Long-Term Use of Rimegepant 75 mg for the Acute Treatment of Migraine is Associated with a Reduction in the Utilization of Select Analgesics and Antiemetics.

Purpose: To examine use of concomitant analgesics and antiemetics during treatment with rimegepant in adults with migraine. Patients and Methods: This was a post hoc analysis of a long-term, open-label, safety study in adults with a history of 2-14 moderate or severe migraine attacks per month. Participants self-administered rimegepant 75 mg (1) up to once daily as needed (PRN) for 52 weeks or (2) every other day plus PRN (EOD+PRN) for 12 weeks. The PRN cohort was further divided based on baseline attack frequency, with PRN (2-8) and PRN (9-14) cohorts having a history of 2-8 or 9-14 attacks per month, respectively. Use of select analgesics and antiemetics was analyzed during a 30-day pre-treatment observation period (OP) and during rimegepant treatment. Results: Overall, 1800 rimegepant-treated participants (PRN n = 1514, EOD+PRN n = 286) were included in the analysis. Select analgesics or antiemetics were used by 80.1% of participants during the OP. Among 1441 participants using analgesics or antiemetics during the OP, the proportion who did not use any analgesics or antiemetics following initiation of rimegepant treatment increased during weeks 1-4 (36.9%), 5-8 (52.6%), and 9-12 (56.5%). The mean number of days per month using analgesics or antiemetics was also significantly reduced over time in all cohorts beginning at weeks 1-4 (P < 0.001 vs OP). This pattern of reduced analgesic or antiemetic use was consistent for all rimegepant cohorts, but was most pronounced in the EOD+PRN cohort in which 74.8% of participants reported ≥50% reduction in analgesic/antiemetic days at weeks 9-12. Reduction in use was maintained over time, with 61.3% of participants not using any analgesics or antiemetics during weeks 49-52 of PRN treatment. Conclusion: Long-term treatment with oral rimegepant was associated with reduced analgesic and antiemetic use. Clinicaltrials.gov: NCT03266588.

Characterization of adverse joint outcomes in patients with osteoarthritis treated with subcutaneous tanezumab.

OBJECTIVE: Due to the risk of rapidly progressive osteoarthritis (RPOA), the phase III studies of subcutaneous (SC) tanezumab in patients with moderate to severe hip or knee osteoarthritis (OA) included comprehensive joint safety surveillance. This pooled analysis summarizes these findings. METHOD: Joint safety events in the phase III studies of SC tanezumab (2 placebo- and 1- nonsteroidal anti-inflammatory drug [NSAID]-controlled) were adjudicated by a blinded external committee. Outcomes of RPOA1 and RPOA2, primary osteonecrosis, subchondral insufficiency fracture, and pathological fracture comprised the composite joint safety endpoint (CJSE). Potential patient- and joint-level risk factors for CJSE, RPOA, and total joint replacement (TJR) were explored. RESULTS: Overall, 145/4541 patients (3.2%) had an adjudicated CJSE (0% placebo; 3.2% tanezumab 2.5 mg; 6.2% tanezumab 5 mg; 1.5% NSAID). There was a dose-dependent risk of adjudicated CJSE, RPOA1, and TJR with tanezumab vs NSAID. Patient-level cross-tabulation found associations between adjudicated RPOA with more severe radiographic/symptomatic (joint pain, swelling, and physical limitation) OA. Risk of adjudicated RPOA1 was highest in patients with Kellgren-Lawrence (KL) grade 2 or 3 OA at baseline. Risk of adjudicated RPOA2 or TJR was highest in patients with KL grade 4 joints at baseline. A higher proportion of joints with adjudicated RPOA2 had a TJR (14/26) than those with adjudicated RPOA1 (16/106). CONCLUSION: In placebo- and NSAID controlled studies of SC tanezumab for OA, adjudicated CJSE, RPOA, and TJR most commonly occurred in patients treated with tanezumab and with more severe radiographic or symptomatic OA. NCT02697773; NCT02709486; NCT02528188.

Peripheral Nerve Safety of Nerve Growth Factor Inhibition by Tanezumab: Pooled Analyses of Phase III Clinical Studies in Over 5000 Patients with Osteoarthritis.

