Adalimumab effectiveness for the treatment of ankylosing spondylitis is maintained for up to 2 years: long-term results from the ATLAS trial.

OBJECTIVE: To determine the long-term effect of adalimumab on patients with ankylosing spondylitis (AS) who participated in the Adalimumab Trial Evaluating Long-Term Efficacy and Safety in AS (ATLAS), a randomised, double-blind, placebo controlled, 24-week trial. METHODS: Patients received adalimumab 40 mg every other week (eow) or placebo for 24 weeks in ATLAS. At week 24, patients were switched to open-label adalimumab 40 mg eow. Efficacy measures included 20% improvement in the Assessment in SpondyloArthritis International Society (ASAS) criteria (ASAS20), ASAS40 and ASAS partial remission responses and changes in individual components of the ASAS20 response evaluations, for example, Bath AS Functional Index (BASFI) and Bath AS Disease Activity Index (BASDAI). Two-year interim data were analysed based on the total duration of adalimumab exposure, irrespective of the treatment randomisation group. RESULTS: At 2 years, 255 (82.0%) of the original 311 ATLAS patients continued receiving adalimumab treatment. Improvements in ASAS responses observed in ATLAS were sustained during long-term treatment; 64.5% (200/310) were ASAS20 responders, 50.6% (157/310) were ASAS40 responders and 33.5% (104/310) had maintained ASAS-defined partial remission. Changes in individual ASAS response components were sustained or improved during long-term adalimumab treatment. From ATLAS baseline to 2 years of adalimumab exposure, respectively, BASDAI improved from 6.3 (SD 1.7) to 2.4 (SD 2.3) and BASFI improved from 5.2 (SD 2.4) to 2.9 (SD 2.5). Adalimumab was well tolerated. No cases of tuberculosis, congestive heart failure, lupus-like symptoms, or demyelinating disease were reported. CONCLUSIONS: Adalimumab reduced the signs and symptoms of AS and induced partial remission for up to 2 years. The long-term safety profile was similar to the short-term safety profile. Trial registration information: NCT00085644.

Adalimumab effectively reduces the signs and symptoms of active ankylosing spondylitis in patients with total spinal ankylosis.

OBJECTIVE: To evaluate the long-term safety and efficacy of adalimumab in patients with ankylosing spondylitis (AS) and total spinal ankylosis (TSA). DESIGN: Patients (n = 315) with active AS were randomised in a 2:1 ratio to receive adalimumab 40 mg every other week or placebo for 24 weeks followed by open-label adalimumab for up to 5 years. Two-year efficacy and safety data for 11 patients with investigator-defined TSA were evaluated. The primary end point was the ASsessment in AS International Working Group criteria for 20% improvement (ASAS20) at Week 12. On or after Week 12, ASAS20 non-responders could switch to open-label adalimumab. Other efficacy measurements included ASAS40, ASAS 5/6, ASAS partial remission, and 50% improvement in the Bath AS Disease Activity Index (BASDAI 50). RESULTS: 6 of 11 TSA patients were randomised to adalimumab and 5 to placebo. At Week 12, 50% of the adalimumab-treated patients achieved an ASAS20 response and 33% achieved an ASAS40, ASAS 5/6 and BASDAI 50. No placebo-treated patients achieved any response criteria at Week 12. 4 placebo- and 2 adalimumab-treated patients switched to open-label adalimumab before Week 24. After 1 year of adalimumab treatment, 8 of 11 patients achieved an ASAS20 response. After 2 years, 6 of the remaining 8 patients with TSA reported an ASAS20 response. There were no serious adverse events or adverse event-related study discontinuations. CONCLUSION: In patients with TSA, adalimumab treatment resulted in rapid and clinically significant improvement in the signs and symptoms of active disease. Adalimumab effectiveness and safety were sustained for at least 2 years. TRIAL REGISTRATION NUMBER: NCT00085644.

Safety analyses of adalimumab (HUMIRA) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis.

