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To highlight methodologic challenges pertinent to design, analysis, and reporting of results of randomized clinical trials in OA and offer practical suggestions to overcome these challenges. The topics covered in this paper include subject selection, randomization, approaches to handling missing data, subgroup analysis, sample size, and issues related to changing design mid-way through the study. Special attention is given to standardizing the reporting of results and economic analyses. Key findings include the importance of blinding and concealment, the distinction between superiority and non-inferiority trials, the need to minimize missing data, and appropriate analysis and interpretation of subgroup effects. Investigators may use the findings and recommendations advanced in this paper to guide design and conduct of randomized controlled trials of interventions for osteoarthritis., (Copyright © 2015. Published by Elsevier Ltd.)

Objective/background: Efficacy in osteoarthritis (OA) is principally measured using subjective visual analogue (VAS) and/or Likert scale responses. The relationship between these two scales and their relative precision in discriminating active from placebo treatment in OA patients was determined., Design/methods: Patient overall pain assessment, and patient and investigator global assessments were each measured on a 100mm VAS and on a 0 to 4 point Likert scale in a 6-week OA study of rofecoxib vs placebo. The relationship between the VAS and Likert responses was examined graphically and via summary statistics. Analysis of variance was used to assess consistency of the VAS/Likert relationship over time and across the different endpoints. Precision was compared using effect size, and normality of VAS scale of measurement was assessed using the Shapiro-Wilk test., Results: Mean VAS scores and changes from baseline at individual time points were generally highly correlated with corresponding Likert responses (r-values generally approximately 0.7-0.8). The magnitude of VAS values and changes varied depending on endpoint, on the associated magnitude of increment of Likert score, and on the Likert baseline value (i.e., where on the Likert scale the change was occurring). Precision of VAS and Likert responses to detect difference between treatments was generally similar with effect sizes approximately 1. Normality and homogeneity of variance of VAS scores was most closely approximated by actual changes in comparison to percent change or log-transformed measures., Conclusions: VAS and Likert responses are highly correlated and yield similar precision for discriminating treatments in OA patients. Since Likert responses are easier to administer and interpret, they may be preferable to measure OA response.

Objective: Osteoarthritis (OA) clinical studies generally employ various endpoints to evaluate a spectrum of disease manifestations. Compared with individual endpoints, a composite measure might (1) provide a uniform outcome measure of OA efficacy with greater face validity, (2) address multiplicity, and (3) enhance precision. Combinations of endpoints were analyzed to investigate precision of composite measures of OA efficacy., Methods: We reanalyzed three 6 week, placebo controlled, double blind, parallel group studies (2 by the same protocol) of the cyclooxygenase-2 (COX-2) specific inhibitor rofecoxib. The average change from baseline at study weeks 2, 4, and 6 was assessed for 10 individual response variables, including patient and investigator global assessments, WOMAC 3.0V OA Index pain, stiffness and physical function subscales, graded study joint tenderness, and rescue analgesic use. Relationships among variables were evaluated using pairwise correlations and principal components analysis. The precision of variables to differentiate rofecoxib from placebo was evaluated using effect size (i.e., mean difference between rofecoxib versus placebo divided by pooled SD)., Results: Correlations among all pairs of response variables ranged from 0.5 to 0.9, except those with tenderness (0.4 to 0.6) and those with analgesic use (0.2 to 0.4). The first principal component explained about 70% of the total variability, with weights generally similar (0.17 for rescue analgesic use, 0.25 for tenderness, and 0.30 to 0.37 for the others). These results indicate that nearly all measures are closely related. Based on these results, various linear combinations of the 9 endpoints were formed and their precision to discriminate active treatment from placebo was compared to that of the individual endpoints. Effect sizes of the individual endpoints ranged from 0.6 to 1.1; those of the composites from 0.7 to 0.9. The results were very consistent between study protocols., Conclusion: In comparison to individual endpoints, composite analyses of OA clinical endpoints do not increase precision to discriminate active treatment from placebo.

