Postoperative Outcome of Patients Who Underwent Total Joint Replacement During the Tanezumab Phase 3 Osteoarthritis Development Program: A 24-Week Observational Study.

INTRODUCTION: This prospective cohort study (ClinicalTrials.gov identifier: NCT02674386) evaluated the postoperative outcomes of patients who had undergone total joint replacement (TJR) while participating in one of three tanezumab (a nerve growth factor inhibitor) randomized phase 3 osteoarthritis (OA) studies. MATERIALS AND METHODS: Eligible patients were those who underwent TJR (knee, hip, or shoulder) at any time during any of three tanezumab randomized phase 3 OA studies. Consenting patients were followed for 24 weeks post-surgery. Patients undergoing sub-total arthroplasty procedures were not eligible; there were no further protocol-defined exclusion criteria. Outcomes assessed in relation to joint adjudication outcome and prior tanezumab treatment included: 1) surgeon's assessment of procedural difficulty (uneventful, minor complications, major complications) at the time of the TJR; 2) postsurgical complications (clinically significant events attributable to the TJR, derived from adverse events) up to week 24; and 3) additional/corrective procedures (procedures or investigations related to the TJR) up to week 24. RESULTS: The 150 patients had received placebo (n=20), tanezumab 2.5mg (n=52), tanezumab 2.5mg titrated to 5mg (tanezumab 2.5/5mg, n=8), tanezumab 5mg (n=53), or a nonsteroidal anti-inflammatory drug (n=17) in the parent studies. The 150 patients were adjudicated to have primary osteonecrosis (n=1), rapidly progressive OA (RPOA) type 2 (n=8), RPOA type 1 (n=3), other joint outcome (n=6), normal progression of OA (NPOA) (n=130), or insufficient information to determine RPOA versus NPOA (n=2). Surgeon's assessment of procedural difficulty was uneventful for 95.1% (116/122) of patients. Through the 24-week study, there were no postsurgical complications for 96.0% (144/150) of patients; the 6 patients who had complications were all adjudicated as NPOA (tanezumab 2.5mg, n=2; tanezumab 5mg, n=4). There were no additional/corrective procedures for 93.3% (140/150) of patients. CONCLUSION: Procedural difficulty of minor complications during surgery, postsurgical complications, and additional/corrective procedures were infrequent, although more common with tanezumab 5mg, typically occurring in patients adjudicated as NPOA. Adjudication outcome (RPOA/primary osteonecrosis vs. NPOA) was not associated with postoperative outcome.

Development and validation of a Level A in-vitro in-vivo correlation for tofacitinib modified-release tablets using extrudable core system osmotic delivery technology.

PURPOSE: To determine if a validated Level A in-vitro in-vivo correlation (IVIVC) could be achieved with the extrudable core system (ECS) osmotic tablet platform. Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis. METHODS: Fast-, medium-, and slow-release modified-release formulations of 11 mg tofacitinib ECS tablets, and one formulation of 22 mg tofacitinib ECS tablet, were manufactured. In vitro dissolution of the tofacitinib ECS tablets was performed using USP Apparatus 2 (paddles) and in vivo pharmacokinetic (PK) data were obtained from a Phase 1 study in healthy volunteers. A 5 mg immediate-release formulation tablet was included to support deconvolution of the tofacitinib ECS PK tablet data to obtain the in vivo absorption profiles. A linear, piecewise correlation and a simple linear correlation were used to build and validate two IVIVC models. RESULTS: The prediction errors (PEs) for the linear, piecewise correlation met the Food and Drug Administration's criteria for establishing a Level A IVIVC, with a maximum absolute individual internal PE of 4.6%, a maximum absolute average internal PE of 3.9%, and a maximum absolute external PE of 8.4% obtained. CONCLUSIONS: This study demonstrates that the tofacitinib ECS osmotic tablet platform can achieve a Level A IVIVC, similar to other osmotic delivery systems.

Long-term safety and effectiveness of tanezumab as treatment for chronic low back pain.

