A comparative efficacy study: treatments of non-healing diabetic foot ulcers

描述（由申请人提供）： 慢性、不愈合的足部溃疡是成人糖尿病患者的常见并发症，发生在约15-20%的糖尿病患者中，并且通常导致足部截肢。由此产生的糖尿病足溃疡（DFU）和随后的截肢产生显著的患者发病率和数百万美元的医疗保健支出。即使采用最好的护理标准，即清创非活性组织，减轻负重和治疗感染，预计只有30%的糖尿病足溃疡可以在20周的治疗期内愈合。显然，对于改善这些溃疡的愈合的更好和更有效的治疗存在未满足的需求。新的治疗方法是有限的，但其中包括生物工程皮肤替代品，其结合了细胞外基质的元素，该细胞外基质被提议促进血管生成和新组织的向内生长，与活细胞一起沿着，以产生伤口修复所需的细胞因子。然而，工程组织的成本可能是惊人的：每次应用1,800美元，需要8次应用才能达到临床试验中提到的50%的愈合率。我们注意到，其他生物组织也已被证明可有效提高糖尿病溃疡的愈合率，并且这些组织不含活细胞且制备使用更简单，也被发现可有效愈合溃疡，与标准治疗相比，报告的愈合率相似。然而，这些非细胞组织比生物工程组织便宜几个数量级。我们假设这两种产品类型之间的疗效没有差异，并且使用较便宜的基质可以在不损害患者健康的情况下为我们的医疗保健系统节省数百万美元。我们在这个提案中的目标是使用随机临床试验来检验这一假设。我们提出了一个随机的、单盲的临床试验，有四个组：护理标准、护理标准加Dermagraft（R）（含有活的成纤维细胞的生物工程细胞外基质）、护理标准加Apliferase（R）（含有活的角质形成细胞和成纤维细胞的生物工程细胞外双层基质）、护理标准加Oasis（R）（Healthpoint，Ltd.），细胞外基质缺乏活细胞的非愈合性糖尿病足溃疡患者。我们计划确定：具体目标1：每个治疗组在达到12周时伤口闭合的主要终点和20周时完全闭合的次要结局方面的有效性，以及每个治疗组的愈合率。具体目标2：成本分析，以确定用于治疗糖尿病足溃疡的生物工程细胞外基质在降低医疗费用方面最具成本效益。具体目标3：未愈合与愈合糖尿病溃疡的基因特征，以确定预测伤口将在治疗后12-20周内愈合的生物标志物。我们的工作不仅可以为我们的医疗保健系统节省大量资金，而且还可以改善获得肢体和挽救生命的治疗方法，为数百万受影响的个人治愈DFU。

DESCRIPTION (provided by applicant): Chronic, non-healing ulcers of the feet are common complications of adults with diabetes, occurring in about 15-20% of diabetics, and often leading to foot amputation. The resulting diabetic foot ulcers (DFU) and subsequent amputations generate significant patient morbidity and millions of dollars of health care expenditures. Even with the best standard of care, which is debridement of non-viable tissue, off-loading of weight-bearing and treatment of infection, only 30% of diabetic foot ulcers can be expected to heal within a 20 week treatment period. There is clearly an unmet need for better and more effective treatments to improve healing of these ulcers. New therapies are limited, but among them are bioengineered skin substitutes that incorporate elements of an extracellular matrix that is proposed to encourage angiogenesis and in-growth of new tissue, along with living cells, to generate the cytokines needed for wound repair. However the cost of engineered tissue can be staggering: $1,800 per application, and 8 applications required-to achieve the 50% healing rate noted in the clinical trials. We note that other biological tissues have also been shown to be effective in improving the rate of healing of diabetic ulcers, and these tissues, devoid of living cells and simpler to prepare for use, have also been found to be effective in healing ulcers with reported similar increased rates compared to standard of care. These non-cellular tissues however, are orders of magnitude cheaper than bioengineered tissues. We hypothesize that there is no difference in efficacy between these two product types, and that using the less expensive matrix could save our health care system millions of dollars without compromising patient health. Our goal in this proposal is to test this hypothesis using a randomized clinical trial. We propose a randomized, single blinded, clinical trial with four arms: standard of care, standard of care plus Dermagraft(R) (bioengineered extracellular matrix containing living fibroblasts), standard of care plus Apligraf(R) (bioengineered extracellular bilayered matrix containing living keratinocytes and fibroblasts), standard of care plus Oasis(R) (Healthpoint, Ltd.), extracellular matrix devoid of living cells in patients with non-healing diabetic foot ulcers. We plan to determine: Specific Aim 1: Effectiveness of each treatment arm in achieving the primary endpoint of wound closure at 12 weeks and secondary outcomes of complete closure at 20 weeks, and rate of healing in each treatment arm. Specific Aim 2: Cost analysis to determine which bioengineered extracellular matrix for the treatment of diabetic foot ulcers is most cost effective in reducing healthcare costs. Specific Aim 3: The genetic signature of non-healing vs. healing diabetic ulcers to identify biomarkers predictive for a wound that will heal within 12-20 weeks of treatment. Our work could provide not only important savings to our health care system, but also improved access to limb and life saving therapies for healing DFU to millions of affected individuals.