Colchicine for treatment of Osteoarthritis of the knee (CLOAK)—A phase 2, double-blind, placebo-controlled trial

Abstract

Purpose: Current treatments for osteoarthritis (OA) remain inadequate. Accumulating evidence suggests that OA is an inflammatory disease, with a particular role for interleukin-1β (IL-1β) a product of the NLRP3 inflammasome. Additionally, both calcium and urate crystals have been suggested to play potential roles in OA and both are recognized to activate the NLRP3 inflammasome to produce IL-1β. Colchicine is an ancient and well-tolerated anti-inflammatory agent and has recently been shown to inhibit inflammasome activation and IL-1β generation. Several studies have examined the impact of colchicine on various aspects of OA, with varying Results. We are assessing the potential benefits of colchicine on several short-term features of knee OA. Methods: The CLOAK (CoLchicine for treatment of OsteoArthritis of the Knee) study is a randomized, double-blind, placebo-controlled trial of colchicine (0.8 mgs daily) for 90 days. (Figure 1). We are identifying patients as they are seen in the rheumatology clinics, as well as calling patients from our knee OA database of prior studies. The recruitment goal is to enroll 120 subjects at least 50 years of age who have symptomatic knee OA with radiographic confirmation (Kellgren-Lawrence grade 2 or 3), and who are willing to forego other anti-inflammatory therapy (i.e., topical or oral NSAID and/or intraarticular steroids or hyaluronic acid) during the trial. The primary clinical outcome is the difference between treatment and placebo groups in pain improvement by visual analog scale, along with changes in the Knee Injury and Osteoarthritis Outcome Score (KOOS) and mean doses of analgesics used. Inflammatory outcomes between the two groups include changes in plasma inflammatory markers (such as hsCRP, PGE2, and IL-1Ra) and peripheral blood leukocyte genomic studies. All patients are scanned by knee ultrasound pre- and post-treatment, with assessment for synovitis and effusion. We also aspirate synovial fluid when appropriate, and will analyze all available samples together for inflammatory markers. Results: To date, 78 patients have been contacted or approached, 18 screened, and 17 enrolled. Six have completed the study, with a mean BMI of 30.3. All 6 remain blinded as to study group; however, the mean VAS pain score among the group decreased by 1.7 in the index knee (which had greater pain at baseline), while the mean KOOS scores for symptoms, pain, activities of daily living, sports activity, quality of life and KOOS global all improved. Individually, 4 of the 6 completing subjects demonstrated VAS score improvement with 2 of 6 demonstrating worsening, a pattern that was duplicated in most of the KOOS scores. Conclusions: The CLOAK trial is testing the potential benefit of colchicine on pain and inflammation in knee OA, specifically in patients with moderate radiographic disease who are not taking other anti-inflammatory agents. Supported by an investigator-initiated grant from Hikma Pharmaceuticals.