Clinical Rheumatology

, Volume 25, Issue 1, pp 42–53 | Cite as

Lumiracoxib is effective in the treatment of osteoarthritis of the knee: a prospective randomized 13-week study versus placebo and celecoxib

  • Roy Fleischmann
  • Eric Sheldon
  • José Maldonado-Cocco
  • Dipen Dutta
  • Sue Yu
  • Victor S. Sloan
Original Article

Abstract

The objective of this study was to evaluate the efficacy, safety and tolerability of lumiracoxib compared with placebo and celecoxib in patients with osteoarthritis (OA). Following a 3- to 7-day washout period for previous non-steroidal anti-inflammatory drugs, 1600 patients aged ≥18 years with primary knee OA were randomized to receive lumiracoxib 200 or 400 mg once daily (o.d.), celecoxib 200 mg o.d. or placebo for 13 weeks. Primary efficacy variables were OA pain intensity in the target knee, patient’s global assessment of disease activity and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale and total scores at week 13. Secondary variables included OA pain intensity in the target knee and physician’s and patient’s global assessments of disease activity by visit. Exploratory analysis of responder rates using the Outcomes Measures in Rheumatology Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) criteria was performed. Safety and tolerability were assessed. Lumiracoxib was superior to placebo in all primary and secondary variables and was generally similar to celecoxib. There were no statistically significant differences between the two doses of lumiracoxib. All active treatments were significantly more effective than placebo at weeks 2 and 13 in terms of response to treatment assessed using OMERACT-OARSI criteria. The incidence of adverse events was similar across the groups. Lumiracoxib 200 mg o.d. is a well-tolerated and effective treatment option for OA of the knee, providing pain relief and improved functional status with efficacy superior to placebo and similar to celecoxib. Lumiracoxib demonstrated a tolerability profile similar to placebo and celecoxib.

Keywords

Celecoxib Lumiracoxib Osteoarthritis Pain relief Selective cyclooxygenase-2 inhibitor 

Notes

Acknowledgements

Study supported by Novartis Pharma AG. The authors would like to acknowledge Ornella Della Casa Alberighi for her invaluable contribution on the OARSI-OMERACT data interpretation.