Background: Cyclooxygenase (COX)-2-selective inhibitors are a new type of nonsteroidal anti-inflammatory drug (NSAID) for the management of pain caused by osteoarthritis (OA). The most recent OA guidelines from the American College of Rheumatology were published in 2000 because new therapies such as the COX-2-selective inhibitors had been introduced for the management of OA., Objective: Because more data are now available on efficacy and safety issues with COX-2-selective inhibitors, NSAIDs, and acetaminophen, this review focuses on how COX-2-selective inhibitors may change the pharmacologic management of patients with OA., Methods: References were obtained from MEDLINE, BIOSIS, EMBASE, and Internet searches of the literature., Conclusions: The safety and efficacy of two COX-2-selective inhibitors, rofecoxib and celecoxib, have been examined in a number of clinical trials, and these agents have been shown to offer efficacy similar to that of NSAIDs. Acetaminophen continues to be the initial drug of choice for the management of OA because of its efficacy, safety, cost, and availability. COX-2-selective inhibitors should be considered in patients with OA who do not respond to or cannot tolerate therapy with acetaminophen. COX-2-selective inhibitors have an improved gastrointestinal (GI) safety profile compared with traditional NSAIDs and should be chosen over NSAIDs if prescription plan access and/or expense is not a concern. COX-2-selective inhibitors are clinically indicated for patients at increased risk of developing NSAID-induced GI complications, a population in whom the use of COX-2-selective inhibitors may be cost-effective because the incidence and mortality associated with serious GI adverse events and use of expensive GI comedications would be reduced.

Objective: To demonstrate that in patients receiving naproxen for the pain of osteoarthritis (OA), the addition of tramadol will allow a reduction in the naproxen dosage without compromising pain relief., Methods: This trial consisted of a 5-week open-label run-in and an 8-week double-blind phase. Patients with at least moderate pain (> or =40 mm on a 100-mm visual analog scale) of OA of the knee after a 1-week medication washout were treated with naproxen 500 mg/day for 1 week. Patients whose pain scores were reduced to <20 mm were discontinued. The remaining patients received naproxen 1,000 mg/day for 3 weeks. Tramadol 200 mg/day was added during the third week. Patients were then randomized in a double-blind manner to continue tramadol 200 mg/day or to begin placebo in addition to naproxen. Randomization was stratified based on response to naproxen 1,000 mg/day. During the double-blind phase, the naproxen dose was reduced by 250 mg every 2 weeks. The primary efficacy end point was the minimum effective naproxen dose (MEND). The MEND was defined as 250 mg above the naproxen daily dosage at which pain relief was no longer adequate. Patients discontinuing the double-blind phase of the study for reasons other than lack of efficacy were assigned a MEND equal to the last naproxen dose received. If the effect of treatment between the responder and nonresponder groups was statistically different, the difference in the MEND was assessed separately within the groups., Results: Of 236 patients randomized (mean age 61 years; 147 females), 90 were stratified as naproxen responders and 146 as naproxen nonresponders. There was a significant difference (P = 0.040) in the treatment effect between the naproxen responders and nonresponders, thus demonstrating a difference in the way responders and nonresponders react to a decrease in naproxen dosage after the addition of tramadol. Among naproxen responders, the MEND was significantly lower in patients receiving tramadol (n = 36) than in patients receiving placebo (n = 54), 221 mg versus 407 mg, respectively (P = 0.021). For the naproxen nonresponders, the mean MEND was 419 mg in the tramadol group and 396 mg in the placebo group (P = 0.706)., Conclusion: In patients with painful OA of the knee responding to naproxen 1,000 mg/day, the addition of tramadol 200 mg/day allows a significant reduction in the dosage of naproxen without compromising pain relief.

Objective: The adduction moment at the knee during gait is the primary determinant of medial-to-lateral load distribution. If the adduction moment contributes to progression of osteoarthritis (OA), then patients with advanced medial tibiofemoral OA should have higher adduction moments. The present study was undertaken to investigate the hypothesis that the adduction moment normalized for weight and height is associated with medial tibiofemoral OA disease severity after controlling for age, sex, and pain level, and to examine the correlation of serum hyaluronan (HA) level with disease severity and with the adduction moment in a subset of patients., Methods: Fifty-four patients with medial tibiofemoral OA underwent gait analysis and radiographic evaluation. Disease severity was assessed using the Kellgren-Lawrence (K-L) grade and medial joint space width. In a subset of 23 patients with available sera, HA was quantified by sandwich enzyme-linked immunosorbent assay. Pearson correlations, a random effects model, and multivariate regression models were used., Results: The adduction moment correlated with the K-L grade in the left and right knees (r = 0.68 and r = 0.60, respectively), and with joint space width in the left and right knees (r = -0.45 and r = -0.47, respectively). The relationship persisted after controlling for age, sex, and severity of pain. The partial correlation between K-L grade and adduction moment was 0.71 in the left knees and 0.61 in the right knees. For every 1.0-unit increase in adduction moment, there was a 0.63-mm decrease in joint space width. In the subset of patients in whom serum HA levels were measured, HA levels correlated with medial joint space width (r = -0.55), but not with the adduction moment., Conclusion: There is a significant relationship between the adduction moment and OA disease severity. Serum HA levels correlate with joint space width but not with the adduction moment. Longitudinal studies will be necessary to determine the contribution of the adduction moment, and its contribution in conjunction with metabolic markers, to progression of medial tibiofemoral OA.

