Randomized placebo-controlled trial comparing efficacy and safety of valdecoxib with naproxen in patients with osteoarthritis

,

Original Research

Randomized placebo-controlled trial comparing efficacy and safety of valdecoxib with naproxen in patients with osteoarthritis

J Fam Pract. 2002 June;51(6):530-537

PDF Download

References

1. Klippel J, et al. Primer on the Rheumatic Diseases. 12th ed. Atlanta, GA: Arthritis Foundation; 2001.

2. Felson DT. Epidemiology of hip and knee osteoarthritis. Epidemiol Rev 1988;10:1-28.

3. Borda IT, Koff R. NSAIDs: A Profile of Adverse Effects. Philadelphia: Hanley and Belfus; 1995.

4. Bensen WG, Fiechtner JJ, McMillen JI, et al. Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: a randomized controlled trial. Mayo Clin Proc 1999;74:1095-105.

5. Geis GS. Update on clinical developments with celecoxib, a new specific COX-2 inhibitor: what can we expect? J Rheumatol 1999;26(suppl 56):31-6.

6. Altman R, Asch E, Bloch G, et al. The American College of Rheumatology criteria for the classification and reportings of osteoarthritis of the knee. Arthritis Rheum 1986;29:1039-49.

7. Schumacher HR. Primer on the Rheumatic Diseases. Atlanta, GA: Arthritis Foundation; 1986.

8. Cooperating Clinics Committee of American Rheumatism Association. A seven day variability study of 499 patients with peripheral rheumatoid arthritis. Arthritis Rheum 1965;8:302-34.

9. Ward JR, Williams HJ, Boyce E, et al. Comparison of auranofin, gold sodium thiomalate, and placebo in the treatment of rheumatoid arthritis. Subsets of responses. Am J Med 1983;75:133-7.

10. Bellamy N. WOMAC Osteoarthritis Index: A User’s Guide. London, Ontario, Canada: The Western Ontario and McMaster Universities; 1995.

11. Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika 1998;75:800-2.

12. Miller R. Survival Analyses. New York: John Wiley & Sons; 1998.

13. Simon R, Lee YJ. Nonparametric confidence limits for survival probabilities and median survival time. Cancer Treat Rep 1982;66:37-42.

14. Amin AR, Attur M, Patel RN, et al. Superinduction of cyclooxygenase-2 activity in human osteoarthritis-affected cartilage. Influence of nitric oxide. J Clin Invest 1997;99:1231-7.

15. Hay C, de Belleroche J. Carrageenan-induced hyperalgesia is associated with increased cyclooxygenase-2 expression in spinal cord. Neuroreport 1997;8:1249-51.

16. Kang RY, Freire Moar, Sigal E, et al. Expression of cyclooxygenase-2 in human and an animal model of rheumatoid arthritis. Br J Rheumatol 1996;35:711-8.

17. Bensen WG, Zhao SZ, Burke TA, et al. Upper gastrointestinal tolerability of celecoxib, a COX-2 specific inhibitor, compared to naproxen and placebo. J Rheumatol 2000;27:1876-83.

18. Day R, Morrison B, Luza A, et al. A randomized trial of the efficacy and tolerability of the COX-2 inhibitor rofecoxib vs ibuprofen in patients with osteoarthritis. Rofecoxib/Ibuprofen Comparator Study Group. Arch Intern Med 2000;160:1781-7.

19. Fiechtner J, Sikes D, Recker D. A double-blind, placebo-controlled dose ranging study to evaluate the efficacy of valdecoxib, a novel COX-2 specific inhibitor, in treating the signs and symptoms of osteoarthritis of the knee. Paper presented at: European League Against Rheumatism (EULAR); May 13–16, 2001; Prague, Czech Republic.

20. Garcia Rodriguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual nonsteroidal anti-inflammatory drugs. Lancet 1994;343:769-72.

21. Singh G, Ramey DR, Morfeld D, et al. Gastrointestinal tract complications of nonsteroidal anti-inflammatory drug treatment in rheumatoid arthritis. A prospective observational cohort study. Arch Intern Med 1996;156:1530-6.

22. Singh G, Rosen Ramey D. NSAID induced gastrointestinal complications: the ARAMIS perspective-1997. Arthritis, Rheumatism, and Aging Medical Information System. J Rheumatol 1998;51(suppl):8-16.

23. Watson DJ, Harper SE, Zhao PL, et al. Gastrointestinal tolerability of the selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib compared with nonselective COX-1 and COX-2 inhibitors in osteoarthritis. Arch Intern Med 2000;160:2998-3003.

24. Simon LS, Weaver AL, Graham DY, et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA 1999;282:1921-8.

25. Langman MJ, Jensen DM, Watson DJ, et al. Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs. JAMA 1999;282:1929-33.

