PURPOSE: Carbylan Osteoarthritis Research 1.0 (COR 1.0) was a prospective, multicenter, randomized, double-blind feasibility study to evaluate the safety and performance of Hydros Joint Therapy (Hydros) and Hydros-TA Joint Therapy (Hydros-TA) in subjects with Kellgren&Lawrence grade 2 and 3 osteoarthritis (OA) of the knee. METHODS: A total of 98 subjects were enrolled, treated, and followed for six months post-treatment. Subjects were randomized 1:1:1 to Hydros (PEG cross linked HA without TA), Hydros-TA (PEG cross linked HA with TA), or Synvisc-One Hylan G-F 20 (Synvisc-One). Hydros is a bioresorbable hyaluronan-based hydrogel suspended in a hyaluronan solution. Hydros-TA incorporates a low dose (10mg) corticosteroid, triamcinolone acetonide, suspended within the hyaluronan hydrogel, and is designed to retain steroid locally in the joint. All randomized subjects received one 6 mL intra-articular (IA) injection in the treatment knee by an unblinded injecting physician. The treatment knee was the knee that met the inclusion criteria on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A (pain) subscale score (50-90mm on 100mm VAS). Subjects and evaluating physicians who followed subjects post-treatment were blinded to treatment. Subjects were seen by a treatment-blinded evaluating physician for post-treatment follow-up at 2 weeks, 6 weeks, 13 weeks, and 26 weeks. Subjective symptom rating and physical assessment including the full WOMAC questionnaire were obtained at screening and each follow-up visit. Subject global assessment was obtained at 13 weeks and subject and physician global assessments were obtained at 26 weeks. Adverse events were solicited at all visits. The primary efficacy endpoint was the time-weighted change from baseline in the WOMAC A (pain) subscale average score for the treatment knee over 26 weeks. Differences between treatment were assessed using an analysis of covariance (ANCOVA) model. RESULTS: For the primary outcome, Hydros demonstrated a 41.2mm reduction, Hydros-TA demonstrated a 42.2mm reduction and Synvisc-One demonstrated a 37.5mm reduction from baseline pain. These results represented an improvement of 3.7mm and 4.7mm over Synvisc-One for Hydros and Hydros-TA respectively. Greater reductions in pain for Hydros-TA vs Synvisc-One were observed at all timepoints over the course of the study. The percentage of subjects who responded favorably to the product (as measured by the OMERACT-OARSI responder rate) was also higher in the Hydros and Hydros-TA groups when compared to Synvisc-One. Hydros-TA showed a trend towards a faster onset of pain relief compared to the non-steroid containing products evaluated in the study. Hydros-TA provided a 43.5mm mean reduction from baseline pain at the 2 week time point compared to a mean reduction of 37.7mm and 32.3mm for Synvisc-One and Hydros, respectively. In the Hydros-TA treatment group there were 3 reports of product related adverse events compared to 9 reports in the Synvisc-One group and 7 events reported in the Hydros group. Arthralgia was the most commonly reported product-related adverse event (5 reports with Synvisc-One, 4 with Hydros, and 1 with Hydros-TA). CONCLUSIONS: A single injection of Hydros or Hydros-TA was well tolerated and relieved pain associated with symptomatic OA of the knee over 26 weeks. The study endpoints showed strong trends toward an enhanced effect compared to Synvisc-One. In fact, in patients with OA Grade 3, the improvement in pain scores at 2 weeks was significantly greater in the Hydros-TA group compared with the Synvisc-One group. Future clinical evaluations will be required to further demonstrate the safety and the superiority of Hydros and Hydros-TA compared to Synvisc-One.
BACKGROUND: Studies have evaluated the concomitant use of hyaluronan (HA) with steroids, anti-inflammatory drugs and analgesic agents in an attempt to magnify the extent and duration of pain relief due to knee osteoarthritis. To date there has not been an intra-articular combination therapy available for relief of knee osteoarthritis symptoms--one that combines the fast acting onset of symptom relief provided by a corticosteroid with the long-lasting symptom relief provided by HA in a single injection. The objective of this study was to evaluate the safety and preliminary performance of two new HA formulations, Hydros (hyaluronan-based hydrogel suspended in hyaluronan solution) and Hydros-TA (HA plus 10 mg of triamcinolone acetonide [TA]) in subjects with knee osteoarthritis.
METHODS: We conducted a Phase 2 prospective, multicenter, randomized, double-blind feasibility trial. Participants (n = 98; mean age 60 years) with knee osteoarthritis (Kellgren-Lawrence grade 2 or 3) were randomized to three treatment groups: Hydros, Hydros-TA, and Synvisc-One® (hylan G-F 20). Participants received one 6 ml intra-articular injection in the treatment knee and were evaluated at 2, 6, 13, and 26 weeks post-treatment. Safety was assessed from adverse events at all study visits. The primary efficacy outcome was the change from baseline on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A (Pain) score for the treatment knee.