BACKGROUND: Tanezumab, a humanized anti-nerve growth factor antibody, was developed for the treatment of pain associated with osteoarthritis. Due to its mechanism of action, peripheral nerve safety was assessed in all clinical studies. OBJECTIVES: To summarize the neurological safety of intravenous (IV) and subcutaneous (SC) tanezumab versus placebo in patients with osteoarthritis. METHODS: Data were pooled from 3389 patients across seven studies that investigated IV administration, and from 1840 patients across three studies that investigated SC administration. The treatment period of each study ranged from 16 to 24 weeks, and follow-up periods ranged from 8 to 24 weeks. Neurological safety evaluations focused on adverse events (AEs) of abnormal peripheral sensation (APS), neurologic examinations, and consultations. RESULTS: Across datasets, the incidence of AEs of APS was higher in tanezumab groups versus placebo. Paresthesia and hypoesthesia were the most frequently reported AEs in tanezumab-treated patients, compared with placebo. In both datasets, most AEs were of mild severity, resolved, and rarely resulted in discontinuation. In all treatment groups in both IV and SC studies, over 90% of patients had no new or worsened neurological examination abnormalities at the last study visit. Across datasets, mononeuropathy was diagnosed more frequently in tanezumab groups compared with placebo. Polyneuropathy was diagnosed in ≤ 0.9% of patients in tanezumab and placebo groups. CONCLUSIONS: Tanezumab IV or SC had an increased incidence of AEs of APS, such as paresthesia and hypoesthesia, and diagnoses of mononeuropathy compared with placebo. However, tanezumab was not associated with generalized peripheral neuropathy. GOV IDENTIFIERS: NCT00733902, NCT00744471, NCT00830063, NCT00863304, NCT00863772, NCT01089725, NCT00985621, NCT02697773, and NCT02709486.

Efficacy, General Safety, and Joint Safety of Tanezumab in Japanese Patients with Osteoarthritis: Subgroup Analyses from Two Randomized, Phase 3 Studies.

INTRODUCTION: Tanezumab is a monoclonal antibody against nerve growth factor that is under investigation for the treatment of osteoarthritis (OA) pain. We conducted subgroup analyses of two randomized phase 3 studies to summarize efficacy, general safety, and adjudicated joint safety of tanezumab in Japanese patients with moderate-to-severe OA. METHODS: In Study 1 (NCT02528188), patients received subcutaneous tanezumab 2.5 mg or 5 mg every 8 weeks or daily oral nonsteroidal anti-inflammatory drugs (NSAID) for 56 weeks. The co-primary efficacy endpoints were change from baseline in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain subscale score and WOMAC Physical Function subscale score at Week 16 (overall study and Japan-specific endpoints) as well as Patient Global Assessment (PGA)-OA score at Week 16 (overall study endpoint only). In Study 2 (NCT02709486), patients received subcutaneous tanezumab 2.5 mg, 5 mg, or placebo every 8 weeks for 24 weeks. Safety monitoring included adjudicated composite joint safety endpoint (CJSE) including rapidly progressive osteoarthritis type 1 (RPOA1), RPOA2, primary osteonecrosis, pathological fracture, or subchondral insufficiency fracture. RESULTS: For Study 1, Japanese patients (n = 200) treated with tanezumab 2.5 mg and 5 mg showed numerically greater improvements in WOMAC Pain, WOMAC Physical Function, and PGA-OA scores versus NSAID at Week 16. Incidences of treatment-emergent adverse events were generally similar between tanezumab 2.5 mg, 5 mg, and NSAID groups. In the integrated safety analysis (Studies 1 + 2; n = 306), ten patients were adjudicated to have a component of CJSE: RPOA1 [tanezumab 2.5 mg (n = 2), tanezumab 5 mg (n = 5)], RPOA2 [tanezumab 2.5 mg (n = 1), tanezumab 5 mg (n = 1)], or primary osteonecrosis [tanezumab 2.5 mg (n = 1)]. Time-adjusted adjudicated rates of RPOA1 and RPOA2 were higher with tanezumab than NSAID or placebo and increased with dose of tanezumab. CONCLUSION: Observations from the Japanese subgroup were generally consistent with the overall study populations.

Observed efficacy and clinically important improvements in participants with osteoarthritis treated with subcutaneous tanezumab: results from a 56-week randomized NSAID-controlled study.