OBJECTIVE: To assess the safety of adalimumab in global clinical trials and postmarketing surveillance among patients with rheumatoid arthritis (RA). METHODS: Safety data for adalimumab treated patients from randomised controlled trials, open label extensions, and two phase IIIb open label trials were analysed. In addition, postmarketing spontaneous reports of adverse events in the United States were collected following Food and Drug Administration approval of adalimumab on 31 December 2002. RESULTS: As of 15 April 2005, the RA clinical trial safety database analysed covered 10,050 patients, representing 12,506 patient-years (PYs) of adalimumab exposure. The rate of serious infections, 5.1/100 PYs, was comparable to that reported on 31 August 2002 (4.9/100 PYs), and to published reports of RA populations naive to anti-tumour necrosis factor (TNF) therapy. Following implementation of tuberculosis (TB) screening in clinical trials, the rate of TB decreased. There were 34 cases of TB as of this analysis (0.27/100 PYs). The standardised incidence ratio for lymphoma was 3.19 (95% CI 1.78 to 5.26), consistent with the observed increased incidence in the general RA population. As of 30 June 2005, there were an estimated 78 522 PYs of exposure to adalimumab in the US postmarketing period. Seventeen TB cases were spontaneously reported (0.02/100 PYs) from the US. Rates of other postmarketing events of interest, such as congestive heart failure, systemic lupus erythematosus, opportunistic infections, blood dyscrasias, lymphomas, and demyelinating disease, support observations from clinical trials. CONCLUSION: Analyses of these data demonstrate that long term adalimumab treatment is generally safe and well tolerated in patients with RA.

Safety of extended treatment with anakinra in patients with rheumatoid arthritis.

OBJECTIVE: To determine the safety profile of anakinra after extended exposure in a diverse clinical trial population of patients with rheumatoid arthritis. METHODS: A six month, randomised, double blind phase comparing anakinra (100 mg/day) with placebo was followed by open label anakinra treatment for up to three years in patients with rheumatoid arthritis. Concomitant non-steroidal anti-inflammatory drugs, corticosteroids, and other disease modifying antirheumatic drugs were permitted. RESULTS: In all 1346 patients with rheumatoid arthritis received anakinra for up to three years. Patients had varying levels of disease severity, concomitant drug use, and comorbid conditions. Cumulative, exposure adjusted event (EAE) rates for all adverse events (AEs), serious AEs, and deaths were similar during each year of anakinra treatment; the overall rate (0 to 3 years) was similar to that observed for controls during the blinded phase. The most frequent AEs were injection site reactions (122.26 events/100 patient-years), rheumatoid arthritis progression (67.80 events/100 patient-years), and upper respiratory infections (26.09 events/100 patient-years). The EAE rate of serious infections was higher for patients treated with anakinra for 0 to 3 years (5.37 events/100 patient-years) than for controls during the blinded phase (1.65 events/100 patient-years). However, if the patient was not receiving corticosteroid treatment at baseline, the serious infection rate was substantially lower (2.87 event/100 patient-years). The overall incidence of malignancies was consistent with expected rates reported by SEER. Neutralising antibodies developed in 25 patients, but appeared to be transient in 12; neutralising antibody status did not appear related to occurrence of malignancies or serious infections. There were no clinically significant trends in laboratory data related to anakinra. CONCLUSION: Anakinra is safe and well tolerated for up to three years of continuous use in a diverse population of patients with rheumatoid arthritis.

A simplified disease activity index for rheumatoid arthritis for use in clinical practice.

OBJECTIVE: The objective of this study was to verify the usefulness of a simple disease activity index (SDAI) for rheumatoid arthritis (RA). METHODS: The SDAI is the numerical sum of five outcome parameters: tender and swollen joint count (based on a 28-joint assessment), patient and physician global assessment of disease activity [visual analogue scale (VAS) 0-10 cm] and level of C-reactive protein (mg/dl, normal <1 mg/dl). Analysis initially focused on MN301, one of the three phase III clinical trials of leflunomide, in order to assess possible correlations between the SDAI and the Health Assessment Questionnaire (HAQ) and Disease Activity Score 28 (DAS 28). Results were then compared with the other two trials, MN302 and US301. A total of 1839 patients were evaluated. At baseline, 6 and 12 months, the SDAI, DAS 28, American College of Rheumatology (ACR) response criteria and mean HAQ scores were determined for each patient and compared by linear regression for significant correlation. The SDAI was compared qualitatively to the ACR 20% at 3, 6 and 12 months. The index was further validated by comparing the SDAI with survey results obtained from rheumatologists' evaluations of disease activity in test cases. The survey results included defining categorical changes in the SDAI indicating major, minor or no improvement in disease activity in response to treatment. Changes in total Sharp score at 6 and 12 months of treatment were determined for each of these categories of the SDAI and for comparable categories of the DAS 28. RESULTS: The mean SDAI calculated for patients at baseline in study MN301 was 50.06 (range 25.10-96.10) and was, respectively, 50.55 (range 22.10-98.10) and 43.20 (range 12.90-78.20) in studies MN302 and US301. In all three trials, the SDAI was correlated with a high level of statistical significance to the DAS 28 and HAQ scores at baseline, endpoint and change at endpoint. Patients achieving the ACR 20, 50, 70 or 90% response showed proportionate changes in the SDAI. Analysis of surveyed physician responses showed a significant association between the perception of disease activity and the SDAI, as well as changes in the SDAI. Qualitative analysis of radiographic progression at 6 and 12 months for patients showing either major, minor or no improvement of the SDAI showed correspondingly larger increases of the total Sharp score at 12 months. CONCLUSION: The SDAI is a valid and sensitive assessment of disease activity and treatment response that is comparable with the DAS 28 and ACR response criteria; it is easy to calculate and therefore a viable tool for day-to-day clinical assessment of RA treatment. Overall results indicate that the SDAI has content, criterion and construct validity.

