Real-World Comparative Effectiveness Assessment Study of a Native Type I Collagen Matrix Plus Polyhexamethylene Biguanide Antimicrobial and a Cryopreserved Cadaveric Skin Allograft for Use in Diabetic Foot Ulcers – A Non-inferiority Analysis

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A real-world data (RWD) comparative effectiveness assessment (CEA) study was conducted in a large diabetic foot ulcer (DFU) patient population at 181 US treatment facilities evaluating a purified native cross-linked extracellular matrix scaffold plus polyhexamethylene biguanide antimicrobial barrier (PCMP; PuraPlyAM, Organogenesis Inc) and a cryopreserved cadaveric skin allograft (CCSA; Theraskin, Misonix).

Diabetic foot ulcers are a common and costly health condition in the US, increasing patient morbidity and mortality.^1,2 A summary schematic of the etiology of diabetic foot ulceration is shown in Figure 1. The Agency for Healthcare Research & Quality estimates more than 1 million individuals in the US develop DFUs annually.^2,3 DFUs represent a major burden of sickness and reduced quality of life for patients and their caregivers.¹ Medical management of DFUs costs the US health care system approximately $20 billion per year.⁴ A series of photographs (Figure 2) show one DFU located at the mid-foot at baseline (Figure 2A) and weeks 2 (Figure 2B), 6 (Figure 2C), and 8 (Figure 2D). Figure 2 photographs demonstrate epithelialization over 8 weeks ending in full epithelialization with the absence of drainage (ie, healed).

Figure 1. Etiology of diabetic foot ulceration.

Figure 2. Epithelialization from baseline through week 8 (full epithelialization with the absence of drainage). (A) Diabetic foot ulcer at baseline; (B) week 2; (C) week 6; (D) week 8. 

PCMP^(a) (PuraPlyAM; Organogenesis Inc) is a purified, native type I collagen extracellular matrix (ECM) scaffold with polyhexamethylene biguanide hydrochloride (PHMB) antimicrobial barrier.^5-8 PCMP is a class II medical device that has been 510(k) cleared by the FDA as a wound dressing for the management of wounds.⁵ CCSA^(b) (Theraskin; Misonix) is a cryopreserved cadaveric skin allograft marketed under Section 361 of the Public Health Service (PHS) Act as human cells, tissues, and cellular and tissue-based products (PHS 361; HCT/Ps) ⁹. Real-world data CEA non-inferiority equivalence studies have not been performed to investigate the use of PCMP versus CCSA in DFUs. More than 1000 US clinical centers in the US use WoundExpert (Net Health)^(c) electronic medical record (EMR).^10,11 This retrospective analysis of de-identified EMRs included an adequate plan to protect all identifiers from improper use and disclosure and was exempt from IRB review in accordance with 45CFR.164.514. In our study we compared PCMP plus standard of care versus CCSA plus standard of care.^3,12

Objectives

The objectives of this study were to: (1) evaluate real-world effectiveness of PCMP versus CCSA in a large DFU patient population using an EMR database, and (2) employ non-inferiority statistical methods to test for equivalence in effectiveness endpoints between treatment groups.

Electronic medical records (WoundExpert; Net Health)^(c) collected of 906 patients (989 DFUs) from 2016-2020 were analyzed. Exclusion criteria were lack of baseline wound measurements or follow-up visits. Evaluations were performed on 294 PCMP patients (325 DFUs) and 612 CCSA patients (664 DFUs). Cox proportional hazards regression (Cox) analyses that included ulcer size, depth, and duration were used to compute frequency and probability of wound closure. A non-inferiority analysis was used to determine whether the lower limit of the confidence interval was greater than 0.8 (clinical margin; M = 20%).

Patient Population

An analysis was conducted on 906 DFU patients managed with PCMP (n = 294) or CCSA (n = 612) from 2016-2020. DFUs over anatomical locations below the medial aspect of the malleolus extending at least through the epidermis into dermis, subcutaneous tissue, muscle, tendon, or bone were included. Patients with at least one study treatment with a location coded as foot, toe, heel, metatarsal head, toe web space, toe amputation site, or transmetatarsal amputation site were eligible for inclusion. Other criteria for entry into the analysis included ulcer size ≥1 to ≤50 cm². Wounds that lacked baseline or follow-up wound area measurements were excluded. Evaluations were performed on 989 DFUs.

