Randomised, double-blind comparison of a fixed co-formulation of intra-articular polynucleotides and hyaluronic acid versus hyaluronic acid alone in the treatment of knee osteoarthritis: two-year follow-up

Abstract

Background: A first-year interim analysis of this two-year study suggested that intra-articular injections of highly purified, natural-origin polynucleotides and hyaluronic acid (HA) as a fixed combination (PNHA) might improve knee function and joint pain more effectively than HA alone in patients with knee osteoarthritis (OA). Purpose of the second-year analysis herein described was verifying whether the first-year interim outcomes persist over the whole two-year period. Methods: Randomised, double-blind, HA-controlled clinical trial in 100 knee OA patients (98 randomised, 69 completing the study) in a high-specialisation tertiary care setting. The hypothesised difference of efficacy between PNHA and HA for the original sample size estimate is 20%. Treatment cycle: 3 weekly intra-articular knee injections of either PNHA or HA. Evaluations: Western Ontario and McMaster Universities (WOMAC) score and Knee Society Score (KSS) as, respectively, primary and secondary endpoints, evaluated at baseline and after 2, 6, 12, and 24 months; synovial fluid levels of proinflammatory mediators (biochemical and immunoenzymatic assays at baseline and the end of the treatment cycle). Adverse effects investigated at each control visit. Statistical analysis: Kruskal-Wallis test for independent samples (nonparametric one-way analysis of variance) after correction of means for age, Body Mass Index and Kellgren-Lawrence grade. If significant, pairwise post-hoc Sidak multiple comparisons. Results: KSS total score and KSS pain item: significant improvement in both groups, with significantly more pain improvement in patients treated with PNHA (2-point reduction) than HA (1-point reduction). Both groups experienced significant long-term reductions in WOMAC total scores: significantly stronger in PNHA-treated patients after 24 months with a steady difference of 16% favouring PNHA in WOMAC pain subscore. No clinically significant adverse events in either group. Conclusions: The outcomes of the 2-year study confirmed that a short cycle of intra-articular treatment (3 weekly double-blind injections) with polynucleotides (long-acting viscosupplementation properties, pro-trophic activity on chondrocytes, pain-relieving properties) in fixed combination with high molecular weight hyaluronic acid is more effective in improving knee function and pain in knee OA patients than HA alone. PNHA may be elective for viscosupplementation in knee OA patients with fastidious and resistant pain, signs of inflammation or worsening disease.

Clinical effects of the adjunctive use of polynucleotide and hyaluronic acid‐based gel in the subgingival re‐instrumentation of residual periodontal pockets: A randomized, split‐mouth clinical trial

“…The concentration of the fixed combination of PN and HA used in this trial was supported by previous studies in other medical fields where its use has shown to be promising for the treatment of wounds and ulcers and in intradermal and intra-articular infiltrations. [37][38][39] Furthermore, the concentration used for this clinical in vivo study did not cause adverse events or complications and was well tolerated and safe.…”

“…16 Furthermore, it has been reported that, because of the synergy between PN and HA (based in viscoelastic and mechanical properties) and the high molecular weight HA used in the formulation, it may not be necessary to perform repeated applications of this gel to obtain better and/or stable results over time. 39…”

“…36 Data from in vitro and in vivo studies showed that PN in a fixed coformulation with HA: (a) has a high trophic effect and accelerates venous lower limb ulcers healing rate 37 ; and (b) improves properties of synovial fluid and reduces pain in patients with knee osteoarthritis. 38,39 Recently, an in vitro study investigating the effect of PN with or without HA on gingival fibroblasts concluded that the addition of HA further increased the effectiveness of PN and that this combination has been effective in stimulating primary gingival fibroblast growth, thus promoting wound healing. 40 However, to the best of our knowledge, no study has been performed to evaluate whether subgingival reinstrumentation of residual pockets after active initial periodontal therapy could benefit from the adjunctive nonsurgical application of a gel containing PN and HA.…”

Innovations in the intra-articular therapeutic management of osteoarticular pain

“…Highly purified polynucleotides have been tested in association with HA due to their water-binding properties and potential in promoting chondrocyte repair. This combination therapy showed significant improvement in pain and mobility over the use of HA alone, thus demonstrating a synergistic activity of polynucleotides and HA [29][30][31] .…”