Wound Conforming Matrix Containing Purified Homog
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Wound Conforming Matrix Containing Purified Homogenate of Dermal Collagen Promotes Healing of Diabetic Neuropathic Foot Ulcers:
Comparative Analysis Versus Standard of Care
Lois A. Chandler,1,* Oscar M. Alvarez,2 Peter A. Blume,3 Paul J. Kim,4 Robert S. Kirsner,5 John C. Lantis,6
and William A. Marston7
1Olaregen Therapeutix, Inc., New York, New York.
2Vascular and Wound Care Center, University Hospital, Newark, New Jersey.
3Departments of Surgery, Anesthesia, and Cardiology, Yale School of Medicine, New Haven, Connecticut.
4Department of Plastic Surgery and Orthopedic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas. 5Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida. 6Division of Vascular and Endovascular Surgery, Mount Sinai St. Luke’s–West Hospitals, New York, New York.
7Division of Vascular Surgery, Department of Surgery, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
Objective: To compare outcomes of diabetic foot ulcers (DFUs) treated with a collagen Wound Conforming Matrix (WCM) or standard of care (SOC). Approach: WCM, a highly purified homogenate of 2.6% fibrillar bovine dermal collagen that conforms to the wound surface, was evaluated in comparison to daily saline-moistened gauze dressing changes (SOC) as part of a retrospective subset analysis of a randomized controlled trial in DFU. Following a 2-week run-in period during which patients received SOC, patients whose wounds did not reduce in area by >30% during run-in were randomly assigned to receive WCM (one or two applications) or SOC.
Results: Statistically significant acceleration of early healing rates was ob- served following a single application of WCM with weekly outer dressing changes compared with daily saline-moistened gauze dressing changes (SOC). Over a 4-week period, 50% of patients receiving a single application of WCM achieved ‡75% reduction in wound area compared with 13% for SOC. WCM appeared to be safe and well tolerated, with no adverse events related to treatment and no evidence of an immunologic reaction to bovine collagen.
Innovation: WCM is unique in its intimate contact with the wound bed and its ability to progress a wound toward healing with a single application. Conclusion: WCM is a treatment modality to accelerate DFU healing rates, with the potential to reduce the likelihood of infection and other complica- tions, and cost of care.
Keywords: diabetic foot ulcer, collagen, platelet activation, randomized con- trolled trial, wound healing rate
a Lois A. Chandler, et al. 2019; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/ 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ADVANCES IN WOUND CARE, VOLUME 00 NUMBER 00
2019 by Mary Ann Liebert, Inc. DOI: 10.1089/wound.2019.1024
Lois A. Chandler, PhD
Submitted for publication August 29, 2019. Accepted in revised form August 27, 2019.
*Correspondence: Olaregen Therapeutix, Inc., 1001 Avenue of the Americas, 2nd Floor, New York, NY 10018
(e-mail: lois.chandler@olaregen.com).
j1
2 CHANDLER ET AL.
INTRODUCTION
Diabetic foot ulcers (DFUs) are a common complication of diabetes mellitus (DM), affecting 19–34% of patients during their lifetime, and are associated with significant morbidity, mortality,
1
andhealthcarecosts. ThefinancialburdenofDFU
on public and private payers accounts for approxi- mately one-third of the total cost of diabetic care and
2,3
type 2 DM over age 18 years with a lower extremity Wagner Classification Grade 1 ulcer present for at least 6 weeks. To limit the study to refractory DFUs, exclusion criteria included a decrease in ulcer area of >30% with SOC during a 2-week run-in period. For complete study criteria, refer to https:// clinicaltrials.gov/ct2/show/NCT00493051 website.
Following qualification and written informed consent, patients underwent sharp debridement of the ulcer, a 4 mm wound biopsy for culture, clin- ical ulcer assessment, and ulcer photograph on day- 14 to start a screening 2-week run-in period with offloading and daily saline-moistened gauze dressing changes (SOC). Sharp debridement was conducted to remove all necrotic soft tissue, hyper- keratotic wound margins, bacterial burden, cellular debris, sinus tracts, fistulae, undermined borders, and callus to produce viable wound margins and a bleeding wound bed. If either beta-hemolytic streptococci (in any amount) or total bacterial load of 1 · 106 colony-forming unit per gram of tissue was present in the screening biopsy, the patient was given a single 7-day course of topical antibiotics and then re-debrided and biopsied for quantitative cul- ture. A second biopsy and culture result exceeding the limits above resulted in exclusion from the study. During the run-in period, all patients were provided supplies for daily at-home SOC, consisting of application of saline-moistened gauze directly to the wound, coverage of the moist dressing with nonadherent TelfaÒ (Cardinal Health, Dublin, OH), securing the dressings with a stretch bandage, and offloading with a special orthopedic shoe (DH WalkerÒ; Ossur, Coconut Creek, FL).
On day-3, repeat clinical ulcer assessment was performed and qualified patients were randomly assigned 1:1:1 to the treatment groups that are the subject of this retrospective, exploratory subset analysis: (1) SOC, (2) WCM, single application on day 1, and (3) WCM, application on days 1 and 29. All patients wore the orthopedic offloading shoe throughout the study period.
