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Clinical and Economic Assessment of Diabetic Foot Ulcer Debridement with Collagenase: Results of a Randomized Controlled Study

Open AccessPublished:October 21, 2013DOI:https://doi.org/10.1016/j.clinthera.2013.09.013

      Abstract

      Background

      Despite significant advances, the treatment of diabetic foot ulcers (DFUs) remains a major therapeutic challenge for clinicians, surgeons, and other health care professionals. There is an urgent need for new strategies with clinically effective interventions to treat DFUs to reduce the burden of care in an efficient and cost-effective way.

      Objective

      This randomized trial evaluated and compared the clinical effectiveness, tolerability, and costs of clostridial collagenase ointment (CCO) debridement to that of debridement using saline moistened gauze (SMG) and selective sharp debridement for the treatment of DFUs.

      Methods

      Randomized, controlled, parallel group, multicenter, open-label, 12-week study of 48 patients with neuropathic DFUs randomized to 4 weeks of treatment with either CCO or SMG after baseline surgical debridement. The primary end point was the condition of the ulcer bed at the end of treatment as measured using a standardized wound assessment tool. Secondary end points were the percentage of reduction in wound area and therapeutic response rates. Adverse events were monitored for the tolerability analysis. In addition, a comparative cost-effectiveness analysis was performed from the perspective of the Centers for Medicare and Medicaid Services as a payer.

      Results

      Both the CCO and SMG groups had significantly improved wound assessment scores after 4 weeks of treatment (CCO, −2.5, P = 0.007; SMG, −3.4, P = 0.006). Only CCO treatment resulted in a statistically significant decrease from baseline in the mean wound area at the end of treatment (P = 0.0164) and at the end of follow-up (P = 0.012). In addition, the CCO group exhibited a significantly better response rate at the end of follow-up compared with the SMG group (0.92 vs 0.75, P < 0.05). Reported adverse events were similar between the 2 treatment groups. None of the reported adverse events were considered to be related to treatment. The economic analysis indicated that the direct mean costs per responder in the physician office setting of care were $832 versus $1042 for the CCO group versus the SMG group, whereas the direct mean costs per responder in the hospital outpatient department setting were $1607 versus $1980.

      Conclusions

      CCO treatment provides equivalent debridement of DFUs similar to SMG while fostering better progress toward healing as measured by decreasing wound area over time and improved response rates at the end of follow-up. In addition, CCO yields a more favorable cost-effectiveness ratio in both the physician office and hospital outpatient department settings of care. ClinicalTrials.gov identifier: NCT01056198.

      Key words

      Introduction

      Diabetic foot ulcers (DFUs) are a frequent and serious complication of diabetes mellitus, with an annual incidence rate of 1% to 4% and a lifetime risk of 15% to 25%.
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      The pathogenesis of DFU is complex and multifactorial.
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      Despite significant progress and technological advances, the treatment of DFUs is a great challenge for clinicians and other health care personnel. Debridement of the nonviable material from the DFU bed has been used for many years to enhance healing.
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      Debridement is thought to reduce the rate of infection and to provide an ideal healing environment.
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      There are several procedures of debridement used in the management of DFUs. These procedures include sharp surgical, enzymatic, autolytic, mechanical, and hydrotherapy.
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      The chronic wound: impaired healing and solutions in the context of wound bed preparation.
      Selective sharp debridement followed by saline moistened cotton gauze has been used widely in managing these wounds. This technique involves cutting away dead and infected tissue followed by daily application of saline moistened cotton gauze.
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      Management of diabetic foot ulcers.
      Dead and infected tissue adheres to the gauze as it dries. When the remoistened gauze is removed to change the dressing each day, the undesirable tissue comes with it. This action and subsequent sharp surgical debridements that are typically performed as needed in weekly visits repeatedly remove undesirable tissue.
      Clostridial collagenase has been part of the armamentarium for the debridement of wounds for nearly 50 years.
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      • et al.
      Topical silver sulfadiazine vs collagenase ointment for the treatment of partial thickness burns in children: a prospective randomized trial.
      During that time, numerous less specific and potentially more destructive enzymatic debriders (eg, papain/urea, fibrinolysin, trypsin, and streptodornase) have left or been removed from the market for various reasons. Collagenase is an enzyme that effectively removes detritus without harming healthy tissue. It thereby contributes to the formation of granulation tissue and subsequent epithelialization of dermal ulcers. It is possible that collagenase may help reset the conditions in the wound bed, stimulating proliferation and migration of keratinocytes and fibroblasts by rendering the wound bed permissive for migration or via the release of stimulatory peptide fragments.
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      The activity of collagenase-1 is required for keratinocyte migration on a type I collagen matrix.
      Whether these effects are mediated directly by collagenase contact with cells or through byproducts of extracellular matrix digestion is not clearly understood. However, evidence supports a role for collagenase in aiding the extent and rate of wound healing.
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      Enzymatic debriding agents are safe in wounds with high bacterial bioburdens and stimulate healing.
      A multicenter, 12-week randomized comparative clinical trial was initiated to assess the relative effectiveness of enzymatic debridement using clostridial collagenase ointment
      Trademark: Santyl® (Smith & Nephew, Hull, United Kingdom).
      (CCO) with standard debridement using saline moistened gauze (SMG) and selective sharp debridement in diabetic patients. The SMG was selected as the comparator to CCO because of its action as a mechanical debrider
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      and, more importantly, because it is not known to otherwise promote wound healing, allowing its use as a negative control in comparisons with CCO. Although gauze, in particular wet-to-dry gauze, is not a generally recommended dressing choice by wound care experts,
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      it remains a commonly used dressing in the United States.
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      In this randomized comparative clinical trial, we sought to answer 3 important questions on the clinical utility of CCO in the debridement of DFUs. First, how effectively does the selective action of CCO clean the DFU wound bed compared with SMG, which is universally accepted as an effective, albeit nonselective, technique to remove nonviable necrotic tissue? Second, does wound reepithelialization proceed differently between the 2 approaches (ie, does it progress appreciably faster with CCO)? Third, how do the outcomes achieved with the 2 methods compare economically from the perspective of the US payer (ie, the Centers for Medicare and Medicaid Services [CMS])?

