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The CLASS Study: A Randomized Controlled Trial

Fred E. Silverstein, MD; Gerald Faich, MD; Jay L. Goldstein, MD; Lee S. Simon, MD; Theodore Pincus, MD; Andrew Whelton, MD; Robert Makuch, PhD; Glenn Eisen, MD; Naurang M. Agrawal, MD; William F. Stenson, MD; Aimee M. Burr, MS; William W. Zhao, PhD; Jeffrey D. Kent, MD; James B. Lefkowith, MD; Kenneth M. Verburg, PhD; G. Steven Geis, PhD, MD

JAMA. 2000;284:1247-1255.

Context  Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with a spectrum of toxic effects, notably gastrointestinal (GI) effects, because of inhibition of cyclooxygenase (COX)-1. Whether COX-2–specific inhibitors are associated with fewer clinical GI toxic effects is unknown.

Objective  To determine whether celecoxib, a COX-2–specific inhibitor, is associated with a lower incidence of significant upper GI toxic effects and other adverse effects compared with conventional NSAIDs.

Design  The Celecoxib Long-term Arthritis Safety Study (CLASS), a double-blind, randomized controlled trial conducted from September 1998 to March 2000.

Setting  Three hundred eighty-six clinical sites in the United States and Canada.

Participants  A total of 8059 patients (18 years old) with osteoarthritis (OA) or rheumatoid arthritis (RA) were enrolled in the study, and 7968 received at least 1 dose of study drug. A total of 4573 patients (57%) received treatment for 6 months.

Interventions  Patients were randomly assigned to receive celecoxib, 400 mg twice per day (2 and 4 times the maximum RA and OA dosages, respectively; n = 3987); ibuprofen, 800 mg 3 times per day (n = 1985); or diclofenac, 75 mg twice per day (n = 1996). Aspirin use for cardiovascular prophylaxis (325 mg/d) was permitted.

Main Outcome Measures  Incidence of prospectively defined symptomatic upper GI ulcers and ulcer complications (bleeding, perforation, and obstruction) and other adverse effects during the 6-month treatment period.

Results  For all patients, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.76% vs 1.45% (P = .09) and 2.08% vs 3.54% (P = .02), respectively. For patients not taking aspirin, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.44% vs 1.27% (P = .04) and 1.40% vs 2.91% (P = .02). For patients taking aspirin, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 2.01% vs 2.12% (P = .92) and 4.70% vs 6.00% (P = .49). Fewer celecoxib-treated patients than NSAID-treated patients experienced chronic GI blood loss, GI intolerance, hepatotoxicity, or renal toxicity. No difference was noted in the incidence of cardiovascular events between celecoxib and NSAIDs, irrespective of aspirin use.

Conclusions  In this study, celecoxib, at dosages greater than those indicated clinically, was associated with a lower incidence of symptomatic ulcers and ulcer complications combined, as well as other clinically important toxic effects, compared with NSAIDs at standard dosages. The decrease in upper GI toxicity was strongest among patients not taking aspirin concomitantly.

Author Affiliations: Department of Medicine, University of Washington, and Partner Frazier & Co, Seattle (Dr Silverstein); Pharmaceutical Safety Assessments Inc, Narberth, Pa (Dr Faich); Department of Medicine, Section of Digestive and Liver Diseases, College of Medicine, University of Illinois at Chicago, Chicago, Ill (Dr Goldstein); Division of Rheumatology and Metabolic Bone Disease, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass (Dr Simon); Divisions of Rheumatology and Immunology (Dr Pincus) and Gastroenterology (Dr Eisen), Vanderbilt University School of Medicine, Nashville, Tenn; Department of Medicine, Johns Hopkins University, Baltimore, Md (Dr Whelton); Department of Biostatistics, Yale University, New Haven, Conn (Dr Makuch); Division of Gastroenterology, Duke University, Durham, NC (Dr Agrawal); Division of Gastroenterology, Washington University, St Louis, Mo (Dr Stenson); and Clinical Research and Development, Pharmacia, Skokie, Ill (Ms Burr and Drs Zhao, Kent, Lefkowith, Verburg, and Geis).

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