Management is multifaceted: Palliation of pain should be accompanied by physical and occupational therapy and use of adaptive devices to improve performance. New techniques aim to interrupt disease progression and to induce biologic repair.

Etodolac (Lodine) has been marketed in the United States since 1991 for managing pain and for acute and longterm treatment of the signs and symptoms of osteoarthritis (OA). Etodolac was recently approved for the treatment of rheumatoid arthritis. We review the results of 3 recent 4 week, multicenter, placebo controlled, parallel group studies that compared the efficacy and safety of etodolac with naproxen and nabumetone. Because studies of etodolac in the treatment of OA concentrated on bid doses, the first study compared etodolac 800 mg/day given as 400 mg bid (106 patients) and 200 mg qid (105 patients) with naproxen 1000 mg/day (109 patients) and placebo (104 patients). Etodolac was as effective as naproxen, and the 2 dosage schedules of etodolac were comparable. The 2nd study compared etodolac 400 mg bid (86 patients) with naproxen 500 bid (82 patients) and placebo (86 patients). Etodolac was again found to be as effective as naproxen. The 3rd study compared etodolac 400 mg bid (91 patients) with nabumetone 1500 mg/day (89 patients) and placebo (90 patients). The results indicated that the efficacy of etodolac was comparable to that of nabumetone and resulted in significantly better scores at endpoint on the investigator's overall assessment and patient's global assessment. In all 3 studies there were no significant differences among the groups in the frequency of study events or premature discontinuations as a result of study events. The most common adverse event was digestive system disturbance, which was mild to moderate in severity. The results of these studies confirm the efficacy and safety of etodolac in managing the signs and symptoms of OA.

Treatment of patients with OA of the knee should be individualized and tailored to the severity of the symptoms. In individuals with mild symptomatic OA, treatment may be limited to patient education, physical and occupational therapy and other nonpharmacologic modalities, and pharmacologic therapy including non-opioid oral and topical analgesics. In patients who are unresponsive to this treatment regimen, the use of NSAIDs in addition to nonpharmacologic therapy is appropriate unless medically contraindicated. Judicious use of intraarticular steroid injections has a role either as monotherapy or an adjunct to systemic therapy in patients with knee OA who have symptomatic effusions. The role of joint lavage and arthroscopic debridement in patients with OA of the knee who are unresponsive to conservative medical therapy needs further study, and these procedures cannot be routinely recommended for all patients at this time. Patients with severe symptomatic OA of the knee require an aggressive approach to decreasing pain, increasing mobility, and decreasing functional impairment; such patients may benefit from orthopedic consultation and evaluation for osteotomy or total joint arthroplasty.

This 4-week, randomized, double-blind, double-dummy, placebo-controlled, parallel-group, multicenter study was designed to compare the efficacy and safety of etodolac and nabumetone in the treatment of patients with active osteoarthritis (OA) of the knee. Ninety-one patients received etodolac 400 mg twice daily, 89 received nabumetone 1500 mg once daily, and 90 received placebo. Both active treatments significantly improved the patients' condition relative to baseline (P < or = 0.001) at all evaluations during treatment and relative to placebo (P < or = 0.05) by visit 4. Improvement relative to placebo in investigator's global assessments was earlier in the etodolac group (ie, by visit 3) than in the nabumetone group. At visit 4, improvement in investigator's and patient's global assessment scores, and in the distribution of investigator's assessment scores, was significantly (P < or = 0.05) greater in the etodolac group than in the nabumetone group. Other than hypokalemia, which occurred only in three patients in the nabumetone group (P = 0.035), there were no significant differences among the groups in the frequency of study events or premature discontinuation from the study as a result of study events. Study events considered at least possibly treatment related were reported for 26 patients in the etodolac group (28.6%), 20 in the nabumetone group (22.5%), and 23 in the placebo group (25.6%). The most frequently reported symptoms for all groups were dyspepsia, nausea, and headache. Four patients treated with nabumetone (4.5%) had elevations in aspartate aminotransferase or alanine aminotransferase during treatment. The results of this study show that etodolac 400 mg twice daily is at least as effective as nabumetone 1500 mg once daily and is equally well tolerated in the treatment of patients with active OA of the knee; etodolac may have an earlier onset of action and/or a relatively greater efficacy in patient and investigator global assessments than nabumetone.

