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


In this multicenter study conducted in Poland, 85 subjects with chronic leg ulcers of venous or mixed origin were treated with HA cream vs 83 with a neutral comparator. Subjects treated with the HA 0.2% cream daily for 20 weeks were more likely to experience complete healing, with an effect on ulcer size apparent after 8 weeks. The reduction in ulcer size was most significant in smaller ulcers (≤20 cm2) and in those of shorter duration. To date, the use of topical HA in subjects with vascular leg ulcers has largely been empirical or in studies of shorter duration. To the authors' knowledge, this study is the first to investigate the application of an HA cream in the context of a randomized controlled trial in which subjects were followed up for more than 20 weeks. The study design was rigorous, with appropriately selected endpoints that were consistent with recent recommendations of scientific and regulatory bodies.[23–25] To minimize bias, the test and comparator treatments were randomly allocated using a standard central randomization system, and access to the randomization code information was strictly regulated and monitored, and the clinical assessment of the primary efficacy variable was centrally and independently performed by an experienced, blinded assessor judging clinical results via standardized photography of the target ulcer. All personnel involved in the trial were blinded to the treatment, and the presentation, packaging, and labeling of the HA cream and neutral comparator cream were fully indistinguishable.

In terms of ulcer size, presence of necrotic tissue, target ulcer duration, ankle-brachial pressure index albuminemia, and other demographic and target ulcer characteristics at baseline, the subject population was comparable to that of other studies in the indication.[14–17,19] However, subjects with leg ulcers of mixed origin, for whom treatment is more difficult, were allowed in this study.

By 23 weeks, the primary efficacy endpoint of complete ulcer healing in the FAS, as measured by a blinded central assessor on standard digital images of the target ulcer using validated image analysis software, was 31.3% in the HA cream group, compared with 14.8% in the neutral cream group, a clinically and statistically significant difference that was achieved regardless of ulcer size (≤20 cm2 or >20 cm2) at baseline. Results in the PPS and when assessed by the investigator were fully consistent with the primary endpoint findings. For subjects with a completely healed target ulcer, the median time to complete healing was significantly shorter (12 weeks) in the HA cream group than in the neutral cream group (16 weeks).

No new or critical safety signals were identified in the study, and the results support the established favorable safety profile of this HA cream in the treatment of subjects with acute and chronic wounds.

Compression therapy to reduce the ambulant venous hyperpressure remains the mainstay for the management of venous ulcers, with the aim of transforming the chronic wound into an acute wound that can heal through the regular process of wound healing, a coordinated cascade of cell proliferation, migration, and differentiation.[12] However, subjects with compromised arterial circulation require a lower level of compression to avoid the risk of pressure-related complications, including critical ischemia and tissue necrosis.[26]

A number of therapeutic interventions combined with standard or modified compression therapy have been investigated to reduce the time required for ulcer healing. Pharmaceutical treatments, surgical interventions, the use of negative pressure devices, electrical stimulation therapy, physiotherapy, and topical agents have been investigated with varying degrees of success.[2,27] However, high-quality evidence to support specific interventions in venous leg ulcers is lacking because of factors such as small sample sizes, short follow-up, study design limitations, lack of appropriate control procedures, and inconsistencies in reporting measurements.[24,25]

Hyaluronic acid has a number of chemical and physical properties that explain its ability to elicit tissue healing in chronic wounds. The high molecular weight and negative charge of HA confer a capacity to bind large amounts of water, essential for regulating tissue hydration. In combination with collagen and elastin, HA contributes to the stabilization of intracellular structures via the formation of a viscoelastic network.[28,29] Hyaluronic acid also helps protect against the deleterious effects of the free radicals that play a key role in skin aging and is involved in nutrient exchanges essential for wound healing and biologic processes, such as cell differentiation and motility.[12,29,30] Finally, as a component of the extracellular matrix, the dynamic tridimensional structure of HA creates favorable physiologic conditions for proliferation, migration, and structuring of the epidermis, all processes involved in wound healing.[7,8,28,29]

The topical application of exogenous HA as an HA-containing cream or HA-impregnated dressings has long been routine to encourage tissue healing of chronic wounds, including leg ulcers.[19] Although the exact mechanisms of wound healing are still under investigation with the aim of improving chronic wound management, the results obtained in this trial are in line with the current understanding of the multifaceted role of endogenous HA in the wound repair process and support the hypothesis that HA delivered as a cream formulation is effective in promoting and accelerating the wound healing process and in reducing pain in leg ulcers of venous or mixed origin.