BACKGROUND: A recent phase 3 study demonstrated that treatment with tanezumab, a nerve growth factor inhibitor, or nonsteroidal anti-inflammatory drugs (NSAIDs) improves pain and physical function in participants with moderate-to-severe osteoarthritis (OA) of the hip or knee. Here, we evaluated the time course and clinical importance of these initial efficacy findings using a mixture of primary, secondary, and post hoc endpoints. METHODS: Participants on stable NSAID therapy and with a history of inadequate response to other standard OA analgesics were enrolled in an 80-week (56-week treatment/24-week safety follow-up), randomized, NSAID-controlled, phase 3 study primarily designed to assess the safety of tanezumab for moderate-to-severe OA of the knee or hip. Participants received oral NSAID (twice daily naproxen, celecoxib, or diclofenac) or subcutaneous tanezumab (2.5mg or 5mg every 8 weeks). Non-responders were discontinued at week 16. Changes from baseline in WOMAC Pain and Physical Function, Patient's Global Assessment of Osteoarthritis (PGA-OA), and average pain in the index joint were compared between tanezumab and NSAID groups over the 56-week treatment period. Clinically meaningful response (e.g., ≥30% and ≥50% improvement in WOMAC Pain and Physical Function), rescue medication use, and safety were also assessed. RESULTS: All groups improved WOMAC Pain, WOMAC Physical Function, PGA-OA, and average pain in the index joint over the 56-week treatment period relative to baseline. Across all groups, improvements generally occurred from the time of first assessment (week 1 or 2) to week 16 and then slightly decreased from week 16 to 24 before stabilizing from weeks 24 to 56. The magnitude of improvement and the proportion of participants achieving ≥30% and ≥50% improvement in these measures was greater (unadjusted p≤0.05) with tanezumab than with NSAID at some timepoints on or before week 16. Adverse events of abnormal peripheral sensation, prespecified joint safety events, and total joint replacement surgery occurred more frequently with tanezumab than with NSAID. CONCLUSIONS: Tanezumab and NSAID both provided early and sustained (up to 56 weeks) efficacy relative to baseline. Improvements in pain and function were clinically meaningful in a substantial proportion of participants. Adverse events of abnormal peripheral sensation and joint safety events occurred more frequently with tanezumab than with NSAID. TRIAL REGISTRATION: ClinicalTrials.gov NCT02528188 . Registered on 19 July 2015.

Neurological safety of subcutaneous tanezumab versus NSAID in patients with osteoarthritis.

OBJECTIVE: To assess the long-term neurological safety of tanezumab, a monoclonal antibody against nerve growth factor. METHODS: Patients with osteoarthritis of the hip or knee received stable doses of oral nonsteroidal anti-inflammatory drugs (NSAIDs) before study entry and during a ≤ 37-day screening period. Patients were randomized 1:1:1 to double-dummy tanezumab (2.5 mg or 5 mg, subcutaneous every 8 weeks) or oral NSAIDs (twice-daily) for 56 weeks, with a 24-week follow-up. Neurological safety evaluation focused on peripheral and sympathetic adverse events (AEs), neurologic examinations, and consultations with blinded, external diagnostic reviews. RESULTS: During the treatment period, 6.2%, 9.0%, and 4.6% of patients experienced AEs of abnormal peripheral sensation (APS) in the tanezumab 2.5 mg, 5 mg, and NSAID groups, respectively. Hypoesthesia, paresthesia, and carpal tunnel syndrome were the most common AEs of APS. Clinically significant worsening on examination occurred in <1% in any treatment group at the last study assessment. Diagnoses following external neurological consultation included mononeuropathy (1.3%, 2.1%, and 1.0%), radiculopathy (0.9%, 0.4%, and 0.5%), and polyneuropathy (0.3%, 0.5%, and 0%) in tanezumab 2.5 mg, 5 mg, and NSAID groups, respectively. AEs potentially associated with sympathetic neuropathy were reported for 1.8%, 2.3%, and 2.9% of patients in the tanezumab 2.5 mg, 5 mg, and NSAID groups, respectively. No patient was diagnosed with sympathetic neuropathy. CONCLUSION: Tanezumab had an increased incidence of AEs of APS versus NSAID; these were typically mild/moderate in severity, resolved during the study, and rarely resulted in discontinuation. Tanezumab was not associated with peripheral neuropathy and did not adversely affect the sympathetic nervous system. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02528188 (https://clinicaltrials.gov/ct2/show/NCT02528188).

General Safety and Tolerability of Subcutaneous Tanezumab for Osteoarthritis: A Pooled Analysis of Three Randomized, Placebo-Controlled Trials.

