DFU Clinical Study

A Randomized, Multi-Center, Prospective Analysis of Diabetic Foot Ulcers treated with TheraGauze™ alone or TheraGauze+Becaplermin

Presented at July, 2008 APMA National Scientific Meeting
Awarded 1st Place for “Outstanding Poster Abstract”

Adam Landsman, DPM, PhD
Assistant Professor of Surgery
Harvard Medical School
Division of Podiatric Surgery
Beth Israel Deaconess Medical Center
Boston, MA

ABSTRACT:

This is a summary of the first randomized, prospective clinical analysis involving TheraGauze, a new polymer Smart dressing designed to differentially regulate moisture to a precise degree over the entire surface of a wound. It was hypothesized that precise moisture regulation would result in local wound conditions more amenable to healing, and would result in faster and more frequent wound closure. We compared wounds treated with TheraGauze alone and TheraGauze + Bercaplermin (Regranex 0.01%) with historic controls using saline moistened gauze, and Bercaplermin with saline moistened gauze. Our data indicates that the rate of wound closure is faster with TheraGauze (0.37cm2/week) and with TheraGauze + Bercaplermin (0.41cm2/week), than either saline moistened gauze alone (0.16cm2/week) or Bercaplermin covered with saline moistened gauze (0.24cm2/week). We also found that a larger percentage of wounds closed after 12 and 20 weeks, with TheraGauze and with TheraGauze + Bercaplermin as compared to saline moistened gauze alone and Bercaplermin covered with saline moistened gauze.

INTRODUCTION:

Foot ulcers that occur on patients with diabetes represent a monumental health problem. In addition to triggering a cascade of events that frequently leads to amputation, it is also a primary source of serious infections such as community acquired MRSA. In fact, peripheral vascular disease and infections associated with diabetic foot ulcers is now the leading cause of non-traumatic foot amputations in the United States. One third of every dollar spent on the treatment of diabetes goes to the management of these difficult wounds.

Although the etiology of diabetic foot ulcers appears to be a combination of diminished blood supply, mechanical pressure, neuropathy, bacteria load, and biochemical conditions related to diabetes, the treatment of these wounds remains more elusive. In particular, most strategies for achieving wound closure focus on optimization of the wound environment. This becomes even more complex when the clinician considers the fact that a variety of conditions may exist within a single wound, making management more daunting. In response to the need for a dressing capable of managing a variety of conditions within a single wound, a new generation of Smart dressings have emerged. Smart dressings are capable of adjusting to the multitude of conditions that co-exist within a wound, acting at the wound surface and at the cellular level, in order to add or take away components required to achieve wound closure.

TheraGauze is one of the first of this new generation of wound dressings. In its simplest form, TheraGauze is able to dispense or absorb fluid from the wound bed, simultaneously and to a different degree, across the entire wound surface. In the current study, we looked at the most fundamental example - moisture regulation. TheraGauze can be used to precisely regulate the presence of saline across the wound surface, thereby preventing both maceration and desiccation. Although we have used this product to dispense antibiotics, steroids, and a host of other pharmaceuticals, the dressings used in this study were only used to regulate saline.

For our purposes, the following null hypothesis was proposed:

There is no difference in the rate of wound closure and the percentage of wounds that close when comparing those treated with a precise moisture regulating dressing (TheraGauze) to wounds treated with the same dressing plus Bercaplermin (Regranex 0.01%).

Furthermore, the following hypothesis was proposed:

A precise moisture regulating dressing (TheraGauze) will result in a positive difference in the rate of wound closure and percentage of wounds that close, as study results are compared to historic rates of wound closure and percentage of wounds closed for saline moistened gauze alone and Bercaplermin (Regranex 0.01%) covered with saline moistened gauze.

METHODS:

This clinical trial was a prospective, randomized, two arm study. The two cohorts consisted of:

Group TG: Treated with standard wound debridement as needed, off-loading with a fixed ankle walker (Royce Medical Diabetic boot), and dressing changes every other day, with TheraGauze applied directly to the wound surface.

Group TG+B: Treated with standard wound debridement as needed, off-loading with a fixed ankle walker (Royce Medical Diabetic boot), and application of Bercaplermin (Regranex 0.01%) on a daily basis in accordance with the manufacturers recommendations, along with application of TheraGauze each time.

In order to qualify for participation in this study, all participants had to sign an IRB- approved informed consent, and meet the inclusion/exclusion criteria (Table 1). Patients were followed on a weekly basis for the first 12 weeks, and then bi-weekly through the 20th week. Data was recorded weekly during the first 4 weeks, then bi-weekly for the next 8 weeks. After week 12, data was recorded upon wound closure or on a monthly basis. Patients were monitored for adverse events at every visit throughout the study. Professional, independent monitoring and centralized randomization was provided by Arkios, Inc. (Virginia Beach, VA). A total of 4 clinical trial sites representing both private and university-affiliated clinics were utilized.

Data collection including clinical appearance, wound measurements (cross-sectional area and wound stage), and documentation of adverse events such as infection or worsening of the wound. Analysis included ANOVA to determine if the two groups were comparable in wound severity, as well as the basic parameters of the members of each group (i.e. age, sex, etc.). Endpoints were either total wound closure or reaching the 20th week. Wound progress was measured using 2 parameters: time to closure (i.e. full epithelialization) and rate of change in wound surface area. These values were compared to information captured from the historic literature which described the time to closure and allowed for calculation of rate of change in wound surface area. This information was gathered for both saline moistened gauze and Bercaplermin used in the traditional fashion (with saline moistened gauze). Student’s t-test was used to determine statistically significant differences between groups.