References

  1. 1.
    Todd C (2002) Meeting the therapeutic challenge of the patient with osteoarthritis. J Am Pharm Assoc (Wash) 42:74–82CrossRefGoogle Scholar
  2. 2.
    Reginster JY (2002) The prevalence and burden of arthritis. Rheumatology 41 [Suppl 1]:3–6CrossRefPubMedGoogle Scholar
  3. 3.
    Schnitzer TJ, American College of Rheumatology (2002) Update of ACR guidelines for osteoarthritis: role of the coxibs. J Pain Symptom Manage 23 [Suppl 4]:S24–S30CrossRefPubMedGoogle Scholar
  4. 4.
    Dougados M (2001) The role of anti-inflammatory drugs in the treatment of osteoarthritis: a European viewpoint. Clin Exp Rheumatol 19 [Suppl 25]:S9–S14PubMedGoogle Scholar
  5. 5.
    American College of Rheumatology (2000) Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum 43:1905–1915Google Scholar
  6. 6.
    Vane JR, Botting RM (1998) Mechanism of action of non-steroidal anti-inflammatory drugs. Am J Med 104 [Suppl 3A]:2S–8SCrossRefGoogle Scholar
  7. 7.
    Masferrer JL, Zweifel BS, Manning PT, Hauser SD, Leahy KM, Smith WG, Isakson PC, Seibert K (1994) Selective inhibition of inducible cyclooxygenase 2 in vivo is antiinflammatory and nonulcerogenic. Proc Natl Acad Sci U S A 91:3228–3232PubMedGoogle Scholar
  8. 8.
    Needleman P, Isakson PC (1997) The discovery and function of COX-2. J Rheumatol 24 [Suppl 49]:6–8PubMedGoogle Scholar
  9. 9.
    Jouzeau JY, Terlain B, Abid A, Nedelec E, Netter P (1997) Cyclo-oxygenase isoenzymes. How recent findings affect thinking about nonsteroidal anti-inflammatory drugs. Drugs 53:563–582PubMedGoogle Scholar
  10. 10.
    Bensen WG, Fiechtner JJ, McMillen JI, Zhao WW, Yu SS, Woods EM, Hubbard RC, Isakson PC, Verburg KM, Geis GS (1999) Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: a randomized controlled trial. Mayo Clin Proc 74:1095–1105PubMedGoogle Scholar
  11. 11.
    Cannon GW, Caldwell JR, Holt P, McLean B, Seidenberg B, Bolognese J, Ehrich E, Mukhopadhyay S, Daniels B (2000) Rofecoxib, a specific inhibitor of cyclooxygenase 2, with clinical efficacy comparable with that of diclofenac sodium: results of a one-year, randomized, clinical trial in patients with osteoarthritis of the knee and hip. Rofecoxib Phase III Protocol 035 Study Group. Arthritis Rheum 43:978–987CrossRefPubMedGoogle Scholar
  12. 12.
    Bensen WG, Zhao SZ, Burke TA, Zabinski RA, Makuch RW, Maurath CJ, Agrawal NM, Geis GS (2000) Upper gastrointestinal tolerability of celecoxib, a COX-2 specific inhibitor, compared to naproxen and placebo. J Rheumatol 27:1876–1883PubMedGoogle Scholar
  13. 13.
    Day R, Morrison B, Luza A, Castanedo O, Strusberg A, Nahim M, Helgetveit KB, Kress B, Daniels B, Bolognese J, Krupa D, Seidenberg B, Ehrich E (2000) 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 160:1781–1787CrossRefPubMedGoogle Scholar
  14. 14.
    Hawkey C, Laine L, Simon T, Beaulieu A, Maldonado-Cocco J, Acevedo E, Shahane A, Quan H, Bolognese J, Mortensen E (2000) Comparison of the effect of rofecoxib (a cyclooxygenase 2 inhibitor), ibuprofen, and placebo on the gastroduodenal mucosa of patients with osteoarthritis: a randomized, double-blind, placebo-controlled trial. The Rofecoxib Osteoarthritis Endoscopy Multinational Study Group. Arthritis Rheum 43:370–377CrossRefPubMedGoogle Scholar
  15. 15.
    Mangold JB, Gu H, Rodriguez LC, Bonner J, Dickson J, Rordorf C (2004) Pharmacokinetics and metabolism of lumiracoxib in healthy male subjects. Drug Metab Dispos 32:566–571CrossRefPubMedGoogle Scholar
  16. 16.
    Scott G, Rordorf C, Blood P, Branson J, Milosavljev S, Greig G (2002) Dose escalation study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of COX189 in healthy subjects (abstract FRI0300). Ann Rheum Dis 61 [Suppl I]:242CrossRefPubMedGoogle Scholar
  17. 17.
    Scott G, Rordorf C, Reynolds C, Kalbag J, Looby M, Milosavljev S, Weaver M, Huff JP, Ruff DA (2004) Pharmacokinetics of lumiracoxib in plasma and synovial fluid. Clin Pharmacokinet 43:467–478PubMedGoogle Scholar
  18. 18.
    Hartmann S, Scott G, Rordorf C, Campestrini J, Branson J, Keller U (2003) Lumiracoxib demonstrates high absolute bioavailability in healthy subjects (abstract P-199). In: Proceedings of the Sixth European Association of Clinical Pharmacology and Therapeutics (EACPT) June 24–28, Istanbul, TurkeyGoogle Scholar
  19. 19.
    Scott G, Rordorf C, Milosavljev S, Chase W, Fleischmann RM, Kivitz AJ (2003) Multiple-dose lumiracoxib shows rapid absorption and COX-2 selectivity without accumulation in patients with rheumatoid arthritis (abstract P-197). In: Tulunay FC, Orme M (eds) European collaboration: towards drug development and rational drug therapy. Proceedings of the Sixth Congress of the European Association for Clinical Pharmacology and Therapeutics. Springer-Verlag, Berlin p 124Google Scholar
  20. 20.
    Brune K, Hinz B (2004) Selective cyclooxygenase-2 inhibitors: similarities and differences. Scand J Rheumatol 33:1–6PubMedGoogle Scholar
  21. 21.
    Warner TD, Mitchell JA (2004) Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic. FASEB J 18:790–804CrossRefPubMedGoogle Scholar
  22. 22.
