We retrospectively examined prospective data on the incidence and time to total knee replacement (TKR) in (1) patients with grade IV osteoarthritis (OA) treated with hylan G-F 20 from 1997 to 2010 (full cohort; 1,863 knees) and (2) a patient subset treated from 1997 to 2003 (original cohort; 1,187 knees) to determine any continued hylan G-F 20 influence on TKR delay. In both the cohorts, 25 to 28% knees underwent a TKR, with an average of 2.8 to 3.1 years occurring between hylan G-F 20 and surgery. Age was a significant predictor of time to TKR. Knee synovitis increased slightly with repeat courses; most cases considered mild or moderate. Survival analysis showed that TKR was delayed for > 7 years in 75% of 1,863 grade IV OA knees (1,342 patients) treated with hylan G-F 20 in an orthopedic practice. Consistent with our previous report (Waddell and Bricker, 2007), we show hylan G-F 20 continues to delay the need for TKR.
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.
The main goal of our study was to examine the effectiveness and safety of Fermathron plus, a specific brand of hyaluronic acid (HA), in patients with mild to moderate knee osteoarthritis. In a randomized, controlled, double-blind trial, 196 patients with symptomatic knee osteoarthritis (mean age ± SD, 59.4 ± 9.9 years, Kellgren-Lawrence grade 1-3) were given either 3 weekly intra-articular injections of HA or saline (placebo). Although pain and functional scores (WOMAC scale) improved significantly from baseline up to 6 months, HA was not superior to placebo at any follow-up (VAS pain 50 m walking from 56.4 to 38.1, P < .001, and 58.2 to 39.6, P < .001, respectively). No subgroup analysis resulted in superior outcomes. No serious adverse events were noticed.
INTRODUCTION: Knee osteoarthritis (OA) is the most common articular disease. Different methods are used to alleviate the symptoms of patients with knee OA, including analgesics, physical therapy, exercise prescription, and intra-articular injections (glucocorticoids, hyaluronic acid [HA], etc). New studies have focused on modern therapeutic methods that stimulate cartilage healing process and improve the damage, including the use of platelet-rich plasma (PRP) as a complex of growth factors. Due to the high incidence of OA and its consequences, we decided to study the long-term effect of intraarticular injection of PRP and HA on clinical outcome and quality of life of patients with knee OA. METHOD: This non-placebo-controlled randomized clinical trial involved 160 patients affected by knee OA, grade 1-4 of Kellgren--Lawrence scale. In the PRP group (n = 87), two intra-articular injections at 4-week interval were applied, and in the HA group (n = 73), three doses of intra-articular injection at 1-week interval were applied. All patients were prospectively evaluated before and at 12 months after the treatment by Western Ontario and McMaster Universities Arthritis Index (WOMAC) and SF-36 questionnaires. The results were analyzed using SPSS 16.1 software (RCT code: IRCT2014012113442N5). RESULTS: At the 12-month follow-up, WOMAC pain score and bodily pain significantly improved in both groups; however, better results were determined in the PRP group compared to the HA group (P < 0.001). Other WOMAC and SF-36 parameters improved only in the PRP group. More improvement (but not statistically significant) was achieved in patients with grade 2 OA in both the groups. CONCLUSION: This study suggests that PRP injection is more efficacious than HA injection in reducing symptoms and improving quality of life and is a therapeutic option in select patients with knee OA who have not responded to conventional treatment.
Improvements in nitrogen use efficiency in crop production are critical for addressing the triple challenges of food security, environmental degradation and climate change. Such improvements are conditional not only on technological innovation, but also on socio-economic factors that are at present poorly understood. Here we examine historical patterns of agricultural nitrogen-use efficiency and find a broad range of national approaches to agricultural development and related pollution. We analyse examples of nitrogen use and propose targets, by geographic region and crop type, to meet the 2050 global food demand projected by the Food and Agriculture Organization while also meeting the Sustainable Development Goals pertaining to agriculture recently adopted by the United Nations General Assembly. Furthermore, we discuss socio-economic policies and technological innovations that may help achieve them.
