Stratification of patients by baseline WOMAC was performed as a em post hoc /em analysis. Results Patient disposition and disease characteristics Patient disposition is presented in Figure ?Figure1.1. 4 weeks for 12 weeks. The clinical effect of AMG 108 was measured in Part B by using the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index pain score. Results In Part A, 68 patients were randomized, and 64 received investigational product. In Part B, 160 patients were randomized, and 159 received investigational product. AMG 108 was well tolerated. Most adverse events (AEs), infectious SBE 13 HCl AEs, serious AEs and infections, as well as withdrawals from the study due to AEs occurred at similar rates in both active and placebo groups. One death was reported in an 80-year-old patient (Part A, 300 mg IV AMG 108; due to complications of lobar pneumonia). AMG 108 serum concentration-time profiles exhibited nonlinear PK. The AMG 108 group in Part B had statistically insignificant but numerically greater improvement in pain compared with the placebo group, as shown by the WOMAC pain scores (median change, -63.0 versus -37.0, respectively). Conclusions The safety profile of AMG 108 SC and IV was comparable with placebo in patients with OA of the knee. Patients SBE 13 HCl who received AMG 108 showed statistically insignificant but numerically greater improvements in pain; however, minimal, if any, clinical benefit was observed. Trial Registration This study is registered with ClinicalTrials.gov with the identifier “type”:”clinical-trial”,”attrs”:”text”:”NCT00110942″,”term_id”:”NCT00110942″NCT00110942. Intro Osteoarthritis (OA) is definitely a chronic, painful, and potentially disabling disease of the joints that is manifested by cartilage damage, changes in the underlying bone, and varying examples of synovial swelling. The prevalence of OA raises with age; 60% to 70% of individuals aged 70 to 80 years have pathologic evidence of OA [1]. The exact cause of OA is unfamiliar. Recent debate suggests that cytokines produced by triggered synovial cells or articular cartilage may be as important in the pathogenesis of OA like a concomitant response to mechanical causes or molecular events from your cartilage and synovium [2]. Cytokines such as interleukin-1 (IL-1) stimulate the synthesis of SBE 13 HCl proteolytic enzymes such as matrix metallo-proteinases, nitric oxide (NO), prostaglandins, and additional mediators and effectors of cells damage [3]. IL-1 also inhibits chondrocyte restoration of degraded cartilage extracellular matrix [4]. In animal models, IL-1 has been shown to induce cartilage damage, as measured by glycosaminoglycan (GAG) launch, inside a NO-dependent manner [5,6]. A relative deficiency of endogenous IL-1 receptor antagonist (IL-1ra), the natural antagonist to IL-1 beta (IL-1), Rabbit polyclonal to Complement C3 beta chain has been found in the synovial fluid [7] and diseased cartilage cells of individuals with OA [8]. Cartilage from OA individuals who experienced undergone joint-replacement surgery has also been shown to respond to IL-1 activation with higher NO production than RA cartilage [8]. Animal studies have suggested that intraarticular (IA) injections of IL-1ra may sluggish the progression of cartilage lesions in OA [9-12]. These findings suggest that obstructing the activity of IL-1 may protect against structural changes in OA [13,14]. Finally, IL-1 antagonists may also play a role in the pain of OA [15]. In a small study of individuals with OA, IA injections of the competitive inhibitor of IL-1, anakinra, were well tolerated and contributed to some improvements in their pain [16]. AMG 108 is definitely a fully human being, immunoglobulin subclass G2 (IgG2) monoclonal antibody that binds the third immunoglobulin domain of the interleukin-1 receptor type 1 (IL-1R1) and nonselectively inhibits the activity of both forms of IL-1 (IL-1 and IL-1). Inhibiting the proinflammatory effects of these IL-1 isoforms with AMG 108 may be useful in treating OA. The objectives of this two-part study were to compare the security and pharmacokinetics (PK) of AMG 108, given either subcutaneously (SC).
