A Prospective Noninterventional Study of Type I Collagen Matrix Plus Polyhexamethylene Biguanide Antimicrobial for the Treatment of Venous Leg Ulcers: A Secondary Analysis

Venous leg ulcers (VLUs) are the most common chronic wounds that typically occur along the medial or lateral distal (lower) leg and are caused by a combination of macroscopic and microscopic pathophysiologic processes. Macroscopic processes involve the development
of venous insufficiency and chronic venous hypertension. Venous hypertension results in microscopic changes that include an induction of a chronic inflammatory injury in the lower extremities. Two of the most active areas in VLU research include chronic extravasation of macromolecules in the dermis and iron overload in the skin and subcutaneous tissues.¹ In this regard, current approaches for VLU treatment mainly focus on improving venous hypertension and reversing the local inflammatory status of the ulcer and the peri-ulcer area.^2,3 The standard of care for the treatment of VLUs is the correction of venous hypertension, compression therapy, and aggressive local wound care.

In general, predictors of poor wound healing include advanced patient age, 

large wound area, and long wound duration.^4,5 In a randomized controlled trial of 120 patients, the duration of a VLU was the most significant risk factor for nonhealing ulcers.⁴ The results of a cohort study of 20,000 patients with VLUs showed that wound area was a significant risk factor of nonhealing wounds and that reductions in wound area of ≥40% were strong predictors of healing.⁵ From a systematic review of 39 randomized controlled clinical trials, it was estimated that <75% of VLUs achieve complete closure within 6 months and as many as 25% of healed wounds recur annually.⁶ The results of a large cohort study that included more than 56,000 VLUs in approximately 30,000 patients demonstrated that the percentage change in area, healing rate, and area ratio after 4 weeks of treatment are surrogate markers for complete wound healing by 12 or 24 weeks of care.⁷ Consistently, in developing an algorithm for the treatment of VLUs, using an extensive literature review that included more than 60,000 VLUs and their treatments, it was suggested that if a wound size reduction is <40% within 4 weeks of compression therapy then the prognosis for complete healing is poor, requiring other interventions.⁸

In chronic wounds, the healing process often is arrested in the inflammatory phase, characterized by increased levels of inflammatory mediators and matrix metalloproteinases (MMPs), which in turn damage growth factors and the extracellular matrix (ECM) necessary for wound healing. Compared with fluid from wound beds without ulcers, fluids obtained from chronic VLUs have demonstrated 10-fold increases in levels of MMP-2 and MMP-9 and a 116-fold increase in MMP-1.¹

Like other chronic wounds, VLUs are commonly associated with the formation of a biofilm that stimulates the immune cells to release proteolytic enzymes damaging the ECM, thus impairing the diffusion of inflammatory cells and other factors (eg, neutrophils, macrophages, and antibodies) as well as antibiotics.^9,10 Surface debridement is effective in reducing the biofilm; however, because biofilms can begin to reform within 24 hours, current guidelines recommend using debridement in combination with topical antiseptics to reduce bacterial counts and prevent biofilm reformation.^11-14

Topical and/or systemic antibiotics primarily target metabolically active bacteria and not the metabolically inactive microbes in biofilms.⁹ In addition, while antimicrobials may control the bioburden, at the same time, they have the propensity to be deleterious to normal cells.¹⁵ Polyhexamethylene biguanide (PHMB) is a positively charged, broad-spectrum antimicrobial agent that binds the bacterial cell walls and membranes with broad antimicrobial activity, low cytotoxicity, high tissue compatibility, and no microbial resistance.^16,17 Furthermore, topically applied PHMB is not systemically absorbed through the skin or wounds.¹⁷

Native collagen-based wound dressings have been reported to have the ability to absorb wound exudates and act as a substrate to decrease the high levels of elastase and excessive MMPs that are often present in chronic wounds.^18-20 PuraPly AM (Organogenesis)^21,22 is a purified native type 1 collagen ECM plus PHMB antimicrobial (further referenced as PCMP) that is a US Food and Drug Administration 510(k)-cleared (#K051647) class II medical device and is intended for wound management (package insert, 501(k) premarket notification).^19,23 A post-marketing, open-label, prospective, observational, multicenter registry study (RESPOND, Real-World Effectiveness Study of PuraPly AM on Wounds) was conducted to examine the use of PCMP on various types of wounds in real-world clinical settings.^6,24 The majority of the wounds in the study were classified as chronic and included 307 patients with VLUs, diabetic foot ulcers, pressure-related injuries, postsurgical wounds, and other wounds. The results demonstrated that the use of PCMP was associated with substantial reductions in wound area (81%), depths (70%), and volumes (85%), with a median time to wound closure of 17 weeks overall across all wound types.²⁴

The current report presents a detailed secondary analysis of the effectiveness of PCMP in the 67 patients with VLUs who participated in the RESPOND registry trial.

