Intra-articular hylastan versus steroid for knee osteoarthritis

Transcription

1 DOI /s KNEE Intra-articular versus steroid for knee osteoarthritis Lawrence Housman Nigel Arden Thomas J. Schnitzer Charles Birbara Thierry Conrozier Nebojsa Skrepnik Nathan Wei Barry Bockow David Waddell Hasan Tahir Anthony Hammond Philippe Goupille Bernd-Jan Sanson Clare Elkins François Bailleul Received: 15 June 2012 / Accepted: 29 January 2013 Ó Springer-Verlag Berlin Heidelberg 2013 Abstract Purpose To assess the efficacy and safety of one and two intra-articular (IA) injections of the new viscosupplement,, compared with a single IA corticosteroid injection for pain due to knee osteoarthritis (OA). Hylastan is a high-molecular-weight hyaluronan derivative prepared from bacterial fermented sodium hyaluronate that was developed to remain in the joint for longer than most other viscosupplements. Methods This 6-month, double-blind, randomized, parallel group, multicenter trial enrolled patients aged C40 years who met American College of Rheumatology criteria for knee OA and had continued pain despite conservative treatment. Patients were randomized 1:1:1 to one of three arms: ml (n = 129; arthrocentesis then IA Day 0, same treatment Week 2); ml (n = 130; arthrocentesis then IA Day 0, arthrocentesis only Week 2); steroid (n = 132; arthrocentesis then IA methylprednisolone acetate 40 mg Day 0, arthrocentesis only Week 2). Participants and evaluators were blinded to treatment. The primary clinical outcome measure was change from baseline in WOMAC A pain score over all postbaseline visits to Week 26. Results Statistically significant pain reduction was observed in all three arms, with similar mean (95 % CI) changes in WOMAC A: 2 9 4mL -0.9 (-1.0, -0.7); L. Housman N. Skrepnik Tucson Orthopaedic Institute, 2424 N Wyatt Dr, Tucson, AZ 85712, USA N. Arden MRC Lifecourse Epidemiology Unit, Southampton General Hospital, Southampton, UK N. Arden NDORMS, University of Oxford, Windmill Road, Oxford OX3 7HE, UK T. J. Schnitzer Northwestern University Feinberg School of Medicine, Abbott Hall Suite 102, 710 N Lake Shore Drive, Chicago, IL 60611, USA C. Birbara Clinical Pharmacology Study Group, 26 Queen Street, Worcester, MA 01610, USA T. Conrozier Centre Hospitalier Lyon-Sud University Hospital, Chemin du Grand Revoyet, Pierre Bénite, France N. Wei Arthritis Treatment Center, 71 Thomas Johnson Drive, Frederick, MD 21702, USA B. Bockow Arthritis Northwest, th Ave SW Ste D3, Seattle, WA, USA D. Waddell Orthopedics Specialists of Louisiana, 1500 Line Avenue, Suite 100, Shreveport, LA 71101, USA H. Tahir Whipps Cross University Hospital NHS Trust, Whipps Cross Road, Leytonstone, London E11 1NR, UK A. Hammond Maidstone General Hospital, Hermitage Lane, Maidstone, Kent ME16 9QQ, UK P. Goupille CHU Hôpital Trousseau, Tours Cedex 9, France

2 1 9 4 ml -0.8 (-0.9, -0.7); steroid -0.9 (-1.0, -0.8); all P \ versus baseline. Changes in secondary outcomes (OMERACT-OARSI and WOMAC A responder rates, patient/clinical observer global assessments, and WO- MAC A1 walking pain) were similar in all three arms. Target knee adverse events were comparable for all treatments. Conclusions Both IA injection regimens were effective in relieving pain with an acceptable safety profile. IA did not show a difference versus IA corticosteroid; therefore, the hypothesis of superior pain relief was not met. Further research is needed to compare the efficacy and safety of with other viscosupplements. Level of evidence Therapeutic study, Level I. Keywords Corticosteroid Hyaluronic acid Intra-articular injection Knee Osteoarthritis Viscosupplement Introduction Osteoarthritis (OA) is characterized by the gradual loss of articular cartilage, remodeling of adjacent bone, and joint inflammation [2, 16, 24, 29]. The elastoviscous properties of the synovial fluid are also diminished owing to a reduction in the concentration and molecular weight of the key component hyaluronan (hyaluronic acid), increasing the potential for cartilage damage due to mechanical stress [28, 30]. The main clinical features are pain and loss of function, which may significantly affect patient quality of life [3, 21, 25]. Primary treatment goals are to reduce pain and stiffness, improve function and quality of life, and limit disease progression if possible, while minimizing toxicity [20, 35, 39, 40]. Clinical guidelines for the management of OA in the knee recommend combining nonpharmacologic and pharmacologic approaches [20, 26, 35, 39, 40]. If acetaminophen (paracetamol), nonselective non-steroidal anti-inflammatory drugs (NSAIDs), and cyclooxygenase-2 (COX-2) inhibitors are ineffective or poorly tolerated, most B.