Diclofenac-hyaluronate conjugate (diclofenac etalhyaluronate) intra-articular injection for hip, ankle, shoulder, and elbow osteoarthritis: a randomized controlled trial.

BACKGROUND: To evaluate the efficacy and safety of intra-articular injection of diclofenac etalhyaluronate (DF-HA) in patients with osteoarthritis (OA) of the hip, ankle, shoulder, or elbow. METHODS: In this randomized, placebo-controlled, double-blind study in Japan, Japanese patients aged ≥20 years diagnosed with OA of the hip, ankle, shoulder, or elbow were randomly assigned 1:1 to DF-HA 30 mg or placebo (citric acid-sodium citrate buffered solution). Subjects received three injections of the study drug in each joint cavity every 4 weeks and were assessed for 12 weeks after the first injection. The primary endpoint was the mean change from baseline in a diary-based 11-point numerical rating scale (NRS) for pain over 12 weeks, analyzed for each joint. Treatment-emergent adverse events were recorded, and morphological changes in each joint were evaluated radiographically. RESULTS: The study drug (DF-HA vs placebo) was injected into 90, 60, 90, or 50 subjects with OA of the hip, ankle, shoulder, or elbow (46 vs 44, 30 vs 30, 45 vs 45, and 25 vs 25, respectively). The group differences in the mean change from baseline in the pain NRS over 12 weeks were - 0.81 (95% confidence interval: - 1.48 to - 0.13), - 0.07 (- 1.03 to 0.89), 0.15 (- 0.48 to 0.78), and 0.61 (- 0.41 to 1.62) for the hip, ankle, shoulder, and elbow joints, respectively, with statistically significant differences observed only in the hip joint. The change from baseline in the hip joint was greater with DF-HA than placebo at all time points from Weeks 1-12. No clinically significant adverse events or radiographic changes were observed. CONCLUSIONS: Intra-articularly administered DF-HA for hip OA produced a rapid response and was safe, with analgesia maintained for 12 weeks when administered every 4 weeks. TRIAL REGISTRATION: JapicCTI-173,678 (First registered date: 21 August 2017).

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

OBJECTIVE: To confirm the efficacy and safety of intraarticular (IA) injection of diclofenac covalently linked to hyaluronic acid (diclofenac etalhyaluronate [DF-HA]; ONO-5704/SI-613) in patients with knee osteoarthritis (OA). METHODS: In a phase III multicenter, randomized, double-blind, placebo-controlled trial, eligible subjects ages 40-75 years with symptomatic knee OA (Kellgren/Lawrence score of 2 or 3) were randomly assigned to receive IA injections of DF-HA 30 mg or placebo (citric acid-sodium citrate buffered solution; 1:1) once every 4 weeks for 20 weeks (a total of 6 injections). Subjects were followed up for 24 weeks. The primary end point was the mean change from baseline to 12 weeks in Western Ontario and McMaster Universities Osteoarthritis Index version 3.1 (WOMAC) pain subscale scores, measured on a 100-mm visual analog scale. Safety was evaluated by adverse event monitoring. RESULTS: All 440 subjects received investigational products (220 received placebo and 220 received DF-HA). The full analysis set and safety population comprised 438 subjects (220 in the placebo group and 218 in the DF-HA group) and 440 subjects, respectively. At 12 weeks, subjects receiving DF-HA showed significant improvement from baseline in the WOMAC pain subscale score (-23.2 mm) compared to subjects receiving placebo ( -17.1 mm), with a difference of -6.1 mm (95% confidence interval -9.4, -2.8; P < 0.001). The difference between groups was significant as early as week 1, and a difference was maintained for 24 weeks, although the difference at week 24 was not significant. Anaphylactic reactions were observed in 2 subjects receiving DF-HA. CONCLUSION: Our findings indicate that treatment with DF-HA results in significant improvement in the WOMAC pain subscale score compared to placebo over 12 weeks. Anaphylactic reactions were observed, and further safety evaluation is needed.

Open-label phase 3 study of diclofenac conjugated to hyaluronate (diclofenac etalhyaluronate: ONO-5704/SI-613) for treatment of osteoarthritis: 1-year follow-up.

BACKGROUND: We evaluated the 1-year safety and efficacy of diclofenac etalhyaluronate (DF-HA), a diclofenac-conjugated hyaluronate, in patients with osteoarthritis (OA). METHODS: In this multi-centre, open-label, noncomparative phase 3 study in Japan, patients with a diagnosis of knee, shoulder, elbow, hip, or ankle OA received an intra-articular (IA) injection of DF-HA 30 mg every 4 weeks for 1 year (13 times in total). The safety outcomes included treatment-emergent adverse events (TEAEs) and target joint structural changes by X-ray imaging tests. Efficacy outcomes included joint pain scores on an 11-point numerical rating scale. Concomitant use of analgesics was not restricted. RESULTS: Overall, 166 eligible patients were enrolled, comprising knee OA (n = 126) and other OA (n = 40). All TEAEs were experienced by 126/166 patients (75.9%). The incidence of treatment-related TEAEs was not associated with the treatment period. No significant worsening of joint status was observed in X-ray imaging tests at week 52 or at last assessment. The mean joint pain scores (± standard deviation) were 5.9 ± 1.2, 4.9 ± 1.9, and 3.1 ± 2.3 at baseline, and weeks 2 and 52, respectively. Improvement of pain score was observed after the first injection and was maintained until week 52 regardless of knee OA or other joint OA. CONCLUSIONS: Repeated IA injections of DF-HA every 4 weeks for 1 year were well tolerated with no clinically significant adverse events indicating they might lead to the long-term improvement of OA symptoms. DF-HA might be a useful treatment for patients with OA. TRIAL REGISTRATION NUMBER: JapicCTI-183855 (First registered date: 6th February 2018).

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

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.