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

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 trial²² (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 al²¹ 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. 

Design and objectives

This study utilized a confirmatory, prospective, multicenter, multinational, parallel-group, randomized, double-blind clinical design to compare the results of using the previously described HA-infused gauze pad with a neutral (gauze with no HA) comparator (the investigational medical devices [IMDs]). The objective of the study was to confirm the superiority of a local application of the HA-containing gauze pad as compared to a neutral comparator gauze pad in the treatment of chronic leg ulcers of venous or mixed origin. The clinical investigation was designed to provide clinically relevant data verifying the efficacy of topical treatment with the HA gauze pads when applied for up to 20 weeks. 

The study was conducted among 12 outpatient centers, either private or of public hospitals, including 10 in Poland and 2 in France with experience in chronic lower extremity ulcer care. Patients presenting for treatment of chronic leg ulcers were invited to consider participation in the study if assessed as eligible. The research was performed in accordance with the Declaration of Helsinki and its modifications, the rules of Good Clinical Practice, and the International Organization for Standardization 14155 requirements and conformed to the Consolidated Standards of Reporting Trials 2010 extension for randomized controlled trials. Approval for the protocol and protocol amendments was obtained from the Bioethics Committee of the Regional Medical Chamber, Lodz (Poland), and from the Comité de Protection des Personnes du Sud-ouest et Outre-mer IV, Limoge (France) before starting the trial; written informed consent was obtained from all participants.

The project was managed and monitored by the contract research organization CROMSOURCE through its local organizations in Poland and France.

Patient population

Adult male and female persons older than 18 years were eligible for the study if they experienced 1 or more chronic leg ulcers of venous or mixed (venous and arterial, with a predominant venous component) origin of more than 2 months and less than 4 years’ duration. In patients presenting with more than 1 ulcer, a target ulcer was selected by the investigator (ie, the physician at the study site), based on the following priorities: the target ulcer met the study inclusion criteria; if more than 1 ulcer was adherent with the inclusion criteria, the largest was identified as the target ulcer; if more than 1 adhering ulcer was of the same/similar size, the ulcer of oldest duration was identified as the target ulcer; and if more than 1 adherent ulcer was of the same/similar size and of the same/similar age, the investigator decided on the selection of the target ulcer.

In all patients, the target ulcer area was required to be between 5 cm² and 40 cm², with less than 50% necrotic tissue. Other inclusion criteria included daily use of an appropriate compression system, albuminemia less than or equal to 25 g/L, negative pregnancy test and use of reliable contraception for women of childbearing age, and coverage by a health insurance system (France). Persons with an ulcer of nonvascular origin or related to a general cause, evidence of dominant significant arterial insufficiency and/or ankle-brachial pressure index (ABPI) that was not between between 0.8 and 1.2, diabetes mellitus, hepatic or renal failure, clinical suspicion of wound infection, an ulcer with exposed tendon or bone or due to malignancy, recent history of venous thrombosis, and/or ongoing treatment with drugs known to adversely affect the healing process were excluded. Prohibited medications or measures included treatment known to delay the healing process (high-dose systemic corticosteroids, cytostatic drugs, immunosuppressants), other topical treatments of the target ulcer, the use of proteolytic enzyme for wound debridement, vein surgery, or any other systemic or general therapy that might positively or negatively influence the healing of the target ulcer. 

Study protocol

For each study participant, a target ulcer was selected by the investigator and randomly assigned 1:1 using a centralized randomization system to be locally treated once daily with either a gauze pad containing HA 0.05% or a neutral comparator gauze pad for a maximum of 20 weeks (active treatment period) or until complete ulcer healing, whichever occurred first. Nontarget ulcers were treated according to the same standard of care rules but were not included in the data. Healing was defined as 100% reepithelialization of the wound area at 20 weeks or at any earlier visit if healing occurred. The trial was stratified according to target ulcer size (≤ 20 cm² or > 20 cm²). 

The HA-containing gauze pad was a 10 cm x 10 cm, sterile, ready-to-use, fixed-dose dressing for topical use, impregnated with 0.05% sodium hyaluronate, additionally containing macrogol, glycerol, and purified water. For the study, the gauze pad dressing was supplied in packs of 10. The neutral comparator contained the same ingredients except for HA and had identical visual and physical characteristics to the test product.