26. Scholes D, Stergachis A, Penna P, Normand E, Hansten P. Nonsteroidal anti-inflammatory drug discontinuation in patients with osteoarthritis. J Rheumatol 1995;22:708-12.

Efficacy assessments

The following arthritis assessments were made at baseline and at 2, 6, and 12 weeks or at early termination after study drug administration. PaGAA or PhGAA was measured on a 5-point categorical scale, where 1 = very good, 2 = good, 3 = fair, 4 = poor, and 5 = very poor. The PAAP-VAS was measured on a scale of 0 to 100 mm, where 0 = no pain and 100 = most severe pain. The Western Ontario and McMaster’s Universities (WOMAC) Osteoarthritis indices including Pain, Stiffness, Physical Function, and Composite were measured as described previously.¹⁰

Upper gastrointestinal assessments

Upper gastrointestinal tract endoscopy was performed within 7 days before the first study dose and at the 12-week assessment or at early termination if the patient withdrew. An endoscopy could be performed at any time if the patient experienced symptoms suggestive of an ulcer. The endoscopists performing baseline and 12-week (early termination) assessments remained blinded throughout the study.

General safety assessments

Clinical laboratory tests were performed at screening, baseline, weeks 2, 6, and 12, or at early termination, and a complete physical examination was performed at screening and final visits. The incidence of adverse events occurring in each treatment arm was monitored throughout the study. Adverse events occurring within 7 days and serious adverse events occurring within 30 days of the last study dosage of medication were included in the safety analyses.

Statistical analyses

A sample size of 200 patients per treatment group was deemed sufficient to detect a difference in ulcer rates of 5% for valdecoxib vs 16% for naproxen, with 80% power and type 1 error at .017 (adjusted for 3 primary comparisons against placebo). Homogeneity of treatment groups at baseline with respect to age, height, weight, duration of osteoarthritis, PAAP-VAS, and WOMAC Osteoarthritis Index scores was assessed with 2-way analysis of variance, with treatment group and center as factors. All other demographics and baseline characteristics were compared with the Cochran-Mantel-Haenszel (CMH) test, stratified by center.

All efficacy assessments were performed on the modified intent-to-treat (ITT) cohort by using the last observation carried forward approach. The ITT cohort comprised all patients who were randomized and had taken at least 1 dose of study medication. Analyses of mean change from baseline for PaGAA, PhGAA, PAAP-VAS, and WOMAC Osteoarthritis indices were performed by using analysis of covariance, with treatment and center as factors and the corresponding baseline score as the covariate. Pairwise comparisons of valdecoxib at dosages of 10 and 20 mg once daily vs placebo were interpreted with the Hochberg procedure.¹¹ Primary pairwise comparisons were amended in the statistical analysis plan before data unblinding to compare placebo with 10 and 20 mg valdecoxib, but not with the 5-mg dose. For all other comparisons, including 5 mg valdecoxib and naproxen vs placebo, differences were considered significant if the pairwise P values were less than .05. The incidence of withdrawal due to treatment failure was analyzed by the Fisher exact test, and the time to withdrawal in each treatment group was analyzed by log-rank test and plotted with the Kaplan-Meier product limit.^12,13

Upper gastrointestinal tract endoscopic analyses were performed on the upper gastrointestinal tract ITT population. Randomized patients were included in this cohort if they received at least 1 dose of study medication and had undergone pretreatment and posttreatment endoscopies. Overall and pairwise comparisons of gastroduodenal, gastric, and duodenal ulcers and erosions were assessed with the CMH test stratified by center. The incidence of adverse events was compared between treatment groups with the Fisher exact test. Changes in vital signs were compared between treatment groups with an analysis of covariance using pairwise treatment comparisons, with treatment group as a factor and baseline value as a covariate.

Results

Patient baseline characteristics

Of the 1019 eligible randomized patients, 1 patient randomized to 10 mg/day valdecoxib, 1 to 20 mg/day valdecoxib, and 1 to 500 mg naproxen twice daily did not take the study medication and were excluded from efficacy and safety analyses. The remaining 1016 randomized patients received study medication and were included in the ITT cohort on which analyses of all efficacy end points were based. A total of 269 patients withdrew before the end of the study due to treatment failure, preexisting protocol violations, noncompliance, or adverse signs and symptoms, or were lost to follow-up: 74 patients in the placebo group, 39 in the 5-mg valdecoxib group, 56 in the 10-mg valdecoxib group, 44 in the 20-mg valdecoxib group, and 56 in the naproxen group. The upper gastrointestinal tract ITT cohort comprised 908 patients who were included in the upper gastrointestinal tract safety analyses. More than 90% of patients included in the study evaluated their osteoarthritis as poor to very poor as assessed by baseline PaGAA scores. Treatment groups were homogeneous with respect to demographics, vital signs, medical history, and all baseline arthritis assessments (Table 1).