      Patients and Methods

       Study Participants

      This study was registered at clinicaltrials.gov as NCT01056198. Patients 18 years or older with a diagnosis of type 1 or type 2 diabetes requiring medications to normalize blood glucose levels were included. Eligible patients had neuropathic foot ulcers of at least 1 month’s duration between 0.5 and 10 cm2 in area. Key eligibility criteria are presented in Table I. This study was performed in compliance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice. The study protocol, investigators, and consent documents were reviewed and approved by accredited institutional review boards, and all patients provided written informed consent before taking part in the study.
      Table IKey Eligibility Criteria.
      Eligibility Criteria
      Adults of any race and either sex
      Full-thickness neuropathic foot ulcer, 0.5–10 cm2 (inclusive)
      Ulcer duration of at least 1 month
      Willing and able to perform dressing changes daily at home
      Willing and able to use appropriate off-loading device
      Adequate perfusion to target ulcer foot (transcutaneous oxygen pressure >40 mm Hg or toe pressure >40 mm Hg)
      Adequate nutrition (albumin ≥2.0 g/dL and prealbumin ≥15 mg/dL)
      No active infection
      No target wound tunneling
      Target wound could not be on heel or over a Charcot deformity

       Study Design

      This was a randomized, parallel group, open-label, multicenter, 12-week clinical study (Figure 1) performed at 7 sites in Arizona, Nebraska, Pennsylvania, and Texas. The study participants were recruited between April 2010 and May 2011 when enrollment objectives had been met. Randomization to treatment was centralized. For each qualified patient, investigative sites contacted the central call center for the next sequential treatment assignment from a predetermined computer-generated randomization sequence.
      Figure thumbnail gr1
      Figure 1Flowchart of patient enrollment and study schema. ITT = intent to treat.
      Patients with DFUs were evaluated for eligibility at a Screening Visit that included a blood draw for assessment of hematology and blood chemistry. Eligible patients reported for the baseline (randomization) visit 1 to 5 days later. The baseline wound bed assessment and measurement were performed followed by sharp surgical debridement performed for all patients. Patients were then randomly assigned to treatment in an equal allocation ratio to either the CCO group or SMG group. CCO was applied once daily at the thickness of a nickel (~2 mm) on the DFUs of the patients in the CCO group and, saline moistened cotton gauze
      Trademark: Sterilux® (Hartmann, Rock Hill, South Carolina).
      was applied and changed daily for the patients in the SMG group. These bandages were covered by an adhesive hydrocellular dressing.
      Trademark: Allevyn® (Smith & Nephew, Hull, United Kingdom).
      In either case, treatment was given for 4 weeks and patients were followed up for up to an additional 8 weeks or to complete wound closure, whichever came first. All patients agreed to wear an offloading boot or other appropriate device to aid the wound healing. Patients randomized to the SMG group received surgical debridement, as deemed medically necessary by the investigator, at any weekly visit. Patients randomized to the CCO group received surgical debridement if deemed medically necessary.
      Patients were seen every week during the treatment and follow-up phases. Patients were instructed in daily wound cleansing with sterile saline, dressing changes, and application of either CCO or SMG. Patients randomized to the SMG group were told to gently peel away the dressing moistening with sterile saline to facilitate removal. At the end of the 4-week treatment period and throughout follow-up, wounds were dressed daily with a soft silicone contact layer
      Trademark: Mepitel® (Mölnlycke Health Care, Norcross, Georgia).
      covered by foam dressing
      Trademark: Copa® (Covidien, Mansfield, Massachusetts).
      .

       Study Assessments

      The primary efficacy analysis was a treatment group comparison of changes from baseline in wound status total score using a standardized wound assessment method (Table II), modified from the Bates-Jensen Wound Assessment Tool,

      Bates-Jensen Wound Assessment Tool.Instructions for use. http://www.geronet.med.ucla.edu/centers/borun/modules/Pressure_ulcer_prevention/puBWAT. pdf. Accessed February 2013.

