Intra-Articular Injection of a Novel DVS Cross-Linked Hyaluronic Acid Manufactured by Biological Fermentation (YYD302) in Patients With Knee Osteoarthritis: A Double-Blind, Randomized, Multicenter, Noninferiority Study

Abstract

This double-blind, randomized, Phase III clinical trial was conducted to assess the efficacy and safety of the novel divinyl sulfone cross-linked hyaluronate (YYD302) compared with the 1,4-butanediol diglycidyl ether cross-linked hyaluronate (Synovian) in patients with knee osteoarthritis. A total of 184 patients with osteoarthritis (Kellgren-Lawrence grade I-III) were randomized to 1 of 2 study groups (YYD302 group, n=95; Synovian group, n=89). A single injection of YYD302 or Synovian was given to both groups, and 182 participants completed the study (YYD302 group, n=95; Synovian group, n=87). The primary end point was the change in weight-bearing pain (WBP) at 12 weeks after the primary single injection. Secondary end points included the Knee Injury and Osteoarthritis Outcome Score; the Western Ontario and McMaster Universities Osteoarthritis Index score; the Patient Global Assessment and Investigator Global Assessment; the range of motion, swelling, and tenderness of the target knee; OMERACT-OARSI responder rate; WBP responder rate (the proportion of patients achieving at least 20 mm or 40% decrease in WBP); and rate of rescue medicine use and its total consumption at weeks 2, 4, and 12. Based on the efficacy results at week 12, the responders were administered an additional single injection of the same study drug at week 24, and safety and efficacy were additionally assessed at week 36. Mean changes of WBP at 12 weeks after the primary injection were -31.76 mm with YYD302 and -29.74 mm with Synovian, proving noninferiority of the YYD302 group to the Synovian group as the lower bound of the 95% CI (-4.3 to 8.3) was well above the predefined margin (-10 mm). At week 2, the Knee Injury and Osteoarthritis Outcome Score (total, pain, activities of daily living, and sports/recreation) and Western Ontario and McMaster Universities Osteoarthritis Index scores (total, stiffness) were significantly better in the YYD302 group than in the Synovian group. There were no significant differences between the groups in all other end points. Local overall adverse events (pain, heat, erythema, or swelling) at the injection site were observed in 48.4% of the YYD302 group and in 47.7% of the Synovian group. No serious reactions were reported. There was no statistically significant difference between the 2 groups regarding re-injected patients (YYD302 group, n=54; Synovian group, n=46) in any of the efficacy outcomes at week 36. The results of this study support that YYD302 is comparable to Synovian in terms of the efficacy and safety of the intra-articular injection treatment for osteoarthritis of the knee joint. Furthermore, YYD302 provided faster improvements in some efficacy assessments compared with Synovian. ClinicalTrials.gov identifier: NCT03561779.