The day 1 visit consisted of clinical assessment of the ulcer site, ulcer photograph, and sharp debride- ment. WCM was applied to wounds by site personnel at a volume of 0.1 mL/cm2 of post-debridement wound area and in the presence of a small influx of blood, and the wound was covered with non- adherent Telfa and left undisturbed for 1 week. This procedure was repeated at week 4 for those assigned to the WCM two-application group. Pa- tients assigned to SOC continued with daily at- home saline-moistened gauze dressing changes. All patients were seen and assessed weekly in the clinic until ulcer closure or week 12. Sharp de-
is estimated to range from $9 to $13 billion. describe results from a retrospective, exploratory subset analysis of a randomized, controlled, multi- center clinical trial in DFU,4 comparing the efficacy and safety of one (n = 10) or two (n = 16) applications of a type I bovine fibrillar collagen-based Wound Conforming Matrix (WCM) versus daily saline- moistened gauze dressing changes (SOC, n = 15).
CLINICAL PROBLEM ADDRESSED
DFUs are a common complication of DM and are
associated with significant morbidity, mortality, and
1
healthcarecosts. ThemajorityofDFUinthisstudy
were located on the plantar surface of the foot.
Plantar shear stress is a major causative agent in the
development of DFU and in the poor healing of
5
DFU. Although the principles of DFU care are
established, including offloading to redistribute
pressure away from an ulcer, sharp debridement,
moisture balance, and infection control,3,6 there re-
main gaps between desired and realized healing
7
MATERIALS AND METHODS
Design of the U.S. clinical study followed the guidelines put forth by the U.S. Food and Drug Administration in their June 2006 guidance docu- ment entitled, ‘‘Chronic Cutaneous Ulcer and Burn Wounds—Developing Products for Treatment,’’8 and the study was approved at each participating site by the institutional review board and conducted in compliance with the Declaration of Helsinki (as amended in 2000). The study period was from No- vember 2007 (first patient randomized) to October 2009 (last patient visit). The primary endpoint of the study was the incidence of complete ulcer closure by week 12 (complete epithelialization of the ulcer with no drainage, with closure confirmed at the next 2 weekly visits). After closure, wound assessments continued for 12 weeks to assess durability. Sec- ondary endpoints included changes in ulcer area from baseline at weekly intervals, and safety. En- rollment criteria included patients with type 1 or
outcomes.
promote healing of chronic DFU and accelerate DFU healing rates, with potential to reduce the likelihood of infection and other complications, and cost of care.
New treatment modalities are needed to
We
WOUND CONFORMING MATRIX PROMOTES HEALING OF DFU
3
bridement was performed at screening, before treatment, and as clinically necessary at the weekly clinic visits. Ulcer closure was defined as complete epithelialization of the ulcer with no drainage, with closure confirmed at the next 2 weekly visits. Rate of healing was determined us- ing weekly wound areas as measured by tracing calibrated photos using the NIH ImageJ software. Statistical comparisons between treatment groups were performed using Fisher’s exact two- sided test and the Wilcoxon–Mann–Whitney test.
Activation of human platelets by WCM was evaluated in vitro in collaboration with Piedmont Research Center (Morrisville, NC). Fixed amounts of human platelet concentrate (ZenBio, Research Triangle Park, NC) were incubated with phosphate- buffered saline (negative control), bovine thrombin (positive control; King Pharmaceuticals, Bristol, TN), or increasing amounts of WCM and incubated for 20 min at 37°C. After further incubation for 24 h, samples were centrifuged and supernatants were assayed for human PDGF A/B by ELISA (R&D Systems, Minneapolis, MN). The PDGF A/B isoform was selected for measurement based on favorable assay sensitivity.
RESULTS
In the clinical study, a total of 37 patients were randomly assigned to receive WCM (one or two ap- plications), and 19 patients were randomly assigned to receive daily saline-moistened gauze dressing changes (SOC). As reported by Blume et al.,4 com- parison of baseline wound areas determined by ac- etate tracing and photograph analysis revealed systematically inaccurate (larger) measurements with acetate tracings. Therefore, the analyses re- ported herein were conducted using photo-based measurements, excluding patients with protocol violations and/or with wounds that achieved wound area reduction of >30% during the run-in period.
The original clinical study protocol was designed
Demographics for the subset patient population are presented in Table 1. No significant difference between WCM and SOC was found for any baseline variable. Sharp debridement was performed at
Table 1. Patient demographics Variable
Age (years), mean–SD Gender, n (%)
Male Female
Baseline ulcer size (cm2), mean – SD Ulcer duration (months), mean – SD Ulcer location, n (%)
Plantar
Lateral surface Dorsal
WCM a (N = 26) 55–12
19 (73) 7 (27)
2.0 – 1.2 12.1 – 11.8
22 (85) 3 (11) 1 (4)
SOC (N = 15) 57–13
11 (73) 4 (27)
2.7 – 1.7 12.9 – 13.1
13 (87) 0 (0) 2 (13)
to exclude patients with baseline wound areas of 2
SD, standard deviation; SOC, standard of care; WCM, Wound Conforming Matrix.
screening, on the day 1 visit, and as clinically necessary thereafter during the weekly clinic visits for both WCM and SOC. Frequency of debridement at clinic visits was 62% for WCM and 68% for SOC, a nonsignificant difference.
