Long term efficacy and safety of a combined low and high molecular weight hyaluronic acid in the treatment of osteoarthritis of the knee

The primary objective was to determine the efficacy of intraarticular combined hyaluronic acid versus placebo in patients with grade 1-3 medial compartment osteoarthritis of the knee as evaluated through the self-paced 40 m walking pain visual analog scale (VAS) at week 16, 52 and 104. Secondary objectives included pain at rest: a 10 cm VAS, patient global satisfaction using a 5-point numerical scale, consumption of concomitant medications, patients with <45 mm pain at followup 52 and 104 weeks. Safety was determined through the number of recorded adverse events. The study was designed as a prospective, randomized, double-blind, placebo controlled and comparative study. 200 patients were randomized in a 1:1 ratio to one of four treatment groups, to receive 3 weekly intra-articular injections of either: DMW (combined HA of different molecular weight and concentrations); HMW (high molecular weight HA); LMW (low molecular weight HA); PL (placebo, saline). Patients were assessed baseline and at week 16, 52, 104. Analyses were conducted using sigma stat (SPSS Inc., Chicago, Illinois) and Microsoft Excel (Microsoft Corp, Redmond, Washington). Significance was established at P<0.05. Analysis of variance with repeated measures and c2 tests were used to test for differences from baseline characteristics of the group among the primary and secondary outcomes at each injection series interval. At 16, 52 and 104 weeks respectively, walking VAS pain was significantly improved in all treatment groups vs. Placebo: DMW (89.3%, P<0.001; 87.4%, P<0.001; 88.1%, P<0.001); LMW (81.3%, P<0.001; 78.2%, P<0.001; 77.0%, P<0.001) and HMW (79.1%, P<0.001; 81.1%, P<0.001; 79.4%, P<0.001). At 52 weeks, 8 patients in DMW group had resting VAS <45 mm. DMW had lower (62 mm, P <0.001) compared to LMW (76 mm) and HMW (88 mm) VAS at rest. Similar differences were observed for walking VAS 39, 41 and 43 (DMW, LMW, HMW) received repeat injections. At 104 weeks, these differences were similar. DMW and LMW had no reported adverse events; HMW had 2 local reactions at 52 weeks and 1 at 104 weeks. There were no serious adverse events. Non- serious adverse events included pain and local swelling at the injection site (21%), erythema at the injection site (12%) and stiffness in the index knee (7%). Intra-articular hyaluronic acid injections using any of low, high or combined MW were highly effective in improving resting and moreso, walking pain in patients with osteoarthritis of the knee. Greater improvement in both rest and activity outcomes in patients who received the DMW product, with concomitantly greater patient satisfaction and fewer use of concomitant therapeutic modalities at 16, 52 and 104 weeks suggest that combining a range of MW hyaluronic acid may be advantageous long term, particularly among active osteoarthriris patients.