IMPORTANCE Patients with osteoarthritis (OA) may remain symptomatic with traditional OA treatments. OBJECTIVE To assess 2 subcutaneous tanezumab dosing regimens for OA. DESIGN, SETTING, AND PARTICIPANTS A randomized, double-blind, multicenter trial from January 2016 to May 14, 2018 (last patient visit). Patients enrolled were 18 years or older with hip or knee OA, inadequate response to OA analgesics, and no radiographic evidence of prespecified joint safety conditions. INTERVENTIONS Patients received by subcutaneous administration either tanezumab, 2.5 mg, at day 1 and week 8 (n = 231); tanezumab, 2.5 mg at day 1 and 5 mg at week 8 (ie, tanezumab, 2.5/5 mg; n = 233); or placebo at day 1 and week 8 (n = 232). MAIN OUTCOMES AND MEASURES Co-primary end points were change from baseline to week 16 in Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) Pain (0-10, no to extreme pain), WOMAC Physical Function (0-10, no to extreme difficulty), and patient global assessment of osteoarthritis (PGA-OA) (1-5, very good to very poor) scores. RESULTS Among 698 patients randomized, 696 received 1 or more treatment doses (mean [SD] age, 60.8 [9.6] years; 65.1% women), and 582 (83.6%) completed the trial. From baseline to 16 weeks, mean WOMAC Pain scores decreased from 7.1 to 3.6 in the tanezumab, 2.5 mg, group; 7.3 to 3.6 in the tanezumab, 2.5/5 mg, group; and 7.3 to 4.4 in the placebo group (least squares mean differences [95% CI] vs placebo were −0.60 [−1.07 to −0.13; P = .01] for tanezumab, 2.5 mg, and −0.73 [−1.20 to −0.26; P = .002] for tanezumab, 2.5/5 mg). Mean WOMAC Physical Function scores decreased from 7.2 to 3.7 in the 2.5-mg group, 7.4 to 3.6 in the 2.5/5-mg group, and 7.4 to 4.5 with placebo (differences vs placebo, −0.66 [−1.14 to −0.19; P = .007] for tanezumab, 2.5 mg, and −0.89 [−1.37 to −0.42; P < .001] for tanezumab, 2.5/5 mg). Mean PGA-OA scores decreased from 3.4 to 2.4 in the 2.5-mg group, 3.5 to 2.4 in the 2.5/5-mg group, and 3.5 to 2.7 with placebo (differences vs placebo, −0.22 [−0.39 to −0.05; P = .01] for tanezumab, 2.5 mg, and −0.25 [−0.41 to −0.08; P = .004] for tanezumab, 2.5/5 mg). Rapidly progressive OA occurred only in tanezumab-treated patients (2.5 mg: n = 5, 2.2%; 2.5/5 mg: n = 1, 0.4%). The incidence of total joint replacements was 8 (3.5%), 16 (6.9%), and 4 (1.7%) in the tanezumab, 2.5 mg; tanezumab, 2.5/5 mg; and placebo groups, respectively. CONCLUSIONS AND RELEVANCE Among patients with moderate to severe OA of the knee or hip and inadequate response to standard analgesics, tanezumab, compared with placebo, resulted in statistically significant improvements in scores assessing pain and physical function, and in PGA-OA, although the improvements were modest and tanezumab-treated patients had more joint safety events and total joint replacements. Further research is needed to determine the clinical importance of these efficacy and adverse event findings.

Objective To assess the long‐term safety and 16‐week efficacy of subcutaneous tanezumab in patients with hip or knee osteoarthritis (OA). Methods This was a phase III randomized, double‐blind, active treatment–controlled (using nonsteroidal antiinflammatory drugs [NSAIDs] as the active treatment control) safety trial of tanezumab (56‐week treatment/24‐week posttreatment follow‐up) in adults who were receiving stable‐dose NSAID therapy at the time of screening and who had Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and physical function scores of ≥5; patient global assessment (PtGA) of OA of fair, poor, or very poor; history of inadequate pain relief with standard analgesics; and no history or radiographic evidence of prespecified bone/joint conditions beyond OA. Patients received oral naproxen, celecoxib, or diclofenac twice daily (NSAID group; n = 996) or tanezumab 2.5 mg (n = 1,002) or 5 mg (n = 998) subcutaneously every 8 weeks. Coprimary efficacy end points at week 16 were changes in WOMAC pain and physical function scores and changes in PtGA. The primary joint safety end point over 80 weeks comprised adjudicated rapidly progressive OA type 1 or 2, primary osteonecrosis, subchondral insufficiency fracture, or pathologic fracture. Mean values, least squares mean values, and least squares mean differences between groups (with 95% confidence intervals [95% CIs]) were calculated. Results Of 3,021 randomized patients, 2,996 received ≥1 treatment dose. Adverse events (AEs) were similar between patients treated with tanezumab 2.5 mg and those treated with NSAIDs, and were more prevalent in those treated with tanezumab 5 mg. Composite joint safety events were significantly more prevalent with tanezumab 2.5 mg and tanezumab 5 mg than with NSAIDs (observation time–adjusted rate/1,000 patient‐years 38.3 [95% CI 28.0, 52.5] and 71.5 [95% CI 56.7, 90.2], respectively, versus 14.8 [95% CI 8.9, 24.6]; P = 0.001 for tanezumab 2.5 mg versus NSAIDs; P < 0.001 for tanezumab 5 mg versus NSAIDs). Tanezumab 5 mg significantly improved pain and physical function but did not improve PtGA at week 16 when compared to NSAIDs; corresponding differences between the tanezumab 2.5 mg and NSAID groups were not statistically significant. Conclusion In patients previously receiving a stable dose of NSAIDs, tanezumab administered subcutaneously resulted in more joint safety events than continued NSAIDs, with differences being dose dependent. Pain and physical function improved with both doses of tanezumab compared to NSAIDs, reaching statistical significance with tanezumab 5 mg at 16 weeks.