The cumulative mean area reductions over the first 4 weeks, at which time all WCM patients had received a single application, are presented in Fig. 1. The data demonstrate a greater reduction in wound area between WCM (n = 26) and SOC (n = 15) at all 4 weeks, with statistically significant differ- ences at weeks 1 (p=0.02), 2 (p=0.04), and 4 (p=0.02). At week 4, the average wound area re- duction with WCM was 63% compared with 38% for SOC. There was no significant difference in the percent wound area reduction at week 4 for patients assigned to receive one versus two applications of WCM (69% vs. 61%, respectively), and 13 (87%) of the patients receiving a second application of WCM received £0.1 mL at the second application, reflect- ing the dramatic reduction in wound area by week 4.
The 12-week complete closure incidences were 42% (11/26) for WCM and 27% (4/15) for SOC, a nonsignificant difference. Of the 11 wounds that closed following treatment with WCM, 1 reopened after 4 weeks, and 1 reopened after 12 weeks. More patients were progressing to closure with a single application of WCM compared with daily SOC, and WCM demonstrated acceleration of healing after application. By 2 weeks after a single application of WCM, 38% (10/26) of patients achieved ‡75% wound area reduction, compared with 7% (1/15) for SOC, a significant difference ( p = 0.03). At 4 weeks after a single application of WCM, 50% (13/26) of patients achieved ‡75% wound area reduction, compared with 13% (2/15) for SOC, a significant difference ( p = 0.02). Wound photos from two WCM-treated patients and two SOC-treated pa- tients, with plantar location and approximate size- matched baseline areas, are presented in Fig. 2.
<1.5 cm . However, even small DFU can be difficult to heal, and the potential complications from small DFU can be as devastating and costly as large DFU. Therefore, wounds with baseline areas of <1.5cm2 (WCM mean duration 9 months, SOC mean duration 7 months) are included in the ana- lyses reported herein, resulting in 26 WCM-treated patients and 15 SOC-treated patients for analysis.
aOne application, n = 10; Two applications, n = 16.
4 CHANDLER ET AL.
Figure 1. Cumulative percent wound area reduction from baseline through week 4 (mean–SD). WCM (n=26), SOC (n=15). WCM versus SOC: week 1 ( p = 0.02); week 2 ( p = 0.04); week 3 ( p = 0.11); week 4 ( p = 0.02). WCM and SOC compared by the Wilcoxon–Mann–Whitney test. SD, standard deviation; SOC, standard of care; WCM, Wound Conforming Matrix.
Safety of topically applied WCM was assessed
by adverse events, clinical laboratory measure-
ments, vital signs, concomitant medications, ies.
physical examination findings, and serum anti- body concentrations to collagen. There were no application site infections in any of the WCM- or SOC-treated patients during the study period. There were no obvious or concerning safety trends in the hematology, chemistry, urine analysis, and other laboratory parameters for the WCM-treated patients compared with SOC. Safety of WCM was also assessed by monitoring levels of collagen antibodies at screening and week 5. Week 5 an- tibody titers to bovine collagen were positive for one patient treated with WCM and one patient treated with SOC. Both these patients also had positive collagen antibody titers at screening. Pre-existing antibodies to collagen did not affect treatment response, with wound closure achieved at week 5 for the WCM-treated patient. All other patients tested negative for collagen antibodies pre- and post-treatment. Therefore, there was no detectable serum antibody response to treatment with WCM.
The subset analyses reported herein were con- ducted due to the unexpected finding that WCM, originally intended as a control group, resulted in accelerated healing and wound closure incidences compared with daily saline-moistened gauze
4
dressing changes (SOC). This finding prompted
further investigation into the potential mecha- nism of action of WCM, in addition to its ability to
We confirmed in vitro that exposure of human platelets to WCM results in platelet activation and dose-dependent release of platelet-derived growth factor (PDGF), an essential mediator of the wound healing cascade (Fig. 3).
function as a structural scaffold in dermal wound healing, as was demonstrated in preclinical stud-
9
DISCUSSION
Although the basic principles of DFU care are established, including offloading to redistribute pressure away from an ulcer, sharp debridement, dressings to promote moisture balance, and infec- tion control,3,6 there remain gaps between desired and realized healing outcomes with current stan- dard of care strategies. There are numerous topi- cal products available for use in the early management of DFU, including wet-to-dry dress- ings, hydrogels, hydrocolloids, alginates, and foam dressings. DFUs are heterogeneous, and unfortu- nately, DFU and other chronic wounds often fail to respond to conservative standard of care, requir- ing more advanced treatment options including
10
wounds overall.
atory analysis, a single application of WCM ac- celerated healing with an average wound area reduction of 63% at 4 weeks.
cellular- and tissue-based products.
reduction of >50% after 4 weeks of treatment has been found to be predictive of wound closure out- comes for DFU, venous leg ulcers, and chronic
11–13
In this retrospective explor-
Wound area
Figure 2. (A) A 59-year-old male with DFU of 3 months duration on plantar surface of left foot. Application of WCM on day 1 and week 4. (
A 51-year-old female with DFU of 4 months duration on plantar surface of left foot. Daily saline-moistened gauze dressing changes. (C) A 42-year-old female with DFU of 13 months duration on plantar surface of right foot. Application of WCM on day 1. (D) A 63-year-old male with DFU of 51 months duration on plantar surface of right foot. Daily saline-moistened gauze dressing changes.
