Chronic diabetic foot ulcers (DFUs) remain a serious therapeutic challenge worldwide.1-2 Patients with DFUs are at higher risk for infections, which may lead to limb loss.1-5 In fact, 1 in 6 patients with DFUs will undergo an amputation.6 The long-term consequences of DFUs are numerous and can severely affect patients’ quality of life, including loss of productivity.7 The current standard of care for DFUs consists of debridement of the necrotic tissue, application of a moist dressing, and use of an off-loading device that protects the wound from pressure or trauma related to ambulation and other acts of daily living.4-6,8 Unfortunately, studies have shown that the best standard of care (SOC) only heals 30% of DFUs after 20 weeks of therapy.9 With the estimated cost per episode of care approaching $40,000, DFUs remain a costly and important problem.10
The altered extracellular matrix (ECM) in DFUs has been a target for the development of new therapeutic devices that provide a new matrix that is either devoid of cells or can be enriched with fibroblasts.8,11 These bioengineered skin substitutes stimulate the growth of new vessels and generate cytokines essential for tissue repair. In 2013, Lev-Tov et al12 published this study protocol (Dermagraft Oasis Longitudinal Comparative Efficacy [DOLCE] trial) to compare the effectiveness of 2 advanced wound care devices, specifically to evaluate the clinical efficacy of a cellular matrix versus an acellular matrix, which we have amended. The cellular matrix used in the study is a dermal substitute composed of viable newborn foreskin fibroblasts seeded onto a bioabsorbable polyglactin mesh on which fibroblasts generate an ECM.13,14 It is supplied frozen and requires specific thawing steps prior to application. The recommended regimen for treatment of DFUs for this cellular matrix is 8 weekly applications.13,14 In 2016, the cost of the product was reported as $1411 per 5.0×7.5-cm sheet.15 The acellular matrix product used in the study is a bioabsorbable ECM that is derived from porcine small intestinal submucosa.16,17 It is stored at room temperature and has a long shelf life, with a current price of $112.6 for a 3.0×3.5-cm single-layer fenestrated sheet ($1126.60 per box of 10 sheets). The industry-supported randomized controlled trials for each of these devices have reported a 20% added benefit in the rate of wound closure at week 12 compared to SOC.14,17However, our hypothesis is that these therapeutic devices will yield equivalent clinical outcomes, each being equally more effective than SOC, supporting the wider adoption of the less expensive, cell-free matrix device that has a longer shelf life and is easier to apply.
This article provides the interim report of the trial (registered at www.clinicaltrials.gov with the identifier NCT01450943) described in the published protocol and initiated in 2011,12 focusing on elements that required modification during the trial’s duration.
The clinical trial was approved by the Veterans’ Affairs Institutional Research and Development Committee and their institutional review board. This study was funded by the Veteran’s Administration Merit Award (#10554640), which was awarded to 2 of the investigators (S.E.D. and R.R.I.). Eligible veterans were recruited from all 7 sites of the VA Northern California Healthcare System. This trial is a randomized, single-blinded, 3-armed, controlled clinical equivalence trial comparing the effectiveness of an SOC treatment, cellular ECM, and acellular ECM.
The SOC dressing applied in the clinical trial included a sterile antimicrobial gel, a nonadherent dressing, and gauze.12 The SOC dressing also was used as a secondary dressing for the active treatment arms. Bacitracin antibiotic ointment was used as an alternative for patients with allergy to iodine.12
The inclusion and exclusion criteria were previously outlined.12 After a 2-week screening phase to exclude rapid healers, patients were randomized into a treatment arm and entered the active phase for 12 weeks. Patients then were seen once monthly for 16 weeks in a follow-up phase.12
Primary and Secondary Outcomes
The primary outcome was complete wound closure by week 12.12 Complete healing was defined as full reepithelialization with no drainage or dressing requirement. The secondary outcomes included healing at 28 weeks, rate of healing, ulcer recurrence at week 20, association of wound healing with ulcer characteristics or patients’ characteristic, incidence of adverse events, and cost-effectiveness of each treatment compared to the SOC arm.12
To detect a 25% difference in the incidence of ulcer closure between the 2 study groups and the SOC group, the estimation of the sample size was based on 80% power with a significance level of 0.05. Specifically, it was expected that 50% of the cellular and acellular matrix groups and 25% of the SOC group would reach complete wound closure. The protocol indicated that 57 participants would be enrolled in each arm (total of 171 participants). Lev-Tov et al12 discussed the statistical analysis in more detail.