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In this study, researchers looked at the safety of tanezumab (a medication that blocks nerve growth factor) in Japanese people with chronic low back pain (CLBP). Researchers also looked at how well tanezumab improves the symptoms (pain and difficulty doing activities) of CLBP. People in the study were given oral (taken by mouth) celecoxib (a medication commonly used to treat CLBP) or injections of tanezumab (5 or 10 mg doses) under the skin of the belly or upper leg every 8 weeks for a total of 56 weeks. Side effects (something expected or unexpected that people experienced during the study that may or may not be due to the medication they received) occurred in 63.0% of people receiving tanezumab 5 mg, 54.8% of people receiving tanezumab 10 mg and 67.4% of patients receiving celecoxib. More people receiving tanezumab 5 mg (9.8% of people) had a side effect related to abnormal peripheral sensation (tingling, burning, numbness or sensitivity to heat or cold hands or feet) than people receiving tanezumab 10 mg (4.3% of people) or celecoxib (4.3% of people). More people receiving tanezumab (5 mg = 1.1% of people, 10 mg = 2.2% of people) had a problem with one of their joints (knees or hips) during the study than people receiving celecoxib (0% of people). All treatments improved pain and the ability to do activities. Overall, the researchers concluded that tanezumab was well tolerated in most people and may improve the symptoms of CLBP.

Introduction: Combining measures of key core domains (especially pain and function) into a composite endpoint that requires each patient to meet a threshold of improvement for each domain provides information on multiple aspects of osteoarthritis within individual patients. This pooled analysis of two phase 3 studies (NCT02697773, NCT02709486) explored single and composite endpoints for assessing within-patient improvement in knee or hip osteoarthritis symptoms following subcutaneous administration of tanezumab or placebo. Methods: Endpoints at week 16 included proportions of responders (C 30% improvement) in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function, WOMAC Pain/Function composite, and weekly average pain; and patient acceptable symptom state (PASS) composite responders, minimal clinically important improvement (MCII) composite responders, IntroductionCombining measures of key core domains (especially pain and function) into a composite endpoint that requires each patient to meet a threshold of improvement for each domain provides information on multiple aspects of osteoarthritis within individual patients. This pooled analysis of two phase 3 studies (NCT02697773, NCT02709486) explored single and composite endpoints for assessing within-patient improvement in knee or hip osteoarthritis symptoms following subcutaneous administration of tanezumab or placebo.MethodsEndpoints at week 16 included proportions of responders (≥ 30% improvement) in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function, WOMAC Pain/Function composite, and weekly average pain; and patient acceptable symptom state (PASS) composite responders, minimal clinically important improvement (MCII) composite responders, Outcome Measures in Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) responders, and sustained weekly average pain responders.ResultsPooled population comprised 1545 patients. Of patients who had a ≥ 30% improvement in WOMAC Pain and/or WOMAC Physical Function, 88.5% were WOMAC Pain/Function composite responders, 7.0% were WOMAC Pain (but not Function) responders, and 4.4% were WOMAC Function (but not Pain) responders. Of weekly average pain responders, 43.1% were PASS composite responders. Odds ratios (tanezumab 2.5 mg and 5 mg groups, respectively, vs placebo) were 1.75 and 1.86 (WOMAC Pain/Function composite responders), 1.41 and 1.65 (weekly average pain responders), 1.60 and 1.73 (PASS composite responders), 1.52 and 1.68 (MCII composite responders), 1.75 and 1.88 (OMERACT-OARSI responders), and 1.85 and 1.48 (sustained weekly average pain responders). Subgroup analyses suggested a greater magnitude of effect for patients with a knee index joint compared with hip on some endpoints.ConclusionResponders on single pain endpoints were in many cases also responders on function or composite endpoints. Separation of tanezumab from placebo was similar and consistent across single and composite endpoints.

Supplemental Digital Content is Available in the Text. Placebo and tramadol-controlled study assessing long-term safety and efficacy of tanezumab in patients with chronic low back pain and inadequate response to standard analgesics., This randomized, double-blind, phase 3 study (56-week treatment; 24-week follow-up) assessed tanezumab in patients with chronic low back pain and history of inadequate response to standard-of-care analgesics (NCT02528253). Patients received placebo, subcutaneous tanezumab (5 or 10 mg every 8 weeks), or oral tramadol prolonged-release (100-300 mg/day). Primary endpoint was change in low back pain intensity (LBPI) at week 16 for tanezumab vs placebo. Key secondary endpoints were proportion of patients with ≥50% decrease in LBPI at week 16, change in Roland Morris Disability Questionnaire at week 16, and change in LBPI at week 2 for tanezumab vs placebo. Adverse events and joint safety were assessed through weeks 56 and 80, respectively. Tanezumab 10 mg met the primary endpoint by significantly improving LBPI at week 16 vs placebo; least squares (LS) mean (95% CI) difference = −0.40 (−0.76 to −0.04; P = 0.0281). Tanezumab 10 mg significantly improved all key secondary endpoints. Tanezumab 5 mg did not meet the primary endpoint (LS mean [95% CI] treatment difference vs placebo = −0.30 [−0.66 to 0.07; P = 0.1117]), preventing formal testing of key secondary endpoints for this dose. The proportion of patients with ≥50% improvement in LBPI at week 16 was 37.4% in the placebo group, 43.3% in the tanezumab 5 mg group (Odds ratio [95% CI] vs placebo = 1.28 [0.97 to 1.70; P = 0.0846]), and 46.3% in the tanezumab 10 mg group (Odds ratio [95% CI] vs placebo = 1.45 [1.09 to 1.91; P = 0.0101]). Prespecified joint safety events were more frequent with tanezumab 10 mg (2.6%) than tanezumab 5 mg (1.0%), tramadol (0.2%), or placebo (0%). Seven patients, all in the tanezumab 10 mg group (1.4%), underwent total joint replacement. In conclusion, tanezumab 10 mg significantly improved pain and function vs placebo in patients with difficult-to-treat chronic low back pain. Tanezumab was associated with a low rate of joint safety events, some requiring joint replacement.