    Clark K, Kulathila R, Koehn J, Rieffel S, Strauss A, Hu S, Kalfoglou M, Szeto D, Lasala D, Sabio M, Wang X, Marshall P (2004) Crystal structure of the lumiracoxib:cyclooxygenase-2 complex (abstract 178). American Chemical Society (ACS) Book of Abstracts; 22–26 August, Philadelphia, USAGoogle Scholar
  23. 23.
    Weaver ML, Flood DJ, Kimble EF, Fujimoto RA (2003) Lumiracoxib demonstrates preferential distribution to inflamed tissue in the rat following a single oral dose: an effect not seen with other cyclooxygenase-2 inhibitors (abstract AB0044). Ann Rheum Dis 62 [Suppl I]:378CrossRefPubMedGoogle Scholar
  24. 24.
    Dawson J, Jagher B, Toscano KT, Fujimoto RA, Quadros E (2003) Lumiracoxib shows rapid distribution to inflamed sites in a rat tissue chamber model compared with rofecoxib and celecoxib (abstract AB0042). Ann Rheum Dis 62 [Suppl I]:377CrossRefPubMedGoogle Scholar
  25. 25.
    Wallis WJ, Simkin PA (1983) Antirheumatic drug levels in human synovial fluid and synovial tissue: observations on extravascular pharmacokinetics. Clin Pharmacokinet 8:496–522PubMedGoogle Scholar
  26. 26.
    Shire Pharmaceuticals Ltd (2002) Lodine SR Capsules UK Summary of Product Characteristics. Available at http://emc.medicines.org.uk/emc/assets/c/html/ displaydoc.asp?documentid=3581 (accessed 10 December 2004)
  27. 27.
    Schnitzer TJ, Beier J, Geusens P, Hasler P, Patel SJ, Senftleber I, Gitton X, Moore A, Sloan VS, Poor G (2004) Efficacy and safety of four doses of lumiracoxib versus diclofenac in patients with knee or hip primary osteoarthritis: a phase II, four-week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Care Res 51:549–557CrossRefGoogle Scholar
  28. 28.
    Benevolenskaya L, Tüzün S, Hagin E, Moore A, Gimona A (2003) Lumiracoxib is effective in relieving symptoms of knee or hip osteoarthritis after 4 weeks of treatment: results from a randomized, placebo-controlled trial (abstract FRI0246). Ann Rheum Dis 62 [Suppl I]:270CrossRefPubMedGoogle Scholar
  29. 29.
    Grifka JK, Zacher J, Brown JP, Seriolo B, Lee A, Moore A, Gimona A (2004) Efficacy and tolerability of lumiracoxib versus placebo in patients with osteoarthritis of the hand. Clin Exp Rheumatol 22:589–596PubMedGoogle Scholar
  30. 30.
    Schnitzer TJ, Burmester GR, Mysler E, Hochberg MC, Doherty M, Ehrsam E, Gitton X, Krammer G, Mellein B, Matchaba P, Gimona A, Hawkey CJ, TARGET Study Group (2004) Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet 364:665–674CrossRefPubMedGoogle Scholar
  31. 31.
    Antiplatelet Trialists’ Collaboration (1994) Collaborative overview of randomised trials of antiplatelet therapy–I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Br Med J 308:81–106Google Scholar
  32. 32.
    Farkouh ME, Kirshner H, Harrington RA, Ruland S, Verheugt FW, Schnitzer TJ, Burmester GR, Mysler E, Hochberg MC, Doherty M, Ehrsam E, Gitton X, Krammer G, Mellein B, Gimona A, Matchaba P, Hawkey CJ, Chesebro JH, TARGET Study Group (2004) Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: randomised controlled trial. Lancet 364:675–684CrossRefPubMedGoogle Scholar
  33. 33.
    Dougados M, LeClaire P, van der Heijde D, Bloch DA, Bellamy N, Attman RD (2000) A report of the Osteoarthritis Research Society International Standing Committee for the Clinical Trial Response Criteria Initiative. Osteoarthritis Cartilage 8:395–403CrossRefPubMedGoogle Scholar
  34. 34.
    Pham T, van der Heijde D, Lassere M, Altman RD, Anderson JJ, Bellamy N, Hochberg M, Simon L, Strand V, Woodworth T, Dougados M, OMERACT-OARSI (2003) Outcome variables for osteoarthritis clinical trials: the OMERACT-OARSI set of responder criteria. J Rheumatol 30:1648–1654PubMedGoogle Scholar
  35. 35.
    Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K, Christy W, Cooke TD, Greenwald R, Hochberg M (1986) Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Arthritis Rheum 29:1039–1049PubMedGoogle Scholar
  36. 36.
    Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW (1988) Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol 15:1833–1840PubMedGoogle Scholar
  37. 37.
    Tubach F, Ravaud P, Baron G, Falissard B, Logeart I, Bellamy N, Bombardier C, Felson DT, Hochberg MC, Van Der Heijde D, Dougados M (2005) Evaluation of clinically relevant changes in patient-reported outcomes in knee and hip osteoarthritis: the minimal clinically important improvement. Ann Rheum Dis 64:29–33CrossRefPubMedGoogle Scholar
  38. 38.
    Moore A, Della Casa Alberighi O, Gitton X, Sloan V, Gimona A (2002) Responder rate of COX189 in osteoarthritis: a multinational study (abstract THU0265). Ann Rheum Dis 61 [Suppl I]:137CrossRefPubMedGoogle Scholar
  39. 39.
    McKenna F, Borenstein D, Wendt H, Wallemark C, Lefkowith JB, Geis GS (2001) Celecoxib versus diclofenac in the management of osteoarthritis of the knee. Scand J Rheumatol 30:11–18CrossRefPubMedGoogle Scholar

Copyright information

© Clinical Rheumatology 2005

Authors and Affiliations

  • Roy Fleischmann
    • 1
  • Eric Sheldon
    • 2
  • José Maldonado-Cocco
    • 3
  • Dipen Dutta
    • 4
  • Sue Yu
    • 4
  • Victor S. Sloan
    • 4
  1. 1.University of Texas Southwestern Medical Center, Radiant Research DallasDallasUSA
  2. 2.Miami Research AssociatesMiamiUSA
  3. 3.Rheumatology Section, IREPBuenos AiresArgentina
  4. 4.Novartis Pharmaceuticals CorporationEast HanoverUSA

Personalised recommendations