The randomization list was prepared by the Data Management and Statistics Department of the sponsor according to standard operating procedures, using validated software (SAS Institute Inc). The study was conducted in double-blind fashion, with treatment allocation hidden to the participants, investigator, sponsor, contract research organization team, and the central assessor, located separately from any of the study sites. Strict procedures were adopted to maintain the blind throughout the study. 

Study treatments were used in conjunction with standard local therapy that specified cleansing the target ulcer with sterile saline before each application, with or without the use of surgical debridement or local anesthesia as necessary. In the event of clinical evidence of infection (confirmed on swabbing), therapy with systemic antibiotics was considered, but the use of topical antimicrobials and antiseptics was prohibited. 

After wound cleansing, the HA gauze pad or neutral comparator was applied directly to the target ulcer once daily by the study nurse or authorized study personnel either at the participant’s home or at the clinic. During the study visits, the gauze pad was applied by the investigator (or designee). The gauze pads were placed onto the entire cavity of the target ulcer, and the wound area was then covered with a sterile dressing and finally completed by appropriate pressure bandaging. Wound debridement, dressing, and compression were only applied by personnel with knowledge and experience in the assessment and management of patients with leg ulcers.

An adapted and efficient compression (BIFLEX 16+ PRACTIC bandage; Thuasne) was provided to all sites, applied to all participants according to the standard of care, and to be worn daily throughout the investigation period. The compression was set up before the patient got up in the morning, and it was removed before the patient went to bed in the evening. Daily compression use was confirmed by the study nurse when visiting the study participant at home or by the study personnel at each in-clinic visit. Patients who discontinued study participation continued to receive standard of care (compression socks or compression bandages). 

Data collection

Data collected included age, gender, smoking status, medical and leg ulcer history, and target ulcer measurement and duration. Each participant had 8 visits with the same investigator at the same study site. Visits comprised screening/inclusion (visit 0); randomization and first treatment (visit 1); care and assessment weeks 4, 8, 12, 16, and 20 of treatment (visits 2 through 6); and a final evaluation (follow-up) visit (visit 7) at day 162 (week 23) or 3 weeks after complete healing, if complete epithelialization occurred before 20 weeks. An unscheduled visit to confirm healing could be arranged on request of the study nurse if he/she considered that complete healing had been achieved between scheduled visits. 

Assessment of vital signs, concomitant medications, pain intensity, periulcerous skin, and adverse events (AEs), as well as ulcer cleaning and preparation, were conducted at all visits. The healing status of the target ulcer was assessed and recorded at each study visit after treatment was initiated. The target ulcer was evaluated by the investigator and documented by standardized digital photography after cleansing and wound preparation were completed at randomization, before the IMD was applied at each study visit, and at the follow-up visit. Photographs of the target ulcer were uploaded into an electronic data capture system. During each evaluation visit, the investigator assessed the periulcerous skin, and evidence of edema, purpura, erythema, oozing and/or maceration were identified and rated on a 4-grade scale of intensity (none = 0, mild = 1, moderate = 2, and severe = 3), and recorded in the patient medical records and study electronic case report form. 

Adherence with the study treatment, defined as the number and percent of once-daily applications of the IMD as compared with the theoretical number was checked at each visit; at which time, the patient returned the monthly kit issued at the previous visit and received a new kit. The nurse or authorized study personnel recorded the participants’ and nurses’ data in the study-dedicated diary, carbon copies of which were collected by the contract research organization and sent to the sponsor for data entry into the study database. During the treatment phase, daily medication renewal comprising changing of the gauze pad and application of a secondary sterile dressing, application of the compression bandage, and any oral analgesic use also were recorded. 

For the primary efficacy parameter as well as for the secondary parameters relevant to assessment of ulcer closure at the specified control timepoints, patients with missing information/data on ulcer healing for any reason other than complete healing were treated as treatment failures. Last observation carried forward was used for complete healing, relative percentage of the ulcer area, and visual analog scale (VAS) pain intensity score. No further imputation for post-randomization missing data was considered. If the randomization visit took place on the same day as the screening visit, baseline data were taken from the electronic case report form relating to the screening visit.

Primary and secondary endpoints

The primary efficacy endpoint was ulcer healing as evaluated by the central assessor blinded to the product used and confirmed 3 weeks after the end of treatment. The clinical assessment of the primary efficacy variable was centralized and independently performed by 1 experienced assessor (a dermatologist blinded to the product) based on standardized photography of the target ulcer and accessed from a validated data capture system.