Figure 3. WCM-activated PDGF release. Fixed amounts of human platelet concentrate were incubated with PBS (negative control), bovine thrombin (positive control), or 80–720 lL of WCM and incubated for 20 min at 37°C. After 24 h, samples were assayed for human PDGF A/B by ELISA (mean – SD). ELISA, enzyme- linked immunosorbent assay; PBS, phosphate-buffered saline; PDGF, platelet-derived growth factor.
j5
6 CHANDLER ET AL.
The majority of DFU in this study were located on the plantar surface of the foot. Plantar shear stress is a major causative agent in the develop-
5
care of DFU, including hydrogels, hydrocolloids, alginates, and foam dressings. Detailed informa- tion regarding prior treatments was insufficient to determine specific product classes that failed to heal the study wounds before study enrollment. A larger clinical data set based on real-world expe- rience with WCM is needed to establish the efficacy of WCM in healing DFU that have failed to heal with other specific classes of product. The potential benefits of the early acceleration of healing ob- served with WCM include reduced risk of infection, hospitalization and amputation, decreased health care costs, and positive impact on patients’ quality of life.
INNOVATION
WCM has unique properties that promote heal- ing of DFU, which is critical for predicting healing, reducing the risk of complications, and decreasing the cost of care. Manufactured as a sterile homog- enate of purified fibrillar collagen, WCM conforms to the entire wound surface without the manipu- lations required with sheet-based products (e.g., trimming and fixation). The acceleration of healing observed following a single application of WCM is attributed to its three-dimensional fibrillar struc- ture, which provides a structural scaffold for repair cells, including those potentially stimulated by PDGF release from platelets activated by interac- tion with WCM.
ACKNOWLEDGMENTS AND FUNDING SOURCES
This work received no specific grant from any funding agency in the public, commercial, or not- for-profit sectors. The clinical study was approved at each participating site by the institutional re- view board, and all enrolled patients provided written informed consent before any study proce- dures.
AUTHOR DISCLOSURE AND GHOSTWRITING
L.A.C. is a paid advisor to Olaregen Ther- apeutix. O.M.A., P.A.B., P.J.K., R.S.K., J.C.L., and W.A.M. have no conflict of interest to declare. The content of this article was expressly written by the authors listed. No ghostwriters were used to write the article.
ABOUT THE AUTHORS
Lois A. Chandler, PhD, is the Inventor of WCM and serves as Scientific Consultant for
ment and poor healing of DFU.
tion of WCM, with weekly outer dressing changes, demonstrated statistically significant acceleration of healing within 1 week of application, and per- sisting for 4 weeks, compared with daily saline- moistened gauze dressing changes (SOC). The average wound duration of the WCM and SOC treatment groups was *1 year. It is feasible that the daily dressing changes associated with SOC disrupted the healing process compared with once weekly outer dressing changes for WCM-treated patients. Debridement was performed on all wounds at the day 1 treatment visit, and frequency of de- bridement at subsequent visits was similar for WCM and SOC. Furthermore, there were no treat- ment site infections during the study period in any of the WCM- or SOC-treated patients.
The WCM manufacturing process was specifi- cally designed to generate a highly purified ho- mogenate of type I collagen that could conform to the wound bed while retaining the three- dimensional scaffold structure of native fibrillar collagen. The ability of WCM to activate human
14
platelets is confirmation of its fibrillar structure. Endogenous PDGF plays an important role in each phase of the wound healing process, including stimulation of chemotactic recruitment and prolif-
15
eration of cells involved in wound repair. clinical studies using animal models of wound healing have demonstrated that WCM provides a structural scaffold for cellular migration and pro- liferation,9 and this function combined with plate- let activation may account for the acceleration of healing observed following a single application of WCM. In future clinical studies, it will be of value to measure PDGF levels within the wound follow- ing treatment with WCM to identify potential cor- relations between healing response and platelet activation by WCM.
The clinical trial protocol was limited to Wagner Grade 1 DFU and limited treatment with WCM to one or two applications, with the second applica- tion being applied at week 4. In the real-world setting, weekly application of WCM may be bene- ficial to maintain accelerated DFU healing rates and to increase closure incidences. Furthermore, the strict inclusion/exclusion criteria required by the clinical study protocol may not accurately rep- resent the general population of patients with DFU. In addition to daily wet-to-dry dressings, the SOC employed in this exploratory analysis, there are other topical products available for standard of
A single applica-
Pre-
WOUND CONFORMING MATRIX PROMOTES HEALING OF DFU 7
Olaregen Therapeutix. Oscar M. Alvar-
ez, PhD, is Program Director of the Vascular and Wound Care Center and
Director of Clinical Research at University Hospital, Newark, New Jersey. Peter A.
Blume, DPM, FACFAS, is Director and President at Affiliated Foot and Ankle Surgeons, New Haven, Connecticut, and Assistant Clinical Professor at Yale Uni-
versity School of Medicine Departments of Orthopaedics and Surgery. Paul J. Kim,
DPM, MS, is Medical Director of the
Wound Program and Professor in the Department of Plastic Surgery and Orthopedic Surgery at the University of Texas Southwestern Medical Center, Dallas, Texas. Robert S. Kirsner, MD, PhD, is Chairman and Professor at the Dr. Phillip Frost Department of Dermatology and Cutaneous Sur- gery, University of Miami Miller School of Medicine.
John C. Lantis, MD, is Chief of Vascular and En- dovascular Surgery, Mt. Sinai West and St. Luke’s Hospitals, New York, New York. William A. Mar- ston, MD, is Professor in the Division of Vascular Surgery at the University of North Carolina School of Medicine and Medical Director of the UNC Limb Salvage/Wound Healing Center.