      including wound edge appearance, undermining, necrotic tissue type, necrotic tissue amount, exudate type, exudate amount, periwound skin color, and granulation tissue appearance, at each of the 4 treatment period visits for the intent-to-treat (ITT) population. Secondary efficacy was assessed as percentage of the wound area change from baseline during the 4-week treatment period and at the end of the follow-up period. The wound area was measured manually with a ruler as length of long axis × greatest width perpendicular to long axis. Lastly, a post hoc analysis was performed on the response rates of the 2 debridement modalities at the 12-week end-of-study (EOS) visit. The response rate were categorized as follows: a reduction in the baseline wound surface area (WSA) of ≤10% at the 12-week EOS visit was classified as a stalled wound, a reduction in baseline WSA >10% but <50% was classified as a moderate response, and a reduction in baseline WSA ≥50% at the 12-week EOS visit was classified as a large response.
      Table IIStandardized Wound Assessment Tool.
      Modified from the Bates-Jensen Wound Assessment Tool.
      ItemAssessment
      Edges1 = Indistinct, diffuse, none clearly visible
      2 = Distinct, outline clearly visible, attached, even with wound base
      3 = Well-defined, not attached to wound base
      4 = Well-defined, not attached to base, rolled under, thickened
      5 = Well-defined, fibrotic, scarred or hyperkeratotic
      Undermining1 = None present
      2 = Undermining <2 cm in any area
      3 = Undermining 2–4 cm involving <50% wound margins
      4 = Undermining 2–4 cm involving >50% wound margins
      5 = Undermining >4 cm or tunneling in any area
      Necrotic tissue type1 = None visible
      2 = White/gray nonviable tissue and/or nonadherent yellow slough
      3 = Loosely adherent yellow slough
      4 = Adherent, soft, black eschar
      5 = Firmly adherent, hard, black eschar
      Necrotic tissue amount1 = None visible
      2 = <25% of wound bed covered
      3 = 25%–50% of wound covered
      4 = >50% and <75% of wound covered
      5 = 75% to 100% of wound covered
      Exudate type1 = None
      2 = Bloody
      3 = Serosanguineous: thin, watery, pale red/pink
      4 = Serous: thin, watery, clear
      5 = Purulent: thin or thick, opaque, tan/yellow, with or without odor
      Exudate amount1 = None, dry wound
      2 = Scant, wound moist but no observable exudate
      3 = Small
      4 = Moderate
      5 = Large
      Skin color surrounding wound1 = Pink or normal for ethnic group
      2 = Bright red and/or blanches to the touch
      3 = White or gray pallor or hypopigmented
      4 = Dark red or purple and/or nonblanchable
      5 = Black or hyperpigmented
      Granulation tissue1 = Skin intact or partial thickness wound
      2 = Bright, beefy red; 75%–100% of wound filled and/or tissue overgrowth
      3 = Bright, beefy red; between 25% and 75% of wound filled
      4 = Pink or dull dusky red and/or fills ≤25% of wound
      5 = No granulation tissue present
      low asterisk Modified from the Bates-Jensen Wound Assessment Tool.
      Neuropathy was confirmed by subject inability to perceive 10 g of pressure in the periwound area using a nylon monofilament test. Adequate perfusion to the affected foot was confirmed by either a transcutaneous oxygen pressure >40 mm Hg, a great toe pressure of >40 mm Hg, or Doppler waveform consistent with adequate blood flow.
      Tolerability was assessed through analysis of adverse events. Adverse events were collected from the date a patient provided informed consent through follow-up and exit from the study.

       Resource Use and Costs

      A cost-effectiveness analysis was performed (Excel 2007; Microsoft, Redmond, Washington) to evaluate the cost per responder between the 2 therapeutic alternatives. The portion of patients with a positive response served as the clinical measure of effectiveness in the economic analysis. Similar to the clinical trial, the time horizon for the economic analysis was 12 weeks. The economic analysis assumes that the costs for DFU cover dressings were essentially the same between the 2 debridement approaches and consequently were not included in the assessment of resource use and cost.
      Because this is neither a Markov nor decision analytic model, there is no model structure per se. This is simply an economic report of the incremental resources used in the prospective clinical trial and their associated incremental costs relative to the clinical outcomes. Resource use estimates for DFU therapy include frequency of selective sharp debridement procedures and physician office visits associated with the evaluation and management of DFU patients and collagenase ointment use.
      Collagenase ointment use was estimated based on WSA and proper allocation guidelines using the following equation:
      CU=cm2×PA×pco×28days


      where CU is collagenase use, cm2 is the WSA (2.7 cm2), PA is proper application (0.2 cm thick, applied daily), and Pco is the density of collagenase ointment (0.8 g/mL).
      On the basis of the collagenase ointment use formula, it was estimated that one 30-g tube of collagenase ointment per patient was necessary to complete the full 4-week treatment period. Costs between the 2 debridement alternatives were estimated for both the physician office and the wound clinic facility (hospital outpatient department wound care center) settings of care. The CMS varies reimbursement rates based on settings of care (eg, wound clinic facility vs physician office). Moreover, the CMS reimburses wound clinic facilities for overhead costs associated with the provision of patient care performed at the wound clinic facility. Resource costs were taken from standard cost references as listed in Table III. Only direct costs of debridement and patient evaluation and management were used in the analysis. The economic perspective included in the study was based on the reimbursement by the payer (ie, CMS). No cost discounting was performed because of the short time horizon of the analysis (12 weeks).
      Table IIIResources and Associated Costs in the Prospective, Randomized, 12-Week Clinical Study.
      ResourceCode (CPT, HCPCS, NDC, APC)Cost (US $)Source
      Evaluation and management physician office visit (wound clinic facility)9921225.19CMS
       Evaluation and management physician office visit (physician office)9921242.55CMS
       Selective sharp debridement (wound clinic facility)9759723.83CMS
       selective sharp debridement (physician office)9759775.22CMS
      Evaluation and management facility use060572.12CMS
       Selective sharp debridement useG0247104.86CMS
       Collagenase ointment 30-g tube00064-5010-30176.92Smith & Nephew
      APC = Ambulatory Payment Classification; CMS = Centers for Medicare and Medicaid Services; CPT = Current Procedural Terminology; HCPCS = Healthcare Common Procedural Coding System; NDC = National Drug Code.
      The direct costs of debridement and patient evaluation and management were calculated using the following equation:
      nCCX=Rt×Ct=1


      where CCx is the cumulative cost for therapy x, Rt is the resources in units used at time t, C is the cost of resource per unit, and t is time in weeks.

