AB0860 STUDY DESIGN OF ROCCELLA: A PHASE 2 CLINICAL TRIAL WITH A DISEASE-MODIFYING OSTEOARTHRITIS DRUG CANDIDATE GLPG1972/S201086

Abstract

Background:Loss of articular cartilage is one of the major signs of osteoarthritis (OA). Aggrecan, the main proteoglycan component of the extracellular matrix of articular cartilage is cleaved by ADAMTS-5 (A Disintegrin And Metalloproteinase with ThromboSpondin-motif-5).1GLPG1972/S201086, a potent and highly selective inhibitor of ADAMTS-5, is an oral Disease-Modifying OsteoArthritis Drug (DMOAD) candidate. In a pooled Phase 1 safety analysis involving 171 participants GLPG1972/S201086 was shown to be well tolerated.Objectives:To present the study design of ROCCELLA, a large Phase 2 clinical trial in knee OA (KOA) patients, evaluating the efficacy and safety of GLPG1972/S201086 in reducing cartilage loss in OA.Methods:ROCCELLA is a multinational 52-week, multicentre randomized double-blind placebo-controlled dose-ranging phase 2 trial for the treatment of OA (NCT03595618). Eligible patients were aged 40–75 years with a diagnosis of primary femorotibial KOA, a pain score of 40–90mm on a 100 mm Visual Analogue Scale (VAS), predominant medial disease and a combined Kellgren/Lawrence (KL) 2 or 3 and Osteoarthritis Research Society International (OARSI) medial joint space narrowing (JSN) 1 or 2 severity grading range upon central reading of the X-ray. If both knees were eligible, the target knee was selected based first on the highest KL grade, then on the highest JSN grade and finally on the highest pain VAS score at baseline. Patients were randomized 1:1:1:1 to take placebo or three dose levels of GLPG1972/S201086 orally once daily for 52 weeks. The target knee was evaluated by quantitative Magnetic Resonance Imaging (qMRI) at baseline visit, week 28 and week 52, or at early withdrawal.The primary endpoint of the study is change from baseline to week 52 in cartilage thickness of the central medial tibio-femoral compartment (cMTFC) of the target knee. Secondary objectives are safety and tolerability including treatment emergent serious adverse events. Additional secondary structural and clinical efficacy objectives are based on changes from baseline in the target knee: cartilage thickness and bone area on qMRI, KOA “progressor” rates, Joint Space Width on X-ray, pain VAS, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total and sub scores, Patient Global Assessment VAS and the proportion of Outcome Measures in Rheumatology (OMERACT)-OARSI responders. Blood will be collected to assess the pharmacokinetics of GLPG1972/S201086. Planned, exploratory analyses include biochemical biomarkers of cartilage and bone turn-over. The study is designed to maintain the experiment wise type I error at 5%. A Mixed-effects Model for Repeated Measures will be used for the primary analysis. The randomisation was stratified by geographic region.Results:The study started in August 2018 and was fully recruited (N=938) by June 2019. Large numbers of patients with KOA had to be screened to meet the stringent pre-specified selection criteria. The study completion is expected by end of 2020.Conclusion:This is the first large Phase 2 study where patients with primary KOA are treated for 52 weeks with GLPG1972/S201086, an orally administered DMOAD candidate. This clinical trial was designed with a combination of two radiological selection criteria to ensure sufficient structural progression (cartilage loss) in the study population.