RESULTS:

In this study, n=32 wounds, and these were assessed according to the study protocol. There was no statistically significant difference in the character of the two groups with regard to age (x=56.2 years TG vs. x=58.1 years TG+B; p=0.67) and wound size (x=5.6cm2 TG vs. x=3.8cm2 TG+B; p=0.42). (Fig. 1).

We evaluated the wound closure rates and the percentage of wounds achieving closure. In this study, we found that 46.2% of the wounds achieved closure at 12 weeks in both the TG and TG+B groups (Fig. 2). At 20 weeks, this value increased to 69.2% for TG+B and to 61.5% for the TG group. The difference between the groups was statistically insignificant at both time points (Fig. 3). The rate of closure was evaluated at each time point. We found that the rate of closure was higher during the first 4 weeks, as compared to subsequent periods of time (Fig. 4). According to Sheehan, et al, this is a critical point because earlier rapid closure of a wound may be a good predictor of which wounds will go on to achieve complete closure7. The average rate of closure for the TG group was 0.37cm2/week, and was 0.41cm2/week for the TG+B group. This difference was also not statistically significant (p=0.34) (Fig. 5).

There were very few adverse events and no serious adverse events noted during this study. The events recorded are as follows: 2 wounds (6.3%) infected, 1 wound (3.1%) lost to follow-up, and 1 wound (3.1%) worsened. No amputations were reported by participants in this study.

DISCUSSION:

The data accumulated in this study was compared to historic controls. We utilized several sources in the literature to ascertain the average rates of wound closure and percentage of wounds achieving closure. Based on our review of the literature, we found that saline moistened gauze achieved total wound closure after 12 weeks in 33% of the cases, and Bercaplermin achieved closure in 34% of the cases during the same time period. This compares to values in the current study of 46.2% of the time in the TG and TG+B groups (Fig. 2). At the 20 week mark, the saline moistened dressing group closed 32% of the time while the Bercaplermin group achieved closure 43.3% of the time. This compares to the current study where the TG group achieved closure 61.5% of the time and the TG+B group closed 69.2% of the time (Fig. 3).

When comparing the rate of wound closure, there was insufficient data available in the literature to determine the weekly rate of wound closure, however, the average change in cm2 could be determined over the range of wounds that closed. We found that the average rate of wound closure associated with saline moistened dressings was 0.18cm2/week. Closure rate with Bercaplermin was 0.24cm2/week. This compares to 0.37cm2/week with in the TG group, and 0.41cm2/week in the TG+B group (Fig. 5).

Based on this data, we found that the percentage of wounds which went on to full closure was doubled and the rate was twice as fast, when comparing regular saline moistened gauze to wounds where moisture was precisely regulated with TheraGauze. This finding illustrates the value of precision moisture control and the role it plays in achieving wound healing.

In order to gain a better understanding for the mechanism by which TheraGauze is able to control wound moisture content, the proprietary polymer dressing was examined under electron microscopy. Based on this assessment it was noted that the dressing structure consists of a series of microscopic tubules of approximately 10 microns in diameter, set up in an array. These tubules are oriented perpendicular to the wound surface, and act like a straw to draw fluid up or release it to the surface of the wound, depending on the where the greater quantity of fluid is located. So in the face of a dry area, fluid will be released from the tubules, and in wet areas, moisture is drawn away. The array of tubules is interconnected by a capillary-like network of canals which allow for minimal transport of fluid to adjacent areas (Fig. 6) Based on our clinical experiences in this trial, we found that wounds remained moist without any signs of maceration or desiccation.

CONCLUSIONS:

Based on the results presented here, there appears to be a clear advantage associated with precise moisture control. In particular, the study data suggests that it is not simply the addition of saline to a wound bed that is beneficial, but rather the addition of precisely regulated saline. TheraGauze is unique in its ability to both absorb and release saline to the wound bed. Unlike hydrogels, sponges, and gauze which simply absorb, and plastic barrier dressings which prevent evaporation, TheraGauze actually regulates the amount of moisture found within the wound bed.

There are other aspects of treatment with TheraGauze which may have an influence on the outcome observed here. TheraGauze is non-adherent to the wound bed. As a result, the autodebridment affect normally associated with dressing changes that use adherent materials does not occur here. It has been hypothesized that this may be beneficial in the healing process as well.

One result that requires further analysis is the fact that Bercaplermin used in conjunction with TheraGauze did not perform any better then TheraGauze alone. One difference that was noted between these 2 groups can be seen on figure 4, which compares the weekly rate of wound closure. On this graph, we do see that the TG+B group heals faster in the initial 4 weeks, as compared to the TG group. This can be logically explained by the rapid increase in cellular proliferation that would be expected with the application of PDGF growth factor.

The current study was compared to historic controls drawn from values reported in the literature. Although those values are believed to be highly reliable, we did not have access to the detailed raw data that the current study provided for us. In addition, the power of the current study is low, due to the relatively small sample size.

In conclusion, we believe that this study clearly illustrates that wounds are more likely to close, and to close more quickly, with precise moisture regulation. The future of Smart dressings which provide precise regulation of the wound environment will surely be expanded in the future as new applications that take advantage of this unique technology are explored.

ACKNOWLEDGEMENTS:

I would like to acknowledge my co-investigators in this study:

Patrick Agnew, DPM
Coastal Podiatry, Virginia Beach, VA

Robert Joseph, DPM, PhD
Private Practice, Dayton, OH

Lawrence Parish, MD
Thomas Jefferson University, Philadelphia, PA

Robert Galiano, MD
Northwestern University, Chicago, IL

The authors would also like to thank The College of William and Mary, Applied Research Center, Materials Characterization Laboratory, Newport News, VA, for providing scanning electron micrographs of the TheraGauze material.