       Statistical Analysis

      The change from baseline in the wound assessment scores for the 2 treatment groups were compared at each of the 4 postbaseline treatment weeks and at the end of the follow-up period using a mixed-effects analysis of covariance for the ITT population. Treatment and treatment week, as well as their interaction, were defined as fixed effects, with patients as a random effect. The corresponding wound assessment score at baseline was used as a covariate. Missing values for any of the individual subscales were imputed with the mean score for that assessment (at that visit) and rounded up to the nearest integer provided that the total number of missing subscale values did not exceed 20% of the total item number. Otherwise, the assessment score was set to missing. Missing wound area measures at any of the treatment weeks, resulting from wound healing, early discontinuations, or any other reason, were imputed using the method of last observation carried forward. Paired t tests were used to assess the change from baseline in wound area. A χ2 likelihood ratio test was used to assess the differences in response rates between the 2 debridement alternatives. All efficacy data were analyzed in the ITT population, defined as all randomized patients. A significance level of P < 0.05 was used in all statistical analyses.

       Sample Size

      The number of patients (N = 40) was calculated to be sufficient to detect an effect size (Cohen’s d) of 0.80 with α = 0.05 and 1 − β = 0.80. Given the short time and standard nature of treatments used in the study, dropouts were expected to be <10%. Assuming a 10% attrition rate, the sample size was set at 24 patients in each arm. Therefore, it was expected that at least 20 patients from each group would complete the study.

      Results

      The study was conducted from April 2010 to August 2011 at 7 sites in the United States. A total of 48 patients with DFUs were randomized at 7 sites (24 to each group). Demographic and baseline wound characteristics are given in Table IV. The mean (SD) age of the patients was 61.0 (11.8) years. Most patients were white (94%) and male (67%). No significant differences were found between the CCO and SMG groups for any demographic variables. The DFUs were located primarily on the plantar surface (60%) and were round or oval in shape (60%), with a mean ulcer area of 2.7 cm2 (range, 0.5-9.25 cm2). No significant differences were found in the characteristics of DFUs between the 2 groups.
      Table IVDemographic and Baseline Wound Characteristics.
      Treatment Group
      CharacteristicTotal (N = 48)CCO (n = 24)SMG (n = 24)P (ANOVA or χ2 Test)
      Age (y)
       Mean61.058.563.50.1483
       Median61.059.063.5
       SD11.813.39.8
       Range38–8638–8647–85
      Age group, No. (%)
       <65 years28 (58)15 (62)13 (54)
       ≥65 years20 (42)9 (38)11 (46)
      Sex, No. (%)
       Female16 (33)8 (33)8 (33)>0.99
       Male32 (67)16 (67)16 (67)
      Race/ethnicity, No. (%)
       Black/African American3 (6)2 (8)1 (4)0.5510
      White45 (94)22 (92)23 (96)
       Hispanic/Latino9 (19)5 (21)4 (17)0.7115
       Non-Hispanic/non-Latino39 (81)19 (79)20 (83)
      Wound area (cm2)
       Mean2.73.02.40.3014
       Median1.92.61.6
       SD2.12.12.1
       Range0.5–9.00.5–9.00.5–7.6
      Wound location, No. (%)
       Distal3 (6)2 (8)1 (4)0.6003
       Dorsal4 (8)1 (4)3 (12)
       Lateral4 (8)2 (8)2 (8)
       Medial2 (4)2 (8)
       Plantar29 (60)15 (62)14 (58)
       Plantar/distal5 (10)2 (8)3 (12)
       Plantar/lateral1 (2)1 (4)
      Wound side, No. (%)
       Left21 (44)10 (42)11 (46)0.7711
       Right27 (56)14 (58)13 (54)
      Wound shape, No. (%)
       Bowl/boat2 (4)2 (8)0.3059
       Irregular17 (35)9 (38)8 (33)
       Round/oval29 (60)13 (54)16 (67)
      CCO = clostridial collagenase ointment; SMG = saline moistened gauze.
      Eight patients discontinued participation before study completion (n = 5 in the CCO group and n = 3 in the SMG group). The most frequent reason was an adverse event unrelated to test article (n = 3 in the CCO group and n = 2 in the SMG group), with the remainder due to either patient or investigator decision or lost to follow-up (Figure 1).