Statistical Analysis

A Cox analysis that adjusted for variables including ulcer area and duration was used to compute frequency, time to, and probability of wound closure. From the Cox model, the hazard ratio (HR), 95% CI, and P value were computed. Non-inferiority statistical methodology was applied to compare the effectiveness of PCMP (T = treatment) to CCSA (C = control). For non-inferiority testing, the null hypothesis (H0) was that PCMP performed worse than CCSA by a non-inferiority clinical margin (M) of 20%. The non-inferiority test was done to determine if adequate evidence was accumulated to show that PCMP did not perform worse than CCSA by an amount at least as large as M = 0.20.

Treatment cohorts were reasonably comparable for patient demographics, wound, and treatment characteristics (Tables 1 and 2). For PCMP and CCSA, baseline mean areas (SD) were 6.07 (10.54) and 7.86 (15.47) cm², mean depths were 4.1 (4.4) and 3.5 (3.6) mm, and median durations were 9.58 (17.80) and 6.99 (10.25) months, respectively (Table 2). The median number of treatment applications was 2.0 in both groups, and the mean interval between treatment applications was 14.2 (17.2) and 24.2 (25.3) days for PCMP and CCSA, respectively (Table 2). The PCMP versus CCSA frequencies of wound closure were comparable at all study timepoints including week 4 (12% vs 10%), 8 (27% vs 24%), 12 (39% vs 37%), and 24 (60% vs 64%), respectively; P = .95 (Figure 3). Median time to healing was 18 weeks versus 17 weeks for PCMP and CCSA; P = .95 (Figure 4). PCMP demonstrated a comparable probability of wound healing versus CCSA treatment; HR = 0.99; 95% CI (0.85, 1.17). Cox analysis for group-to-group percentages healed, median time to healing, 95% CI of the HR, and the computed P value of non-inferiority all demonstrated consistent findings of equivalence between PCMP and CCSA. These results proved robust and were statistically significant with low variability (P = .01).

TABLE 1. Patient Characteristics

TABLE 2. Wound and Treatment Characteristics

Figure 3. Percentage of diabetic foot ulcers healed*

*P = .95

Figure 4. Median time to healing (weeks)*

*P = .95

We disproved that the lower limit of the CI for the HR was ≤0.80. We showed that the HR = 0.99; 95% CI (0.85, 1.17). The PCMP versus CCSA non-inferiority test for equivalence was P = .01; (M = 0.20). Therefore, we accepted the non-inferiority hypothesis at a level of significance of P < .05 with a clinical margin of 0.20.

The disparity in the number of DFUs between the comparator groups could have impacted effective off-loading. For the same power, a trial with a 2:1 distribution of DFUs between treatment groups needs 12% more DFUs than a trial with a 1:1 distribution. We conclude nevertheless that non-inferiority results demonstrated in the study are valid (power > 90%; P < .05). However, no data exist to draw meaningful conclusions on whether unequal group-to-group sample sizes affect therapeutic off-loading.

Real-world data CEA analyses with prospectively defined non-inferiority analyses for appropriate primary (time and frequency of healing) and secondary endpoints (eg, patient-reported outcomes, patient-centric outcomes, quality of life, and pain) are expected to become increasingly important as secondary databases to inform clinicians, regulatory bodies, third-party payers, and other policy makers on the comparative benefits of wound treatments.^13-16

In the current non-inferiority study, we showed that a class II medical device PCMP was equivalent to a human cellular and tissue product; P = .01. PCMP versus CCSA demonstrated that median time, percentage, and probability of healing were statistically, significantly comparable by non-inferiority hypothesis testing at a level P < .05.

Real-world data CEA are expected to become increasingly important as secondary databases to inform health care providers, regulatory bodies, third-party payers, and other policy makers on the comparative benefits of wound treatments.^13-15 Data from RWD CEAs can help guide clinicians to limit overuse of ineffective therapies and underuse of effective therapies.^14,17