Objective: The purpose of this study was to assess the accuracy of fast spin-echo MR imaging for depicting the severity of articular cartilage abnormalities in patients with osteoarthritis., Subjects and Methods: Twenty-three subjects (10 volunteers less than 35 years old and 13 patients with proved, symptomatic, idiopathic osteoarthritis of the knee of 6 months' to 10 years' clinical duration) underwent fast spin-echo MR imaging of the knee. Two observers graded each articular surface using a five-category scale that took into account abnormalities in the signal intensity of cartilage as well as thickness and contour. The 13 patients also underwent arthroscopic evaluation (as part of a separate protocol) in which cartilage abnormalities were graded by using a similar five-category grading scale, without the graders knowing the results of MR imaging. Articular cartilage was assumed to be normal in the volunteers., Results: One hundred thirty-seven joint surfaces were graded; one surface was obscured by artifact and was excluded. The Spearman rank linear correlation between arthroscopic and MR grading was highly significant (p < .002) for each of the six articular regions evaluated. The MR and arthroscopic grades were the same in 93 (68%) of 137 joint surfaces, they were the same or differed by one grade in 123 surfaces (90%), and they were the same or differed by one or two grades in 129 surfaces (94%)., Conclusion: Our results suggest that fat-presaturated fast spin-echo MR imaging depicts the severity of articular cartilage abnormalities in osteoarthritis with reasonable accuracy, as compared with arthroscopic evaluation as the standard of reference.

Objective: To determine whether the use of a nonsteroidal antiinflammatory drug (NSAID) in patients with painful osteoarthritis (OA) of the knee would result in alterations in specific biomechanical parameters of gait., Methods: Eighteen patients with symptomatic knee OA and varus knee deformity underwent initial clinical evaluation for pain and activities of daily living, and assessment of parameters of gait utilizing a well-described computerized system. All patients were then treated with piroxicam at 20 mg once daily, and clinical and gait analyses were repeated after 4 weeks., Results: Fifteen of the 18 patients studied had a significant increase in the knee adduction moment after treatment. In the group as a whole there was a significant increase in knee adduction moment (mean percent body weight times height [%BWTH] 4.11 pretreatment versus 4.57 after 4 weeks of treatment; P < 0.01) and maximum quadriceps moment (mean %BWTH 2.13 pretreatment, 2.62 posttreatment; P < 0.01), as well as changes in other gait parameters that might be expected to be altered as a result of relief of pain. Sixteen of 18 patients experienced symptomatic relief, with a significant reduction in pain in the group as a whole after 4 weeks (P < 0.001)., Conclusion: NSAID treatment in patients with knee OA results in a reduction in symptomatic pain and an increase in loading of the knee. Whether the increased loading is due to the analgesic effects of the treatment is unknown, but if so, the development of agents capable of relieving pain while reducing loads at the knee may be desirable.

Osteoarthritis is a chronic disease that has exacerbations and remissions. Pain is the symptom that patients want addressed. It is important to remember, however, that simple alleviation of pain does not alter the underlying problem. Attention must be directed toward using physical therapy and other physical measures in conjunction with pharmacologic intervention for symptom relief. Use of simple analgesic agents is the safest initial approach, perhaps in conjunction with topical treatment with a compound such as capsaicin (Zostrix). If pain relief is inadequate, use of nonsteroidal anti-inflammatory agents should be considered, with careful monitoring of gastrointestinal symptoms and renal status, particularly in the elderly. For flares of disease, intra-articular injection of a corticosteroid may give short-term relief. Relief of pain and restoration of function can be accomplished in some patients with early disease, particularly if an integrated approach to treatment is used. Advanced disease can be made more tolerable but may eventually require surgical intervention, which generally provides excellent results.