Leslie Tive,1 Alfonso E Bello,2 David Radin,3 Thomas J Schnitzer,4 Ha Nguyen,1 Mark T Brown,5 Christine R West5 1Pfizer Inc, New York, NY, USA; 2Illinois Bone and Joint Institute, Glenview, IL, USA; 3Stamford Therapeutics Consortium, Stamford, CT, USA; 4Department of Physical Medicine and Rehabilitation, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 5Pfizer Inc, Groton, CT, USA Purpose: A pooled analysis was conducted to evaluate tanezumab efficacy and safety in patients with osteoarthritis (OA), including subgroup analyses of at-risk patients with diabetes, severe OA symptoms, and those aged ≥65 years.Patients and methods: Data from phase III placebo-controlled clinical trials of patients with moderate-to-severe OA of the knee or hip were pooled to evaluate tanezumab efficacy (four trials) and safety (nine trials). Patients received intravenous tanezumab, tanezumab plus an oral NSAID (naproxen, celecoxib, or diclofenac), active comparator (naproxen, celecoxib, diclofenac, or oxycodone), or placebo. Efficacy assessments included change from baseline to week 16 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and physical function scores, Patient’s Global Assessment (PGA) of OA, and percentage of patients with ≥30%, ≥50%, ≥70%, and ≥90% improvement in WOMAC pain. Safety assessments included adverse event (AE) documentation and physical and neurologic examinations.Results: Tanezumab significantly improved all efficacy end points in the overall population. Efficacy in at-risk patient subgroups was similar to the overall population. Incidence of AEs was highest in the tanezumab plus NSAID group and lowest in the placebo group. Incidence of AEs in the tanezumab monotherapy and active comparator groups was similar. Overall incidence of AEs was similar across subgroups. AEs of abnormal peripheral sensation were more frequently reported in tanezumab-treated patients compared with placebo or active comparator. Patients receiving active comparator had a slightly higher incidence of AEs suggestive of postganglionic sympathetic dysfunction.Conclusion: Tanezumab consistently provided significant improvement of pain, physical function, and PGA in individuals with OA, including patients with diabetes, severe OA symptoms, or aged ≥65 years. No increased safety risk was observed in at-risk patient subgroups.Trial registration: NCT00733902, NCT00744471, NCT00830063, NCT00863304, NCT00809354, NCT00864097, NCT00863772, NCT01089725, NCT00985621. Keywords: tanezumab, efficacy, safety, osteoarthritis, nerve growth factor

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.

[Abstract] Background: To evaluate if early improvements in pain and function with subcuta-neous tanezumab are meaningful and sustained over 24 weeks. Methods: Patients with moderate- to- severe osteoarthritis (hip or knee) in Europe and Japan were randomized to placebo, tanezumab 2.5 mg or tanezumab 5 mg (baseline, Week 8 and Week 16). Outcomes included: average daily index joint pain score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) subscales, rescue medication use, WOMAC responders (within- patient ≥30% reduction in WOMAC Pain or Physical Function), Outcome Measures in Rheumatology- Osteoarthritis Research Society International (OMERACT- OARSI) responders (within- patient) and Patient- reported Treatment Impact Assessment- Modified questionnaire. Results: Patients received placebo (n = 282), tanezumab 2.5 mg (n = 283) or tanezumab 5 mg (n = 284). Changes from baseline in average daily index joint pain (within the first week) and WOMAC subscales (Week 2 through Week 24) were greater for each tanezumab group versus placebo (least squares [LS] mean, unadjusted p ≤ .05). Rescue medication use (days/week) was lower for each tan-ezumab group versus placebo from Week 2 through Week 12 (LS mean, unad-justed p ≤ .05) but not at Week 16 or 24. A higher proportion of each tanezumab group than placebo achieved ≥30% reduction from baseline in WOMAC Pain or Physical Function, or OMERACT- OARSI response (Week 2 through Week 24, unadjusted p ≤ .05), or were satisfied with treatment at Week 24 (unadjusted p ≤ .05). Conclusions: Subcutaneous tanezumab, compared with placebo, reduced pain within the first week, and pain and function were improved throughout 24 weeks. The propor-tions of responders and patients satisfied were higher with tanezumab than placebo. ClinicalTrials.gov:NCT02709486. Significance: This exploratory analysis of data from a placebo- controlled, Phase 3 study of patients with moderate- to- severe osteoarthritis of the hip or knee for whom standard analgesics were not effective or could not be taken, found that onset of efficacy of subcutaneous tanezumab was within the first week, and efficacy was maintained through the 24- week treatment period. Tanezumab was effective in those patients with the most radiologically severe osteoarthritis.

Background The HIV epidemic in Ethiopia is concentrated in urban areas. Ethiopia conducted a Population-based HIV Impact Assessment (EPHIA) in urban areas between October 2017 and April 2018 to measure the status of the country’s response to the epidemic. Methods We conducted field data collection and HIV testing in randomly selected households using the national, rapid testing algorithm with laboratory confirmation of seropositive samples using a supplemental assay. In addition to self-report on HIV diagnosis and treatment, all HIV-positive participants were screened for a set of HIV antiretroviral (ARV) drugs indicative of the first- and second-line regimens. We calculated weighted frequencies and 95% confidence intervals to assess regional variation in participants’ level of unawareness of their HIV-positive status (adjusted for ARV status). Results We interviewed 20,170 survey participants 15–64 years of age, of which 19,136 (95%) were tested for HIV, 614 (3.2%) tested positive, and 119 (21%) of HIV-positive persons were unaware of their HIV status. Progress towards the UNAIDS first 90 target (90% of people living with HIV would be aware of their HIV status by 2020) substantially differed by administrative region of the country. In the bivariate analysis using log binomial regression, three regions (Oromia, Addis Ababa, and Harari), male gender, and young age (15–24 years) were significantly associated with awareness of HIV positive status. In multivariate analysis, the same variables were associated with awareness of HIV-positive status. Conclusion One-fifth of the HIV-positive urban population were unaware of their HIV-positive status. The number of unaware HIV-positive individuals has a different distribution than the HIV prevalence. National and regional planning and monitoring activities could address this potentially substantial source of undetected HIV infection by increasing HIV testing among young people, men and individuals who do not use condoms.

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.

ObjectiveTanezumab, a nerve growth factor inhibitor, was investigated for osteoarthritis (OA) of the hip or knee in a study with 24-week treatment and 24-week safety follow-up.MethodsThis double-blind, randomised, phase III study enrolled adults in Europe and Japan with moderate-to-severe OA who had not responded to or could not tolerate standard-of-care analgesics. Patients were randomised to tanezumab 2.5 mg or 5 mg subcutaneously or matching placebo every 8 weeks (three doses). Co-primary end points were change from baseline to week 24 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain and Physical Function, and Patient’s Global Assessment of OA (PGA-OA). Joint safety and neurological assessments continued throughout the 48-week study.ResultsFrom March 2016 to December 2017, 849 patients were randomised and evaluated (placebo n=282, tanezumab 2.5 mg n=283, tanezumab 5 mg n=284). At week 24, there was a statistically significant improvement from baseline for tanezumab 5 mg compared with placebo for WOMAC Pain (least squares mean difference±SE –0.62±0.18, p=0.0006), WOMAC Physical Function (–0.71±0.17, pConclusionTanezumab 5 mg statistically significantly improved pain, physical function and PGA-OA, but tanezumab 2.5 mg only achieved two co-primary end points. RPOA occurred more frequently with tanezumab 5 mg than tanezumab 2.5 mg. TJRs were similarly distributed across all three groups.Trial registration numberNCT02709486.

Therapeutic agents commonly used in the management of chronic pain have limited effectiveness and may be associated with issues of dependence and tolerability. Thus, a large unmet medical need exists for the development of safe and effective therapeutics for treatment of chronic pain. A novel approach includes identification of intracellular signals involved in the pain transduction pathway, such as nerve growth factor (NGF). Monoclonal antibodies targeting NGF, such as tanezumab, fulranumab and fasinumab, have been investigated for the treatment of chronic pain conditions. Due to unexpected joint adverse events in clinical studies and concerns about sympathetic nervous system toxicity in animals, these agents were placed on 2 separate partial clinical holds, which were subsequently lifted after rigorous evaluations were conducted to understand how inhibition of NGF impacts safety. To share learnings regarding the rigorous evaluation of clinical and nonclinical safety data which contributed to the removal of these partial clinical holds, this article reviews the rationale for developing agents that target NGF as potential treatments for chronic pain, describes nonclinical and clinical studies of these agents, and describes strategies used to evaluate whether inhibition of NGF has negative effects on joint or sympathetic nervous system safety.