OBJECTIVE: This pooled analysis of 3 randomized, placebo-controlled trials (16-24 week treatment and 8-24 week follow-up) assessed safety of subcutaneous tanezumab (2.5-10 mg every 8 weeks) in 1,840 patients with hip or knee osteoarthritis. METHODS: Overall treatment-emergent adverse events (TEAEs) and TEAEs of abnormal peripheral sensation (APS) were prospectively assessed in 3 trials. Joint safety events (primary osteonecrosis, rapidly progressive osteoarthritis [RPOA], subchondral insufficiency fracture, and pathologic fracture; adjudicated by an independent expert committee) and TEAEs potentially associated with sympathetic neuropathy were prospectively assessed in 2 trials. RESULTS: During the treatment period, overall TEAE rates were 51.7% for placebo and 39.5-54.8% for tanezumab 2.5-10 mg; treatment discontinuation rates were 2.0% for placebo and 0-1.3% for tanezumab. Rates of composite joint safety events (predominantly RPOA type 1) over the treatment plus follow-up period were 0% for placebo and 0.5-3.2% for tanezumab 2.5-5 mg (5 mg was statistically greater than placebo); total joint replacement rates with tanezumab (5.9-7.0%) were not significantly different from placebo (4.5%). Rates of TEAEs of APS (predominantly paresthesia and hypoesthesia) were 2.2% for placebo and 3.2-12.8% for tanezumab 2.5-10 mg. Rates of TEAEs potentially associated with sympathetic neuropathy (predominantly bradycardia and orthostatic hypotension) were 0.8% for placebo and 0.5-2.8% for tanezumab 2.5-5 mg (exposure-adjusted rates were not significantly different from placebo). CONCLUSION: Tanezumab was generally well tolerated. TEAEs of APS (mostly mild and transient) and joint safety events were infrequent but more common with tanezumab than placebo. A tanezumab dose of 2.5 mg demonstrated a more favorable safety profile than higher doses.

Inter-Reader Consistency and Exclusionary Findings During Radiographic Screening for Phase 3 Trials of Tanezumab in Patients With Osteoarthritis.

Objective: Describe the radiograph-based screening program and frequencies of ineligibility in 3 large, international, randomized, double-blind, phase 3 studies of subcutaneous tanezumab in patients with osteoarthritis (OA). Design: Standardized bilateral shoulder, hip, and knee screening radiographs were obtained by trained imaging technologists and centrally read by 1 of 5 musculoskeletal radiology experts trained using a program-specific imaging atlas. Inter-reader consistency was tracked with test cases blindly inserted into the reader queue. Readers attended quarterly calibration meetings. Protocol-specified radiographic exclusion criteria included rapidly progressive OA (RPOA) or risk factors for RPOA (including severe malalignment of the knee, subchondral insufficiency fracture, atrophic OA, and osteonecrosis). Patients reporting disproportionate pain to radiographic evidence of OA in the hip or knee (without other pathology) were ineligible under a nonradiographic exclusion criterion. Results: At >480 international sites, 23,079 patients entered screening and 13,797 were radiographically assessed. Across 6 sets of quarterly testing, pairwise central reader agreement on radiographic eligibility was 72-87% (kappa: 0.41-0.71) and on radiographic OA grading 77-84% (kappa: 0.68-0.75). Among the 5,773/13,797 (41.8%) patients who met exclusionary criteria, 27% had disproportionate pain to radiographic findings (~10% of knee/hip radiographs). RPOA or risk factors for RPOA were each identified in <5% of patients (usually 1 joint) and <3% of knee/hip/shoulders. Conclusions: The phase 3 tanezumab screening program demonstrated the utility of radiographs to screen patients entering NGF inhibitor trials. A high degree of reader concordance was achieved. RPOA and risk factors for RPOA were not commonly observed. NCT02697773, NCT02709486, NCT02528188.

Long-Term Safety and Efficacy of Subcutaneous Tanezumab Versus Nonsteroidal Antiinflammatory Drugs for Hip or Knee Osteoarthritis: A Randomized Trial.

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.

Onset and maintenance of efficacy of subcutaneous tanezumab in patients with moderate to severe osteoarthritis of the knee or hip: A 16-week dose-titration study.