KEY FINDINGS
Comparative Analysis Versus Standard of Care
Lois A. Chandler,1,* Oscar M. Alvarez,2 Peter A. Blume,3 Paul J. Kim,4 Robert S. Kirsner,5 John C. Lantis,6
and William A. Marston7
1Olaregen Therapeutix, Inc., New York, New York.
2Vascular and Wound Care Center, University Hospital, Newark, New Jersey.
3Departments of Surgery, Anesthesia, and Cardiology, Yale School of Medicine, New Haven, Connecticut.
4Department of Plastic Surgery and Orthopedic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas. 5Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida. 6Division of Vascular and Endovascular Surgery, Mount Sinai St. Luke’s–West Hospitals, New York, New York.
7Division of Vascular Surgery, Department of Surgery, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
Objective: To compare outcomes of diabetic foot ulcers (DFUs) treated with a collagen Wound Conforming Matrix (WCM) or standard of care (SOC). Approach: WCM, a highly purified homogenate of 2.6% fibrillar bovine dermal collagen that conforms to the wound surface, was evaluated in comparison to daily saline-moistened gauze dressing changes (SOC) as part of a retrospective subset analysis of a randomized controlled trial in DFU. Following a 2-week run-in period during which patients received SOC, patients whose wounds did not reduce in area by >30% during run-in were randomly assigned to receive WCM (one or two applications) or SOC.
Results: Statistically significant acceleration of early healing rates was ob- served following a single application of WCM with weekly outer dressing changes compared with daily saline-moistened gauze dressing changes (SOC). Over a 4-week period, 50% of patients receiving a single application of WCM achieved ‡75% reduction in wound area compared with 13% for SOC. WCM appeared to be safe and well tolerated, with no adverse events related to treatment and no evidence of an immunologic reaction to bovine collagen.
Innovation: WCM is unique in its intimate contact with the wound bed and its ability to progress a wound toward healing with a single application. Conclusion: WCM is a treatment modality to accelerate DFU healing rates, with the potential to reduce the likelihood of infection and other complica- tions, and cost of care.
Keywords: diabetic foot ulcer, collagen, platelet activation, randomized con- trolled trial, wound healing rate
a Lois A. Chandler, et al. 2019; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/ 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ADVANCES IN WOUND CARE, VOLUME 00 NUMBER 00
2019 by Mary Ann Liebert, Inc. DOI: 10.1089/wound.2019.1024
Lois A. Chandler, PhD
Submitted for publication August 29, 2019. Accepted in revised form August 27, 2019.
*Correspondence: Olaregen Therapeutix, Inc., 1001 Avenue of the Americas, 2nd Floor, New York, NY 10018
(e-mail: lois.chandler@olaregen.com).
j1
2 CHANDLER ET AL.
INTRODUCTION
Diabetic foot ulcers (DFUs) are a common complication of diabetes mellitus (DM), affecting 19–34% of patients during their lifetime, and are associated with significant morbidity, mortality,
1
andhealthcarecosts. ThefinancialburdenofDFU
on public and private payers accounts for approxi- mately one-third of the total cost of diabetic care and
2,3
type 2 DM over age 18 years with a lower extremity Wagner Classification Grade 1 ulcer present for at least 6 weeks. To limit the study to refractory DFUs, exclusion criteria included a decrease in ulcer area of >30% with SOC during a 2-week run-in period. For complete study criteria, refer to https:// clinicaltrials.gov/ct2/show/NCT00493051 website.
Following qualification and written informed consent, patients underwent sharp debridement of the ulcer, a 4 mm wound biopsy for culture, clin- ical ulcer assessment, and ulcer photograph on day- 14 to start a screening 2-week run-in period with offloading and daily saline-moistened gauze dressing changes (SOC). Sharp debridement was conducted to remove all necrotic soft tissue, hyper- keratotic wound margins, bacterial burden, cellular debris, sinus tracts, fistulae, undermined borders, and callus to produce viable wound margins and a bleeding wound bed. If either beta-hemolytic streptococci (in any amount) or total bacterial load of 1 · 106 colony-forming unit per gram of tissue was present in the screening biopsy, the patient was given a single 7-day course of topical antibiotics and then re-debrided and biopsied for quantitative cul- ture. A second biopsy and culture result exceeding the limits above resulted in exclusion from the study. During the run-in period, all patients were provided supplies for daily at-home SOC, consisting of application of saline-moistened gauze directly to the wound, coverage of the moist dressing with nonadherent TelfaÒ (Cardinal Health, Dublin, OH), securing the dressings with a stretch bandage, and offloading with a special orthopedic shoe (DH WalkerÒ; Ossur, Coconut Creek, FL).
On day-3, repeat clinical ulcer assessment was performed and qualified patients were randomly assigned 1:1:1 to the treatment groups that are the subject of this retrospective, exploratory subset analysis: (1) SOC, (2) WCM, single application on day 1, and (3) WCM, application on days 1 and 29. All patients wore the orthopedic offloading shoe throughout the study period.
