Effects of pentosan polysulfate sodium on synovial fluid biomarkers in moderate to severe knee osteoarthritis: an exploratory, phase 2, randomized, double-blind, placebo-controlled trial.

backgroundTo evaluate synovial fluid biomarkers of cartilage degradation, inflammation, and pain in participants with knee osteoarthritis pain treated with subcutaneous injectable pentosan polysulfate sodium (iPPS).

methodsIn an exploratory phase 2, double-blind trial, 61 participants were randomized 1:1:1 to twice-weekly iPPS, once-weekly iPPS, or placebo for 39 days, with a 365-day follow-up. The primary endpoint was change from baseline in synovial fluid biomarkers at Day 56. Secondary endpoints included serum and urinary biomarker analysis at Days 56 and 168, and synovial fluid biomarkers at Day 168. Further secondary endpoints evaluated clinical responses through to Day 365. Adverse events were assessed for safety.

resultsSubcutaneous iPPS treatment was associated with altered synovial fluid biomarkers at Day 56. In iPPS-treated versus placebo-treated participants at Day 56, the adjusted change from baseline least squares mean difference of cartilage metabolism markers COMP and ARGS decreased -23.60% (-62.60, 15.40) and -56.60% (-106.59, -6.62; p = 0.028), respectively. Endogenous inhibitor of cartilage degradation, TIMP-1, increased 10.55% (-35.35, 56.45) in iPPS versus placebo. Inflammation biomarker TNF-α decreased -110.15% (-270.57, 50.27) and pain modulator βNGF decreased -36.05% (-97.86, 25.77). Serum biomarkers COMP and C2C decreased -10.64% (-21.82, 0.55) and -7.30% (-17.48, 2.88) respectively, and serum CTX-I increased 35.74% (5.46, 66.01; p = 0.022). Synovial fluid ARGS remained significantly decreased at Day 168 -74.01% (-137.57, -10.45; p = 0.024), and serum CTX-I remained significantly increased 65.52% (8.73, 122.31; p = 0.025) at Day 168. At Day 168, synovial and serum COMP remained decreased -24.40% (-68.99, 20.20) and -10.85% (-26.03, 4.33), respectively; and serum ARGS decreased -7.79% (-16.22, 0.63). Serum C2C further decreased -29.25% (-54.45, -4.04; p = 0.024), and serum CTX-I further increased 65.52% (8.73, 122.31; p = 0.025) versus placebo, suggesting ongoing iPPS effects on osteoarthritis biomarkers. Urinary CTX-II decreased at both timepoints -53.27% (-157.40, 50.86) and -8.03% (-38.00, 21.94) respectively. iPPS was well tolerated with no serious related AEs or AEs of special interest.

conclusionThis study provides insight into local and systemic activity of subcutaneous iPPS via anti-inflammatory, pain, and cartilage degradation pathways. Changes in synovial fluid ARGS, serum CTX-I, and serum C2C suggest potential mechanisms for iPPS in knee osteoarthritis.

trial registrationProspectively registered on the Australian New Zealand Clinical Trials Registry at anzctr.org.au (ACTRN12621000136808) on February 10, 2021.