Hyaluronic Acid Clinical Studies

Hyaluronic acid: a unique topical vehicle for the localized delivery of drugs to the skin.
J Eur Acad Dermatol Venereol. 2005 May;19(3):308-18.

Hyaluronic acid is a naturally occurring polyanionic, polysaccharide that consists of N-acetyl-d-glucosamine and beta-glucoronic acid. It is present in the intercellular matrix of most vertebrate connective tissues especially skin where it has a protective, structure stabilizing and shock-absorbing role. The unique viscoelastic nature of Hyaluronic acid along with its biocompatibility and non-immunogenicity has led to its use in a number of clinical applications, which include: the supplementation of joint fluid in arthritis; as a surgical aid in eye surgery; and to facilitate the healing and regeneration of surgical wounds. More recently, Hyaluronic acid has been investigated as a drug delivery agent for various routes of administration, including ophtalmic, nasal, pulmonary, parenteral and topical. In fact, regulatory approval in the USA, Canada and Europe was granted recently for 3% diclofenac in 2.5% Hyaluronic acid gel, Solaraze(R), for the topical treatment of actinic keratoses, which is the third most common skin complaint in the USA. The gel is well tolerated, safe and efficacious and provides an attractive, cost-effective alternative to cryoablation, curettage or dermabrasion, or treatment with 5-fluorouracil. The purpose of this review is to describe briefly the physical, chemical and biological properties of Hyaluronic acid together with some details of its medical and pharmaceutical uses with emphasis on this more recent topical application.

Intra-articular hyaluronic acid for the treatment of osteoarthritis of the knee: systematic review and meta-analysis.
CMAJ. 2005 Apr 12;172(8):1039-43.

Osteoarthritis of the knee affects up to 10% of the elderly population. The condition is frequently treated by intra-articular injection of hyaluronic acid. We performed a systematic review and meta-analysis of randomized controlled trials to assess the effectiveness of this treatment. We searched MEDLINE, EMBASE, CINAHL, BIOSIS and the Cochrane Controlled Trial Register from inception until April 2004 using a combination of search terms for knee osteoarthritis and hyaluronic acid and a filter for randomized controlled trials. We extracted data on pain at rest, pain during or immediately after movement, joint function and adverse events. Twenty-two trials that reported usable quantitative information on any of the predefined end points were identified and included in the systematic review. Even though pain at rest may be improved by hyaluronic acid, the data available from these studies did not allow an appropriate assessment of this end point. According to the currently available evidence, intra-articular hyaluronic acid has not been proven clinically effective and may be associated with a greater risk of adverse events. Large trials with clinically relevant and uniform end points are necessary to clarify the benefit-risk ratio.

Hyaluronic acid for the treatment of knee osteoarthritis: long-term outcomes from a naturalistic primary care experience.
Am J Phys Med Rehabil. 2005 Apr;84(4):278-83; quiz 284, 293. Petrella RJ. Department of Family Medicine, University of Western Ontario, Ontario, Canada.

Intraarticular hyaluronic acid is indicated for patients with osteoarthritis of the knee. However, clinical experience, especially efficacy and adverse events, with repeated injection series in the long term are limited. DESIGN: Patients were referred to a large primary care center for management of osteoarthritis of the knee. All were naive to intraarticular hyaluronic acid therapy and met our entry criteria, including resting visual analog scale pain of > 45 mm, radiographic confirmation of unilateral knee grade 1-3 osteoarthritis, and willingness to receive intraarticular therapy. Patients received a three-intraarticular injection series with Suplasyn (10 mg/ml, 2-ml injection) over 3 wks. CONCLUSIONS: Intraarticular hyaluronic acid injections were highly effective in improving resting and walking pain in patients with osteoarthritis of the knee on a first and a second treatment series. Duration of symptom control was about 6 mos, and the therapy was highly satisfactory to patients and was associated with very few local adverse events and limited use of concomitant therapeutic modalities. These data support the potential role of intraarticular hyaluronic acid as an effective long-term therapeutic option for patients with osteoarthritis of the knee.

