weekly (every 7 days +/- 2-day window) for twelve weeks total and then transitioned to an equivalent dose of BRIXADI (monthly) (every 28 days, +/- 7-day window) for the remaining twelve weeks. Dose adjustments were permitted for the duration of the study. Supplemental 8 mg BRIXADI (weekly) injections were allowed during the second phase of the study and were also used in the active-controlled group. Overall, supplemental 8 mg injections were given to 14 patients (6.6%) in the BRIXADI arm and 17 patients (7.9%) in the SL BPN/NX arm. Table 8 shows the doses of BRIXADI (weekly) administered following the initial titration period and at the final visit before transition to BRIXADI (monthly) was allowed. Table 9 shows the first and final BRIXADI (monthly) dose administered to each patient. 

For the first twelve weeks patients completed weekly visits. For the final twelve weeks patients were transitioned to monthly visits. Patients were also required to complete three additional randomly scheduled visits during the final twelve weeks. Efficacy was evaluated using urine drug screens combined with self-reported use of illicit opioid use. Missing urine drug screen samples and/or self-reports were counted as positive for illicit opioids.

A total of 428 patients were randomized equally (215 patients in the SL BPN/NX group and 213 in the BRIXADI group). Of the randomized patients, 69.0% (147/213) of the patients in BRIXADI treatment group and 72.6% (156/215) of the patients in the SL BPN/NX treatment group completed the 24-week period. Patient demographics and baseline characteristics are provided in Table 10.

Table 11 below illustrates the proportion of patients who were considered to be responders. A patient was a responder if they met all of the following criteria:

  * Negative opioid assessment (urinalysis and self-report) during week 12 (evaluated during week 13 visit).
  * No more than one positive opioid assessment in the three illicit opioid use assessments performed during week 9 to 11 (evaluated during visits at weeks 10 to 12).
  * Negative opioid assessment during the final month of the study.
  * No more than one positive opioid assessment at the three scheduled monthly visits and three random site visits.



This responder definition was designed to identify patients who were successfully treated with both BRIXADI (weekly) (administered in the first 12 weeks of treatment) and BRIXADI (monthly) (administered in the second 12 weeks of treatment). Therefore, patients were required to have negative opioid assessments at the end of each treatment phase. Each phase also included an allowable grace period (an initial period of time when positive opioid assessments were not taken into account) and the definition also allowed for sporadic positive assessments. Based on the results of this trial, the efficacy of BRIXADI was demonstrated. Table 11 shows the response rate for each treatment arm along with the associated 95% confidence interval for their difference.

The cumulative distribution function (CDF) of the percentage of negative opioid assessments (urine samples negative for illicit opioid use combined with self-reports negative for illicit opioid use) from Week 4 through Week 24 are shown in Figure 17 and Table 12. The figure and table are cumulative, so that a patient whose percentage of opioid-free assessments is, for example 50%, is also included at every level of negative opioid assessments below 50%. Missing values and values after premature discontinuation were considered positive. Based on the CDF of the percentage of negative opioid assessments, superiority was demonstrated with BRIXADI with statistical significance compared with SL BPN/NX. However, on the right-hand side of the curves where patients were reporting mostly negative opioid assessments (80% or greater) there was little to no difference between BRIXADI and SL BPN/NX.

Figure 17: Patients Achieving Varying Percentages of Negative Opioid Assessments (urine and self-report) in weeks 4 through 24