Efficacy and Safety of a Hyaluronic Acid-Containing Gauze Pad in the Treatment of Chronic Venous or Mixed-Origin Leg Ulcers

A Prospective, Multicenter, Randomized Controlled Trial

Jacek Mikosinski, MD, PhD; Anna Di Landro, MD; Krzysztofa Łuczak-Szymerska, MSc; Emilie Soriano, MSc, PharmD; Carol Caverzasio, MSc; Daniela Binelli, MStat; Bruno Falissard, MD, PhD; Olivier Dereure, MD, PhD

Disclosures

Wounds. 2021;33(6):147-157. 

In This Article

Abstract and Introduction

Abstract

Introduction: Hyaluronic acid (HA)-containing formulations routinely are utilized along with standard therapy to promote faster healing of chronic wounds; evidence to guide clinical decisions on the use of topical HA in the healing of vascular leg ulcers is limited.

Objective: This study compared the efficacy and safety of an HA-impregnated gauze pad with an identical gauze pad without HA in the treatment of chronic leg ulcers of vascular origin.

Materials and Methods: A prospective, multicenter, multinational, parallel-group, randomized, double-blind, clinical study was conducted between June 13, 2017, and December 31, 2018. Adults with 1 or more chronic leg ulcers of venous or mixed origin between 2 months and 4 years' duration were eligible to participate. Participants were randomized to treatment consisting of standard care (ie, ulcer cleansing, debridement/anesthesia as necessary, and optimized compression) and either application of a gauze pad containing 0.05% HA or a neutral comparator once daily for a maximum of 20 weeks. The primary efficacy endpoint was complete ulcer healing (100% reepithelialization of the wound area centrally assessed by 1 independent and experienced assessor blinded with respect to the treatment applied, as shown on digital photographs taken under standardized conditions at or before 20 weeks and confirmed 3 weeks later). Secondary efficacy endpoints included the percentage of completely healed target ulcers, residual area of target ulcer relative to baseline, the condition of the periulcerous skin, the total amount of analgesics used, the incidence of infection at the ulcer site of the target ulcer, patient adherence to treatment, time to achieve complete healing as centrally assessed, and pain intensity as measured by a visual analog scale.

Results: Among the 168 participants (82 in the HA gauze pad group and 86 in the neutral gauze pad group), 33 (39.8%) in the HA group experienced complete healing of the target ulcer, which was significantly higher than the neutral comparator group (15, 18.5%; P = .002). Results in the full analysis and per-protocol sets were consistent with the primary results; no significant difference was noted in outcomes when participants' wounds were stratified according to baseline ulcer size.

Conclusions: HA delivered in a gauze pad formulation could be a beneficial treatment for chronic leg ulcers of venous or mixed origin.

Introduction

Chronic ulcerations of the lower extremities do not go through a normal healing process and may not heal if left untreated; venous insufficiency accounts for approximately 80% of venous leg ulcers.[1] Venous leg ulcers affect an estimated 1% to 3% of the population and are more common in the elderly and in women of all age groups.[2] These ulcers cause considerable pain, morbidity, and decreased quality of life, having an annual recurrence rate of up to 15% and a risk of 30% to 57% recurrence within the first year.[2] Risk factors for venous ulcers include older age, female sex, obesity, and previous medical history or family history of varicosity, leg ulcer, venous thrombosis, vascular disorders, previous leg trauma, and phlebitis.[2]

About 75% of leg ulcers are venous in origin; other etiologies include arterial insufficiency, mixed (arterial and venous) etiology, ulceration due to prolonged pressure injury, diabetic neuropathy, vasculitis, skin malignancies, or other conditions.[2–5]

Chronic leg ulcers are defined as wounds that take longer than 6 weeks to heal; chronic ulcers that have not healed within 1 year despite optimal interventional management are considered therapy-resistant.[2] Compression therapy to reduce venous hypertension is still considered the mainstay for the treatment of venous ulcers, with the aim of transforming the ulcer into an acute wound that progresses to wound healing through a coordinated cascade of cell proliferation, cell migration, and differentiation.[2] The degree of compression for mixed-origin leg ulcers should be modified to avoid the risk of complications related to overcompression.[4]

Adequate wound and skin management is central to promoting the healing process, and regular wound cleansing and debridement to remove necrotic tissue and fibrin are key elements of therapy.[2] If conservative measures fail to provide a satisfactory outcome, further treatment should be considered; options include topical and systemic medications, sclerotherapy, and surgery.[1,2,6] The use of appropriate dressings under compression bandages promotes faster healing and prevents adherence of the bandage to the ulcer,[1] but no specific type of dressing has been shown to be superior.