OBJECTIVE: To examine the onset and maintenance of efficacy of subcutaneous tanezumab for pain relief and functional improvement in difficult-to-treat patients with moderate-to-severe osteoarthritis (OA) in a 16-week dose-titration study (NCT02697773). METHODS: Patients were randomized to placebo (placebo group) or tanezumab 2.5 mg at baseline and week 8 (tanezumab 2.5 mg group), or tanezumab 2.5 mg at baseline and tanezumab 5 mg at week 8 (tanezumab 2.5/5 mg group). Analyses included change from baseline in average daily index joint pain and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain and Physical Function, and treatment responses (WOMAC Pain improvement criteria and Outcome Measures in Rheumatology-Osteoarthritis Research Society International [OMERACT-OARSI] criteria). RESULTS: The 696 patients received placebo (n = 232), tanezumab 2.5 mg (n = 231), or tanezumab 2.5/5 mg (n = 233). Average daily index joint pain was statistically significantly improved within the first week (day 3-5) with tanezumab 2.5 mg compared with placebo. On first post-randomization WOMAC measurement (week 2), both tanezumab groups had statistically significant improvements compared with placebo in WOMAC Pain and Physical Function, and more tanezumab-treated patients achieved treatment response criteria (≥30%, ≥50%, or ≥70% reduction in WOMAC Pain or OMERACT-OARSI response). Efficacy was generally maintained throughout the 16-week treatment period. CONCLUSION: Subcutaneous tanezumab provided statistically significant improvements compared with placebo in average daily index joint pain within the first week and WOMAC Pain and Physical Function (week 2) that were generally maintained throughout the 16-week treatment period. Tanezumab 5 mg provided only modest additional efficacy over tanezumab 2.5 mg.

Safety and tolerability of ALO-02 (oxycodone hydrochloride and sequestered naltrexone hydrochloride) extended-release capsules in older patients: a pooled analysis of two clinical trials.

Objective: To assess the impact of age on the safety and tolerability of ALO-02, an abuse-deterrent opioid formulation consisting of oxycodone hydrochloride and sequestered naltrexone hydrochloride, in patients with chronic pain.Methods: Data from two clinical studies in patients with chronic low back pain or chronic non-cancer pain were analyzed. Patients aged ≥18 years who required continuous around-the-clock opioid analgesia for an extended period were grouped into ≥65 years and <65 years age groups. Treatment-emergent adverse events (TEAEs), use of concomitant medications, clinical laboratory measurements, and occurrences of opioid withdrawal using reported adverse events (AEs) and Clinical Opiate Withdrawal Scale (COWS) scores assessed safety. Data pooling was employed for the titration and maintenance phases of both studies.Results: Respectively 805 and 436 patients received ≥1 dose of ALO-02 in the titration and maintenance phases; 121 (15.0%) and 83 (14.6%) patients, respectively, were aged ≥65 years in the titration and maintenance phases. Average doses of ALO-02 were lower in the older patients in both phases. Incidences of TEAEs were comparable between age groups in both phases and generally lower in the maintenance phase. Concomitant medications were taken more often by patients aged ≥65 years. Incidences of potentially clinically significant laboratory results were low in both phases with no clinically important differences between age groups. There were few reports of opioid withdrawal events as assessed by reported AEs and COWS scores. One patient aged ≥65 years experienced an AE of opioid withdrawal.Conclusions: The safety and tolerability of ALO-02 is similar in those aged ≥65 years and those aged <65 years with chronic pain.ClinicalTrials.gov identifiers: NCT01571362, NCT01428583.

Effects of naltrexone exposure observed in two phase three studies with ALO-02, an extended-release oxycodone surrounding sequestered naltrexone.

OBJECTIVE: To evaluate the clinical effects of naltrexone following ALO-02 administration. DESIGN: Two phase three studies: an open-label, single-arm safety study, and a double-blind, placebo-controlled, randomized withdrawal, efficacy study (ClinicalTrials.gov identifiers: NCT01428583, NCT01571362). SETTING: Seventy US research centers. PATIENTS: Eight hundred and five patients with moderate-to-severe chronic noncancer pain (n = 395) or moderate-to-severe chronic low back pain (n = 410). INTERVENTIONS: Oral ALO-02 capsules (daily dose 20-160 mg oxycodone): openlabel titration followed by double-blind fixed dose ALO-02 or placebo (12 weeks) for the efficacy study; and open-label administration (≤12 months) for the safety study. MAIN OUTCOME MEASURES: Brief Pain Inventory-Short Form (BPI-sf), withdrawal-related adverse events, Clinical Opiate Withdrawal Scale (COWS), and naltrexone plasma concentrations. RESULTS: ALO-02 was received for = 30 days by 592 patients (73.5 percent), = 90 days by 348 patients (43.2 percent), and ≤361 days by 105 patients (13.0 percent). Maximum COWS scores were below the cutoff for mild withdrawal for the majority of patients: 86.6 percent of patients in the safety study, and for the efficacy study, 96.8 percent during titration and 95.0 percent during double-blind treatment. The frequency of quantifiable naltrexone plasma concentrations was similar between studies (18-23 percent of samples), and the levels were low, generally not exceeding 200 pg/mL. There was no apparent relationship between naltrexone plasma concentrations and COWS scores (total or change from baseline), or change from baseline in BPI-sf scores in the efficacy (R2 = 0.0184, 0.0224, and 0.0173, respectively) or safety studies (R2 = 0.0010, 0.0000, and 0.0122, respectively). CONCLUSIONS: Naltrexone plasma concentrations were low, not correlated with COWS or BPI-sf scores, and considered clinically insignificant.

