Abstract
We performed a randomized, double-blind, placebo-controlled, multicenter, parallel-group, dose-response study of the efficacy and safety of the oral administration of PG-116800, a matrix metalloproteinase (MMP) inhibitor, in patients with mild to moderate knee osteoarthritis. The primary efficacy endpoints included the progression of joint space narrowing in the osteoarthritic knee, as measured by microfocal radiography with fluoroscopic positioning, and the reduction of symptoms (pain and stiffness) and/or the improvement of function, as measured by the Western Ontario and McMaster Universities osteoarthritis index (WOMAC). Four hundred and one patients were randomly assigned to either placebo (n = 80) or one of fourdoses of PG-116800: 25 mg (n = 81), 50 mg (n = 80), 100 mg (n = 80), or 200 mg (n = 80) taken twice daily for 12 months. During the study, the 200-mg dose was discontinued based on an increased frequency of musculoskeletal adverse effects. After 1 year of treatment, no statistically significant difference was observed between placebo and PG-116800 with regard to mean changes in minimum joint space width of the knee or to WOMAC scores. The most frequent adverse effect was arthralgia (35%). Twenty-three percent of evaluable patients had at least a 30% decrease from baseline of at least onerange-of-motion measurement of either shoulder at a follow-up visit. The percentage of patients with reduction in range of motion was significantly greater in the twohighest dose groups relative to placebo. Thirteen percent of patients, half of whom were in the 200-mg group, reported hand adverse events (oedema, palmar fibrosis, Dupuytren contracture, or persistent tendon thickness or nodules). The threemost frequent shoulder adverse events were reversible arthralgia, stiffness, and myalgia, which mostly affected the twohighest dose groups. The unfavorable risk-benefit balance of the MMP inhibitor PG-116800 in patients with knee osteoarthritis precludes further development of the compound for this indication. This study adds to the weight of evidence suggesting that side effect profiles of MMP inhibitors in general make them unsuitable for use in osteoarthritis.ClinicalTrials.gov NCT00041756.
Highlights
Osteoarthritis (OA) is a chronic, progressive disorder of the synovial joints, characterized by focal loss of cartilage and changes in subchondral and marginal bone, synovium, and periarticular structures [1]
matrix metalloproteinase (MMP) have long been implicated in the joint destruction process that occurs in arthritis, and MMP inhibitors have been studied in the treatment of both rheumatoid arthritis and OA [5,6,7]
Twenty-one patients in the 200-mg dose group were withdrawn from the study for safety reasons per Independent Data Monitoring Committee (IDMC) recommendation, which was classified as a major protocol deviation
Summary
Osteoarthritis (OA) is a chronic, progressive disorder of the synovial joints, characterized by focal loss of cartilage and changes in subchondral and marginal bone, synovium, and periarticular structures [1]. IDMC = Independent Data Monitoring Committee; ITT = intent-to-treat; IVRS = Interactive Voice Response System; JSW = joint space width; MedDRA = Medical Dictionary for Regulatory Activities; MMP = matrix metalloproteinase; MSS = musculoskeletal syndrome; NF = National Formulary; NSAID = nonsteroidal anti-inflammatory drug; OA = osteoarthritis; ROM = range of motion; SERM = selective estrogen-receptor modulator; WOMAC = Western Ontario and McMaster Universities osteoarthritis index. As the understanding of the pathogenesis of joint destruction in OA increases, new therapeutic approaches are targeting the tissue degradation process. MMPs have long been implicated in the joint destruction process that occurs in arthritis, and MMP inhibitors have been studied in the treatment of both rheumatoid arthritis and OA [5,6,7]. No controlled long-term studies with MMP inhibitors in OA have been performed to date
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
