Fixed-dose combination of enteric-coated naproxen and immediate-release esomeprazole has comparable efficacy to celecoxib for knee osteoarthritis: two randomized trials

Abstract

Objective:

To demonstrate that a fixed-dose combination of enteric-coated naproxen 500 mg and immediate-release esomeprazole magnesium 20 mg has comparable efficacy to celecoxib for knee osteoarthritis.

Research design and methods:

Two randomized, double-blind, parallel-group, placebo-controlled, multicenter phase III studies (PN400-307 and PN400-309) enrolled patients aged ≥50 years with symptomatic knee osteoarthritis. Following an osteoarthritis flare, patients received naproxen/esomeprazole magnesium twice daily, celecoxib 200 mg once daily, or placebo for 12 weeks.

Clinical trial registration:

NCT00664560 and NCT00665431.

Main outcome measures:

Three co-primary efficacy endpoints were mean change from baseline to week 12 in Western Ontario and McMaster Osteoarthritis Index (WOMAC) pain and function subscales, and Patient Global Assessment of osteoarthritis using a visual analog scale (PGA-VAS).

Results:

In Study 307, 619 patients were randomized and 614 treated. In Study 309, 615 patients were randomized and 610 treated. Both naproxen/esomeprazole magnesium and celecoxib were associated with improvements (least squares mean change from baseline to week 12) in WOMAC pain (Study 307: −42.0 and −41.8, respectively; Study 309: −44.2 and −42.9, respectively), WOMAC function (Study 307: −36.4 and −36.3, respectively; Study 309: −38.9 and −36.8, respectively), and PGA-VAS (Study 307: 21.2 and 21.6, respectively; Study 309: 29.0 and 25.6, respectively). A prespecified non-inferiority margin of 10 mm between naproxen/esomeprazole magnesium and celecoxib was satisfied for each co-primary endpoint at week 12 in both studies. Significant improvements were observed with naproxen/esomeprazole magnesium versus placebo in both studies (p < 0.05). Celecoxib was significantly different from placebo in Study 307 (p < 0.05); however, the improvements were not significant in Study 309. Acetaminophen use and patient expectation of receiving active treatment (80% probability) may have contributed to a high placebo response observed.

Conclusions:

Naproxen/esomeprazole magnesium has comparable efficacy to celecoxib for the management of pain associated with osteoarthritis of the knee over 12 weeks.

Key words::

• COX inhibitors
• Esomeprazole magnesium
• Naproxen
• Non-inferiority
• Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Osteoarthritis

Transparency

Declaration of funding

These studies were sponsored and conducted by POZEN Inc.

Declaration of financial/other relationships

M.H. receives research grants from the National Institutes of Health, and consulting fees from AstraZeneca, Bayer HealthCare LLC, Bioiberica SA, CombinatoRx, Eli Lilly, Endo Pharmaceuticals, GlaxoSmithKline, Merck, Merck Serono International, NicOx SA, Novartis, Pfizer, POZEN Inc., and Sanofi-Aventis. J.F. is an employee of POZEN Inc. with stock ownership. M.S., C.H., and O.S. are employees of AstraZeneca.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.

Acknowledgments

We thank Lynsey Stevenson, of Complete Medical Communications, who provided medical writing support funded by AstraZeneca.

Poster presented at the 74th Annual Scientific Meeting of the American College of Rheumatology, Atlanta, GA, USA, November 7–11, 2010.