Effect of Tanezumab on Joint Pain, Physical Function, and Patient Global Assessment of Osteoarthritis Among Patients With Osteoarthritis of the Hip or Knee: A Randomized Clinical Trial.

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. Trial Registration: ClinicalTrials.gov Identifier: NCT02697773.

Extended-release morphine sulfate and naltrexone hydrochloride (EMBEDA): naltrexone-associated withdrawal and abuse-related effects in patients with chronic pain and recreational opioid users.

OBJECTIVE: To review the effects of naltrexone on withdrawal-related adverse events (AEs) and euphoria-related effects, and the relationship between plasma naltrexone concentrations and withdrawal across EMBEDA (MSN; extended-release morphine sulfate with sequestered naltrexone) studies. METHODS: Five studies in pain patients and a safety review summarizing AE reports during the first year following approval of MSN were assessed for withdrawal reports. Three of these studies also assessed Clinical Opiate Withdrawal Scale (COWS) scores. Plasma naltrexone concentrations of MSN-treated individuals were summarized. Abuse potential was assessed in four studies in non-dependent recreational opioid users. RESULTS: Withdrawal AEs occurred in 13/1781 patients across five MSN studies, and 25/182 cases involving withdrawal were reported in the safety review. In three of these studies, 11/964 patients experienced moderate withdrawal (COWS score = 13-24) and 1/964 patients experienced moderately severe withdrawal (score = 28); all were either non-compliant with study drug, had undetectable plasma naltrexone concentrations, or were tapering to placebo. In ≥89% of plasma naltrexone concentration samples from patients who took MSN (n = 166), naltrexone was below the limit of quantification (4.0 pg/mL). In four studies with non-dependent recreational opioid users (n = 118), crushed MSN was associated with significantly lower scores of drug liking, high, and take drug again than crushed morphine sulfate (p ≤ 0.005). CONCLUSIONS: When taken intact as directed, naltrexone in MSN does not precipitate withdrawal. However, when MSN is crushed, naltrexone mitigates, but does not eliminate, the euphorigenic effects of crushed morphine sulfate.

Patient-reported health-related quality of life, work productivity, and activity impairment during treatment with ALO-02 (extended-release oxycodone and sequestered naltrexone) for moderate-to-severe chronic low back pain.

BACKGROUND: The efficacy of ALO-02, an abuse-deterrent formulation containing extended-release oxycodone and sequestered naltrexone, in the treatment of chronic low back pain (CLBP) was studied in a 12-week randomized controlled trial. Primary efficacy endpoint results have been published previously (Rauck et al., 2015). The current paper focuses on patient-reported outcomes for health-related quality of life (HRQL), work productivity, and activity impairment that were assessed during this study. METHODS: This was a double-blind, placebo-controlled, randomized withdrawal study in patients with moderate-to-severe CLBP. After a screening period (≤2 weeks), patients entered an open-label titration period (4-6 weeks). Treatment responders were then randomized to a double-blind placebo-controlled treatment period (12 weeks). HRQL was assessed using changes in the Short Form-36 v2 Health Survey (SF-36v2) and the EuroQol-5 Dimensions Health Questionnaire 3-Level version (EQ-5D-3L). Work productivity and regular activities were evaluated using the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP). RESULTS: A total of 410 patients received ALO-02 during the open-label titration period, of which 280 (intent-to-treat (ITT) population) were treated during the double-blind placebo-controlled treatment period (placebo, n = 134; ALO-02, n = 146). Significant improvement was observed for all SF-36v2 subscales and component scores (p < 0.005) and the EQ-5D-3L summary index and visual analog scale (p < 0.0001) during the titration period. Improvement was also significant (p < 0.0001) for all WPAI:SHP outcomes except 'work time missed due to CLBP' for the titration period. Significant differences favoring ALO-02 compared with placebo were only observed for the SF-36v2 Bodily Pain subscale (p ≤ 0.0232; ITT population) during the double-blind treatment period and the overall study period (screening to the end of the double-blind treatment period). The percentage change in activity impairment due to low back pain subscale of the WPAI:SHP significantly favored ALO-02 compared with placebo for the ITT population when considering the overall study period (p = 0.0040). CONCLUSIONS: HRQL, work productivity, and activity impairment may be improved with ALO-02 treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT01571362 , registered April 3, 2012.

