A Study Comparing 4 Dose Regimens of PLA-695, Naproxen, and Placebo In Subjects With Osteoarthritis Of The Knee

Objectives: Primary:To assess the efficacy and safety of PLA-695 in subjects with active osteoarthritis (OA) of the knee.

Secondary:To determine the pharmacokinetics (PK) and pharmacodynamics (PD) of PLA-695 among dose levels. To assess health outcome measures. To assess the effect of PLA-695 on biomarkers related to clinical responses. To assess PLA-695 exposure-response relationship on PD, efficacy, and safety measures. To assess pharmacogenomics (PGX) analysis in OA.

This is a multi-center, randomized, double-blind, double-dummy, parallel, placebo- and positive-control (naproxen), dose-ranging study to assess the efficacy and safety of 3 oral doses of PLA-695 administered QD and 1 dose of PLA-695 administered BID for 6 weeks. Subjects will be randomized to 1 of 6 treatment groups: PLA-695 50 mg, 200 mg, or 400 mg QD, PLA-695 200 mg BID, placebo, or naproxen 500 mg BID. Subjects will undergo a washout period of 2 to 14 days. The number of days for washout will be determined by the pre-study NSAID of each subject. Subjects who washout from previous therapy with an increase in signs and symptoms of OA will be randomly assigned to receive PLA-695.

Inclusion Criteria: The main inclusion criteria is listed below, additional inclusion criteria is in the protocol.

• Men or women 50 to 75 years of age. Women must be of non-childbearing potential. Sexually active men who are not surgically sterile must agree and commit to use of barrier contraception during the study and for at least 12 weeks after the last dose of PLA.
• Diagnosed with idiopathic OA of the knee for at least 3 months duration in accordance with [1986] American College of Rheumatology (ACR) clinical and radiographic criteria: knee pain, the presence of osteophytes, and any one of the following: age >50 years, crepitus, or morning stiffness <30 minutes.
• Radiographic confirmation of OA at the target joint (weight-bearing anteroposterior and lateral views) within 1 year of screening.
• Must be currently treated for OA with a stable daily dose of 1 NSAID, including COX-2 inhibitors, not exceeding the maximum recommended dose in the product label, and taken as prescribed by the physician, starting at least 4 weeks before the screening visit.

Exclusion Criteria: These are some of the main exclusion criteria for the the study. Additional exclusion are included in the protocol.

• History of or suspected current esophageal or gastrointestinal bleeding, ulcers, obstruction, or perforation, or pancreatitis.
• Grade 4 severity on the Kellgren-Lawrence Scale on the screening target knee radiograph.
• Any significant cardiovascular, hematologic, blood dyscrasia, endocrine, respiratory, neurologic, psychiatric, metabolic, immunologic, infectious, hepatic, or renal condition that the investigator considers detrimental to the subject's participating in the study or that may prevent the successful completion of the study.
• Any clinically significant laboratory abnormality.