-J. Sanson Genzyme Europe BV, Gooimeer 10, 1411 DD Naarden, The Netherlands C. Elkins Genzyme, 500 Kendall Street, Cambridge, MA 02142, USA Present Address: C. Elkins Alexion Pharmaceuticals, 55 Cambridge Parkway, Cambridge, MA 02142, USA F. Bailleul (&) Genzyme, Boulevard de la Paix, Parc d Activités du Bel-Air, Saint Germain en Laye Cedex, France fbailleul11@gmail.com guidelines recommend intra-articular (IA) corticosteroids or viscosupplements [20, 35, 39, 40]. Intra-articular (IA) corticosteroids reduce pain but are generally short-acting [8, 10], and injection more than four times per year is not universally recommended [39]. Viscosupplementation describes the temporary supplementation of synovial fluid in the OA joint with hyaluronan to restore normal elastoviscosity and physiological function, thereby decreasing pain and improving mobility [9]. Several pilot clinical studies suggest that viscosupplements also have disease-modifying effects, including possible reduction of synovial inflammation [6, 14, 17, 22, 23, 27, 38]. Several viscosupplements are available, but vary by source (animal or biofermentation), molecular weight (with or without cross-linking), concentration, volume, and number of injections required. Most are administered via multiple injections. A Cochrane meta-analysis of viscosupplement studies supported their efficacy versus placebo in relieving pain, with an acceptable safety profile, and also suggested longer duration of benefit versus IA corticosteroids [9]. Hylastan soft gel-80 ( SGL-80; Jonexa TM, Genzyme Biosurgery, Cambridge, MA, USA) is a sterile, nonpyrogenic viscosupplement intended for the treatment of pain due to knee OA. It is a new, high-molecular-weight hyaluronan derivative prepared from bacterial fermented sodium hyaluronate. Hylastan is a formulation with more gel (80 %) than fluid and its soft gel component was developed to remain in the joint for longer (3 4 weeks after injection) compared with most other viscosupplements, which has the potential to increase the duration of treatment effect and minimize the number of injections required. The objective of this study was to compare two IA injection regimens with a single IA injection of corticosteroid (methylprednisolone acetate; MPA) in terms of pain reduction, responder rates, and improvements in target knee global assessment scores, in patients with symptomatic OA of the knee. We also compared the safety profiles of all three treatments, and a repeat treatment phase was carried out to evaluate safety and efficacy in patients receiving a second treatment. IA corticosteroid therapy was selected as the comparator as it is a widely accepted treatment option and the most comparable therapy to viscosupplementation at the time of the study. The study hypothesis was that one or two IA injections would provide superior pain relief over 26 weeks compared with steroid. Two different dosing schedules of were tested in order to determine the most effective regimen. Materials and methods This prospective, double-blind, randomized, parallel group trial was conducted at 25 centers in the USA, Canada,

3 France, UK, and Germany between October 4, 2004 and September 19, 2007 (EudraCT ; ClinicalTrials.gov identifier NCT ). The study was carried out in compliance with the principles of Good Clinical Practice, the International Organization for Standardization 14155, and other country-specific regulations. The protocol and informed consent form were reviewed and approved by an Institutional Review Board/Independent Ethics Committee that complied with national regulations and the International Conference on Harmonisation. All patients provided informed consent at screening. The study comprised a screening phase, a 2-week initial treatment phase with follow-up to Week 26, and a repeat treatment phase with additional follow-up to Repeat Week 26. Patients Men and women aged C40 years with an active lifestyle were eligible (selected) if they were in good general health, ambulatory, and currently meeting American College of Rheumatology criteria for OA [1]. Patients were required to have primary OA knee pain despite conservative treatment, defined as a score of on the Western Ontario and McMaster Universities Osteoarthritis Index Likert version 3.1 (WOMAC Ò LK 3.1) pain subscore (WOMAC A), and moderate or severe walking pain (a WOMAC A1 walking pain subscore of 2 3). The main exclusion criteria were modified Kellgren-Lawrence (KL) Grade 0 or IV; clinically apparent tense effusion; significant valgus/varus deformities, ligament laxity, or meniscal instability; inflammatory disease, or other condition that affects the joints (e.g., rheumatoid arthritis, metabolic bone disease, gout, active infection); prior or current symptomatic peripheral vascular disease of the study leg; any musculoskeletal condition that would impede assessment of clinical outcomes; significant mechanical problems; viscosupplementation within the prior 12 months; systemic/ia corticosteroids within the