A randomized clinical trial of a human acellular dermal matrix demonstrated superior healing rates for chronic diabetic foot ulcers over conventional care and an active acellular dermal matrix comparator

TL;DR

In a multicenter randomized controlled trial of 168 chronic diabetic foot ulcer subjects, a human acellular dermal matrix (D-ADM) achieved significantly higher healing rates than conventional care, while the active comparator human ADM (GJ-ADM) did not show significantly greater healing than conventional care at the studied endpoints. D-ADM also produced greater wound area reduction and better maintenance of healed wounds at 4 weeks posttermination.

Key findings

• In the per-protocol population, single-application D-ADM had significantly greater healing than conventional care at Week 12 (65.0% vs. 41.1%; HR 1.969; 95% CI 1.1–3.5; p=0.0123), Week 16 (82.5% vs. 48.1%; HR 2.397; 95% CI 1.4–4.1; p=0.0003), and Week 24 (89.7% vs. 67.3%; HR 2.107; 95% CI 1.3–3.5; p=0.0008). Median time to healing was 9.0 weeks for single-application D-ADM vs. 16.5 weeks for conventional care (p=0.0020).
• All-application D-ADM also showed significantly greater healing than conventional care at Week 16 (67.9% vs. 48.1%; HR 1.716; 95% CI 1.04–2.831; p=0.0283) and Week 24 (83.7% vs. 67.3%; HR 1.546; 95% CI 0.9821–2.435; p=0.0489). GJ-ADM did not show a significantly greater healing rate over conventional care at any time point, and no significant differences were seen between GJ-ADM and conventional care or between D-ADM and GJ-ADM.
• Healed ulcers in the single-application D-ADM arm remained closed at a significantly higher rate than conventional care at 4 weeks posttermination (100% [29/29] vs. 86.7% [26/30]; p=0.0435); GJ-ADM was 88.9% (8/9; p=0.8629 vs. conventional care). Single-application D-ADM demonstrated significantly greater average percent wound area reduction than conventional care for Weeks 2–24, while single-application GJ-ADM showed significantly greater reduction for Weeks 4–6, 9, and 11–12.
• No adverse events or serious adverse events were deemed related to the procedure or study product by site investigators. One death occurred in the D-ADM arm after healing and was determined not related to study procedures or product. Osteomyelitis was the most common severe infection: 5.6% in D-ADM, 5.9% in conventional care, and 10.7% in GJ-ADM.

Methods

• Prospective, multicenter, randomized, controlled, open-label trial enrolling 168 diabetic foot ulcer subjects at 13 outpatient wound care centers across 9 states; subjects were randomized 2:2:1 to D-ADM, conventional care, or GJ-ADM. ADM arms received one application and could receive one additional application if medically necessary; follow-up was through 24 weeks with major endpoints at Weeks 12, 16, and 24.
• Primary endpoint was proportion of chronic DFUs completely closed at 12 weeks, with complete closure defined as 100% reepithelialization without drainage or dressing requirements confirmed at two consecutive study visits 2 weeks apart. Secondary endpoints included proportion completely healed, time to closure, proportion of healed wounds remaining closed posttermination, percent wound area reduction, and safety.
• Analyses included Fisher’s exact test, ANOVA, Kaplan-Meier survivorship with Logrank (Mantel-Cox) tests, hazard ratios with 95% CIs, logistic regression, t tests, and Cohen’s kappa for interrater reliability; two-sided alpha was 0.05. A blinded third-party adjudicator assessed healing at Week 12 and expressed “strong” agreement (κ=0.837).

Limitations

• Stated: the trial was open-label and treatment could not be blinded to the implanting surgeon or subject because the ADM is visible on the wound surface; this was mitigated by blinded clinician review of wound images, laser-based wound area measurement, and a blinded third-party adjudicator. The GJ-ADM arm was not powered to detect a difference and was added only to establish a baseline ADM healing rate.
• Stated: the study was erroneously powered using healing rates from other human ADM studies that reported only single application with 12-week follow-up; all-subject healing did not become statistically significant until Week 15 even though percent wound area reduction was significant from Week 6. Multiple probability tests were applied without correcting related probabilities, and the effect of a second application was not considered during protocol development; timing criteria for second applications are not standardized. Wound depth data were not used because the Silhouette System had difficulty reliably determining depth.
• Stated/evident: the strict AHRQ healing definition may have artificially lowered the healing rate for as many as 9 D-ADM wounds (17% of the D-ADM arm) that could have been labeled healed in previous studies. The study was funded by LifeNet Health, the manufacturer of DermACELL, and some authors are employees of LifeNet Health (evident from the acknowledgements and conflict-of-interest statement).