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

Disclosures

Wounds. 2021;33(11):285-295. 

In This Article

Results

Twenty centers in Poland experienced in the assessment and management of chronic leg ulcers participated in the study between June 13, 2017, and April 17, 2019. A total of 199 European subjects were screened, and 168 (85 in the HA cream group and 83 in the neutral cream group) were eventually enrolled in the study and received at least 1 application of the IMD (safety analysis set). Of these subjects, 164 were included in the full analysis set (FAS; all subjects in the safety analysis set who had at least 1 postbaseline efficacy assessment), with 83 in the HA cream group and 81 in the neutral cream group.

Almost all subjects (96.4%) were receiving other concomitant medications, most commonly bioflavonoids (33.3%), platelet aggregation inhibitors (32.7%), and angiotensin-converting enzyme inhibitors (32.1%). The most frequently used medications were acetylsalicylic acid (26.8%), spironolactone (22.0%), and pentoxifylline (21.4%).

The demographic and target ulcer characteristics of subjects overall were similar between groups (Table 1).

A total of 144 subjects (HA cream group, 70; neutral cream group, 74) completed the study. Twenty-six subjects (HA cream group, n =17; neutral cream group, n =9) discontinued treatment. Of those, 14 subjects (HA cream group, n =9; neutral cream group, n =5) withdrew from the study for personal reasons. Three subjects (HA cream group, n =2; neutral cream group, n =1) withdrew for AEs and 3 (HA cream group, n =1; neutral cream group, n =2) for SAEs. Three subjects in the HA cream group withdrew because of a protocol violation (n =1) or were lost to follow-up (n =2), and 3 subjects (HA cream group, n =2; neutral cream group, n =1) withdrew for other reasons. One subject in each group was lost to follow-up. A total of 5 subjects (HA cream group, n =4; neutral cream group, n =1) had at least 1 major protocol deviation, most commonly for prohibited concomitant medication.

Adherence to treatment was almost 100% in both groups, as expected, because daily medication change was performed by the study nurse.

Efficacy

At study completion, the proportion of subjects in the FAS with centrally assessed complete healing of the target ulcer at week 20 or at any control visit and 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) (Table 2). There was no significant difference in treatment effect for complete ulcer healing between strata (baseline ulcer size ≤20 cm2 vs >20 cm2; Breslow-Day P =.637) (Table 2). There was a similar trend for primary efficacy performance in the per-protocol set (PPS) (data not shown). Pictures of the target ulcer area taken before treatment, at inclusion, and at selected time points during the study in 2 participants, representative of the big ulcer (>20 cm2) and of the small ulcer (≤20 cm2) subgroups, are shown in Figure 1A and Figure 1B, respectively.

Figure 1.

Target ulcer area evolution: standardized pictures taken at inclusion, before treatment, and at subsequent time points during the study in 2 participants, representative of the (A) big ulcer (>20cm2) and (B) small ulcer (≤20cm2) subgroups.

Similarly, the proportion of subjects in the FAS with complete healing of the target ulcer and confirmed 3 weeks later was higher in the HA cream group in comparison with the neutral comparator group when assessed by the investigator at the site (28.9% vs. 14.8%, P =.029) (Table 2). The results obtained in the per-protocol set (PPS) for the primary efficacy performance and all secondary endpoints were consistent with those in the FAS (data not shown).

Cumulative Kaplan-Meier estimates of the probability of complete healing over the entire study period showed that a statistically significantly higher proportion of subjects in the HA cream group achieved complete ulcer healing as compared with the neutral cream group when centrally assessed (P =.006) and according to the assessment of the investigator at the site (P =.017) (Figure 2). Achievement of complete healing of target ulcers was significantly better in the HA cream group by week 8 (P =.017), but the difference between groups was only of borderline significance at the final follow-up visit (P =.067). In the subgroup of subjects in the HA cream group who achieved complete healing of the target ulcer, the median time to healing was approximately 12 weeks, according to the central assessor.

Figure 2.

Time to complete healing of target ulcer (A) as centrally assessed and (B) as assessed by the investigator (full analysis set). Week 1 corresponds to the screening visit. Week 23 (day 162) corresponds to the follow-up visit and includes all values from all patients who were in the study until at least day 156 (week 22).

Logistic regression analysis of explanatory variables on ulcer healing showed that target ulcer size at baseline (≤ 20 cm2 vs > 20 cm2), treatment (HA cream vs neutral cream), and prior target ulcer duration at baseline were all significantly associated with ulcer healing (all P <.01). Other potentially confounding variables tested in the model were subject age (years), baseline pain (VAS score), sex, baseline weight, and body mass index, and clinical site; none of these were found to have a significant effect on the primary outcome. Although the reduction in residual target ulcer area relative to baseline was numerically higher in the HA cream group at all time points, the difference did not reach statistical significance (Figure 3).

Figure 3.

Mean of the relative percentage of target ulcer area by visit (full analysis set). Week 23 (day 162) corresponds to the follow-up visit and includes all values from all patients who were in the study until at least day 156 (week 22).

There was no statistically significant difference between groups for the condition of the periulcerous skin, with the exception of a slightly lower incidence of purpura and erythema in the neutral cream group at week 16. However, it should be noted that the condition of the periulcerous skin was, overall, more compromised in the HA cream group at baseline.

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

The mean VAS score for pain intensity diminished over time during the study period, in a similar manner in both groups. Ulcer pain was mild, on average, at the final visit in both groups, with more than 50% reduction as compared to pretreatment levels. Results obtained in the PPS were fully consistent with those in the FAS (data not shown).

Safety

A total of 64 TEAEs were reported by 34 subjects (40.0%) in the HA cream group, and 84 were reported by 38 subjects (45.8%) in the neutral cream group (Table 3 and Table 4). Most TEAEs were mild to moderate in severity.

The most commonly affected system organ classes were skin and subcutaneous tissue disorders and infections and infestations, occurring in 21.2% and 11.8% of subjects, respectively, in the HA cream group and in 16.9% and 15.7% of subjects, respectively, in the neutral cream group.

There were 11 treatment-emergent SAEs(Table 3). There was no statistically significant difference between groups in the proportion of subjects reporting at least 1 TEAE, serious TEAEs, or AEs leading to study discontinuation. Furthermore, there was no statistically significant difference between groups in the proportion of subjects reporting at least one AE involving a device, and there was no statistically significant difference between groups either in terms of TEAEs severity or relationship to treatment.

Treatment-related TEAEs were reported in 10 subjects (11.8%) in the HA cream group (12 events) and 7 subjects (8.4%, 8 events) in the neutral cream group. Ulcer pain was the most frequently reported TEAE (3 AEs in 3 subjects in both groups). Treatment-related dermatitis (3 subjects), erythema (3 subjects), pruritus (1 subject), and rash (1 subject) were also occasionally reported in one or both treatment groups.

One case of target ulcer infection was reported in the HA cream-treated group; the event was mild in severity and resolved without consequence.

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