The efficacy of BELBUCA has been evaluated in three 12-week double-blind, placebo-controlled clinical trials in opioid-naïve and opioid-experienced patients with moderate-to-severe chronic low back pain using pain scores as the primary efficacy variable. Two of these studies, described below, demonstrated efficacy in patients with low back pain. One study in low back pain did not show a statistically significant pain reduction for BELBUCA compared to placebo.

12-Week Study in Opioid-Naïve Patients with Chronic Low Back Pain

A total of 749 patients with chronic low back pain entered an open-label, dose-titration period for up to eight weeks. Potential subjects were excluded from participation for QTcF interval of 450 ms or more, hypokalemia, clinically unstable cardiac disease, a history of Long QT Syndrome or an immediate family member with this condition, or taking Class IA or Class III antiarrhythmic medications. Patients initiated therapy with a single 75 mcg dose of BELBUCA on Day 1 and continued taking BELBUCA 75 mcg either once daily or every 12 hours for 4-8 days as tolerated. The dose was then increased to 150 mcg every 12 hours, and patients could continue to dose escalate in 150 mcg dose increments every 4-8 days for up to 6 weeks if the adverse effects were tolerable and the analgesic effects were not adequate. Patients who achieved adequate analgesia and tolerable adverse effects on BELBUCA for at least 2 weeks were then randomized to continue their titrated dose of BELBUCA or matching placebo. Sixty-one percent (61%) of the patients who entered the open-label dose titration period were able to titrate to a tolerable and effective dose and were randomized into a 12-week, double-blind treatment period. Fifteen percent of patients discontinued due to an adverse event and 4% discontinued due to lack of a therapeutic effect. The remaining 20% of patients discontinued due to various non-drug related administrative reasons.

During the first 2 weeks of double-blind treatment, patients were allowed up to 2 tablets per day of hydrocodone/acetaminophen 5/325 mg as supplemental analgesia to minimize opioid withdrawal symptoms in patients randomized to placebo. Thereafter, the supplemental analgesia was limited to 1 to 2 tablets of acetaminophen 500 mg per day. Seventy-six percent of the patients treated with BELBUCA completed the 12-week treatment compared to 73% of the patients treated with placebo. Of the 209 patients randomized to BELBUCA, 4% discontinued due to lack of efficacy and 8% due to adverse events. Of the 211 patients randomized to placebo, 11% discontinued due to lack of efficacy and 4% due to adverse events.

Of the patients who were randomized, the mean pain (SD) scores on a 0 to 10 numeric rating scale (NRS) were 7.1 (1.06) and 7.2 (1.05) prior to open-label titration and 2.8 (1.01) and 2.8 (1.12) at the beginning of the double-blind period for BELBUCA and placebo, respectively. The change from double-blind baseline to week 12 in mean pain (SD) NRS score was statistically significant favoring patients treated with BELBUCA compared with patients treated with placebo.

A higher proportion of BELBUCA patients (62%) had at least a 30% reduction in pain score from prior to open-label titration to study endpoint when compared to patients who received placebo buccal film (47%). A higher proportion of BELBUCA patients (41%) also had at least a 50% reduction in pain score from prior to open-label titration to study endpoint compared to patients who received placebo (33%).

The proportion of patients with various degrees of improvement, from prior to open-label titration (Titration-Baseline) to study endpoint, is shown in Figure 1 below.

Figure 1: Percentage Improvement in Pain Intensity from Titration-Baseline to Week 12

12-Week Study in Opioid-Experienced Patients with Chronic Low Back Pain

Eight hundred and ten (810) patients on chronic opioid therapy (total daily dose 30-160 mg in oral morphine sulfate equivalents (MSE) for at least 4 weeks) entered an open-label, dose-titration period with BELBUCA for up to 8 weeks, following taper of their prior opioids to 30 mg oral MSE daily. Potential subjects were excluded from participation for QTcF interval of 450 ms or more, hypokalemia, clinically unstable cardiac disease, a history of Long QT Syndrome or an immediate family member with this condition, or taking Class IA or Class III antiarrhythmic medications. Patients were initiated with BELBUCA 150 mcg every 12 hours if they were on 30 to 89 mg oral MSE daily and 300 mcg every 12 hours if they were on 90 to 160 mg oral MSE daily prior to taper. If a patient tolerated the adverse events and the analgesic effects were not adequate, the dose was increased in increments of 150 mcg every 12 hours after 4 to 8 days for up to 6 weeks. Patients were permitted to take hydrocodone/acetaminophen 5/325 mg as analgesic rescue as needed up to a maximum of 4 doses per day during the open-label dose titration period. After a dose was reached with adequate analgesia and tolerable adverse effects for a period of 2 weeks, patients were randomized to continue their titrated dose of BELBUCA or matching placebo. Sixty-three percent (63%) of the patients who entered the open-label titration period were able to titrate to a tolerable and effective dose and were randomized into a 12-week double-blind treatment phase. Ten percent (10%) of patients discontinued due to an adverse event, 8% discontinued due to lack of a therapeutic effect, and 0.1% discontinued due to opioid withdrawal during the open-label titration period. The remaining 20% of patients discontinued due to various non-drug related administrative reasons.

During the double-blind period, patients were permitted to take up to 2 doses of 5/325 mg or 10/650 mg of hydrocodone/acetaminophen per day for the first 2 weeks to minimize opioid withdrawal symptoms in patients randomized to placebo. After the first 2 weeks, patients were permitted to take 1 dose of 5/325 mg or 10/650 mg per day. Eighty-three percent of patients treated with BELBUCA and 57% of patients treated with placebo buccal film completed the 12-week treatment period. Of the 243 patients randomized to BELBUCA, 8% discontinued due to lack of efficacy and 2% due to adverse events. Of the 248 patients randomized to placebo buccal film, 25% discontinued due to lack of efficacy and 5% due to adverse events.

Of the patients who were randomized into the double-blind period, the mean pain (SD) NRS scores were 6.8 (1.28) and 6.6 (1.32) prior to open-label titration and 2.9 (0.985) and 2.8 (1.05) at the beginning of the double-blind period for BELBUCA and placebo, respectively. The change from baseline to week 12 in mean pain (SD) NRS score was statistically significant in favor of patients treated with BELBUCA compared with patients treated with placebo.

A higher proportion of BELBUCA patients (64%) had at least a 30% reduction in pain score from prior to open-label titration to study endpoint when compared to patients who received placebo buccal film (31%). A higher proportion of BELBUCA patients (39%) also had at least a 50% reduction in pain score from prior to open-label titration to study endpoint compared to patients who received placebo (17%).

The proportion of patients with various degrees of improvement from prior to open-label titration (Titration-Baseline) to study endpoint is shown in Figure 2 below.

Figure 2: Percentage Improvement in Pain Intensity from Titration-Baseline to Week 12