Establish a biomarker panel associated with all-cause total joint replacement (TJR) through identification of patients with osteoarthritis (OA) who do or do not progress to TJR and investigate effects of nonsteroidal anti-inflammatory drugs (NSAIDs).Serum samples from patients enrolled in phase III trials of tanezumab who experienced TJR (n = 174) or matched patients who did not (n = 321) were analyzed for bone, cartilage, soft tissue, and inflammation markers. Classification and Regression Tree (CART) analysis was used to identify biomarker phenotypes associated with TJR.At baseline, biomarker combinations for patients who did not use NSAIDs before starting tanezumab and used NSAIDs during tanezumab treatment90 days ("nonNSAID"), identified 77% (95% confidence interval [CI]: 71-84%) of patients who experienced TJR and 77% (95% CI: 65-86%) who did not over a 6-month study period (on average). These biomarker combinations increased odds of identifying patients to remain free of a TJR by 3.3-fold. In patients who used NSAIDs continuously (during screening and ≥90 days during tanezumab treatment), 64% (95% CI: 54-73%) who had TJR and 75% (95% CI: 68-83%) who did not were identified by biomarker combinations different from nonNSAID patients, with an increase in odds of identifying patients to remain free of a TJR by two-fold.Although validation on other cohorts is necessary, biomarkers may assist in identifying patients who will need TJR. The profiles suggest NSAID use increases importance of bone metabolism in TJR pathology.

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.

There is a general decline in gastrointestinal function in old age including decreased intestinal motility, sensory signaling, and afferent sensitivity. There is also increased prevalence of significant constipation in aged populations. We hypothesized this may be linked to reduced colonic motility and alterations in vagal-gut-brain sensory signaling. Using in vitro preparations from young (3 months) and old (18–24 months) male CD1 mice we report functional age-related differences in colonic motility and jejunal mesenteric afferent firing. Furthermore, we tested the effect of the aminosterol squalamine on colonic motility and jejunal vagal firing rate. Old mice had significantly reduced velocity of colonic migrating motor complexes (MMC) by 27% compared to young mice (p = 0.0161). Intraluminal squalamine increased colonic MMC velocity by 31% in old mice (p = 0.0150), which also had significantly reduced mesenteric afferent single-unit firing rates from the jejunum by 51% (p < 0.0001). The jejunal vagal afferent firing rate was reduced in aged mice by 62% (p = 0.0004). While the time to peak response to squalamine was longer in old mice compared to young mice (18.82 ± 1.37 min vs. 12.95 ± 0.99 min; p = 0.0182), it significantly increased vagal afferent firing rate by 36 and 56% in young and old mice, respectively (p = 0.0006, p = 0.0013). Our results show for the first time that the jejunal vagal afferent firing rate is reduced in aged-mice. They also suggest that there is translational potential for the therapeutic use of squalamine in the treatment of age-related constipation and dysmotility.

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

Background Tanezumab, a monoclonal antibody against nerve growth factor, is in development for treatment of osteoarthritis (OA) pain. Objectives To assess efficacy and safety of tanezumab in patients with moderate to severe OA pain who have not responded to or cannot tolerate standard of care analgesics. Methods A randomized, double-blind, placebo-controlled study (24 week treatment; 24 week follow-up) was conducted in patients in Europe and Japan with moderate to severe OA pain of the knee or hip and history of insufficient pain relief or intolerance to acetaminophen, oral nonsteroidal anti-inflammatory drug, and either tramadol or opioids (or unwilling to take opioids). Patients received subcutaneous tanezumab (2.5 or 5 mg) or placebo at baseline, week 8, and week 16. Co-primary endpoints were change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function, and Patient Global Assessment of OA (PGA-OA) scores at week 24. Safety, including independent adjudication of joint safety events, was assessed. Results Tanezumab 5 mg met all co-primary endpoints (Fig. 1). Tanezumab 2.5 mg met WOMAC Pain and Physical Function endpoints but not the PGA-OA endpoint; thus, this dose did not meet pre-specified efficacy criteria. The occurrence of adverse events (AEs) and discontinuations due to AEs were similar across groups, though serious AEs occurred more frequently in both tanezumab groups relative to placebo. Two deaths in the 5 mg tanezumab group were deemed unrelated to treatment. The only AE occurring in =3% of patients in any group, and more frequently (>1% difference) in both tanezumab groups relative to placebo, was OA. Total joint replacements (TJR) occurred in 6.7%, 7.8%, and 7.0% of patients in the placebo, tanezumab 2.5 mg, and tanezumab 5 mg groups, respectively. Joint safety events, including TJRs, were mostly adjudicated as normal progression of OA (58/79; 73.4%). Pre-specified joint safety events occurred in 0% and 2.5% (n = 14) of patients in the placebo and tanezumab (2.5 mg = 1.8%; 5 mg = 3.2%) groups, respectively. These 14 events in the tanezumab groups included rapidly progressive OA (2.5 mg n = 4; 5 mg n = 8), subchondral insufficiency fracture (2.5 mg n = 1), and primary osteonecrosis (5 mg n = 1). Conclusion Tanezumab 5 mg significantly improved all co-primary endpoints of pain, physical function, and PGA-OA. Tanezumab 2.5 mg significantly improved pain and physical function, but did not reach significance on PGA-OA. AEs are consistent with previous studies of tanezumab in OA. A similar number of TJRs were reported across groups, though overall joint safety events were more frequent with tanezumab than placebo. Disclosure of Interests Francis Berenbaum Grant/research support from: TRB Chemedica (through institution), MSD (through institution), Pfizer (throughinstitution), Consultant for: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Bone Therapeutics, Regulaxis, Peptinov, Paid instructor for: Sandoz, Speakers bureau: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Sandoz, Francisco J. Blanco Grant/research support from: Galapagos NV, Abbvie, Sanofi, Bristol MS, UCB, Novartis, Genentech Inc., Regeneron, Lilly, Celgene, Amgen, Janssen, kiniksa Pharmaceuticals, Ltd., Tedec Meiji., Consultant for: Pfizer, Gebro, Bioiberica, Sanofi., Ali Guermazi Consultant for: AstraZeneca, Pfizer, TissueGene, Galapagos, Roche and MerckSerono., Eric Vignon Consultant for: Pfizer/Eli Lilly, Kenji Miki Speakers bureau: Pfizer, Janssen, Ayumi, Hisamitsu, Takaharu Yamabe Shareholder of: Pfizer, Employee of: Pfizer, Lars Viktrup Shareholder of: Eli Lilly & Company, Grant/research support from: Astella, Lundbeck, Coloplast, Employee of: Ciba Geigy, Eli Lilly and Company (currently), Rod Junor Shareholder of: Pfizer, Employee of: Pfizer, William Carey Shareholder of: Pfizer, Employee of: J&J, Pfizer (currently), Mark Brown Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ken Verburg Shareholder of: Pfizer, Employee of: Pfizer, Christine West Shareholder of: Pfizer, Employee of: Pfizer

This article summarizes the results of a meeting convened by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) on key considerations and best practices governing the design of acute pain clinical trials. We discuss the role of early phase clinical trials, including pharmacokinetic-pharmacodynamic (PK-PD) trials, and the value of including both placebo and active standards of comparison in acute pain trials. This article focuses on single-dose and short-duration trials with emphasis on the perioperative and study design factors that influence assay sensitivity. Recommendations are presented on assessment measures, study designs, and operational factors. Although most of the methodological advances have come from studies of postoperative pain after dental impaction, bunionectomy, and other surgeries, the design considerations discussed are applicable to many other acute pain studies conducted in different settings.

