A METHODOLOGY FOR TESTING THE EFFICACY AND SAFETY OF AN INTRA-ARTICULAR TREATMENT FOR OSTEOARTHRITIS OF THE KNEE JOINT

Abstract

The purpose of this work was to develop a methodology for testing the efficacy and safety of an intra-articular treatment for osteoarthritis of the knee in a phase III clinical trial. Osteoarthritis (OA) is a degenerative joint disease which affects millions of Americans and is characterized by degeneration of articular cartilage and hypertrophy of bone. Healthy articular cartilage, lubricated by the synovial fluid in the knee joint, provides almost frictionless movement. The cartilage absorbs and dissipates compressive loads on the knee joint and provides resistance to tensile forces. OA is characterized by the site-specific loss of cartilage and the subsequent formation of osteophytes. Immunoassays of joint fluid aspirated from patients with OA demonstrate increased concentrations of collagenase and fibronectin in comparison to joint fluid from healthy subjects. The degenerative loss of knee joint cartilage during the progression of OA over a period of years results in knee joint pain on movement and even at rest due to inflammation from friction in the joint. Common treatment of this disease includes the use of non-steroidal anti-inflammatory drugs and steroid injections. Both of these treatments have questionable effectiveness and harmful side effects when used chronically. A promising new treatment for OA is the use of intra-articular knee joint injections containing hyaluronic acid (HA). HA has been shown to suppress fibronectin, stimulate tissue inhibitor of metalloproteinases and enhance cartilage reparative properties. These new intra-articular treatments must demonstrate efficacy and safety in order to gain federal approval for use in treating patients suffering from OA. The development of a carefully planned phase III clinical trial will facilitate the process of gaining market approval for a new osteoarthritis treatment. In order to develop a phase III clinical trial, a phase II pilot study must be conducted utilizing preliminary study methodology which will enable the sponsor to identify the most appropriate study design to be used in the phase III clinical trial. The study methodology of the phase II pilot study is determined based on previous research conducted with the new treatment and other similar products, FDA directives, and the expertise of physicians in the field of OA. Once the pilot study is conducted and the results of the pilot study are analyzed, whether the methodologies utilized in the pilot study are adequate for use in the phase III trial or whether certain methodologies require revisions can be determined. These decisions are based on the success of the pilot study in demonstrating the effectiveness of the treatment. If the results are successful, as seen in previous trials, the methodology of the pilot study can be assumed to be adequate for use in the larger definitive phase III trial. If the results of the pilot study are not successful, the literature must be re-explored and the opinion of experienced physicians in the field of OA must be re-consulted in order to modify the methodology as appropriate. In this study, the results of the pilot study demonstrated both the active product and the placebo to demonstrate effectiveness at the primary endpoint, which was one week after the last of a series of five weekly injections. Previous studies have demonstrated HA to be superior to placebo, as well as to active NSAIDs. Therefore, it was determined that certain methodologies utilized in the pilot study were inadequate to demonstrate the effect of the product. The methodologies were redesigned for implementation in the phase III study.