       Wound Assessment Scores

      The wound assessments consisted of 8 subscales from the Bates-Jensen Wound Assessment Tool. Each subscale had a possible score of 1 to 5, with 1 indicating intact skin and 5 indicating the worst possible rating. The combined score could thus range from 8 for normal skin to 40 for an ulcer that has hyperkeratotic edges, no granulation tissue, complete coverage with hard black eschar, and large amounts of purulent exudate. Mean wound assessment scores were not significantly different among the CCO and SMG groups at baseline, at any of the treatment visits (weeks 1–4), or at study exit (Figure 2). Significant improvement in mean total scores was seen for both groups beginning as early as 1 week after the start of treatment for the CCO group (P = 0.005) and at 2 weeks after the start of treatment for the SMG group (P = 0.049). No significant differences were seen between the 2 treatment groups for any of the individual wound assessment subscales at any assessment time point (data not shown). Mean (SD) wound assessment total score at week 12 was 14.5 (5.6) (95% CI, 12.3–16.7) for the CCO group and 13.8 (6.4) (95% CI, 11.2–16.4) for the SMG group. The decrease in mean (SD) total score at week 12 from baseline was 3.7 (5.2) for the CCO group and 3.5 (7.1) for the SMG group. The scores at week 12 correspond to a mean subscale score of 1.8 and 1.7, respectively. Both treatment groups provided a clinically meaningful reduction from baseline in wound assessment total score.
      Figure thumbnail gr2
      Figure 2Mean wound assessment total scores. No significant differences were found between the saline moistened gauze (SMG) group and the clostridial collagenase ointment (CCO) group at any of the time points (P > 0.05). *P < 0.05; P < 0.01; P < 0.001. NA = not applicable; ns = not significant.
      Examination of the exudate amount subscale provides useful information regarding the wound environment in terms of moisture. CCO is formulated in an occlusive petrolatum base, whereas gauze, if not moistened and when applied to ulcers with little or no exudate, could result in a dry ulcer environment. The exudate amount subscale score definitions are given in Table II. No significant differences were found between the CCO and SMG groups in this assessment at any of the treatment weeks or at study exit (mean values for treatment weeks 1–4 and study exit: CCO, 2.3, 2.0, 2.1, 2.2, and 1.9; SMG: 2.0, 2.1, 1.7, 1.8, and 1.9). Values for both groups at all assessment time points were approximately 2, corresponding to a moist wound with scant exudate.

       Percentage Change in DFU Area

      DFUs randomized to CCO had a mean percent change from baseline in area of −44.9% at the end of treatment visit and −53.8% at study exit. Both findings were statistically significant (P = 0.016; P = 0.012). The corresponding changes for the SMG group were +0.8% at end of treatment and +8.1% at study exit; neither was significantly different from baseline (Figure 3). The relatively poor outcome observed for the SMG group should not be interpreted to mean that none of the DFUs in the SMG group failed to improve in healing. In a post hoc analysis assessed at the 12-week study exit visit, patients were categorized as having a large response (ulcer area reduction from baseline ≥50%), a moderate response (ulcer area reduction from baseline <50% but >10%, a stalled response (ulcer area reduction from baseline ≤10%, or an increase in size) (Figure 4). Although there were similar numbers of large responses in the 2 groups at the end of study visit (week 12), there were more stalled ulcers in the SMG group (n = 5) compared with the CCO group (n = 1) and more moderate responses in the CCO group (n = 6) compared with the SMG group (n = 1). This imbalance in clinical response between the 2 alternative debridement modalities was statistically significant (P < 0.05).
      Figure thumbnail gr3
      Figure 3Mean percentage reduction in wound area. End of treatment indicates assessment after 4 weeks of treatment. Exit visit assessment after 4-week treatment and 8-week follow-up period or at final visit for wounds achieving closure or patients discontinued from the study. CCO = clostridial collagenase ointment; SMG = saline moistened gauze.
      Figure thumbnail gr4
      Figure 4Response rates at week 12 study exit. Large response (ulcer area reduction from baseline ≥50%), moderate response (ulcer area reduction from baseline <50% but >10%), stalled response (ulcer area reduction from baseline ≤10%, or increase in size). CCO = clostridial collagenase ointment; SMG = saline moistened gauze.
      The mean number of surgical debridements performed on DFUs during the entire study (treatment and follow-up periods combined) was 6.9 for the SMG group and 1.0 (the baseline debridement) for the CCO group. During the posttreatment follow-up period, a mean of 2.8 debridements were performed in the SMG group compared with 0 in the CCO group. There was a single instance of sharp debridement after the treatment phase in the CCO group; however, this did not affect the mean. Both groups had approximately 4 follow-up visits after treatment.

       Tolerability

      Of the 48 patients, 23 experienced 61 treatment-emergent adverse events. Adverse events were distributed evenly between the treatment groups, with 28 reported in the CCO group and 33 in the SMG group. Most were considered mild (51%) or moderate (39%). Reported adverse events were similar between the 2 treatment groups. None of the reported adverse events were assessed as being related to treatment by the investigators.