prior 3 months; target knee arthroplasty at any time; or other surgery within the prior 6 months. Randomization and treatment Randomization was carried out on Day 0 (baseline) using a computer-generated randomization scheme and Interactive Voice Response System (IVRS) provided by Genzyme. Patients were randomized to one of three treatment arms in a 1:1:1 ratio. All patients underwent arthrocentesis on Day 0. Subjects in the ml arm then received a single IA injection of SGL-80 on Day 0 and arthrocentesis only at Week 2. Those in the ml group received IA SGL-80 on Day 0 and the same treatment at Week 2 (two separate injections). Subjects in the steroid group received a single 1-mL IA injection of MPA (40 mg/ml) at Day 0 and arthrocentesis only at Week 2. Patients and clinical evaluators were blinded to treatment; the injecting physician was unblinded. To maintain blinding, the injection procedure and related supplies were screened from patients. Acetaminophen (paracetamol) 500-mg tablets were provided as rescue medication for target knee pain relief, with 1 2 to be taken every 4 6 h as needed (not exceeding 8 tablets in 24 h) except for within 48 h prior to a study visit. Clinical assessments Clinical assessments were carried out at baseline and at follow-up Weeks 4, 8, 12, 16, 20, and 26. WOMAC Ò LK 3.1 questionnaires were provided to the patient by the investigator or a research colleague and completed by the patient. The WOMAC A pain subscore comprises five separate questions to measure pain during walking, using stairs, in bed, sitting/lying, and standing. It was assessed for each patient using a 5-point, ordinal Likert scale (0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = extreme) to capture their response to each question. Secondary clinical assessments were: proportion of responders according to the Outcomes Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT-OARSI) response criteria [32, 33], walking pain (using the subscore from the WOMAC A1 walking pain question, as described above), proportion of WOMAC A responders (1-category improvement from baseline at each postbaseline assessment), patient global assessment (PTGA), and clinical observer global assessment (COGA). For the PTGA and the COGA, the patient or blinded evaluator, respectively, assessed the target knee using a Likert scale (0 = very well, 1 = well, 2 = fair, 3 = poor, 4 = very poor). As the WOMAC LK 3.1, OMERACT-OARSI, PTGA, and COGA are all well-validated assessment tools, measurement of test retest reliability was not necessary. Treatment-emergent adverse events (AEs) were recorded at all visits and categorized using the Medical Dictionary for Regulatory Activities (MedDRA). For the first 102 patients enrolled, antibody testing was carried out using serum samples and urinalysis to evaluate inflammatory response. Repeat treatment phase Patients with a favorable response to initial treatment (1-point decrease in WOMAC A1 at any time and WOMAC A1 score C1) and no major safety concerns, who continued to meet the inclusion/exclusion criteria, were

4 assigned to repeat treatment through the IVRS on Repeat Day 0. Patients initially randomized to remained in the same group and those previously receiving steroid were re-randomized to one of the arms. Treatment was administered on Repeat Day 0 and Repeat Week 2. WOMAC A/A1, PTGA, and COGA were assessed at Repeat Weeks 4, 8, 12, 16, 20, and 26. Statistical analysis Approximately 372 patients would provide [80 % power to detect an overall mean difference of 0.32 (common SD 0.74) between the and steroid groups in WOMAC A change from baseline over 26 weeks, assuming a 15 % dropout rate and a two-sided significance level of 5 %. This was based on a previous study comparing viscosupplement and IA steroid [11], as a function of their different longitudinal responses. The primary clinical outcome measure was the WO- MAC A change from baseline for versus steroid over all postbaseline study visits in the intent-to-treat population (all patients randomized). This was analyzed using the average of the scores comprising the WOMAC LK 3.1 A subsection and a repeated measures ANCOVA model, including terms for treatment, center, time, baseline, KL grade, and relevant interactions. Means are presented to 1 decimal place more than that at which the outcome was recorded, according to the standard statistical procedures of the study sponsor. Sequential hypothesis testing was used to maintain a Type I error rate of 5 %: ml was tested against steroid first and if the difference was significant at the 0.05 level, 1 9 4mL was then tested against steroid. Generalized estimating equations were used to estimate the odds ratio of a positive response over 26 weeks according to OMERACT- OARSI responder criteria. For the PTGA, COGA, WO- MAC A1, and WOMAC A responders, the odds ratio for