RESULTS: Adverse events were similar across treatment groups with the most common being arthralgia, joint swelling, back pain, and joint stiffness. Arthralgia was reported 5 times with Synvisc-One, 4 with Hydros, and 1 with Hydros-TA. Each group demonstrated a reduction in the WOMAC A (Pain) score over 26 weeks: [least-square mean (standard error)] 30.5 (5.1) mm for Hydros; 34.4 (4.7) mm for Hydros-TA; 28.0 (5.4) mm for Synvisc-One and an observed improvement of 2.5 mm (p = 0.64) and 6.4 mm (p = 0.24) over Synvisc-One for Hydros and Hydros-TA, respectively.
CONCLUSIONS: A single injection of Hydros or Hydros-TA was well-tolerated and relieved pain associated with knee osteoarthritis over 26 weeks. Data indicate that Hydros-TA had a more rapid pain relief compared to Hydros alone. A Phase 3 trial is underway to confirm these preliminary results.
TRIAL REGISTRATION NUMBER: NCT01134406.
Carbylan Osteoarthritis Research 1.0 (COR 1.0) was a prospective, multicenter, randomized, double-blind feasibility study to evaluate the safety and performance of Hydros Joint Therapy (Hydros) and Hydros-TA Joint Therapy (Hydros-TA) in subjects with Kellgren&Lawrence grade 2 and 3 osteoarthritis (OA) of the knee.
METHODS:
A total of 98 subjects were enrolled, treated, and followed for six months post-treatment. Subjects were randomized 1:1:1 to Hydros (PEG cross linked HA without TA), Hydros-TA (PEG cross linked HA with TA), or Synvisc-One Hylan G-F 20 (Synvisc-One). Hydros is a bioresorbable hyaluronan-based hydrogel suspended in a hyaluronan solution. Hydros-TA incorporates a low dose (10mg) corticosteroid, triamcinolone acetonide, suspended within the hyaluronan hydrogel, and is designed to retain steroid locally in the joint. All randomized subjects received one 6 mL intra-articular (IA) injection in the treatment knee by an unblinded injecting physician. The treatment knee was the knee that met the inclusion criteria on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A (pain) subscale score (50-90mm on 100mm VAS). Subjects and evaluating physicians who followed subjects post-treatment were blinded to treatment. Subjects were seen by a treatment-blinded evaluating physician for post-treatment follow-up at 2 weeks, 6 weeks, 13 weeks, and 26 weeks. Subjective symptom rating and physical assessment including the full WOMAC questionnaire were obtained at screening and each follow-up visit. Subject global assessment was obtained at 13 weeks and subject and physician global assessments were obtained at 26 weeks. Adverse events were solicited at all visits. The primary efficacy endpoint was the time-weighted change from baseline in the WOMAC A (pain) subscale average score for the treatment knee over 26 weeks. Differences between treatment were assessed using an analysis of covariance (ANCOVA) model.
RESULTS:
For the primary outcome, Hydros demonstrated a 41.2mm reduction, Hydros-TA demonstrated a 42.2mm reduction and Synvisc-One demonstrated a 37.5mm reduction from baseline pain. These results represented an improvement of 3.7mm and 4.7mm over Synvisc-One for Hydros and Hydros-TA respectively. Greater reductions in pain for Hydros-TA vs Synvisc-One were observed at all timepoints over the course of the study. The percentage of subjects who responded favorably to the product (as measured by the OMERACT-OARSI responder rate) was also higher in the Hydros and Hydros-TA groups when compared to Synvisc-One. Hydros-TA showed a trend towards a faster onset of pain relief compared to the non-steroid containing products evaluated in the study. Hydros-TA provided a 43.5mm mean reduction from baseline pain at the 2 week time point compared to a mean reduction of 37.7mm and 32.3mm for Synvisc-One and Hydros, respectively. In the Hydros-TA treatment group there were 3 reports of product related adverse events compared to 9 reports in the Synvisc-One group and 7 events reported in the Hydros group. Arthralgia was the most commonly reported product-related adverse event (5 reports with Synvisc-One, 4 with Hydros, and 1 with Hydros-TA).
CONCLUSIONS:
A single injection of Hydros or Hydros-TA was well tolerated and relieved pain associated with symptomatic OA of the knee over 26 weeks. The study endpoints showed strong trends toward an enhanced effect compared to Synvisc-One. In fact, in patients with OA Grade 3, the improvement in pain scores at 2 weeks was significantly greater in the Hydros-TA group compared with the Synvisc-One group. Future clinical evaluations will be required to further demonstrate the safety and the superiority of Hydros and Hydros-TA compared to Synvisc-One.
