Efficacy and Safety of a Hyaluronic Acid–Containing Cream 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; Karolina Kasztalska-Kazmierczak, PhD; Emilie Soriano, MSc, PharmD; Carol Caverzasio, MSc; Daniela Binelli, MStat; Bruno Falissard, MD, PhD; Olivier Dereure, MD, PhD


Wounds. 2021;33(11):285-295. 

In This Article

Abstract and Introduction


Introduction: Topical applications of hyaluronic acid (HA)–containing formulations, based on the complex and vital role of HA in all stages of the wound-healing process, are routinely used with standard therapy to promote faster healing of chronic wounds. However, 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 topical application of a hyaluronic acid cream vs a neutral comparator (identical cream without HA) in treating subjects with chronic leg ulcers of vascular origin.

Materials and Methods: This was a prospective, multicenter double-blind randomized controlled trial. One hundred sixty-eight subjects with chronic leg ulcers of venous or mixed (venous and arterial) origin were randomized to receive either topical applications of 0.2% HA cream or neutral comparator cream for a maximum of 20 weeks. The primary efficacy endpoint was complete ulcer healing (100% reepithelialization of the wound area centrally assessed at 20 weeks or before and confirmed 3 weeks later). In both groups, topical treatment was associated with standard therapy (ulcer cleansing and optimized compression).

Results: The proportion of subjects with centrally assessed complete healing of the target ulcer that was confirmed 3 weeks later (primary efficacy endpoint) was substantially higher in the HA cream group (31.3%) than in the neutral cream group (14.8%; P =.009). Results in the full analysis, per protocol, and as assessed by the investigator were consistent with primary results. No significant difference in treatment effect was observed when subjects were stratified according to baseline ulcer size (≤20 cm2 or >20 cm2) regardless of topical treatment. Safety and tolerability were comparable between treatments.

Conclusions: Treatment of subjects with chronic leg ulcers of venous or mixed origin with HA cream is safe, well tolerated, and results in a higher rate of healing than a neutral comparator cream.


Chronic venous insufficiency is a condition that occurs when the venous wall and/or valves in the veins of the legs are not working effectively, making it difficult for blood to return to the heart from the legs. It commonly results in aching or pain in the lower extremities, swelling, a feeling of heaviness, and skin changes, with chronic ulceration as the most severe manifestation.[1–3] Prevalence estimates of chronic venous insufficiency vary widely, but the condition is one of the most common vascular diseases in Western populations, affecting as many as 40% of women and 17% of men, with open or healed venous leg ulcers present in more than 1% of the population.[4] The socioeconomic effect of leg ulcers is major; the individual's ability to participate in social and occupational activities is impaired and there is a substantial financial burden on individuals, families, caregivers, and the health care system.[2–5]

Most chronic leg ulcers are of venous origin. However, an increasing proportion of ulcers are of mixed (arterial and venous) origin and are associated with less frequent causes, including infections, diabetes mellitus, and vasculitis.[2,6] The overall prognosis of venous leg ulcers is relatively poor, marked by a high frequency of delayed healing and recurrence.[1] Leg ulcer-related disability is likely to result in loss of productivity of subjects in the workforce and may necessitate early retirement.[1] Venous ulcers are most often seen in women and are seldom seen in men or women younger than 60 years. Chronic leg ulcers that do not heal within 1 year, despite optimal therapy, are considered to be therapy resistant.[2]

Appropriate wound and skin management of both venous and mixed-origin leg ulcers is important in order to cleanse and debride the wound to remove dead skin, fibrin remnants, and any other debris that may impede the healing process.[2] Appropriate dressings used under compression bandages help to promote faster healing and prevent adherence of the bandage to the ulcer. However, no specific type of dressing has been shown to be superior.

Hyaluronic acid (hyaluronan, HA), a large, nonsulfated mucopolysaccharide of the class of glycosaminoglycans (GAGs) and an essential component of the extracellular matrix of the skin and other connective tissues, is a linear polysaccharide consisting of repetitive chains of disaccharide units of N-acetyl-D-glucosamine and D-glucuronate.[7] The specific hygroscopic, rheologic, and viscoelastic properties of HA, which impart critical chemical and physical characteristics to the extracellular matrix, are responsible for the role of HA in tissue hydration[7] and underpin the use of HA as a topical cream or cream-impregnated gauze as a rational and effective therapeutic approach to treat subjects with chronic wounds. Endogenous HA is generally complexed with other GAGs, collagen, and elastin, binding with water into a large viscoelastic macromolecular aggregate that forms a viscous complex that encapsulates cells, fills open spaces in the fiber network, and lubricates the moveable tissue layers, stabilizing intracellular structures and protecting the tissue against mechanical stress.[7–9] Hyaluronic acid plays a complex and important role at all stages of the wound healing process, including organization of the granulation tissue matrix, cell migration and proliferation, modulation of the inflammatory response, reepithelialization, and angiogenesis.[7–13]

A cream containing 0.2% HA as an active ingredient has been developed and marketed for the topical treatment of noninfected wounds, (exuding or superinfected), including leg ulcers for more than 20 years. The 0.2% HA product (ialuset cream*) is biocompatible and creates a moist environment around the wound that promotes optimal conditions for healing and supports the reepithelialization process. An HA gauze pad preparation is also available.

The value of topical application of HA in improving the wound-healing process and reducing time to healing has been substantiated in in vitro, in vivo, and clinical studies.[12–19] Cream and gauze dressing formulations of HA are as well tolerated as reference or neutral comparators, are highly rated for ease of use and treatment satisfaction by both subjects and practitioners, and have been shown to be effective in treating subjects with venous or mixed-origin leg ulcers.[14–20] Although the topical application of HA is a therapy approach routinely used to promote tissue healing in the management of chronic wounds, data to base clinical decisions on the use of HA in the healing of chronic leg ulcers of venous or mixed origin are mostly limited to short-term studies.[21]

This study describes the results of a randomized controlled trial that compared the use of an HA cream with that of a neutral comparator cream in the treatment of subjects with chronic leg ulcers of venous or mixed (venous and arterial) origin. A parallel study evaluated the use of an HA–containing gauze pad in a similar subject population and will be reported separately.

*The tested cream (Global Medical Device Nomenclature System [GMDNS] Code 47671) is a CE mark-certified class IIb medical device manufactured by IBSA Pharma SAS (previously Laboratoires Genevrier), Antibes (France), a partner of the IBSA Institut Biochimique S.A. Group (Pambio-Noranco, Switzerland), and marketed in several European countries within the range of the ialuset®/ialugen® products.