To study the efficacy and safety of naproxcinod vs. placebo and naproxen in the treatment of signs and symptoms of Osteoarthritis.

This is a 13-week double-blind study followed by a 52-week, open-label, roll-over on active treatment study. These are randomized, parallel group, multicenter studies comparing efficacy and safety of naproxcinod, placebo and naproxen.

Inclusion Criteria:

• Men and women (40 or older) with a diagnosis of primary OA of the knee
• Must be a current chronic user of NSAIDS or acetaminophen
• Must discontinue all analgesic therapy at screening

Exclusion Criteria:

• Uncontrolled hypertension or diabetes
• Hepatic or renal impairment
• Current or expected use of anticoagulant
• A history of alcohol or drug abuse
• Candidates for imminent joint replacement
• Diagnosis of gastric or duodenal ulceration and/or history of significant gastro-duodenal bleeding, within the last 6 months
• Current medical disease that could confound or interfere with the evaluation of efficacy
• Participation within 30 days prior to screening in another investigational study