Early referral recommendation for newly diagnosed rheumatoid arthritis: evidence based development of a clinical guide.

BACKGROUND: Effective treatment of active rheumatoid arthritis (RA) requires early diagnosis and early disease modifying antirheumatic drug (DMARD) treatment to have an impact on long term morbidity and mortality. Clinical criteria would facilitate early referral of the patient with suspected RA to a rheumatologist for definitive diagnosis and initiation of DMARD treatment at that point in the disease most likely to have an impact on the long term outcome. OBJECTIVE: To develop a referral recommendation that may serve as a clinical guide for primary care doctors, enabling them to identify patients with suspected RA during the early inflammatory stages. METHODS: Key points of the referral criteria were formed based on a thorough literature review targeting early RA, early arthritis clinics, DMARD treatment for early RA, prognostic factors of disease progression, early RA clinical trials, and quality of life. Evidence was graded using the methods defined by Shekelle et al. A draft version of the criterion was circulated among the authors for critical evaluation. A consensus integrated these comments. RESULTS: Clinical evidence strongly supports the observations that structural damage occurs early in active RA and that early DMARD treatment improves the long term outcome of the disease. The observations indicate that rapid referral to a rheumatologist is advised when RA is suspected. This may be supported by the presence of any of the following: >or=3 swollen joints, metatarsophalangeal/metacarpophalangeal involvement, and morning stiffness of >or=30 minutes. CONCLUSION: The proposed early referral recommendation is a viable tool for primary care doctors to identify potential patients with active RA early in the disease. Early referral to a rheumatologist for definitive diagnosis and early DMARD treatment should improve the long term outcome of RA.

Long-term safety and efficacy of etanercept in patients with rheumatoid arthritis.

OBJECTIVE: Patients with rheumatoid arthritis (RA) treated with etanercept (Enbrel) in controlled studies of 3 to 6 months' duration had rapid and sustained improvement of their disease, with minimal safety issues. In this study, we examine safety and clinical benefit after longer term treatment with etanercept. METHODS: All adult patients with RA with a previously inadequate response to one or more disease modifying antirheumatic drugs, and who received at least one dose of etanercept as monotherapy in controlled or open label clinical trials were evaluated for safety and clinical benefit. Adverse event rates were compared as was evidence of continued benefit over time. RESULTS: Etanercept continued to be safe and well tolerated in 628 adult patients treated for a median of 25 mo (maximum 43 mo; 1109 patient-years). Nine percent of patients withdrew due to lack of efficacy and 7% due to adverse events. Most adverse events were mild, and no statistically significant increases in frequency of events were seen when patients received etanercept over longer periods of time. Clinical benefit was maintained with longterm therapy. A 100% improvement in individual disease activity measures was achieved by 17% to 28% of the patients. Fifty-five percent of patients who were taking corticosteroids (mean dose at baseline 6.6 mg/day) decreased or discontinued corticosteroid therapy while maintaining control of their arthritis symptoms. CONCLUSION: Etanercept continued to be safe and well tolerated, and its clinical benefit was sustained for a median of 25 mo and for as long as 43 mo in patients with RA.

Renal toxicity associated with disease-modifying antirheumatic drugs used for the treatment of rheumatoid arthritis.

