Pivotal Trial (Study 13-0001)
The primary outcome in Study 13-0001 was the percentage abstinence, for which both 300 mg/100 mg and 300 mg/300 mg treatment regimen arms of BUP-ER were found to be superior to placebo from week 5 to week 24, with a mean percentage abstinence of 42.7% and 41.3% in the 300 mg/100 mg and 300 mg/300 mg arms, respectively, compared with 5.0% in the placebo arm (P < 0.0001 for each regimen compared with placebo). In each of the BUP treatment groups, 12% to 13% of patients had no positive or missing urine drug samples or self-reports of illicit opioid use over this period of time, compared with 1% in the placebo group. Treatment success (defined as any patient with 80% or more of urine samples negative for opioids combined with negative self-reports) was statistically significantly higher in the 300 mg/100 mg (28%) and 300 mg/300 mg (29%) arms, compared with 2% in placebo (P < 0.0001). Also, the percentage of patients abstinent at any week from week 5 to week 24 was numerically higher in both the 300 mg/100 mg and 300 mg/300 mg groups compared with the placebo group in the full analysis set, ranging from 35.1% to 48.5% in the 300 mg/300 mg group and 38.5% to 45.4% in the 300 mg/100 mg group versus 2.0% to 11.1% in the placebo group.
In Study 13-0001, the mean Clinical Opioid Withdrawal Scale (COWS) and Subjective Opioid Withdrawal Scale (SOWS) were numerically low at baseline and at week 24 in all treatment groups (mean COWS 1.9 or lower; SOWS 4.9 or lower). Regarding the desire- or need-to-use Visual Analog Scale (VAS) scores, mean scores in the placebo group were slightly higher at baseline (9.5) compared with active treatment groups (5.5 in the 300 mg/100 mg group and 7.1 in the 300 mg/100 mg group). There was an increase in the placebo group noted at week 2 (26.9), and values remained high until week 24, indicating a higher desire to use. Final mean scores in the placebo group for the desire- or need-to-use VAS scores at week 24 (17.1) were significantly higher than in the active treatment groups (6.8 in the 300 mg/100 mg group and 3.2 in the 300 mg/300 mg group). Analyses for these outcomes were not adjusted for multiplicity, and therefore should be interpreted with consideration of the risk of Type I errors.
Other Studies
The extension study, Study 13-0003 (N = 669), was an open-label study designed to evaluate the safety and tolerability of BUP-ER over 48 weeks, and included a combination of patients who had completed Study 13-0001 with six doses of BUP-ER treatment or placebo, as well as newly enrolled patients.8 Roll-over patients received six additional doses of BUP-ER and de novo patients received 12 doses of BUP-ER. Using the same efficacy end point as in the pivotal trial, mean percentage abstinence after 48 weeks of BUP-ER treatment was found to be 46% in newly initiated patients (de novo patients) compared with 57% of roll-over patients from Study 13-0001. No formal statistical tests were outlined a priori for this analysis; therefore, interpretations of the results are limited. About 8% of de novo patients achieved 100% abstinence compared with 18% of roll-over patients. Mean COWS, SOWS, and desire- or need-to-use VAS scores were also recorded throughout this study; however, according to the statistical analysis plan, results were not compared between groups. Mean COWS and SOWS scores were generally low at baseline and remained low in both groups until week 48. Mean opioid craving VAS scores were generally low in both groups at baseline (5.9 in de novo patients and 4.4 in roll-over patients); however, mean opioid craving VAS scores at week 48 were numerically different (4.2 in roll-over patients compared with 8.3 in de novo patients). Limitations of this trial include the inability to draw comparisons from the data due to its study design, and the assumption that missing data in patient withdrawal symptoms scores (i.e., COWS, SOWS, and VAS scores) were missing at random, as it is possible that patients who completed the trial and those who did not were from different populations. Also, BUP-ER doses administered subsequent to the initial BUP-ER 300 mg dose were able to be adjusted either down to 100 mg or maintained at 300 mg based on the medical judgment of the investigator. No comparisons were made to establish differences in tolerability or efficacy between patients maintained on 300 mg per month and 100 mg per month in this trial. Finally, due to the open-label nature of this study, all efficacy results COWS, SOWS, and opioid craving VAS scores are subject to bias.
The NMA was submitted by the manufacturer and summarized indirect evidence comparing BUP-ER with other drugs currently used to treat OUD in their effect on treatment retention and opioid test positivity.9 Interventions included BUP-ER 300 mg/100 mg, BUP-ER 300 mg/300 mg, methadone (variable dose), sublingual buprenorphine (variable dose), buprenorphine implants, and a different buprenorphine depot injection (CAM2038) for the outcomes of opioid test positivity and treatment retention. BUP-ER 300 mg/100 mg was associated with a significantly decreased likelihood of opioid test positivity compared with placebo (odds ratio [OR], 0.12; 95% credible interval [CrI], 0.06 to 0.24), sublingual buprenorphine (OR, 0.34; 95% CrI, 0.12 to 0.90), and buprenorphine implants (OR, 0.32; 95% CrI, 0.12 to 0.78). Similar results were observed in the BUP-ER 300 mg/300 mg arm. Neither BUP-ER dosage arm was significantly different than sublingual buprenorphine, buprenorphine implants, and CAM2038 with respect to study dropout. Using the same model, treatment with methadone was associated with a significantly lower rate of study dropout than both the BUP-ER 300 mg/100 mg and BUP-ER 300 mg/300 mg arms. Key limitations include the lack of transparency in systematic review methods, limited heterogeneity analyses performed, and the inclusion of studies with sparse baseline data, further limiting the generalizability of this study’s findings.
The observational study, RECOVER (N = 826), was a longitudinal, observational study that included patients who had participated in studies 13-0001 and 13-0003 and received at least one study injection.10 Data were collected up to 12 months before patients were treated with BUP-ER and up to 24 months after treatment initiation, to examine differences in criminal activity, opioid abstinence and withdrawal, depression and psychological stress, work attendance, and performance over time. Changes in criminal activity from the 12 months leading up to study enrolment until up to 12 months after initiation of BUP-ER treatment found a numerically lower number of total arrests; however, the proportion of patients receiving felony charges remained the same. Patients receiving placebo as well as those receiving BUP-ER treatment for 13 months or longer had a lower proportion of missed work days compared with patients receiving BUP-ER treatment for one to two months, three to eight months, and nine to 12 months. Also, patients with the longest recorded treatment duration with BUP-ER were associated with numerically lower mean scores on the K6 psychological distress scale (7.8 among patients in the one-to-two month group compared with 4.0 in the 13 to 18 month group), as well as a numerically lower proportion of patients with severe depression (Beck’s depression inventory score 29 or greater). Results from this study should be interpreted with caution as these data were largely self-reported, and therefore limited by recall bias and truthfulness of responses. Results were also subject to bias in the differential length of follow-up between treatment groups, and losses to follow-up. Criminal data were obtained from public records, for which only 65% of patient records were found.