A noncontrolled, randomized, multicenter study (NCT00924664) evaluated long-term safety and effectiveness of tanezumab in patients with chronic low back pain following a randomized placebo- and active-controlled parent study that evaluated analgesic efficacy. Patients were randomized to tanezumab 10mg (n=321) or 20mg (n=527) administered at 8-week intervals via 3 intravenous injections followed by 4 subcutaneous injections. Effectiveness analyses included change from parent study baseline in Brief Pain Inventory Short Form, Roland Morris Disability Questionnaire, and Patient's Global Assessment of low back pain. Safety assessments included adverse event documentation, physical/neurological examinations, and laboratory tests. Mean treatment duration during the extension study was 194 and 202 days with tanezumab 10 and 20mg, respectively. Both tanezumab doses provided similar and sustained improvements in all effectiveness outcomes. The most frequently reported adverse events were arthralgia, paresthesia, and hypoesthesia. Adverse events initially described as osteonecrosis were reported in 6 patients (tanezumab 10mg, n=2; tanezumab 20mg, n=4); 9 additional patients (tanezumab 10mg, n=7; tanezumab 20mg, n=2) underwent total joint replacement (TJR). A blinded, independent adjudication committee reviewed all 6 patients with reported osteonecrosis and 4 of the 9 patients undergoing TJR. Adjudication outcomes were osteonecrosis (n=0), worsening osteoarthritis (n=5; 1 rapidly progressive), and another diagnosis or indeterminate (n=5). Tanezumab 10mg had better tolerability than tanezumab 20mg, and may represent an effective long-term treatment for chronic low back pain.

Efficacy and safety of tanezumab versus naproxen in the treatment of chronic low back pain.

Tanezumab is a humanized monoclonal antibody that specifically inhibits nerve growth factor as a treatment for chronic pain. This phase IIB study investigated the efficacy and safety of tanezumab for chronic low back pain vs placebo and naproxen. Patients (N=1347) received intravenous tanezumab (5, 10, or 20mg every 8weeks), naproxen (500mg twice daily), or placebo. The primary efficacy end point was mean change in daily average low back pain intensity (LBPI) from baseline to week 16. Secondary end points included mean change from baseline to week 16 in the Roland Morris Disability Questionnaire and Patient's Global Assessment (PGA) of low back pain. Tanezumab 10 and 20mg had similar efficacy profiles and significantly improved LBPI, Roland Morris Disability Questionnaire, and PGA scores vs both placebo and naproxen (P⩽.05). Tanezumab 5mg provided improvement of PGA scores vs placebo (P⩽.05), and naproxen resulted in significant improvement of LBPI vs placebo (P⩽.05). Adverse event incidence was comparable across tanezumab doses but higher than with placebo or naproxen. Arthralgia, pain in extremity, headache, and paresthesia were the most commonly reported adverse events by tanezumab-treated patients. The most frequently reported adverse events resulting in discontinuation of tanezumab treatment were arthralgia and paresthesia; the highest frequency was observed with tanezumab 20mg (both 1.4%). Serious adverse event incidence was similar across treatments. In conclusion, tanezumab provided significantly greater improvement in pain, function, and global scores vs placebo and naproxen in patients with chronic low back pain.

Efficacy and safety of tanezumab in the treatment of chronic low back pain.

Increased nerve growth factor levels are associated with chronic pain conditions, including chronic low back pain (LBP). This study examined safety and analgesic efficacy of tanezumab, a humanized anti-nerve growth factor antibody, in adults with chronic LBP. Patients received intravenous tanezumab 200 µg/kg plus oral placebo (n=88), intravenous placebo plus oral naproxen 500 mg twice a day (n=88), or intravenous placebo plus oral placebo (n=41). Primary outcome was average LBP intensity (aLBPI) at Week 6. Secondary outcomes were proportion of patients with ≥30% or ≥50% reduction in aLBPI, Roland-Morris Disability Questionnaire and Brief Pain Inventory-short form scores, Patients' Global Assessment of LBP, Patients' Global Evaluation of study medication, and rescue medication use. Mean aLBPI change from baseline to Week 6 was greater with tanezumab vs naproxen (P=0.004) and placebo (P<0.001). Greater proportions of patients reported ≥30% and ≥50% reduction in aLBPI with tanezumab vs naproxen (P≤0.013) and placebo (P<0.001), and greater improvements in Roland-Morris Disability Questionnaire (P<0.001) and other secondary outcomes except rescue medication use. Tanezumab was associated with adverse events (AEs) of abnormal peripheral sensation that were generally mild and resolved before study completion; however, there were no serious AEs. Nine patients (4 of whom were tanezumab-treated) discontinued due to AEs. In conclusion, tanezumab resulted in analgesic efficacy that was clinically and statistically superior to placebo and naproxen in patients with chronic LBP. Tanezumab clinical development is on regulatory hold due to AEs in osteoarthritis patients.