Objective Tanezumab, a monoclonal antibody against nerve growth factor, has demonstrated efficacy in clinical trials of chronic pain in osteoarthritis (OA) and chronic low back pain. Unexpected adverse events (AEs) described as osteonecrosis (ON) occurred during tanezumab development, leading the US Food and Drug Administration to impose a partial clinical hold for all indications except cancer pain. A blinded Adjudication Committee (AC) including orthopedic surgeons, rheumatologists, and an orthopedic pathologist reviewed and adjudicated joint-related AEs in the tanezumab clinical program. Methods The AC adjudicated all reported cases of ON as well as cases of total joint replacements (TJRs) not reported as ON for which radiographs obtained within 9 months of the surgery were available. The AC prespecified categories for joint safety events including primary ON, worsening OA (rapid progression of OA [RPOA], normal progression of OA, insufficient information to distinguish between rapid and normal progression of OA), other, or insufficient information to distinguish between primary ON and worsening OA or another diagnosis. Results The AC reviewed events in 249 of 386 patients with an investigator-reported AE of ON and/or a TJR. Two events were adjudicated as primary ON, 200 events were adjudicated as worsening OA (68 of which were classified as RPOA), 29 events had another diagnosis, 11 had insufficient information to distinguish primary ON from worsening OA, and 7 did not have committee member consensus. Conclusion Despite initial reports, tanezumab treatment was not associated with an increase in ON but was associated with an increase in RPOA. Higher doses of tanezumab, tanezumab administered with nonsteroidal antiinflammatory drugs, and preexisting subchondral insufficiency fractures were risk factors for RPOA in this cohort.

Background:Tanezumab, a monoclonal antibody against nerve growth factor, was recently evaluated in an 80 week placebo and tramadol-controlled trial in patients with chronic low back pain (CLBP) and a history of inadequate response to standard-of-care analgesics (NSAIDs, opioids, etc). Primary endpoint was change in Low Back Pain Intensity (LBPI) at week 16 vs placebo. Key secondary endpoints were the proportion of patients with ≥50% improvement in LBPI at week 16, change in Roland Morris Disability Questionnaire score at week 16, and change in LBPI at week 2 (all vs placebo). Tanezumab 10mg met the primary and all key secondary endpoints. Tanezumab 5mg did not meet the primary endpoint, but improved 2 of 3 key secondary endpoints. Due to the primary endpoint result and the statistical gate-keeping approach to control for multiple comparisons, a conclusion of superiority over placebo could not be made for the 5mg dose.Objectives:To further characterize tanezumab’s effects on pain and function in this trial through analysis of Brief Pain Inventory-short form (BPI-sf) scores.Methods:Patients received placebo (n=406), subcutaneous (SC) tanezumab 5mg (every 8 weeks; n=407), SC tanezumab 10mg (every 8 weeks; n=407) or oral tramadol prolonged-release (100-300mg/day; n=605). Pre-specified secondary endpoints included BPI-sf worst pain, average pain, the overall pain interference index, and selected individual domains of the index (general activity, walking ability, sleep, and normal work). Least squares (LS) mean (standard error [SE]) changes from baseline in BPI-sf scores were compared between groups (unadjusted for multiplicity) at week 16 using an analysis of covariance model. Scores range from 0-10 with higher scores indicating greater pain severity or functional impairment.Results:LS mean (SE) differences from placebo for worst pain were -0.52 (0.19) for tanezumab 5mg (p≤0.01), -0.54 (0.19) for tanezumab 10mg (≤0.01), and -0.24 (0.17) for tramadol (p=0.17). LS mean (SE) differences from placebo for average pain were -0.37 (0.18) for tanezumab 5mg (p=0.04), -0.46 (0.18) for tanezumab 10mg (≤0.01), and -0.17 (0.16) for tramadol (p=0.29). LS mean (SE) differences from placebo for the pain interference index were -0.41 (0.18) for tanezumab 5mg (p=0.03), -0.58 (0.18) for tanezumab 10mg (≤0.01), and -0.15 (0.17) for tramadol (p=0.39). Effects of tanezumab were not statistically different (p>0.05) from tramadol for worst pain, average pain, and the pain interference index, with exception of the pain interference index for tanezumab 10mg (p=0.01). Mean dose of tramadol was 203mg/day at week 16.Tanezumab 10mg significantly (pConclusion:Tanezumab 5mg and 10mg significantly improved worst pain, average pain, and overall pain interference index scores vs placebo in patients with CLBP. Tanezumab 10mg also significantly improved the overall pain interference index vs tramadol. Tanezumab 5mg significantly improved most individual domains of the pain interference index vs placebo, while tanezumab 10mg significantly improved all domains assessed vs placebo and vs tramadol.Disclosure of Interests:John Markman Consultant of: Consultant: Trigemina, Editas Medicine, and Plasma Surgical; Advisory board: Clexio Biosciences, Flexion Therapeutics, Quark Pharmaceuticals, Quartet Medicine, Collegium Pharmaceutical, Purdue Pharma, Biogen, Novartis, Aptinyx, Nektar, Allergan, Grünenthal, Eli Lilly and Company, Depomed, Janssen Pharmaceuticals, Teva Pharmaceutical Industries, KemPharm, Abbott Laboratories, Plasma Surgical, Chromocell, Convergence Pharmaceuticals, Inspirion, Pfizer, Sanofi, Daiichi Sankyo, and Trevena; Data safety monitoring boards for Novartis and Allergan, Serge Perrot Consultant of: Grunenthal, Pfizer, Lilly, MSD, Sanofi, Menarini, Seiji Ohtori: None declared, Thomas Schnitzer Consultant of: Pfizer, Lilly, AstraZeneca, GSK, Said Beydoun Grant/research support from: Argenx, Catalyst Pharma, Mallinckrodt, Pfizer, UCB, Consultant of: Alexion, Akcea, Alnylam, CSL, Takeda, Mitsubishi Tanabe, Speakers bureau: Alexion, Akcea, Alnylam, CSL, Takeda, Mitsubishi Tanabe, Lars Viktrup Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Ruoyong Yang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Candace Bramson Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Christine West Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ken Verburg Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Background:Tanezumab, a monoclonal antibody against nerve growth factor (NGF), is in development for the treatment of osteoarthritis (OA).Objectives:To assess the effects of gender, age and body mass index (BMI) on the incidence of adverse events (AEs) in patients (pts) treated with subcutaneous (SC) tanezumab in pooled data from three phase 3 OA studies. Anti-NGF therapy has been associated with joint safety events1. Here we focus on treatment emergent AEs, including abnormalities of peripheral sensation (APS).Methods:All three randomised, double-blind, placebo-controlled studies enrolled pts with radiographically-confirmed OA of the hip or knee, who had inadequate response or could not tolerate standard of care analgesics. In the 16-week (wk) Study 1 (NCT01089725), pts received placebo, tanezumab 2.5 mg, 5 mg or 10 mg at baseline and wk 82. Due to a clinical hold on NGF antibodies, nddose at wk 8. Pts in the 16-wk Study 2 (NCT02697773), received placebo or tanezumab 2.5 mg at baseline and wk 8 or tanezumab 2.5mg at baseline and 5mg at wk 81. Pts in the 24-wk Study 3 (NCT02709486), received placebo, tanezumab 2.5 mg or 5 mg at baseline, wks 8 and 16. All treatments were given SC. AE data from the treatment period of each study were pooled for placebo, tanezumab 2.5 mg and 5 mg groups and examined by subgroups of gender, age and BMI. Data from the 10 mg group of Study 1 were not included due to the low sample size.Results:The incidence of any AE was numerically higher in females across treatment groups and in pts with a BMI ≥30 kg/m2in the tanezumab 5mg, but not 2.5 mg group, vs the overall population (Table 1). SAEs were infrequent but numerically higher across all tanezumab 5 mg subgroups vs placebo (Table 2). Paraesthesia and hypoaesthesia were the most common AEs of APS and were increased in all tanezumab groups in the overall population vs placebo. In any of the subgroups, the incidence of paraesthesia or hypoaesthesia was ≤7.8% and ≤3.9%, respectively. The difference within a patient subgroup for paraesthesia or hypoaesthesia was typically comparable with that of the overall population across treatments.Table 1.Incidence of AEs during the treatment period% of pts with an AE in each subgroupPlacebon=586Tanezumab2.5 mgn=602Tanezumab2.5 mg/5 mg n=219Tanezumab5 mgn=347Overall population51.752.347.054.8Gender Male51.149.741.346.6 Female52.053.650.459.0Age (years) 55.054.044.054.5 ≥6547.250.052.654.9BMI (kg/m2) 58.146.651.945.5 25–51.455.943.750.0 30–49.251.543.258.9 ≥3552.752.355.360.9BMI, body mass index; kg/m2, kilogram per square metreTable 2.Incidence of SAEs during the treatment period% of pts with a SAE in each subgroupPlacebon=586Tanezumab2.5 mgn=602Tanezumab2.5 mg/5 mg n=219Tanezumab5 mgn=347Overall population1.52.21.42.6Gender Male1.63.01.32.5 Female1.51.71.42.6Age (years) 1.22.61.41.9 ≥652.01.61.33.1BMI (kg/m2) 1.61.102.3 25–1.62.702.7 30–1.62.01.43.1 ≥351.32.34.31.6BMI, body mass index; kg/m2, kilogram per square metreConclusion:This pooled analysis showed that the safety profile of tanezumab in the subgroups studied is broadly similar to that of the overall study population.References:[1]Schnitzer, T. J.et al. JAMA(2019)[2]Birbara, C.et al. J Pain Res(2018)Disclosure of Interests:Francis Berenbaum Grant/research support from: TRB Chemedica (through institution), MSD (through institution), Pfizer (through institution), Consultant of: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Bone Therapeutics, Regulaxis, Peptinov, 4P Pharma, Paid instructor for: Sandoz, Speakers bureau: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Sandoz, Alan Kivitz Shareholder of: AbbVie, Amgen, Gilead, GSK, Pfizer Inc, Sanofi, Consultant of: AbbVie, Boehringer Ingelheim,,Flexion, Genzyme, Gilead, Janssen, Novartis, Pfizer Inc, Regeneron, Sanofi, SUN Pharma Advanced Research, UCB, Paid instructor for: Celgene, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron, Sanofi, Speakers bureau: AbbVie, Celgene, Flexion, Genzyme, Horizon, Merck, Novartis, Pfizer Inc, Regeneron, Sanofi, Thomas Schnitzer Consultant of: Pfizer, Lilly, AstraZeneca, GSK, Mark Brown Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Sean Donevan Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., Anne Hickman Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Lars Viktrup Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Christine West Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Takaharu Yamabe Shareholder of: Pfizer, Employee of: Pfizer

