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

Skerrett DL, Stapledon CJM, Ahuja M, et al. · Arthritis Research & Therapy

The primary endpoint was change at day 56 in one or more of eleven synovial-fluid biomarkers. Synovial-fluid ARGS-aggrecan rose in both arms and rose less on PPS — an adjusted 23.1% against 79.3% on placebo, a difference of -56.6% (95% CI -106.6 to -6.6; p=0.028) — and serum CTX-I rose 35.7% more than placebo (p=0.022), which the authors read as possibly favourable while saying the role of CTX-I in osteoarthritis needs further work. At day 168 synovial ARGS held (-74.0%, p=0.024), serum C2C fell (-29.3%, p=0.024) and serum CTX-I rose further (+65.5%, p=0.025); COMP, TIMP-1, IL-6, TNF-α, βNGF and CTX-II moved without reaching significance. On the clinical secondaries the pooled PPS arms did not separate from placebo on WOMAC pain (+0.4, NS); the twice-weekly arm did, on pain (-20.2%, p=0.049), function (-24.8%, p=0.019) and total score (-23.5%, p=0.025), and the once-weekly arm did not.

Population

Adults with moderate-to-severe knee OA (Paradigm PARA_OA_008; ACTRN12621000136808)

Intervention

Subcutaneous injectable PPS once or twice weekly over 39 days, followed to day 365

Comparator

Placebo injections

Limitations

The authors call the statistics hypothesis-generating rather than confirming: no sample-size calculation, eleven biomarkers and no correction for multiplicity. Five of the eleven synovial-fluid markers were not evaluable, 86.4-100% of placebo participants needed saline lavage to yield an aspirate and the uncorrected analysis was discordant enough that the authors set it aside; they also note the lavage itself may have helped the earlier-stage knees. Osteoarthritis duration was imbalanced, about 7.5 years on PPS against 2.5 on placebo. Attrition left the day-168 synovial ARGS analysis at 18 of 34 treated participants, and the once-weekly result at seven. Injection-site reactions ran 35.0% and 68.4% across the two PPS arms against 4.5% on placebo, and six participants stopped drug for adverse events, all of them on PPS. Six authors are Paradigm employees or shareholders and a seventh holds Paradigm research grants.