Celecoxib in the treatment of primary dysmenorrhea: results from two randomized, double-blind, active- and placebo-controlled, crossover studies.

BACKGROUND: Celecoxib, a cyclooxygenase-2 inhibitor, has established analgesic efficacy for the treatment of acute pain resulting from a variety of causes. OBJECTIVE: This article describes 2 studies designed to assess the efficacy and tolerability of celecoxib in patients with primary dysmenorrhea. METHODS: Two identical, 3-day, multiple-dose, randomized, double-blind, active- and placebo-controlled, crossover studies were carried out in women aged 18 to 44 years with primary dysmenorrhea (studies 1 and 2). The studies employed a 6-sequence, 3-period, complete-block crossover design over 3 menstrual cycles. Patients received celecoxib 400 mg, followed by celecoxib 200 mg no sooner than 12 hours after first dose (day 1), then celecoxib 200 mg q12h as necessary (days 2 and 3); naproxen sodium 550 mg followed by naproxen sodium 550 mg no sooner than 12 hours after first dose (day 1), then naproxen sodium 550 mg q12h as necessary (days 2 and 3); or placebo. Primary efficacy measures were time-weighted sum of total pain relief and time-weighted sum of pain intensity difference at 8 hours after administration of the first dose of study medication (TOTPAR[8] and SPID[8], respectively). Tolerability was assessed using routine physical examination, including vital sign measurements, and clinical laboratory analyses at screening and end of study. RESULTS: In total, 149 and 154 patients were randomized to 1 of the 6 treatment sequences in studies 1 and 2, respectively. Across treatment sequences, mean age ranges were 23.4 to 26.9 years (study 1) and 28.3 to 34.1 years (study 2). Mean weight ranges were 62.7 to 74.5 kg (study 1) and 69.2 to 86.7 kg (study 2). Most patients (96.6% in study 1, 80.5% in study 2) were white. Mean TOTPAR[8] values with celecoxib (study 1/study 2, 18.28/17.98) and naproxen sodium (20.59/21.27) were significantly greater than with placebo (12.82/12.98) (all, P < 0.001). Mean SPID[8] values were significantly greater with celecoxib (10.06/9.60) and naproxen sodium (11.48/11.71) than with placebo (5.96/6.41) (all, P < 0.001). Naproxen sodium was significantly different from celecoxib in TOTPAR[8] (study 2 only) and SPID[8] (both studies) (all, P < 0.001). In both studies, the adverse-events (AEs) profile was not significantly different between treatments, with the majority of AEs being related to primary dysmenorrhea and not medication. Less than 10% of patients experienced severe AEs in any treatment period. CONCLUSIONS: In these 2 identically designed studies in women aged 18 to 44 years, celecoxib 400 mg (followed by 200 mg q12h) was more effective, as measured using pain scores, in the treatment of primary dysmenorrhea compared with placebo. In each study, the primary efficacy measures-TOTPAR[8] and SPID[8] scores-were significantly improved with celecoxib and naproxen sodium compared with placebo. SPID[8] in both studies and TOTPAR[8] in study 2 were significantly improved with naproxen sodium compared with celecoxib. Both celecoxib and naproxen sodium were well tolerated and provided relief from menstrual pain within 1 hour of administration.