Abstract
As the incidence of diabetic foot ulcers (DFU) increases, better treatments that improve healing should reduce complications of these ulcers including infections and amputations. We conducted a randomized controlled trial comparing outcomes between a novel purified reconstituted bilayer membrane (PRBM) to the standard of care (SOC) in the treatment of non-healing DFUs. This study included 105 patients who were randomized to either of two treatment groups (n = 54 PRBM; n = 51 SOC) in the intent to treat (ITT) group and 80 who completed the study per protocol (PP) (n = 47 PRBM; n = 33 SOC). The primary endpoint was the percentage of wounds closed after 12 weeks. Secondary outcomes included percent area reduction, time to healing, quality of life, and cost to closure. The DFUs that had been treated with PRBM healed at a higher rate than those treated with SOC (ITT: 83% vs. 45%, p = 0.00004, PP: 92% vs. 67%, p = 0.005). Wounds treated with PRBM also healed significantly faster than those treated with SOC with a mean of 42 versus 62 days for SOC (p = 0.00074) and achieved a mean wound area reduction within 12 weeks of 94% versus 51% for SOC (p = 0.0023). There were no adverse events or serious adverse events that were related to either the PRBM or the SOC. In comparison to the SOC, DFUs healed faster when treated with PRBM. Thus, the use of this PRBM is an effective option for the treatment of chronic DFUs.
| Original language | English (US) |
|---|---|
| Article number | e14882 |
| Journal | International Wound Journal |
| Volume | 21 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2024 |
Funding
David Armstrong, DPM, MD, PhD received research funds from PERI to design and administrate the trial and also assist with the writing and review of the manuscript. Dennis Orgill, MD, PhD received research funds to serve as a validating/adjudicating plastic surgeon to review study photos and assist with the writing and review of the manuscript. Robert Galiano, MD received research funds to serve as a validating/adjudicating plastic surgeon to review study photos and assist with the writing and review of the manuscript. Paul Glat, MD received research funds to serve as a validating/adjudicating plastic surgeon to review study photos and assist with the writing and review of the manuscript. Jarrod Kauffman MD received research funds to assist in study design and in manuscript preparation. Marissa Carter, PhD received research funds to provide the statistical analysis plan, provide the statistical analysis for this trial and assist with writing the result section of the manuscript. Lawrence Didomenico, DPM is the medical director of the LEIRT and his company received research funds for enrollment in the clinical trial and write the paper for publication. Charles M Zelen, DPM is the medical director of the PERI and his company received research funds to administrate the clinical trial and write the paper for publication. There are no other conflict of interests with any of the authors in relation to this study, or with regard to Geistlich Pharma. IRB conflict of interest statements are on file with PERI. This study was funded through a research grant from Geistlich Pharma AG; provided to the Professional Education and Research Institute (PERI), which Charles M Zelen, DPM is medical director. Sterile, shelf-stable PRBM (Derma-Gide\u00AE; Geistlich Pharma AG, Wolhusen Switzerland) was provided in individual dry packaging in sizes from 1.1 to 12 cm2. The PRBM was manually trimmed to match the size of each wound and placed dry with the porous lower layer facing down, directly onto the wound bed, thus allowing for uptake of wound fluids. If the PRBM was not completely hydrated by wound fluid, sterile saline was added in order to assure complete hydration, allowing the graft to conform to the wound bed before the application of a routine dressing. Sterile, shelf-stable PRBM (Derma-Gide\u00AE; Geistlich Pharma AG, Wolhusen Switzerland) was provided in individual dry packaging in sizes from 1.1 to 12 cm2. The PRBM was manually trimmed to match the size of each wound and placed dry with the porous lower layer facing down, directly onto the wound bed, thus allowing for uptake of wound fluids. If the PRBM was not completely hydrated by wound fluid, sterile saline was added in order to assure complete hydration, allowing the graft to conform to the wound bed before the application of a routine dressing. A moisture-retentive, conformable collagen alginate dressing (FIBRACOL Plus Dressing; 3 M Maplewood, MN) was the primary wound dressing in the SOC study arm. This dressing has been rigorously tested with favourable results and was chosen as a well-known, clinically accepted SOC product readily available in wound clinics. The primary study endpoint was a comparison of the proportion of index ulcers healed at 12 weeks. Secondary endpoints included comparisons of time to heal at 6 and 12 weeks, percentage area reduction (PAR) of the wound at 6 and 12 weeks, patient-reported quality of life outcomes, safety and cost to closure. After obtaining informed consent, participants were screened over a 14-day run-in period to determine eligibility according to inclusion and exclusion criteria (Table\u00A02). The run-in preceded randomization to eliminate those patients in whom a short course of routine therapy would demonstrate effectiveness as measured by a >20% reduction in wound area. A review of each patient's medical history and a complete physical examination were performed including visual assessment of all foot ulcers with attention to signs of infection. The index ulcer was selected, imaged, and measured for area and depth. All wounds were managed during run-in using a standard protocol including cleaning, appropriate sharp