Secondary efficacy endpoints included the percentage of completely healed target ulcers as assessed by the investigator and at all other scheduled study visits as assessed by the blinded central assessor. Endpoints also included target ulcer residual area relative to baseline, calculated as percentage relative to the ulcer area at the time of randomization, the condition of the periulcerous skin, the total amount of analgesics used, the percentage of patients presenting with infection after application of the first IMD confirmed by swabbing of the target ulcer, patient adherence to treatment, time to achieve complete healing as centrally assessed, and pain intensity as measured by VAS. 

The healing ulcers were assessed at or before 20 weeks and confirmed 3 weeks later. Digital photographs of target ulcers were all evaluated by 1 independent, experienced assessor (a dermatologist), who was fully blinded to the treatment received. To do so, the assessor accessed a remote data capture system different from the main electronic case report form created to record the study data, and to which all target ulcer photographs were uploaded by the individual site investigators. The photographs were identified by a unique ID code, including the site number and the patient’s screening number but not the random (treatment) number, so that the independent blind assessor could be entirely blinded to which treatment (active HA-impregnated gauze or neutral comparator) was utilized on the ulcer to be assessed (as healed or non-healed). The same electronic data capture system was independently used by a second blind operator for measuring the residual ulcer area using a validated image analysis system. After cleaning and wound preparation, digital photographs of the target ulcer were taken in JPEG image format under standardized conditions (ie, 3888 x 2592 pixels of image resolution; digital camera positioned at 20 cm from the centre of the target ulcer; background uniformly black by using a black screen and flash lamp as the light source; positioning of the legs in a stretching position in order to better characterize the edges of the lesions; with an 18 mm round white HERMA label positioned as close as possible to the target ulcer, ensuring the label was visible within the camera display). 

Safety endpoint

Safety was assessed by noting the incidence of any AEs, adverse device events (ADEs), and treatment-emergent AEs (TEAEs) occurring at any time during the trial regardless of relationship to the investigational medical device, vital signs (at each study visit), and physical examination (assessed at screening, randomization, and final visit). Adverse events and serious adverse events (SAEs) were coded using the Medical Dictionary for Regulatory Activities version 20.1. The frequency of TEAEs and serious TEAEs and the proportion of participants experiencing TEAEs were calculated. 

Statistical analysis

The anticipated percentage of participants with completely healed target ulcers at week 20 or the earliest visit when healing was complete and confirmed after 3 weeks was estimated to be 43% for the HA gauze pad group and 20% for the neutral comparator group. A sample size of 84 evaluable participants in each group was calculated to have greater than 90% power to detect a difference of 23% between the HA gauze pad group and the neutral comparator group in terms of successes, according to the assessment of the central blinded assessor judging, in favor of HA gauze pad group (superiority study), when using a chi-squared test with two-sided α = 0.05.

The proportion of completely healed target ulcers was compared in primary analysis between treatment groups using the Cochran-Mantel-Haenszel Chi-squared test, with target ulcer size at baseline (≤ 20 cm² or > 0 cm²) as a stratification factor. For the safety analysis, the difference between the proportions of persons in treatment groups was analyzed using the chi-squared test. Kaplan-Meier analysis was used to assess time to complete ulcer healing, and logistic regression analysis was performed on the primary efficacy endpoint. 

Twelve centers in Poland and 2 in France with experience in the assessment and management of chronic leg ulcers participated in the study, conducted between June 13, 2017, and December 31, 2018. A total of 189 patients were screened, 169 were randomized, and 168 (82 in the HA gauze pad group and 86 in the neutral gauze pad group) were eventually enrolled in the study and received at least 1 application of the IMD (safety analysis set; SAF). Of these, 164 (83 in the HA gauze pad group and 81 in the neutral gauze pad group) were included in the full analysis set (FAS; all persons in the SAF who received 1 or more post-baseline efficacy assessment). Overall, 144 patients (71 in the HA gauze pad group; 73 in the neutral gauze pad group) completed the study; 25 discontinued treatment (13 in the HA group; 12 in the neutral gauze pad group). Of those, 18 withdrew (9 in each group) for personal reasons—3 in the HA group (2 for AEs and 1 for other reasons) and 2 in the neutral gauze pad group due to lack of efficacy. One person in each group was lost to follow-up. Among the 5 participants who had more than 1 major protocol deviation (3 in the HA group; 2 in the neutral gauze pad group), the most common reason was violation of exclusion criteria. 