We examined the relationship between serum and synovial fluid (SF) levels of antigenic keratan sulfate (KS) and the clinical, laboratory, and radiologic features of disease in 125 well-characterized patients with knee osteoarthritis (OA). KS was quantified by enzyme-linked immunosorbent assay, using an antibody specific for a highly sulfated epitope on KS chains; the results were calculated as equivalents of an international standard of KS from human costal cartilage. The mean level of serum KS (393 ng/ml) was significantly higher than those previously reported for populations of adults without OA. There was a wide scatter of serum KS values (range 156-912 ng/ml), with little correlation with clinical or radiologic features. Men had significantly higher levels than women (456 +/- 135 ng/ml versus 368 +/- 110 ng/ml, mean +/- SD), and there was a statistically significant but weak association with indicators of polyarticular involvement (number of symptomatic joints, Heberden's nodes, hip symptoms) in women. Despite the wide scatter of results in the population as a whole, individual levels of KS were stable for up to 4 consecutive years in the 9 patients studied. Levels of KS were much higher in SF (n = 25) than in serum, but the two were not correlated. There was an inverse correlation between radiographic evidence of cartilage loss and the level of KS in SF. The large variations in serum KS values suggest that this measure may not be of diagnostic significance among populations of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

The neuropeptide substance P has been implicated in the pathogenesis of inflammation and pain in arthritis. In this double-blind randomized study, 70 patients with osteoarthritis (OA) and 31 with rheumatoid arthritis (RA) received capsaicin (a substance P depletor) or placebo for four weeks. The patients were instructed to apply 0.025% capsaicin cream or its vehicle (placebo) to painful knees four times daily. Pain relief was assessed using visual analog scales for pain and relief, a categorical pain scale, and physicians' global evaluations. Most of the patients continued to receive concomitant arthritis medications. Significantly more relief of pain was reported by the capsaicin-treated patients than the placebo patients throughout the study; after four weeks of capsaicin treatment, RA and OA patients demonstrated mean reductions in pain of 57% and 33%, respectively. These reductions in pain were statistically significant compared with those reported with placebo (P = 0.003 and P = 0.033, respectively). According to the global evaluations, 80% of the capsaicin-treated patients experienced a reduction in pain after two weeks of treatment. Transient burning was felt at the sites of drug application by 23 of the 52 capsaicin-treated patients; two patients withdrew from treatment because of this side effect. It is concluded that capsaicin cream is a safe and effective treatment for arthritis.

The serum level of a highly sulfated epitope present on long keratan sulfate chains provides a direct measure of the rate of catabolism of cartilage proteoglycans. Levels of the keratan sulfate epitope are elevated in patients with generalized osteoarthritis (OA), indicating these individuals have elevated rates of cartilage proteoglycan catabolism. In the Pond-Nuki model of canine OA, the serum level of the keratan sulfate epitope rises rapidly after the transection of the anterior cruciate ligament, long before OA lesions can be detected, and remains high for at least 13 weeks.

Serum levels of keratan sulfate (KS), measured by an enzyme-linked immunosorbent-inhibition assay, were found to be significantly higher in 31 patients with hypertrophic osteoarthritis (OA) than those in 41 adults without joint disease. Seventy-seven percent of patients with OA, but only 12% of control subjects, had serum levels which were more than 1 SD above the mean of the control group. Following replacement of a single osteoarthritic hip joint, serum KS levels decreased, at first, in all patients. Subsequently, the concentration of serum KS progressively increased; 6 months following surgery, KS levels were similar or close to the preoperative levels in virtually all patients. The results suggest that patients with hypertrophic OA may have a generalized imbalance of cartilage proteoglycan metabolism. Measurements of serum KS are likely to prove most useful in studying this particular subset of patients with generalized OA.

Concentrations of circulating cartilage-derived keratan sulfate (KS) are significantly higher in patients with osteoarthritis (OA) than in adults without cartilage disease. The increases in serum KS levels in the OA group are likely the result, at least in part, of cartilage degradation in affected joints. If the appearance of elevated levels of serum KS do indeed correlate with the extent of cartilage erosion or destruction in individuals with OA, measurements of serum KS levels will prove extremely useful in the assessment and diagnosis of this joint disease.