a positive response was analyzed using logistic regression. Results Patient flow through the study is shown in Fig. 1. Patient characteristics and target knee history were similar in all three arms (Table 1). Clinical outcomes For the WOMAC A pain score, the estimated mean changes from baseline over 26 weeks were similar in all three arms: ml -0.9 (95 % CI -1.0, -0.7); ml -0.8 (-0.9, -0.7); steroid -0.9 (-1.0, -0.8), with no significant difference between and steroid. Within-group changes from baseline over 26 weeks were statistically significant in all three arms (all P \ ; Fig. 2). OMERACT-OARSI and WOMAC A responder rates at Week 26, and the improvements from baseline to Week 26 in PTGA, COGA, and WOMAC A1 walking pain, were similar in all three treatment groups (Table 2). There were no significant differences between treatment groups in the overall estimates of the odds ratio for a positive response for any of the secondary clinical outcomes (data not shown). A significantly higher mean daily dose of rescue medication was taken in the 2 9 4mL group versus the steroid group (Table 2); there was no statistically significant difference between the ml and steroid groups. Tolerability The frequencies of overall AEs and target knee AEs were comparable between treatment groups (Table 3). The most frequent target knee TEAEs in all three groups were arthralgia, stiffness, swelling, and effusion, with no differences between the three groups. The majority of target knee AEs were assessed as mild or moderate: 163 of 210 events (78 %) in the ml group; 124 of 180 (69 %) in the ml group; 137 of 202 (68 %) in the steroid group. One death was reported; a patient in the steroid group withdrew due to a severe SAE of metastatic pancreatic carcinoma (unrelated to study treatment/ procedure). There were no clinically significant changes in vital signs or antibody testing results and no laboratory safety concerns. Repeat treatment phase In the repeat treatment phase, mean scores improved from Repeat Day 0 to Repeat Week 26 in all treatment groups for all four efficacy measures (data not shown). The acceptable safety profile was confirmed in the repeat treatment phase; there was no increase in severity or incidence of target knee AEs in patients receiving repeat : 28 % of patients in the ml group, 32 % in the ml group, 23 % in the steroid ml group, and 38 % in the steroid ml group. In all groups, arthralgia (24 %), joint swelling (13 %), joint stiffness (10 %), and joint effusion (6 %) were the most common target knee AEs. Discussion The principal finding of this study was the statistically significant improvement in WOMAC A pain score from baseline over 26 weeks in all three arms. The improvements

5 Assessed for eligibility (n = 588) Randomized (N = 391) 2x4 ml (n = 129) 1x4 ml (n = 130) Steroid (n = 132) Initial treatment phase Completed (n = 108) Discontinued (n = 21) Adverse event (n = 2) Non-compliance (n = 2) Patient request (n = 9) Lost to follow-up (n = 3) Lack of efficacy (n = 4) Other (n = 1) Completed (n = 106) Discontinued (n = 24) Adverse event (n = 3) Non-compliance (n = 0) Patient request (n = 9) Lost to follow-up (n = 3) Lack of efficacy (n = 6) Other (n = 3) Completed (n = 112) Discontinued (n = 20) Adverse event (n = 7) Non-compliance (n = 0) Patient request (n = 1) Lost to follow-up (n = 3) Lack of efficacy (n = 8) Other (n = 1) Analyzed Safety (n = 124) a ITT (n = 129) Analyzed Safety (n = 135) a ITT (n = 130) Analyzed Safety (n = 131) b ITT (n = 132) Repeat treatment phase 2x4 ml (n = 79) ITT (n = 66) Repeat safety (n = 66) Completed (n = 57) Discontinued (n = 9) Adverse event (n = 4) Non-compliance (n = 0) Patient request (n = 2) Lack of efficacy (n = 2) Lost to follow-up (n = 1) Other (n = 0) 1x4 ml (n = 74) ITT (n = 61) Repeat safety (n = 61) Completed (n = 51) Discontinued (n = 10) Adverse event (n = 3) Non-compliance (n = 1) Patient request (n = 3) Lack of efficacy (n = 2) Lost to follow-up (n = 1) Other (n = 0) Steroid-2x4 ml (n = 42) ITT (n = 39) Repeat safety (n = 39) Completed (n = 36) Discontinued (n = 3) Adverse event (n = 0) Non-compliance (n = 0) Patient request (n = 1) Lack of efficacy (n = 2) Lost to follow-up (n = 0) Other (n = 0) Steroid-1x4 ml (n = 41) ITT (n = 35) Repeat safety (n = 35) Completed (n = 30) Discontinued (n = 5) Adverse event (n = 0) Non-compliance (n = 0) Patient request (n = 3) Lack of efficacy (n = 1) Lost to follow-up (n = 1) Other (n = 0) Fig. 1 Patient flow. a Six patients were randomized to the 2 9 4mL group but received ml in error; they were included in the ml group for safety analyses but in the ml group for clinical outcome analyses. One patient was randomized to the ml group but received ml in error and was included in the ml group for safety but in the ml group for ITT clinical outcome. b One patient in the steroid group was randomized