Background:Tanezumab, a monoclonal antibody against nerve growth factor, is in development for the treatment of signs and symptoms of osteoarthritis (OA).Objectives:To assess the safety and tolerability of subcutaneous (SC) tanezumab in patients with OA.Methods:Data were derived from 3 randomized placebo-controlled OA trials. SC treatment (every 8 weeks for 16–24 weeks with 8–24 week follow-up) included placebo, tanezumab 2.5 mg, tanezumab 2.5/5 mg (2.5 mg at day 1 and 5 mg at week 8), and tanezumab 5 mg. Overall treatment-emergent adverse events (TEAEs) and TEAEs of abnormal peripheral sensation were pooled from all 3 trials (placebo N = 586; tanezumab: 2.5 mg N = 602, 2.5/5 mg N = 219, 5 mg N = 347). Pre-specified TEAEs potentially associated with sympathetic neuropathy (anhidrosis, bradycardia, hypohidrosis, orthostatic hypotension, or syncope) and pre-specified joint events (primary osteonecrosis, rapidly progressive OA [RPOA] type 1 or type 2, subchondral insufficiency fracture, or pathological fracture; adjudicated by an independent committee of experts) were pooled from the 2 trials that included prospective evaluation of sympathetic and joint safety (placebo N = 514; tanezumab: 2.5 mg N = 528, 2.5/5 mg N = 219, 5 mg N = 284). TEAEs are presented for the treatment period; joint safety is presented for the full study (treatment plus follow up) period.Results:Patient demographics (80.7% white, 66.8% female, mean age ≈ 63 years) and clinical characteristics were similar across groups. TEAE rates were: placebo = 51.7%, tanezumab 2.5 mg = 52.3%, tanezumab 2.5/5 mg = 47.0%, and tanezumab 5 mg = 54.8%. Of TEAEs occurring in ≥2% of patients in any group, only oedema peripheral, joint stiffness, and paraesthesia had a higher incidence (95% confidence interval excluded 0) in any tanezumab group relative to placebo. Serious TEAE rates were: placebo = 1.5%, tanezumab 2.5 mg = 2.2%, tanezumab 2.5/5 mg = 1.4%, and tanezumab 5 mg = 2.6%. Rates of treatment and/or study discontinuation due to TEAEs were: placebo = 2.2%, tanezumab 2.5 mg = 1.8%, tanezumab 2.5/5 mg = 0.5%, and tanezumab 5 mg = 1.4%. Only arthralgia and OA led to discontinuation in >1 patient in any group. TEAEs of abnormal peripheral sensation rates were: placebo = 2.2%, tanezumab 2.5 mg = 5.1%, tanezumab 2.5/5 mg = 3.2%, and tanezumab 5 mg = 6.1%. Paraesthesia and hypoaesthesia were the most common events. Potential sympathetic neuropathy TEAE rates were: placebo = 0.8%, tanezumab 2.5 mg = 1.5%, tanezumab 2.5/5 mg = 0.5%, and tanezumab 5 mg = 2.8%; exposure-adjusted rates were not statistically different between any tanezumab group and placebo. Bradycardia and orthostatic hypotension were the most common events. No patient was considered to have a sympathetic neuropathy. TEAEs of abnormal peripheral sensation and potential sympathetic neuropathy were mostly mild and resolved. Joint safety event rates were statistically different for tanezumab 5mg (3.2%), but not 2.5mg (1.9%) or 2.5/5mg (0.5%), compared to placebo (0%). RPOA type-1 was the most common event. Total joint replacement rates were: placebo = 4.5%, tanezumab 2.5 mg = 5.9%, tanezumab 2.5/5 mg = 6.8%, and tanezumab 5 mg = 7.0%; rates were not statistically different between any tanezumab group and placebo.Conclusion:Tanezumab was generally safe and well tolerated in most patients, with rates of overall TEAEs and treatment/study discontinuations similar to placebo and no evidence of a sympathetic safety signal. TEAEs of abnormal peripheral sensation and joint safety events were infrequent but more common with tanezumab than placebo.Disclosure of Interests:Francis Berenbaum Grant/research support from: TRB Chemedica (through institution), MSD (through institution), Pfizer (through institution), Consultant of: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Bone Therapeutics, Regulaxis, Peptinov, 4P Pharma, Paid instructor for: Sandoz, Speakers bureau: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Sandoz, Thomas Schnitzer Consultant of: Pfizer, Lilly, AstraZeneca, GSK, Alan Kivitz Shareholder of: AbbVie, Amgen, Gilead, GSK, Pfizer Inc, Sanofi, Consultant of: AbbVie, Boehringer Ingelheim,,Flexion, Genzyme, Gilead, Janssen, Novartis, Pfizer Inc, Regeneron, Sanofi, SUN Pharma Advanced Research, UCB, Paid instructor for: Celgene, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron, Sanofi, Speakers bureau: AbbVie, Celgene, Flexion, Genzyme, Horizon, Merck, Novartis, Pfizer Inc, Regeneron, Sanofi, Lars Viktrup Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Anne Hickman Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Glenn Pixton Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Mark Brown Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Isabelle Davignon Shareholder of: Pfizer, Employee of: Pfizer, Christine West Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

