Sustained-release diclofenac conjugated to hyaluronate (diclofenac etalhyaluronate) for knee osteoarthritis: a randomized phase 2 study

Abstract

Objective To evaluate the efficacy and safety of diclofenac etalhyaluronate (DF-HA) (ONO-5704/SI-613), a novel DF-conjugated hyaluronate, in patients with knee OA in Japan. Methods In this randomized, double-blind, placebo-controlled phase 2 study, patients were randomly assigned (1:1) to receive either 30 mg of DF-HA or placebo intra-articularly at weeks 0, 4 and 8 and were followed up for 24 weeks. The primary outcomes were changes from baseline in the WOMAC pain subscores, 50-foot walk test pain score and daily pain score. The secondary outcomes were the WOMAC physical function subscores, patient global assessment, responder rate and safety outcome. Results Overall, 176 patients received the investigational drugs (87 received DF-HA and 89 received placebo). The mean changes in the WOMAC pain subscores and daily pain score from baseline over 12 weeks after the first injection were significantly higher in the DF-HA than placebo group; the mean difference was −7.0 mm [95% CI, −12.7, −1.2; P =0.018] and −0.61 (95% CI, −1.06, −0.16; P =0.008), respectively. The difference in the 50-foot walk test pain score was −5.0 mm (95% CI, −10.3, 0.3; P =0.065). Improvement of pain by DF-HA was observed at week 1 and maintained from week 12 to week 24. Significantly greater improvements in the secondary outcomes were also observed with DF-HA than with placebo. No clinically significant adverse events occurred. Conclusion DF-HA reduced pain in patients with knee OA without major safety concerns. Trial registration UMIN Clinical Trials Registry, https://www.umin.ac.jp/ctr/index.htm, UMIN000015858

Efficacy and Safety of Diclofenac–Hyaluronate Conjugate (Diclofenac Etalhyaluronate) for Knee Osteoarthritis: A Randomized Phase III Trial in Japan

“…Similar to the primary outcome, most of the secondary outcomes indicated the superiority of 12 weeks of treatment with DF‐HA compared to placebo. These results confirmed the efficacy of DF‐HA and reproduced the results of our previous phase II study ( 18 ).…”

“…The efficacy and safety of DF-HA in knee OA patients was confirmed in a previous trial (18), where DF-HA injected three times, once every 4 weeks for 12 weeks, showed statistically significant improvements in Western Ontario and McMaster University Osteoarthritis 3.1 Index (WOMAC) (19) pain subscores over placebo with no major safety concerns.…”

“…Furthermore, the sustained release of DF from DF‐HA after 1 injection into the joint tissue has potential analgesic effects lasting up to 28 days ( 16 ). The efficacy and safety of DF‐HA in patients with knee OA was confirmed in a previous trial ( 18 ), in which patients who received a total of 3 injections of DF‐HA, one every 4 weeks for 12 weeks, showed significant improvements in the Western Ontario and McMaster Universities Osteoarthritis Index 3.1 (WOMAC) ( 19 ) pain subscale score compared to patients who received placebo, with no major safety concerns.…”

“…We estimated that a sample size of 220 subjects per group would be needed to attain at least 90% power to detect a significant difference between groups with a 2‐sided significance level of 5%, assuming that the difference between groups in the change from baseline in WOMAC pain subscale score was −7.5 mm, with an SD of 23 mm and a dropout rate of ~10% ( 18 ).…”

“…The estimated sample size was 220 subjects per group to achieve a power of at least 90% with a two-sided significance level of 5%, assuming that the group difference in the change from baseline in WOMAC pain subscores was −7.5 mm, with an SD of 23 mm and dropout rate of approximately 10% (18).…”