       Health Economic Outcomes

      The mean number of physician evaluation and management visits per patient was 12 in the CCO group and 6 in the SMG group. The mean numbers of surgical debridements performed in the clinical trial were 1 and 7 per patient in the CCO and SMG groups, respectively. As stated in the Patients and Methods section, the amount of collagenase ointment used per patient was 1 30-g tube per patient in the CCO group (Table V).
      Table VComparative Cost-Effectiveness of SMG and CCO in the Prospective, Randomized, 12-Week Clinical Study.
      Payer (CMS) Costs (US $)Physician OfficeWound Clinic Facility
      SMGCCOSMGCCO
      Selective Sharp Debridement
      No. of debridements
       Mean7171
       Median (range)5 (2–12)1 (1–2)5 (2–12)1 (1–2)
      CMS cost per debridement
      National mean CMS allowable costs.
      (US $)
      7575129129
      Total debridement costs (US $)
       Mean52775901129
       Median (range)376 (150–903)75 (75–150)643 (257–1544)129 (129–257)
      Evaluation and Management
      No. of visits
       Mean612612
       Median (range)5 (2–12)12 (11–12)5 (2–12)12 (11–12)
      Cost per visit
      National mean CMS allowable costs.
      (US $)
      $43$43$97$97
      Total costs of visits (US $)
       Mean2555115841168
       Median (range)340 (43–468)511 (618–945)778 (97–1070)1168 (1070–1168)
      CCO
      No. of CCO tubes
       Mean0101
       Median (range)1 (1–2)1 (1–2)
      Cost per CCO tube
      National mean CMS allowable costs.
      (US $)
      01770177
      Total CCO cost (US $)
       Mean01770177
       Median (range)177 (177–354)177 (177–354)
      Total cost of the therapy (US $)
       Mean78276314851473
       Median (range)717 (618–945)763 (763–940)1422 (1328–1642)1473 (1473–1650)
      Mean (SD) response rates0.75 (0.41)0.92 (0.28)0.75 (0.41)0.92 (0.28)
      Cost per responder (US $)
       Mean104283219801607
      Median (range)955 (1260–825)829 (1021–829)1546 (1784–1443)1601 (1794–1601)
      CMS = Centers for Medicare and Medicaid services; CCO = clostridial collagenase ointment; SMG = saline moistened gauze.
      low asterisk National mean CMS allowable costs.
      The findings presented in Table V give the estimated cost differences by physician office versus wound clinic facility between the SMG and CCO groups at the end of the 12-week study. The physician office mean cost of debridement per patient in the SMG group was >6-fold higher than in the CCO group (US $527 vs $75) for the management of DFUs. Conversely, the physician office mean cost of evaluation and management visits per patient in the CCO group was 2-fold higher than in the SMG group (US $511 vs $255). In addition, the CCO group incurred US $177 per patient for collagenase ointment. Overall, the cost-effectiveness ratios were US $1042 versus $832 per responder in the SMG and CCO groups, respectively, for DFU therapy in the physician office setting.
      A similar trend in economic outcomes was derived in the wound clinic facility setting for the 2 treatment approaches in the management of DFU. The wound clinic facility’s mean cost of debridement per patient in the SMG group was ~7-fold higher compared with the CCO group (US $901 vs US $129). However, the wound clinic facility’s mean cost of evaluation and management visits per patient in the CCO group was twice that of SMG group (US $1168 vs $584). The collagenase ointment costs remain unchanged from physician office setting to wound clinic facility setting. Overall, the cost-effectiveness ratios were US $1980 versus $1607 per responder in the SMG and CCO groups, respectively, for DFUs treated in the hospital outpatient department wound care clinic (Table V).