OBJECTIVE: To provide a review of the renal toxicity of disease-modifying antirheumatic drugs (DMARDs) currently used for the treatment of rheumatoid arthritis. METHODS: Papers in American and European medical journals related to renal toxicity of DMARDs used for the treatment of rheumatoid arthritis were reviewed. Specific DMARDs reviewed were cyclosporine, gold, D-penicillamine, methotrexate, azathioprine, antimalarials, sulfasalazine, leflunomide, etanercept, infliximab, and DMARD combination therapy. RESULTS: The renal toxicity of DMARDs varies widely. Cyclosporine, gold, and D-penicillamine all have a serious potential for renal side effects, particularly in the elderly or in patients with compromised renal function. Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) increases the potential for renal damage. In contrast, methotrexate, azathioprine, antimalarials, sulfasalazine, leflunomide, etanercept, and infliximab have relatively little renal toxicity. CONCLUSIONS: The potential for renal toxicity should always be considered when determining which DMARD to use for RA therapy. DMARDs that combine efficacy with negligible renal adverse effects should be used for the treatment of patients susceptible to DMARD-associated renal damage.

A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis.

BACKGROUND: Etanercept, which blocks the action of tumor necrosis factor, reduces disease activity in patients with long-standing rheumatoid arthritis. Its efficacy in reducing disease activity and preventing joint damage in patients with active early rheumatoid arthritis is unknown. METHODS: We treated 632 patients with early rheumatoid arthritis with either twice-weekly subcutaneous etanercept (10 or 25 mg) or weekly oral methotrexate (mean, 19 mg per week) for 12 months. Clinical response was defined as the percent improvement in disease activity according to the criteria of the American College of Rheumatology. Bone erosion and joint-space narrowing were measured radiographically and scored with use of the Sharp scale. On this scale, an increase of 1 point represents one new erosion or minimal narrowing. RESULTS: As compared with patients who received methotrexate, patients who received the 25-mg dose of etanercept had a more rapid rate of improvement, with significantly more patients having 20 percent, 50 percent, and 70 percent improvement in disease activity during the first six months (P<0.05). The mean increase in the erosion score during the first 6 months was 0.30 in the group assigned to receive 25 mg of etanercept and 0.68 in the methotrexate group (P= 0.001), and the respective increases during the first 12 months were 0.47 and 1.03 (P=0.002). Among patients who received the 25-mg dose of etanercept, 72 percent had no increase in the erosion score, as compared with 60 percent of patients in the methotrexate group (P=0.007). This group of patients also had fewer adverse events (P=0.02) and fewer infections (P= 0.006) than the group that was treated with methotrexate. CONCLUSIONS: As compared with oral methotrexate, subcutaneous [corrected] etanercept acted more rapidly to decrease symptoms and slow joint damage in patients with early active rheumatoid arthritis.

Role of interleukin 1 and interleukin 1 receptor antagonist in the mediation of rheumatoid arthritis.

Chronic arthritis is characterised by chronic joint inflammation and concurrent joint erosion and destruction. The inflammatory cytokine interleukin 1 (IL1) has been shown to be a key mediator in the autoimmune disease rheumatoid arthritis (RA). Interleukin 1 mediates bone resorption and cartilage destruction, but may not play as dominant a part in joint swelling and inflammation. Interleukin 1 receptor antagonist (IL1Ra) selectively inhibits the effects of IL1 by competing for the IL1 receptor on all surfaces of the synovium. In a randomised controlled trial in 472 patients with active disease, IL1Ra 30 mg/day, 75 mg/day or 150 mg/day given by subcutaneous injection significantly reduced the signs and symptoms of RA at 24 weeks. An American College of Rheumatology (ACR) 20% response was seen in 43% of the patients treated with 150 mg/day at 24 weeks. IL1Ra was well tolerated; injection site reactions were the most common adverse event. In another trial, in 419 patients with active RA treated concomitantly with methotrexate, there were ACR 20% responses after 24 weeks in 42% of the patients treated with 1 mg/kg/day by subcutaneous injection and in 35% of those treated with 2 mg/kg/day. I1Ra offers a unique selective, targeted mechanism of action to block the IL1 mediated effects of RA.

Microemulsion formulation of cyclosporin (Sandimmun Neoral) vs Sandimmun: comparative safety, tolerability and efficacy in severe active rheumatoid arthritis. On behalf of the OLR 302 Study Group.