We thank Riddle and Perera1 for their interest in our publication.2 In our article, we adhered to recognised statistical methods and appropriate association with meaningfulness. We agree with the American Statistical Association guidance that a statistically significant effect does not inform its size or importance,3 and therefore, a change needs to be associated with clinical impact. In this study (ClinicalTrials.gov: NCT02709486), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain subscale and Physical Function subscale were measured using an 11-point numeric rating scale (specifically, the WOMAC NRS3.1 V5 US). As specified in the WOMAC User Guide, each WOMAC subscale is to be summed and can be normalised on a 0–10 scale for the numeric rating scale. Therefore, in this study, the five questions for the Pain subscale and the 17 questions for the Physical Function subscale were summed and averaged, respectively, to determine each mean subscale score. This differs from subscale scores that are not normalised …

There is a need for efficacious and safe pain treatments for OA (osteoarthritis). The nerve growth factor (NGF) antibody tanezumab is associated with high efficacy, but when combined with chronic NSAID treatment shows an increased risk of rapidly progressive osteoarthritis (RPOA) in a small group of patients.The aim of this study was to phenotype with biochemical biomarkers of bone, cartilage, soft tissue, synovial metabolism OA patients who are at risk of developing RPOA type-2, for both limited and chronic NSAIDs users.The dataset consisted of OA patients participating in tanezumab trials who used NSAIDs90 days (limited NSAID users) or chronic users (NSAIDs ≥90 days) over an average 10 month period. Biomarker data were available for 47 cases (RPOA type-2) and 92 controls. Non-linear and linear multivariable predictive models were developed.By use of two biomarkers at baseline the receiver operating characteristic (ROC) curve area for RPOA type-2 in limited NSAID users was 71%, [CI] (60-83%). OA subjects with this biomarker phenotype had 8-fold higher confidence interval [CI][(2-33)] relative risk of developing RPOA type-2 as compared to OA patients without this phenotype. The AUC of the model in chronic NSAIDs users based on 5 biomarkers was 78%, [CI](69-88%), with 4-fold [CI (2-6)] relative risk of developing RPOA type-2.In this hypothesis generating and exploratory study, we identified combinations of biomarkers associated with OA patients who develop RPOA type-2, which may be related to the pathology of the RPOA type-2 joint.

Charles Birbara,1 Eugene J Dabezies JR,2 Aimee M Burr,3 Robert J Fountaine,3 Michael D Smith,3 Mark T Brown,3 Christine R West,3 Rosalin H Arends,3 Kenneth M Verburg3 1Department of Medicine, University of Massachusetts School of Medicine, Worcester, MA, 2Pensacola Research Consultants, Pensacola, FL, 3Clinical Development and Operations Business Unit, Pfizer Inc., Groton, CT, USA Background/objective: The objective of this study was to investigate the safety and efficacy of subcutaneous (SC) and intravenous (IV) tanezumab administration in osteoarthritis (OA) patients.Materials and methods: Study 1027 (NCT01089725), a placebo-controlled trial, evaluated the efficacy of SC tanezumab (ie, 2.5, 5, and 10 mg) and the therapeutic equivalence of 10mg tanezumab given subcutaneously versus intravenously every 8 weeks in the symptomatic treatment of OA. Coprimary endpoints were: change from baseline in Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) Pain and Physical Function indices, and Patient’s Global Assessment (PGA) of OA. Study 1043 (NCT00994890) was a long-term, noncontrolled safety study of tanezumab (ie, 2.5, 5, and 10 mg) subcutaneously administered every 8 weeks. Both studies were discontinued prematurely due to a US Food and Drug Administration partial clinical hold. Results: Due to the clinical hold, Study 1027 was underpowered, and no statistical analyses were performed. Mean (standard error [SE]) change from baseline to week 8 in WOMAC Pain in tanezumab groups ranged from −3.59 (0.26) to −3.89 (0.32), versus −2.74 (0.25) with placebo. Mean (SE) change from baseline to week 8 in WOMAC Physical Function ranged from −3.13 (0.25) to −3.51 (0.28) with tanezumab and was −2.26 (0.24) with placebo. PGA mean (SE) change from baseline to week 8 ranged from −0.90 (0.11) to −1.08 (0.12) with tanezumab and was −0.78 (0.10) with placebo. Similar effectiveness was associated with tanezumab in Study 1043. Few patients in either study (1.4%–5.2%) discontinued due to adverse events. Five patients required total joint replacements in Study 1027 (placebo, n=2 [2.8%]; tanezumab 2.5 mg, n=3 [4.1%]) and 34 patients in Study 1043 (tanezumab 2.5 mg, n=11 [4.8%]; tanezumab 5 mg, n=8 [3.6%]; tanezumab 10 mg, n=15 [6.6%]). Conclusion: Preliminary results show similar efficacy and safety for both SC and IV administration of tanezumab based on the direct comparisons reported here and indirect comparisons with published results, confirming pharmacokinetic/pharmacodynamic modeling predictions. Keywords: tanezumab, subcutaneous, osteoarthritis, efficacy, safety

