Evaluation of GW406381 for treatment of osteoarthritis of the knee: two randomized, controlled studies

Context: GW406381 is an investigational, highly selective cyclooxygenase-2 (COX-2) inhibitor that is effective in animal models of central sensitization and of inflammatory pain.

Objective: To examine dose response for efficacy and safety of GW406381 in adults with osteoarthritis (OA) of the knee.

Design: Two randomized, double-blind, placebo- and positive-control studies: Study A, a 6-week nonflare design; Study B, a 12-week flare design.

Patients: 649 patients entered Study A; 1331 patients entered Study B.

Study a: GW406381 10, 20, 35, or 50 mg, celecoxib 200 mg, or placebo. Study B: GW406381 1, 5, 10, 25, or 50 mg, celecoxib 200 mg, or placebo.

Main outcome measures: Study A, co-primary endpoints were change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscore and WOMAC question 1. Study B co-primary endpoints were change from baseline in WOMAC pain and function subscores and Patient Global Assessment of Arthritis Condition. A closed hierarchical test procedure was prespecified.

Results: Study A demonstrated that GW406381 50 mg was superior to placebo on WOMAC pain subscore (mean difference from placebo -6.9 mm; P= .012). No clear dose response was observed, and the results with celecoxib were no different from those of placebo. In Study B, no dose of GW406381 was superior to placebo on the co-primary endpoints. Celecoxib was superior to placebo on all co-primary endpoints. Dose-related blood pressure and renovascular effects were seen with GW406381.

Conclusions: Overall, clinically meaningful efficacy in pain related to OA of the knee was not demonstrated for GW406381 despite its peripheral and central sites of action.