The day 1 visit consisted of clinical assessment of the ulcer site, ulcer photograph, and sharp debride- ment. WCM was applied to wounds by site personnel at a volume of 0.1 mL/cm2 of post-debridement wound area and in the presence of a small influx of blood, and the wound was covered with non- adherent Telfa and left undisturbed for 1 week. This procedure was repeated at week 4 for those assigned to the WCM two-application group. Pa- tients assigned to SOC continued with daily at- home saline-moistened gauze dressing changes. All patients were seen and assessed weekly in the clinic until ulcer closure or week 12. Sharp de-
is estimated to range from $9 to $13 billion. describe results from a retrospective, exploratory subset analysis of a randomized, controlled, multi- center clinical trial in DFU,4 comparing the efficacy and safety of one (n = 10) or two (n = 16) applications of a type I bovine fibrillar collagen-based Wound Conforming Matrix (WCM) versus daily saline- moistened gauze dressing changes (SOC, n = 15).
CLINICAL PROBLEM ADDRESSED
DFUs are a common complication of DM and are
associated with significant morbidity, mortality, and
1
healthcarecosts. ThemajorityofDFUinthisstudy
were located on the plantar surface of the foot.
Plantar shear stress is a major causative agent in the
development of DFU and in the poor healing of
5
DFU. Although the principles of DFU care are
established, including offloading to redistribute
pressure away from an ulcer, sharp debridement,
moisture balance, and infection control,3,6 there re-
main gaps between desired and realized healing
7
MATERIALS AND METHODS
Design of the U.S. clinical study followed the guidelines put forth by the U.S. Food and Drug Administration in their June 2006 guidance docu- ment entitled, ‘‘Chronic Cutaneous Ulcer and Burn Wounds—Developing Products for Treatment,’’8 and the study was approved at each participating site by the institutional review board and conducted in compliance with the Declaration of Helsinki (as amended in 2000). The study period was from No- vember 2007 (first patient randomized) to October 2009 (last patient visit). The primary endpoint of the study was the incidence of complete ulcer closure by week 12 (complete epithelialization of the ulcer with no drainage, with closure confirmed at the next 2 weekly visits). After closure, wound assessments continued for 12 weeks to assess durability. Sec- ondary endpoints included changes in ulcer area from baseline at weekly intervals, and safety. En- rollment criteria included patients with type 1 or
outcomes.
promote healing of chronic DFU and accelerate DFU healing rates, with potential to reduce the likelihood of infection and other complications, and cost of care.
New treatment modalities are needed to
We
WOUND CONFORMING MATRIX PROMOTES HEALING OF DFU
3
bridement was performed at screening, before treatment, and as clinically necessary at the weekly clinic visits. Ulcer closure was defined as complete epithelialization of the ulcer with no drainage, with closure confirmed at the next 2 weekly visits. Rate of healing was determined us- ing weekly wound areas as measured by tracing calibrated photos using the NIH ImageJ software. Statistical comparisons between treatment groups were performed using Fisher’s exact two- sided test and the Wilcoxon–Mann–Whitney test.
Activation of human platelets by WCM was evaluated in vitro in collaboration with Piedmont Research Center (Morrisville, NC). Fixed amounts of human platelet concentrate (ZenBio, Research Triangle Park, NC) were incubated with phosphate- buffered saline (negative control), bovine thrombin (positive control; King Pharmaceuticals, Bristol, TN), or increasing amounts of WCM and incubated for 20 min at 37°C. After further incubation for 24 h, samples were centrifuged and supernatants were assayed for human PDGF A/B by ELISA (R&D Systems, Minneapolis, MN). The PDGF A/B isoform was selected for measurement based on favorable assay sensitivity.
RESULTS
In the clinical study, a total of 37 patients were randomly assigned to receive WCM (one or two ap- plications), and 19 patients were randomly assigned to receive daily saline-moistened gauze dressing changes (SOC). As reported by Blume et al.,4 com- parison of baseline wound areas determined by ac- etate tracing and photograph analysis revealed systematically inaccurate (larger) measurements with acetate tracings. Therefore, the analyses re- ported herein were conducted using photo-based measurements, excluding patients with protocol violations and/or with wounds that achieved wound area reduction of >30% during the run-in period.
The original clinical study protocol was designed
Demographics for the subset patient population are presented in Table 1. No significant difference between WCM and SOC was found for any baseline variable. Sharp debridement was performed at
Table 1. Patient demographics Variable
Age (years), mean–SD Gender, n (%)
Male Female
Baseline ulcer size (cm2), mean – SD Ulcer duration (months), mean – SD Ulcer location, n (%)
Plantar
Lateral surface Dorsal
WCM a (N = 26) 55–12
19 (73) 7 (27)
2.0 – 1.2 12.1 – 11.8
22 (85) 3 (11) 1 (4)
SOC (N = 15) 57–13
11 (73) 4 (27)
2.7 – 1.7 12.9 – 13.1
13 (87) 0 (0) 2 (13)
to exclude patients with baseline wound areas of 2
SD, standard deviation; SOC, standard of care; WCM, Wound Conforming Matrix.
screening, on the day 1 visit, and as clinically necessary thereafter during the weekly clinic visits for both WCM and SOC. Frequency of debridement at clinic visits was 62% for WCM and 68% for SOC, a nonsignificant difference.
The cumulative mean area reductions over the first 4 weeks, at which time all WCM patients had received a single application, are presented in Fig. 1. The data demonstrate a greater reduction in wound area between WCM (n = 26) and SOC (n = 15) at all 4 weeks, with statistically significant differ- ences at weeks 1 (p=0.02), 2 (p=0.04), and 4 (p=0.02). At week 4, the average wound area re- duction with WCM was 63% compared with 38% for SOC. There was no significant difference in the percent wound area reduction at week 4 for patients assigned to receive one versus two applications of WCM (69% vs. 61%, respectively), and 13 (87%) of the patients receiving a second application of WCM received £0.1 mL at the second application, reflect- ing the dramatic reduction in wound area by week 4.