A double blind, randomized, multicenter, parallel group study of the effectiveness and tolerance of intraarticular hyaluronan in osteoarthritis of the knee.
J Rheumatol. 2004 Apr;31(4):775-82.

To investigate the efficacy and tolerability of a course of 5 injections of hyaluronan ( HA or hyaluronic acid ) given at intervals of one week in patients with symptomatic, mild to moderate osteoarthritis (OA) of the knee. A double blind, randomized, parallel group, multicenter (17 centers), saline vehicle-controlled study was conducted over 18 weeks. Patients received either 25 mg (2.5 ml) hyaluronic acid in a phosphate buffered solution or 2.5 ml vehicle containing only the buffer by intraarticular injection. Five injections were given at one week intervals and the patients were followed for a further 13 weeks. Of 240 patients randomized for inclusion in the study, 223 were evaluable for the modified intention to treat analysis. The hyaluronic acid treatment and control groups were comparable for demographic details, OA history, and previous treatments. Scores for the pain and stiffness were modestly but significantly lower in the hyaluronic acid -treated group overall and the statistically significant difference from the control was not apparent until after the series of injections was complete. The physical function subscale did not reach statistical significance. Tolerability of the procedure was good and there were no serious adverse events that were considered to have a possible causal relationship with hyaluronic acid. CONCLUSION: Intraarticular hyaluronic acid treatment was significantly more effective than saline vehicle in mild to moderate OA of the knee for the 13 week postinjection period of the study.
 

Intra-articular hyaluranic acid compared with progressive knee exercises in osteoarthritis of the knee: a prospective randomized trial with long-term follow-up.
Rheumatol Int. 2005 Mar 18;

The goal of this study was to determine whether hyaluronic acid or progressive knee exercises (PE) can improve functional parameters in patients with osteoarthritis (OA) of the knee. In a prospective clinical trial 200 knees (105 patients) with radiographic Kellgren Lawrence grade III OA were randomized and received either three intra-articular injections of hyaluronic acid (Hylan G-F 20) at one-week intervals or PE for 6 weeks. Patients were evaluated by use of the Hospital for Special Surgery (HSS) Knee Score and followed-up for 18 months. Total HSS score for hyaluronic acid and PE patients improved from 62.6+/-13.8 to 88.8+/-11.1 and from 65.4+/-12.3 to 88.3+/-9.1, respectively, at the end of the trial (P<0.01). There were no statistically significant differences between the groups. Twenty-one patients of the hyaluronic acid group were excluded from the study because they had received another form of therapy. All patients in the PE group completed the trial. The patients who dropped out had also significant improvement. This prospective randomized trial confirmed that both hyaluronic acid injections and PE result in functional improvement. Hyaluronic acid injections also increase the levels of satisfaction of the OA patients.
 

A one-year, randomised, placebo (saline) controlled clinical trial of 500-730 kDa sodium hyaluronate (Hyalgan, Hyaluronic acid) on the radiological change in osteoarthritis of the knee.
Int J Clin Pract. 2003 Jul-Aug;57(6):467-74.

The primary objective of this study was to investigate structural changes, as measured by joint space narrowing (JSN), within the knee joint during treatment with intra-articular sodium hyaluronate ( Hyaluronic acid ) of molecular weight 500-730 kDa in patients with osteoarthritis (OA) of the knee. Patients received a weekly intra-articular injection of either 20 mg2/ml Hyaluronic acid or a 2 ml vehicle placebo (saline) for three weeks. This course was repeated twice more at four-monthly intervals. Concomitant treatment with analgesics or NSAIDs was allowed. The primary efficacy measure was the reduction in mean joint space width (JSW) of the medial compartment at 52 weeks. A total of 408 patients were randomised and 319 completed the one-year study (Hyaluronic acid: n=160, placebo: n=159); 273 of the 319 were included in the primary analysis. Analysis of variance on these 273 patients did not show a statistically significant difference between the two treatment groups. However, there was a significant difference in response to treatment in terms of the baseline JSW (p=0.01), indicating that outcome of treatment may depend on-baseline JSW. Therefore, a subgroup analysis by baseline JSW was conducted. This compared patients with a JSW >4.6 mm with those with a JSW <4.6 mm. In those with radiologically milder disease at baseline and receiving Hyaluronic acid, the JSN was significantly reduced compared with placebo (p=0.02). In patients with radiologically more severe disease there was no difference in JSN between the two treatments. Although, in this one-year study, no overall treatment effect was seen, those with radiologically milder disease at baseline had less progression of joint space narrowing when treated with Hyaluronic acid.
 