Patients with metastatic bone cancer report life-altering pain. Nerve growth factor is involved in pain signaling. Tanezumab, a nerve growth factor monoclonal antibody, has demonstrated efficacy in chronic pain. Placebo-controlled parent (NCT00545129; study 1003) and noncontrolled open-label extension (NCT00830180; study 1029) studies evaluated efficacy and safety of tanezumab in patients with painful bone metastases taking daily opioids. Patients in study 1003 received a single intravenous injection of 10 mg tanezumab or placebo and were followed up to 16 weeks. Efficacy analyses included change from baseline in daily average and worst pain at week 6 on an 11-point numeric rating scale. At week 8, patients could enroll in study 1029 and receive 4 infusions of 10 mg tanezumab at 8-week intervals with follow-up to 40 weeks. Safety assessments included adverse events and physical and neurologic examinations. Overall, 59 patients were randomized and treated (placebo, n = 30; tanezumab, n = 29). At the primary endpoint of study 1003, least squares mean (SE) difference in change from baseline in daily average pain vs placebo was -0.26 (0.45; P = 0.569). Post hoc analyses suggested that tanezumab had greater efficacy in patients with lower baseline opioid use and/or higher baseline pain. Mean (SE) pain scores in study 1029 were reduced through week 40 compared with study 1029 or 1003 baselines (-0.21 [0.76] and -1.27 [0.68], respectively). Adverse event incidence of study 1003 was similar between groups. Although the primary endpoint was not achieved, tanezumab may provide additional sustained analgesia in patients with metastatic bone pain taking daily opioids. Additional larger studies are warranted.

Objective Nerve growth factor antibodies (NGF-ab) have shown promising analgesic efficacy. Aim was to describe reader training efforts and present reliability data focusing on radiographic eligibility in the tanezumab program. Methods A multi-step process was used for reader calibration and reliability testing. First, a reference standard set of cases was created and diagnostic performance was evaluated. A second exercise focused on agreement of ordinal assessment (Kellgren–Lawrence grading) of radiographic osteoarthritis. Subsequently, 11 readers were trained and read a test set of 100 cases focused on eligibility assessments. Additional reliability testing and calibration of five core readers assessing eligibility of 30 cases was performed 3 and 6 months after study start. Results Sensitivity for the reference standard readings ranged from 0.50 to 0.90 and specificity from 0.40 to 0.83. Overall agreement for Kellgren–Lawrence grading ranged from 71.4% to 82.9%. For the 11 reader exercise, in 76% of cases at least 8 of 11 readers agreed on eligibility status. For the reliability testing 3 months after study start, in 80.0% of cases at least 4 of 5 readers agreed on eligibility with a κ = 0.43 (95% CI: 0.32–0.54). For the reliability testing after 6 months, in 83.3% of cases at least 4 of 5 readers agreed on eligibility with a κ = 0.52 (95% CI: 0.41–0.63). Conclusions After intense efforts spent in the development of an imaging program for an NGF-ab clinical program, the achieved reliability for eligibility assessment is substantial but not perfect. Ongoing efforts of calibration prior to including additional readers to the program and during study conduct between current readers will be needed to ensure agreement on potential adverse events and radiographic disease severity.

Objective.Two studies evaluated efficacy and safety of tanezumab versus naproxen for treatment of knee or hip osteoarthritis (OA).Methods.Randomized controlled studies [NCT00830063 (Study 1015, n = 828) and NCT00863304 (Study 1018, n = 840)] of subjects with hip or knee OA compared intravenous tanezumab (5 mg or 10 mg) to placebo and naproxen (500 mg twice daily). Coprimary outcomes were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, WOMAC Physical Function (0–10 numerical rating scale), and patient’s global assessment of OA at Week 16.Results.In both studies, tanezumab reduced pain versus placebo [least squares mean differences, 95% CI, tanezumab 5 mg: −1.21 (−1.72, −0.70); −1.13 (−1.65, −0.62); tanezumab 10 mg: −0.91 (−1.42, −0.40); −0.80 (−1.32, −0.29)], and improved function and global scores. Tanezumab 5 mg produced greater pain reduction [−0.76 (−1.28, −0.25); −0.69 (−1.21, −0.17)], and favorable functional and global outcomes versus naproxen. Pain reductions with tanezumab 10 mg versus naproxen did not reach significance, unlike functional (both studies) and global (1 study) outcomes; thus, tanezumab 10 mg was not superior to naproxen, and predefined statistical testing procedures were not met, allowing for conclusion of superiority of tanezumab 5 mg over naproxen despite replicated favorable coprimary outcomes. Tanezumab was associated with greater incidence of peripheral sensory adverse events (paresthesia, hyperesthesia, hypoesthesia, burning sensation), pain in extremity, peripheral edema, and arthralgia. Overall frequency and discontinuations as a result of adverse events were similar to placebo and naproxen.Conclusion.Tanezumab provides efficacious treatment of knee or hip OA and may have therapeutic utility in patients with OA who experience inadequate analgesia with nonsteroidal antiinflammatory drugs.

Assaults on workers in health care and social service settings have been widely documented (Gerberich et al., 2004; McPhaul & Lipscomb, 2004; Myers, Kriebel, Kerasek, Punnett, & Wegman, 2005; Nachreiner, Gerberich, Ryan, & McGovern, 2007). According to the U.S. Bureau of Labor Statistics, U.S. Department of Labor (2007), 60% of all assaults that result in an injury requiring days away from work occurred in health care and social assistance settings and mainly involved patients or residents assaulting nurses or direct care staff. Few studies have examined factors related to these types of assaults in public Intermediate Care Facilities for Individuals with Mental Retardation (ICF/MR) and other related residential facilities for residents with intellectual and developmental disabilities. The current evaluation was in response to a request for a National Institute for Occupational Safety and Health (NIOSH) Health Hazard Evaluation from the management of a state-run ICF/MR. Because of the high number of staff injuries due to resident assaults at their center, the researchers determined the extent of injuries due to assaults, identified risk factors for aggressive and violent resident behavior toward staff, and provided recommendations to decrease assaults. This evaluation consisted of observation of the work setting, interviews with center staff, analyses of Occupational Safety and Health Administration (OSHA) Form 300 Logs of Work-Related Injuries and Illnesses, and review of policies relevant to the request. The staff of this center cared for residents with developmental disabilities, mental illness, or aggressive behavior and employed 251 resident care aides and nursing, medical, and therapy staff, as well as 158 administrative, housekeeping, and maintenance staff. The largest groups of employees at the center were resident care aides, licensed practical nurses, and registered nurses. The U.S. Department of Labor defines direct care workers as nursing aides, orderlies, and attendants in any setting (institutional or residential) (Bureau of Labor Statistics, 2009). Similarly, in this evaluation, the researchers refer to resident care aides as direct care workers. Because of the nature of their work, nurses and direct care workers had the most contact with residents; they provided for residents’ physical, health-related, and habilitation needs as specified in their individual program and care plans. Nursing staff and direct care workers worked one of three 8-hour shifts per day and one 8-hour overtime shift per week to provide 24-hour staffing of the center. Overtime was needed to cover understaffed shifts and supervisors assigned mandatory overtime to staff for uncovered shifts if staff did not volunteer. Typically, staff worked one 8-hour overtime shift per week. The center’s residents lived in a series of buildings split into four sex-segregated apartments. Each apartment provided common areas for residents to eat, watch television, play games, and engage in other activities. Residents also participated in activities and treatment in other buildings at the center. One building housed residents with mental and physical disabilities who required extensive care and assistance with all activities of daily living. Many of these individuals used wheelchairs and had substantial functional limitations. The other buildings included residents with mild mental retardation and/or mental illness who were able-bodied and moved freely around their apartments and the center’s grounds. Admission to the center was considered only when no local resources or less restrictive residential options were available. Some residents were placed at the center because of their aggressive behavior.