The objective of this multicenter, double-blind, placebo-controlled, randomized withdrawal study was to evaluate the efficacy and safety of ALO-02, an abuse-deterrent formulation containing pellets of extended-release oxycodone hydrochloride (HCl) surrounding sequestered naltrexone HCl, compared with placebo in the treatment of moderate-to-severe chronic low back pain. An open-label titration period in which all patients received ALO-02 was followed by a double-blind treatment period where patients meeting treatment response criteria were randomized to either a fixed dose of ALO-02 or placebo. Daily average low back pain was assessed using an 11-point numeric rating scale (NRS)-Pain. Of the 663 patients screened, 410 received ALO-02 during the open-label conversion and titration period and 281 patients were randomized to the double-blind treatment period (n = 134, placebo; n = 147, ALO-02). Change in the mean NRS-Pain score from randomization baseline to the final 2 weeks of the treatment period was significantly different favoring ALO-02 compared with placebo (P = 0.0114). Forty-four percent of patients treated with placebo and 57.5% of patients treated with ALO-02 reported ≥30% improvement in weekly average NRS-Pain scores from screening to the final 2 weeks of the treatment period (P = 0.0248). In the double-blind treatment period, 56.8% of patients in the ALO-02 group and 56.0% of patients in the placebo group experienced a treatment-emergent adverse event (TEAE). The most common treatment-related TEAEs for ALO-02 during the treatment period were nausea, vomiting, and constipation, consistent with opioid therapy. ALO-02 has been demonstrated to provide significant reduction of pain in patients with chronic low back pain and has a safety profile similar to other opioids.

SUMMARYPurpose: A diazepam auto-injector (AI) has been developed for intramuscular administration to treat acute repetitive seizures (ARS). The objective of this study was to evaluate the efficacy and safety of the diazepam AI when administered by caregivers to control an episode of ARS. Methods: In this phase III, randomized, double-blind, parallel-group, placebo-controlled, multicenter study, subjects with epilepsy on a stable antiepileptic drug regimen who required intermittent medical intervention to control ARS were randomized 1:1 to the placebo AI or the diazepam AI group. Subjects were stratified according to age (2-5, 6-11, ≥12 years). Dose (5, 10, 15, or 20 mg) was based on age and weight. A single dose of study medication was dispensed to be administered by caregivers in an outpatient setting when required. The primary end point was time to next seizure or rescue from 15 min to 12 h postdose. Secondary end points included rescue medication use, number of seizures postdose, caregiver and physician treatment assessments, and safety measures. Key Findings: Of 234 subjects randomized, 81/110 in the placebo AI group and 82/124 in the diazepam AI group were included in the intent-to-treat analysis. Baseline characteristics were similar for both groups. Time to next seizure or rescue was significantly longer in the diazepam AI group compared with the placebo AI group, with a hazard ratio of 0.55 (95% confidence interval (CI) 0.34-0.88; p = 0.012) for diazepam AI versus placebo AI, adjusted for age group. The 25th percentile for time to the next seizure or rescue was 1.18 h (95% CI 0.38-2.03) for placebo AI and 2.70 h (95% CI 0.48-11.42) for diazepam AI; the median was 5.9 h for placebo AI and was inestimable for diazepam AI due to the low number of events experienced by subjects in that group. The proportion of subjects using rescue medication postdose was 30% (24/81) placebo AI versus 17% (14/82) diazepam AI (p = 0.066). An event (seizure or rescue) occurred in 55.6% of subjects in the placebo AI group and 35.4% in the diazepam AI group. The number of seizures experienced during the 12-h postdose period was significantly lower for diazepam AI (median 0.0) compared with placebo AI (median 1.0; p = 0.010). Treatment-emergent adverse events (TEAEs) were reported in 44% (35/79) of subjects in the placebo AI group and 42% (34/81) in the diazepam AI group. The most common TEAEs reported were injection site pain (15% placebo AI, 17% diazepam AI) and injection site hemorrhage (6% placebo AI, 5% diazepam AI). Significance: The diazepam AI was significantly more effective than placebo AI at delaying the next seizure or rescue. Secondary efficacy end points were generally supportive of the primary outcome. Diazepam AI administered by trained caregivers was effective for the treatment of ARS and was well-tolerated, with a safety profile similar to placebo.

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