Global Assessment Of Osteoarthritis Research Articles

Efficacy and safety of tanezumab, NSAIDs, and placebo in patients with moderate to severe hip or knee osteoarthritis and a history of depression, anxiety, or insomnia: post-hoc analysis of phase 3 trials

Objective: Treatment outcomes for chronic pain can be poor in patients with depression, anxiety, or insomnia. This analysis evaluated the efficacy and safety of subcutaneous tanezumab, nonsteroidal anti-inflammatory drugs (NSAIDs), and placebo in patients with osteoarthritis (OA) and a history of these conditions using data from three phase 3 studies. Methods: A post-hoc analysis of data from two pooled placebo-controlled studies and one NSAID-controlled study of subcutaneous tanezumab. All patients had moderate to severe knee or hip OA that was inadequately controlled with standard-of-care analgesics. Efficacy outcomes were least-squares mean change from baseline to Week 16 in Western Ontario McMaster Universities OA Index (WOMAC) Pain, WOMAC Physical Function, Patient’s global assessment of OA, and EQ-5D-5L scores. Results were summarized for patients with and without a history of depression, anxiety, or insomnia at baseline. Results: 1545 patients were treated in the pooled placebo-controlled studies (history of depression, 12%; anxiety, 8%; insomnia, 10%; any, 23%) and 2996 in the NSAID-controlled study (16%, 11%, 13%, 28%, respectively). In groups with positive histories, 38–80% took antidepressant or anxiolytic medications at baseline. Within treatments, largely similar improvements in efficacy outcomes were observed in patients with and without a history of depression, anxiety, or insomnia; the types of treatment-emergent adverse events were similar. Conclusions: Patients with OA and a history of depression, anxiety, or insomnia did not appear to experience reduced efficacy outcomes or an altered safety profile in response to tanezumab or NSAID treatment as compared with those without. NCT02697773; NCT02709486; NCT02528188

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

BackgroundA 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.MethodsParticipants 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.ResultsAll 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.ConclusionsTanezumab 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 registrationClinicalTrials.govNCT02528188. Registered on 19 July 2015.

Subcutaneous tanezumab for osteoarthritis of the hip or knee: efficacy and safety results from a 24-week randomised phase III study with a 24-week follow-up period

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...

Efficacy and safety of diclofenac sodium 2% topical solution for osteoarthritis of the knee: a randomized, double-blind, vehicle-controlled, 4 week study

Objective:Nonsteroidal anti-inflammatory drugs (NSAIDs) are standard therapy for osteoarthritis (OA). Topically applied NSAIDs reduce systemic exposure compared with oral NSAIDS, and European guidelines recommend their use. The NSAID diclofenac is available in a range of topical formulations. Diclofenac 1% gel and 1.5% four times daily and 2% twice daily (BID) solutions are approved to reduce pain from OA of the knee(s). The objective of this study was to investigate the efficacy and safety of diclofenac sodium 2% topical solution BID versus vehicle control solution for treating pain associated with OA of the knee.Research design and methods:A phase II, 4 week, randomized, double-blind, parallel-group, two-arm, vehicle-controlled study compared pain relief with diclofenac sodium 2% topical solution versus control (vehicle only) in patients aged 40 to 85 years with radiographically confirmed primary OA of the knee.Clinical trial registration:ClinicalTrials.gov identifier NCT01119898.Main outcome measures:The primary efficacy outcome was change from baseline to the final visit in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale. Secondary outcomes included additional WOMAC subscales and patient global assessment of OA. Treatment-emergent adverse events (TEAEs), skin irritation, and vital signs were assessed and collected throughout the study.Results:Of 260 patients randomized, 259 received ≥1 dose of study drug. Significantly greater reductions in least-squares mean (standard error) WOMAC pain scores were observed for diclofenac-treated (−4.4 [0.4]) versus vehicle-treated patients (−3.4 [0.4]) at the final visit (p = 0.040). The most commonly reported TEAEs were administration site conditions. The vehicle-treated group experienced slightly more TEAEs than the active treatment group (38.8% vs. 31.5%). No serious adverse events were reported.Conclusions:Administration of diclofenac sodium 2% topical solution BID resulted in significantly greater improvement in pain reduction in patients with OA of the knee versus vehicle control and was generally well tolerated.