The demographic and target ulcer characteristics of the participants were similar between groups (Table 1). Almost all (N = 166, 98.8%) of the participants in both groups were taking 1 or more concomitant medications, most commonly bioflavonoids (n = 75, 44.6%), heparin group (n = 56, 33.3%), and aldosterone antagonists (n = 51, 30.4%). Individual medications most frequently taken were sulodexide (n = 52, 31.0%), spironolactone (n = 46, 27.4%), and acetylsalicylic acid (n = 36, 21.4%). The proportion of participants using concomitant medications was similar in both groups. 

Adherence with treatment was close to 100% in both groups (99.7% and 99.3% for the HA and neutral gauze pad groups, respectively), which was as expected because the daily dressing change was performed by the study nurse.

Efficacy

At study completion, the proportion of participants in the FAS with centrally assessed complete healing of the target ulcer at week 20 or at any control visit, confirmed 3 weeks later (primary efficacy endpoint), was substantially higher in the HA gauze pad group (39.8%) than in the neutral gauze pad group (18.5%; P = .002) (Table 2). No significant difference in treatment effect for complete ulcer healing was noted between the 2 baseline ulcer size stratifications (≤ 20 cm² vs > 20 cm²; Breslow-Day P = .757) (Table 2). 

Similarly, the proportion of persons in the FAS with complete healing of the target ulcer confirmed 3 weeks later was higher in the HA gauze pad group compared with the neutral gauze pad group when assessed by the investigator at the site (32.5% vs 13.6%, P = .004) (Table 2). The results obtained in the PPS for the primary efficacy performance and all secondary endpoints were consistent with the FAS (data not shown).

Kaplan-Meier analysis showed that the probability of achieving complete healing of the target ulcer at each evaluation over the study period was significantly higher in the HA gauze pad group as compared to the neutral gauze pad group when centrally assessed (P = .003) and according to the assessment of the investigator at the site (P = .005) (Figure 1). In the subgroup of participants who achieved a complete healing of the target ulcer, the median time to healing was approximately 12 weeks.

At the week 23 follow-up, the residual target ulcer area relative to baseline was significantly smaller in the HA gauze pad group (41.1%) compared with the neutral gauze pad group (81.6%; P = .008). Figure 2 shows the relative percentage of the target ulcer area by visit for the FAS. The target ulcer area was significantly smaller in the HA gauze pad group compared with the neutral gauze pad group at all evaluation visits starting from week 4.

Logistic regression analysis of explanatory variables on ulcer healing showed that target ulcer size at baseline (≤ 20 cm² vs > 20 cm²), treatment (HA gauze pad vs neutral gauze pad), and prior target ulcer duration at baseline were all significantly associated with ulcer healing (all P < .01).

No statistically significant difference was noted between groups for the conditions of the periulcerous skin, except for a higher incidence of purpura and oozing in the neutral gauze pad group. 

No statistically significant difference was noted between groups in the proportion of participants who reported the use of analgesics or in the proportion of participants with reported infection of target ulcer. Additionally, no correlation was observed in either group between the achievement of complete healing and concomitant use of pentoxifylline (data not shown). 

Both the proportion of participants using oral analgesics in the FAS (HA group, 44.6%; neutral comparator group, 42.0%) and the mean total number of doses taken by participants during the 6-month study period were comparable in the HA gauze pad group and in the neutral comparator group (mean, 61.6 vs 61.4 doses, respectively). 

In the HA gauze pad group, the mean VAS pain score decreased from 48.3 ± 28.02 mm at randomization to 17.9 ± 28.11 mm at week 20 and further reduced to 15.1 ± 25.20 mm at the follow-up visit. In comparison, in the neutral comparator group the mean VAS score decreased from 39.1 ± 25.66 mm at randomization to 17.4 ± 23.45 mm at week 20 and further reduced to 16.0 ± 21.66 mm at follow-up. The difference in mean pain intensity was statistically significant at weeks 4 and 12 and at the follow-up visit and almost significant at week 16 (Figure 3), but did not reach statistical significance at week 8 despite the greater mean pain reduction in the HA gauze pad group (-20.5 ± 29.62 mm vs -13.4 ± 30.84 mm, respectively; P = .100). Results obtained in the PPS were fully consistent with those in the FAS (data not shown).