BACKGROUND: Celecoxib is an effective treatment for osteoarthritis (OA). However, information on its efficacy and safety profile in different racial/ethnic groups is limited. Noticeable differences among racial groups are found in other disease states, but a thorough investigation of OA is lacking. The objective of this study was to determine if celecoxib 200 mg once daily is as effective as naproxen 500 mg twice daily in the treatment of OA of the knee in Hispanic patients.
METHODS: Hispanic patients aged ≥45 years with knee OA were randomized to receive celecoxib 200 mg once daily, naproxen 500 mg twice daily, or placebo for 6 weeks. The primary efficacy variable was the change in Patient's Assessment of Arthritis Pain at 6 weeks compared with baseline. Secondary variables were change in Patient's and Physician's Global Assessments of Arthritis from baseline to week 6/early termination, change in Western Ontario and McMaster Universities OA Index (WOMAC) from baseline to week 6/early termination, change in American Pain Society pain score, Pain Satisfaction Scale, Patient Health Questionnaire (PHQ-9), and measurements of upper gastrointestinal tolerability.
RESULTS: In total, 239 patients completed the trial (96 celecoxib, 96 naproxen, 47 placebo). Celecoxib was as effective as naproxen in reducing OA pain (least squares mean change from baseline [standard error] -39.7 [2.7] for celecoxib and -36.9 [2.6] for naproxen). Patient's and Physician's Global Assessments of Arthritis, WOMAC scores, upper gastrointestinal tolerability, Pain Satisfaction Scale, and PHQ-9 showed no statistically significant differences between the celecoxib and naproxen groups. The incidence of adverse events and treatment-related adverse events were similar among the treatment groups.
CONCLUSION: Celecoxib 200 mg once daily was as effective as naproxen 500 mg twice daily in the treatment of signs and symptoms of knee OA in Hispanic patients. Celecoxib was shown to be safe and well tolerated in this patient population.
<b>PURPOSE: </b>To assess the efficacy and safety of one and two intra-articular (IA) injections of the new viscosupplement, hylastan, 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.<b>METHODS: </b>This 6-month, double-blind, randomized, parallel group, multicenter trial enrolled patients aged ≥40 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: 2 × 4 mL hylastan (n = 129; arthrocentesis then IA hylastan Day 0, same treatment Week 2); 1 × 4 mL hylastan (n = 130; arthrocentesis then IA hylastan 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.<b>RESULTS: </b>Statistically significant pain reduction was observed in all three arms, with similar mean (95 % CI) changes in WOMAC A: 2 × 4 mL hylastan -0.9 (-1.0, -0.7); 1 × 4 mL hylastan -0.8 (-0.9, -0.7); steroid -0.9 (-1.0, -0.8); all P < 0.0001 versus baseline. Changes in secondary outcomes (OMERACT-OARSI and WOMAC A responder rates, patient/clinical observer global assessments, and WOMAC A1 walking pain) were similar in all three arms. Target knee adverse events were comparable for all treatments.<b>CONCLUSIONS: </b>Both IA hylastan injection regimens were effective in relieving pain with an acceptable safety profile. IA hylastan 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 hylastan with other viscosupplements.
