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Evaluation of GW406381 for treatment of osteoarthritis of the knee: two randomized, controlled studies
Diane J Boswell1, Keld Ostergaard, Richard S Philipson
1Clinical Development, GlaxoSmithKline, Harlow, United Kingdom. diane.j.boswell@gsk.com
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.
Insights
GW406381, a selective cyclooxygenase-2 inhibitor, did not demonstrate clinically meaningful efficacy for osteoarthritis knee pain in human trials. Although effective in animal models, it failed to show superiority over placebo in adult patients.
Area of Science:
- Pharmacology
- Rheumatology
- Clinical Trials
Background:
- GW406381 is an investigational, selective cyclooxygenase-2 (COX-2) inhibitor.
- It has shown efficacy in animal models for central sensitization and inflammatory pain.
Purpose of the Study:
- To evaluate the dose-response relationship for the efficacy and safety of GW406381.
- The study focused on adult patients diagnosed with osteoarthritis (OA) of the knee.
Main Methods:
- Two randomized, double-blind, placebo- and positive-controlled studies (Study A and Study B) were conducted.
- Patients received varying doses of GW406381, celecoxib, or placebo.
- Primary endpoints included changes in WOMAC pain and function subscores and Patient Global Assessment.
Main Results:
- Study A showed GW406381 50 mg was superior to placebo for WOMAC pain (P=.012), but no clear dose response was observed.
- In Study B, no dose of GW406381 demonstrated superiority over placebo for the co-primary endpoints.
- Dose-related increases in blood pressure and renovascular effects were noted with GW406381.
Conclusions:
- GW406381 did not show clinically meaningful efficacy in alleviating knee osteoarthritis pain.
- Despite promising preclinical data, the drug failed to meet primary endpoints in human studies.
- Safety concerns included dose-related blood pressure and renovascular effects.
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