Study design and patients. The data from patients with VLUs presented in this study were collected from the original RESPOND Registry, which was a noninterventional, prospective, multisite, cohort study examining the “real-world” effectiveness of PCMP on various types of wounds, as previously described.²⁴ The study’s primary purpose was to describe the effectiveness of PCMP in wound treatment over 32 weeks. Additional analyses included the incidence of wounds demonstrating >60% reduction from baseline in wound area and depth as well as the incidence of wounds demonstrating >75% reduction from baseline in wound volume. The study was approved by the Sterling Institutional Review Board. Written informed consent was obtained from all participants before any study-related activities.

Male and female patients, 18 years or older, with a target wound (partial or full thickness) suitable for the use of PCMP were eligible for participation. A total of 307 patients were enrolled from 28 sites in the United States and included the following wound categories: VLUs (n = 67), diabetic foot ulcers (n = 62), postsurgical wounds (n = 54), pressure-related injuries (n = 45), and other wounds (n = 79).²⁴

The treating physician categorized the wounds based on clinical assessment of patient-reported signs and symptoms. The physician also made the choice to use PCMP for wound treatment without regard to the patient’s decision to participate in the study. Due to the nature of this study to collect data for the use of PCMP in a real-world situation, patients received standard of care therapy for the treatment of VLUs.

Eligible enrolled patients were followed-up on an approximately weekly basis for up to 32 weeks. Although multiple wounds may have been treated simultaneously, a single wound was identified as the target wound for evaluation, and characteristics regarding this wound were consistently documented. Participating patients may have had any type of wound, other than a third-degree burn. Potential wounds studied included chronic wounds (such as diabetic foot ulcers and venous leg ulcers), acute wounds (such as wounds following general or plastic surgery), or traumatic wounds (such as abrasions, lacerations, or first- or second-degree burns).

Statistical analysis. The secondary analyses conducted for this study included data obtained from only patients with VLUs. These types of analyses were the same as those conducted for all patients in the original RESPOND study.²⁴ All data were descriptively analyzed to include mean, standard deviations (SD), median, frequencies, and percentages. Frequency of and median time to wound closure were determined by Kaplan-Meier time to event analysis through study end for all wounds and subgroups of wounds.

A forward selection Cox proportional hazards regression model that adjusted for patient demographics (ie, age, race, sex, and body mass index [BMI]) and wound characteristics (ie, area, depth, volume, and age of the ulcer at baseline) was performed to compute the adjusted wound closure rates for all wounds from PCMP treatment application day 0 through week 32. Cox analyses were used to estimate the frequency of wound closure at every time point at which patients were evaluated. All analyses were intent to treat and included data from all patients in the registry who received PCMP.

A total of 67 patients with VLUs were included in the original RESPOND Registry study.²⁴ This subpopulation of patients with VLUs included older adults (mean age, 76 years) and overweight (mean BMI, 31 kg/m²) (Table 1). Patients were predominantly White (87%), with a higher proportion of females (58%). At baseline, all VLUs were on the lower leg, with the majority undergoing treatment for a long duration (mean, 89 days) and were large (mean wound area, 20.1 cm²; mean wound volume, 64 cm³; and mean wound depth, 2.2 mm) (Table 2).

The frequency of wound closure was 33% by week 8 and continued to increase at every study visit through week 32 (Figure 1). Wound closure frequencies were 42%, 45%, 53%, and 73% at weeks 12, 16, 24, and 32, respectively, with a median time to wound closure of 22 weeks. For all 67 of these PCMP-treated VLUs, the incidence of achieving greater than a 60% reduction in baseline area and depth were 78% and 70%, respectively, with approximately 87% showing reduction of greater than 75% in volume (Figure 2).