Study Finds Anti-NGF Factor Effective for Hip Arthritis

Treatment with the anti–nerve growth factor (NGF) tanezumab was associated with significant improvements over placebo in pain, physical function, and Patient's Global Assessment of osteoarthritis (OA) results, after 16 weeks in a phase III study of patients with OA of the hip. In the randomized, double-blind, placebo-controlled study of 621 patients with painful hip OA, treatment with tanezumab (an “anti-NGF”) was also well tolerated, according to Dr. Mark Brown and his associates. The study was funded by Pfizer, the manufacturer of tanezumab, and Dr. Brown and three of the five other authors are full-time employees of the company. Tanezumab “may eventually be useful in OA patients who are intolerant of or nonresponsive to nonopioid treatment,” the authors concluded. The study was published in Arthritis & Rheumatism (Arthritis Rheum. 2013;65[7];1795-1803). Anti-NGFs are monoclonal antibodies directed against nerve growth factor, which is associated with injury, inflammation, and chronic pain, according to the authors. Tanezumab is one of several anti-NGFs being studied for OA and other chronic pain conditions and is the furthest along in development. In 2010, the Food and Drug Administration (FDA) placed a partial hold on anti-NGF clinical trials after cases of osteonecrosis and avascular necrosis were reported in patients treated with tanezumab and in those treated with another anti-NGF. After an FDA advisory panel said that the anti-NGFs showed promise as analgesics, the clinical hold on tanezumab trials was lifted in August 2012, Dr. Brown's team noted. The development of the anti-NGFs “is an exciting potential addition to our present inadequate control of pain,” and research is resuming with a careful review of the risk of bone and joint changes, Dr. Roy Altman said in an interview. In his view, “the known risks would be acceptable to many people with poorly controlled pain.” Dr. Altman, professor of medicine, rheumatology, at the University of California, Los Angeles, was not an investigator in the study. The Pfizer study compared three tanezumab doses (2.5 mg, 5 mg, and 10 mg) administered intravenously at baseline, 8 weeks, and 16 weeks, with placebo, in 621 people with OA of the hip (mean age, 62-63 years) who could not or did not want to take nonopiate pain medications, did not get enough relief from these medications, or were candidates for hip surgery or other invasive treatments. Almost half were candidates for invasive treatment. At 16 weeks, tanezumab, at all three doses, “produced greater, clinically meaningful, and statistically significant improvements,” compared with placebo, in pain, physical function, and patient assessment of OA. Differences between placebo and treatment were greatest for the two higher doses. About two-thirds of the patients on treatment remained in the study through week 24 (considered the end of the study because of tanezumab's long half-life), compared with 38% of those on placebo. Overall, more patients on tanezumab reported adverse effects (55%-58% vs. 44% on placebo). Serious adverse events occurred in 3%-4.5% of patients in the treatment groups. The rate of total hip replacement was similar in the treatment and placebo groups, with a total of eight patients who had the operation (three in the placebo group, two each in the 2.5-mg and 5-mg groups, and one in the 10-mg group). These included two patients on tanezumab who had osteonecrosis thought to be related to tanezumab. The authors pointed out that an outside adjudication committee, however, did not confirm osteonecrosis in either of these patients and concluded that the reasons for joint replacements in the eight patients were inflammatory arthropathy, end-stage OA, rapidly progressive OA, or worsening OA. Dr. Altman said that he has consulted with Abbott and its now discontinued program on anti-NGF drugs.

Efficacy and safety of tanezumab added on to diclofenac sustained release in patients with knee or hip osteoarthritis: a double-blind, placebo-controlled, parallel-group, multicentre phase III randomised clinical trial

ObjectivesTanezumab, a monoclonal antibody, inhibits nerve growth factor and reduces chronic pain. This randomised, double-blind, controlled multicentre study was conducted to evaluate the efficacy and safety of tanezumab added to...

Tanezumab Reduces Osteoarthritic Hip Pain: Results of a Randomized, Double‐Blind, Placebo‐Controlled Phase III Trial

To compare the efficacy of tanezumab versus placebo for reducing pain and improving physical function in patients with osteoarthritis (OA) of the hip. 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. 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). 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.

Tanezumab Reduces Osteoarthritic Knee Pain: Results of a Randomized, Double-Blind, Placebo-Controlled Phase III Trial

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. PerspectiveThis 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.

A double-masked comparison of naprelan ® and nabumetone in osteoarthritis of the knee

The efficacy and safety of Naprelan ® (naproxen sodium) 1000 mg once daily (QD) and nabumetone 1500 mg QD were compared in a multicenter, randomized, parallel-group, placebo-controlled, double-masked, 4-week study of adult outpatients with active osteoarthritis (OA) of the knee. Nabumetone 1500 mg was chosen for comparison because it is commonly prescribed in a QD dosing regimen for OA. After a washout period free of non-steroidal anti-inflammatory drugs, 279 patients were enrolled and assigned randomly to treatment with either Naprelan 1000 mg QD (n = 92), nabumetone 1500 mg QD (n = 93), or placebo (n = 94). All treatments were evaluated for efficacy and safety at baseline and at weeks 2 and 4 of the treatment period or at discontinuation. Demographic characteristics were comparable among all treatment groups. As might be expected in a study of OA of the knee, a majority of patients enrolled were women (68.8%), and many were obese (mean weight, 195.6 lb; mean height, 66 in). Significantly fewer patients (13) treated with Naprelan prematurely discontinued the study than did patients treated with placebo (27); there was a lower rate of discontinuation for insufficient therapeutic effect in the Naprelan group compared with the nabumetone and placebo groups. Using an intent-to-treat model, the overall distribution of scores in all three primary efficacy assessments (investigator's global assessment of OA, patient's global assessment of OA, and walking pain) at week 2 and at the last visit was significantly better for the Naprelan group compared with both the nabumetone and placebo groups. The mean improvement from baseline was also significant for Naprelan compared with the nabmetone and placebo groups for all three assessments at week 2 and for investigator's global assessment of OA and walking pain at the last visit. The nabumetone-treated group showed significant improvement over the placebo-treated group in only one primary assessment: mean change from baseline in patient's global assessment of OA at week 2. At week 2, significant differences favoring Naprelan versus nabumetone and placebo were measured in overall distribution of scores for joint tenderness and nighttime pain. Distribution of quality of sleep and inactivity stiffness scores also improved relative to placebo at week 2. At the last visit, nighttime pain scores were still significantly better for patients receiving Naprelan versus nabumetone and placebo. Patients receiving nabumetone had statistically significant improvement from baseline in inactivity stiffness compared with placebo at week 2. There were no clinically important differences among treatment groups in the occurrence of adverse events or laboratory abnormalities. The results of this 4-week study of Naprelan 1000 mg QD compared with nabumetone 1500 mg QD demonstrate at least equal efficacy (superior efficacy was demonstrated for several parameters) and equal safety in adult outpatients with active OA of the knee.