OBJECTIVE: To compare the safety, tolerability and efficacy of the new oral microemulsion formulation of cyclosporin A (CyA; Sandimmun Neoral) and the original CyA formulation (Sandimmun), in patients with severe active rheumatoid arthritis (RA), over a 12-month period. METHODS: In this double-blind, multicentre study, patients were randomized to treatment with Neoral or Sandimmun, starting with 2.5 mg/kg/day, with dose adjustments after 4 weeks. Primary efficacy criteria included patients' assessment of disease activity. Pharmacokinetic and safety assessments were performed at regular intervals. RESULTS: Compared with Sandimmun, Neoral showed a consistent trend towards greater clinical efficacy from week 12 onwards, including a significant difference in patients' assessment of disease activity at the study end-points. A significantly lower increase in dose from baseline was observed with Neoral at week 24. Pharmacokinetic assessments at week 24 showed increased absorption and decreased variability with Neoral. No differences in safety were found between treatment groups. CONCLUSION: These observations indicate that Neoral is as safe and at least as effective as Sandimmun and have important implications for patient management given the increasing role for CyA in the treatment of severe, active RA.

Leflunomide: efficacy and safety in clinical trials for the treatment of rheumatoid arthritis.

Leflunomide is a new disease modifying antirheumatic drug (DMARD) that inhibits lymphocyte proliferation by blocking dihydroorotate dehydrogenase (DHODH), the enzyme critical for the production of pyrimidine necessary for DNA synthesis. Through this mode of action, leflunomide inhibits the lymphocyte proliferation associated with the clonal expansion of T cells in rheumatoid arthritis (RA). In clinical trials, leflunomide was superior to placebo and comparable to sulfasalazine and methotrexate for improving both the signs and symptoms of RA. Leflunomide was also superior to placebo and sulfasalazine and comparable to methotrexate in overall improvement of physical function. Leflunomide was equivalent to methotrexate and sulfasalazine in retarding disease progression measured radiographically. Due to its unique mode of action in the treatment of RA, leflunomide shows value in combination therapy with methotrexate for patients refractory to methotrexate alone. The most common adverse reactions associated with leflunomide therapy include gastrointestinal symptoms, allergic reactions, reversible alopecia and elevated liver enzymes. Adverse events were generally mild to moderate, and resolved without complication. The results of phase II and phase III clinical trials indicate that leflunomide is a safe and efficacious drug for the treatment of RA.

Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial.

BACKGROUND: In a phase II study, etanercept (recombinant human tumor necrosis factor receptor [p75]:Fc fusion protein) safely produced rapid, dose-dependent improvement in rheumatoid arthritis over 3 months. OBJECTIVE: To confirm the benefit of etanercept therapy of longer duration and simplified dosing in patients with rheumatoid arthritis. DESIGN: Randomized, double-blind, placebo-controlled trial with blinded joint assessors. SETTING: 13 North American centers. PATIENTS: 234 patients with active rheumatoid arthritis who had an inadequate response to disease-modifying antirheumatic drugs. INTERVENTION: Twice-weekly subcutaneous injections of etanercept, 10 or 25 mg, or placebo for 6 months. MEASUREMENTS: The primary end points were 20% and 50% improvement in disease activity according to American College of Rheumatology (ACR) responses at 3 and 6 months. Other end points were 70% ACR responses at 3 and 6 months and other measures of disease activity at 3 and 6 months. RESULTS: Etanercept significantly reduced disease activity in a dose-related fashion. At 3 months, 62% of the patients receiving 25 mg of etanercept and 23% of the placebo recipients achieved 20% ACR response (P < 0.001). At 6 months, 59% of the 25-mg group and 11% of the placebo group achieved a 20% ACR response (P < 0.001); 40% and 5%, respectively, achieved a 50% ACR response (P < 0.01). The respective mean percentage reduction in the number of tender and swollen joints at 6 months was 56% and 47% in the 25-mg group and 6% and -7% in the placebo group (P < 0.05). Significantly more etanercept recipients achieved a 70% ACR response, minimal disease status (0 to 5 affected joints), and improved quality of life. Etanercept was well tolerated, with no dose-limiting toxic effects. CONCLUSIONS: Etanercept can safely provide rapid, significant, and sustained benefit in patients with active rheumatoid arthritis.

Leflunomide versus methotrexate: a comparison of the European and American experience.