in error and did not receive treatment (baseline Kellgren Lawrence Grade IV); this patient was not included in the safety population. ITT intent-to-treat (all patients randomized) were of similar magnitude, with comparable longitudinal profiles, in all arms. As there were no significant differences between and steroid, the primary objective of superior pain relief with was not met. Similar improvements from baseline in secondary clinical outcomes were also seen, but there were no significant differences between and steroid. Repeat treatment with (one or two injections) provided continued pain relief for an additional 26 weeks. The frequency and type of target knee AEs was comparable in all three groups and the majority were mild or moderate, indicating an acceptable safety profile for. This was confirmed in the repeat treatment phase, with no changes in frequency or type of AEs in patients receiving a second treatment 6 months later. The AEs observed here correspond with those reported for other IA viscosupplements, and there were no unexpected AEs with this new viscosupplement. All three treatments resulted in the relief of OA-associated knee pain, as demonstrated by a reduction in WO- MAC A pain score by approximately one point. This was evident in all groups at first assessment (Week 4) and was maintained to Week 26. Walking pain was also reduced. The positive effect of treatment on pain and function was also confirmed by the increase in patients classed as OMERACT-OARSI responders. The patient self-assessment of the target knee OA condition was also improved with treatment, along with the clinical observer global

6 Table 1 Subject characteristics at initial treatment phase baseline (ITT population) 2 9 4mL (n = 129) 1 9 4mL (n = 130) Steroid (n = 132) ITT intent-to-treat (all patients randomized), SD standard deviation, BMI body mass index, OA osteoarthritis, IA intra-articular a One patient in the 2 9 4mL group had Kellgren Lawrence Grade IV OA and therefore was erroneously enrolled into the study Age in years, mean (SD) (range) 62.0 (9.7) (39 82) 60.6 (9.9) (43 85) 60.1 (9.3) (42 85) Men/women, n (%) 38 (29)/91 (71) 51 (39)/79 (61) 41 (31)/91 (69) BMI in kg/m 2, mean (SD) 31.7 (6.6) 31.2 (6.4) 30.8 (6.5) Kellgren Lawrence grade, n (%) I 2 (2) 9 (7) 7 (5) II 30 (24) 45 (33) 39 (30) III 91 (73) 81 (60) 85 (65) IV 1 a 0 0 Target knee history Months since OA diagnosis, mean (SD) 30.2 (37.5) 38.9 (45.7) 38.3 (38.4) (range) ( ) ( ) ( ) Previous treatment, n (%) Viscosupplementation 17 (14) 35 (26) 23 (18) IA corticosteroids 48 (39) 60 (44) 53 (41) Arthrocentesis 10 (8) 28 (21) 26 (20) Arthroscopy 44 (36) 56 (42) 43 (33) Arthroplasty Other surgical procedures 12 (10) 11 (8) 13 (10) Fig. 2 WOMAC A pain scores over the initial 26-week treatment period. Circles denote the ml group, squares the ml group, and triangles the steroid group. ***P \ versus baseline (all groups). WOMAC Western Ontario and McMaster Universities Osteoarthritis Index assessment. Our findings are in line with previous studies, which showed pain relief and improvements in function and patient global assessment in knee OA with viscosupplements [9] and pain relief with corticosteroids [8, 10]. However, the similar duration of pain relief with and steroid was unexpected and differs from most other studies comparing viscosupplements and steroid for knee OA. A Cochrane review found no statistically significant differences between IA corticosteroids and viscosupplements 1 4 weeks postinjection, but at 5 13 weeks, viscosupplements were more effective [8]. This was supported by another meta-analysis of seven of these studies, all comparing hyaluronan with corticosteroids [7]. In the first 2 weeks, corticosteroids were more effective in relieving pain, but at Week 4, both were equally effective, and from Week 8, hyaluronan was more effective to last assessment (Week 26) [7]. As IA corticosteroids (including MPA 40 mg) have been shown to be effective in relieving pain versus placebo in clinical trials [8, 10], it is unlikely that our findings reflect a lack of clinical effect in all three arms. However, the lack of placebo group precludes assessment of the true magnitude and duration of effect for both treatments. Limited evidence suggests that sustained effects can occur with IA corticosteroids; an earlier metaanalysis noted that benefit with corticosteroids (cortivazol 3.75 mg or MPA 120 mg) remained at weeks compared with placebo [5], and a single-blind, randomized study comparing joint tidal irrigation and triamcinolone acetonide 40 mg found maintenance of pain relief to Week 26 in 29 % of patients receiving corticosteroid [4]. There are likely to be differences according to dose and injection regimens, and the extended benefit in these studies may be related to the doses used. Studies assessing the same MPA dose as the present study (40 mg) reported loss of pain relief by 8 weeks versus placebo [18] and improvements from baseline that were maintained up to the last assessment at 8 weeks [34]. There is also potential for different responses according to level of inflammation and radiological grade. Steroid efficacy may be greater in earlier