<b>OBJECTIVE: </b>NASHA hyaluronic acid is administered as a single intra-articular injection to treat the symptoms of osteoarthritis (OA). In a previous trial, post-hoc analysis indicated that NASHA provides significantly greater pain relief than saline in patients with OA confined to the study knee. We aimed to evaluate the safety and efficacy of NASHA in patients with unilateral knee OA.<b>RESEARCH DESIGN AND METHODS: </b>This was a randomized, double-blind, saline-controlled trial. All patients had knee OA confirmed by American College of Rheumatology criteria and a WOMAC pain score of 7-17 in the study knee, but no pain in the previous 3 months in the non-study knee. Treatment comprised a single intra-articular injection of NASHA or saline control. The follow-up period was 6 weeks.<b>Clinical Trial Registration: </b>ClinicalTrials.gov NCT01806207.<b>MAIN OUTCOME MEASURES: </b>The primary efficacy endpoint was the responder rate, defined as the percentage of patients with ≥40% improvement from baseline in WOMAC pain score and an absolute improvement of ≥5 points.<b>RESULTS: </b>A total of 218 patients received study treatment (NASHA: 108, saline: 110). In the main intention-to-treat (ITT) analysis, no statistically significant difference in responder rate was found between the two groups at 6 weeks (NASHA: 30.6%; saline: 26.4%). A post-hoc subgroup analysis of patients without clinical effusion in the study knee at baseline showed a significantly higher 6 week responder rate with NASHA than with saline: 40.6% versus 19.7% (p = 0.0084). A total of 68 adverse events were reported among 44 patients in the NASHA group, compared with 69 adverse events among 44 patients in the saline group. The main weakness of the study was the short, 6 week follow-up duration. In addition, image guidance was not used to ensure injection as intended into the intra-articular space.<b>CONCLUSIONS: </b>Single-injection NASHA was well tolerated and, although there was no significant benefit versus saline control in the primary analysis, post-hoc analysis showed a statistically significant improvement in pain relief at 6 weeks among patients without clinical effusion at baseline.
<b>OBJECTIVE: </b>To compare NASHA hyaluronic acid gel as single-injection intra-articular (IA) treatment for knee osteoarthritis (OA) against methylprednisolone acetate (MPA).<b>DESIGN: </b>This was a prospective, multi-centre, randomized, active-controlled, double-blind, non-inferiority clinical trial. A unique, open-label extension phase (OLE) was undertaken to answer further important clinical questions. Subjects with painful unilateral knee OA were treated and followed for 26 weeks (blinded phase). All patients attending the clinic at 26 weeks were offered NASHA treatment, with a subsequent 26-week follow-up period (extension phase). The primary objective was to show non-inferiority of NASHA vs MPA in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain responder rate (percentage of patients with ≥40% improvement from baseline in WOMAC pain score and an absolute improvement of ≥5 points) at 12 weeks.<b>RESULTS: </b>In total, 442 participants were enrolled. The primary objective was met, with NASHA producing a non-inferior response rate vs MPA at 12 weeks (NASHA: 44.6%; MPA: 46.2%; difference [95% CI]: 1.6% [-11.2%; +7.9%]). Effect size for WOMAC pain, physical function and stiffness scores favoured NASHA over MPA from 12 to 26 weeks. In response to NASHA treatment at 26 weeks, sustained improvements were seen in WOMAC outcomes irrespective of initial treatment. No serious device-related adverse events (AEs) were reported.<b>CONCLUSIONS: </b>This study shows that single-injection NASHA was well tolerated and non-inferior to MPA at 12 weeks. The benefit of NASHA was maintained to 26 weeks while that of MPA declined. An injection of NASHA at 26 weeks conferred long-term improvements without increased sensitivity or risk of complications. STUDY IDENTIFIER: NCT01209364 (www.clinicaltrials.gov).
We retrospectively examined prospective data on the incidence and time to total knee replacement (TKR) in (1) patients with grade IV osteoarthritis (OA) treated with hylan G-F 20 from 1997 to 2010 (full cohort; 1,863 knees) and (2) a patient subset treated from 1997 to 2003 (original cohort; 1,187 knees) to determine any continued hylan G-F 20 influence on TKR delay. In both the cohorts, 25 to 28% knees underwent a TKR, with an average of 2.8 to 3.1 years occurring between hylan G-F 20 and surgery. Age was a significant predictor of time to TKR. Knee synovitis increased slightly with repeat courses; most cases considered mild or moderate. Survival analysis showed that TKR was delayed for > 7 years in 75% of 1,863 grade IV OA knees (1,342 patients) treated with hylan G-F 20 in an orthopedic practice. Consistent with our previous report (Waddell and Bricker, 2007), we show hylan G-F 20 continues to delay the need for TKR.