Hyaluronic acid (hyaluronan HA), a large mucopolysaccharide belonging to the class of glycosaminoglycans (GAGs), is an essential component of the extracellular matrix of the skin and other connective tissues. The only nonsulfated GAG found in connective tissue, HA is a linear polysaccharide consisting of repetitive chains of disaccharide units of N-acetyl-D-glucosamine and D-glucuronate.[7] Hylauronic acid imparts important chemical and physical characteristics to the extracellular matrix due to its hygroscopic, rheological, and viscoelastic properties and is responsible for tissue hydration related to the large water-binding capacity of its high molecular weight and negative charge.[7,8] The chemical and physical properties of HA support its local application as a cream or cream-impregnated gauze as an effective therapeutic approach to treating chronic wounds.

Hyaluronic acid, together with collagen and elastin, has an important role in the stabilization of the intracellular structures via formation of a viscoelastic network and plays a complex and important role in all stages of the wound healing process, including organization of the granulation tissue matrix, cell migration, cell proliferation, modulation of the inflammatory response, reepithelialization, and angiogenesis.[7–14] The dynamic tridimensional structure of HA acts as a framework at the wound site for the cell migration and adhesion necessary for healing;[7,12,15] several in vitro and in vivo studies on animals and humans have confirmed that topical application of HA on wounds improves the healing process and decreases time to healing.[11,14]

Gauze pads that contain HA have been developed and marketed for more than 20 years for the treatment of noninfected, exuding, or superinfected wounds, including leg ulcers. One product (ialuset gauze pad*) is a sterile, biocompatible dressing that creates a moist environment around the wound to promote optimal healing conditions; it supports the reepithelialization process and does not stick to the wound, thus inducing no pain during removal.

A number of studies have investigated the efficacy and safety of cream and gauze dressing formulations of HA for the management of chronic wounds,[16–21] including an open-label trial[22] (N = 43) among patients with trauma wounds, surgical sutures, burns, and dermabrasions. Hyaluronic acid was applied either as a 0.2% cream or a 0.05% dressing according to wound type within a timeframe of less than 28 days with no more than 9 applications. Mean wound surface area decreased approximately 70% by the sixth application, a point at which 56% of the wounds had healed at a mean of 10.8 days after the initiation of treatment. Both formulations were well tolerated and highly rated for comfort and satisfaction both by study participants and nurses.[22]

A 60-day, double-blind, randomized, controlled superiority study (N = 89) by Humbert et al[21] showed that a 0.05% HA-impregnated gauze pad was significantly more effective than a neutral comparator in treating venous ulcers. The percentage of ulcer surface reduction, number of healed ulcers at day 45 and day 60, and reduction in pain intensity at day 30 were all significantly greater in the HA gauze pad group. Overall tolerance of the HA gauze pad was similar to that of the neutral comparator.

However, despite routine HA use in the topical treatment of chronic wounds, published data to guide decisions on the use of HA in the healing of venous or mixed-etiology leg ulcers are limited and largely confined to short-term treatment.[23]

The current study sought to compare the use of an HA-containing gauze pad with that of a neutral comparator in the treatment of chronic leg ulcers of venous or mixed (venous and arterial, with a predominant venous component) origin over 20 weeks. The study is the first to employ this observation period.

*The tested gauze pad (Global Medical Device Nomenclature System [GMDNS] Code 58133) is a CE mark-certified class IIb medical device manufactured by Laboratoires Genevrier (Antibes, France), a partner of the IBSA Group (Pambio-Noranco, Switzerland), and marketed in several European countries within the ialuset®/ialugen® products range.

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