7 Table 2 Secondary clinical outcomes (ITT population) OMERACT-OARSI responders at Week 26, n (%) 2 9 4mL (n = 129) 1 9 4mL (n = 130) Steroid (n = 132) 73 (57) 64 (49) 66 (50) PTGA for target knee, mean (SD) Baseline 2.4 (0.7) 2.4 (0.6) 2.4 (0.6) Week (0.9) 1.7 (1.0) 1.6 (0.9) COGA for target knee, mean (SD) Baseline 2.3 (0.7) 2.3 (0.7) 2.3 (0.8) Week (1.0) 1.4 (1.0) 1.5 (1.1) WOMAC A1 walking pain, mean (SD) Baseline 2.3 (0.5) 2.3 (0.5) 2.3 (0.5) Week (0.9) 1.4 (0.9) 1.5 (0.8) WOMAC A responders a 45 (35) 45 (35) 40 (30) at Week 26, n (%) Rescue medication use mg/day, mean (SD) (952.5) b (1054.5) (763.8) ITT intent-to-treat (all patients randomized), OMERACT-OARSI Outcomes Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International, PTGA patient global assessment, SD standard deviation, COGA clinical observer global assessment, WOMAC Western Ontario and McMaster Universities Osteoarthritis Index a Defined as a 1-category improvement from baseline in WOMAC A at a postbaseline assessment b P = versus steroid (two-sample t test) disease (KL Grade I/II) and when there is greater inflammation, but study data supporting this hypothesis are limited. Arden and colleagues noted greater benefit with IA triamcinolone acetonide in patients with KL Grade 0/I/II disease [4]. The presence of knee effusion predicted a better response to IA corticosteroid in two studies [4, 15], but others did not support this association [12, 18, 31]. In the present study, exploratory analyses (data not shown) indicated a greater WOMAC A change from baseline for KL Grade I/II disease in the steroid group versus the groups (P = versus ml ), whereas in patients with KL Grade III, the changes favored the groups (not significant versus steroid). Similar outcomes were seen in hip OA studies [36, 37], although data from another hip OA study were contradictory [13]. This possible effect of radiological grade on duration of corticosteroid effect requires further exploration. It is also possible that strict application of the correct IA injection technique may result in a prolonged effect with IA corticosteroids. In the present study, there was significant emphasis on the correct technique, but this may not always Table 3 Treatment-emergent adverse events (AEs) in the initial treatment phase (safety population a ) n (%) 2 9 4mL (n = 124) 1 9 4mL (n = 135) Steroid (n = 131) Overall Any AE 86 (69.4) 91 (67.4) 81 (61.8) Injection-related AE 18 (14.5) 22 (16.3) 13 (9.9) Treatment-related AE 33 (26.6) 36 (26.7) 29 (22.1) Serious AE 5 (4.0) 5 (3.7) 8 (6.1) Discontinued due to an AE 0 5 (3.7) 7 (5.3) Target knee Any AE 52 (41.9) 61 (45.2) 46 (35.1) Injection-related AE 18 (14.5) 21 (15.6) 13 (9.9) Treatment-related AE 31 (25.0) 36 (26.7) 26 (19.8) Serious AE 0 1 (0.7) b 0 AEs occurring in C1 % patients Arthralgia 39 (31.5) 44 (32.6) 39 (29.8) Joint stiffness 19 (15.3) 29 (21.5) 25 (19.1) Joint swelling 13 (10.5) 25 (18.5) 18 (13.7) Joint effusion 7 (5.6) 11 (8.1) 16 (12.2) Joint warmth 4 (3.2) 9 (6.7) 3 (2.3) Joint crepitation 5 (4.0) 5 (3.7) 5 (3.8) Injection-site pain 6 (4.8) 4 (3.0) 2 (1.5) Contusion 3 (2.4) 4 (3.0) 0 Joint instability 2 (1.6) 2 (1.5) 2 (1.5) Joint lock 2 (1.6) 2 (1.5) 0 Posttraumatic pain 0 4 (3.0) 0 a All patients who received the first injection b Progressive joint disease; judged unrelated to study treatment/procedure by investigator be practiced, which could lead to extraarticular injection and reduced duration of effect [19]. It is unlikely that the similar outcomes are due to a lack of assessment sensitivity at later time points, as the standard deviation was consistent for all three arms throughout the study (Fig. 2). The findings of this study are relevant to current clinical practice as they confirm that the new viscosupplement,, is well tolerated and provides symptomatic relief of knee pain due to OA for up to 6 months with a single injection. This information is pertinent to physicians who are involved in the management of patients with OA of the knee, especially those patients with continued pain despite conservative treatment. Furthermore, repeat treatment with was effective in reducing pain in patients who had previously received treatment, with no change in severity or incidence of adverse events in the target knee. These findings indicate that multiple treatments