debridement, infection management, dressing, and offloading using a diabetic offloading boot or when the patient's foot could not be accommodated with the offloading boot, a total contact cast was used. Subjects were instructed to keep the wound site dry and informed on the importance of offloading. They received education on infection indicators and asked to contact the clinic with concerns. Patients completed the wound quality-of life (Wound-QoL) questionnaire and scored their pain intensity on a scale of 0 to 10 using a visual analogue scale (VAS). After failing sufficient progress during the 2-week run-in period, subject eligibility was reconfirmed, and all eligible patients proceeded to randomization. A multi-centre, prospective, parallel-group, RCT was designed to evaluate the treatment of full-thickness, non-infected non-ischaemic (Wagner Grade 1/University of Texas 1A) DFUs with PRBM or standard of care (SOC). The study was registered on the German clinical trial register (DRKS) with a reference number of DRKS00016754 and approved by Western IRB (Protocol #20190130) and conducted in compliance with Good Clinical Practice standards and was in conformance with the ethical guidelines of the Declaration of Helsinki. Prior to any study activities, patients provided written, informed consent. The trial was performed at multiple specialty wound care centres between February 2019 and April 2023. The protocol schedule is shown in Table\u00A01. Randomization (Week 3) If randomized to SOC: Apply SOC therapy with Fibracol and outer dressing If Randomized to PRBM: Apply SOC therapy with PRBM and outer dressing Weekly assessment of index ulcer, measurement, cleaning, debridement and repeat dressings If Index ulcer is healed, no further treatment After 6 treatment visits, if wound <50% healed, treatment phase ended; treatment failure Sterile, shelf-stable PRBM (Derma-Gide\u00AE; Geistlich Pharma AG, Wolhusen Switzerland) was provided in individual dry packaging in sizes from 1.1 to 12 cm2. The PRBM was manually trimmed to match the size of each wound and placed dry with the porous lower layer facing down, directly onto the wound bed, thus allowing for uptake of wound fluids. If the PRBM was not completely hydrated by wound fluid, sterile saline was added in order to assure complete hydration, allowing the graft to conform to the wound bed before the application of a routine dressing. A moisture-retentive, conformable collagen alginate dressing (FIBRACOL Plus Dressing; 3 M Maplewood, MN) was the primary wound dressing in the SOC study arm. This dressing has been rigorously tested with favourable results and was chosen as a well-known, clinically accepted SOC product readily available in wound clinics. The primary study endpoint was a comparison of the proportion of index ulcers healed at 12 weeks. Secondary endpoints included comparisons of time to heal at 6 and 12 weeks, percentage area reduction (PAR) of the wound at 6 and 12 weeks, patient-reported quality of life outcomes, safety and cost to closure. After obtaining informed consent, participants were screened over a 14-day run-in period to determine eligibility according to inclusion and exclusion criteria (Table\u00A02). The run-in preceded randomization to eliminate those patients in whom a short course of routine therapy would demonstrate effectiveness as measured by a >20% reduction in wound area. A review of each patient's medical history and a complete physical examination were performed including visual assessment of all foot ulcers with attention to signs of infection. The index ulcer was selected, imaged, and measured for area and depth. All wounds were managed during run-in using a standard protocol including cleaning, appropriate sharp debridement, infection management, dressing, and offloading using a diabetic offloading boot or when the patient's foot could not be accommodated with the offloading boot, a total contact cast was used. Subjects were instructed to keep the wound site dry and informed on the importance of offloading. They received education on infection indicators and asked to contact the clinic with concerns. Patients completed the wound quality-of life (Wound-QoL) questionnaire and scored their pain intensity on a scale of 0 to 10 using a visual analogue scale (VAS). After failing sufficient progress during the 2-week run-in period, subject eligibility was reconfirmed, and all eligible patients proceeded to randomization. Subjects were randomized to either the PRBM arm or SOC arm. To assure a balanced randomization, envelopes were created with a random allocation sequence in block sizes of 10. Wound assessment at conclusion of treatment was performed by a clinician, other than the investigator, who was blinded to the treatment. Additionally, confirmation of wound healing was overseen by an independent plastic surgeon adjudication committee. Regardless of the study arm, wounds were managed with accepted routine SOC practices, including weekly sharp debridement as indicated. Patients randomized to PRBM arm were treated with a PRBM graft followed by a silicone non-adherent dressing (Adaptic Touch, 3 M Maplewood, MN) or equivalent, and those randomized to SOC arm were treated with calcium alginate dressing (FIBRACOL Plus 3 M Maplewood, MD). All wounds received an outer dressing comprised of a padded 3-layer dressing (Dynaflex, 3 M Maplewood, MN) or equivalent. Study visits were performed weekly until either complete healing of the index ulcer or for 12 weeks, whichever came first. At each visit, the subject's overall health, glucose control, and offloading were assessed, and closure of the index ulcer was gauged by a blinded investigator. If the index ulcer was not completely reepithelialised, the wound was evaluated for signs of