Clinical Trials of Coxibs in Osteoarthritis (OA)

Clinical Trials of Coxibs in OA

Celecoxib

The first published trial of a coxib was a 2-week, placebo-controlled, dose-ranging study of celecoxib 40 mg, 100 mg, or 200 mg twice daily in 293 patients with OA of the knee. Although all three doses demonstrated clinical improvement, only the two higher doses maintained mean improvements significantly greater than with placebo (P ² .048).(8)

Another study, conducted in 1,003 patients with OA of the knee, was reported the following year. In this 12-week trial, clinical improvements with celecoxib 100 mg or 200 mg twice daily were greater than with celecoxib 50 mg twice daily and comparable to naproxen 500 mg twice daily. Mean measures of efficacy with celecoxib 100 mg or 200 mg twice daily or naproxen 500 mg twice daily were significantly superior to outcomes with placebo (P ² ≤.05).(34)

Another placebo- and active-comparator controlled study of celecoxib in OA involved 600 patients with OA of the knee who were treated for 6 weeks with celecoxib 100 mg twice daily, diclofenac 50 mg three times daily, or placebo. Mean improvements with celecoxib or diclofenac were comparable and significantly superior to outcomes with placebo (P <.001).(35)

A 6-week, placebo-controlled study compared treatment with celecoxib 100 mg twice daily to celecoxib 200 mg once daily in 718 patients with OA of the knee. Both regimens achieved comparable outcomes (P <.05).(26) In a recent 12-week study designed to examine safety, 13,194 patients with OA of the knee, hip, or hand were treated with celecoxib 100 mg or 200 mg twice daily, naproxen 500 mg twice daily, or diclofenac SR 50 mg twice daily. Mean improvements with either regimen of celecoxib were comparable to those achieved with diclofenac or naproxen.(36)

The efficacy of coxibs in the treatment of osteoarthritis

—Celecoxib, rofecoxib, and valdecoxib are approved for the treatment of OA in the United States.

—The efficacy of celecoxib 100 mg twice daily, 200 mg once daily, and 200 mg twice daily in OA is comparable to that of diclofenac 50 mg three times daily and naproxen 500 mg twice daily and significantly superior to placebo.

—The efficacy of rofecoxib 12.5 mg once daily and 25 mg once daily in OA is comparable to ibuprofen 800 mg three times daily, nabumetone 1,500 mg once daily, and diclofenac 50 mg three times daily and significantly superior to placebo.

—In direct comparisons in OA patients, rofecoxib 25 mg when given once daily in the morning was significantly more effective than celecoxib 200 mg once daily or acetaminophen 1,000 mg four times daily.

—The efficacy of valdecoxib 5 mg once daily, 10 mg twice daily, or 10 mg once daily in OA is comparable to naproxen 500 mg twice daily and superior to placebo.

—Etoricoxib 60 mg once daily and 90 mg once daily are significantly more effective than placebo and comparable to naproxen 500 mg twice daily in the treatment of OA.

—COX-189, an experimental coxib, 50 mg, 100 mg, 200 mg twice daily or 400 mg once daily, provides relief of OA symptoms comparable to diclofenac SR 75 mg twice daily and is significantly superior to placebo.

Rofecoxib

Ten studies of the efficacy of rofecoxib in the treatment of OA have been reported to date.

Two phase II studies tested a range of rofecoxib dosages during a 6-week period.(37-39) In the first, the efficacy of rofecoxib 5 mg, 12.5 mg, 25 mg, or 50 mg once daily was compared with a placebo in 672 patients with OA of the hip or knee.(39) Mean improvements with rofecoxib at all doses were superior to those with placebo. The outcomes with rofecoxib 12.5 mg, 25 mg, and 50 mg once daily were superior to those seen with rofecoxib 5 mg once daily. The second study was conducted in 219 patients with OA of the knee treated with rofecoxib 25 mg or 125 mg once daily, or placebo. Both rofecoxib regimens demonstrated comparable efficacy, each resulting in significantly better responses than seen with placebo (P <.001).(37)

Six phase III studies compared the efficacy of rofecoxib with a nonselective NSAID and/or placebo. Two 6-week trials enrolled patients with OA of the hip or knee who were treated with rofecoxib 12.5 mg or 25 mg once daily, ibuprofen 800 mg three times daily, or placebo. Mean improvements seen with rofecoxib were comparable to those with ibuprofen and significantly superior to those with placebo (P ² .009 and P <.001, respectively).(29,40)

Another 6-week trial compared the efficacy of rofecoxib 12.5 mg once daily with nabumetone 1,000 mg once daily or placebo in 1,042 patients with OA. In this study, the efficacy of rofecoxib was significantly superior to nabumetone (P <.05), and both treatments had greater efficacy than placebo (P < .001).(41) In an elderly population of 341 patients at least 80 years of age with OA of the hip or knee who were treated for 6 weeks with rofecoxib 12.5 mg or 25 mg once daily, nabumetone 1,500 mg once daily, or placebo, the mean improvements with rofecoxib were comparable to those with nabumetone and significantly superior to placebo (P < .05).(13)

