Venous Ulcers Treated With a Hyaluronic Acid Extracellular Matrix and Compression Therapy: Interim Analysis of a Randomized Controlled Trial

Objective. This is an interim analysis of a prospective, parallel, randomized, single-center study involving 16 subjects in an outpatient wound care center setting, and the objective of the study is to evaluate the safety and effectiveness of a hyaluronic acid extracellular matrix (HA) for the treatment of chronic venous leg ulcers (VLUs). Materials and Methods. Each subject with a VLU was randomized (1:1) to receive either HA plus compression with a multilayer compression bandage (MLC) or standard care consisting of a nonadherent primary dressing plus a MLC (control). All wounds were VLUs (confirmed by duplex imaging) and all had adequate arterial circulation (ankle-brachial index > 0.75). All VLUs had a history of not healing > 6 months, and all were in the lower leg (between the midcalf and below malleoli). Traditional MLC with a short stretch and elastic cohesive bandage was used in all patients. The primary endpoint was incidence of wound healing at 12 and 16 weeks, and secondary endpoints were time to healing and ulcer recurrence. Wound evaluations were performed weekly and wound surface area was measured by photodigital planimetry. Results. The incidence of wound healing at 12 weeks was 66.6% for the HA group and 14.2% for the control (P = .066). At week 16, 87.5% were healed in the HA group compared with 42.8% in the control (P = .059). The mean time to healing in the HA-treated group was 41 days compared with 104 days in the control (P = .029). Conclusion. Results of this interim analysis indicate that continuation of the present study is warranted and provides a more reliable power calculation forecasting that the inclusion of 50 to 60 subjects would be needed to achieve the statistical goal (P < .05) related to the primary endpoint. 

Chronic venous insufficiency is the most common cause of lower leg ulceration, affecting nearly 7 million people in the United States.^1-3 Venous leg ulcers (VLUs) usually develop on the medial or lateral aspects of the lower leg over a perforating vein, along the line of the long or short saphenous vein, or anywhere below the knee if precipitated by trauma. The ulcers may be single or multiple and are typically tender and shallow. They can vary significantly in size and can be difficult to manage, particularly if they are painful, complicated with dermatitis, or draining profusely. In most cases, compression therapy with multilayer bandages is a simple and effective treatment modality for uncomplicated venous ulcers in the ambulatory care setting.^4-6 Local wound care (topical treatments and dressings), on the other hand, is more controversial, and plentiful options exist for the treatment of VLUs. 

Several extracellular matrix (ECM) materials or collagen-containing wound dressings and tissue-engineered constructs with and without cells have been shown to accelerate the healing of VLUs.^7-10 These ECM materials may have several advantageous features. It has been postulated that their use in chronic wounds leads to a reduction in collagenase and gelatinase (matrix metalloproteinase [MMP]-2, MMP-9) activity.¹¹ It has also been suggested that ECMs bind growth factors, promote angiogenesis, increase fibroblast production, and provide an antibacterial effect to the wound by their natural degradation.^7,10 Hyaluronic acid (HA) is a particularly compelling scaffold because it is a naturally occurring glycosaminoglycan found ubiquitously in the ECM¹² and is involved in all phases of wound healing (inflammation, proliferation, scarring). It has also been shown to facilitate the natural reepithelialization process and promote the proliferation of granulation tissue and vasculature.¹³  

This study is a parallel, randomized controlled trial comparing 2 treatment regimens: (1) Hyalomatrix Wound Matrix (HA group; Fidia Farmaceutici S.p.a.,  Abano Terme, Italy), and (2) control arm consisting of standard local wound care alone. The HA is an ECM engineered of HYAFF (Anika Therapeutics Inc, Bedford, MA), the benzyl ester of hyaluronic acid, and coated onto a semipermeable silicone membrane. Standard wound care consisted of a nonadherent silicone foam dressing.  All subjects were treated with either a 2-layer short stretch compression bandage or 4-layer compression bandage. Treatments and wound evaluations were performed once weekly at the University Wound Care Center, Center for Vascular Health (Bronx, NY), and wound surface area was measured by photodigital planimetry (PictZar Digital Planimetry Software; BioVisual Technologies LLC, Elmwood Park, NJ).¹⁴ The primary endpoint was incidence of wound healing at 12 and 16 weeks, and secondary endpoints were rate of wound healing and incidence of ulcer recurrence. 

Patient characteristics from the 2 treatment groups are presented in the Table. Of the 16 subjects enrolled, 9 were randomized to the HA group and 7 to the control. The mean ulcer surface area between the 2 groups was similar (489 mm² in the HA group compared with 535 mm² in the control). There were no statistical differences in any of the parameters measured between the 2 treatment groups. 

The incidence of wound healing between the treatment groups is shown in Figure 1. At 12 weeks, incidence of wound closure was 66.6% for the HA group and 14.2% for the control (P =.066).  At week 16, 87.5% were healed in the HA group compared with 42.8% in the control (P = .059). 

Mean time to healing in the HA-treated group was significantly less than in the control (P = .029). The average time to complete healing in the HA group was 41 days compared with 104 days in the control (Figure 2). Representative photographs depicting healing of VLUs treated with HA are shown in Figures 3 and 4.

The limitations of this interim analysis include small population size (only 16 study subjects), open label study design, and results from a single clinical center. 

Results of this interim analysis indicate that continuation of the present study is warranted.  A more reliable power calculation from these results forecasts that the inclusion of 50 to 60 subjects would be needed to achieve the statistical goal (P < .05) related to the primary endpoint.

Affiliations: University Hospital, Newark, NJ; and University Wound Care Center, Center for Vascular Health, Bronx, NY

Correspondence:
Oscar M. Alvarez, PhD
Vascular and Wound Care Center
University Hospital
150 Bergen Street (Room D-125) 
PO Box 27050
Newark, NJ 07101-6750 
alvareom@uhnj.org

Disclosure: This study was investigator initiated and funded by Medline Industries Inc, Mundelein, IL. This study was registered at clinicaltrials.gov as NCT02930499. This paper was presented as a poster at the Symposium on Advanced Wound Care Spring 2017.