Treatment of gingivitis with hyaluronan ( hyaluronic acid ).
J Clin Periodontol. 2003 Feb;30(2):159-64.

Hyaluronic acid (hyaluronan) is a glycosaminoglycan with anti-inflammatory and antiedematous properties. It was evaluated in a gel formulation for its effect in the treatment of plaque-induced gingivitis. METHOD: In a randomised double-blind study, 50 male subjects with plaque-induced gingivitis were divided into two groups and used a verum or placebo gel twice daily additionally to oral hygiene for a 3-week treatment period. Clinical indices (API, Turesky index, PBI) and crevicular fluid variables (peroxidase, lysozyme) were determined at baseline and after 4, 7, 14 and 21 days, respectively. Significant improvements could be found for all clinical variables in both groups. The Hyaluronic acid group showed significant improvement in the study area for the plaque indices beginning with day 4 and the PBI beginning with day 7in comparison with the placebo group. The crevicular fluid variables were significantly improved in the centre of the studied inflammation area in the Hyaluronic acid group. Here all studied sites had significant decreases in peroxidase and lysozyme activities after 7, 14 and 21 days, whereas in the placebo group only one site showed a significant decrease for lysozyme after 7 and 21 days. These data suggest that a Hyaluronic acid containing gel has a beneficial effect in the treatment of plaque-induced gingivitis.
 

Comparison of two hyaluronan drugs and placebo in patients with knee osteoarthritis. A controlled, randomized, double-blind, parallel-design multicentre study.
Rheumatology (Oxford). 2002 Nov;41(11):1240-8.

To compare the efficacy and safety of intra-articular injections of two different hyaluronan ( hyaluronic acid ) preparations and placebo in patients with knee osteoarthritis. In a randomized, patient- and observer-blind, placebo-controlled and multicentre trial with parallel groups, 210 patients, aged 60 yr or above, with knee osteoarthritis were included in a per protocol analysis. The patients were treated with three injections, once weekly, of either native high-molecular-weight hyaluronan (Artzal((R))) or cross-linked hyaluronan (Synvisc) or with placebo and were followed for 52 weeks. The primary efficacy measures were weight-bearing pain during study weeks 0-26 and the duration of clinical benefit measured with Kaplan-Meier survival analysis for weeks 0-52. The secondary outcome measures were resting and maximum pain, Lequesne index, WOMAC (Western Ontario and McMaster University Osteoarthritis Index) and SF-36 (Medical Outcomes Study Short Form Health Survey) scores. RESULTS: The intra-articular injections produced a significant reduction in weight-bearing pain, resting pain, maximum pain and Lequesne and WOMAC scores after 26 weeks. There were no significant differences in outcome between any of the three study groups during the first 26 weeks. In direct comparison against placebo for weeks 0-52, neither hyaluronan treatment (Artzal or Synvisc) showed a significantly longer duration of clinical benefit than placebo. However, when data for the two hyaluronan-treated groups were pooled, treatment with hyaluronan had a significantly longer duration of benefit compared with placebo (P = 0.047). CONCLUSION: Patients with knee osteoarthritis who were treated by injection into the knee of either of two hyaluronan preparations or placebo showed clinical improvement during the first 26 weeks of treatment, though neither hyaluronan preparation gave a longer duration of clinical benefit than placebo. However, when data for the two hyaluronan treatments were pooled, there was a significantly longer duration of clinical benefit for hyaluronan treatment than for placebo.
 

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