Evaluating the abuse potential of opioids and abuse-deterrent -opioid formulations: A review of clinical study methodology.

With the development of opioid abuse-deterrent formulations (ADFs), there is a need to conduct well-designed human abuse potential studies to evaluate the effectiveness of their deterrent properties. Although these types of studies have been conducted for many years, largely to evaluate inherent abuse potential of a molecule and inform drug scheduling, methodological approaches have varied across studies. The focus of this review is to describe current "best practices" and methodological adaptations required to assess abuse-deterrent opioid formulations for regulatory submissions. A literature search was conducted in PubMed® to review methodological approaches (study conduct and analysis) used in opioid human abuse potential studies. Search terms included a combination of "opioid," "opiate," "abuse potential," "abuse liability," "liking," AND "pharmacodynamic," and only studies that evaluated single doses of opioids in healthy, nondependent individuals with or without prior opioid experience were included. Seventy-one human abuse potential studies meeting the prespecified criteria were identified, of which 21 studies evaluated a purported opioid ADF. Based on these studies, key methodological considerations were reviewed and summarized according to participant demographics, study prequalification, comparator and dose selection, route of administration and drug manipulation, study blinding, outcome measures and training, safety, and statistical analyses. The authors recommend careful consideration of key elements (eg, a standardized definition of a "nondependent recreational user"), as applicable, and offer key principles and "best practices" when conducting human abuse potential studies for opioid ADFs. Careful selection of appropriate study conditions is dependent on the type of ADF technology being evaluated.

Prescription opioid abuse and misuse: gap between primary-care investigator assessment and actual extent of these behaviors among patients with chronic pain.

OBJECTIVES: To compare the results of two open-label primary care-based studies that examined investigator assessment of patient risk for prescription opioid misuse, abuse, and diversion relative to patient self-reports and urine drug tests (UDTs). METHODS: Risk assessment data from two open-label, multicenter, primary care-based US studies in patients with chronic pain were compared. RESULTS: In one study (n = 1487), 54.4% of patients were at moderate, 24.8% at high, and 20.8% at low risk based on patients' self-reports at baseline on the Screener and Opioid Assessment for Patients with Pain®-Revised questionnaire. Investigators assigned 1.3% of patients as high risk despite 5.0% self-reporting prior illicit drug use and 15.3% with positive UDT(s) for an illicit drug at baseline. In the second study (n = 684), few patients were considered by investigators to be at high risk for misuse (1.6%), abuse (1.8%), or diversion (1.0%). However, 10.4% of patients reported prior illicit drug use; 23.4% had at least one abnormal baseline UDT; 60% of 537 patients reported on the Self-Reported Misuse, Abuse, and Diversion questionnaire they took more opioids than prescribed; and 10.9% reported chewing/crushing opioids in the past. Of patients completing the Current Opioid Misuse Measure, 40.6% were classified as having aberrant behaviors. CONCLUSION: A comparison of risk assessment across two studies indicates a tendency for investigators to assess patients as lower risk for opioid-related aberrant behaviors despite a significant proportion self-reporting aberrant behavior and/or presenting with illicit UDTs. These consistent findings underline the importance of appropriate implementation of objective measures and self-reporting tools when evaluating risk in patients. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifiers: NCT00640042 and NCT01179191.

Measurement of Drug Liking in Abuse Potential Studies: A Comparison of Unipolar and Bipolar Visual Analog Scales.

