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.

TABLE 1
Patient baseline characteristics

		Valdecoxib			Naproxen
	Placebo (n = 205)	5 mg qd (n = 201)	10 mg qd (n = 206)	20 mg qd (n = 202)	500 mg bid (n = 205)
Mean (SD) age, y	60.3 (10.5)	58.7 (11.9)	59.8 (11.0)	59.6 (10.4)	60.4 (10.7)
Mean (SD) weight, kg	87.5 (21.2)	91.4 (22.6)	89.3 (21.4)	92.6 (23.7)	88.1 (21.7)
Race, n (%)
White	162 (79)	155 (77)	154 (75)	160 (79)	163 (80)
Black	21 (10)	26 (13)	24 (12)	24 (12)	23 (11)
Asian	1 (0)	1 (0)	1 (0)	1 (0)	2 (1)
Hispanic	19 (9)	18 (9)	25 (12)	15 (7)	15 (7)
Male sex, n (%)	73 (36)	73 (36)	72 (35)	66 (33)	76 (37)
Mean (SD) disease duration, y	8.3 (8.0)	9.8 (9.5)	8.7 (8.0)	9.2 (8.0)	9.4 (8.7)
History of GI bleeding, n (%)	2 (1)	0 (0)	3 (1)	2 (1)	3 (1)
History of gastroduodenal ulcer, n (%)	20 (10)	21 (10)	24 (12)	28 (14)	31 (15)
PaGAA, n (%)
Poor	168 (82)	175 (87)	168 (82)	162 (80)	169 (82)
Very poor	33 (16)	23 (11)	32 (16)	36 (18)	31 (15)
PhGAA, n (%)
Poor	179 (87)	181 (90)	176 (85)	173 (86)	175 (85)
Very poor	24 (12)	18 (9)	25 (12)	24 (12)	25 (12)
No significant differences were observed between treatment groups at any baseline characteristic.
bid, twice daily; GI, gastrointestinal; PaGAA, Patient’s Global Assessment of Arthritis; PhGAA, Physician’s Global Assessment of Arthritis; qd, once daily.

Efficacy

The least square mean change in the PaGAA was significantly improved at most assessments in response to valdecoxib (10 and 20 mg/day) and 500 mg naproxen twice daily compared with placebo (Table 2). However, the improvement in response to valdecoxib 5 mg qd did not reach statistical significance (Table 2). Significant improvements in the PhGAA were observed in response to valdecoxib and naproxen at all assessments (Table 2).

The dosages of 20 mg/day valdecoxib and 500 mg naproxen twice daily were associated with a reduction in pain, as assessed by the PAAP-VAS scores. Pain reduction associated with 5 and 10 mg/day valdecoxib was significantly better than that with placebo at all assessments except for week 12 (Table 2).

Valdecoxib and naproxen treatments improved the WOMAC Pain, Stiffness, Physical Function, and Composite indices compared with placebo at 2, 6, and 12 weeks. Valdecoxib 20 mg/day and naproxen 500 mg twice daily produced statistically significant changes in all WOMAC Osteoarthritis scores throughout the 12-week study period compared with placebo (P < .05). WOMAC Pain scores for 10 mg valdecoxib were significantly different from those for placebo at 2 weeks (P < .001) but not at 6 or 12 weeks. No significant differences were noted between any of the valdecoxib treatment doses and naproxen in terms of improvement in WOMAC indices.

The incidences of withdrawal due to treatment failure were 20% (95% confidence interval [CI], 15.3–26.8) in the placebo group; 8% (95% CI, 4.8–12.8), 12% (95% CI, 7.8–17.1), and 10% (95% CI, 6.3–15.2) in the 5-, 10-, and 20-mg/day valdecoxib groups; and 6% (95% CI, 3.6–10.9) in the 500-mg naproxen group (P < .05; Table 3). Patients in the placebo group withdrew at a significantly faster rate than those in the 4 active treatment groups (P < .05), but there were no significant differences in withdrawal rates across the 4 active treatment groups.