infection, cleaned, imaged, and measured. When the index ulcer was deemed to be 100% reepithelialised, further treatment ceased, and the patient was scheduled for a wound healing confirmation to visit 2 weeks later. Final wound area measurement and conclusive imaging were performed, and patients completed the Wound-QoL questionnaire at the final visit. Subjects whose index ulcer did not improve by 50% after 6 weeks were designated per protocol as a treatment failure and were allowed to receive alternative treatments outside of the study. Details specific to PRBM including trimmed size and handling characteristics were noted. Any adverse events (AEs), which were tracked using CTCAE v5, were identified, investigated, and managed as clinically appropriate. Suspected wound infections were diagnosed via wound swabs, and appropriate systemic antibiotics were prescribed. Topical antibiotics were contraindicated per protocol. According to the a priori power analysis, group sample sizes of 50 in each group would have achieved 88% power to detect a difference between the groups. Power calculations for the primary endpoint were based on a two-sided Z-test with pooled variance. Statistical testing between treatment groups at baseline was carried out to examine the success of randomization. For categorical variables, chi-square or Fisher exact tests were performed and for continuous variables independent t-tests or Mann\u2013Whitney tests were used (depending on variable normality) to test for statistical differences. The primary endpoint was evaluated by a Fisher exact test using an intent-to-treat (ITT) analysis of all randomized patients. Time to heal within 6 and 12 weeks was analysed using Kaplan\u2013Meier log-rank test, while PAR at 6 and 12 weeks analysed using the Mann\u2013Whitney test. The primary and secondary endpoints were tested hierarchically in a confirmatory manner. Other endpoints assessed in an exploratory manner included the Wound-QoL and pain score changes from baseline to 12 weeks. Statistical tests were two-sided and performed at a significance threshold of 0.05. The last observation carried forward (LOCF) principle was used in regard to missing data at study visits. Statistical Analysis was performed using SPSS Statistics 27 (IBM, Armonk, NY). It is estimated that 9% of the worldwide population is diabetic, and this is expected to affect over 600 million people in coming years.1 A notable consequence of this is likely to be an increase in the incidence of diabetic foot ulcers (DFUs), which currently affect 19%\u201334% of diabetics.2 As most clinicians can attest, the management of DFUs can be challenging, as the interruption of the normal healing cascade can result in 30% of these wounds becoming chronic.3 Sadly, the 5-year mortality for DFUs is comparable to many cancers4,5 and patients whose DFUs progress to amputation have a 5-year mortality of 55%.6,7 With such a substantial burden on patients, and the healthcare system in general, there is an obvious demand for therapies that can ameliorate the healing process, thus leading to wound closure and preventing the complications that lead to the worst of the morbidities and subsequent premature mortality. In light of the consequences that DFUs can have on patients' lives, as well as the prognosis for the increased cases, there is a clear need for methods of successfully treating these wounds. This is reflected in the current recognition, by the Centers for Medicare and Medicaid Services, of 76 skin substitutes of varied material properties for the treatment of DFUs.8 The significance is further underscored by the ongoing clinical research, with Clinicaltrials.gov currently listing 838 studies for the treatment of DFUs.9 Whether the grafts are derived from allogeneic, xenogeneic, or synthetic sources, they all have the same goals of providing a local environment that fosters the healing of the wound. While many devices purport to enhance healing, the results of the peer-reviewed publications point to evidence gaps and therefore there is a call for better information on wound healing and recurrence when using skin substitute products.8 With clinical necessity for modalities that will improve the chances of successful healing, the introduction of a Purified Reconstituted Bilayer Wound Matrix (PRBM, Geistlich Derma-Gide\u00AE, Geistlich Pharma AG, Switzerland) may offer clinicians another option. This bilayer matrix, which has been processed to remove cells, lipids, antigens and inactivate potential viruses, has a 3-dimensional structure that is similar to the human dermis. Importantly, the PRBM may impact the physiological processes and the wound environment. The growth factors TGF-\u03B21, bFGF, and VEGF are essential constituents in wound healing,10 while matrix metalloproteases (MMP) can impede healing.11 The in vitro data for this PRBM has shown that the material allows the binding and proliferation of growth factors while also appearing to modulate MMP activity.12 With promising in vitro results, a pilot study in patients with chronic DFUs reported rapid healing in 90% of the patients.13 While this was a small study (n = 10) it provided a reason to pursue further clinical research on this device. The recent interim results of this Randomized controlled trial (RCT), in which the PRBM was compared to a collagen alginate dressing (Fibracol; 3 M Maplewood, MN), showed that wounds treated with the PRBM healed significantly faster and were more likely to close.14 Here we present the safety and efficacy results of the final completed RCT in which the targeted enrolment of over 100 subjects was met.
Keywords
- advanced wound care
- advanced wound matrix
- diabetic foot ulcers
- standard of care
- wound healing
ASJC Scopus subject areas
- Surgery
- Dermatology