      Discussion

      The management of DFU remains a major therapeutic challenge to the treating physicians, surgeons, and other health care professionals. There is an urgent need for new strategies with clinically effective medicines to treat DFUs to reduce the burden of care in an efficient and cost-effective way. To promote healing of DFUs, a healthy ulcer environment must be created by removing necrotic tissue, managing bacterial load, and maintaining an appropriate moisture balance.
      Standard treatment for DFU has been wound bed preparation by removal of necrotic tissue, reducing excessive ulcer exudate, decreasing bacterial level, and elimination of deleterious chemical mediators. Ulcer debridement is necessary for removal of devitalized tissue to create an optimal wound bed. Removal of nonviable tissue permits better visualization of the wound base, removes a growth medium for bacteria, and stimulates release of growth factors. In addition, repeated or maintenance debridement of DFUs is required whenever devitalized tissue is present.
      • Frykberg R.G.
      • Zgonis T.
      • Armstrong D.G.
      • et al.
      Diabetic foot disorders: a clinical practice guideline (2006 revision).
      • Falabella A.F.
      Debridement and wound bed preparation.
      A variety of techniques have been commonly used for wound debridement in clinical practice. The choice of debridement methods depends on the clinician. Enzymatic debridement using CCO is an efficient alternative treatment approach to surgical debridement. Several studies have reported that enzymatic debridement using CCO is tolerable and clinically effective in achieving the removal of nonviable tissue in wound bed preparation.
      • Shi L.
      • Carson D.
      Collagenase Santyl ointment: a selective agent for wound debridement.
      • Ramundo J.
      • Gray M.
      Collagenase for enzymatic debridement: a systematic review.
      • Shi L.
      • Ramsay S.
      • Ermis R.
      • Carson D.
      pH in the bacteria-contaminated wound and its impact on clostridium histolyticum collagenase activity: implications for the use of collagenase wound debridement agents.
      • Ostlie D.J.
      • Juang D.
      • Aguayo P.
      • et al.
      Topical silver sulfadiazine vs collagenase ointment for the treatment of partial thickness burns in children: a prospective randomized trial.
      • Milne C.T.
      • Ciccarelli A.O.
      • Lassy M.
      A comparison of collagenase to hydrogel dressings in wound debridement.
      • Palmieri B.
      • Magri M.
      A new formulation of collagenase ointment (iruxol((r)) mono) in the treatment of ulcers of the lower extremities: a randomised, placebo-controlled, double-blind study.
      In this study, we assessed the clinical efficacy, tolerability, and costs of enzymatic debridement (CCO) in diabetic patients with foot ulcers. The study primarily focused on examining the wound healing properties, such as reduction in WSA and ulcer bed condition, after CCO or SMG therapy. In addition, we assessed and compared the health economic outcomes after CCO or SMG therapy. To our knowledge, this is the first randomized, prospective study that evaluated and compared the clinical efficacy, tolerability, and costs of enzymatic debridement using CCO to standard debridement in patients with DFUs. The findings clearly indicate that daily treatment with collagenase ointment is as effective as daily treatment with SMG and weekly sharp debridement. When compared with baseline, wound assessment scores improved significantly at each treatment visit with CCO, indicating that CCO provides effective debridement. A similar improvement in wound assessment scores was also observed in the SMG group from baseline. However, the differences in the wound assessment scores were not significantly different between the CCO and SMG groups, indicating similar debridement efficacy. The results of the study are consistent with those previously published reports in which collagenase was found to provide complete and effective debridement of pressure ulcers without sharp surgical debridement.
      • Milne C.T.
      • Ciccarelli A.O.
      • Lassy M.
      A comparison of collagenase to hydrogel dressings in wound debridement.
      Earlier studies have found that CCO therapy accelerates wound healing through mechanisms distinct, although consequent to its debridement activity.
      • Shi L.
      • Carson D.
      Collagenase Santyl ointment: a selective agent for wound debridement.
      • Riley K.N.
      • Herman I.M.
      Collagenase promotes the cellular responses to injury and wound healing in vivo.
      • Hansbrough J.F.
      • Achauer B.
      • Dawson J.
      • et al.
      Wound healing in partial-thickness burn wounds treated with collagenase ointment versus silver sulfadiazine cream.
      • Payne W.G.
      • Salas R.E.
      • Ko F.
      • et al.
      Enzymatic debriding agents are safe in wounds with high bacterial bioburdens and stimulate healing.
      The results of the present study are consistent with such a mechanism. DFUs treated with either CCO or SMG had by the end of the 4-week treatment period significant and clinically relevant improvement in the wound bed (as documented by decreases in the wound assessment scores). However, at the end of treatment, mean reduction from baseline in wound area for the DFUs treated with CCO was statistically significant (reductions in wound area of ~50%) but not for the SMG treatment group. Moreover, mean reduction in wound area continued (albeit more slowly) throughout the 8-week (untreated) follow-up period for the CCO group, whereas the mean wound area remained static for the SMG group. It is worth noting that this difference in the mean healing between the 2 groups is primarily due to the influence of several stalled ulcers. One-fourth of the ulcers in the SMG group did not progress toward closure (or actually enlarged), whereas only 1 to 2 ulcers of the 24 treated with CCO (depending on the time point) were categorized as stalled.
      It is well established that clostridial collagenase is specific for peptide bonds in the triple helical domains of collagen. At therapeutic doses, it can only digest collagen but not keratin, fat, or fibrin; thus, it has no effect on intact skin.
      • Shi L.
      • Carson D.
      Collagenase Santyl ointment: a selective agent for wound debridement.
      Because it specifically attacks collagen and attacks specific peptide bonds, only a subset of all possible proteolytic fragments is produced. These peptide fragments may influence cellular activities, such as migration and proliferation.
      • Riley K.N.
      • Herman I.M.
      Collagenase promotes the cellular responses to injury and wound healing in vivo.
      The healing benefits of CCO may thus be unique and not generalizable to other proteases. In addition, collagenase itself may contribute to the migration and activity of important cells, such as wound macrophages, fibroblasts, and keratinocytes, and promote ulcer healing.
      • Herman I.M.
      Stimulation of human keratinocyte migration and proliferation in vitro: insights into the cellular responses to injury and wound healing.
      In this study, the number of surgical debridements performed was not a planned end point; however, the difference in debridement frequency between the 2 groups merits discussion. On the basis of clinical need, surgical debridement was performed in the SMG group at weekly visits. If surgical debridement was deemed necessary for a patient in the CCO group, the patient was removed from the study because continuation would make a clear-cut distinction between the groups in regard to removal of healthy tissue and impact on rate of healing impossible. Nevertheless, the appearance of the wound was the only factor in the decision of whether to debride. Investigative sites were not provided additional compensation for follow-up study visits if debridement was performed. Only 1 patient in the CCO group required debridement (during follow-up), whereas each patient in the SMG group was debrided a mean of 6 times in addition to baseline debridement performed on all patients. Despite no sharp debridement, the CCO group had a 54% reduction in the wound area compared with no decrease, on average, for the SMG group.
      These results further suggest that the wound healing is accelerated in the CCO group because of continued effects of collagenase during the rest of the follow-up period. Unlike endogenous (mammalian) collagenase that cleaves collagen at 1 site, producing 2 fragments,
      • Stricklin G.P.
      • Eisen A.Z.
      • Bauer E.A.
      • Jeffrey J.J.
      Human skin fibroblast collagenase: chemical properties of precursor and active forms.
      clostridial collagenase cleaves all 3 helical domains of collagen to produce several breakdown products.
      • Sugasawara R.
      • Harper E.
      Purification and characterization of three forms of collagenase from Clostridium histolyticum.
      Thus, the facilitation of early debridement in the CCO group could be because collagenase acts as the rate-determining enzyme in collagen degradation, catalyzing cleavage of native collagen triple helix. With its specificity, collagenase could promote debridement by digesting collagen bundles that bind nonviable tissue to the wound bed. In addition, collagenase may provide additional benefits to DFUs that go beyond debridement while decreasing the need for frequent surgical debridement. Additional benefits of collagenase could be that it promotes the migration and proliferation of vascular endothelial cells and keratinocytes
      • Herman I.M.
      Stimulation of human keratinocyte migration and proliferation in vitro: insights into the cellular responses to injury and wound healing.
      and the release and activation of endogenous promoters of growth. Moreover, there is ample evidence to indicate that collagenase not only successfully debrides wounds but also hastens wound closure.
      • Hansbrough J.F.
      • Achauer B.
      • Dawson J.
      • et al.
      Wound healing in partial-thickness burn wounds treated with collagenase ointment versus silver sulfadiazine cream.
      Health economic benefits assessed through the cost-effectiveness analysis have been used as indicators to improve the allocation of scarce health care resources.
      • Harrington C.
      • Zagari M.J.
      • Corea J.
      • Klitenic J.
      A cost analysis of diabetic lower-extremity ulcers.
      • Langer A.
      • Rogowski W.
      Systematic review of economic evaluations of human cell-derived wound care products for the treatment of venous leg and diabetic foot ulcers.
      • Dougherty E.J.
      An evidence-based model comparing the cost-effectiveness of platelet-rich plasma gel to alternative therapies for patients with nonhealing diabetic foot ulcers.
      • Sibbald R.G.
      • Torrance G.
      • Hux M.
      • Attard C.
      • Milkovich N.
      Cost-effectiveness of becaplermin for nonhealing neuropathic diabetic foot ulcers.
      Given finite resources, efficient allocation of resources is required to optimize the health benefit per dollar spent on providing care for the patients. DFUs significantly affect patient resource use and costs. Therefore, we assessed the cost-effectiveness associated with the CCO treatment and compared it with the SMG therapy for the management of DFUs. Our findings clearly indicate that CCO treatment is more cost-effective than SMG in promoting the healing of DFUs. In this study, CCO debridement of DFUs produced better results than selective sharp debridement at similar costs of care.
      The strength of the study was that it was a prospective, parallel group, open-label, multicenter, randomized trial that compared head to head the clinical and health outcomes of CCO and SMG in conjunction with surgical debridement in the management DFUs. However, the 12-week trial duration was comparatively short, considering that DFU healing studies often last ≥20 weeks. A limitation of this study was that the decision regarding the necessity of debridement was left to the subjective judgment of individual investigators. In addition, it was a small study with 12-week follow-up, and the health economics findings are sensitive to the number of debridement procedures performed relative to the number of physician evaluation and management visits of the patients. In addition, the WSA, which has a direct relationship on the amount of collagenase ointment, may influence the health economics findings of the study. Moreover, because this study was based on Medicare and Medicaid reimbursement assumptions, the health economics outcomes may not be representative of all patients with different types of insurance. An additional shortcoming of the study was that the health economic outcomes cannot be generalized to wounds of other origins and to care provided in non–ambulatory care settings. Nonetheless, this study has shed light on the clinical and health economics of 2 treatment approaches in providing care for patients with DFUs.

