Purpose: Hyaluronic acid (HA) has been included in European League Against Rheumatology, Osteoarthritis Research Society International, American College of Rheumatology, American Pain Society and American Academy of Orthopedic Surgeons recommendations for treatment of painful knee osteoarthritis (OA). Intra-articular (IA) sodium hyaluronate has proven efficacious and well tolerated for the treatment of pain associated with knee OA, but optimal molecular weight of HA and dosing regimen is still not known. HYADD4-G is a novel hydrogel obtained with a new linear (not cross-linked) derivative of HA of bacterial origin (partial hexadecylamide of 500-730 kDa hyaluronic acid Pat. No. EU 1095064) that shows higher viscoelastic properties than the native HA with preservation of hyaluronan biocompatibility. The study objective was to evaluate the efficacy and tollerability of 2 different HYADD4-G dosing regimens (2 versus 3 i.a. injections) against phosphate-buffered saline (PB-Saline) up to 6 months in patients with knee OA. Methods: Prospective, multicentre, parallel, randomized, double-blind (masked observed), PB-Saline controlled, 6 months study in knee OA. Patients: primary knee OA according to ACR criteria, Kellgren-Lawrence II-III stage, pain on walking >40 mm on VAS at baseline. Primary outcome measure: pain during 50 ft (15 m) walk test, measured by Visual Analogue Scale (VAS) at visits 2-9. Statistical Analysis: efficacy evaluated in intent-to-treat (ITT) population. Two-sided superiority tests of 2 different regimens of HYADD4-G vs PB-saline for all primary and secondary outcome measures. Results: A total of 439 patients were randomized either to HYADD4-G 2 inj. group (n=145), HYADD4-G 3 inj. (n=150) and PB-saline (n=144). There were no significant differences in demographic and disease activity parameters between groups at baseline. Symptomatic outcome measures showed a significant improvement from baseline in the three treatment groups. In particular, considering the HYADD4-G 2 injections group, the mean change (%) between baseline and final visit for the 50 ft walk test (VAS) was -36,5 mm (-58,9%), for WOMAC pain-19,8 mm (-40,4%), for WOMAC Stiffness-20,5 mm (-27,1%), and for WOMAC physical function-18,2 mm (-35,4%). However, due to a huge and unexpected placebo response, for primary and secondary end points, no statistically significant differences between the treatment groups at any of the Visits 5 to 9 were observed. In exploratory sub-group analysis of patients with age <65 years the pain in the target knee was improved from baseline Visit 2 to Visit 5 in all treatment groups. The comparison regarding pain in the target knee during walk test between the HYADD4-G 2 injections group and the PB-Saline group for patients <65 years revealed the following p-values: P=0,1561 at the first visit after the last injection (day 28), P=0,0267 at day 60, P=0,0397 at day 90, P=0,0499 at day 120, and P=0,3329 at day 180 (2-sided t-test). There were no clinically relevant and/or statistically significant differences between the treatment groups with regard to frequency, distribution, intensity, premature termination, or seriousness, but for probable relationship to study group and occurrence of AEs in target knee. Conclusions: New HA formulations HYADD4-G were effective and well tolerated in symptomatic treatment of painful knee OA. The reductions in VAS knee pain for patients <65 years were significantly more effective in HYADD4-G given in a 2 IA injections than PB-saline. A clinically significant decrease in analgesic consumption, was also observed in the same HYADD4-G study group. Keywords: osteoarthritis, hyaluronic acid, IA therapy.
Pavelka, K., Niethard, F. U., & Giordan, N. (2010). 326 A MULTICENTRE, INTERNATIONAL, DOUBLE BLIND, RANDOMIZED, PLACEBO – CONTROLLED STUDY TO ASSESS THE EFFICACY AND SAFETY OF 2 DIFFERENT REGIMENS OF HYADD4-G IN KNEE OSTEOARTHRITIS. Osteoarthritis and Cartilage, 18, S144. https://doi.org/10.1016/s1063-4584(10)60353-6