This paper compares and contrasts the results of two major Phase III clinical trials that compared the efficacy and safety of leflunomide, a new disease-modifying antirheumatic drug (DMARD), and methotrexate. In both the American trial (US301) and the multinational trial (MN302), patients with active rheumatoid arthritis (RA) were given either leflunomide (20 mg/day after a loading dose of 100 mg/day for 3 days) or methotrexate (7.5-15 mg/week) for 52 weeks. US301 was also placebo-controlled. Folate supplementation was mandatory in US301 but was given to < 10% of the patients in MN302. In US301, American College of Rheumatology (ACR) 20% response rates and improvement in tender and swollen joints were significantly better than placebo in both treatment groups, but were not significantly different from each other. Both treatments significantly retarded radiographically assessed progression of RA compared to placebo, but the degree of retardation was significantly greater with leflunomide. In MN302, the ACR response rate and improvement in tender and swollen joints with leflunomide were similar to those seen in US301. The ACR response rate and improvements in all efficacy variables with methotrexate were significantly greater than with leflunomide, however. Radiographically assessed disease progression was not statistically different with the two treatments. Use of methotrexate without folate in MN302 was associated with a higher incidence of clinically significant elevations of liver enzyme levels. These results indicate that both leflunomide and methotrexate are effective DMARDs. The symptomatic relief provided by both drugs is similar when they are given with folate supplementation.

Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein.

BACKGROUND: Tumor necrosis factor (TNF) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis, and antagonism of TNF may reduce the activity of the disease. This study evaluated the safety and efficacy of a novel TNF antagonist - a recombinant fusion protein that consists of the soluble TNF receptor (p75) linked to the Fc portion of human IgG1 (TNFR:Fc). METHODS: In this multicenter, double-blind trial, we randomly assigned 180 patients with refractory rheumatoid arthritis to receive subcutaneous injections of placebo or one of three doses of TNFR:Fc (0.25, 2, or 16 mg per square meter of body-surface area) twice weekly for three months. The clinical response was measured by changes in composite symptoms of arthritis defined according to American College of Rheumatology criteria. RESULTS: Treatment with TNFR:Fc led to significant reductions in disease activity, and the therapeutic effects of TNFR:Fc were dose-related. At three months, 75 percent of the patients in the group assigned to 16 mg of TNFR:Fc per square meter had improvement of 20 percent or more in symptoms, as compared with 14 percent in the placebo group (P<0.001). In the group assigned to 16 mg per square meter, the mean percent reduction in the number of tender or swollen joints at three months was 61 percent, as compared with 25 percent in the placebo group (P<0.001). The most common adverse events were mild injection-site reactions and mild upper respiratory tract symptoms. There were no dose-limiting toxic effects, and no antibodies to TNFR:Fc were detected in serum samples. CONCLUSIONS: In this three-month trial TNFR:Fc was safe, well tolerated, and associated with improvement in the inflammatory symptoms of rheumatoid arthritis.

A comparison of Naprelan and Naprosyn in the treatment of osteoarthritis of the knee.

This double-blind, double-dummy, placebo-controlled, randomized study compared the safety and efficacy of Naprelan (Wyeth-Ayerst Laboratories, Philadelphia, Pennsylvania), a once-daily, controlled-release formulation of naproxen sodium with that of Naprosyn (Syntex Laboratories, Inc., Palo Alto, California), a conventional naproxen formulation. A total of 347 patients with osteoarthritis (OA) of the knee were assigned to receive Naprelan 1,000 mg once daily, Naprosyn 500 mg BID, or placebo for 12 weeks. Two hundred twenty-eight patients who completed the study then entered an open-label extension in which they received Naprelan 1,000 mg daily for as many as 9 additional months. In the double-blind phase, Naprelan and Naprosyn demonstrated comparable efficacy with no significant differences in mean efficacy scores. After 12 weeks, three primary variables significantly favored Naprelan and Naprosyn over placebo, while a fourth approached significance. Statistical analysis confirmed that Naprelan and Naprosyn were equally effective. Significantly more Naprosyn--than placebo-treated patients had at least one drug-related adverse event (AE) and at least one drug-related gastrointestinal (GI) system AE, but there were no significant differences between Naprelan and placebo. During the open-label phase, patients initially treated with Naprelan or Naprosyn maintained the improvement achieved in the double-blind phase, while those initially treated with placebo showed significantly greater improvement after the first month of Naprelan treatment than the other two groups. As assessed by one of two primary efficacy measures, the greater improvement in those initially treated with placebo was maintained until the end of the study. The AE profile for patients treated with Naprelan for up to 1 year was not significantly different than that for the double-blind phase. The results of this study have confirmed the efficacy of Naprelan 1,000 mg once daily in the treatment of OA as superior to placebo and equivalent to Naprosyn 500 mg BID.