8 may be given in an individual patient as part of their chronic treatment for knee OA. This double-blind, randomized study is limited by the lack of placebo group, although the selected comparator is a widely accepted standard of care for knee OA pain. A placebo arm was not included for ethical reasons and to facilitate enrollment. The power calculation was informed by clinical study data and based on the assumption that pain relief with corticosteroid would be of shorter duration versus. However, this was not reflected by the data. Conclusion Hylastan had an acceptable tolerability profile; there were no safety concerns in the initial or the repeat 26-week treatment phases, and target knee AEs were similar to those reported in the steroid group. Hylastan has potential as an additional treatment option for patients with continued knee OA pain despite conservative treatment. Further welldesigned studies should be conducted to compare clinical efficacy and safety with those of other knee OA therapies or other viscosupplements. Acknowledgments We thank the other participating investigators: Jeffrey Dugas M.D., Gregory D Angelo M.D., Kathleen Weber M.D., Frederick Dietz M.D., Frank Smith M.D., David Fox M.D., Jon Zoltan M.D., James Yates M.D., James Van Horne M.D., George Morris M.D., Dr. Pieter Beks, Dr. Torsten Drescher, Dr. Christophe Baudot, Dr. Fraser Birrell. This study was funded by Genzyme Corporation, Cambridge, MA, USA. Medical writing assistance was provided by Helen Varley, Ph.D., UBC-Envision Group, Horsham, UK, which was supported by Genzyme Corp., Cambridge, MA, USA. Conflict of interest The institution of B.B. has received funding from Genzyme Corp. B.J.S. is a paid employee of Genzyme Corp.; C.E. and F.B. were paid employees of Genzyme Corp. at the time of the study and manuscript writing. The other authors declare that they have no conflict of interest. References 1. Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K, Christy W, Cooke TD, Greenwald R, Hochberg M et al (1986) Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Arthritis Rheum 29(8): Altman RD (2009) Practical considerations for the pharmacologic management of osteoarthritis. Am J Manag Care 15(8 Suppl):S236 S Altman RD (2010) Early management of osteoarthritis. Am J Manag Care 16(Suppl Management):S41 S47 4. Arden NK, Reading IC, Jordan KM, Thomas L, Platten H, Hassan A, Ledingham J (2008) A randomised controlled trial of tidal irrigation vs corticosteroid injection in knee osteoarthritis: the KIVIS Study. Osteoarthr Cartil 16(6): Arroll B, Goodyear-Smith F (2004) Corticosteroid injections for osteoarthritis of the knee: meta-analysis. BMJ (Clinical Research Ed) 328(7444): Bagga H, Burkhardt D, Sambrook P, March L (2006) Longterm effects of intraarticular hyaluronan on synovial fluid in osteoarthritis of the knee. J Rheumatol 33(5): Bannuru RR, Natov NS, Obadan IE, Price LL, Schmid CH, McAlindon TE (2009) Therapeutic trajectory of hyaluronic acid versus corticosteroids in the treatment of knee osteoarthritis: a systematic review and meta-analysis. Arthritis Rheum 61(12): Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G (2006) Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane Database Syst Rev (2):CD Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G (2006) Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev (2):CD Bjordal JM, Klovning A, Ljunggren AE, Slordal L (2007) Shortterm efficacy of pharmacotherapeutic interventions in osteoarthritic knee pain: a meta-analysis of randomised placebo-controlled trials. Eur J Pain 11(2): Caborn D, Rush J, Lanzer W, Parenti D, Murray C (2004) A randomized, single-blind comparison of the efficacy and tolerability of hylan G-F 20 and triamcinolone hexacetonide in patients with osteoarthritis of the knee. J Rheumatol 31(2): Chao J, Wu C, Sun B, Hose MK, Quan A, Hughes TH, Boyle D, Kalunian KC (2010) Inflammatory characteristics on ultrasound predict poorer longterm response to intraarticular corticosteroid injections in knee osteoarthritis. J Rheumatol 37(3): Deshmukh AJ, Panagopoulos G, Alizadeh A, Rodriguez JA, Klein DA (2011) Intra-articular hip injection: does pain relief correlate with radiographic severity of osteoarthritis? Skeletal Radiol 40(11): Frizziero L, Govoni E, Bacchini P (1998) Intra-articular hyaluronic acid in the treatment of osteoarthritis of the knee: clinical and morphological study. Clin Exp Rheumatol 16(4): Gaffney K, Ledingham J, Perry JD (1995) Intra-articular triamcinolone hexacetonide in knee osteoarthritis: factors influencing the clinical response. Ann Rheum Dis 54(5): Goldring SR, Goldring MB (2006) Clinical aspects, pathology and pathophysiology of osteoarthritis. J Musculoskelet Neuronal Interact 6(4): Guidolin DD, Ronchetti IP, Lini E, Guerra D, Frizziero L (2001) Morphological analysis of articular cartilage biopsies from a randomized, clinical study comparing the effects of kda sodium hyaluronate (Hyalgan) and methylprednisolone acetate on primary osteoarthritis of the knee. Osteoarthr Cartil 9(4): Jones