The 12-week complete closure incidences were 42% (11/26) for WCM and 27% (4/15) for SOC, a nonsignificant difference. Of the 11 wounds that closed following treatment with WCM, 1 reopened after 4 weeks, and 1 reopened after 12 weeks. More patients were progressing to closure with a single application of WCM compared with daily SOC, and WCM demonstrated acceleration of healing after application. By 2 weeks after a single application of WCM, 38% (10/26) of patients achieved ‡75% wound area reduction, compared with 7% (1/15) for SOC, a significant difference ( p = 0.03). At 4 weeks after a single application of WCM, 50% (13/26) of patients achieved ‡75% wound area reduction, compared with 13% (2/15) for SOC, a significant difference ( p = 0.02). Wound photos from two WCM-treated patients and two SOC-treated pa- tients, with plantar location and approximate size- matched baseline areas, are presented in Fig. 2.
<1.5 cm . However, even small DFU can be difficult to heal, and the potential complications from small DFU can be as devastating and costly as large DFU. Therefore, wounds with baseline areas of <1.5cm2 (WCM mean duration 9 months, SOC mean duration 7 months) are included in the ana- lyses reported herein, resulting in 26 WCM-treated patients and 15 SOC-treated patients for analysis.
aOne application, n = 10; Two applications, n = 16.
4 CHANDLER ET AL.
Figure 1. Cumulative percent wound area reduction from baseline through week 4 (mean–SD). WCM (n=26), SOC (n=15). WCM versus SOC: week 1 ( p = 0.02); week 2 ( p = 0.04); week 3 ( p = 0.11); week 4 ( p = 0.02). WCM and SOC compared by the Wilcoxon–Mann–Whitney test. SD, standard deviation; SOC, standard of care; WCM, Wound Conforming Matrix.
Safety of topically applied WCM was assessed
by adverse events, clinical laboratory measure-
ments, vital signs, concomitant medications, ies.
physical examination findings, and serum anti- body concentrations to collagen. There were no application site infections in any of the WCM- or SOC-treated patients during the study period. There were no obvious or concerning safety trends in the hematology, chemistry, urine analysis, and other laboratory parameters for the WCM-treated patients compared with SOC. Safety of WCM was also assessed by monitoring levels of collagen antibodies at screening and week 5. Week 5 an- tibody titers to bovine collagen were positive for one patient treated with WCM and one patient treated with SOC. Both these patients also had positive collagen antibody titers at screening. Pre-existing antibodies to collagen did not affect treatment response, with wound closure achieved at week 5 for the WCM-treated patient. All other patients tested negative for collagen antibodies pre- and post-treatment. Therefore, there was no detectable serum antibody response to treatment with WCM.
The subset analyses reported herein were con- ducted due to the unexpected finding that WCM, originally intended as a control group, resulted in accelerated healing and wound closure incidences compared with daily saline-moistened gauze
4
dressing changes (SOC). This finding prompted
further investigation into the potential mecha- nism of action of WCM, in addition to its ability to
We confirmed in vitro that exposure of human platelets to WCM results in platelet activation and dose-dependent release of platelet-derived growth factor (PDGF), an essential mediator of the wound healing cascade (Fig. 3).
function as a structural scaffold in dermal wound healing, as was demonstrated in preclinical stud-
9
DISCUSSION
Although the basic principles of DFU care are established, including offloading to redistribute pressure away from an ulcer, sharp debridement, dressings to promote moisture balance, and infec- tion control,3,6 there remain gaps between desired and realized healing outcomes with current stan- dard of care strategies. There are numerous topi- cal products available for use in the early management of DFU, including wet-to-dry dress- ings, hydrogels, hydrocolloids, alginates, and foam dressings. DFUs are heterogeneous, and unfortu- nately, DFU and other chronic wounds often fail to respond to conservative standard of care, requir- ing more advanced treatment options including
10
wounds overall.
atory analysis, a single application of WCM ac- celerated healing with an average wound area reduction of 63% at 4 weeks.
cellular- and tissue-based products.
reduction of >50% after 4 weeks of treatment has been found to be predictive of wound closure out- comes for DFU, venous leg ulcers, and chronic
11–13
In this retrospective explor-
Wound area
Figure 2. (A) A 59-year-old male with DFU of 3 months duration on plantar surface of left foot. Application of WCM on day 1 and week 4. (
A 51-year-old female with DFU of 4 months duration on plantar surface of left foot. Daily saline-moistened gauze dressing changes. (C) A 42-year-old female with DFU of 13 months duration on plantar surface of right foot. Application of WCM on day 1. (D) A 63-year-old male with DFU of 51 months duration on plantar surface of right foot. Daily saline-moistened gauze dressing changes. Figure 3. WCM-activated PDGF release. Fixed amounts of human platelet concentrate were incubated with PBS (negative control), bovine thrombin (positive control), or 80–720 lL of WCM and incubated for 20 min at 37°C. After 24 h, samples were assayed for human PDGF A/B by ELISA (mean – SD). ELISA, enzyme- linked immunosorbent assay; PBS, phosphate-buffered saline; PDGF, platelet-derived growth factor.
j5
6 CHANDLER ET AL.
The majority of DFU in this study were located on the plantar surface of the foot. Plantar shear stress is a major causative agent in the develop-
5
care of DFU, including hydrogels, hydrocolloids, alginates, and foam dressings. Detailed informa- tion regarding prior treatments was insufficient to determine specific product classes that failed to heal the study wounds before study enrollment. A larger clinical data set based on real-world expe- rience with WCM is needed to establish the efficacy of WCM in healing DFU that have failed to heal with other specific classes of product. The potential benefits of the early acceleration of healing ob- served with WCM include reduced risk of infection, hospitalization and amputation, decreased health care costs, and positive impact on patients’ quality of life.