      Conclusions

      The results of the study indicate that CCO is tolerable and clinically effective in achieving the removal of nonviable tissue in the preparation of a healthy wound bed. The clinical utility of CCO is better or comparable to that of standard of care with SMG plus weekly sharp debridement. Significant improvement in wound bed appearance was obtained more rapidly with CCO therapy than SMG therapy. In addition, CCO-treated DFUs had an enhanced rate of healing during the treatment period and for several weeks after the cessation of treatment, whereas the SMG therapy had no effect. Moreover, the clinical benefits with CCO accrued in the absence of additional surgical debridement, whereas patients in the SMG group continue to require surgical debridement during follow-up.
      Although delivering similar or better clinical outcomes, depending on the clinical assessment used, enzymatic debridement of DFUs with CCO offers better value compared with the SMG regardless of the ambulatory care setting. In particular, CCO therapy is a cost-effective method of debridement in the management of patients with DFUs.

      Conflicts of Interest

      Drs. Dickerson, Slade, and Waycaster are employees of Smith & Nephew Biotherapeutics, the study sponsor. Drs. Motley, Tallis, and Wunderlich have no conflict of interest. This study was supported by Smith & Nephew Biotherapeutics. The investigators and representatives from Smith & Nephew Biotherapeutics were responsible for the study design, protocol, statistical analysis plans, analysis, and reporting of results. Final responsibility for the decision to submit the manuscript for publication was made jointly by all authors.

      Acknowledgments

      G. Kesava Reddy, PhD, MHA, Creative Medical Communications, LLC, provided medical writing support. We are grateful to Dr. Innes Cargill, Dr. Dennis Carson, Dr. Darrell Lange, Mr. Tommy Lee, Mrs. Kathleen Schaum (all of Healthpoint Biotherapeutics), and Dr. John Lantis (Department of Surgery, St. Luke’s Roosevelt Hospital, New York, New York) for their critique and suggestions. All authors reviewed and edited the manuscript and contributed to the discussion of the data. Drs. Dickerson and Waycaster prepared the initial draft manuscript. Dr. Slade is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The members of the Collagenase Diabetic Foot Ulcer Study Group are as follows: Arthur Tallis, DPM, Associated Foot and Ankle Specialists, LLC, Phoenix, Arizona; Travis T. Motley, DPM, University of North Texas Health Science Center, Fort Worth, Texas; Robert P. Wunderlich, DPM, San Antonio, Texas; Paul Sullivan, DPM, St Mary Medical, Langhorne, Pennsylvania; L. Jolene Moyer, DPM, Advanced Regional Center for Foot and Ankle Care, Altoona, Pennsylvania; Philip Croyle, MD, Providence Health Center, Waco, Texas; and David Voigt, MD, St Elizabeth Regional Medical Center, Lincoln, Nebraska.

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