TABLE 2
Baseline arthritis assessments and mean changes from baseline scores

		Valdecoxib			Naproxen
	Placebo (n = 205)	5 mg qd (n = 201)	10 mg qd (n = 205)	20 mg qd (n = 201)	500 mg bid (n = 204)
PhGAA^§
Baseline mean	4.10	4.07	4.09	4.09	4.10
LSM change
Week 2 (CI)	-1.04 (-1.16, -0.91)	-1.31^‡(-1.44, -1.19)	-1.37^‡(-1.50, -1.25)	-1.42^‡(-1.54, -1.29)	-1.35^‡(-1.48, -1.23)
Week 6 (CI)	-1.22 (-1.35, -1.08)	-1.44*(-1.58, -1.31)	-1.50^†(-1.63, -1.36)	-1.41* (-1.55, -1.28)	-1.45* (-1.59, -1.32)
Week 12 (CI)	-1.22 (-1.36, -1.08)	-1.43* (-1.58, -1.28)	-1.52^†(-1.67, -1.38)	-1.45* (-1.60, -1.31)	-1.43* (-1.58, -1.29)
PAAP^║
Baseline mean	71.20	71.42	72.41	72.54	72.36
LSM change
Week 2 (CI)	-21.19 (-24.80, -17.58)	-28.46^†(-32.11, -24.82)	-30.21^‡(-33.83, -26.59)	-32.07^‡(-35.73, -28.41)	-31.03^‡(-34.66, -27.40)
Week 6 (CI)	-23.92 (-27.72, -20.12)	-30.81^†(-34.65, -26.97)	-29.85* (-33.67, -26.04)	-32.28^†(-36.13, -28.42)	-31.84^†(-35.66, -28.02)
Week 12 (CI)	-25.97 (-30.02, -21.92)	-31.33 (-35.42, -27.24)	-30.41 (-34.47, -30.41)	-32.70* (-36.81, -32.70)	-31.83* (-35.90, -27.76)
WOMAC OA, Stiffness ^¶
Baseline mean	4.84	4.87	4.91	4.73	4.94
LSM change
Week 2 (CI)	-0.78 (-0.98, -0.57)	-1.03 (-1.24, -0.82)	-1.20^†(-1.41, -0.99)	-1.24^†(-1.45, -1.03)	-1.28^‡(-1.49, -1.08)
Week 6 (CI)	-1.04 (-1.27, -0.82)	-1.25 (-1.48, -1.02)	-1.42* (-1.65, -1.20)	-1.43* (-1.66, -1.20)	-1.40^†(-1.62, -1.17)
Week 12 (CI)	-1.12 (-1.36, -0.89)	-1.33 (-1.57, -1.09)	-1.41 (-1.65, -1.17)	-1.46* (-1.70, -1.22)	-1.54* (-1.78, -1.30)
WOMAC OA, Composite ^#
Baseline mean	53.49	53.03	54.73	53.42	53.67
LSM change
Week 2 (CI)	-10.13 (-12.28, -7.99)	-13.26* (-15.42, -11.09)	-15.05^‡(-17.20, -12.90)	-15.44^‡(-17.63, -13.32)	-15.47^‡(-17.63, -13.32)
Week 6 (CI)	-12.98 (-15.45, -10.51)	-15.47 (-17.97, -12.98)	-16.74* (-19.22, -14.26)	-17.33* (-19.48, -14.51)	-16.99* (-19.48, -14.51)
Week 12 (CI)	-13.48 (-16.07, -10.89)	-16.84 (-19.46, -14.23)	-17.34* (-19.93, -14.74)	-17.22* (-20.64, -15.44)	-18.04* (-20.64, -15.44)
*P < .05 vs placebo, significant.
^† P < .01 vs placebo, significant.
^‡ P < .001 vs placebo, significant.
^§ Scale = 1 (very good) to 5 (very poor).
^║ Scale = 0 mm (no pain) to 100 mm (most severe pain).
^¶ Scale = 0 (no symptoms) to 8 (worse symptoms).
^# Scale = 0 (no symptoms) to 96 (worse symptoms).
bid, twice daily; CI, 95% confidence interval; LSM, least square mean; PAAP, Patient’s Assessment of Arthritis Pain; PhGAA, Physician’s Global Assessment of Arthritis; qd, once daily; WOMAC OA, Western Ontario and McMaster’s Universities Osteoarthritis Index.

TABLE 3
Incidence of gastroduodenal, gastric, and duodenal ulcers (>5 mm) at final endoscopic evaluation

		Valdecoxib			Naproxen
	Placebo (n = 178)	5 mg qd (n = 188)	10 mg qd (n = 174)	20 mg qd (n = 185)	500 mg bid (n = 183)
Gastroduodenal^§	8 (4) [2.1, 9.0]	6 (3)^† [1.3, 7.1]	5 (3)^† [1.1, 6.9]	10 (5) [2.8, 10.0]	18 (10)* [6.1, 15.3]
Gastric^§	8 (4) [2.1, 9.0]	4 (2)^‡ [0.7, 5.7]	3 (2)^‡ [0.4, 5.4]	9 (5) [2.4, 9.3]	16 (9) [5.2, 14.1]
Duodenal^§	0 (0) [0.05, 2.6]	2 (1) [0.2, 4.2]	2 (1) [0.2, 4.5]	1 (1) [0.0, 3.4]	2 (1) [0.2, 4.3]
Symptomatic ulcers (n)	0	1	2	3	7
*P < .05 vs placebo.
^† P < .05 vs naproxen.
^‡ P < .01 vs naproxen.
^§ Data are presented as n (%) [95% confidence interval].
bid, twice daily; qd, once daily.