The standard of care for VLUs is compression therapy, but up to 75% of patients with VLUs exhibit poor healing rates with this type of treatment.⁶ In addition, up to 50% of the ulcers in these patients fail to heal completely by 6 months.²⁵ Compression therapy also can be contraindicated in some patients who have gross arterial disease with an ankle-brachial index <0.7.²⁶ For these reasons, topical treatment options should be considered to treat VLUs in combination with compression therapy. PCMP is one such treatment option that is composed of a native collagen matrix with the addition of the antimicrobial barrier effects of PHMB to control the bacterial bioburden of chronic wounds.

The analysis of data from the subpopulation of 67 patients with VLUs included in the RESPOND Registry indicated that PCMP had clinically meaningful benefits for these patients.²⁴ The patients in this registry were representative of the typical population with VLUs; they were primarily older, had large wounds with a mean area of approximately 20 cm², and were treated for a long duration (89 days). Despite these baseline criteria, the use of PCMP was successful in healing a considerable number of the VLUs in these registry patients and demonstrating reductions in area, depth, and volume.

In these 67 patients with VLUs, complete wound closure was observed from as early as 4 weeks (9%) of treatment; by week 12, the frequency increased to 42% and reached up to 73% by week 32. In addition, with a median time to wound closure of 22 weeks, a large proportion of wounds demonstrated reductions in wound area, depth, and volume. This time course of wound closure was similar to those in the complete RESPOND Registry with 307 patients with various wounds.²⁴ At week 32, the frequency of wound closure in the VLU subpopulation (73%) was the same as that observed for all wound types included in the full registry.

In a retrospective study using prognostic modeling with data from more than 20,000 patients with VLUs treated with conventional compression therapy alone, it was shown that VLUs with a duration <12 months and ≥10 cm² in size achieved a closure rate of 44% in 24 weeks.²⁷ With PCMP and standard of care, the wound closure rates observed were up to 53% at 24 weeks. This suggests the importance of including a combination native type I collagen matrix with PHMB that acts as an effective broad-spectrum antimicrobial barrier during wound healing.

Currently, there are many choices for skin substitutes for the topical treatment of venous ulcers, but as per the WHS guidelines, the selection of the appropriate product should be based on clinical judgement.²⁶ The results of this analysis suggest that PCMP appears to be a valuable adjunct for the treatment of venous leg ulcers.

As is typical of a registry study, the RESPOND study was observational and noninterventional, conducted in a real-world setting. The patients with VLUs in the analyses presented were a subset of all patients with chronic wounds that were included in the original RESPOND study.

The purpose of this secondary analysis was to describe the effectiveness of PCMP in VLUs present in a subgroup of patients who had participated in the RESPOND Registry trial, a noninterventional, prospective, multi-site, cohort study examining the “real-world” effectiveness of PCMP on various types of wounds. In the 67 patients with VLUs, the use of PCMP resulted in successful healing in a considerable number of these patients (73%) and demonstrated reductions in area, depth, and volume. Overall, PCMP appears to be a valuable adjunct to the standard of care for the treatment of chronic wounds such as VLUs.

The authors thank the RESPOND Study Group, the local principal investigators, and staff at the study sites.

George J. Koullias, MD¹; Michael A. Bain, MD²; Kerry Thibodeaux, MD³; and Michael Sabolinski, MD⁴

¹Department of Surgery, Division of Vascular & Endovascular Surgery, Stony Brook School of Medicine, Stony Brook, New York
²Medical Director Outpatient Wound and Hyperbaric Medicine Center, Department of Plastic Surgery, Hoag Hospital, Newport Beach & Irvine, California
³Medical Director, The Wound Treatment Center, Opelousas General Health System, Opelousas, Louisiana
⁴Sabolinski LLC, Franklin, Massachusetts

Address all correspondence to: Michael L Sabolinski, MD, Sabolinski LLC, 55 Jefferson Road, Franklin, MA 02038; tel: 508-507-1130; fax: 781-575-1570; email: sabolinski@gmail.com.

Medical writing support was provided by Guissou Dabiri, PhD, of GD Scientific & Medical Writing, LLC and was funded by Organogenesis. Dr Koullias, Dr Bain, and Dr Thibodeaux serve on the Organogenesis Speakers Bureau. Dr Sabolinski is a paid consultant for Organogenesis.