To evaluate the efficacy and safety of the anti-catabolic ADAMTS-5 inhibitor S201086/GLPG1972 for the treatment of symptomatic knee osteoarthritis. ROCCELLA (NCT03595618) was a randomized, double-blind, placebo-controlled, dose-ranging, phase 2 trial in adults (aged 40–75 years) with knee osteoarthritis. Participants had moderate-to-severe pain in the target knee, Kellgren–Lawrence grade 2 or 3 and Osteoarthritis Research Society International joint space narrowing (grade 1 or 2). Participants were randomized 1:1:1:1 to once-daily oral S201086/GLPG1972 75, 150 or 300 mg, or placebo for 52 weeks. The primary endpoint was change from baseline to week 52 in central medial femorotibial compartment (cMFTC) cartilage thickness assessed quantitatively by magnetic resonance imaging. Secondary endpoints included change from baseline to week 52 in radiographic joint space width, Western Ontario and McMaster Universities Osteoarthritis Index total and subscores, and pain (visual analogue scale). Treatment-emergent adverse events (TEAEs) were also recorded. Overall, 932 participants were enrolled. No significant differences in cMFTC cartilage loss were observed between placebo and S201086/GLPG1972 therapeutic groups: placebo vs 75 mg, P = 0.165; vs 150 mg, P = 0.939; vs 300 mg, P = 0.682. No significant differences in any of the secondary endpoints were observed between placebo and treatment groups. Similar proportions of participants across treatment groups experienced TEAEs. Despite enrolment of participants who experienced substantial cartilage loss over 52 weeks, during the same time period, S201086/GLPG1972 did not significantly reduce rates of cartilage loss or modify symptoms in adults with symptomatic knee osteoarthritis. [ABSTRACT FROM AUTHOR]

Summary The goal of this document is to update the original OARSI recommendations specifically for the design, conduct, and reporting of clinical trials that target symptom or structure modification among individuals with knee osteoarthritis (OA). To develop recommendations for the design, conduct, and reporting of clinical trials for knee OA we initially drafted recommendations through an iterative process. Members of the working group included representatives from industry and academia. After the working group members reviewed a final draft, they scored the appropriateness for recommendations. After the members voted we calculated the median score among the nine members of the working group who completed the score. The document includes 25 recommendations regarding randomization, blocking and stratification, blinding, enhancing accuracy of patient-reported outcomes (PRO), selecting a study population and index knee, describing interventions, patient-reported and physical performance measures, structural outcome measures, biochemical biomarkers, and reporting recommendations. In summary, the working group identified 25 recommendations that represent the current best practices regarding clinical trials that target symptom or structure modification among individuals with knee OA. These updated recommendations incorporate novel technologies (e.g., magnetic resonance imaging (MRI)) and strategies to address the heterogeneity of knee OA. [ABSTRACT FROM AUTHOR]

We performed a randomized, double-blind, clinical trial to evaluate pain relief efficacy of rofecoxib and celecoxib at highest indicated once daily doses in osteoarthritis. 1082 patients meeting entry criteria for OA, responsive to NSAIDs, were randomized 3:3:1 to treatment with rofecoxib 25 mg QD (n = 471), celecoxib 200 mg QD (n = 460) or placebo (n = 151). Efficacy was assessed over the first 6 days of therapy and at weeks 2, 4 and 6 by WOMAC questionnaire and patient global assessment of response to therapy (PGART). Demographics were well balanced. Significantly more patients on placebo discontinued prematurely compared to both active groups (p < 0.001) mainly due to lack of pain relief efficacy. Rofecoxib provided statistically superior relief of night pain (p = 0.023), morning stiffness (p = 0.002), rest pain (p = 0.023), and walking pain (p = 0.005) compared to celecoxib. Rofecoxib was significantly superior to celecoxib on all WOMAC subscales including pain (p = 0.008), stiffness (p = 0.001) and physical function (p = 0.01). Rofecoxib was superior to celecoxib in % of patients with good or excellent PGART over 6 weeks (p = 0.014) and provided quicker onset of pain relief as assessed by time to first report of good or excellent response (p < 0.001). Both active groups were superior to placebo on efficacy endpoints. Incidence of clinical AEs, drug related AEs, serious AEs, and discontinuations due to AEs was similar between active groups. In this study, once daily doses of rofecoxib provided superior relief of pain and other related symptoms in OA compared to celecoxib and placebo. All treatments were generally well tolerated. [ABSTRACT FROM AUTHOR]