Safety

A total of 43 TEAEs were reported by 27 (32.9%) persons in the HA gauze pad group, and 44 were reported by 34 (39.5%) persons in the neutral gauze pad group (Table 3). Nine treatment-related TEAEs were reported among 6 (7.3%) persons in the HA group and among 8 (9.3%) persons in the neutral comparator group. Most TEAEs were mild-to-moderate in severity.

The most commonly affected system organ classes were infections and infestations (14.6% vs 15.1% in the HA and neutral comparator groups, respectively), skin and subcutaneous tissue disorders (11.0% vs 12.8%, respectively), and venous ulcer pain (6.1% vs 4.7%, respectively). None of the 6 treatment-emergent SAEs (4 reported by persons in the HA group and 5 in the neutral gauze group) was considered to be related to the IMD (Table 3). In total, 3 persons (1 in the HA group and 2 in the neutral gauze pad group) had an AE leading to permanent discontinuation of the study.

As such, no statistically significant difference was found between groups with regard to the proportion of participants reporting at least 1 AE, TEAE, serious TEAE, or AE leading to study discontinuation. Furthermore, the proportion of participants reporting at least 1 ADE was similar between groups, as was the severity of TEAEs or their relationship to treatment (Table 3). 

In this multicenter study in Poland and France, 168 persons with chronic leg ulcer of venous or mixed origin were treated with the HA-infused gauze pad (n = 82) or a neutral comparator (n = 86). In general, the baseline characteristics (ulcer size, presence of necrotic tissue, target ulcer duration, ABPI, albuminemia) of the current study population were comparable with other studies,^16-19,21 although leg ulcers of mixed etiology were included in this study. However, the majority of studies of topical applications of HA among patients with venous leg ulcers have been of shorter duration, and this study, to the best of our knowledge, is the first to encompass more than 20 weeks of treatment and follow-up. The design of the study was rigorous, with appropriate endpoints consistent with recent recommendations of scientific and regulatory bodies.^24-26 Patients treated with the HA gauze pad daily for 20 weeks were more likely to have completely healed ulcers over the study period than those treated with the neutral comparator, with improvement most significant in smaller ulcers (≤ 20 cm²) and an impact on ulcer size that was clinically apparent after 4 weeks, suggesting a timely initiation of the healing process.

The primary efficacy endpoint—complete ulcer healing, as centrally assessed—was achieved by 39.8% of participants in the HA group, compared with 18.5% in the neutral gauze pad group, a clinically and statistically significant difference that was noted regardless of ulcer size (≤ 20 cm² or > 20 cm²) at baseline. The rate of healing was influenced by treatment (HA gauze pad vs neutral gauze pad), ulcer size at baseline, and prior target ulcer duration at baseline. As expected, the improvement was most marked in smaller ulcers and ulcers with a shorter duration since presentation. These findings align with other published studies of HA use in chronic venous leg ulcers.^16-18,21 Persons treated with HA gauze pad achieved complete healing of the target ulcer in a median time of approximately 12 weeks, and the probability of achieving complete healing of the target ulcer over the whole study period was significantly higher in the HA gauze pad group as compared to the neutral gauze pad group.

Participants in the HA gauze pad group reported a greater reduction in VAS pain scores compared with the neutral gauze pad group starting from week 4, with between-group differences reaching statistical significance at all time points except the week 8 and week 20 visits.

Overall, no new or critical safety signals emerged in the study, and the results support the well-established and favorable safety profile of HA-infused gauze pad used in the study for the treatment of acute and chronic wounds. 

Compression therapy is the accepted evidence-based strategy to manage venous leg ulcers;^2,3 modified compression therapy also may be appropriate when arterial insufficiency contributes to ulceration, depending on the degree of arterial disease.^4,5 Numerous approaches in combination with standard therapy have been investigated with the aim of shortening the time to ulcer healing and relieving the burden of treatment, with varying degrees of success. Approaches have included pharmaceutical treatment, surgical interventions, the use of negative pressure devices, electrical stimulation therapy, physiotherapy, and topical agents.^2,27 However, high-quality evidence to support specific interventions in venous leg ulcers is limited due to a range of problems, including small sample sizes, study design, inconsistent reporting measurements, and other issues.^25,26