Two 1-year trials evaluated the efficacy of rofecoxib 12.5 mg or 25 mg once daily and diclofenac 50 mg three times daily in patients with OA of the knee or hip. The efficacy of both rofecoxib regimens was comparable to that with diclofenac.(11,30)

Comparative trials of rofecoxib and celecoxib

Several phase IV studies comparing the efficacy of rofecoxib with that of celecoxib have been done. In one study, patients with OA of the knee were treated for 6 weeks with rofecoxib 12.5 mg or 25 mg once daily, celecoxib 200 mg once daily, or acetaminophen 1,000 mg four times daily; no rescue analgesics were allowed, and all medications given once daily were dosed in the morning. By all outcome measures, rofecoxib 25 mg once daily was significantly superior to acetaminophen. In addition, rofecoxib 25 mg once daily was significantly more efficacious than celecoxib 200 mg once daily as assessed by patient global assessment of response to therapy and by mean improvement on the WOMAC pain and stiffness scales.(42)

A second, larger study involving 1,082 patients with OA evaluated rofecoxib 25 mg once daily, celecoxib 200 mg once daily, or placebo after 6 weeks of treatment; again, all medications were dosed in the morning. All outcome measures were significantly superior with rofecoxib than with celecoxib or placebo.(43)

Such findings have clinical significance, bolstering their statistical significance. Another study, however, found the efficacy of celecoxib 200 mg once daily and rofecoxib 25 mg once daily in treating OA of the knee to be comparable (both were superior to placebo).(44) However, in this study, all medications were dosed once in the evening. These results are consistent with the half-life of each of the two agents.

The findings that the recommended dose of rofecoxib for the treatment of OA was significantly more effective than the recommended dose of celecoxib for the treatment of OA may be related to the fact that rofecoxib has a longer half-life compared with that of celecoxib.(45) It is likely that this results in clinically significant sustained relief of pain and stiffness throughout the day with rofecoxib when both drugs are dosed once daily in the morning.

Valdecoxib

Valdecoxib was recently approved in the United States for the treatment of OA at a dosage of 10 mg once daily, making it the third coxib available for that indication. The efficacy of valdecoxib in OA was shown in a 6-week, dose-ranging trial conducted in 642 patients with OA of the knee. Patients were treated with valdecoxib 10 mg either twice daily or once daily, 0.5 mg, 1.25 mg, 2.5 mg, or 5 mg twice daily; or naproxen 500 mg twice daily; or placebo. Maximum efficacy with valdecoxib was achieved with the 5 mg once daily, 10 mg twice daily, and 10 mg once daily regimens. These were comparable to naproxen and superior to placebo in all outcome measures.(47)

Etoricoxib

Currently under investigation, etoricoxib is a second- generation coxib that has demonstrated efficacy for the treatment of OA. A 6-week, dose-ranging study was conducted in 617 patients with OA of the knee. Treatment with etoricoxib 5 mg, 10 mg, 30 mg, 60 mg, and 90 mg once daily produced dosedependent efficacy that was superior to placebo and maximal at a dosage of 60 mg once daily (P <.05). Patients receiving either placebo or etoricoxib 5 mg or 10 mg once daily were then reallocated to treatment with etoricoxib 30 mg, 60 mg, or 90 mg once daily or diclofenac 50 mg three times daily for an additional 46 weeks. Etoricoxib 60 mg once daily or 90 mg once daily was more effective than 30 mg once daily in all outcome measures and comparable to diclofenac.(32)

A second study of etoricoxib efficacy was conducted in 496 patients with OA of the knee or hip. In the initial phase of the trial, patients were treated with etoricoxib 60 mg once daily, naproxen 500 mg twice daily, or placebo for 12 weeks. Placebotreated patients were then reallocated to treatment with either etoricoxib 60 mg once daily or naproxen 500 mg twice daily for an additional 40 weeks. By all outcome measures, the efficacy of etoricoxib at week 12 was significantly superior to the outcomes with placebo, and at week 12 and week 52 was comparable to that of naproxen.(33)

COX-189

A multinational, dose-ranging trial evaluated the efficacy of an experimental coxib, COX-189, in 583 patients with OA of the hip or knee. Patients were treated for 4 weeks with COX-189 400 mg once daily; COX-189 50 mg, 100 mg, 200 mg twice daily; diclofenac SR 75 mg twice daily; or placebo. The minimum effective COX-189 dosage was 50 mg twice daily. By both primary and secondary outcome measures, all regimens of COX-189 provided comparable efficacy to diclofenac and significantly better improvement than placebo (P <.05).(48)

Schnitzer TJ, Hochberg MC. COX-2-selective inhibitors in the treatment of arthritis. Cleve Clin J Med 2002;69:SI20-30.