Abuse liability studies usually measure drug liking using 100-mm visual analog scales (VAS), presented as unipolar (liking measured on entire scale) or bipolar (liking and disliking measured with a neutral midpoint). These 2 types of VAS were compared using drug liking ratings from a randomized double-blind crossover study of immediate-release and controlled-release oxycodone in 2 cohorts of nondependent recreational opioid users. Cohort 1 (n = 19) received intact oxycodone 40 mg, intact OxyContin® 40 and 80 mg, crushed OxyContin® 40 mg, and placebo, while cohort 2 (n = 16) received intact oxycodone 20, 40, and 80 mg and placebo. In general, bipolar and unipolar ratings were positively correlated (r = 0.72) for all values (n = 2,477). Emax for both scales generally had higher correlation than individual responses for active drug or placebo. The correlation for individual scores after placebo treatment for the 2 scales was poor in both cohorts (r = -0.11, cohort 1 and r = 0.17, cohort 2). Both scales performed similarly within the context of the study, but bipolar scales can also assess disliking, which may be a consideration depending on anticipated drug effects. Appropriate participant training on the use of these scales is also necessary to reduce variability.

Safety profile of extended-release morphine sulfate with sequestered naltrexone hydrochloride in older patients: pooled analysis of three clinical trials.

OBJECTIVE: Clinical trial safety data following chronic administration of extended-release opioids within an older population is limited. Embeda * is an extended-release formulation of morphine sulfate surrounding sequestered naltrexone hydrochloride (MSN) and is designed to deter opioid misuse and abuse. The present analysis compared pooled safety outcomes among patients aged ≥65 years and those aged <65 years from three phase 2/3 studies (ranging from 2 weeks to 12 months) in patients treated with MSN. RESEARCH DESIGN AND METHODS: Subgroup analysis of patients aged ≥65 years and <65 years was performed on pooled data for adverse events (AEs), potentially clinically significant laboratory values (hematology/chemistry), and signs/symptoms of opioid withdrawal using the Clinical Opiate Withdrawal Scale (COWS) (phase 3 trials only) for patients who received at least one dose (short-term studies, maximum dose was 160 mg/d or 320 mg/d depending on study; long-term study, no maximum dose) of study medication during titration and maintenance phases. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT00420992, NCT00415597. RESULTS: During titration, 173 (17.1%) of 1012 patients treated with MSN were aged ≥65 years, while during maintenance 76/564 (13.5%) patients were aged ≥65 years. Treatment-emergent AEs were similar in frequency and type between the two cohorts, with the most common being constipation, nausea, and somnolence; no consistent patterns relating to age and only one possibly treatment-related serious AE in patients ≥65 years was noted. No clinically significant differences in laboratory values or COWS scores (average maximum score ≤2.5) were observed between age groups. CONCLUSIONS: Safety outcomes following daily administration of MSN (2 weeks-12 months) were similar between patients aged ≥65 years and <65 years. Key limitations include the variable study designs and length of treatment (2 weeks-12 months), small sample size, and the inclusion of only those patients who were otherwise in relatively good health with restrictions on concomitant medications.

A multicenter, primary care-based, open-label study to identify behaviors related to prescription opioid misuse, abuse, and diversion in opioid-experienced patients with chronic moderate-to-severe pain.

OBJECTIVE: To compare the investigator assessment of patient risk for prescription opioid misuse, abuse, and diversion with patient self-reports of these activities in a population with chronic pain. METHODS: As a secondary objective of an open-label, multicenter, primary care-based clinical study to evaluate the success of converting opioid-experienced patients with chronic pain to morphine sulfate with sequestered naltrexone hydrochloride, risk for misuse, abuse, and diversion was assessed using two nonvalidated questionnaires: one was completed by the investigator and another by the patient (Self-Reported Misuse, Abuse, and Diversion [SR-MAD]). In addition, the validated Current Opioid Misuse Measure (COMM) test and urine drug test were used. RESULTS: Of the 684 patients assessed by the investigators, 537 returned the self-assessment, SR-MAD. Most patients were assigned by the investigator as low risk for misuse (84.2%), abuse (89.3%), and diversion (94.3%). Of the patients who returned SR-MAD, 60% indicated having taken more opioids than prescribed and 10.9% reported chewing or crushing their opioids in the past. Of the patients who completed COMM, 40.6% were deemed as having aberrant behaviors. COMM results correlated with the risk levels from the investigator assessment. One-third of patients (33.8%) had at least one abnormal urine drug test result. CONCLUSION: More research is needed to better understand the gap between the investigator assessment of potential risk for misuse, abuse, and diversion and the actual extent of these behaviors among patients with chronic pain.