The use of topical application of exogenous HA under dressings or as a cream or gel formulation has long been routine to encourage tissue healing in the management of chronic wounds, including in the treatment of chronic leg ulcers,²¹ supported by a number of studies that have demonstrated the efficacy and favorable tolerability of cream and gauze dressing formulations of HA.^16-22 As a key component of the extracellular matrix, the specific hygroscopic and viscoelastic properties of HA play a pivotal role in each phase of the wound healing cascade (hemostasis, inflammation, proliferation, remodeling), contributing to a series of overlapping physiological processes essential for successful wound healing (fibrinogen binding and activation of the extrinsic clotting pathway, moderation of the inflammatory process, angiogenesis, granulation, keratocyte and fibroblast migration, re-epithelialization, normal and pathological scarring).¹² 

Although the specific mechanisms of leg ulcer healing remain poorly identified, our findings are consistent with current knowledge of the role of endogenous HA in the wound repair process and support and expand the premise that HA delivered in a gauze pad formulation effectively contributes to the wound healing process in leg ulcers of vascular origin by reducing pain and accelerating healing. 

In this prospective study, several measures were implemented in order to minimize bias. A standard central randomization system was used to randomly allocate participants to the test and comparator treatment groups, with strict regulation of access to the randomization code information. All personnel involved in the trial were blinded to the treatment, and the HA gauze pads and neutral gauze pads, packaging, and labeling were indistinguishable from one another. In addition, the clinical assessment of the primary efficacy variable (target ulcer healing) was centrally and independently performed by an experienced, blinded assessor judging clinical results on standardized photography of the target ulcer. However, the majority of participants were recruited in Poland, which could limit the generalizability of the study findings to other countries due to possible differences in health care infrastructures and resources.

The treatment of chronic leg ulcers of venous or mixed (venous and arterial, with a predominant venous component) origin with the HA gauze pad was shown to be safe and well-tolerated as well as result in a higher rate of healing than a neutral comparator gauze pad over a clinically relevant study duration. The findings of this study support and expand the premise that HA delivered in a gauze pad formulation effectively contributes to the wound healing process in leg ulcers of vascular origin by accelerating healing. Additional studies across other sites and populations are warranted to confirm the place of the HA gauze pad in the treatment of chronic leg ulcers of venous or mixed origin.

The authors thank Ray Hill, an independent medical writer, who provided technical writing support funded by IBSA Institut Biochimique S.A. (Lugano, Switzerland). The authors thank Simone Cazzaniga, a member of Centro Studi GISED, who measured target ulcer areas using a validated image analysis system in blind conditions. The authors thank all the CROMSOURCE (Verona, Italy) staff involved in coordinating and managing the clinical trial. The authors thank all the clinical research sites that participated in the study.

Authors: Jacek Mikosinski, MD, PhD¹; Anna Di Landro, MD²; Krzysztofa Łuczak-Szymerska, MSc³; Emilie Soriano, MSc, PharmD⁴; Carol Caverzasio, MSc⁵; Daniela Binelli, MStat⁵; Bruno Falissard, MD, PhD⁶; and Olivier Dereure, MD, PhD⁷

Affiliations: ¹Nzoz Mikomed, ul, Łódź, Poland; ²Centro Studi GISED, Bergamo, Italy; ³CROMSOURCE, Verona, Italy; ⁴Laboratoires GENEVRIER, Antibes France; ⁵IBSA Institut Biochimique S.A., Pambio-Noranco, Lugano, Switzerland; ⁶Director, Centre de Recherche en Epidemiologie et Santé des Populations, Maison de Solenn, 75679 Paris, France; ⁷Department of Dermatology, Hospital Saint-Eloi, Montpellier, France

Correspondence: Carol Caverzasio, MSc, IBSA Institut Biochimique S.A., Via del Piano, 29, 6915 Pambio-Noranco (TI), Switzerland; carol.caverzasio@ibsa.ch 

Disclosure: The study was sponsored by IBSA Institut Biochimique S.A. CC and DB are employees of IBSA. ES is an employee of Laboratoires Genevrier. Centro Studi GISED received a grant from IBSA, ADL is a member of GISED. JM was the coordinating investigator of the study. BF and OD were members of the data review board of the study, and both received a grant from Laboratoires Genevrier. The study was funded by IBSA Institut Biochimique S.A. (Lugano, Switzerland).