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.

Objective To compare the efficacy of tanezumab versus placebo for reducing pain and improving physical function in patients with osteoarthritis (OA) of the hip. Methods This was a 32-week, randomized, double-blind, placebo-controlled, phase III trial. Patients with baseline Western Ontario and McMaster Universities OA Index (WOMAC) Pain and Physical Function subscale scores of ≥5 and ≥4, respectively, and patient's global assessment of OA as “fair,” “poor,” or “very poor” were treated at baseline and weeks 8 and 16. Coprimary efficacy end points were change from baseline to week 16 in WOMAC Pain and Physical Function subscales and patient's global assessment, analyzed using analysis of covariance. Adverse events (AEs) were monitored throughout. Results Patients (n = 621) were randomized 1:1:1:1 to treatment with intravenous tanezumab 2.5 mg, 5 mg, or 10 mg or placebo. Each tanezumab group showed significant improvement for the 3 coprimary end points versus placebo (P ≤ 0.001 for all). AE incidence ranged from 55% to 58% across tanezumab groups versus 44% for placebo. Safety findings were similar to those previously reported. The tanezumab OA clinical program was temporarily placed on hold because of AEs leading to joint replacement. Total joint replacements were reported in 8 patients: 1 in the 10 mg, 2 in the 5 mg, 2 in the 2.5 mg, and 3 in the placebo group. A total of 9 joints were replaced (8 hips [7 index joints] and 1 shoulder). Conclusion Our findings indicate that tanezumab provides superior pain relief and improvement in physical function and patient's global assessment versus placebo in patients with painful hip OA, and is generally well tolerated.

The objective was to derive dosing recommendations for the use of celecoxib in patients with juvenile rheumatoid arthritis (JRA) using pharmacokinetic (PK) and exposure-response data. PK and efficacy data from a randomized, double-blind, 12-week study of celecoxib dosed at 3 and 6 mg/kg twice a day (bid) as an investigational suspension formulation in 152 JRA patients aged 2 to 17 years, PK data from 36 adult RA patients, and relative bioavailability data in healthy adults comparing suspension or capsule sprinkles with the commercial capsule were analyzed. Typical oral clearance (L/h) values were 40% and 24% lower in patients weighing 10 and 25 kg, respectively, compared with a 70-kg patient. Longitudinal, logistic pharmacodynamic models incorporating linear effects of dose/area under the plasma concentration-time curve (AUC) over 0 to 12 hours (AUC(0-12)) suggested that the percentage of responders increased with celecoxib exposure. Systemic exposures (AUC) were similar for the suspension, capsule sprinkles, and intact capsule. Administration of a 50-mg bid capsule (or sprinkles) for patients weighing 10 to 25 kg and 100 mg bid for patients >25 kg was predicted to yield similar exposures and response rates as those observed in the JRA trial. Doses and dosage forms not studied in the JRA trial were approved based on the results of this analysis.

The objective of this study was to compare the analgesic efficacy of tanezumab versus placebo in patients with osteoarthritis (OA) of the knee. This was a 32-week, randomized, double-blind, placebo-controlled phase III trial (NCT00733902). The patient criteria included diagnosis of OA; Western Ontario and McMaster Universities OA Index (WOMAC) Pain and Physical Function subscale scores of ≥5 and ≥4, respectively; Patient's Global Assessment of Osteoarthritis (PGA) ≥3; and failure of nonopiate pain medications or candidacy for invasive interventions. Patients received 3 intravenous doses of tanezumab (2.5, 5, or 10 mg) or placebo. The co-primary efficacy end points were changes in WOMAC subscales and PGA at week 16. Adverse events were monitored throughout. Overall, 690 patients (61% female) were randomized and treated. Those treated with tanezumab showed significant improvement in the 3 co-primary end points ( P ≤ .015 for all). The incidence of adverse events was 55 to 60% for tanezumab-treated patients versus 48% for placebo-treated patients. Joint replacement was reported in 4 patients, 1 in each treatment group; a total of 5 joints were replaced (1 index knee and 4 hips). The tanezumab OA clinical program is currently on clinical hold due to potential adverse reactions leading to joint replacement. Perspective This is the first phase III randomized, controlled trial to demonstrate that nerve growth factor blockade by tanezumab has superior analgesic efficacy in OA of the knee compared with placebo. Tanezumab was well tolerated, and reports of worsening OA and/or joint replacement were evenly distributed across the treatment groups.

Introduction:. The neurotrophin nerve growth factor has a demonstrated role in pain transduction and pathophysiology. Objectives:. Two randomized, double-blind, placebo-controlled, phase 1 studies were conducted to evaluate safety, tolerability, and analgesic efficacy of single doses of tanezumab, a humanized anti–nerve growth factor monoclonal antibody, in chronic or acute pain. Methods:. In the first study (CL001), patients with moderate to severe pain from osteoarthritis (OA) of the knee received a single intravenous infusion of tanezumab (3–1000 μg/kg) or placebo in a dose-escalation (part 1; N = 42) or parallel-arm (part 2; N = 79) study design. The second study (CL002) was a placebo-controlled dose-escalation (tanezumab 10–1000 μg/kg; N = 50) study in patients undergoing bunionectomy surgery. Results:. Adverse event rates were generally similar across treatments. Most adverse events were generally mild to moderate in severity and no patients discontinued as a result of adverse events. Adverse events of abnormal peripheral sensation were more common with higher doses of tanezumab (≥100 μg/kg) than with placebo. These were generally mild to moderate in severity. Tanezumab provided up to 12 weeks of effective analgesia for OA knee pain, with statistically significant improvements at doses ≥100 μg/kg (P < 0.05). By contrast, no trend for analgesic activity was found when tanezumab was administered 8 to 16 hours before bunionectomy. Conclusions:. The demonstration of a favorable safety profile and clinical efficacy in OA pain supports clinical development of tanezumab as a potential treatment for chronic pain conditions.