INNOVATION
WCM has unique properties that promote heal- ing of DFU, which is critical for predicting healing, reducing the risk of complications, and decreasing the cost of care. Manufactured as a sterile homog- enate of purified fibrillar collagen, WCM conforms to the entire wound surface without the manipu- lations required with sheet-based products (e.g., trimming and fixation). The acceleration of healing observed following a single application of WCM is attributed to its three-dimensional fibrillar struc- ture, which provides a structural scaffold for repair cells, including those potentially stimulated by PDGF release from platelets activated by interac- tion with WCM.
ACKNOWLEDGMENTS AND FUNDING SOURCES
This work received no specific grant from any funding agency in the public, commercial, or not- for-profit sectors. The clinical study was approved at each participating site by the institutional re- view board, and all enrolled patients provided written informed consent before any study proce- dures.
AUTHOR DISCLOSURE AND GHOSTWRITING
L.A.C. is a paid advisor to Olaregen Ther- apeutix. O.M.A., P.A.B., P.J.K., R.S.K., J.C.L., and W.A.M. have no conflict of interest to declare. The content of this article was expressly written by the authors listed. No ghostwriters were used to write the article.
ABOUT THE AUTHORS
Lois A. Chandler, PhD, is the Inventor of WCM and serves as Scientific Consultant for
ment and poor healing of DFU.
tion of WCM, with weekly outer dressing changes, demonstrated statistically significant acceleration of healing within 1 week of application, and per- sisting for 4 weeks, compared with daily saline- moistened gauze dressing changes (SOC). The average wound duration of the WCM and SOC treatment groups was *1 year. It is feasible that the daily dressing changes associated with SOC disrupted the healing process compared with once weekly outer dressing changes for WCM-treated patients. Debridement was performed on all wounds at the day 1 treatment visit, and frequency of de- bridement at subsequent visits was similar for WCM and SOC. Furthermore, there were no treat- ment site infections during the study period in any of the WCM- or SOC-treated patients.
The WCM manufacturing process was specifi- cally designed to generate a highly purified ho- mogenate of type I collagen that could conform to the wound bed while retaining the three- dimensional scaffold structure of native fibrillar collagen. The ability of WCM to activate human
14
platelets is confirmation of its fibrillar structure. Endogenous PDGF plays an important role in each phase of the wound healing process, including stimulation of chemotactic recruitment and prolif-
15
eration of cells involved in wound repair. clinical studies using animal models of wound healing have demonstrated that WCM provides a structural scaffold for cellular migration and pro- liferation,9 and this function combined with plate- let activation may account for the acceleration of healing observed following a single application of WCM. In future clinical studies, it will be of value to measure PDGF levels within the wound follow- ing treatment with WCM to identify potential cor- relations between healing response and platelet activation by WCM.
The clinical trial protocol was limited to Wagner Grade 1 DFU and limited treatment with WCM to one or two applications, with the second applica- tion being applied at week 4. In the real-world setting, weekly application of WCM may be bene- ficial to maintain accelerated DFU healing rates and to increase closure incidences. Furthermore, the strict inclusion/exclusion criteria required by the clinical study protocol may not accurately rep- resent the general population of patients with DFU. In addition to daily wet-to-dry dressings, the SOC employed in this exploratory analysis, there are other topical products available for standard of
A single applica-
Pre-
WOUND CONFORMING MATRIX PROMOTES HEALING OF DFU 7
Olaregen Therapeutix. Oscar M. Alvar-
ez, PhD, is Program Director of the Vascular and Wound Care Center and
Director of Clinical Research at University Hospital, Newark, New Jersey. Peter A.
Blume, DPM, FACFAS, is Director and President at Affiliated Foot and Ankle Surgeons, New Haven, Connecticut, and Assistant Clinical Professor at Yale Uni-
versity School of Medicine Departments of Orthopaedics and Surgery. Paul J. Kim,
DPM, MS, is Medical Director of the
Wound Program and Professor in the Department of Plastic Surgery and Orthopedic Surgery at the University of Texas Southwestern Medical Center, Dallas, Texas. Robert S. Kirsner, MD, PhD, is Chairman and Professor at the Dr. Phillip Frost Department of Dermatology and Cutaneous Sur- gery, University of Miami Miller School of Medicine.
John C. Lantis, MD, is Chief of Vascular and En- dovascular Surgery, Mt. Sinai West and St. Luke’s Hospitals, New York, New York. William A. Mar- ston, MD, is Professor in the Division of Vascular Surgery at the University of North Carolina School of Medicine and Medical Director of the UNC Limb Salvage/Wound Healing Center.
KEY FINDINGS
(2)
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Disclaimer: Of course, all of this is my opinion and you should not make any investment decisions based on my opinion. I have not received any non-public information.
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