A, Doherty M (1996) Intra-articular corticosteroids are effective in osteoarthritis but there are no clinical predictors of response. Ann Rheum Dis 55(11): Jones A, Regan M, Ledingham J, Pattrick M, Manhire A, Doherty M (1993) Importance of placement of intra-articular steroid injections. BMJ (Clinical Research Ed) 307(6915): Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma JW, Dieppe P, Gunther K, Hauselmann H, Herrero-Beaumont G, Kaklamanis P et al (2003) EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis 62(12): Kauppila AM, Kyllonen E, Mikkonen P, Ohtonen P, Laine V, Siira P, Niinimaki J, Arokoski JP (2009) Disability in end-stage knee osteoarthritis. Disabil Rehabil 31(5): Listrat V, Ayral X, Patarnello F, Bonvarlet JP, Simonnet J, Amor B, Dougados M (1997) Arthroscopic evaluation of potential structure modifying activity of hyaluronan (Hyalgan) in osteoarthritis of the knee. Osteoarthr Cartil 5(3):

9 23. Maneiro E, de Andres MC, Fernandez-Sueiro JL, Galdo F, Blanco FJ (2004) The biological action of hyaluronan on human osteoarthritic articular chondrocytes: the importance of molecular weight. Clin Exp Rheumatol 22(3): Martel-Pelletier J, Boileau C, Pelletier JP, Roughley PJ (2008) Cartilage in normal and osteoarthritis conditions. Best Pract Res Clin Rheumatol 22(2): Moskowitz RW (2009) The burden of osteoarthritis: clinical and quality-of-life issues. Am J Manag Care 15(8 Suppl):S223 S National Institute for Health and Clinical Excellence (2008) Osteoarthritis: national clinical guideline for care and management in adults. pdf/english 27. Pasquali Ronchetti I, Guerra D, Taparelli F, Boraldi F, Bergamini G, Mori G, Zizzi F, Frizziero L (2001) Morphological analysis of knee synovial membrane biopsies from a randomized controlled clinical study comparing the effects of sodium hyaluronate (Hyalgan) and methylprednisolone acetate (Depomedrol) in osteoarthritis. Rheumatology (Oxford) 40(2): Pelletier JP, Martel-Pelletier J (1993) The pathophysiology of osteoarthritis and the implication of the use of hyaluronan and hylan as therapeutic agents in viscosupplementation. J Rheumatol Suppl 39: Pelletier JP, Martel-Pelletier J (2007) DMOAD developments: present and future. Bull NYU Hosp Jt Dis 65(3): Pelletier JP, Martel-Pelletier J, Raynauld JP (2006) Most recent developments in strategies to reduce the progression of structural changes in osteoarthritis: today and tomorrow. Arthritis Res Ther 8(2): Pendleton A, Millar A, O Kane D, Wright GD, Taggart AJ (2008) Can sonography be used to predict the response to intra-articular corticosteroid injection in primary osteoarthritis of the knee? Scand J Rheumatol 37(5): Pham T, van der Heijde D, Altman RD, Anderson JJ, Bellamy N, Hochberg M, Simon L, Strand V, Woodworth T, Dougados M (2004) OMERACT-OARSI initiative: Osteoarthritis Research Society International set of responder criteria for osteoarthritis clinical trials revisited. Osteoarthr Cartil 12(5): Pham T, Van Der Heijde D, Lassere M, Altman RD, Anderson JJ, Bellamy N, Hochberg M, Simon L, Strand V, Woodworth T et al (2003) Outcome variables for osteoarthritis clinical trials: the OMERACT-OARSI set of responder criteria. J Rheumatol 30(7): Pyne D, Ioannou Y, Mootoo R, Bhanji A (2004) Intra-articular steroids in knee osteoarthritis: a comparative study of triamcinolone hexacetonide and methylprednisolone acetate. Clin Rheumatol 23(2): Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines (2000). Arthritis Rheum 43(9): Robinson P, Keenan AM, Conaghan PG (2007) Clinical effectiveness and dose response of image-guided intra-articular corticosteroid injection for hip osteoarthritis. Rheumatology (Oxford) 46(2): Spitzer AI, Bockow BI, Brander VA, Yates JW, Maccarter DK, Gudger GK, Haller S, Lake SL, Magilavy DB (2010) Hylan G-F 20 improves hip osteoarthritis: a prospective, randomized study. Phys Sportsmed 38(2): Wang Y, Hall S, Hanna F, Wluka AE, Grant G, Marks P, Feletar M, Cicuttini FM (2011) Effects of Hylan G-F 20 supplementation on cartilage preservation detected by magnetic resonance imaging in osteoarthritis of the knee: a two-year single-blind clinical trial. BMC Musculoskelet Disord 12: Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N, Bierma-Zeinstra S, Brandt KD, Croft P, Doherty M et al (2008) OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthr Cartil 16(2): Zhang W, Nuki G, Moskowitz RW, Abramson S, Altman RD, Arden NK, Bierma-Zeinstra S, Brandt KD, Croft P, Doherty M et al (2010) OARSI recommendations for the management of hip and knee osteoarthritis: part III: changes in evidence following systematic cumulative update of research published through January Osteoarthr Cartil 18(4):

10 本文献由 学霸图书馆 - 文献云下载 收集自网络, 仅供学习交流使用 学霸图书馆 ( 是一个 整合众多图书馆数据库资源, 提供一站式文献检索和下载服务 的 24 小时在线不限 IP 图书馆 图书馆致力于便利 促进学习与科研, 提供最强文献下载服务 图书馆导航 : 图书馆首页文献云下载图书馆入口外文数据库大全疑难文献辅助工具