Efficacy and safety of single injection of cross-linked sodium hyaluronate vs. three injections of high molecular weight sodium hyaluronate for osteoarthritis of the knee: a double-blind, randomized, multi-center, non-inferiority study

Chul-Won Ha, Yong-Beom Park, Chong-Hyuk Choi, Hee-Soo Kyung, Ju-Hong Lee, Jae Doo Yoo, Ju-Hyung Yoo, Choong-Hyeok Choi, Chang-Wan Kim, Hee-Chun Kim, Kwang-Jun Oh, Seong-Il Bin, Myung Chul Lee, Chul-Won Ha, Yong-Beom Park, Chong-Hyuk Choi, Hee-Soo Kyung, Ju-Hong Lee, Jae Doo Yoo, Ju-Hyung Yoo, Choong-Hyeok Choi, Chang-Wan Kim, Hee-Chun Kim, Kwang-Jun Oh, Seong-Il Bin, Myung Chul Lee

Abstract

Background: This randomized, double-blind, multi-center, non-inferiority trial was conducted to assess the efficacy and safety of a cross-linked hyaluronate (XLHA, single injection form) compared with a linear high molecular hyaluronate (HMWHA, thrice injection form) in patients with symptomatic knee osteoarthritis.

Methods: Two hundred eighty seven patients with osteoarthritis (Kellgren-Lawrence grade I to III) were randomized to each group. Three weekly injections were given in both groups but two times of saline injections preceded XLHA injection to maintain double-blindness. Primary endpoint was the change of weight-bearing pain (WBP) at 12 weeks after the last injection. Secondary endpoints included Western Ontario and McMaster Universities Osteoarthritis index; patient's and investigator's global assessment; pain at rest, at night, or in motion; OMERACT-OARSI responder rate; proportion of patients achieving at least 20 mm or 40% decrease in WBP; and rate of rescue medicine use and its total consumption.

Results: Mean changes of WBP at 12 weeks after the last injection were -33.3 mm with XLHA and -29.2 mm with HMWHA, proving non-inferiority of XLHA to HMWHA as the lower bound of 95% CI (-1.9 mm, 10.1 mm) was well above the predefined margin (-10 mm). There were no significant between-group differences in all secondary endpoints. Injection site pain was the most common adverse event and no remarkable safety issue was identified.

Conclusions: This study demonstrated that a single injection of XLHA was non-inferior to three weekly injections of HMWHA in terms of WBP reduction, and supports XLHA as an effective and safe treatment for knee osteoarthritis.

Trial registration: ClinicalTrials.gov ( NCT01510535 ). This trial was registered on January 6, 2012.

Keywords: Hyaluronic acid; Inflammation; Knee osteoarthritis; Treatment.

Figures

Fig 1
Fig 1
Patient Distribution. The bars in the far left indicate each visit; however, the distance between each visit is not proportional to the actual time because of the limited space. Patients randomized to the cross-linked hyaluronate (XLHA) group received two placebo injections before the third injections, which was given as XLHA
Fig 2
Fig 2
Mean Changes from Baseline in Weight-bearing Pain. Significant reduction in WBP was observed at 1 week after the last injection (−18 mm in HMWHA, P < 0.001 and −20 mm in XLHA, P < 0.001); and it was further evident at week 6 week and week 12. The changes observed at 12 weeks after the last injection were still significant in both groups (−29 mm in HMWHA, P < 0.001 and −33 mm in XLHA, P < 0.001). Reductions in WBP at V5, V6 and V7 from baseline were all significant (P < 0.001, paired t-test) in both groups. V, Visit; W, Week; Vertical arrows represent injections of investigational products; Error bars indicate 95% confidence interval of mean change

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